diff --git "a/storage/docstore.json" "b/storage/docstore.json" new file mode 100644--- /dev/null +++ "b/storage/docstore.json" @@ -0,0 +1 @@ +{"docstore/data": {"e5011731-4122-4588-83d0-19ff6364dcc8": {"__data__": {"id_": "e5011731-4122-4588-83d0-19ff6364dcc8", "embedding": null, "metadata": {"page_label": "1", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "daef8c7f-68a7-4a78-b143-4aba0b3421b9", "node_type": null, "metadata": {"page_label": "1", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b52078834492e0b1e70718d81e74dae1c7e3ed96947cb6ccdaaa5d11e0bec1fd"}}, "hash": "b52078834492e0b1e70718d81e74dae1c7e3ed96947cb6ccdaaa5d11e0bec1fd", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 383, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b7f2083c-7828-489d-a91a-99387ea61990": {"__data__": {"id_": "b7f2083c-7828-489d-a91a-99387ea61990", "embedding": null, "metadata": {"page_label": "2", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c20c8323-7f5f-4553-80b3-1a6d2dff3232", "node_type": null, "metadata": {"page_label": "2", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e155a184f1cdd44dd68a843a46cdacc486bba9db86dcdfab2de66c84e15e1baa"}}, "hash": "e155a184f1cdd44dd68a843a46cdacc486bba9db86dcdfab2de66c84e15e1baa", "text": "RANG AND DALE\u2019S\nPharmacologymebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 507, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bc1d5998-8b4c-42d7-a90c-0fa61f209ad1": {"__data__": {"id_": "bc1d5998-8b4c-42d7-a90c-0fa61f209ad1", "embedding": null, "metadata": {"page_label": "3", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "08ea18da-4415-43d0-bfc5-e4af7a31d8f2", "node_type": null, "metadata": {"page_label": "3", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ee30bb8903bf9d7d2ec51113a89ed295db489c7ead07c2f531c254c00a25e35"}}, "hash": "1ee30bb8903bf9d7d2ec51113a89ed295db489c7ead07c2f531c254c00a25e35", "text": "28 CHEMICAL TRANSMISSION AND DRUG ACTION IN THE CENTRAL NERVOUS SYSTEM\nRANG AND DALE\u2019S \nPharmacology\nNINTH EDITION\nJAMES M. RITTER DPhil FRCP HonFBPhS FMedSci\nEmeritus Professor of Clinical Pharmacology, King\u2019s College London\nFellow Commoner, Trinity Hall, Senior Physician Advisor CUC (GSK), Addenbrooke\u2019s Hospital\nCambridge, United Kingdom\nROD FLOWER PhD LLD DSc HonFBPhS FMedSci FRS\nEmeritus Professor of Pharmacology\nBart\u2019s and the London School of Medicine\nQueen Mary, University of London\nLondon, United Kingdom\nGRAEME HENDERSON PhD, FRSB, HonFBPhS\nProfessor of PharmacologyUniversity of Bristol\nBristol, United Kingdom\nYOON KONG LOKE MBBS MD FRCP FBPhS\nProfessor of Medicine and Pharmacology\nNorwich Medical School, University of East Anglia\nNorwich, United Kingdom\nDAVID M acEWAN PhD FRSB FBPhS SFHEA\nProfessor of Molecular Pharmacology/Toxicology & Head of Department\nDepartment of Molecular and Clinical Pharmacology\nUniversity of Liverpool\nLiverpool, United Kingdom\nHUMPHREY P. RANG MB BS MSc MA DPhil HonFBPhS FMedSci FRS\nEmeritus Professor of PharmacologyUniversity College London\nLondon, United Kingdom\nFor additional online content visit StudentConsult.com\nEdinburgh London New York Oxford Philadelphia St Louis Sydney 2020mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1724, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f6251b43-a4a4-4d52-9280-eb75f885891e": {"__data__": {"id_": "f6251b43-a4a4-4d52-9280-eb75f885891e", "embedding": null, "metadata": {"page_label": "4", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6b6b4aa2-3d5a-4ad2-94ee-8a74e2c01f6c", "node_type": null, "metadata": {"page_label": "4", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7def9058c001593030019dcd0c9af2998fbc9ea05e668f88edd2ccbf8993f60c"}}, "hash": "7def9058c001593030019dcd0c9af2998fbc9ea05e668f88edd2ccbf8993f60c", "text": "\u00a9 2020, Elsevier Ltd. All rights reserved.\nFirst edition 1987\nSecond edition 1991Third edition 1995Fourth edition 1999Fifth edition 2003Sixth edition 2007Seventh edition 2012Eighth edition 2016\nThe right of James M. Ritter, Rod Flower, Graeme Henderson, Yoon Kong Loke, David MacEwan, and \nHumphrey P. Rang to be identified as authors of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988.\nNo part of this publication may be reproduced or transmitted in any form or by any means, electronic or \nmechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher\u2019s permissions policies and our arrangements with organisations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.\nThis book and the individual contributions contained in it are protected under copyright by the \nPublisher (other than as may be noted herein).\nPotential Competing Financial Interests Statements for Rang and Dale 9E (2014\u20132018)HPR: has no competing financial interests to declare.\nJMR: has received salary from Quintiles and GSK.GH: has no competing financial interests to declare.YKL: has received funding from Polpharma and Thame Pharmaceuticals.DJM: has no competing financial interests to declare.RJF: serves as a board member for Antibe Therapeutics.\nNotices\nPractitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or the value of such product or the claims made of it by its manufacturer.\nISBN: 978-0-7020-7448-6\nPrinted in China\nLast digit is the print number: 9 8 7 6 5 4 3 2 1\nContent Strategist: Alexandra Mortimer\nContent Development Specialists: Trinity Hutton, Sam CroweProject Manager: Joanna SouchDesign: Renee DuenowIllustration Manager: Nichole BeardMarketing Manager: Deborah WatkinsThe \npublisher\u2019s \npolicy is to use\npaper manufactured \nfrom sustainable forestsmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3294, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "608e54d8-1a22-47f6-b62d-72f076ecf05d": {"__data__": {"id_": "608e54d8-1a22-47f6-b62d-72f076ecf05d", "embedding": null, "metadata": {"page_label": "5", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2fbdcbb4-e5ed-44e8-9db4-a06b11cf5946", "node_type": null, "metadata": {"page_label": "5", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "958aacfe52990e25e9af260cf43f225f33eb311d547495e2f0af07306181be5e"}, "3": {"node_id": "48c9d5b6-fbea-4458-881a-1bf0b6d1a3db", "node_type": null, "metadata": {"page_label": "5", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a123d0d07604b48c945759283db79cbd8feed6b891ee11c3adea96f13215a62"}}, "hash": "9613015189d72b4748dab9e150fba8b1ea306a594936a84d95111a76c2efe7ca", "text": "xvxvRang and Dale\u2019s Pharmacology \nNinth Edition Preface\nIn this edition, as in its predecessors, we set out to explain \nwhat drugs do in terms of the mechanisms by which they act. \nThis entails analysis not only at the cellular and molecular \nlevel, where knowledge and techniques are advancing \nrapidly, but also at the level of physiological mechanisms \nand pathological disturbances. Pharmacology has its roots \nin therapeutics, where the aim is to ameliorate the effects \nof disease, so we have attempted to make the link between \neffects at the molecular and cellular level and the range of \nbeneficial and adverse effects that humans experience when \ndrugs are used for therapeutic or other reasons. Therapeutic \nagents have a high rate of obsolescence. In the decade 2008 \nto 2017, 301 new drugs gained regulatory approval for \nuse as therapeutic agents. The majority exploit the same \nmolecular targets as drugs already in use. Knowledge of \nthe mechanisms of action of the class of drugs to which \na new agent belongs provides a good starting point for \nunderstanding and using a new compound intelligently.\nSignificantly, however, one-third of these new arrivals \nare \u2018first-in-class\u2019 drugs. That is, they act on novel molecular \ntargets not previously exploited for therapeutic purposes, \nand are therefore likely to produce effects not previously \ndescribed. Not all will succeed clinically, but some will \nstimulate the development of improved follow-up com -\npounds of the same type. Furthermore, about a quarter of \nthe new compounds are \u2018biopharmaceuticals\u2019 \u2013 mainly \nproteins produced by bioengineering rather than synthetic \nchemistry. These are growing in importance as therapeutic \nagents, and generally have characteristics somewhat different \nfrom conventional drugs and are covered in a revised chapter. \nThe very high rate of innovation in drug discovery is a recent \n\u2013 and very welcome \u2013 change, due in large part to the rapid \nadvances in molecular and cell biology that have stemmed \nfrom the sequencing of the human genome in 2003. We have \ntried to strike a balance between the need to keep up with \nthese modern developments and the danger of information \noverload. Our emphasis is on explaining the general principles \nunderlying drug action, which apply to old and new alike, \nand to describe in more detail the actions and mechanisms \nof familiar, established drugs, while including references \nthat cover modern and future developments.\nPharmacology is a lively scientific discipline in its own \nright, with an importance beyond that of providing a basis \nfor the use of drugs in therapy, and we aim to provide a \ngood background, not only for future doctors but also for \nscientists in other disciplines who need to understand how \ndrugs act. We have, therefore, where appropriate, described \nhow drugs are used as probes for elucidating cellular and \nphysiological functions, to improve our understanding of \nhow the human body functions normally and what goes \nwrong with it in disease, even when the compounds have \nno clinical use. Besides therapeutic applications, drugs have \nother impacts on society, which we cover in chapters on \npsychoactive drugs, drug abuse, and the use of drugs in sport.\nNames of drugs and related chemicals are established \nthrough usage and sometimes there is more than one name \nin common use. For prescribing purposes, it is important \nto use standard names, and we follow, as far as possible, the World Health Organization\u2019s list of recommended \ninternational non-proprietary names (rINN). Sometimes \nthese conflict with the familiar names of drugs (e.g. the \nendogenous mediator prostaglandin I 2 \u2013 the standard name \nin the scientific literature \u2013 becomes \u2018epoprostenol\u2019 \u2013 a name \nunfamiliar to most scientists \u2013 in the rINN list). In these \ncases, we generally adopt", "start_char_idx": 0, "end_char_idx": 3841, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "48c9d5b6-fbea-4458-881a-1bf0b6d1a3db": {"__data__": {"id_": "48c9d5b6-fbea-4458-881a-1bf0b6d1a3db", "embedding": null, "metadata": {"page_label": "5", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2fbdcbb4-e5ed-44e8-9db4-a06b11cf5946", "node_type": null, "metadata": {"page_label": "5", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "958aacfe52990e25e9af260cf43f225f33eb311d547495e2f0af07306181be5e"}, "2": {"node_id": "608e54d8-1a22-47f6-b62d-72f076ecf05d", "node_type": null, "metadata": {"page_label": "5", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9613015189d72b4748dab9e150fba8b1ea306a594936a84d95111a76c2efe7ca"}}, "hash": "6a123d0d07604b48c945759283db79cbd8feed6b891ee11c3adea96f13215a62", "text": "scientists \u2013 in the rINN list). In these \ncases, we generally adopt conventional scientific nomen -\nclature. Sometimes English and American usage varies (as \nwith adrenaline/epinephrine and noradrenaline/norepine -\nphrine). Adrenaline and noradrenaline are the official names \nin EU member states and are used in this book.\nDrug action can be understood only in the context of \nwhat else is happening in the body. So, at the beginning \nof most chapters, we briefly discuss the physiological and \nbiochemical processes relevant to the action of the drugs \ndescribed in that chapter. We have included the chemical \nstructures of drugs only where this information helps in \nunderstanding their pharmacological and pharmacokinetic \ncharacteristics, since chemical structures are readily available \nfor reference online.\nThe overall organisation of the book has been retained, \nwith sections covering: (1) the general principles of drug \naction; (2) the chemical mediators and cellular mechanisms \nwith which drugs interact in producing their therapeutic \neffects; (3) the action of drugs on specific organ systems; (4) \nthe action of drugs on the nervous system; (5) the action of \ndrugs used to treat infectious diseases and cancer; and (6) a \nrange of special topics such as adverse effects, non-medical \nuses of drugs, etc. This organisation reflects our belief that \ndrug action needs to be understood, not just as a description \nof the effects of individual drugs and their uses, but as a \nchemical intervention that perturbs the network of chemical \nand cellular signalling that underlies the function of any \nliving organism. In addition to updating each chapter, we \nhave added new material on biopharmaceuticals, and on \npersonalised medicine, topics of particular current interest. \nAdditional current material on cognition-enhancing drugs \nhas been included in Chapter 48.\nDespite the fact that pharmacology, like other branches \nof biomedical science, advances steadily, with the acquisition \nof new information, the development of new concepts and \nthe introduction of new drugs for clinical use, we have \navoided making the ninth edition any longer than its \npredecessor by cutting out dated and obsolete material, \nand have made extensive use of small print text to cover \nmore specialised and speculative information that is not \nessential to understanding the key message, but will, we \nhope, be helpful to students seeking to go into greater \ndepth. In selecting new material for inclusion, we have \ntaken into account not only new agents but also recent \nextensions of basic knowledge that presage further drug \ndevelopment. And, where possible, we have given a brief \noutline of new treatments in the pipeline. Reference lists \nare largely restricted to guidance on further reading, together \nwith review articles that list key original papers.\nFinally, we hope that we have conveyed something of \nour own enthusiasm for the science and importance of \npharmacology in the modern world.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3774, "end_char_idx": 7254, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "95fe44f7-8f1c-4739-b658-6a679337c8f6": {"__data__": {"id_": "95fe44f7-8f1c-4739-b658-6a679337c8f6", "embedding": null, "metadata": {"page_label": "6", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b6becbbb-c6af-443b-aa69-2711a3e83fbf", "node_type": null, "metadata": {"page_label": "6", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1dad55586517d0fe8427ad49d1ee9e75ef37ee887129d806619fba43e0f35bce"}}, "hash": "1dad55586517d0fe8427ad49d1ee9e75ef37ee887129d806619fba43e0f35bce", "text": "xvi\nRANG AND DALE\u2019S PHARMACOLOGY NINTH EDITION PREFACE\nxviACKNOWLEDGEMENTS\nWe are grateful to many colleagues who have helped us \nwith comments and suggestions, and would particularly \nlike to thank the following for their help and advice in the \npreparation of this edition: Dr Steve Alexander, Professor \nEmma Baker, Dr Barbara Jennings, Professor Eamonn Kelly, \nProfessor Munir Pirmohamed and Professor Emma Rob -\ninson. We would also like to thank Dr Christine Edmead \nfor her work on the self-assessment questions which are \navailable as additional material on the online edition of \nthis book.We would like to put on record our appreciation of the \nteam at Elsevier who worked on this edition: Alexandra \nMortimer (content strategist), Trinity Hutton (content \ndevelopment specialist), Joanna Souch (project manager), \nNichole Beard (illustration manager).\nLondon, 2018\nHumphrey P. Rang\nJames M. Ritter\nRod Flower\nGraeme Henderson\nDavid MacEwan\nYoon Kong Lokemebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1444, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f5056f2f-9577-4148-8c95-720a9c306847": {"__data__": {"id_": "f5056f2f-9577-4148-8c95-720a9c306847", "embedding": null, "metadata": {"page_label": "7", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d06b9b0d-9b63-4a60-8114-aace544631b0", "node_type": null, "metadata": {"page_label": "7", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92a6517477a0d4bd8d811aef73e110a06d88e87836c23d2cfdd690351be2ea14"}, "3": {"node_id": "abe6dc81-5c17-4d3d-a1c1-848d79df2747", "node_type": null, "metadata": {"page_label": "7", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "829964a4259930a485aefdb628eab758b549d932bdae98820fa0efca3e1998b6"}}, "hash": "22748495f290b8bc13ed3d80834c7d6d636e7479c3bfa2fae379401715d764a2", "text": "1\nGENERAL PRINCIPLES SECTION 1 \nWhat is pharmacology? 1 \nOVERVIEW\nIn this introductory chapter we explain how phar -\nmacology came into being and evolved as a scientific \ndiscipline, and describe the present-day structure \nof the subject and its links to other biomedical sciences. \nThe structure that has emerged forms the basis of \nthe organisation of the rest of the book. Readers in \na hurry to get to the here-and-now of pharmacology can safely skip this chapter.\nWHAT IS A DRUG?\nFor the purposes of this book, a drug can be defined as a \nchemical substance of known structure, other than a nutrient or \nan essential dietary ingredient,1 which, when administered to a \nliving organism, produces a biological effect.\nA few points are worth noting. Drugs may be synthetic \nchemicals, chemicals obtained from plants or animals, or \nproducts of biotechnology (biopharmaceuticals). A medicine \nis a chemical preparation, which usually, but not necessarily, contains one or more drugs, administered with the intention of producing a therapeutic effect. Medicines usually contain \nother substances (excipients, stabilisers, solvents, etc.) besides \nthe active drug, to make them more convenient to use. To count as a drug, the substance must be administered as such, rather than released by physiological mechanisms. Many \nsubstances, such as insulin or thyroxine, are endogenous \nhormones but are also drugs when they are administered intentionally. Many drugs are not used commonly in \nmedicine but are nevertheless useful research tools. The \ndefinition of drug also covers toxins, which again are not usually administered in the clinic but nonetheless are critical \npharmacological tools. In everyday parlance, the word drug \nis often associated with psychoactive substances and addic -\ntion \u2013 unfortunate negative connotations that tend to bias uninformed opinion against any form of chemical therapy. \nIn this book we focus mainly on drugs used for therapeutic purposes but also describe psychoactive drugs and provide \nimportant examples of drugs used as experimental tools. \nPoisons fall strictly within the definition of drugs, and indeed \u2018all drugs are poisons\u2026 it is only the dose which \nmakes a thing poison\u2019 (an aphorism credited to Paracelsus, \na 16th century Swiss physician); conversely, poisons may be effective therapeutic agents when administered in sub-toxic doses. Botulinum toxin (Ch. 14) provides a striking example: it is the most potent poison known in terms of its lethal \ndose, but is widely used both medically and cosmetically. \nGeneral aspects of harmful effects of drugs are considered in Chapter 58. Toxicology is the study of toxic effects of \nchemical substances (including drugs), and toxicological \ntesting is undertaken on new chemical entities during their development as potential medicinal products (Ch. 60), but \nthe subject is not otherwise covered in this book.\nORIGINS AND ANTECEDENTS\nPharmacology can be defined as the study of the effects of \ndrugs on the function of living systems. As a science, it \nwas born in the mid-19th century, one of a host of new \nbiomedical sciences based on principles of experimentation rather than dogma that came into being in that remarkable \nperiod. Long before that \u2013 indeed from the dawn of civilisa -\ntion \u2013 herbal remedies were widely used, pharmacopoeias \nwere written, and the apothecaries\u2019 trade flourished. \nHowever, nothing resembling scientific principles was \napplied to therapeutics, which was known at that time as materia medica.\n2 Even Robert Boyle, who laid the scientific \nfoundations of chemistry in the middle of the 17th century, \nwas content, when dealing with therapeutics ( A Collection \nof Choice Remedies, 1692), to recommend concoctions of \nworms, dung, urine and the moss from a", "start_char_idx": 0, "end_char_idx": 3787, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "abe6dc81-5c17-4d3d-a1c1-848d79df2747": {"__data__": {"id_": "abe6dc81-5c17-4d3d-a1c1-848d79df2747", "embedding": null, "metadata": {"page_label": "7", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d06b9b0d-9b63-4a60-8114-aace544631b0", "node_type": null, "metadata": {"page_label": "7", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92a6517477a0d4bd8d811aef73e110a06d88e87836c23d2cfdd690351be2ea14"}, "2": {"node_id": "f5056f2f-9577-4148-8c95-720a9c306847", "node_type": null, "metadata": {"page_label": "7", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "22748495f290b8bc13ed3d80834c7d6d636e7479c3bfa2fae379401715d764a2"}}, "hash": "829964a4259930a485aefdb628eab758b549d932bdae98820fa0efca3e1998b6", "text": "recommend concoctions of \nworms, dung, urine and the moss from a dead man\u2019s skull. \nThe impetus for pharmacology came from the need to \nimprove the outcome of therapeutic intervention by doctors, who were at that time skilled at clinical observation and \ndiagnosis but broadly ineffectual when it came to treatment.\n3 \nUntil the late 19th century, knowledge of the normal and abnormal functioning of the body was too rudimentary to \nprovide even a rough basis for understanding drug effects; at the same time, disease and death were regarded as \nsemi-sacred subjects, appropriately dealt with by authoritar -\nian, rather than scientific, doctrines. Clinical practice often \ndisplayed an obedience to authority and ignored what \nappear to be easily ascertainable facts. For example, cinchona \nbark was recognised as a specific and effective treatment for malaria, and a sound protocol for its use was laid down by Lind in 1765. In 1804, however, Johnson declared it to \nbe unsafe until the fever had subsided, and he recommended \ninstead the use of large doses of calomel (mercurous chloride) in the early stages \u2013 a murderous piece of advice \nthat was slavishly followed for the next 40 years.\n1Like most definitions, this one has its limits. For example, there are a \nnumber of essential dietary constituents, such as iron and various \nvitamins, that are used as medicines. Furthermore, some biological \nproducts (e.g. epoietin) show batch-to-batch variation in their chemical constitution that significantly affects their properties. There is also the \nstudy of pharmaceutical-grade nutrients or \u2018nutraceuticals\u2019.2The name persists today in some ancient universities, being attached to \nchairs of what we would call clinical pharmacology.\n3Oliver Wendell Holmes, an eminent physician, wrote in 1860: \u2018[I] \nfirmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind \nand the worse for the fishes\u2019 (see Porter, 1997).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3723, "end_char_idx": 6201, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0e413ae7-f5cc-45c1-a031-f1ab52756f4f": {"__data__": {"id_": "0e413ae7-f5cc-45c1-a031-f1ab52756f4f", "embedding": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e266a6a0-04d8-4009-a7ce-8c713c283fba", "node_type": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9d953e94fed6de7563c35dc3ea3717ed6cf11fdf567dcba63fb5b19b525bd78"}, "3": {"node_id": "3e1bcd33-40a5-4f6f-a7c9-101972f1537f", "node_type": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "de430c7eb3f1e3352d98056537775ba647951796a6549efd85c165f7dd68be36"}}, "hash": "92e777613f154537892edc1c4f4822e18eba358bc966cb2d48ef19e8827e3fa3", "text": "1 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n2by Chain and Florey during the Second World War, based \non the earlier work of Fleming.\nThese few well-known examples show how the growth \nof synthetic chemistry, and the resurgence of natural product chemistry, caused a dramatic revitalisation of therapeutics \nin the first half of the 20th century. Each new drug class \nthat emerged gave pharmacologists a new challenge, and it was then that pharmacology really established its identity \nand its status among the biomedical sciences.\nIn parallel with the exuberant proliferation of therapeutic \nmolecules \u2013 driven mainly by chemistry \u2013 which gave phar -\nmacologists so much to think about, physiology was also making rapid progress, particularly in relation to chemical \nmediators, which are discussed in depth throughout this book. Many hormones, neurotransmitters and inflammatory \nmediators were discovered in this period, and the realisa -\ntion that chemical communication plays a central role in \nalmost every regulatory mechanism that our bodies possess \nimmediately established a large area of common ground \nbetween physiology and pharmacology, for interactions between chemical substances and living systems were exactly \nwhat pharmacologists had been preoccupied with from the \noutset. Indeed, these fields have developed hand-in-hand as wherever there is either a physiological or pathological \nmechanism, pharmacology could be there to exploit it with \na drug. The concept of \u2018receptors\u2019 for chemical mediators, first proposed by Langley in 1905, was quickly taken up by \npharmacologists such as Clark, Gaddum, Schild and others, \nand is a constant theme in present-day pharmacology (as you will soon discover as you plough through the next two chap -\nters). The receptor concept, and the technologies developed \nfrom it, have had a massive impact on drug discovery and \ntherapeutics. Biochemistry also emerged as a distinct science early in the 20th century, and the discovery of enzymes and \nthe delineation of biochemical pathways provided yet another \nframework for understanding drug effects. The picture of pharmacology that emerges from this brief glance at history \n(Fig. 1.1) is of a subject evolved from ancient prescientific \ntherapeutics, involved in commerce from the 17th century onwards, and which gained respectability by donning the \ntrappings of science as soon as this became possible in the \nmid-19th century. Pharmacology grew rapidly in partnership with the evolution of organic chemistry and other biomedical \nsciences, and was quick to assimilate the dramatic advances \nin molecular and cell biology in the late 20th century. Signs of its carpetbagger past still cling to pharmacology, for the \npharmaceutical industry has become very big business and \nmuch pharmacological research nowadays takes place in a commercial environment, a rougher and more pragmatic place than academia.\n5 No other biomedical \u2018ology\u2019 is so close \nto Mammon.\nALTERNATIVE THERAPEUTIC PRINCIPLES\nModern medicine relies heavily on drugs as the main tool of therapeutics. Other therapeutic procedures, such The motivation for understanding what drugs can and \ncannot do came from clinical practice, but the science could \nbe built only on the basis of secure foundations in physiol -\nogy, pathology and chemistry. It was not until 1858 that \nVirchow proposed the cell theory. The first use of a structural \nformula to describe a chemical compound was in 1868. \nBacteria as a cause of disease were discovered by Pasteur in 1878. Previously, pharmacology hardly had the legs to \nstand on, and we may wonder at the bold vision of Rudolf \nBuchheim, who created the first pharmacology institute (in his own house) in Estonia in 1847.\nIn its beginnings, before the advent of synthetic organic \nchemistry, pharmacology concerned itself exclusively with understanding the effects of natural substances, mainly", "start_char_idx": 0, "end_char_idx": 3898, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3e1bcd33-40a5-4f6f-a7c9-101972f1537f": {"__data__": {"id_": "3e1bcd33-40a5-4f6f-a7c9-101972f1537f", "embedding": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e266a6a0-04d8-4009-a7ce-8c713c283fba", "node_type": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9d953e94fed6de7563c35dc3ea3717ed6cf11fdf567dcba63fb5b19b525bd78"}, "2": {"node_id": "0e413ae7-f5cc-45c1-a031-f1ab52756f4f", "node_type": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92e777613f154537892edc1c4f4822e18eba358bc966cb2d48ef19e8827e3fa3"}, "3": {"node_id": "cc75a578-e997-4ff8-b522-7791df24a429", "node_type": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "047be128ee962d49e4f548bb419e8351da1302bcb06d234a5868f3781cbb3692"}}, "hash": "de430c7eb3f1e3352d98056537775ba647951796a6549efd85c165f7dd68be36", "text": "concerned itself exclusively with understanding the effects of natural substances, mainly plant extracts \u2013 and a few (mainly toxic) chemicals such \nas mercury and arsenic. An early development in chemistry \nwas the purification of active compounds from plants. Friedrich Sert\u00fcrner, a young German apothecary, purified \nmorphine from opium in 1805. Other substances quickly \nfollowed, and, even though their structures were unknown, these compounds showed that chemicals, not magic or vital \nforces, were responsible for the effects that plant extracts \nproduced on living organisms. Early pharmacologists focused most of their attention on such plant-derived drugs \nas quinine, digitalis, atropine, ephedrine, strychnine and \nothers (many of which are still used today and will have become old friends by the time you have finished reading \nthis book).\n4\nPHARMACOLOGY IN THE 20TH AND \n21ST CENTURIES\nBeginning in the 20th century, the fresh wind of synthetic \nchemistry began to revolutionise the pharmaceutical \nindustry, and with it the science of pharmacology. New \nsynthetic drugs, such as barbiturates and local anaesthetics, began to appear, and the era of antimicrobial chemotherapy \nbegan with the discovery by Paul Ehrlich in 1909 of arsenical \ncompounds for treating syphilis. Around the same time, William Blair-Bell was world renowned for his pioneering \nwork at Liverpool in the treatment of breast cancers with \nanother relatively poisonous agent, lead colloid mixtures. The thinking was that yes, drugs were toxic, but they were slightly more toxic to a microbe or cancer cell. This early \nchemotherapy has laid the foundations for much of the \nantimicrobial and anticancer therapies still used today. Further breakthroughs came when the sulfonamides, the \nfirst antibacterial drugs, were discovered by Gerhard \nDomagk in 1935, and with the development of penicillin \n4A handful of synthetic substances achieved pharmacological \nprominence long before the era of synthetic chemistry began. Diethyl \nether, first prepared as \u2018sweet oil of vitriol\u2019 in the 16th century, and \nnitrous oxide, prepared by Humphrey Davy in 1799, were used to liven up parties before being introduced as anaesthetic agents in the mid-19th \ncentury (see Ch. 42). Amyl nitrite (see Ch. 21) was made in 1859 and \ncan claim to be the first \u2018rational\u2019 therapeutic drug; its therapeutic effect in angina was predicted on the basis of its physiological effects \u2013 a true \n\u2018pharmacologist\u2019s drug\u2019 and the smelly forerunner of the \nnitrovasodilators that are widely used today. Aspirin (Ch. 27), the most widely used therapeutic drug in history, was first synthesised in 1853, \nwith no therapeutic application in mind. It was rediscovered in 1897 in \nthe laboratories of the German company Bayer, who were seeking a less toxic derivative of salicylic acid. Bayer commercialised aspirin in 1899 \nand made a fortune.5Some of our most distinguished pharmacological pioneers made their \ncareers in industry: for example, Henry Dale, who laid the foundations of our knowledge of chemical transmission and the autonomic nervous \nsystem (Ch. 13); George Hitchings and Gertrude Elion, who described the antimetabolite principle and produced the first effective anticancer \ndrugs (Ch. 57); and James Black, who introduced the first \n\u03b2-adrenoceptor and histamine H\n2-receptor antagonists (Chs 15 and 31). \nIt is no accident that in this book, where we focus on the scientific \nprinciples of pharmacology, most of our examples are products of \nindustry, not of nature.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3820, "end_char_idx": 7501, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cc75a578-e997-4ff8-b522-7791df24a429": {"__data__": {"id_": "cc75a578-e997-4ff8-b522-7791df24a429", "embedding": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e266a6a0-04d8-4009-a7ce-8c713c283fba", "node_type": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9d953e94fed6de7563c35dc3ea3717ed6cf11fdf567dcba63fb5b19b525bd78"}, "2": {"node_id": "3e1bcd33-40a5-4f6f-a7c9-101972f1537f", "node_type": null, "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "de430c7eb3f1e3352d98056537775ba647951796a6549efd85c165f7dd68be36"}}, "hash": "047be128ee962d49e4f548bb419e8351da1302bcb06d234a5868f3781cbb3692", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7533, "end_char_idx": 7916, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "19692850-fcb7-4989-9fbd-7a45b0c05404": {"__data__": {"id_": "19692850-fcb7-4989-9fbd-7a45b0c05404", "embedding": null, "metadata": {"page_label": "9", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "db4a0856-ce64-4060-9d11-a4981a1985c9", "node_type": null, "metadata": {"page_label": "9", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ab1fb73d49fd2cf38ff66e4459a10bcfe071d0b51191a800c924d3123acc1d58"}, "3": {"node_id": "395f211d-36d6-4687-91fd-e70e60c0a38c", "node_type": null, "metadata": {"page_label": "9", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b480c61e3579e75d808faf97c434f3c35f0f491e4a368c4fe65dfc6047402b3c"}}, "hash": "a95727aec653fb2823426f15bcd7d6e59051d916df299afebc0e1de537cf5aff", "text": "1 WhAt IS P h AR m AC o L o G y?\n3terms, detected by objective means, and influenced benefi -\ncially by appropriate chemical or physical interventions. \nThey focus instead mainly on subjective malaise, which \nmay be disease-associated or not. Abandoning objectivity in defining and measuring disease goes along with a similar \ndeparture from scientific principles in assessing therapeutic \nefficacy and risk, with the result that principles and practices can gain acceptance without satisfying any of the criteria \nof validity that would convince a critical scientist, and that \nare required by law to be satisfied before a new drug can be introduced into therapy. Demand for \u2018alternative\u2019 therapies by the general public, alas, has little to do with \ndemonstrable efficacy.\n6\nTHE EMERGENCE OF BIOTECHNOLOGY\nSince the 1980s, biotechnology has emerged as a major \nsource of new therapeutic agents in the form of antibodies, \nenzymes and various regulatory proteins, including hor -\nmones, growth factors and cytokines (see Clark & Pazdernik, \n2015). Although such products (known as biopharmaceuticals , \nbiologicals or biologics) are generally produced by genetic \nengineering rather than by synthetic chemistry, the pharmacological principles are essentially the same as for \nconventional drugs, although the details of absorption, as surgery, diet, exercise, psychological treatments etc., are also important, of course, as is deliberate non-intervention, \nbut none is so widely applied as drug-based therapeutics.\nBefore the advent of science-based approaches, repeated \nattempts were made to construct systems of therapeutics, many of which produced even worse results than pure empiricism. One of these was allopathy , espoused by James \nGregory (1735\u20131821). The favoured remedies included \nbloodletting, emetics and purgatives, which were used until \nthe dominant symptoms of the disease were suppressed. Many patients died from such treatment, and it was in \nreaction against it that Hahnemann introduced the practice \nof homeopathy in the early 19th century. The implausible \nguiding principles of homeopathy are:\n\u2022\tlike\tcures \tlike\n\u2022\tactivity \tcan \tbe \tenhanced \tby \tdilution\nThe system rapidly drifted into absurdity: for example, Hahnemann recommended the use of drugs at dilutions \nof 1 : 1060, equivalent to one molecule in a sphere the size \nof the orbit of Neptune.\nMany other systems of therapeutics have come and gone, \nand the variety of dogmatic principles that they embodied have tended to hinder rather than advance scientific pro -\ngress. Currently, therapeutic systems that have a basis that lies outside the domain of science remain popular under the general banner of \u2018alternative\u2019 or \u2018complementary\u2019 \nmedicine. Mostly, they reject the \u2018medical model\u2019, which \nattributes disease to an underlying derangement of normal function that can be defined in physiological or structural", "start_char_idx": 0, "end_char_idx": 2904, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "395f211d-36d6-4687-91fd-e70e60c0a38c": {"__data__": {"id_": "395f211d-36d6-4687-91fd-e70e60c0a38c", "embedding": null, "metadata": {"page_label": "9", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "db4a0856-ce64-4060-9d11-a4981a1985c9", "node_type": null, "metadata": {"page_label": "9", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ab1fb73d49fd2cf38ff66e4459a10bcfe071d0b51191a800c924d3123acc1d58"}, "2": {"node_id": "19692850-fcb7-4989-9fbd-7a45b0c05404", "node_type": null, "metadata": {"page_label": "9", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a95727aec653fb2823426f15bcd7d6e59051d916df299afebc0e1de537cf5aff"}}, "hash": "b480c61e3579e75d808faf97c434f3c35f0f491e4a368c4fe65dfc6047402b3c", "text": "to an underlying derangement of normal function that can be defined in physiological or structural %LRPHGLFDO\nVFLHQFHV$SSUR[LPDWH\u0003GDWHV\n!\u0016\u0013\u0013\u0013\u0003%&\na\u0014\u0019\u0013\u0013\u0003$'\na\u0014\u001b\u0013\u0013\na\u0014\u001c\u0013\u0013\na\u0014\u001c\u001a\u0013\n\u0015\u0013\u0013\u00137KHUDSHXWLFV\n0DJLFDO\u0003SRWLRQV\n+HUEDO\u0003UHPHGLHV\n&RPPHUFH\n$SRWKHFDULHV\n3KDUPDFHXWLFDO\nLQGXVWU\\\n6\\QWKHWLF\nGUXJV&KHPLVWU\\\n1DWXUDO\nSURGXFWV\n&KHPLFDO\nVWUXFWXUH\n6\\QWKHWLF\nFKHPLVWU\\3DWKRORJ\\\n3K\\VLRORJ\\\n%LRFKHPLVWU\\\n0ROHFXODU\nELRORJ\\\n%LRSKDUPDFHXWLFDOV\n3KDUPDFRORJ\\3KDUPDFRORJ\\\nFig. 1.1 The development of pharmacology. \n6The UK Medicines and Healthcare Regulatory Agency (MHRA) \nrequires detailed evidence of therapeutic efficacy based on controlled \nclinical trials before a new drug is registered, but no clinical trials data \nfor homeopathic products or for the many herbal medicines that were on sale before the Medicines Act of 1968.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2806, "end_char_idx": 4091, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bf243f19-319f-4950-a05b-d6a362f01b89": {"__data__": {"id_": "bf243f19-319f-4950-a05b-d6a362f01b89", "embedding": null, "metadata": {"page_label": "10", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b5ad4171-80af-4abf-a713-24a35994b1ba", "node_type": null, "metadata": {"page_label": "10", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3bcc848adf4f41c6b8969ae8c833993ee0d2b35317e33d51b506bc6cc92d3855"}, "3": {"node_id": "92d40caa-24b5-41e0-9e72-2831bc5d45c2", "node_type": null, "metadata": {"page_label": "10", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a73f388157986e2e8f3c412bb0a32af57d6db0a5fb505f37eed4e97f78f0ce1"}}, "hash": "4bb37b86713f7d69bd13465a4f9be321cfad504ac206d1745635225870206333", "text": "1 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n4pharmacokinetics, etc.), which are convenient, if not water -\ntight, subdivisions. These topics form the main subject \nmatter of this book. Around the edges are several interface \ndisciplines, not covered in this book, which form important two-way bridges between pharmacology and other fields of \nbiomedicine. Pharmacology tends to have more of these than \nother disciplines. Recent arrivals on the fringe are subjects such as pharmacogenomics, pharmacoepidemiology and \npharmacoeconomics.\nPharmacogenomics. Pharmacogenetics, the study of \ngenetic influences on responses to drugs, initially focused on familial idiosyncratic drug reactions, where affected \nindividuals show an abnormal \u2013 usually adverse \u2013 response to a class of drug (see Nebert & Weber, 1990). Rebranded \nas pharmacogenomics, it now covers broader genetically \nbased variations in drug response, where the genetic basis is more complex, the aim being to use genetic information \nto guide the choice of drug therapy on an individual basis \n\u2013 so-called personalised medicine (Ch. 12). The underlying principle is that differences between individuals in their response to therapeutic drugs can be predicted from their \ngenetic make-up. Examples that confirm this are steadily \naccumulating (see Ch. 12). So far, they mainly involve genetic polymorphism of drug-metabolising enzymes or receptors. \nUltimately, linking specific gene variations with variations \nin therapeutic or unwanted effects of a particular drug should enable the tailoring of therapeutic choices on the \nbasis of an individual\u2019s genotype. Steady improvements \nin the cost and feasibility of individual genotyping will distribution and elimination, specificity, harmful effects and clinical effectiveness all differ markedly between high \nmolecular-weight biopharmaceuticals and low molecular-\nweight drugs \u2013 as does their cost! Looking further ahead, gene- and cell-based therapies (Ch. 5), although still in \ntheir infancy, are beginning to take therapeutics into a new \ndomain. The principles governing gene suppression, the design, delivery and control of functioning artificial genes \nintroduced into cells, or of engineered cells introduced into \nthe body, are very different from those of drug-based therapeutics and will require a different conceptual frame -\nwork, which texts such as this will increasingly need to embrace if they are to stay abreast of modern medical treatment.\nPHARMACOLOGY TODAY\nAs with other biomedical disciplines, the boundaries of pharmacology are not sharply defined, nor are they constant. \nIts exponents are, as befits pragmatists, ever ready to poach \non the territory and techniques of other disciplines. If it ever had a conceptual and technical core that it could really \ncall its own, this has now dwindled almost to the point of \nextinction, and the subject is defined by its purpose \u2013 to understand what drugs do to living organisms, and more \nparticularly how their effects can be applied to therapeutics \n\u2013 rather than by its scientific coherence.\nFig. 1.2 shows the structure of pharmacology as it \nappears today. Within the main subject fall a number of \ncompartments (neuropharmacology, immunopharmacology,", "start_char_idx": 0, "end_char_idx": 3227, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "92d40caa-24b5-41e0-9e72-2831bc5d45c2": {"__data__": {"id_": "92d40caa-24b5-41e0-9e72-2831bc5d45c2", "embedding": null, "metadata": {"page_label": "10", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b5ad4171-80af-4abf-a713-24a35994b1ba", "node_type": null, "metadata": {"page_label": "10", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3bcc848adf4f41c6b8969ae8c833993ee0d2b35317e33d51b506bc6cc92d3855"}, "2": {"node_id": "bf243f19-319f-4950-a05b-d6a362f01b89", "node_type": null, "metadata": {"page_label": "10", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4bb37b86713f7d69bd13465a4f9be321cfad504ac206d1745635225870206333"}}, "hash": "8a73f388157986e2e8f3c412bb0a32af57d6db0a5fb505f37eed4e97f78f0ce1", "text": "a number of \ncompartments (neuropharmacology, immunopharmacology, \n3KDUPDFRORJ\\3KDUPDFRNLQHWLFV\u0012\nGUXJ\u0003PHWDEROLVP%LRFKHPLFDO\nSKDUPDFRORJ\\\n&KHPRWKHUDS\\\n6\\VWHPV\u0003SKDUPDFRORJ\\0ROHFXODU\nSKDUPDFRORJ\\\n1HXUR\u0010\nSKDUPDFRORJ\\&DUGLRYDVFXODU\nSKDUPDFRORJ\\*DVWURLQWHVWLQDO\nSKDUPDFRORJ\\\n,PPXQR\u0010\nSKDUPDFRORJ\\5HVSLUDWRU\\\nSKDUPDFRORJ\\\n3KDUPDFRJHQHWLFV\n*(1(7,&63KDUPDFRJHQRPLFV\n*(120,&63KDUPDFRHSLGHPLRORJ\\\n\u0003&/,1,&$/\u0003(3,'(0,2/2*<3KDUPDFRHFRQRPLFV\n+($/7+\u0003(&2120,&63KDUPDFHXWLFDO\nVFLHQFHV3+$50$&<\n3V\\FKR\u0010\nSKDUPDFRORJ\\36<&+2/2*<\n&OLQLFDO\nSKDUPDFRORJ\\&/,1,&$/\u00030(',&,1(\n7+(5$3(87,&6\n9HWHULQDU\\\nSKDUPDFRORJ\\9(7(5,1$5<\n0(',&,1(\n%LRSKDUPDFHXWLFDOV%,27(&+12/2*<\n7R[LFRORJ\\3$7+2/2*<\n0HGLFLQDO\nFKHPLVWU\\&+(0,675<\nFig. 1.2 Pharmacology today with its various subdivisions. The grey box contains the general areas of pharmacology covered in this \nbook. Interface disciplines (brown boxes) link pharmacology to other mainstream biomedical disciplines (green boxes) . mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3162, "end_char_idx": 4575, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c585a0a7-7a9b-463d-b7d0-a39717280ad7": {"__data__": {"id_": "c585a0a7-7a9b-463d-b7d0-a39717280ad7", "embedding": null, "metadata": {"page_label": "11", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "135ed7de-f1c0-4daf-9541-7c43693bef51", "node_type": null, "metadata": {"page_label": "11", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87a019f8c148c96870c9f720a4133403ebaa4d1bb27278d54bf502ff46c79e2b"}}, "hash": "87a019f8c148c96870c9f720a4133403ebaa4d1bb27278d54bf502ff46c79e2b", "text": "1 WhAt IS P h AR m AC o L o G y?\n5increase its applicability, potentially with far-reaching \nconsequences for therapeutics (see Ch. 12).\nPharmacoepidemiology. This is the study of drug effects \nat the population level (see Strom et al., 2013). It is concerned \nwith the variability of drug effects between individuals in a population, and between populations. It is an increasingly \nimportant topic in the eyes of the regulatory authorities \nwho decide whether or not new drugs can be licensed for therapeutic use. Variability between individuals or popula -\ntions detracts from the utility of a drug, even though its overall effect level may be satisfactory. Pharmacoepide -\nmiological studies also take into account patient compliance \nand other factors that apply when the drug is used under \nreal-life conditions.Pharmacoeconomics. This branch of health economics \naims to quantify in economic terms the cost and benefit of \ndrugs used therapeutically. It arose from the concern of \nmany governments to provide for healthcare from tax revenues, raising questions of what therapeutic procedures \nrepresent the best value for money. This, of course, raises \nfierce controversy, because it ultimately comes down to putting monetary value on health and longevity. As with \npharmacoepidemiology, regulatory authorities are increas -\ningly requiring economic analysis, as well as evidence of \nindividual benefit, when making decisions on licensing. For more information on this complex subject, see Rascati \n(2013).\nREFERENCES AND FURTHER READING\nClark, D.P., Pazderink, N.J., 2015. Biotechnology. Elsevier, New York. \n(General account of biotechnology and its potential applications)\nNebert, D.W., Weber, W.W., 1990. Pharmacogenetics. In: Pratt, W.B., \nTaylor, P. (Eds.), Principles of Drug Action, third ed. Churchill \nLivingstone, New York. (A detailed account of genetic factors that affect \nresponses to drugs, with many examples from the pregenomic literature)\nPorter, R., 1997. The Greatest Benefit to Mankind. Harper-Collins, \nLondon. (An excellent and readable account of the history of medicine, with good coverage of the early development of pharmacology and the \npharmaceutical industry)Rascati, K.L., 2013. Essentials of Pharmacoeconomics, second ed. \nLippincott Williams & Wilkins, Philadelphia. (Introduction to a complex \nand fraught subject)\nStrom, B.L., Kimmel, S.E., Hennessy, S., 2013. Textbook of \nPharmacoepidemiology, second ed. Wiley, Chichester. (A multiauthor book covering all aspects of a newly emerged discipline, including aspects of \npharmacoeconomics)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3065, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2218a423-d7af-4985-b365-c76f18132b49": {"__data__": {"id_": "2218a423-d7af-4985-b365-c76f18132b49", "embedding": null, "metadata": {"page_label": "12", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b5a4db63-f6b1-42b9-b1bb-f4ba855fde52", "node_type": null, "metadata": {"page_label": "12", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c65011f0b32dc7561d9718403c9f9655c1b6b95fdeaf97d27f16647368bdfca9"}, "3": {"node_id": "01fc577c-319b-4aea-8bed-7e4f84eb8457", "node_type": null, "metadata": {"page_label": "12", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fab11316be90ec257059d3a0dea0dd279038d8c2e48a3b689f606b8032121ecb"}}, "hash": "0bbec88277892a010931d164733db03007863c6a48041eaad4c44c353c191a79", "text": "6\nGENERAL PRINCIPLES SECTION 1\nHow drugs act: general principles2 \nOVERVIEW\nThe emergence of pharmacology as a science came \nwhen the emphasis shifted from describing what drugs \ndo to explaining how they work. In this chapter we \nset out some general principles underlying the interaction of drugs with living systems ( Ch. 3 goes \ninto the molecular aspects in more detail). The interaction between drugs and cells is described, followed by a more detailed examination of different \ntypes of drug\u2013receptor interaction. The receptor concept \nhas been described as the \u2018big idea\u2019 of pharmacology (Rang, 2006 ) and will be a recurring theme throughout \nthis book.\nINTRODUCTION\nTo begin with, we should gratefully acknowledge Paul \nEhrlich for insisting that drug action must be explicable in \nterms of conventional chemical interactions between drugs \nand tissues, and for dispelling the idea that the remarkable potency and specificity of action of some drugs put them \nsomehow out of reach of chemistry and physics and required \nthe intervention of magical \u2018vital forces\u2019. Although many drugs produce effects in extraordinarily low doses and \nconcentrations, low concentrations still involve very large \nnumbers of molecules. One drop of a solution of a drug at only 10\n\u221210 mol/L still contains about 3 \u00d7 109 drug molecules, \nso there is no mystery in the fact that it may produce an \nobvious pharmacological response. Some bacterial toxins \n(e.g. diphtheria toxin) act with such precision that a single molecule taken up by a target cell is sufficient to kill it.\nOne of the basic tenets of pharmacology is that drug \nmolecules must exert some chemical influence on one or more cell constituents in order to produce a pharmacological \nresponse. In other words, drug molecules must get so close \nto these constituent cellular molecules that the two interact chemically in such a way that the function of the latter is altered. Of course, the molecules in the organism vastly \noutnumber the drug molecules, and if the drug molecules \nwere merely distributed at random, the chance of interaction with any particular class of cellular molecule would be \nnegligible. Therefore pharmacological effects require, in \ngeneral, the non-uniform distribution of the drug molecule within the body or tissue, which is the same as saying that \ndrug molecules must be \u2018bound\u2019 to particular constituents \nof cells and tissues in order to produce an effect. Ehrlich summed it up thus: \u2018 Corpora non agunt nisi fixata \u2019 (in this \ncontext, \u2018A drug will not work unless it is bound\u2019).\n1These critical binding sites are often referred to as \u2018drug \ntargets\u2019 (an obvious allusion to Ehrlich\u2019s famous phrase \n\u2018magic bullets\u2019, describing the potential of antimicrobial \ndrugs). The mechanisms by which the association of a drug molecule with its target leads to a physiological response \nconstitute the major thrust of pharmacological research. \nMost drug targets are protein molecules. Even general anaesthetics (see Ch. 42), which were long thought to \nproduce their effects by an interaction with membrane lipid, \nnow appear to interact mainly with membrane proteins (see Franks, 2008).\nAll rules need exceptions, and many antimicrobial and \nantitumour drugs (Chs 52 and 57), as well as mutagenic and carcinogenic agents (Ch. 58), interact directly with DNA rather than protein; bisphosphonates, used to treat \nosteoporosis (Ch. 37), bind to calcium salts in the bone \nmatrix, rendering them toxic to osteoclasts, much like rat poison. There are also exceptions among the new generation \nof biopharmaceutical drugs that include nucleic acids, proteins \nand antibodies (see Ch. 5).\nPROTEIN TARGETS FOR", "start_char_idx": 0, "end_char_idx": 3680, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "01fc577c-319b-4aea-8bed-7e4f84eb8457": {"__data__": {"id_": "01fc577c-319b-4aea-8bed-7e4f84eb8457", "embedding": null, "metadata": {"page_label": "12", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b5a4db63-f6b1-42b9-b1bb-f4ba855fde52", "node_type": null, "metadata": {"page_label": "12", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c65011f0b32dc7561d9718403c9f9655c1b6b95fdeaf97d27f16647368bdfca9"}, "2": {"node_id": "2218a423-d7af-4985-b365-c76f18132b49", "node_type": null, "metadata": {"page_label": "12", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0bbec88277892a010931d164733db03007863c6a48041eaad4c44c353c191a79"}}, "hash": "fab11316be90ec257059d3a0dea0dd279038d8c2e48a3b689f606b8032121ecb", "text": "\nand antibodies (see Ch. 5).\nPROTEIN TARGETS FOR DRUG BINDING\nFour main kinds of regulatory protein are commonly \ninvolved as primary drug targets, namely:\n\u2022\treceptors\n\u2022\tenzymes\n\u2022\tcarrier \tmolecules \t(transporters)\n\u2022\tion\tchannels\nFurthermore, many drugs bind (in addition to their primary targets) to plasma proteins (see Ch. 9) and other tissue \nproteins, without producing any obvious physiological \neffect. Nevertheless, the generalisation that most drugs act on one or other of the four types of protein listed above \nserves as a good starting point.\nFurther discussion of the mechanisms by which \nsuch binding leads to cellular responses is given in \nChapters 3\u20134.\nDRUG RECEPTORS\nWHAT DO WE MEAN BY RECEPTORS ?\n\u25bc As emphasised in Chapter 1, the concept of receptors is central \nto pharmacology, and the term is most often used to describe the \ntarget molecules through which soluble physiological mediators \u2013 \nhormones, neurotransmitters, inflammatory mediators, etc. \u2013 produce \ntheir effects. Examples such as acetylcholine receptors, cytokine receptors, steroid receptors and growth hormone receptors abound \nin this book, and generally the term receptor indicates a recognition \nmolecule for a chemical mediator through which a response is \ntransduced.\n\u2018Receptor\u2019 is sometimes used to denote any target molecule with \nwhich a drug molecule (i.e. a foreign compound rather than an \nendogenous mediator) has to combine in order to elicit its specific 1There are, if one looks hard enough, exceptions to Ehrlich\u2019s dictum \u2013 \ndrugs that act without being bound to any tissue constituent (e.g. osmotic \ndiuretics, osmotic purgatives, antacids and heavy metal chelating agents). \nNonetheless, the principle remains true for the great majority.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3632, "end_char_idx": 5858, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "99e35b0a-10ed-4e42-8a39-5019b0a57e6f": {"__data__": {"id_": "99e35b0a-10ed-4e42-8a39-5019b0a57e6f", "embedding": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce635d5b-812e-4505-9290-f47fcdce1108", "node_type": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c2d13b3088d1498d0d3e000239055b7a0bd524ff2f2b5ab3185cc261df69581"}, "3": {"node_id": "ec123fe0-0d47-45bd-89bd-7dce104122bb", "node_type": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a3673c53c5be8abfde30c76e8a5dd6bd5e8b0e12191912fac4e880e3ec711198"}}, "hash": "635dfb69b2292a57c10f0e4e2063abe092074f034d5de2c4758a01465daa99c7", "text": "2 How d RuGS AC t: GENERAL PRINCIPLES\n7influence even when no chemical mediator is present \n(see p. 14).\nThere is an important distinction between agonists, which \n\u2018activate\u2019 the receptors, and antagonists, which combine at \nthe same site without causing activation, and block the \neffect of agonists on that receptor. The distinction between \nagonists and antagonists only exists for pharmacological receptors; we cannot usefully speak of \u2018agonists\u2019 for the \nother classes of drug target described above.\nThe characteristics and accepted nomenclature of \npharmacological receptors are described by Neubig et al. \n(2003). The origins of the receptor concept and its \npharmacological significance are discussed by Rang (2006).\nDRUG SPECIFICITY\nFor a drug to be useful as either a therapeutic or a scientific tool, it must act selectively on particular cells and tissues. \nIn other words, it must show a high degree of binding site \nspecificity. Conversely, proteins that function as drug targets generally show a high degree of ligand specificity; they \nbind only molecules of a certain precise type.\nThese principles of binding site and ligand specificity \ncan be clearly recognised in the actions of a mediator such as angiotensin (Ch. 23). This peptide acts strongly on \nvascular smooth muscle, and on the kidney tubule, but has \nvery little effect on other kinds of smooth muscle or on the intestinal epithelium. Other mediators affect a quite different \nspectrum of cells and tissues, the pattern in each case \nreflecting the specific pattern of expression of the protein receptors for the various mediators. A small chemical \nchange, such as conversion of one of the amino acids in \nangiotensin from L to D form, or removal of one amino acid from the chain, can inactivate the molecule altogether, \nbecause the receptor fails to bind the altered form. The \ncomplementary specificity of ligands and binding sites, which gives rise to the very exact molecular recognition \nproperties of proteins, is central to explaining many of the \nphenomena of pharmacology. It is no exaggeration to say that the ability of proteins to interact in a highly selective \nway with other molecules \u2013 including other proteins \u2013 is \nthe basis of living machines. Its relevance to the understand -\ning of drug action will be a recurring theme in this book.\nFinally, it must be emphasised that no drug acts with \ncomplete specificity. Thus tricyclic antidepressant drugs (Ch. 48) act by blocking monoamine transporters but are notorious for producing side effects (e.g. dry mouth) related \nto their ability to block various other receptors. In general, \nthe lower the potency of a drug and the higher the dose needed, the more likely it is that sites of action other than \nthe primary one will assume significance. In clinical terms, \nthis is often associated with the appearance of unwanted \u2018off-target\u2019 side effects,\n2 of which no drug is free.\nSince the 1970s, pharmacological research has succeeded \nin identifying the protein targets of many different types of drug. Drugs such as opioid analgesics (Ch. 43), can -\nnabinoids \t(Ch. \t20) \tand \tbenzodiazepine \ttranquillisers \t(Ch. \t\n45), whose actions had been described in exhaustive detail for many years, are now known to target well-defined \nreceptors, many of which have been fully characterised by effect. For example, the voltage-sensitive sodium channel is sometimes \nreferred to as the \u2018receptor\u2019 for local anaesthetics (see Ch. 44), or the \nenzyme\tdihydrofolate \treductase \tas \tthe \t\u2018receptor\u2019 \tfor \tmethotrexate \n(Ch. 51). The term drug target, of which receptors are one type, is \npreferable in this context.\nIn the more general context of cell biology, the term receptor is used \nto describe", "start_char_idx": 0, "end_char_idx": 3741, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ec123fe0-0d47-45bd-89bd-7dce104122bb": {"__data__": {"id_": "ec123fe0-0d47-45bd-89bd-7dce104122bb", "embedding": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce635d5b-812e-4505-9290-f47fcdce1108", "node_type": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c2d13b3088d1498d0d3e000239055b7a0bd524ff2f2b5ab3185cc261df69581"}, "2": {"node_id": "99e35b0a-10ed-4e42-8a39-5019b0a57e6f", "node_type": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "635dfb69b2292a57c10f0e4e2063abe092074f034d5de2c4758a01465daa99c7"}, "3": {"node_id": "50bfa380-5158-4a44-9d91-2da6017c9a26", "node_type": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ffa665883bb006c558e32488d4f74658284a358c017ee9631a9ff4c239cabccc"}}, "hash": "a3673c53c5be8abfde30c76e8a5dd6bd5e8b0e12191912fac4e880e3ec711198", "text": "the more general context of cell biology, the term receptor is used \nto describe various cell surface molecules (such as T-cell receptors, \nintegrins, Toll receptors, etc; see Ch. 7) involved in the cell-to-cell \ninteractions that are important in immunology, cell growth, migration and differentiation, some of which are also emerging as drug targets. \nThese receptors differ from conventional pharmacological receptors in that they respond to proteins attached to cell surfaces or extracellular \nstructures, rather than to soluble mediators.\nVarious carrier proteins are often referred to as receptors, such as \nthe low-density lipoprotein receptor that plays a key role in lipid \nmetabolism (Ch. 24) and the transferrin receptor involved in iron \nabsorption (Ch. 26). These entities have little in common with \npharmacological receptors. Though quite distinct from pharmacological \nreceptors, these proteins play an important role in the action of drugs such as statins (Ch. 24).\nRECEPTORS IN PHYSIOLOGICAL SYSTEMS\nReceptors form a key part of the system of chemical com-\nmunication that all multicellular organisms use to coordinate \nthe activities of their cells and organs. Without them, we \nwould be unable to function.\nSome fundamental properties of receptors are illus -\ntrated by the action of adrenaline (epinephrine) on the \nheart. Adrenaline first binds to a receptor protein (the \u03b21 \nadrenoceptor, see Ch. 15) that serves as a recognition site \nfor adrenaline and other catecholamines. When it binds \nto the receptor, a train of reactions is initiated (see Ch. 3), leading to an increase in force and rate of the heartbeat. In \nthe absence of adrenaline, the receptor is normally function -\nally silent. This is true of most receptors for endogenous \nmediators (hormones, neurotransmitters, cytokines, etc.), \nalthough there are examples (see Ch. 3) of receptors that \nare \u2018constitutively active\u2019 \u2013 that is, they exert a controlling Targets for drug action \n\u2022\tA\tdrug\tis \ta \tchemical \tapplied \tto \ta \tphysiological \tsystem \t\nthat\taffects \tits \tfunction \tin \ta \tspecific \tway.\n\u2022\tWith\tsome \texceptions, \tdrugs \tact \ton \ttarget \tproteins, \t\nnamely:\n\u2013\treceptors\u2013\tenzymes\n\u2013\tcarriers\n\u2013\tion\tchannels.\n\u2022\tThe\tterm \treceptor\tis\tused\tin \tdifferent \tways. \tIn \t\npharmacology, \tit \tdescribes \tprotein \tmolecules \twhose \t\nfunction\tis \tto \trecognise \tand \trespond \tto \tendogenous \t\nchemical\tsignals. \tOther \tmacromolecules \twith \twhich \t\ndrugs\tinteract \tto \tproduce \ttheir \teffects \tare \tknown \tas \t\ndrug targets .\n\u2022\tSpecificity \tis \treciprocal: \tindividual \tclasses \tof \tdrug \tbind \t\nonly\tto\tcertain \ttargets, \tand \tindividual \ttargets \trecognise \t\nonly\tcertain \tclasses \tof \tdrug.\n\u2022\tNo\tdrugs \tare \tcompletely \tspecific \tin \ttheir \tactions. \tIn \t\nmany\tcases, \tincreasing \tthe \tdose \tof \ta \tdrug \twill \tcause \tit \t\nto\taffect\ttargets \tother \tthan \tthe \tprincipal \tone, \tand \tthis \t\ncan\tlead\tto \tside \teffects.\n2\u2018On-target\u2019 side effects are unwanted effects mediated through the \nsame receptor as the clinically desired effect, for example constipation \nand respiratory depression by opioid analgesic drugs (see Ch. 43), \nwhereas \u2018off target\u2019 side effects are mediated by a different mechanism.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3675, "end_char_idx": 6961, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "50bfa380-5158-4a44-9d91-2da6017c9a26": {"__data__": {"id_": "50bfa380-5158-4a44-9d91-2da6017c9a26", "embedding": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce635d5b-812e-4505-9290-f47fcdce1108", "node_type": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c2d13b3088d1498d0d3e000239055b7a0bd524ff2f2b5ab3185cc261df69581"}, "2": {"node_id": "ec123fe0-0d47-45bd-89bd-7dce104122bb", "node_type": null, "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a3673c53c5be8abfde30c76e8a5dd6bd5e8b0e12191912fac4e880e3ec711198"}}, "hash": "ffa665883bb006c558e32488d4f74658284a358c017ee9631a9ff4c239cabccc", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6981, "end_char_idx": 7412, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cdf44d3b-ed62-4828-b808-e834961c7558": {"__data__": {"id_": "cdf44d3b-ed62-4828-b808-e834961c7558", "embedding": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c0d7ccc9-7b04-47e5-b913-72d217a1f1c6", "node_type": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c0cad76ddcc20b1a052ac4dcef3ad76c4b6f7e7119176de96ab61a6c3c1ae71"}, "3": {"node_id": "34713ea0-4ca5-4209-b199-af991552b584", "node_type": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d532b2f35a6ee41f80b1d79bb165c7514acb850bed0c321f38136b706fcad907"}}, "hash": "bff15897ad4883261ee2d2eefc4c954adb83d6fa1927cefd6accb4b885753353", "text": "2 SECTION 1 GENERAL PRINCIPLES\n8receptors is governed by its affinity, whereas the tendency \nfor it, once bound, to activate the receptor is denoted by \nits efficacy. These terms are defined more precisely later \n(pp. 9 and 11). Drugs of high potency generally have a \nhigh affinity for the receptors and thus occupy a significant \nproportion of the receptors even at low concentrations. \nAgonists also possess significant efficacy, whereas antago -\nnists,\tin\tthe \tsimplest \tcase, \thave \tzero \tefficacy. \tDrugs \twith \t\nintermediate levels of efficacy, such that even when 100% of the receptors are occupied the tissue response is sub-\nmaximal, are known as partial agonists , to distinguish them \nfrom full agonists, the efficacy of which is sufficient that \nthey can elicit a maximal tissue response. These concepts, though clearly an oversimplified description of events at \nthe molecular level (see Ch. 3), provide a useful basis for characterising drug effects.\nWe now discuss certain aspects in more detail, namely \ndrug binding, agonist concentration\u2013effect curves, competi -\ntive antagonism, partial agonists and the nature of efficacy. Understanding these concepts at a qualitative level is \nsufficient for many purposes, but for more detailed analysis \na quantitative formulation is needed (see pp. 19\u201320).\nTHE BINDING OF DRUGS TO RECEPTORS\n\u25bc The binding of drugs to receptors can often be measured directly \nby the use of drug molecules (agonists or antagonists) labelled with \none or more radioactive atoms (usually 3H, 14C or 125I). The usual \nprocedure is to incubate samples of the tissue (or membrane fragments) \nwith various concentrations of radioactive drug until equilibrium is \nreached (i.e. when the rate of association [binding] and dissociation [unbinding] of the radioactive drug are equal). The bound radioactivity \nis measured after removal of the supernatant.\nIn such experiments, the radiolabelled drug will exhibit both specific \nbinding (i.e. binding to receptors, which is saturable as there are a \nfinite number of receptors in the tissue) and a certain amount of \u2018non-specific binding\u2019 (i.e. drug taken up by structures other than \nreceptors, which, at the concentrations used in such studies, is normally \nnon-saturable), which obscures the specific component and needs to be kept to a minimum (Fig. 2.2A\u2013B). The amount of non-specific gene-cloning and protein crystallography techniques (see \nCh. 3).\nRECEPTOR CLASSIFICATION\n\u25bc Where the action of a drug can be associated with a particular \nreceptor, this provides a valuable means for classification and refine -\nment in drug design. For example, pharmacological analysis of the \nactions of histamine (see Ch. 18) showed that some of its effects (the \nH1 effects, such as smooth muscle contraction) were strongly antago -\nnised by the competitive histamine antagonists then known. Black \nand his colleagues suggested in 1970 that the remaining actions of \nhistamine, which included its stimulant effect on gastric secretion, might represent a second class of histamine receptor (H\n2). Testing a \nnumber of histamine analogues, they found that some were selective \nin producing H 2 effects, with little H 1 activity. By analysing which \nparts of the histamine molecule conferred this type of specificity, they were able to develop selective H\n2 antagonists, which proved to \nbe potent in blocking gastric acid secretion, a development of major therapeutic significance (Ch. 31).\n3 Two further types of histamine \nreceptor (H 3 and H 4) were recognised later.\nReceptor classification based on pharmacological responses continues \nto be a valuable and widely used approach. Subsequently, newer experimental approaches produced other criteria on which", "start_char_idx": 0, "end_char_idx": 3736, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "34713ea0-4ca5-4209-b199-af991552b584": {"__data__": {"id_": "34713ea0-4ca5-4209-b199-af991552b584", "embedding": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c0d7ccc9-7b04-47e5-b913-72d217a1f1c6", "node_type": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c0cad76ddcc20b1a052ac4dcef3ad76c4b6f7e7119176de96ab61a6c3c1ae71"}, "2": {"node_id": "cdf44d3b-ed62-4828-b808-e834961c7558", "node_type": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bff15897ad4883261ee2d2eefc4c954adb83d6fa1927cefd6accb4b885753353"}, "3": {"node_id": "7093aa4c-f087-4c7b-8955-22af77623995", "node_type": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d3754cd36f6a819b3532b7a8ddcef1d30e4a35b0609880b1a507dbcc6a4224e6"}}, "hash": "d532b2f35a6ee41f80b1d79bb165c7514acb850bed0c321f38136b706fcad907", "text": "used approach. Subsequently, newer experimental approaches produced other criteria on which to base \nreceptor classification. The direct measurement of ligand binding to \nreceptors (see later) allowed many new receptor subtypes to be defined that could not easily be distinguished by studies of drug effects. \nMolecular sequencing of the amino acid structure (see Ch. 3) provided \na completely new basis for classification at a much finer level of detail than can be reached through pharmacological analysis. Finally, analysis \nof the biochemical pathways that are linked to receptor activation \n(see Ch. 3) provides yet another basis for classification.\nThe result of this data explosion was that receptor classification sud -\ndenly became much more detailed, with a proliferation of receptor \nsubtypes for all the main types of ligand. As alternative molecular and \nbiochemical classifications began to spring up that were incompatible \nwith the accepted pharmacologically defined receptor classes, the International Union of Basic and Clinical Pharmacology (IUPHAR) \nconvened expert working groups to produce agreed receptor classifica -\ntions for the major types, taking into account the pharmacological, \nmolecular and biochemical information available. These wise people \nhave a hard task; their conclusions will be neither perfect nor final but \nare essential to ensure a consistent terminology. To the student, this may seem an arcane exercise in taxonomy, generating much detail \nbut little illumination. There is a danger that the tedious lists of drug \nnames, actions and side effects that used to burden the subject will be \nreplaced by exhaustive tables of receptors, ligands and transduction \npathways. In this book, we have tried to avoid detail for its own sake and include only such information on receptor classification as seems \ninteresting in its own right or is helpful in explaining the actions \nof important drugs. A comprehensive database of known receptor classes is available (see ), as well \nas a regularly updated summary (Alexander et al., 2015).\nDRUG\u2013RECEPTOR INTERACTIONS\nOccupation of a receptor by a drug molecule may or may \nnot result in activation of the receptor. By activation, we \nmean that the receptor is affected by the bound molecule in such a way as to alter the function of the cell and elicit a tissue response. The molecular mechanisms associated \nwith receptor activation are discussed in Chapter 3. Binding \nand activation represent two distinct steps in the generation of the receptor-mediated response by an agonist ( Fig. 2.1 ). \nIf a drug binds to the receptor without causing activation and thereby prevents the agonist from binding, it is termed a receptor antagonist . The tendency of a drug to bind to the \n3For this work, and the development of \u03b2-adrenoceptor antagonists by a \nsimilar experimental approach, Sir James Black was awarded the 1984 \nNobel\tPrize \tin \tPhysiology \tor \tMedicine.Occupation\ngoverned\nby\naffinityActivation\ngoverned\nby\nefficacy\nDrug\nA\n(agonist)+RA Rk+1\nk-1\u03b2\n\u03b1AR* RESPONSE\nDrug\nB\n(antagonist)NO RESPONSE +RB Rk+1\nk-1\nFig. 2.1\tThe distinction between drug binding and \nreceptor activation. \tLigand\tA\tis\tan\tagonist, \tbecause \twhen \tit \tis \t\nbound,\tthe \treceptor \t(R)\ttends\tto\tbecome \tactivated, \twhereas \t\nligand\tB\tis\tan\tantagonist, \tbecause \tbinding \tdoes \tnot \tlead \tto \t\nactivation. \tIt \tis \timportant \tto \trealise \tthat \tfor \tmost \tdrugs, \tbinding \t\nand\tactivation \tare \treversible, \tdynamic \tprocesses. \tThe \trate \t\nconstants \tk+1,\tk\u22121,\t\u03b1\tand\t\u03b2\tfor\tthe\tbinding, \tunbinding \tand \t\nactivation\tsteps \tvary \tbetween \tdrugs. \tFor \tan \tantagonist, \twhich", "start_char_idx": 3656, "end_char_idx": 7321, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7093aa4c-f087-4c7b-8955-22af77623995": {"__data__": {"id_": "7093aa4c-f087-4c7b-8955-22af77623995", "embedding": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c0d7ccc9-7b04-47e5-b913-72d217a1f1c6", "node_type": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c0cad76ddcc20b1a052ac4dcef3ad76c4b6f7e7119176de96ab61a6c3c1ae71"}, "2": {"node_id": "34713ea0-4ca5-4209-b199-af991552b584", "node_type": null, "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d532b2f35a6ee41f80b1d79bb165c7514acb850bed0c321f38136b706fcad907"}}, "hash": "d3754cd36f6a819b3532b7a8ddcef1d30e4a35b0609880b1a507dbcc6a4224e6", "text": "\tvary \tbetween \tdrugs. \tFor \tan \tantagonist, \twhich \t\ndoes\tnot\tactivate \tthe \treceptor, \t\u03b2\t=\t0.\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7351, "end_char_idx": 7926, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "33a37fe6-3527-4886-ae07-9fdac983f0c7": {"__data__": {"id_": "33a37fe6-3527-4886-ae07-9fdac983f0c7", "embedding": null, "metadata": {"page_label": "15", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5caf8182-1d82-42f4-ad7c-19ea91c92a77", "node_type": null, "metadata": {"page_label": "15", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b51b4e70ecdccdb8bec8904fe7886e690a7d125e8fd6619d6dba1d523c931a4"}, "3": {"node_id": "43fe4d20-827f-43bc-bc04-32dbb980098f", "node_type": null, "metadata": {"page_label": "15", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe1988910eb297d3c26fe707f8672b8d312bce455244baf8a8a5c4460bb1dc84"}}, "hash": "db9b82e22d49efdf514ed82b36b2bfc15df129d541b3c3da56c9e43963afa822", "text": "2 How d RuGS AC t: GENERAL PRINCIPLES\n9R R RSpecific binding to receptor(i) Radioactive drug binds to specific\nand non-specific sites(ii) Increasing concentration of radioactive\ndrug saturates specific sites (iii) Excess non-radioacti ve drug displaces\nradioacti ve drug from specific sites\n20 20 01 01 5 50 51 01 5 100 10 1 0.1 0.01 0.001300\n0100\n0100\n0\nConcentration (nmol/L) Concentration (nmol/L) Concentration (nmol/L, log scale)Non-specificTotal\nKSpecifically bound (fmol/mg)Total bound (fmol/mg)\nSpecifically bound (fmol/mg)BmaxBmaxA\nBC D\nFig. 2.2\tMeasurement of receptor binding. \t(A)\t(i)\tCartoon \tdepicting \tradioligand \t(shown \tin \tred) \tbinding \tto \tits \treceptor \t(R)\tin\tthe\t\nmembrane \tas \twell \tas \tto \tnon-specific \tsites \ton \tother \tproteins \tand \tlipid. \tIn \t(ii) \twhen \tthe \tconcentration \tof \tradioligand \tis \tincreased \tall \tthe \t\nspecific\tsites \tbecome \tsaturated \tbut \tnon-specific \tbinding \tcontinues \tto \tincrease. \tIn \t(iii) \taddition \tof \ta \thigh \tconcentration \tof \ta \tnon-radioactive \t\ndrug\t(shown in green) \tthat\talso\tbinds \tto \tR \tdisplaces \tthe \tradioactive \tdrug \tfrom \tits \treceptors \tbut \tnot \tfrom \tthe \tnon-specific \tsites. \t(B\u2013D) \t\nIllustrate\tactual \texperimental \tresults \tfor \tradioligand \tbinding \tto \t\u03b2\tadrenoceptors \tin \tcardiac \tcell \tmembranes. \tThe \tligand \twas \t\n[3H]-cyanopindolol, \ta \tderivative \tof \tpindolol \t(see \tCh. \t15). \t(B) \tMeasurements \tof \ttotal \tand \tnon-specific \tbinding \tat \tequilibrium. \tNon-specific \t\nbinding\tis\tmeasured \tin \tthe \tpresence \tof \ta \tsaturating \tconcentration \tof \ta \tnon-radioactive \t\u03b2-adrenoceptor \tagonist, \twhich \tprevents \tthe \t\nradioactive \tligand \tfrom \tbinding \tto \t\u03b2\tadrenoceptors. \tThe \tdifference \tbetween \tthe \ttwo \tlines \trepresents \tspecific \tbinding. \t(C) \tSpecific \tbinding \t\nplotted\tagainst \tconcentration. \tThe \tcurve \tis \ta \trectangular \thyperbola \t(Eq. \t2.5). \t(D) \tSpecific \tbinding \tas \tin \t(C) \tplotted \tagainst \tthe \tconcentration \t\non\ta\tlog\tscale. \tThe \tsigmoid \tcurve \tis \ta \tlogistic curve \trepresenting \tthe \tlogarithmic \tscaling \tof \tthe \trectangular \thyperbola \tplotted \tin \tpanel \t(C) \t\nfrom\twhich \tthe \tbinding \tparameters \tK\t(the\tequilibrium \tdissociation \tconstant) \tand \tBmax\t(the\tbinding \tcapacity) \tcan \tbe \tdetermined. \t\nbinding is estimated by measuring the radioactivity taken up in the \npresence of a saturating concentration of a (non-radioactive) ligand", "start_char_idx": 0, "end_char_idx": 2376, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "43fe4d20-827f-43bc-bc04-32dbb980098f": {"__data__": {"id_": "43fe4d20-827f-43bc-bc04-32dbb980098f", "embedding": null, "metadata": {"page_label": "15", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5caf8182-1d82-42f4-ad7c-19ea91c92a77", "node_type": null, "metadata": {"page_label": "15", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b51b4e70ecdccdb8bec8904fe7886e690a7d125e8fd6619d6dba1d523c931a4"}, "2": {"node_id": "33a37fe6-3527-4886-ae07-9fdac983f0c7", "node_type": null, "metadata": {"page_label": "15", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db9b82e22d49efdf514ed82b36b2bfc15df129d541b3c3da56c9e43963afa822"}}, "hash": "fe1988910eb297d3c26fe707f8672b8d312bce455244baf8a8a5c4460bb1dc84", "text": "\nthat inhibits completely the binding of the radioactive drug to the \nreceptors, leaving behind the non-specific component. This is then subtracted from the total binding to give an estimate of specific binding \n(Fig. 2.2C). The binding curve (Fig. 2.2C\u2013D) defines the relationship \nbetween concentration and the amount of drug bound (B), and in \nmost cases it fits well to the relationship predicted theoretically (see \nFig. 2.14), allowing the affinity of the drug for the receptors to be \nestimated, as well as the binding capacity (B\nmax), representing the \ndensity of receptors in the tissue. When combined with functional \nstudies, binding measurements have proved very valuable. It has, \nfor example, been confirmed that the spare receptor hypothesis (p. 10) \nfor muscarinic receptors in smooth muscle is correct; agonists are \nfound to bind, in general, with rather low affinity, and a maximal \nbiological effect occurs at low receptor occupancy. It has also been shown, in skeletal muscle and other tissues, that denervation leads \nto an increase in the number of receptors in the target cell, a finding \nthat accounts, at least in part, for the phenomenon of denervation \nsupersensitivity. More generally, it appears that receptors tend to increase in number, usually over the course of a few days, if the relevant hormone or transmitter is absent or scarce, and to decrease \nin number if the receptors are activated for a prolonged period, a \nprocess of adaptation to continued administration of drugs or hormones \n(see p. 18).Non-invasive imaging techniques, such as positron emission tomography \n(PET), using drugs labelled with an isotope of short half-life (such \nas \n11C or 18Fl), can also be used to investigate the distribution of \nreceptors in structures such as the living human brain. This technique has been used, for example, to measure the degree of dopamine-\nreceptor blockade produced by antipsychotic drugs in the brains of \nschizophrenic \tpatients \t(see \tCh. \t47).\nBinding curves with agonists often reveal an apparent heterogeneity among receptors. For example, agonist binding to muscarinic receptors \n(Ch. 14) and also to \u03b2 adrenoceptors (Ch. 15) suggests at least two \npopulations of binding sites with different affinities. This may be \nbecause the receptors can exist either unattached or coupled within \nthe membrane to another macromolecule, the G protein (see Ch. 3), \nwhich constitutes part of the transduction system through which the receptor exerts its regulatory effect. Antagonist binding does not show \nthis complexity, probably because antagonists, by their nature, do \nnot lead to the secondary event of G protein coupling. Because agonist \nbinding results in activation, agonist affinity has proved to be a surpris -\ningly elusive concept, about which aficionados love to argue.\nTHE RELATION BETWEEN DRUG CONCENTRATION \nAND EFFECT\nAlthough binding can be measured directly, it is usually \na biological response, such as a rise in blood pressure, mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2377, "end_char_idx": 5852, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e3942b7-35e0-42a8-8c92-68755db63aef": {"__data__": {"id_": "8e3942b7-35e0-42a8-8c92-68755db63aef", "embedding": null, "metadata": {"page_label": "16", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b9c9f479-fe67-4ff5-946b-994e82eef357", "node_type": null, "metadata": {"page_label": "16", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad6337d92021aa8955e5d073e81deb20e497323dc62ff6bf226f2772e30aa04b"}, "3": {"node_id": "2a7894d6-240c-4e18-a6a4-015512d90f4c", "node_type": null, "metadata": {"page_label": "16", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "686ac0184dbd5ef8bc39e4c5fd11e9d85c0135f818ac2ed901ddbc4150c30f83"}}, "hash": "13096e5f0e1709508fe1e2eaa4673073d82bb41582d41c5386a281ff808937c1", "text": "2 SECTION 1 GENERAL PRINCIPLES\n10by the use of recombinant receptors expressed in cells in \nculture. Thus, even if the concentration\u2013effect curve, as in \nFig. 2.3, looks just like a facsimile of the binding curve (see \nFig. 2.2D), it cannot be used directly to determine the affinity of the agonist for the receptors.\nSPARE RECEPTORS\n\u25bc Stephenson (1956), studying the actions of acetylcholine analogues \nin isolated tissues, found that many full agonists were capable of \neliciting maximal responses at very low occupancies, often less than \n1%. This means that the mechanism linking the response to receptor \noccupancy has a substantial reserve capacity. Such systems may be said to possess spare receptors, or a receptor reserve. The existence of \nspare receptors does not imply any functional subdivision of the receptor pool, but merely that the pool is larger than the number needed to evoke a full response. This surplus of receptors over the \nnumber actually needed might seem a wasteful biological arrangement. \nBut in fact it is highly efficient in that a given number of agonist\u2013\nreceptor complexes, corresponding to a given level of biological \nresponse, can be reached with a lower concentration of hormone or neurotransmitter than would be the case if fewer receptors were \nprovided. Economy of hormone or transmitter secretion is thus \nachieved at the expense of providing more receptors.\nCOMPETITIVE ANTAGONISM\nThough one drug can inhibit the response to another in \nseveral ways (see p. 16), competition at the receptor level \nis particularly important, both in the laboratory and in the \nclinic, because of the high potency and specificity that can be achieved.\nIn the presence of a competitive antagonist, the agonist \noccupancy (i.e. proportion of receptors to which the agonist is bound) at a given agonist concentration is reduced, \nbecause the receptor can accommodate only one molecule \nat a time. However, because the two are in competition, raising the agonist concentration can restore the agonist occupancy (and hence the tissue response). The antago-\nnism is therefore said to be surmountable, in contrast to \nother types of antagonism (see later) where increasing the \nagonist concentration fails to overcome the blocking effect. \nA simple theoretical analysis (see p. 20) predicts that in \nthe presence of a fixed concentration of the antagonist, the log concentration\u2013effect curve for the agonist will \nbe shifted to the right, without any change in slope or \nmaximum \u2013 the hallmark of competitive antagonism (Fig. 2.4A). The shift is expressed as a dose ratio , r (the ratio by \nwhich the agonist concentration has to be increased in the presence of the antagonist in order to restore a given level of response). Theory predicts that the dose ratio increases \nlinearly with the concentration of the antagonist (see p. \n20). These predictions are often borne out in practice (Fig. 2.5A), providing a relatively simple method for determin -\ning the equilibrium dissociation constant of the antagonist (K\nB; Fig. 2.5B). Examples of competitive antagonism are \nvery common in pharmacology. The surmountability of \nthe block by the antagonist may be important in practice, \nbecause it allows the functional effect of the agonist to be restored by an increase in concentration. With other \ntypes of antagonism (as detailed below), the block is usually \ninsurmountable.\nThe salient features of competitive antagonism are:\n\u2022\tshift\tof \tthe \tagonist \tlog \tconcentration\u2013effect \tcurve \tto \t\nthe right, without change of slope or maximum (i.e. \nantagonism can be overcome by increasing the \nconcentration of the agonist)contraction or relaxation of a strip of smooth muscle in an \norgan\tbath, \tthe \tactivation \tof \tan", "start_char_idx": 0, "end_char_idx": 3742, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2a7894d6-240c-4e18-a6a4-015512d90f4c": {"__data__": {"id_": "2a7894d6-240c-4e18-a6a4-015512d90f4c", "embedding": null, "metadata": {"page_label": "16", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b9c9f479-fe67-4ff5-946b-994e82eef357", "node_type": null, "metadata": {"page_label": "16", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad6337d92021aa8955e5d073e81deb20e497323dc62ff6bf226f2772e30aa04b"}, "2": {"node_id": "8e3942b7-35e0-42a8-8c92-68755db63aef", "node_type": null, "metadata": {"page_label": "16", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "13096e5f0e1709508fe1e2eaa4673073d82bb41582d41c5386a281ff808937c1"}}, "hash": "686ac0184dbd5ef8bc39e4c5fd11e9d85c0135f818ac2ed901ddbc4150c30f83", "text": "of smooth muscle in an \norgan\tbath, \tthe \tactivation \tof \tan \tenzyme, \tor \ta \tbehavioural \t\nresponse, that we are interested in, and this is often plotted \nas a concentration \u2013effect curve (in vitro) or dose\u2013 response curve \n(in vivo), as in Fig. 2.3. This allows us to estimate the maximal \nresponse that the drug can produce ( Emax), and the concentra -\ntion or dose needed to produce a 50% maximal response \n(EC 50 or ED 50). A logarithmic concentration or dose scale \nis often used. This transforms the curve from a rectangular hyperbola to a sigmoidal curve in which the mid portion \nis essentially linear (the importance of the slope of the linear portion will become apparent later in this chapter \nwhen we consider antagonism and partial agonists). The \nE\nmax, EC 50 and slope parameters are useful for comparing \ndifferent drugs that produce qualitatively similar effects \n(see Fig. 2.7 and Ch. 8). Although they look similar to the \nbinding curve in Fig. 2.2D, concentration\u2013effect curves cannot be used to measure the affinity of agonist drugs for \ntheir receptors, because the response produced is not, as \na rule, directly proportional to receptor occupancy. This often arises because the maximum response of a tissue \nmay be produced by agonists when they occupy less than \n100% of the receptors. Under these circumstances the tissue is said to possess spare receptors (see later).\nIn interpreting concentration\u2013effect curves, it must be \nremembered that the concentration of the drug at the receptors may differ from the known concentration in the \nbathing\tsolution. \tAgonists \tmay\tbe\tsubject\tto\trapid\tenzymic\t\ndegradation or uptake by cells as they diffuse from the surface towards their site of action, and a steady state can \nbe reached in which the agonist concentration at the recep -\ntors is very much less than the concentration in the bath. \nIn the case of acetylcholine, for example, which is hydrolysed \nby cholinesterase present in most tissues (see Ch. 14), the \nconcentration reaching the receptors can be less than 1% of that in the bath, and an even bigger difference has been \nfound with noradrenaline (norepinephrine), which is avidly \ntaken up by sympathetic nerve terminals in many tissues (Ch. 15). The problem is reduced but not entirely eradicated Histamine\n(guinea pig heart)\nAcetylcholine\n(frog rectus muscle)\nConcentration (mol/L)10-210-310-410-510-610-7Response (% max)100\n50\n0\nFig. 2.3\tExperimentally observed concentration\u2013effect \ncurves.\tAlthough\tthe \tlines, \tdrawn \taccording \tto \tthe \tbinding \tEq. \t\n2.5,\tfit\tthe \tpoints \twell, \tsuch \tcurves \tdo \tnot \tgive \tcorrect \testimates \t\nof\tthe\taffinity \tof \tdrugs \tfor \treceptors. \tThis \tis \tbecause \tthe \t\nrelationship \tbetween \treceptor \toccupancy \tand \tresponse \tis \t\nusually\tnon-linear. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3682, "end_char_idx": 6944, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fba43e93-a374-4246-91d9-48e62221774d": {"__data__": {"id_": "fba43e93-a374-4246-91d9-48e62221774d", "embedding": null, "metadata": {"page_label": "17", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d217b749-e809-4bd8-8981-51bee2597e91", "node_type": null, "metadata": {"page_label": "17", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8022f2815334a816d84ac1c050d695cce70e8e934fdd4d8c7bfcd6fc8584bab"}, "3": {"node_id": "647409d2-8dc8-40a0-bd7f-fe8fedb872cb", "node_type": null, "metadata": {"page_label": "17", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc2cfef324a7dfc6be6b390d23302842c78c6be08f66cea7d974dd353961dfac"}}, "hash": "04992a866962f5afa4f98768bd7d763a895934144eaae321681895bdb857361a", "text": "2 How d RuGS AC t: GENERAL PRINCIPLES\n11Agonist concentration01 10 100 1000Antagonist\nconcentration1.0\n0.5\n0Fractional agonist occupancy\n10-211 02104106\nAgonist concentration1\n100\nAntagonist\nconcentration1.0\n0.5\n0Fractional agonist occupancy\n10-211 02104106Reversible competitive antagonism\nIrreversible competitive antagonismA\nB\nFig. 2.4\tHypothetical agonist concentration\u2013occupancy \ncurves in the presence of reversible (A) and irreversible (B) \ncompetitive antagonists. \tThe\tconcentrations \tare \tnormalised \t\nwith\trespect \tto \tthe \tequilibrium \tdissociation \tconstants, \tK\t(i.e.\t1.0\t\ncorresponds \tto \ta \tconcentration \tequal \tto \tK\tand\tresults \tin \t50% \t\noccupancy). \tNote \tthat \tin \t(A) \tincreasing \tthe \tagonist \tconcentration \t\novercomes \tthe \teffect \tof \ta \treversible \tantagonist \t(i.e. \tthe \tblock \tis \t\nsurmountable), \tso \tthat \tthe \tmaximal \tresponse \tis \tunchanged, \t\nwhereas\tin \t(B) \tthe \teffect \tof \tan \tirreversible \tantagonist \tis \t\ninsurmountable \tand \tfull \tagonist \toccupancy \tcannot \tbe \tachieved. \t\n\u2022\tlinear\trelationship \tbetween \tagonist \tdose \tratio \tand \t\nantagonist concentration\n\u2022\tevidence \tof \tcompetition \tfrom \tbinding \tstudies.\nCompetitive antagonism is the most direct mechanism by \nwhich one drug can reduce the effect of another (or of an \nendogenous mediator).\n\u25bc The characteristics of reversible competitive antagonism described \nabove reflect the fact that agonist and competitive antagonist molecules \ndo not stay bound to the receptor but dissociate and rebind continu -\nously. The rate of dissociation of the antagonist molecules is sufficiently \nhigh that a new equilibrium is rapidly established on addition of the \nagonist. In effect, agonist molecules are able to replace the antagonist \nmolecules on the receptors when the antagonist unbinds, although they cannot, of course, evict bound antagonist molecules. Displacement \noccurs because, by occupying a proportion of the vacant receptors, \nthe agonist effectively reduces the rate of association of the antagonist \nmolecules; consequently, the rate of dissociation temporarily exceeds \nthat of association, and the overall antagonist occupancy falls.IRREVERSIBLE COMPETITIVE ANTAGONISM\n\u25bc Irreversible competitive (or non-equilibrium ) antagonism occurs when \nthe antagonist binds to the same site on the receptor as the agonist \nbut dissociates very slowly, or not at all, from the receptors, with the \nresult that no change in the antagonist occupancy takes place when the agonist is applied.\n4\nThe predicted effects of reversible and irreversible antagonists are compared in Fig. 2.4.\nIn some cases ( Fig. 2.6A), the theoretical effect is accurately reproduced \nwith the antagonist reducing the maximum response. However, the \ndistinction between reversible and irreversible competitive antagonism \n(or even non-competitive antagonism) is not always so clear. This is because of the phenomenon of spare receptors (see p. 10); if the agonist \noccupancy required to produce a maximal biological response is very \nsmall (say 1% of the total receptor pool), then it is possible to block irreversibly nearly 99% of the receptors without reducing the maximal \nresponse. The effect of a lesser degree of antagonist occupancy will \nbe to produce a parallel shift of the log concentration\u2013effect curve that is indistinguishable from reversible competitive antagonism (Fig. \n2.6B). Only when the antagonist occupancy exceeds 99% will the maximum response will be reduced.\nIrreversible competitive", "start_char_idx": 0, "end_char_idx": 3489, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "647409d2-8dc8-40a0-bd7f-fe8fedb872cb": {"__data__": {"id_": "647409d2-8dc8-40a0-bd7f-fe8fedb872cb", "embedding": null, "metadata": {"page_label": "17", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d217b749-e809-4bd8-8981-51bee2597e91", "node_type": null, "metadata": {"page_label": "17", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8022f2815334a816d84ac1c050d695cce70e8e934fdd4d8c7bfcd6fc8584bab"}, "2": {"node_id": "fba43e93-a374-4246-91d9-48e62221774d", "node_type": null, "metadata": {"page_label": "17", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "04992a866962f5afa4f98768bd7d763a895934144eaae321681895bdb857361a"}}, "hash": "bc2cfef324a7dfc6be6b390d23302842c78c6be08f66cea7d974dd353961dfac", "text": "exceeds 99% will the maximum response will be reduced.\nIrreversible competitive antagonism occurs with drugs that possess \nreactive groups that form covalent bonds with the receptor. These are mainly used as experimental tools for investigating receptor \nfunction, \tand \tfew \tare \tused \tclinically. \tIrreversible \tenzyme \tinhibitors \t\nthat act similarly are clinically used, however, and include drugs such as aspirin (Ch. 27), omeprazole (Ch. 31) and monoamine oxidase \ninhibitors (Ch. 48).\nPARTIAL AGONISTS AND THE CONCEPT \nOF EFFICACY\nSo far, we have considered drugs either as agonists, which \nin some way activate the receptor when they occupy it, or \nas antagonists, which cause no activation. However, the \nability of a drug molecule to activate the receptor \u2013 namely its efficacy \u2013 is actually a graded, rather than an all-or-\nnothing, property. If a series of chemically related agonist \ndrugs acting on the same receptors is tested on a given biological system, it is often found that the largest response \nthat can be produced differs from one drug to another. \nSome compounds (known as full agonists) can produce a \nmaximal response (the largest response that the tissue is capable of giving), whereas others (partial agonists) can \nproduce only a submaximal response. Fig. 2.7A shows \nconcentration\u2013effect curves for several \u03b1-adrenoceptor \nagonists (see Ch. 15), which cause contraction of isolated Competitive antagonism \n\u2022\tReversible \tcompetitive \tantagonism \tis \tthe \tcommonest \t\nand\tmost\timportant \ttype \tof \tantagonism; \tit \thas \ttwo \t\nmain\tcharacteristics.\n\u2013\tIn\tthe\tpresence \tof \tthe \tantagonist, \tthe \tagonist \tlog \t\nconcentration\u2013effect \tcurve \tis \tshifted \tto \tthe \tright \t\nwithout\tchange \tin \tslope \tor \tmaximum, \tthe \textent \tof \t\nthe\tshift\tbeing \ta \tmeasure \tof \tthe \tdose ratio.\n\u2013\tThe\tdose \tratio \tincreases \tlinearly \twith \tantagonist \t\nconcentration.\n\u2022\tAntagonist \taffinity, \tmeasured \tin \tthis \tway, \tis \twidely \t\nused\tas\ta \tbasis \tfor \treceptor \tclassification.\n4This type of antagonism is sometimes called non-competitive, but that \nterm is ambiguous and best avoided in this context.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3410, "end_char_idx": 6008, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fec75ef9-fdd8-436f-a6e1-38b959544a96": {"__data__": {"id_": "fec75ef9-fdd8-436f-a6e1-38b959544a96", "embedding": null, "metadata": {"page_label": "18", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eb1d4577-0462-4846-91ea-60db375e7688", "node_type": null, "metadata": {"page_label": "18", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92525aa48b4e80b01228c1186d91c241e636c2d54070a9ae45b67eb56449829d"}, "3": {"node_id": "af9bcc99-788d-4df4-b65f-1da1c9f2a9de", "node_type": null, "metadata": {"page_label": "18", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9cf45032030d7c5098d047b39b1a68fe0189503fd73f94261569860f021bf038"}}, "hash": "10e11cc6f63e2535b038747d2b4946726a33602d8b3df7f0f9a9b6655337cb39", "text": "2 SECTION 1 GENERAL PRINCIPLES\n12Isoprenaline concentration (mol/L) Propranolol concentration (mol/L)100\n80\n604020\n0Response (% max)\nLog (r \u2212 1)5\n43210\n10-410-510-610-610-710-80\n10-610-710-710-810-810-910-910-1010-11KB = 2.2 x 10-9 mol/L\nA B\nFig. 2.5\tCompetitive antagonism of isoprenaline by propranolol measured on isolated guinea pig atria. \t(A)\tConcentration\u2013effect \t\ncurves\tat\tvarious \tpropranolol \tconcentrations \t(indicated \ton \tthe \tcurves). \tNote \tthe \tprogressive \tshift \tto \tthe \tright \twithout \ta \tchange \tof \tslope \tor \t\nmaximum. \t(B) \tSchild \tplot \t(Eq. \t2.10). \tThe \tequilibrium \tdissociation \tconstant \t(KB)\tfor\tpropranolol \tis \tgiven \tby \tthe \tabscissal \tintercept, \t2.2 \t\u00d7\t\n10\u22129\tmol/L.\tNote \tthat \tthe \tsubscript \t\u2018B\u2019 \tis \tnow \tused \tin \t\u2018KB\u2019\tto\tindicate \tthat \tthe \tequilibrium \tdissociation \tconstant \tis \tthat \tof \tthe \tantagonist \t\n(designated \tdrug \tB) \tmeasured \tin \tthe \tpresence \tof \tthe \tagonist \t(designated \tdrug \tA). \t(Results \tfrom \tPotter, \tL.T., \t1967. \tUptake \tof \tpropranolol \t\nby\tisolated \tguinea \tpig \tatria. \tJ. \tPharmacol. \tExp. \tTher. \t55, \t91\u2013100.) \t\n100\n100 nM\n800 nM50\n0\n10\u2212810\u2212710\u2212610\u2212510\u22124\n00Antagonist concentration\nAntagonist concentration\n2 nM33 nM\n330 nM\n10\u2212810\u2212710\u22126\nHistamine concentration (mol/L)Normorohine concentration (mol/L)\n10\u2212510\u2212410\u22123100\n50\n0Response (% max) Response (% max)A\nB\nFig. 2.6\tEffects of irreversible competitive antagonists \non agonist concentration\u2013effect curves. \t(A)\tRat\tbrain \t\nneurones\tresponding \tto \tthe \topioid \tagonist \tnormorphine \t\nbefore\tand \tafter \tbeing \texposed \tto \tthe \tirreversible \tcompetitive \t\nantagonist \t\u03b2-funaltrexamine \tfor \t30 \tminutes \tand \tthen \twashed \t\nto\tremove \tthe \tantagonist. \tNote \tthe \tdepression \tof \tthe \t\nmaximum \tresponse. \t(B) \tResponses \tof \tthe \tguinea \tpig \tileum \t\nto\thistamine \tbefore \tand \tafter \ttreatment \twith \tincreasing \t\nconcentrations \tof \ta \treceptor \talkylating \tagent \t(GD121) \tfor \t5 \t\nminutes\tand \tthen \twashed \tto \tremove \tthe \tantagonist. \tNote \t\nthe\tconcentration\u2013response \tcurve \tis \tinitially \tshifted \tto \tthe \t\nright\twith\tno \tdepression \tof \tthe \tmaximum \tresponse. \t(Panel \t\n[A]\tafter\tWilliams,", "start_char_idx": 0, "end_char_idx": 2137, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "af9bcc99-788d-4df4-b65f-1da1c9f2a9de": {"__data__": {"id_": "af9bcc99-788d-4df4-b65f-1da1c9f2a9de", "embedding": null, "metadata": {"page_label": "18", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eb1d4577-0462-4846-91ea-60db375e7688", "node_type": null, "metadata": {"page_label": "18", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92525aa48b4e80b01228c1186d91c241e636c2d54070a9ae45b67eb56449829d"}, "2": {"node_id": "fec75ef9-fdd8-436f-a6e1-38b959544a96", "node_type": null, "metadata": {"page_label": "18", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10e11cc6f63e2535b038747d2b4946726a33602d8b3df7f0f9a9b6655337cb39"}}, "hash": "9cf45032030d7c5098d047b39b1a68fe0189503fd73f94261569860f021bf038", "text": "\tJ.T., \tNorth, \tR.A., \t1984. \tMol. \tPharmacol. \t\n26,\t489\u2013497; \tpanel \t[B] \tafter \tNickerson, \tM., \t1955. \tNature \t\n178,\t696\u2013697.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2138, "end_char_idx": 2746, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2726ad77-a61b-4de5-b014-2f49c65c502b": {"__data__": {"id_": "2726ad77-a61b-4de5-b014-2f49c65c502b", "embedding": null, "metadata": {"page_label": "19", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5b85ddb-7406-48d1-9dd0-3b426ca1008f", "node_type": null, "metadata": {"page_label": "19", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "18545ef4792eabac98306e64df6e93e85fb2f56cc24ce80aa23f538a48f35d28"}, "3": {"node_id": "f0c7391a-8fd6-45c0-aa1c-cc6e32cff16c", "node_type": null, "metadata": {"page_label": "19", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a52e58f5d14f4c4eb142be9b041450a48c8dfb818de4b093124daff32e636cda"}}, "hash": "798777939e548f80917484013e8105aee55e71937e459e95fbc160a2ffce2f14", "text": "2 How d RuGS AC t: GENERAL PRINCIPLES\n13strips of rabbit aorta. The full agonist phenylephrine \nproduced the maximal response of which the tissue was \ncapable; the other compounds could only produce sub -\nmaximal responses and are partial agonists. The difference \nbetween full and partial agonists lies in the relationship \nbetween receptor occupancy and response. In the experiment \nshown in Fig. 2.7 it was possible to estimate the affinity \nof the various drugs for the receptor, and hence (based on \nthe theoretical model described later; p. 19) to calculate the \nfraction of receptors occupied (known as occupancy) as a function of drug concentration. Plots of response as a function of occupancy for the different compounds are \nshown in Fig. 2.7B, showing that for partial agonists the \nresponse at a given level of occupancy is less than for full agonists. The weakest partial agonist, tolazoline , produces \na barely detectable response even at 100% occupancy, and is usually classified as a competitive antagonist (see p. 10 \nand Ch. 15).\nThese differences can be expressed quantitatively in terms \nof efficacy (e), a parameter originally defined by Stephenson \n(1956) that describes the \u2018strength\u2019 of the agonist\u2013receptor \ncomplex in evoking a response of the tissue. In the simple \nscheme shown in Fig. 2.1, efficacy describes the tendency of the drug\u2013receptor complex to adopt the active (AR*), \nrather\tthan\tthe\tresting\t(AR),\tstate.\tA\tdrug\twith\tzero\tefficacy\t\n(e = 0) has no tendency to cause receptor activation, and \ncauses no tissue response. A full agonist is a drug whose \nefficacy5 is sufficient that it produces a maximal response \nwhen less than 100% of receptors are occupied. A partial agonist has lower efficacy, such that 100% occupancy elicits \nonly a submaximal response.\n\u25bc Subsequently it was appreciated that efficacy is composed of \ndrug-dependent and tissue-dependent components. The drug-\ndependent component is referred to as the intrinsic efficacy, which is \nthe ability of the agonist drug molecule, once bound, to activate the receptor protein (see Kelly, 2013). The tissue-dependent components of efficacy include the number of receptors that it expresses and the \nefficiency of coupling of receptor activation to the measured tissue \nresponse. The number of receptors expressed is especially relevant to the study of receptors in recombinant expression systems when \nreceptors are often very highly expressed and intermediate efficacy \nagonists then appear as full agonists. Across different cell types \nexpressing the same receptor but at different densities a given drug \nof intermediate efficacy may appear as a full agonist in one tissue (high level of receptor expression), a partial agonist in another (lower \nlevel of receptor expression), and even as an antagonist in another \n(very low level of receptor expression). The term \u2018partial agonist\u2019 is therefore only applicable when describing the action of a drug on a \nspecific tissue or cell type.\nFor G protein\u2013coupled receptors the elucidation of their X-ray crystal \nstructures (described in Ch. 3) and the application of molecular dynamic \nsimulations of drug binding are beginning to tease out the molecular basis of receptor activation and why some ligands are agonists and \nsome are antagonists. For students starting to study pharmacology \nthe simple theoretical two-state model described below provides a useful starting point.\nPARTIAL AGONISTS AS ANTAGONISTS\nIn discussing the efficacy of partial agonists above we \nconsidered the situation in which the tissue was exposed \n5In Stephenson\u2019s formulation, efficacy is the reciprocal of the occupancy \nneeded to produce a 50% maximal response, thus e = 25 implies that a \n50% maximal response occurs at 4% occupancy. There is no theoretical \nupper limit to", "start_char_idx": 0, "end_char_idx": 3813, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f0c7391a-8fd6-45c0-aa1c-cc6e32cff16c": {"__data__": {"id_": "f0c7391a-8fd6-45c0-aa1c-cc6e32cff16c", "embedding": null, "metadata": {"page_label": "19", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5b85ddb-7406-48d1-9dd0-3b426ca1008f", "node_type": null, "metadata": {"page_label": "19", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "18545ef4792eabac98306e64df6e93e85fb2f56cc24ce80aa23f538a48f35d28"}, "2": {"node_id": "2726ad77-a61b-4de5-b014-2f49c65c502b", "node_type": null, "metadata": {"page_label": "19", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "798777939e548f80917484013e8105aee55e71937e459e95fbc160a2ffce2f14"}}, "hash": "a52e58f5d14f4c4eb142be9b041450a48c8dfb818de4b093124daff32e636cda", "text": "response occurs at 4% occupancy. There is no theoretical \nupper limit to efficacy.1.00\n0.800.600.400.200.00\n0.001 0.01 0.1 11 0 100\n1.00\n0.800.600.400.200.00\n0.00 0.20 0.40 0.60 0.80\n1.00Concentration (\u00b5mol/L) (log scale)\nFraction of receptors occupied\nNaphazolineTolazoline OxymetazolinePhenylephrine ClonidineResponse (E/Emax) Response (E/Emax)A\nB\nFig. 2.7\tPartial agonists. \t(A)\tLog\tconcentration\u2013effect \tcurves \t\nfor\ta\tseries \tof \t\u03b1-adrenoceptor \tagonists \tcausing \tcontraction \tof \t\nan\tisolated \tstrip \tof \trabbit \taorta. \tPhenylephrine \tis \ta \tfull \tagonist. \t\nThe\tothers \tare \tpartial \tagonists \twith \tdifferent \tefficacies. \tThe \tlower \t\nthe\tefficacy \tof \tthe \tdrug \tthe \tlower \tthe \tmaximum \tresponse \tand \t\nslope\tof\tthe \tlog \tconcentration\u2013response \tcurve. \t(B) \tThe \t\nrelationship \tbetween \tresponse \tand \treceptor \toccupancy \tfor \tthe \t\nseries.\tNote \tthat \tthe \tfull \tagonist, \tphenylephrine, \tproduces \ta \t\nnear-maximal \tresponse \twhen \tonly \tabout \thalf \tthe \treceptors \tare \t\noccupied, \twhereas \tpartial \tagonists \tproduce \tsubmaximal \t\nresponses \teven \twhen \toccupying \tall \tof \tthe \treceptors. \tThe \t\nefficacy\tof \ttolazoline \tis \tso \tlow \tthat \tit \tis \tclassified \tas \tan \t\n\u03b1-adrenoceptor \tantagonist \t(see \tCh. \t15). \tIn \tthese \texperiments, \t\nreceptor\toccupancy \twas \tnot \tmeasured \tdirectly, \tbut \twas \t\ncalculated \tfrom \tpharmacological \testimates \tof \tthe \tequilibrium \t\nconstants \tof \tthe \tdrugs. \t(Data \tfrom \tRuffolo, \tR.R. \tJr, \tet \tal., \t1979. \t\nJ.\tPharmacol. \tExp. \tTher. \t209, \t429\u2013436.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3741, "end_char_idx": 5736, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "60e1c816-ca53-4e7f-94e8-0fd2d80818ed": {"__data__": {"id_": "60e1c816-ca53-4e7f-94e8-0fd2d80818ed", "embedding": null, "metadata": {"page_label": "20", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9312ded3-2b72-4968-96ff-f8cf24fbca6f", "node_type": null, "metadata": {"page_label": "20", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bb32c437e9017670d7b940734b848227c33d61b6e29d3cd72c6adba782d5193c"}, "3": {"node_id": "2976c590-f20d-4024-b3e1-dfaee4f55177", "node_type": null, "metadata": {"page_label": "20", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "62377ebb3c2aeb8c5d003320410707055fe5891d374648928d996f079b133d27"}}, "hash": "6c260eaf8d523fabec90fe830a80bd51e003631fcb53b839bdd9b81c2811ac98", "text": "2 SECTION 1 GENERAL PRINCIPLES\n14log10[agonist] (mol/L)Full agonist aloneResponse (% max)Response due to\nthe presence of\nthe partial agonist\nPartial agonist\nconcentratio n100\n50\n001 0 100 1000\nFig. 2.8\tHypothetical concentration\u2013response curves for a full agonist in the absence and presence of increasing concentrations \nof a partial agonist. \tThe\tpartial \tagonist \twill \thave \tagonist \taction \tand \thence \tthe \tinitial \tresponse \tincreases \tas \tthe \tpartial \tagonist \t\nconcentration \tincreases, \treaching \ta \tmaximum \tequal \tto \tthe \tmaximum \tresponse \tof \tthe \tpartial \tagonist. \tHowever, \twhen \tthe \tfull \tagonist \tis \t\nadded\tin\tthe \tpresence \tof \tthe \tpartial \tagonist \tits \tconcentration\u2013response \tcurve \tis \tshifted \tto \tthe \tright. \t\npsychosis associated with Parkinson\u2019s disease (see Chs 41 and 47). \nIt turns out that most of the receptor antagonists in clinical use are \nactually inverse agonists when tested in systems showing constitutive \nreceptor activation. However, most receptors \u2013 like cats \u2013 show a preference for the inactive state, and for these there is no practical \ndifference between a competitive antagonist and an inverse agonist.\nThe following section describes a simple model that explains full, \npartial and inverse agonism in terms of the relative affinity of different \nligands for the resting and activated states of the receptor.\nThe two-state receptor model\n\u25bc As illustrated in Fig. 2.1, agonists and antagonists both bind to \nreceptors, but only agonists activate them. How can we express this difference, and account for constitutive activity, in theoretical terms? \nThe two-state model (Fig. 2.10) provides a simple but useful approach.\nAs shown in Fig. 2.1, we envisage that the occupied receptor can \nswitch from its \u2018resting\u2019 (R) state to an activated (R*) state, R* being \nfavoured by binding of an agonist but not an antagonist molecule.\nAs described above, receptors may show constitutive activation (i.e. \nthe R* conformation can exist without any ligand being bound), so \nthe added drug encounters an equilibrium mixture of R and R* (see \nFig. 2.10). If it has a higher affinity for R* than for R, the drug will \ncause a shift of the equilibrium towards R* (i.e. it will promote activa -\ntion and be classed as an agonist). If its preference for R* is very \nlarge, nearly all the occupied receptors will adopt the R* conformation \nand the drug will be a full agonist; if it shows only a modest degree of selectivity for R* (say 5- to 10-fold), a smaller proportion of occupied \nreceptors will adopt the R* conformation and it will be a partial \nagonist; if it shows no preference, the prevailing R : R* equilibrium \nwill\tnot\tbe \tdisturbed \tand \tthe \tdrug \twill \tbe \ta \tneutral \tantagonist \t(zero \t\nefficacy), whereas if it shows selectivity for R it will shift the equilibrium towards R and be an inverse agonist (negative efficacy). We can \ntherefore think of efficacy as a property determined by the relative \naffinity of a ligand for R and R*, a formulation known as the two-state \nmodel, which is useful in that it puts a physical interpretation on the \notherwise mysterious meaning of efficacy, as well as accounting for the existence of inverse agonists.\nBIASED AGONISM\nA major problem with the two-state model is that, as we \nnow know, receptors are not actually restricted to two \ndistinct states but have much greater conformational to only one drug, the partial agonist. What we should also consider is how the presence of a partial agonist would \nalter the response of a tissue to a higher efficacy agonist. This is depicted in Fig. 2.8 where it can be seen that the \npresence of the partial agonist", "start_char_idx": 0, "end_char_idx": 3660, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2976c590-f20d-4024-b3e1-dfaee4f55177": {"__data__": {"id_": "2976c590-f20d-4024-b3e1-dfaee4f55177", "embedding": null, "metadata": {"page_label": "20", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9312ded3-2b72-4968-96ff-f8cf24fbca6f", "node_type": null, "metadata": {"page_label": "20", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bb32c437e9017670d7b940734b848227c33d61b6e29d3cd72c6adba782d5193c"}, "2": {"node_id": "60e1c816-ca53-4e7f-94e8-0fd2d80818ed", "node_type": null, "metadata": {"page_label": "20", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c260eaf8d523fabec90fe830a80bd51e003631fcb53b839bdd9b81c2811ac98"}}, "hash": "62377ebb3c2aeb8c5d003320410707055fe5891d374648928d996f079b133d27", "text": "in Fig. 2.8 where it can be seen that the \npresence of the partial agonist induces some level of \nresponse dependent upon the concentration initially applied but in addition because the partial agonist is competing \nwith the full agonist for the receptors it effectively acts as \na competitive antagonist, shifting the concentration\u2013response curve of the full agonist to the right. This is not just an obscure theoretical point but something which occurs in \nclinical practice. In the treatment of heroin users, buprenor -\nphine, a weak partial agonist, not only acts as a weak opioid \nsubstitute but also acts as an antagonist and reduces the \nlikelihood of overdose when users relapse and take heroin \nagain (see Ch. 50).\nCONSTITUTIVE RECEPTOR ACTIVATION AND \nINVERSE AGONISTS\n\u25bc A lthough we are accustomed to thinking that receptors are activated \nonly when an agonist molecule is bound, there are examples (see De \nLigt et al ., 2000 ) where an appreciable level of activation ( constitutive \nactivation) may exist even when no ligand is present. These include \nreceptors \tfor \tbenzodiazepines \t(see \tCh. \t45), \tcannabinoids \t(Ch. \t20), \t\nserotonin (Ch. 16) and several other mediators. Furthermore, receptor \nmutations occur \u2013 either spontaneously, in some disease states (see \nBond\t&\tIjzerman, \t2006), \tor \texperimentally \tcreated \t(see \tCh. \t4) \t\u2013 \tthat \t\nresult in appreciable constitutive activation. If a ligand reduces the level of constitutive activation; such drugs are known as inverse agonists \n(Fig. 2.9; see De Ligt et al., 2000) to distinguish them from neutral \nantagonists , which do not by themselves affect the level of activation. \nInverse agonists can be regarded as drugs with negative efficacy, to distinguish them from agonists (positive efficacy) and neutral \nantagonists \t(zero \tefficacy). \tNeutral \tantagonists, \tby \tbinding \tto \tthe \t\nagonist binding site, will antagonise both agonists and inverse agonists. \nInverse\tagonism \twas \tfirst \tobserved \tat \tthe \tbenzodiazepine \treceptor \t\n(Ch. 45) but such drugs are proconvulsive and thus not therapeutically useful! New examples of constitutively active receptors and inverse \nagonists are emerging with increasing frequency (mainly among G \nprotein\u2013coupled receptors). Pimavanserin, an inverse agonist at the \n5-HT\n2A receptor, has recently been developed for the treatment of mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3586, "end_char_idx": 6426, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "997870ff-e488-4c33-ab76-db7de7e8f4f4": {"__data__": {"id_": "997870ff-e488-4c33-ab76-db7de7e8f4f4", "embedding": null, "metadata": {"page_label": "21", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c28f14e0-7718-4e24-8d94-0edb8cf67828", "node_type": null, "metadata": {"page_label": "21", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca4d4cfb8824cc33ce008e91ef4f360b373d679ed1cede5b8a60d544d6df4f2b"}, "3": {"node_id": "d938c7c3-d1aa-43f9-97b6-e6d234ce5f8c", "node_type": null, "metadata": {"page_label": "21", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5abe581b3779ef55acea6b16e10ef044832e6ddbf5f2a800146114dd072200a5"}}, "hash": "e88c46d971c054a3aa1ecb404fd81edb4ae4088f90ad0fb3db9a1af22404accb", "text": "2 How d RuGS AC t: GENERAL PRINCIPLES\n15Change in level of receptor activation (%)\nAntagonist concentration (M) Ligand concentration (M)Antagonist in presence \nof inverse agonistInverse agonist \nin presence of \nantagonistInverse agonistConstitutive level of \nreceptor activationAntagonist aloneAntagonist in \npresence of agonistAgonist\nAgonist in presence \nof antagonist100\n50\n100\n\u221250\nChange in level of receptor activation (%)100\n50\n100\n\u221250\n10-1010-810-610-410-1010-810-610-4A B\nFig. 2.9\tInverse agonism. \tThe\tinteraction \tof \ta \tcompetitive \tantagonist \twith \tnormal \tand \tinverse \tagonists \tin \ta \tsystem \tthat \tshows \treceptor \t\nactivation\tin \tthe \tabsence \tof \tany \tadded \tligands \t(constitutive \tactivation). \t(A) \tThe \tdegree \tof \treceptor \tactivation \t(vertical \tscale) \tincreases \tin \tthe \t\npresence\tof \tan \tagonist \t(open squares) \tand\tdecreases \tin \tthe \tpresence \tof \tan \tinverse \tagonist \t(open circles) .\tAddition\tof \ta \tcompetitive \t\nantagonist \tshifts \tboth \tcurves \tto \tthe \tright \t(closed symbols) .\t(B)\tThe\tantagonist \ton \tits \town \tdoes \tnot \talter \tthe \tlevel \tof \tconstitutive \tactivity \t\n(open symbols) ,\tbecause \tit \thas \tequal \taffinity \tfor \tthe \tactive \tand \tinactive \tstates \tof \tthe \treceptor. \tIn \tthe \tpresence \tof \tan \tagonist \t(closed \nsquares)\tor\tan\tinverse \tagonist \t(closed circles) ,\tthe\tantagonist \trestores \tthe \tsystem \ttowards \tthe \tconstitutive \tlevel \tof \tactivity. \tThese \tdata \t\n(reproduced \twith \tpermission \tfrom \tNewman-Tancredi, \tA., \tet \tal., \t1997. \tBr. \tJ. \tPharmacol. \t120, \t737\u2013739) \twere \tobtained \twith \tcloned \thuman \t\n5-hydroxytryptamine \t(5-HT) \treceptors \texpressed \tin \ta \tcell \tline. \t(Agonist, \t5-carboxamidotryptamine; \tinverse \tagonist, \tspiperone; \tantagonist, \t\nWAY\t100635; \tligand \tconcentration \t[M \t=\tmol/L];\tsee \tCh. \t16 \tfor \tinformation \ton \t5-HT \treceptor \tpharmacology.) \t\nInverse\nagonistAgonist\nResting\nstateActivated\nstate\nAntagonistRR * RESPONSE\nFig. 2.10 \tThe two-state model. \tThe\treceptor \tis \tshown \tin \t\ntwo\tconformational \tstates, \tresting (R) \tand\tactivated (R*) ,\twhich\t\nexist\tin\tequilibrium. \tNormally, \twhen \tno \tligand \tis \tpresent, \tthe \t\nequilibrium \tlies \tfar \tto \tthe \tleft, \tand \tfew \treceptors \tare \tfound \tin \tthe \t\nR*\tstate.\tFor \tconstitutively \tactive \treceptors, \tan \tappreciable \t\nproportion \tof \treceptors \tadopt \tthe \tR*", "start_char_idx": 0, "end_char_idx": 2323, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d938c7c3-d1aa-43f9-97b6-e6d234ce5f8c": {"__data__": {"id_": "d938c7c3-d1aa-43f9-97b6-e6d234ce5f8c", "embedding": null, "metadata": {"page_label": "21", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c28f14e0-7718-4e24-8d94-0edb8cf67828", "node_type": null, "metadata": {"page_label": "21", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca4d4cfb8824cc33ce008e91ef4f360b373d679ed1cede5b8a60d544d6df4f2b"}, "2": {"node_id": "997870ff-e488-4c33-ab76-db7de7e8f4f4", "node_type": null, "metadata": {"page_label": "21", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e88c46d971c054a3aa1ecb404fd81edb4ae4088f90ad0fb3db9a1af22404accb"}}, "hash": "5abe581b3779ef55acea6b16e10ef044832e6ddbf5f2a800146114dd072200a5", "text": "\tconformation \tin \tthe \t\nabsence\tof \tany \tligand. \tAgonists \thave \thigher \taffinity \tfor \tR* \tthan \t\nfor\tR,\tso\tshift \tthe \tequilibrium \ttowards \tR*. \tThe \tgreater \tthe \t\nrelative\taffinity \tfor \tR* \twith \trespect \tto \tR, \tthe \tgreater \tthe \tefficacy \t\nof\tthe\tagonist. \tAn \tinverse \tagonist \thas \thigher \taffinity \tfor \tR \tthan \t\nfor\tR*\tand \tso \tshifts \tthe \tequilibrium \tto \tthe \tleft. \tA \tneutral\t\nantagonist \thas \tequal \taffinity \tfor \tR \tand \tR* \tso \tdoes \tnot \tby \titself \t\naffect\tthe\tconformational \tequilibrium \tbut \treduces \tby \tcompetition \t\nthe\tbinding \tof \tother \tligands. \tflexibility, so that there is more than one inactive and active \nconformation. The different conformations that they can \nadopt may be preferentially stabilised by different ligands, \nand may produce different functional effects by activating different signal transduction pathways (see Ch. 3).\nReceptors that couple to second messenger systems (see \nCh. 3) can couple to more than one intracellular effector pathway, giving rise to two or more simultaneous \nresponses. One might expect that all agonists that activate \nthe same receptor type would evoke the same array of responses (Fig. 2.11A). However, it has become apparent that different agonists can exhibit bias for the generation \nof one response over another even though they are acting \nthrough the same receptor (Fig. 2.11B), probably because they stabilise different activated states of the receptor (see \nKelly, 2013 ). Agonist bias has become an important concept \nin pharmacology.\nRedefining and attempting to measure agonist efficacy \nfor such a multistate model is problematic, however, and \nrequires a more complicated state transition model than the two-state model described above. The errors, pitfalls \nand a possible way forward have been outlined by Kenakin \n& Christopoulos (2013).\nALLOSTERIC MODULATION\n\u25bc In addition to the agonist binding site (now referred to as the \northosteric binding site), to which competitive antagonists also bind, \nreceptor proteins possess many other ( allosteric) binding sites (see \nCh. 3) through which drugs can influence receptor function in various ways, by increasing or decreasing the affinity of agonists mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2324, "end_char_idx": 5005, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e8c90c35-e0d8-4dac-a03b-08fd983abb95": {"__data__": {"id_": "e8c90c35-e0d8-4dac-a03b-08fd983abb95", "embedding": null, "metadata": {"page_label": "22", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a1d39c54-ef46-4d67-852a-f06d380f0fb7", "node_type": null, "metadata": {"page_label": "22", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a0f31c65b775e3a3c5edb481b8878c2119ac799f4b3e6eaf744663ad10497d90"}, "3": {"node_id": "d9484a43-97ad-4bad-93ce-261d73415a18", "node_type": null, "metadata": {"page_label": "22", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2b0fb0dc2ac9fdc2bdaa66e0a2a45895e8b890905231d5f62b81ca7430e4b0f8"}}, "hash": "8ac277b5c001b20e0bce33a61258f5ca3492e8ce425ca5e609e47fee568fbdbb", "text": "2 SECTION 1 GENERAL PRINCIPLES\n16The most important ones are:\n\u2022\tchemical \tantagonism\n\u2022\tpharmacokinetic \tantagonism\n\u2022\tblock\tof \treceptor\u2013response \tlinkage\n\u2022\tphysiological \tantagonism\nCHEMICAL ANTAGONISM\nChemical antagonism refers to the uncommon situation \nwhere the two substances combine in solution; as a result, \nthe effect of the active drug is lost. Examples include the \nuse of chelating agents (e.g. dimercaprol) that bind to \nheavy metals and thus reduce their toxicity, and the use \nof the neutralising antibody infliximab, which has an \nanti-inflammatory action due to its ability to sequester \nthe inflammatory cytokine tumour necrosis factor (TNF; \nsee Ch. 19).\nPHARMACOKINETIC ANTAGONISM\nPharmacokinetic antagonism describes the situation in which \nthe \u2018antagonist\u2019 effectively reduces the concentration of the \nactive drug at its site of action. This can happen in various \nways. The rate of metabolic degradation of the active drug may be increased (e.g. the reduction of the anticoagulant \neffect of warfarin when an agent that accelerates its hepatic \nmetabolism, such as phenytoin, is given; see Chs 10 and \n58). Alternatively, the rate of absorption of the active drug from the gastrointestinal tract may be reduced, or the rate \nof renal excretion may be increased. Interactions of this sort, discussed in more detail in Chapter 58, are common and can be important in clinical practice.for the agonist binding site, by modifying efficacy or by producing \na response themselves (Fig. 2.12). Depending on the direction of the \neffect, the ligands may be allosteric antagonists or allosteric facilitators \nof the agonist effect, and the effect may be to alter the slope and maximum of the agonist log concentration\u2013effect curve (see Fig. 2.12). \nThis type of allosteric modulation of receptor function has attracted \nmuch attention recently and occurs at different types of receptors (see review by Changeux & Christopoulos, 2016). Well-known examples \nof allosteric facilitation include glycine at NMDA receptors (Ch. 39), \nbenzodiazepines \tat \tGABA A receptors (Ch. 45) and cinacalcet at the \nCa2+ receptor (Ch. 37). One reason why allosteric modulation may \nbe important to the pharmacologist and future drug development is that across families of receptors such as the muscarinic receptors \n(see Ch. 14) the orthosteric binding sites are very similar and it has proven difficult to develop selective agonists and antagonists for \nindividual subtypes. The hope is that there will be greater variation \nin the allosteric sites and that receptor-selective allosteric ligands can be developed. Furthermore, positive allosteric modulators will exert \ntheir effects only on receptors that are being activated by endogenous \nligands and have no effect on those that are not activated. This might \nprovide a degree of selectivity (e.g. in potentiating spinal inhibition \nmediated by endogenous opioids, see Ch. 43) and a reduction in side effect profile.\nOTHER FORMS OF DRUG ANTAGONISM\nOther mechanisms can also account for inhibitory interac-\ntions between drugs.Biased agonismConventional agonismRag\nRag\nRag\nRagA\nBResponse 1 Response 2 Response 1 Response 2\nResponse 1 Response 2 Response 1 Response 2\nFig. 2.11 \tBiased agonism. \tIn\t(A),\tthe \treceptor \t(R)\tis\tcoupled \t\nto\ttwo\tintracellular \tresponses \t\u2013 \tresponse 1 \tand\tresponse 2 .\t\nWhen\tdifferent \tagonists \tindicated \tin \tred\tand\tgreen\tactivate\tthe \t\nreceptor\tthey \tevoke \tboth \tresponses \tin \ta \tsimilar \tmanner. \tThis \tis \t\nwhat\twe\tcan \tconsider \tas \tbeing \tconventional", "start_char_idx": 0, "end_char_idx": 3546, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d9484a43-97ad-4bad-93ce-261d73415a18": {"__data__": {"id_": "d9484a43-97ad-4bad-93ce-261d73415a18", "embedding": null, "metadata": {"page_label": "22", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a1d39c54-ef46-4d67-852a-f06d380f0fb7", "node_type": null, "metadata": {"page_label": "22", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a0f31c65b775e3a3c5edb481b8878c2119ac799f4b3e6eaf744663ad10497d90"}, "2": {"node_id": "e8c90c35-e0d8-4dac-a03b-08fd983abb95", "node_type": null, "metadata": {"page_label": "22", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8ac277b5c001b20e0bce33a61258f5ca3492e8ce425ca5e609e47fee568fbdbb"}}, "hash": "2b0fb0dc2ac9fdc2bdaa66e0a2a45895e8b890905231d5f62b81ca7430e4b0f8", "text": "\tThis \tis \t\nwhat\twe\tcan \tconsider \tas \tbeing \tconventional \tagonism. \tIn \t(B), \t\nbiased\tagonism \tis \tillustrated \tin \twhich \ttwo \tagonists \tbind \tat \tthe \t\nsame\tsite\ton \tthe \treceptor \tyet \tthe \tred\tagonist\tis \tbetter \tat \t\nevoking\tresponse \t1 \tand \tthe \tgreen\tagonist\tis \tbetter \tat \tevoking \t\nresponse\t2. \tAgonists, antagonists and efficacy \n\u2022\tDrugs\tacting \ton \treceptors \tmay \tbe \tagonists\tor\t\nantagonists.\n\u2022\tAgonists \tinitiate \tchanges \tin \tcell \tfunction, \tproducing \t\neffects\tof\tvarious \ttypes; \tantagonists \tbind \tto \treceptors \t\nwithout\tinitiating \tsuch \tchanges.\n\u2022\tAgonist \tpotency \tdepends \ton \ttwo \tparameters: \taffinity\t\n(i.e.\ttendency \tto \tbind \tto \treceptors) \tand \tefficacy\t(i.e.\t\nability,\tonce \tbound, \tto \tinitiate \tchanges \tthat \tlead \tto \t\neffects).\n\u2022\tFor\tantagonists, \tefficacy \tis \tzero.\n\u2022\tFull agonists \t(which\tcan \tproduce \tmaximal \teffects) \thave \t\nhigh\tefficacy; \tpartial agonists \t(which\tcan \tproduce \tonly \t\nsubmaximal \teffects) \thave \tintermediate \tefficacy.\n\u2022\tAccording \tto \tthe \ttwo-state \tmodel, \tefficacy \treflects \tthe \t\nrelative\taffinity \tof \tthe \tcompound \tfor \tthe \tresting \tand \t\nactivated\tstates \tof \tthe \treceptor. \tAgonists \tshow \t\nselectivity\tfor \tthe \tactivated \tstate; \tantagonists \tshow \tno \t\nselectivity. \tThis \tmodel, \talthough \thelpful, \tfails \tto \t\naccount\tfor \tthe \tcomplexity \tof \tagonist \taction.\n\u2022\tInverse agonists \tshow\tselectivity \tfor \tthe \tresting \tstate \t\nof\tthe\treceptor, \tthis \tbeing \tof \tsignificance \tonly \tin \t\nsituations\twhere \tthe \treceptors \tshow \tconstitutive \nactivity.\n\u2022\tAllosteric modulators \tbind\tto\tsites \ton \tthe \treceptor \t\nother\tthan \tthe \tagonist \tbinding \tsite \tand \tcan \tmodify \t\nagonist\tactivity.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3488, "end_char_idx": 5641, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9799e5b6-f37c-4e29-a53c-85c8740ea93a": {"__data__": {"id_": "9799e5b6-f37c-4e29-a53c-85c8740ea93a", "embedding": null, "metadata": {"page_label": "23", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "de43b34b-5dcb-456b-b0fb-19e0be49f344", "node_type": null, "metadata": {"page_label": "23", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67e14001ea4b52a0bfba37774acabbf6cb364937d19385427dfa37c8df0ca607"}}, "hash": "67e14001ea4b52a0bfba37774acabbf6cb364937d19385427dfa37c8df0ca607", "text": "2 How dRuGS ACt: GENERAL PRINCIPLES\n17100\n50\n0100\n50\n0\n100\n50\n0100\n50\n0Affinity\nmodulationAgonist Allosteric\ndrug\nEfficacy\nmodulation\nAllosteric\nagonismAgonism\n(orthosteric)\nNegative affinity modulation% Max. response\nLog [Agonist] (mol/L)Positive affinity modulation% Max. responseResponse\nLog [Agonist] (mol/L)\nNegative efficacy modulation% Max. response\nLog [Agonist] (mol/L)Positive efficacy modulation% Max. response\nLog [Agonist] (mol/L)A\nB\nFig. 2.12 \tAllosteric modulation. \t(A)\tAllosteric\t drugs\tbind\tat\ta\tseparate\tsite\ton\tthe\treceptor\tto\t\u2018traditional\u2019\t agonists\t(now\toften\treferred\t\nto\tas\t\u2018orthosteric\u2019\t agonists).\t They\tcan\tmodify\tthe\tactivity\tof\tthe\treceptor\tby\t(i)\taltering\tagonist\taffinity,\t(ii)\taltering\tagonist\tefficacy\tor\t(iii)\t\ndirectly\tevoking\ta\tresponse\t themselves.\t (B)\tEffects\tof\taffinity-\tand\tefficacy-modifying\t allosteric\tmodulators\t on\tthe\tconcentration\u2013effect\t curve\t\nof\tan\tagonist\t (blue line).\tIn\tthe\tpresence\t of\tthe\tallosteric\tmodulator\t the\tagonist\tconcentration\u2013effect\t curve\t (now illustrated in red) \tis\tshifted\t\nin\ta\tmanner\tdetermined\t by\tthe\ttype\tof\tallosteric\tmodulator\t until\ta\tmaximum\t effect\tof\tthe\tmodulator\t is\treached.\t(Panel\t[A]\tadapted\twith\t\npermission\t from\tConn\tet\tal.,\t2009.\tNat.\tRev.\tDrug\tDiscov.\t8,\t41\u201354;\tpanel\t[B]\tcourtesy\tof\tChristopoulos,\t A.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1777, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "645bbbd7-4670-4755-bc78-06e88474a21c": {"__data__": {"id_": "645bbbd7-4670-4755-bc78-06e88474a21c", "embedding": null, "metadata": {"page_label": "24", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bca4a9d3-f04e-41a5-99f3-e0fcf5838fd6", "node_type": null, "metadata": {"page_label": "24", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1b0aa9ae6f7e780d8835d1dc55c10a2edcb8e73fec8af155a5e0eba244b1e60e"}, "3": {"node_id": "3b01edf9-a01e-4ff7-8103-bd3b90ee7b17", "node_type": null, "metadata": {"page_label": "24", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f9cd7165d27fd545c85d2b3268daa51e241d3139517391f3a99f27a4d64147f"}}, "hash": "e80cef98dbebfd1c46eba20fb7804152c3ca3a93c0c85c8eb39fe27283fa8bf8", "text": "2 SECTION 1 GENERAL PRINCIPLES\n18BLOCK OF RECEPTOR\u2013RESPONSE LINKAGE\nNon-competitive antagonism describes the situation where \nthe antagonist blocks at some point downstream from the \nagonist binding site on the receptor, and interrupts the \nchain of events that leads to the production of a response by the agonist. For example, ketamine enters the ion channel \npore of the NMDA receptor (see Ch. 39) blocking it, thus preventing ion flux through the channels. Drugs such as verapamil and nifedipine prevent the influx of Ca\n2+ through \nthe cell membrane (see Ch. 23) and thus non-selectively \nblock the contraction of smooth muscle produced by drugs \nacting at any receptor that couples to these calcium channels. As a rule, the effect will be to reduce the slope and maximum \nof the agonist log concentration\u2013response curve, although \nit is quite possible for some degree of rightward shift to occur as well.\nPHYSIOLOGICAL ANTAGONISM\nPhysiological antagonism is a term used loosely to describe the interaction of two drugs whose opposing actions in the \nbody tend to cancel each other. For example, histamine \nacts on receptors of the parietal cells of the gastric mucosa \nto stimulate acid secretion, while omeprazole blocks this \neffect by inhibiting the proton pump; the two drugs can be said to act as physiological antagonists.\nTypes of drug antagonism \nDrug\tantagonism \toccurs \tby \tvarious \tmechanisms:\n\u2022\tchemical \tantagonism \t(interaction \tin \tsolution)\n\u2022\tpharmacokinetic \tantagonism \t(one \tdrug \taffecting \tthe \t\nabsorption, \tmetabolism \tor \texcretion \tof \tthe \tother)\n\u2022\tcompetitive \tantagonism \t(both \tdrugs \tbinding \tto \tthe \t\nsame\treceptors); \tthe \tantagonism \tmay \tbe \treversible \tor \t\nirreversible\n\u2022\tinterruption \tof \treceptor\u2013response \tlinkage\n\u2022\tphysiological \tantagonism \t(two \tagents \tproducing \t\nopposing\tphysiological \teffects)\n\u2022\tactive\textrusion \tof \tdrug \tfrom \tcells \t(mainly \trelevant \tin \t\ncancer chemotherapy; see Ch. 57)\nCHANGE IN RECEPTORS\nAmong receptors directly coupled to ion channels (see Ch. 3), desensitisation is often rapid and pronounced. At the \nneuromuscular junction (Fig. 2.13A), the desensitised state is \ncaused by a conformational change in the receptor, resulting in tight binding of the agonist molecule without the opening \nof the ionic channel. Phosphorylation of intracellular regions \nof the receptor protein is a second, slower mechanism by which ion channels become desensitised.\nMost G protein\u2013coupled receptors (see Ch. 3) also show \ndesensitisation (Fig. 2.13B). Phosphorylation of the receptor interferes with its ability to activate second messenger cascades, although it can still bind the agonist molecule. \nThe molecular mechanisms of this \u2018uncoupling\u2019 are con -\nsidered further in Chapter 3. This type of desensitisation \nPercentage of control100\n80\n604020\n0\n88 56 24 8 4 0Response\u03b2 adrenoceptors\nTime (h)5 mV10 mV5 s A\nB\nFig. 2.13 \tTwo kinds of receptor desensitisation. \t\t\n(A)\tAcetylcholine \t(ACh) \tat \tthe \tfrog \tmotor \tendplate. \tBrief \t\ndepolarisations \t(upward deflections) \tare\tproduced \tby \tshort \t\npulses\tof\tACh \tdelivered \tfrom \ta \tmicropipette. \tA \tlong \tpulse \t\n(horizontal line) \tcauses\tthe \tresponse \tto \tdecline \twith \ta \ttime \t\ncourse\tof\tabout", "start_char_idx": 0, "end_char_idx": 3227, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3b01edf9-a01e-4ff7-8103-bd3b90ee7b17": {"__data__": {"id_": "3b01edf9-a01e-4ff7-8103-bd3b90ee7b17", "embedding": null, "metadata": {"page_label": "24", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bca4a9d3-f04e-41a5-99f3-e0fcf5838fd6", "node_type": null, "metadata": {"page_label": "24", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1b0aa9ae6f7e780d8835d1dc55c10a2edcb8e73fec8af155a5e0eba244b1e60e"}, "2": {"node_id": "645bbbd7-4670-4755-bc78-06e88474a21c", "node_type": null, "metadata": {"page_label": "24", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e80cef98dbebfd1c46eba20fb7804152c3ca3a93c0c85c8eb39fe27283fa8bf8"}}, "hash": "9f9cd7165d27fd545c85d2b3268daa51e241d3139517391f3a99f27a4d64147f", "text": "\tresponse \tto \tdecline \twith \ta \ttime \t\ncourse\tof\tabout \t20 \tseconds, \towing \tto \tdesensitisation, \tand \tit \t\nrecovers\twith \ta \tsimilar \ttime \tcourse. \t(B) \t\u03b2\tadrenoceptors \tof \trat \t\nglioma\tcells \tin \ttissue \tculture. \tIsoproterenol \t(1 \t\u00b5mol/L)\twas \t\nadded\tat\ttime \tzero, \tand \tthe \tadenylyl \tcyclase \tresponse \tand \t\n\u03b2-adrenoceptor \tdensity \tmeasured \tat \tintervals. \tDuring \tthe \tearly \t\nuncoupling \tphase, \tthe \tresponse \t(blue line)\tdeclines\twith \tno \t\nchange\tin \treceptor \tdensity \t(red line).\tLater,\tthe \tresponse \t\ndeclines\tfurther \tconcomitantly \twith \tdisappearance \tof \treceptors \t\nfrom\tthe\tmembrane \tby \tinternalisation. \tThe \tgreen\tand\torange \nlines\tshow\tthe \trecovery \tof \tthe \tresponse \tand \treceptor \tdensity \t\nafter\tthe\tisoproterenol \tis \twashed \tout \tduring \tthe \tearly \tor \tlate \t\nphase.\t(Panel \t[A] \tfrom \tKatz \tB., \tThesleff \tS., \t1957. \tJ. \tPhysiol. \t\n138,\t63;\tpanel \t[B] \tfrom \tPerkins, \tJ.P., \t1981. \tTrends \tPharmacol. \t\nSci.\t2,\t326.)\nDESENSITISATION AND TOLERANCE\nOften, the effect of a drug gradually diminishes when it is \ngiven continuously or repeatedly. Desensitisation and \ntachyphylaxis are synonymous terms used to describe this phenomenon, which often develops in the course of a few minutes. The term tolerance is conventionally used to describe \na more gradual decrease in responsiveness to a drug, taking hours, days or weeks to develop, but the distinction is not a sharp one. The term refractoriness is also sometimes used, \nmainly in relation to a loss of therapeutic efficacy. Drug \nresistance is a term used to describe the loss of effectiveness of antimicrobial or antitumour drugs (see Chs 51 and 57). Many different mechanisms can give rise to these phenom -\nena. They include:\n\u2022\tchange \tin \treceptors\n\u2022\ttranslocation \tof \treceptors\n\u2022\texhaustion \tof \tmediators\n\u2022\tincreased \tmetabolic \tdegradation \tof \tthe \tdrug\n\u2022\tphysiological \tadaptationmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3172, "end_char_idx": 5539, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "25857cda-593f-4e12-9e47-94992cd93b05": {"__data__": {"id_": "25857cda-593f-4e12-9e47-94992cd93b05", "embedding": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d50f1482-997c-458e-99f5-767dc6d7a44f", "node_type": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7ece3bd685d46367d2f643b94d8d2103e53ca8f0b3201ffc231012c0379c52c"}, "3": {"node_id": "1ce2646e-8ab1-4589-b84e-be16c50d0461", "node_type": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed3ebad64467888c5b2099be4b8683c71063536ba11995e6b8e538bbc289f58c"}}, "hash": "675ba44fcc24d13810173e79d1aebc42b7ac63a658acd01def97dbe4cb6f2cea", "text": "2 How d RuGS AC t: GENERAL PRINCIPLES\n19interaction and which has served well as a framework for interpret -\ning a large body of quantitative experimental data (see Colquhoun, \n2006).\nTHE BINDING REACTION\n\u25bc The first step in drug action on specific receptors is the formation \nof a reversible drug\u2013receptor complex, the reactions being governed \nby the Law of Mass Action. Suppose that a piece of tissue, such as \nheart muscle or smooth muscle, contains a total number of receptors, \nNtot, for an agonist such as adrenaline. When the tissue is exposed to \nadrenaline at concentration xA and allowed to come to equilibrium, \na certain number, NA, of the receptors will become occupied, and the \nnumber of vacant receptors will be reduced to Ntot \u2212 NA. Normally, \nthe number of adrenaline molecules applied to the tissue in solution \ngreatly exceeds Ntot, so that the binding reaction does not appreciably \nreduce xA. The magnitude of the response produced by the adrenaline \nwill be related (even if we do not know exactly how) to the number of receptors occupied, so it is useful to consider what quantitative \nrelationship is predicted between N\nA and xA. The reaction can be \nrepresented by:\nAR AR\ndrug free receptor complexk\nk+\n+\n\u2212+\n\u221211/horizontalharpoonextender/arrowrighttophalf/horizontalharpoonextender/horizontalharpoonextender/arrowleftbothalf/horizontalharpoonextender/horizontalharpoonextender/horizontalharpoonextender\n() () ( xN N At ot A N NA)\nThe Law of Mass Action (which states that the rate of a chemical \nreaction is proportional to the product of the concentrations of \nreactants) can be applied to this reaction.\n Rate of forw ard reaction =\u2212 +kx NNAt ot A 1() (2.1)\n Rate of back ward r eaction= \u2212kN A 1 (2.2)\nAt equilibrium, the two rates are equal:\n kx NN kN At ot AA +\u2212 \u2212= 11() (2.3)\nThe affinity constant of binding is given by k+1/k\u22121 and from Eq. 2.3 \nequals NA/xA(Ntot \u2013N A). Unfortunately, this has units of reciprocal \nconcentration (L/mol) which for some of us is a little hard to get our heads around. Pharmacologists therefore tend to use the reciprocal \nof the affinity constant, the equilibrium dissociation constant (K), which \nhas units of concentration (mol/L).\nFor drug A its equilibrium dissociation constant (K\nA)6 can be repre -\nsented as\n Kk kx NN N AA totA A == \u2212 \u2212+11 () (2.4)\nThe proportion of receptors occupied, or occupancy ( PA), is N A/Ntot, \nwhich is independent of N tot.\n Px\nxk kx\nxKAA\nAA\nAA=+=+ \u2212+11 (2.5)\nThus if the equilibrium dissociation constant of a drug is known we \ncan calculate the proportion of receptors it will occupy at any \nconcentration.\nEq. 2.5 can be written:\n PxK\nxKAAA\nAA=+1 (2.6)\nThis important result is known as the Hill\u2013Langmuir equation.7usually takes seconds to minutes to develop, and recovers \nwhen the agonist is removed.\nIt will be realised that the two-state model in its simple \nform, discussed earlier, needs to be further elaborated to \nincorporate additional desensitised states of the receptor.\nTRANSLOCATION OF RECEPTORS\nProlonged exposure to agonists often results in a gradual decrease in the number of receptors expressed on the cell \nsurface, as a result of internalisation of the receptors. This \nis shown", "start_char_idx": 0, "end_char_idx": 3210, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1ce2646e-8ab1-4589-b84e-be16c50d0461": {"__data__": {"id_": "1ce2646e-8ab1-4589-b84e-be16c50d0461", "embedding": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d50f1482-997c-458e-99f5-767dc6d7a44f", "node_type": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7ece3bd685d46367d2f643b94d8d2103e53ca8f0b3201ffc231012c0379c52c"}, "2": {"node_id": "25857cda-593f-4e12-9e47-94992cd93b05", "node_type": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "675ba44fcc24d13810173e79d1aebc42b7ac63a658acd01def97dbe4cb6f2cea"}, "3": {"node_id": "21f55cc6-6024-4a57-bf66-23f308e6a5ee", "node_type": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b811fdc5df01aa820f69f78887ed3a3ce3027658b86a50327f219066815bb7b"}}, "hash": "ed3ebad64467888c5b2099be4b8683c71063536ba11995e6b8e538bbc289f58c", "text": "cell \nsurface, as a result of internalisation of the receptors. This \nis shown for \u03b2 adrenoceptors in Fig. 2.13B and is a slower \nprocess than the uncoupling described above. Similar changes have been described for other types of receptor, \nincluding those for various peptides. The internalised receptors are taken into the cell by endocytosis of patches \nof the membrane, a process that normally depends on \nreceptor phosphorylation and the subsequent binding of arrestin proteins to the phosphorylated receptor (see Ch. 3, Fig. 3.16). This type of adaptation is common for \nhormone receptors and has obvious relevance to the effects \nproduced when drugs are given for extended periods. It is generally an unwanted complication when agonist drugs \nare used clinically.\nEXHAUSTION OF MEDIATORS\nIn some cases, desensitisation is associated with depletion \nof an essential intermediate substance. Drugs such as \namphetamine , which acts by releasing amines from nerve \nterminals (see Chs 15 and 49), show marked tachyphylaxis \nbecause the amine stores become depleted.\nALTERED DRUG METABOLISM\nTolerance to some drugs, for example barbiturates and \nethanol (Ch. 49), occurs partly because repeated administra -\ntion of the same dose produces a progressively lower plasma concentration, as a result of increased metabolic degradation. The degree of tolerance that results is generally modest, \nand in both of these examples other mechanisms contribute \nto the substantial tolerance that actually occurs. However, the pronounced tolerance to nitrovasodilators (see Chs 21 \nand 23) results mainly from decreased metabolism, which reduces the release of the active mediator, nitric oxide.\nPHYSIOLOGICAL ADAPTATION\nDiminution of a drug\u2019s effect may occur because it is nul -\nlified by a homeostatic response. For example, the blood \npressure-lowering effect of thiazide diuretics is limited \nbecause of a gradual activation of the renin\u2013angiotensin system (see Ch. 23). Such homeostatic mechanisms are very \ncommon, and if they occur slowly the result will be a \ngradually developing tolerance. It is a common experience that many side effects of drugs, such as nausea or sleepiness, \ntend to subside even though drug administration is con -\ntinued. We may assume that some kind of physiological \nadaptation is occurring, presumably associated with altered gene expression resulting in changes in the levels of various \nregulatory molecules, but little is known about the mecha -\nnisms involved.\nQUANTITATIVE ASPECTS OF DRUG\u2013\nRECEPTOR INTERACTIONS\n\u25bc Her e we present some aspects of so-called receptor theory, which \nis based on applying the Law of Mass Action to the drug\u2013receptor 6Here we now use \u2018K A\u2019 rather than just \u2018K\u2019 because we will in the next \nsection be going on to consider the situation when two drugs, A and B, \nare present and there we will use \u2018K A\u2019 and \u2018K B\u2019 to denote the \nequilibrium dissociation constants of the two drugs.\n7A.V. Hill first published it in 1909, when he was still a medical student. \nLangmuir, a physical chemist working on gas adsorption, derived it \nindependently \tin \t1916. \tBoth \tsubsequently \twon \tNobel \tPrizes. \tUntil \t\nrecently, it was known to pharmacologists as the Langmuir equation, \neven though Hill deserves the credit.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3145, "end_char_idx": 6698, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "21f55cc6-6024-4a57-bf66-23f308e6a5ee": {"__data__": {"id_": "21f55cc6-6024-4a57-bf66-23f308e6a5ee", "embedding": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d50f1482-997c-458e-99f5-767dc6d7a44f", "node_type": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7ece3bd685d46367d2f643b94d8d2103e53ca8f0b3201ffc231012c0379c52c"}, "2": {"node_id": "1ce2646e-8ab1-4589-b84e-be16c50d0461", "node_type": null, "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed3ebad64467888c5b2099be4b8683c71063536ba11995e6b8e538bbc289f58c"}}, "hash": "0b811fdc5df01aa820f69f78887ed3a3ce3027658b86a50327f219066815bb7b", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6733, "end_char_idx": 6956, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c1427c0d-98eb-431c-8a5b-15bd47be3df8": {"__data__": {"id_": "c1427c0d-98eb-431c-8a5b-15bd47be3df8", "embedding": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cc3bbac8-c9b3-4f34-83f6-020b173f4fcd", "node_type": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c49145042c5e33a9b3d80235354efd15a786447b40ebedb695c79fbce7ff1b5e"}, "3": {"node_id": "3742d94d-500f-4767-8fae-4ad6d2d24bff", "node_type": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "770c350f924a9e0de70f7efcc6a7e958c5006bc10372e3c18c8ba184c9a642ed"}}, "hash": "73fe232920306bd5cb42c8f846bb1756930a3a95ae0b6adf4300cf746cb03f35", "text": "2 SECTION 1 GENERAL PRINCIPLES\n20BINDING WHEN MORE THAN \nONE DRUG IS PRESENT\n\u25bc Suppose that two drugs, A and B, which bind to the same receptor \nwith equilibrium dissociation constants KA and KB, respectively, are \npresent at concentrations x A and x B. If the two drugs compete (i.e. \nthe receptor can accommodate only one at a time), then, by application \nof the same reasoning as for the one-drug situation described above, \nthe occupancy by drug A is given by:\n PxK\nxK xKAAA\nAA BB=++ 1 (2.9)\nComparing this result with Eq. 2.5 shows that adding drug B, as expected, reduces the occupancy by drug A. Fig. 2.4A (p. 11) shows \nthe predicted binding curves for A in the presence of increasing \nconcentrations of B, demonstrating the shift without any change of slope or maximum that characterises the pharmacological effect of a \ncompetitive antagonist (see Fig. 2.5). The extent of the rightward \nshift, on a logarithmic scale, represents the ratio ( r\nA, given by xA\u2032/x A \nwhere xA\u2032 is the increased concentration of A) by which the concentra -\ntion of A must be increased to overcome the competition by B. \nRearranging Eq. 2.9 shows that\n rx K AB B =+() 1 (2.10)\nThus rA depends only on the concentration and equilibrium dissociation \nconstant of the competing drug B, not on the concentration or equilibrium dissociation constant of A.\nIf A is an agonist, and B is a competitive antagonist, and we assume \nthat the response of the tissue will be an unknown function of P\nA, \nthen the value of rA determined from the shift of the agonist \nconcentration\u2013effect curve at different antagonist concentrations can be used to estimate the equilibrium dissociation constant K\nB for the \nantagonist. Such pharmacological estimates of rA are commonly termed \nagonist dose ratios (more properly concentration ratios, although most \npharmacologists use the older term). This simple and very useful Eq. \n(2.10) is known as the Schild equation, after the pharmacologist who \nfirst used it to analyse drug antagonism.\nEq. 2.10 can be expressed logarithmically in the form:\n log( )log log rx K AB B \u2212= \u2212 1 (2.11)\nThus a plot of log (r A\u22121) against log x B, usually called a Schild plot \n(as in Fig. 2.5, earlier), should give a straight line with unit slope (i.e. \nits gradient is equal to 1) and an abscissal intercept equal to log K B. \nFollowing the pH and pK notation, antagonist potency can be expressed as a pA\n2 value; under conditions of competitive antagonism, pA 2 = \n\u2212log KB. Numerically, pA 2 is defined as the negative logarithm of the \nmolar concentration of antagonist required to produce an agonist dose ratio equal to 2. As with pH notation, its principal advantage \nis that it produces simple numbers, a pA\n2 of 6.5 being equivalent to \na KB of 3.2 \u00d7 10\u22127 mol/L.\nFor competitive antagonism, r shows the following characteristics:\n\u2022\tIt\tdepends \tonly \ton \tthe \tconcentration \tand \tequilibrium \t\ndissociation \tconstant \tof \tthe \tantagonist, \tand \tnot \ton \tthe \tsize \tof \t\nresponse that is chosen as a reference point for the measurements (so long as it is submaximal).\n\u2022\tIt\tdoes \tnot \tdepend \ton \tthe \tequilibrium \tdissociation \tconstant \tof \t\nthe agonist.\n\u2022\tIt\tincreases \tlinearly \twith \txB, and the slope of a plot of (r A\u22121) \nagainst xB is equal to 1/K", "start_char_idx": 0, "end_char_idx": 3267, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3742d94d-500f-4767-8fae-4ad6d2d24bff": {"__data__": {"id_": "3742d94d-500f-4767-8fae-4ad6d2d24bff", "embedding": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cc3bbac8-c9b3-4f34-83f6-020b173f4fcd", "node_type": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c49145042c5e33a9b3d80235354efd15a786447b40ebedb695c79fbce7ff1b5e"}, "2": {"node_id": "c1427c0d-98eb-431c-8a5b-15bd47be3df8", "node_type": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "73fe232920306bd5cb42c8f846bb1756930a3a95ae0b6adf4300cf746cb03f35"}, "3": {"node_id": "cb2f8b0e-ca46-4ea8-a2ca-fefab23de5c7", "node_type": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f52083e22423d49cb0356be8385e3382912725d4c51eb8d8895165978f00f1dd"}}, "hash": "770c350f924a9e0de70f7efcc6a7e958c5006bc10372e3c18c8ba184c9a642ed", "text": "of a plot of (r A\u22121) \nagainst xB is equal to 1/K B; this relationship, being independent \nof the characteristics of the agonist, should be the same for an \nantagonist against all agonists that act on the same population \nof receptors.\nThese predictions have been verified for many examples of competitive antagonism (see Fig. 2.5).\nIn this section, we have avoided going into great detail and have \noversimplified the theory considerably. As we learn more about the \nactual molecular details of how receptors work to produce their \nbiological effects (see Ch. 3), the shortcomings of this theoretical The equilibrium dissociation constant , K\nA, is a characteristic of the drug \nand of the receptor; it has the dimensions of concentration and is \nnumerically equal to the concentration of drug required to occupy \n50% of the sites at equilibrium. (Verify from Eq. 2.5 that when xA = \nKA then PA = 0.5.) The higher the affinity of the drug for the receptors, \nthe lower will be the value of K A. Eq. 2.6 describes the relationship \nbetween occupancy and drug concentration, and it generates a \ncharacteristic curve known as a rectangular hyperbola, as shown in \nFig. 2.14A. It is common in pharmacological work to use a logarithmic \nscale of concentration; this converts the hyperbola to a symmetrical \nsigmoid curve (Fig. 2.14B).\nThe same approach is used to analyse data from experiments in which \ndrug binding is measured directly (see pp. 8\u20139, Fig. 2.2). In this case, \nthe relationship between the amount bound ( B) and ligand concentra -\ntion (x A) should be:\n BB xx K maxA AA =+ () (2.7)\nwhere Bmax is the total number of binding sites in the preparation \n(often expressed as pmol/mg of protein). To display the results in \nlinear form, Eq. 2.6 may be rearranged to:\n Bx BK BK Am ax AA =\u2212 (2.8)\nA plot of B/x A against B (known as a Scatchard plot) gives a straight \nline from which both Bmax and KA can be estimated. Statistically, this \nprocedure is not without problems, and it is now usual to estimate these parameters from the untransformed binding values by an iterative \nnon-linear curve-fitting procedure.\nTo this point, our analysis has considered the binding of one ligand \nto a homogeneous population of receptors. To get closer to real-life pharmacology, we must consider (a) what happens when more than \none ligand is present, and (b) how the tissue response is related to \nreceptor occupancy.Concentration (log scale)Concentration (linear scale)KA = 1.0\nKA = 1.01.0\n0.5\n0\n1.00.5\n010 5 0Fractional occupancy Fractional occupancy\n10.0 1.0 0.1 A\nB\nFig. 2.14 \tTheoretical relationship between occupancy and \nligand concentration. \tThe\trelationship \tis \tplotted \taccording \tto \t\nEq.\t2.5.\t(A) \tPlotted \twith \ta \tlinear \tconcentration \tscale, \tthis \tcurve \t\nis\ta\trectangular \thyperbola. \t(B) \tPlotted \twith \ta \tlog \tconcentration \t\nscale,\tit\tis \ta \tsymmetrical \tsigmoid \tcurve. \tKA\tis\tdefined \tin \tthe \ttext \t\nand\tfootnote \t6. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3231, "end_char_idx": 6477, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cb2f8b0e-ca46-4ea8-a2ca-fefab23de5c7": {"__data__": {"id_": "cb2f8b0e-ca46-4ea8-a2ca-fefab23de5c7", "embedding": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cc3bbac8-c9b3-4f34-83f6-020b173f4fcd", "node_type": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c49145042c5e33a9b3d80235354efd15a786447b40ebedb695c79fbce7ff1b5e"}, "2": {"node_id": "3742d94d-500f-4767-8fae-4ad6d2d24bff", "node_type": null, "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "770c350f924a9e0de70f7efcc6a7e958c5006bc10372e3c18c8ba184c9a642ed"}}, "hash": "f52083e22423d49cb0356be8385e3382912725d4c51eb8d8895165978f00f1dd", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6467, "end_char_idx": 6690, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b0c056ad-db75-44a1-908a-ba2759828e38": {"__data__": {"id_": "b0c056ad-db75-44a1-908a-ba2759828e38", "embedding": null, "metadata": {"page_label": "27", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "03fedf93-10c3-41e1-8cca-e57573d8398f", "node_type": null, "metadata": {"page_label": "27", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33593ffdc9eed354da5a6fead2b02be85ce68847b96d59e8923021b3c1d5d45c"}, "3": {"node_id": "930d967e-30f5-4aa9-999c-2ecf77684d77", "node_type": null, "metadata": {"page_label": "27", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "da99dab6bc88e9fa0d46e5d879bd2b5e962f8b016138d7180b5d4bba46f1d3e3"}}, "hash": "ca29031bb979425a3eae182b0efcad41dbb014fea916fbbf4d9b97f212372022", "text": "2 How d RuGS AC t: GENERAL PRINCIPLES\n21Binding of drugs to receptors \n\u2022\tBinding \tof \tdrugs \tto \treceptors \tnecessarily \tobeys \tthe \t\nLaw of Mass Action .\n\u2022\tAt\tequilibrium, \treceptor \toccupancy \tis \trelated \tto \tdrug \t\nconcentration \tby \tthe \tHill\u2013Langmuir equation \t(Eq.\t2.6).\n\u2022\tThe\thigher \tthe \taffinity \tof \tthe \tdrug \tfor \tthe \treceptor, \tthe \t\nlower\tthe\tconcentration \tat \twhich \tit \tproduces \ta \tgiven \t\nlevel\tof\toccupancy.\n\u2022\tThe\tsame \tprinciples \tapply \twhen \ttwo \tor \tmore \tdrugs \t\ncompete\tfor \tthe \tsame \treceptors; \teach \thas \tthe \teffect \t\nof\treducing \tthe \tapparent \taffinity \tfor \tthe \tother.\nTHE NATURE OF DRUG EFFECTS\nIn discussing how drugs act in this chapter, we have focused \nmainly on the rapid consequences of receptor activation. \nDetails of the receptors and their linkage to effects at the \ncellular level are described in Chapter 3. We now have a fairly good understanding at this level. It is important, \nhowever, particularly when considering drugs in a thera -\npeutic context, that their direct effects on cellular function \ngenerally lead to secondary, delayed effects, which are often \nhighly relevant in a clinical situation in relation to both \ntherapeutic efficacy and harmful effects (Fig. 2.15). For example, activation of cardiac \u03b2 adrenoceptors (see Chs 3 \nand 22) causes rapid changes in the functioning of the heart \nmuscle, but also slower (minutes to hours) changes in the \nfunctional state of the receptors (e.g. desensitisation), and even slower (hours to days) changes in gene expression \nthat produce long-term changes (e.g. hypertrophy) in cardiac \nstructure and function. Opioids (see Ch. 43) produce an immediate analgesic effect, but after a time, tolerance and \ndependence ensue, and in some cases long-term addiction. \nIn these and many other examples, the nature of the intervening mechanism is unclear, although as a general \nrule any long-term phenotypic change necessarily involves \nalterations of gene expression. Drugs are often used to treat chronic conditions, and understanding long-term as well Rapid\nphysiological\nresponsesAltered gene\nexpression\nDelayed\nresponsesRapid Rapid\nSlow\nSlowDrug + target\nFig. 2.15 \tEarly and late responses to drugs. \tMany\tdrugs \t\nact\tdirectly \ton \ttheir \ttargets \t(left-hand arrow) \tto\tproduce \ta \trapid \t\nphysiological \tresponse. \tIf \tthis \tis \tmaintained, \tit \tis \tlikely \tto \tcause \t\nchanges\tin \tgene \texpression \tthat \tgive \trise \tto \tdelayed \teffects. \t\nSome\tdrugs \t(right-hand arrow) \thave\ttheir \tprimary \taction \ton \t\ngene\texpression, \tproducing \tdelayed \tphysiological \tresponses. \t\nDrugs\tcan \talso \twork \tby \tboth \tpathways. \tNote \tthe \tbidirectional \t\ninteraction \tbetween \tgene \texpression \tand \tresponse. \t\nDrug effects \n\u2022\tDrugs\tact \tmainly \ton \tcellular \ttargets, \tproducing \teffects \t\nat\tdifferent \tfunctional \tlevels \t(e.g. \tbiochemical, \tcellular, \t\nphysiological \tand", "start_char_idx": 0, "end_char_idx": 2876, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "930d967e-30f5-4aa9-999c-2ecf77684d77": {"__data__": {"id_": "930d967e-30f5-4aa9-999c-2ecf77684d77", "embedding": null, "metadata": {"page_label": "27", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "03fedf93-10c3-41e1-8cca-e57573d8398f", "node_type": null, "metadata": {"page_label": "27", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33593ffdc9eed354da5a6fead2b02be85ce68847b96d59e8923021b3c1d5d45c"}, "2": {"node_id": "b0c056ad-db75-44a1-908a-ba2759828e38", "node_type": null, "metadata": {"page_label": "27", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca29031bb979425a3eae182b0efcad41dbb014fea916fbbf4d9b97f212372022"}}, "hash": "da99dab6bc88e9fa0d46e5d879bd2b5e962f8b016138d7180b5d4bba46f1d3e3", "text": "\tstructural).\n\u2022\tThe\tdirect \teffect \tof \tthe \tdrug \ton \tits \ttarget \tproduces \t\nacute\tresponses \tat \tthe \tbiochemical, \tcellular \tor \t\nphysiological \tlevels.\n\u2022\tProlonged \treceptor \tactivation \tgenerally \tleads \tto \t\ndelayed long-term effects ,\tsuch\tas\tdesensitisation \tor \t\ndown-regulation \tof \treceptors, \thypertrophy, \tatrophy \tor \t\nremodelling \tof \ttissues, \ttolerance, \tdependence \tand \t\naddiction.\n\u2022\tLong-term \tdelayed \tresponses \tresult \tfrom \tchanges \tin \t\ngene\texpression, \talthough \tthe \tmechanisms \tby \twhich \t\nthe\tacute\teffects \tbring \tthis \tabout \tare \toften \tuncertain.\n\u2022\tTherapeutic \teffects \tmay \tbe \tbased \ton \tacute \tresponses \t\n(e.g.\tthe\tuse \tof \tbronchodilator \tdrugs \tto \ttreat \tasthma; \t\nCh.\t29)\tor \tdelayed \tresponses \t(e.g. \tantidepressants; \t\nCh.\t48).treatment become more obvious. The two-state model can be incor -\nporated without difficulty, but complications arise when we include \nthe involvement of G proteins (see Ch. 3) in the reaction scheme (as \nthey shift the equilibrium between R and R*), and when we allow for the fact that receptor activation is not a simple on\u2013off switch, as \nthe two-state model assumes, but may take different forms. Despite \nstrenuous efforts by theoreticians to allow for such possibilities, the molecules always seem to remain one step ahead. Nevertheless, this \ntype of basic theory applied to the two-state model remains a useful \nbasis for developing quantitative models of drug action. The book \nby Kenakin (1997) is recommended as an introduction, and the later \nreview (Kenakin & Christopoulos, 2011) presents a detailed account of the value of quantification in the study of drug action.\nas acute drug effects is becoming increasingly important. \nPharmacologists have traditionally tended to focus on \nshort-term physiological responses, which are much easier \nto study, rather than on delayed effects. The focus is now clearly shifting.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2877, "end_char_idx": 5261, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "42590f5d-b7c7-43b5-ad9e-499261aa3c9f": {"__data__": {"id_": "42590f5d-b7c7-43b5-ad9e-499261aa3c9f", "embedding": null, "metadata": {"page_label": "28", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "aa41831b-efe1-4480-a3ba-f5e13d6a5146", "node_type": null, "metadata": {"page_label": "28", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4414b06f3b10dd2a2853f4adb300d828fbcec9ba65ce4f84f29c76f5ea181b5f"}, "3": {"node_id": "c766fc5e-942c-49cc-a06b-e18ba6582e73", "node_type": null, "metadata": {"page_label": "28", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8cf93f45e12c9b30d49261ff73ad92735f693d334dd336a92743028f267097dc"}}, "hash": "c10cffc99270f63f96bce36c124f26a58f976dd559e2f25be01aa9c013dd474c", "text": "2 SECTION 1 GENERAL PRINCIPLES\n22REFERENCES AND FURTHER READING\nGeneral\nAlexander, S.P.H., Kelly, E., Marrion, N., et al., 2015. The Concise Guide \nto Pharmacology. Br. J. Pharmacol. 172, 5729\u20136202. ( Summary data on a \nvast array of receptors, ion channels, transporters and enzymes and of the \ndrugs that interact with them \u2013 valuable for reference )\nColquhoun, D., 2006. The quantitative analysis of drug\u2013receptor \ninteractions: a short history. Trends Pharmacol. Sci. 27, 149\u2013157. ( An \nilluminating account for those interested in the origins of one of the central \nideas in pharmacology )\nFranks, N.P., 2008. General anaesthesia: from molecular targets to \nneuronal pathways of sleep and arousal. Nat. Rev. Neurosci. 9, \n370\u2013386. ( Describes how we now understand that general anaesthetics \ninteract with specific membrane proteins rather than by accumulating in \nmembrane lipids )\nKenakin, T., 1997. Pharmacologic Analysis of Drug\u2013Receptor \nInteractions, third ed. Lippincott-Raven, New York. ( Useful and \ndetailed textbook covering most of the material in this chapter in greater \ndepth )\nKenakin, T., Christopoulos, A., 2013. Signalling bias in new drug \ndiscovery: detection, quantification and therapeutic impact. Nat. Rev. \nDrug Discov. 12, 205\u2013216. ( Detailed discussion of the difficulties in \nmeasuring agonist efficacy and bias )\nNeubig, R., Spedding, M., Kenakin, T., Christopoulos, A., 2003. \nInternational Union of Pharmacology Committee on receptor \nnomenclature and drug classification: XXXVIII. Update on terms and \nsymbols in quantitative pharmacology. Pharmacol. Rev. 55, 597\u2013606. \n(Summary of IUPHAR-approved terms and symbols relating to \npharmacological receptors \u2013 useful for reference purposes )\nRang, H.P., 2006. The receptor concept: pharmacology\u2019s big idea. Br. J. \nPharmacol. 147 (Suppl. 1), 9\u201316. ( Short review of the origin and status of \nthe receptor concept )\nStephenson, R.P., 1956. A modification of receptor theory. Br. J. \nPharmacol. 11, 379\u2013393. ( Classic analysis of receptor action introducing the \nconcept of efficacy )Receptor mechanisms: agonists and efficacy\nBond,\tR.A.,\tIjzerman,\t A.P.,\t2006.\tRecent\tdevelopments\t in\tconstitutive\t\nreceptor activity and inverse agonism, and their potential for GPCR \ndrug discovery. Trends Pharmacol. Sci. 27, 92\u201396. ( Discussion of \npathophysiological consequences of constitutive receptor activation and \ntherapeutic potential of inverse agonists )\nChangeux, J.P., Christopoulos, A., 2016. Allosteric modulation as a \nunifying mechanism for receptor function and regulation. Cell 166, \n1084\u20131102. ( Extensive review describing allosteric modulation at different \ntypes of receptor )\nDe\tLigt,\tR.A.F.,\tKourounakis,\t A.P.,\tIjzerman,\t A.P.,\t2000.\tInverse\t\nagonism at G protein-coupled receptors: (patho)physiological \nrelevance and implications for drug discovery. Br. J. Pharmacol. 130, \n1\u201312. ( Useful review article giving many examples of constitutively active \nreceptors and inverse agonists, and discussing the relevance of these concepts \nfor disease mechanisms and drug discovery )\nKelly, E., 2013. Efficacy and ligand bias at the \u00b5-opioid receptor. Br. J. \nPharmacol. 169, 1430\u20131446. ( A readable account of the", "start_char_idx": 0, "end_char_idx": 3208, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c766fc5e-942c-49cc-a06b-e18ba6582e73": {"__data__": {"id_": "c766fc5e-942c-49cc-a06b-e18ba6582e73", "embedding": null, "metadata": {"page_label": "28", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "aa41831b-efe1-4480-a3ba-f5e13d6a5146", "node_type": null, "metadata": {"page_label": "28", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4414b06f3b10dd2a2853f4adb300d828fbcec9ba65ce4f84f29c76f5ea181b5f"}, "2": {"node_id": "42590f5d-b7c7-43b5-ad9e-499261aa3c9f", "node_type": null, "metadata": {"page_label": "28", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c10cffc99270f63f96bce36c124f26a58f976dd559e2f25be01aa9c013dd474c"}}, "hash": "8cf93f45e12c9b30d49261ff73ad92735f693d334dd336a92743028f267097dc", "text": "\nPharmacol. 169, 1430\u20131446. ( A readable account of the problems of \nmeasuring efficacy as well as a discussion of agonist bias at an important \nreceptor )\nKenakin, T., Christopoulos, A., 2011. Analytical pharmacology: the \nimpact of numbers on pharmacology. Trends Pharmacol. Sci. 32, \n189\u2013196. ( A theoretical treatment that attempts to take into account recent \nknowledge of receptor function at the molecular level )\nMay, L.T., Leach, K., Sexton, P.M., Christopoulos, A., 2007. Allosteric \nmodulation of G protein-coupled receptors. Annu. Rev. Pharmacol. \nToxicol. 47, 1\u201351. ( Comprehensive review describing the characteristics, \nmechanisms and pharmacological implications of allosteric interactions at \nGPCRs )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3153, "end_char_idx": 4351, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "901c601a-e8e8-4b3a-88c2-2eec11967c90": {"__data__": {"id_": "901c601a-e8e8-4b3a-88c2-2eec11967c90", "embedding": null, "metadata": {"page_label": "29", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ab4feb1-4db5-4a42-b6e2-2021fa7ac4ec", "node_type": null, "metadata": {"page_label": "29", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c14c0f06dbbee50d348b7fb36ee26383b5d8b1bf8767719a1d13fab792c38f7"}, "3": {"node_id": "2ebccc93-1e0b-464f-84f7-b3e34637d809", "node_type": null, "metadata": {"page_label": "29", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d11937fa3899a856e331f364f20723104010e782e218ce7b5891ed04efa7987d"}}, "hash": "3eafd45e620c47bc2ed33adaf92c4e176287262d3bb4d3990fa01f0b0d99b58a", "text": "23\nHow drugs act: molecular aspects 3 GENERAL PRINCIPLES SECTION 1 \nOVERVIEW\nIn this chapter, we move from the general principles \nof drug action outlined in Chapter 2 to the molecules \nthat are involved in recognising chemical signals and translating them into cellular responses. Molecular pharmacology is advancing rapidly, and the new \nknowledge is changing our understanding of drug \naction and opening up many new therapeutic possibili -\nties, further discussed in other chapters.\nFirst, we consider the types of target proteins on \nwhich drugs act. Next, we describe the main families of receptors and ion channels. Finally, we discuss the \nvarious forms of receptor\u2013effector linkage (signal \ntransduction mechanisms) through which receptors are coupled to the regulation of cell function. The \nrelationship between the molecular structure of a \nreceptor and its functional linkage to a particular type of effector system is a principal theme. In the \nnext two chapters, we see how these molecular events \nalter important aspects of cell function \u2013 a useful basis for understanding the effects of drugs on intact living \norganisms. We are confident that tomorrow\u2019s phar -\nmacology will rest solidly on the advances in cellular \nand molecular biology that are discussed here.\nPROTEIN TARGETS FOR DRUG ACTION\nThe protein targets for drug action on mammalian cells \n(Fig. 3.1) that are described in this chapter can be broadly \ndivided into:\n\u2022\treceptors\n\u2022\tion\tchannels\n\u2022\tenzymes\n\u2022\ttransporters \t(carrier \tmolecules)\nThe great majority of important drugs act on one or other \nof these types of protein, but there are exceptions. For \nexample, colchicine used to treat arthritic gout attacks (Ch. \n27) interacts with the structural protein tubulin, while several \nimmunosuppressive drugs (e.g. ciclosporin, Ch. 27) bind \nto cytosolic proteins known as immunophilins. Therapeutic antibodies that act by sequestering cytokines (protein mediators involved in inflammation; see Chs 5 and 27) are \nalso used. Targets for chemotherapeutic drugs (Chs 51\u201357), \nwhere the aim is to suppress invading microorganisms or cancer cells, include DNA and cell wall constituents as well as other proteins.\nRECEPTORS\nReceptors (see Fig. 3.1A) are the sensing elements in the system of chemical communications that coordinates the function and responses of all the different cells in the body, the chemical messengers being the various hormones, transmitters and other mediators discussed in Section 2 of \nthis book. Many therapeutically useful drugs act, either as \nagonists or antagonists, on receptors for known endogenous mediators. In most cases, the endogenous mediator was discovered before \u2013 often many years before \u2013 the receptor \nwas characterised pharmacologically and biochemically. \nIn some cases, such as the cannabinoid and opioid receptors (see Chs 20 and 43), the endogenous mediators were identi -\nfied later; in others, known as orphan receptors (see later) \nthe mediator, if it exists, still remains unknown. The host defence system also utilises a set of receptors (e.g. the \u2018Toll\u2019 \nreceptors) that are adept at recognising fragments of \u2018foreign\u2019 \nbacterial and other invading organisms. These are considered separately in Chapter 7.\nION CHANNELS\nIon channels1 are essentially gateways in cell membranes \nthat selectively allow the passage of particular ions, and \nthat are induced to open or close by a variety of mechanisms. \nTwo important types are ligand-gated channels and voltage-\ngated channels. The former open only when one or more \nagonist molecules are bound, and are properly classified \nas receptors, since agonist binding is needed to activate them. Voltage-gated", "start_char_idx": 0, "end_char_idx": 3683, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2ebccc93-1e0b-464f-84f7-b3e34637d809": {"__data__": {"id_": "2ebccc93-1e0b-464f-84f7-b3e34637d809", "embedding": null, "metadata": {"page_label": "29", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ab4feb1-4db5-4a42-b6e2-2021fa7ac4ec", "node_type": null, "metadata": {"page_label": "29", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c14c0f06dbbee50d348b7fb36ee26383b5d8b1bf8767719a1d13fab792c38f7"}, "2": {"node_id": "901c601a-e8e8-4b3a-88c2-2eec11967c90", "node_type": null, "metadata": {"page_label": "29", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3eafd45e620c47bc2ed33adaf92c4e176287262d3bb4d3990fa01f0b0d99b58a"}}, "hash": "d11937fa3899a856e331f364f20723104010e782e218ce7b5891ed04efa7987d", "text": "receptors, since agonist binding is needed to activate them. Voltage-gated channels are gated by changes in the \ntransmembrane potential rather than by agonist binding.\nIn general, drugs can affect ion channel function in several \nways:\n1. By binding to the channel protein itself, either to the \nligand-binding (orthosteric) site of ligand-gated \nchannels, or to other (allosteric) sites, or, in the \nsimplest case, exemplified by the action of local \nanaesthetics on the voltage-gated sodium channel (see Ch. 44), the drug molecule plugs the channel \nphysically (see Fig. 3.1B), blocking ion permeation. \nExamples of drugs that bind to allosteric sites on the channel protein and thereby affect channel gating \ninclude:\n\u2022\tbenzodiazepines (see Ch. 45). These drugs bind to a \nregion of the GABA\nA receptor\u2013chloride channel \ncomplex (a ligand-gated channel) that is distinct \nfrom the GABA binding site and facilitate the \nopening of the channel by the inhibitory neurotransmitter GABA (see Ch. 39)\n\u2022\tvasodilator \tdrugs \tof \tthe \tdihydropyridine type (see \nCh. 23), which inhibit the opening of L-type calcium \nchannels (see Ch. 4).\n1\u2018Ion channels and the electrical properties they confer on cells are \ninvolved in every human characteristic that distinguishes us from the \nstones in a field\u2019 (Armstrong, C.M., 2003. Voltage-gated K channels. Sci. \nSTKE 188, re10).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3609, "end_char_idx": 5454, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d8047bca-73bf-4c57-896d-bbb73225f47b": {"__data__": {"id_": "d8047bca-73bf-4c57-896d-bbb73225f47b", "embedding": null, "metadata": {"page_label": "30", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "443a6172-5f92-41a6-9e66-ac76a804d2f3", "node_type": null, "metadata": {"page_label": "30", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97045fadf26312cfe48ce4f049c6c5e09b0c09b96a64b9a3378c3606a00844b3"}, "3": {"node_id": "191242ae-e34e-4090-a263-5b5e7bb1f6a5", "node_type": null, "metadata": {"page_label": "30", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "783d3c8614dad8a1bd7c5f3bf93c2b40cff89b43b0e0ac7629e855fde784e7db"}}, "hash": "c7252484a77828a99233570835457ab0f6b9bfb3679a7a9c329238400d736f6b", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n24angiotensin-converting \tenzyme; \tCh. \t23); \tin \tother \tcases, \t\nthe binding is irreversible and non-competitive (e.g. \naspirin, acting on cyclo-oxygenase; Ch. 27). Drugs may \nalso act as false substrates, where the drug molecule \nundergoes chemical transformation to form an abnormal product that subverts the normal metabolic pathway. \nAn example is the anticancer drug fluorouracil, which \nreplaces uracil as an intermediate in purine biosyn -\nthesis but cannot be converted into thymidylate, thus blocking DNA synthesis and preventing cell division \n(Ch. 57).\nIt should also be mentioned that drugs may require \nenzymic\tdegradation \tto\tconvert\tthem\tfrom\tan\tinactive\tform,\t\nthe prodrug (see Ch. 10), to an active form (e.g. enalapril \nis converted by esterases to enalaprilat, which inhibits \nangiotensin-converting \te nzyme).\t Furthermore, \t as \tdi scussed\t\nin\tChapter\t58,\tdrug\ttoxicity\toften\tresults\tfrom\tthe\tenzymic\t\nconversion of the drug molecule to a reactive metabolite. \nParacetamol (see Ch. 27) causes liver damage in this way. \nAs far as the primary action of the drug is concerned, this \nis an unwanted side reaction, but it is of major practical importance.\nTRANSPORTERS\nThe movement of ions and small polar organic molecules across cell membranes generally occurs either through \nchannels, or through the agency of a transport protein \n(see Fig. 3.1D), because the permeating molecules are often insufficiently lipid-soluble to penetrate lipid mem -\nbranes on their own. Many such transporters are known; examples of particular pharmacological importance include those responsible for the transport of ions and many \norganic molecules across the renal tubule, the intestinal \nepithelium and the blood\u2013brain barrier, the transport of Na\n+ and Ca2+ out of cells, the uptake of neurotransmit -\nter precursors (such as choline) or of neurotransmitters \nthemselves (such as amines and amino acids) by nerve \nterminals, and the transport of drug molecules and their metabolites across cell membranes and epithelial barri -\ners. We shall encounter transporters frequently in later \nchapters.\nIn many cases, hydrolysis of ATP provides the energy \nfor transport of substances against their electrochemical gradient. Such transport proteins include a distinct ATP-binding site, and are termed ABC (ATP-Binding Cassette) \ntransporters. Important examples include the sodium \npump (Na\n+-K+-ATPase; see Ch. 4) and multidrug resist-\nance (MDR) transporters that eject cytotoxic drugs from cancer and microbial cells, conferring resistance to these \ntherapeutic agents (see Ch. 57). In other cases, including the neurotransmitter transporters, the transport of organic \nmolecules is coupled to the transport of ions (usually Na\n+), \neither in the same direction (symport) or in the opposite direction ( antiport ), and therefore relies on the electrochemi -\ncal gradient for Na\n+ generated by the ATP-driven sodium \npump. The carrier proteins embody a recognition site that makes them specific for a particular permeating species, and \nthese recognition sites can also be targets for drugs whose effect is to block the transport system (e.g. cocaine blocks \nmonoamine neurotransmitter uptake into nerve terminals; \nsee Ch. 49).\nThe importance of transporters as a source of individual \nvariation in the pharmacokinetic characteristics of various \ndrugs is increasingly recognised (see Ch.", "start_char_idx": 0, "end_char_idx": 3427, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "191242ae-e34e-4090-a263-5b5e7bb1f6a5": {"__data__": {"id_": "191242ae-e34e-4090-a263-5b5e7bb1f6a5", "embedding": null, "metadata": {"page_label": "30", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "443a6172-5f92-41a6-9e66-ac76a804d2f3", "node_type": null, "metadata": {"page_label": "30", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97045fadf26312cfe48ce4f049c6c5e09b0c09b96a64b9a3378c3606a00844b3"}, "2": {"node_id": "d8047bca-73bf-4c57-896d-bbb73225f47b", "node_type": null, "metadata": {"page_label": "30", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c7252484a77828a99233570835457ab0f6b9bfb3679a7a9c329238400d736f6b"}}, "hash": "783d3c8614dad8a1bd7c5f3bf93c2b40cff89b43b0e0ac7629e855fde784e7db", "text": "characteristics of various \ndrugs is increasingly recognised (see Ch. 11).2. By an indirect interaction, involving an activated G \nprotein subunit or other intermediary (see p. 34).\n3. By altering the level of expression of ion channels on \nthe cell surface. For example, gabapentin reduces the insertion of neuronal calcium channels into the \nplasma membrane (Ch. 46).\nA summary of the different ion channel families and their functions is given later.\nENZYMES\nMany\tdrugs \ttarget \tenzymes \t(see \tFig. \t3.1C). \tOften, \tthe \t\ndrug molecule is a substrate analogue that acts as a com -\npetitive\tinhibitor \tof \tthe \tenzyme \t(e.g. \tcaptopril, acting on Abnormal compound\naccumulated Transport\nblockedInhibitor\nFalse\nsubstrateNormaltransportRECEPTORS\nION CHANNELS\nENZYMES\nTRANSPORTERS\nAbnormal product Agonist/substrate\nAntagonist/inhibitor ProdrugDirect\nNo effectEndogenous mediators blockedAntagonistAgonist/\ninverseagonist\nDNAtranscriptionIon channel\nmodulationEnzyme\nactivation/inhibitionIon channel\nopening/closing\nTransduction\nmechanisms\nIncreased ordecreasedopening probabilityModulatorsPermeationblockedBlockers\nActive drug producedAbnormal\nmetabolite producedNormal reaction\ninhibitedInhibitor\nProdrugFalse\nsubstrate\norA\nB\nC\nD\nFig. 3.1 Types of target for drug action. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3358, "end_char_idx": 5112, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c729462e-9904-4a57-9c18-36ce6b5540f5": {"__data__": {"id_": "c729462e-9904-4a57-9c18-36ce6b5540f5", "embedding": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "14ac1dab-ba39-4d7b-a06d-9834e17d41de", "node_type": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46b23885cafc7c83d64f4adba8f45d8ba2297a8acf706f134f308ab54be5d3b0"}, "3": {"node_id": "d91f5410-7ee9-4c66-bced-2b5abc36ccf1", "node_type": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4a11d94be60dc30ebd6fbce9ff35b3dd194b5f5abb83f071c5f53ea174389cf"}}, "hash": "359dac0a023b69156c6508df58dac72e67e7c45f2e706e2e5fcd0a2a023d11a2", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n25agonist-induced receptor conformational changes and how \nsignalling is initiated.\nNow that the genes have been clearly identified, the \nemphasis has shifted to characterising the receptors phar -\nmacologically and determining their molecular character -\nistics and physiological functions.\nTYPES OF RECEPTOR\nReceptors elicit many different types of cellular effect. Some of them are very rapid, such as those involved in fast \nsynaptic transmission, operating within milliseconds, \nwhereas other receptor-mediated effects, such as many of those produced by thyroid hormone or various steroid \nhormones, occur over hours or days. There are many \nexamples of intermediate timescales \u2013 catecholamines, for example, usually act in a matter of seconds, whereas many \npeptides take rather longer to produce their effects. Not \nsurprisingly, very different types of linkage between receptor occupation and the ensuing response are involved. Based on molecular structure and the nature of this linkage (the \ntransduction mechanism), we can distinguish four receptor \ntypes, or superfamilies (Figs 3.2 and 3.3; Table 3.1).\n\u2022\tType\t1: \tligand-gated ion channels (also known as \nionotropic receptors3). The chain of discoveries \nculminating in the molecular characterisation of these \nreceptors is described by Halliwell (2007). Typically, \nthese are the receptors on which fast neurotransmitters act (see Table 3.1).\n\u2022\tType\t2: \tG protein\u2013coupled receptors (GPCRs). These \nare also known as metabotropic receptors or \n7-transmembrane (7-TM, serpentine or heptahelical) \nreceptors. They are membrane receptors that are coupled to intracellular effector systems primarily via \na G protein (see p. 32). They constitute the largest \nfamily,\n4 and include receptors for many hormones and \nslow transmitters (Table 3.1).\n\u2022\tType\t3: \tkinase-linked and related receptors. This is a \nlarge and heterogeneous group of membrane receptors \nresponding mainly to protein mediators. They \ncomprise an extracellular ligand-binding domain linked to an intracellular domain by a single \ntransmembrane helix. In many cases, the intracellular \ndomain\tis \tenzymic \tin \tnature \t(with \tprotein \tkinase \tor \t\nguanylyl \tcyclase \tactivity). \tSome \tlack \tenzymic \tactivity \t\nthemselves \tbut \tlink \tto \tintracellular \teffector \tenzymes \t\nthrough their binding of adaptor proteins. Examples \nof these latter receptor types include cytokine \nreceptors (e.g. tumour necrosis factor [TNF] receptors) \nand pattern recognition receptors (PRRs) that recognise pathogen-associated molecular patterns \n(PAMPs) or danger-associated molecular patterns \n(DAMPs) found in pathogens, which stimulate the innate immune system host defence network (see Ch. \n7). PRR receptors include the cell surface Toll-like \nreceptors (TLRs), and the cytoplasmic receptors such RECEPTOR PROTEINS\nCLONING OF RECEPTORS\nIn the 1970s, pharmacology entered a new phase when receptors, which had until then been theoretical entities, \nbegan to emerge as biochemical realities following the \ndevelopment of receptor-labelling techniques (see Ch. 2), which made it possible to extract and purify the receptor \nmaterial.\nOnce\tr eceptor \tp roteins\tw ere\ti solated\ta nd\tp urified,\ti t\tw as\t\npossible to analyse the amino acid sequence of a short \nstretch, allowing the corresponding base sequence of the \nmRNA to be deduced and full-length DNA to be isolated \nby conventional cloning methods, starting from a cDNA", "start_char_idx": 0, "end_char_idx": 3477, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d91f5410-7ee9-4c66-bced-2b5abc36ccf1": {"__data__": {"id_": "d91f5410-7ee9-4c66-bced-2b5abc36ccf1", "embedding": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "14ac1dab-ba39-4d7b-a06d-9834e17d41de", "node_type": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46b23885cafc7c83d64f4adba8f45d8ba2297a8acf706f134f308ab54be5d3b0"}, "2": {"node_id": "c729462e-9904-4a57-9c18-36ce6b5540f5", "node_type": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "359dac0a023b69156c6508df58dac72e67e7c45f2e706e2e5fcd0a2a023d11a2"}, "3": {"node_id": "8aadec16-f20d-4fc8-9b9e-f8f1f6fa1264", "node_type": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "36578c8bcabb273a3cd043699eea7d0e0feffe7bc960271910a47d816342b816"}}, "hash": "e4a11d94be60dc30ebd6fbce9ff35b3dd194b5f5abb83f071c5f53ea174389cf", "text": "DNA to be isolated \nby conventional cloning methods, starting from a cDNA library obtained from a tissue source rich in the receptor \nof interest. The first receptor clones were obtained in this \nway, but subsequently expression cloning and, with the sequencing of the entire genome of various species, including \nhuman, cloning strategies based on sequence homologies, \nwhich do not require prior isolation and purification of the receptor protein, were widely used, and now several hundred receptors of all four structural families (see Fig. \n3.3) have been cloned. Sequence data so obtained has \nrevealed many molecular variants (subtypes) of known receptors that had not been evident from pharmacological \nstudies (see IUPHAR/BPS, Guide to Pharmacology ). Much \nremains to be discovered about the pharmacological, \nfunctional and clinical significance of this abundant molecu -\nlar polymorphism. It is expected, however, that such vari -\nations will account for part of the variability between individuals in response to therapeutic agents (see Ch. 12)\nEndogenous ligands for many of the novel receptors \nidentified by gene cloning are so far unknown, and they are described as \u2018orphan receptors\u2019.\n2 Identifying ligands \nfor these presumed receptors is often difficult. Increasingly, \nthere are examples (e.g. free fatty acid receptors) where \nimportant endogenous ligands have been linked to hitherto orphan receptors. There is optimism that novel therapeutic \nagents will emerge by targeting this pool of unclaimed \nreceptors.\nMuch information has been gained by introducing the \ncloned DNA encoding individual receptors into cell lines, producing cells that express the foreign receptors in a functional form. Such engineered cells allow much more precise control of the expressed receptors than is possible \nwith natural cells or intact tissues, and the technique is widely \nused to study the binding and pharmacological characteristics of cloned receptors. Expressed human receptors, which often \ndiffer in their sequence and pharmacological properties from \ntheir animal counterparts, can be studied in this way.\nObtaining \tcrystals \tof \ta \tprotein \tallows \tits \tstructure \tto \tbe \t\nanalysed at very high resolution by X-ray diffraction techniques, but unfortunately, since many receptors are \nnormally embedded in membrane lipid, they have, until \nrelatively recently, proven difficult to crystallise. Much of the information obtained relates to how ligands bind to \nreceptors, but we are now beginning to learn more about \n2An oddly Dickensian term that seems inappropriately condescending. \nBecause we can assume that these receptors play defined roles in \nphysiological signalling, their \u2018orphanhood\u2019 reflects our ignorance, not \ntheir status. More information on orphan receptors can be found at .3Here, focusing on receptors, we include ligand-gated ion channels as \nan\texample \tof \ta \treceptor \tfamily. \tOther \ttypes \tof \tion \tchannels \tare \t\ndescribed later (p. 46); many are also drug targets, although not \nreceptors in the strict sense.\n4There are 865 human GPCRs comprising 1.6% of the genome \n(Fredriksson & Schi\u00f6th, 2005). Nearly 500 of these are believed to be \nodorant receptors involved in smell and taste sensations, the remainder \nbeing receptors for known or unknown endogenous mediators \u2013 enough to keep pharmacologists busy for some time yet.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3416, "end_char_idx": 7117, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8aadec16-f20d-4fc8-9b9e-f8f1f6fa1264": {"__data__": {"id_": "8aadec16-f20d-4fc8-9b9e-f8f1f6fa1264", "embedding": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "14ac1dab-ba39-4d7b-a06d-9834e17d41de", "node_type": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46b23885cafc7c83d64f4adba8f45d8ba2297a8acf706f134f308ab54be5d3b0"}, "2": {"node_id": "d91f5410-7ee9-4c66-bced-2b5abc36ccf1", "node_type": null, "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4a11d94be60dc30ebd6fbce9ff35b3dd194b5f5abb83f071c5f53ea174389cf"}}, "hash": "36578c8bcabb273a3cd043699eea7d0e0feffe7bc960271910a47d816342b816", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7132, "end_char_idx": 7403, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f751e2c8-cf66-47c2-83a5-b5660d70b7bf": {"__data__": {"id_": "f751e2c8-cf66-47c2-83a5-b5660d70b7bf", "embedding": null, "metadata": {"page_label": "32", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6a84f021-5c8e-439e-8ade-6387f09dd7ba", "node_type": null, "metadata": {"page_label": "32", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42c7a73f4427a1bc7ddc85e2854096ff4a905ecfa1223561ab95aac641bf476b"}}, "hash": "42c7a73f4427a1bc7ddc85e2854096ff4a905ecfa1223561ab95aac641bf476b", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n262. G protein\u2212coupled\nreceptors\n(metabotropic)1. Ligand-gated ion\nchannels\n(ionotropic receptors)3. Kinase-linked\nreceptors4. Nuclear receptors\nNUCLEUS\nGene\ntranscription\nGene transcription\nCellular effects Cellular effectsProtein\nphosphorylation\nCellular effectsProtein\nphosphorylationOther Ca2+ releaseChange\nin excitability\nCellular effectsHyperpolarisation \nor\ndepolarisation\nHours Hours Seconds MillisecondsTime scaleSecond messengersR R/E\nRE\nGG\nor orIons Ions\nProtein synthesis Protein synthesis\nOestrogen\nreceptorCytokine receptors Muscarinic\nACh receptorNicotinic\nACh receptorExamplesRR\nFig. 3.2 Types of receptor\u2013effector linkage. ACh, acetylcholine; E, enzyme; G, G protein; R, receptor. \n5The term nuclear receptor is something of a misnomer, because some are \nactually located in the cytosol and migrate to the nuclear compartment \nwhen a ligand is present.Table 3.1 The four main types of receptor\nType 1: Ligand-gated \nion channelsType 2: G protein\u2013coupled receptorsType 3: Receptor kinasesType 4: Nuclear receptors\nLocation Membrane Membrane Membrane Intracellular\nEffector Ion channel Channel or enzyme Protein kinases Gene transcription\nCoupling Direct G protein or arrestin Direct Via DNA\nExamples Nicotinic acetylcholine \nreceptor, GABA A receptorMuscarinic acetylcholine receptor, adrenoceptorsInsulin, growth factors, cytokine receptorsSteroid receptors\nStructure Oligomeric assembly of subunits surrounding central poreMonomeric or oligomeric assembly of subunits comprising seven transmembrane helices with intracellular \nG protein\u2013coupling domainSingle transmembrane helix linking extracellular receptor domain to intracellular kinase domainMonomeric structure with \nreceptor- and DNA-binding \ndomains\nas\tRIG-I-like \treceptors \t(RLRs) \tand \tNOD-like \treceptors \t\n(NLRs). All these immune receptors signal their \nintracellular effects through adaptor proteins and \nkinases to alter the cell\u2019s transcription to elicit the \ncorrect immune response needed to fight against any pathogenic invaders.\n\u2022\tType\t4: \tnuclear receptors. These are receptors that \nregulate gene transcription.5 Receptors of this type also recognise many foreign molecules, inducing the \nexpression \tof \tenzymes \tthat \tmetabolise \tthem.\nMOLECULAR STRUCTURE OF RECEPTORS\nThe molecular organisation of typical members of each of these four receptor superfamilies is shown in Fig. 3.3. \nAlthough individual receptors show considerable sequence \nvariation in particular regions, and the lengths of the main intracellular and extracellular domains also vary from one \nto another within the same family, the overall structural \npatterns and associated signal transduction pathways are mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3189, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5cecb105-81e8-43ab-8f17-af9d287dd9d4": {"__data__": {"id_": "5cecb105-81e8-43ab-8f17-af9d287dd9d4", "embedding": null, "metadata": {"page_label": "33", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4cb59c6c-a42e-4926-a599-79e0f620549e", "node_type": null, "metadata": {"page_label": "33", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61bf9e2c87a26ca71e62c110f398c0df4de2e2340ef348b2a0634ae509a81ba3"}, "3": {"node_id": "7620fd55-2d65-488f-bcfb-7b4312cb4346", "node_type": null, "metadata": {"page_label": "33", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b87186cbf5b544387d3aebaa1c1d2fa36a35affdccfd978ef681475747c87923"}}, "hash": "380c51f09e427bd194be3528963bb270149f2a82f9f6151c4b25ddb93865d746", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n27very consistent. The realisation that just four main receptor \nsuperfamilies provide a solid framework for interpreting \nthe complex welter of information about the effects of a \nlarge proportion of the drugs that have been studied has been one of the most refreshing developments in modern \npharmacology.\nRECEPTOR \u2003HETEROGENEITY \u2003AND \u2003SUBTYPES\nReceptors within a given family generally occur in several \nmolecular varieties, or subtypes, with similar architecture \nbut significant differences in their sequences, and often in \ntheir pharmacological properties.6 Nicotinic acetylcholine \nreceptors are typical in this respect; distinct subtypes occur \nin different brain regions (see Table 40.2), and these differ \nfrom the muscle receptor. Some of the known pharm -\nacological differences (e.g. sensitivity to blocking agents) \nbetween muscle and brain acetylcholine receptors correlate \nwith specific sequence differences; however, as far as we know, all nicotinic acetylcholine receptors respond to the \nsame physiological mediator and produce the same kind \nof synaptic response, so why many variants should have \nevolved\tis \tstill \ta \tpuzzle.\n\u25bc Much of the sequence variation that accounts for receptor diversity \narises at the genomic level, that is, different genes give rise to distinct \nreceptor subtypes. Additional variation arises from alternative mRNA \nsplicing, which means that a single gene can give rise to more than \none receptor isoform. After translation from genomic DNA, the mRNA normally contains non-coding regions (introns) that are excised by \nmRNA splicing before the message is translated into protein. Depend -\ning on the location of the splice sites, splicing can result in inclusion \nor deletion of one or more of the mRNA coding regions, giving rise \nto long or short forms of the protein. This is an important source of \nvariation, particularly for GPCRs, producing receptors with different \nbinding characteristics and different signal transduction mechanisms, \nalthough its pharmacological relevance remains to be clarified. Another process that can produce different receptors from the same gene is \nmRNA editing, which involves the mischievous substitution of one \nbase in the mRNA for another, and hence potentially a small variation in the amino acid sequence of the expressed receptor.\nMolecular heterogeneity of this kind is a feature of all kinds \nof receptors \u2013 indeed of functional proteins in general. New \nreceptor subtypes and isoforms continue to be discovered, \nand regular updates of the catalogue are available (www.guidetopharmacology.org/). The problems of clas -\nsification, nomenclature and taxonomy resulting from this flood of data have been mentioned earlier.\nWe will now describe the characteristics of each of the \nfour receptor superfamilies.\nTYPE 1: LIGAND-GATED ION CHANNELS\nThe nicotinic acetylcholine receptor, which we find at the skeletal neuromuscular junction (Ch. 14), in autonomic \nganglia (Ch. 14) and in the brain (Ch. 40), is a typical example \nof a ligand-gated ion channel, known as the cys-loop recep -\ntors (so called because they have in their structure a large \nintracellular domain between transmembrane domains 3 \nand 4 containing multiple cysteine residues [see Fig. 3.3A]). \nOthers\tof\tthis\ttype\tinclude\tthe\tGABA A and glycine receptors \n(Ch. 39) as well as the 5-hydroxytryptamine type 3 (5-HT 3; \nChs\t16\tand \t40) \treceptor. \tOther \ttypes \tof \tligand-gated \tion \tDNA-binding\ndomain(\u2018zinc fingers\u2019)Catalytic\ndomainBindingdomainsChannel\nliningx 4 or 5Bindingdomain\nG", "start_char_idx": 0, "end_char_idx": 3594, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7620fd55-2d65-488f-bcfb-7b4312cb4346": {"__data__": {"id_": "7620fd55-2d65-488f-bcfb-7b4312cb4346", "embedding": null, "metadata": {"page_label": "33", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4cb59c6c-a42e-4926-a599-79e0f620549e", "node_type": null, "metadata": {"page_label": "33", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61bf9e2c87a26ca71e62c110f398c0df4de2e2340ef348b2a0634ae509a81ba3"}, "2": {"node_id": "5cecb105-81e8-43ab-8f17-af9d287dd9d4", "node_type": null, "metadata": {"page_label": "33", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "380c51f09e427bd194be3528963bb270149f2a82f9f6151c4b25ddb93865d746"}}, "hash": "b87186cbf5b544387d3aebaa1c1d2fa36a35affdccfd978ef681475747c87923", "text": "4 or 5Bindingdomain\nG protein\u2212 \ncoupling \ndomain\nBindingdomain\nBinding\ndomainA\nB\nC\nDType 3\nKinase-linked \nreceptors\nType 4\nNuclear \nreceptorsType 1\nLigand-gated\nion channels\n(ionotropic \nreceptors)\nType 2\nG protein\u2212\ncoupled \nreceptors\n(metabotropic \nreceptors)N\nC\nN\nC\nNCN\nC\nFig. 3.3 General structure of four receptor families. The \nrectangular segments represent hydrophobic \u03b1-helical regions of \nthe protein comprising approximately 20 amino acids, which \nform the membrane-spanning domains of the receptors. The pink shaded areas illustrate the region of the orthosteric ligand-binding domains. (A) Type 1: ligand-gated ion channels. The example illustrated here shows the subunit structure of the nicotinic acetylcholine receptor. The subunit structure of other ligand-gated ion channels is shown in Fig. 3.5. Many ligand-gated ion channels comprise four or five subunits of the type shown, the whole complex containing 16\u201320 membrane-spanning segments surrounding a central ion channel. (B) Type 2: G protein\u2013coupled receptors (GPCRs). The two ligand-binding domains shown illustrate the position of the orthosteric ligand-binding domains on different types of GPCRs, there would be only one on each GPCR. (C) Type 3: kinase-linked receptors. Most growth factor receptors incorporate the ligand-binding and enzymatic (kinase) domains in the same molecule, as shown, whereas cytokine receptors lack an \nintracellular kinase domain but link to cytosolic kinase molecules. Other structural variants also exist. (D) Type 4: nuclear receptors that control gene transcription. \n6Receptors for 5-hydroxytryptamine (see Ch. 16) are currently the \nchampions with respect to diversity, with 13 subtypes of GPCR and 1 \nligand-gated ion channel all responding to the same endogenous ligand.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3573, "end_char_idx": 5838, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c325d348-aca5-4088-84fc-79fbc7bb1b57": {"__data__": {"id_": "c325d348-aca5-4088-84fc-79fbc7bb1b57", "embedding": null, "metadata": {"page_label": "34", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5d4fab5-43ca-4deb-9c4c-591c001796a8", "node_type": null, "metadata": {"page_label": "34", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c739c4acd66605f91be348560c2308ecf0e36ce1f66d6596f2825aec4a55f245"}, "3": {"node_id": "3ce57e86-632b-4989-9dca-7e777ecd5a48", "node_type": null, "metadata": {"page_label": "34", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06718980834506961c7772e681eaacfca6907fb5e8d26427adb08df2336fb235"}}, "hash": "9b44552559f053e2ecff7c6def746ba2ed3fafdfb659a89c1b2715ad5a600a13", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n28channel exist \u2013 namely ionotropic glutamate receptors (Ch. \n39) and purinergic P2X receptors (Chs 17 and 40) that differ \nin several respects from the nicotinic acetylcholine receptor \n(see Fig. 3.5). In addition to the ligand-gated ion channels found on the cell membrane that mediate fast synaptic \ntransmission, there are also intracellular ligand-gated ion \nchannels \u2013 namely the inositol trisphosphate (IP\n3) and \nryanodine receptors (see Ch. 4) that release Ca2+ from \nintracellular stores.\nMOLECULAR \u2003STRUCTURE\nLigand-gated ion channels have structural features in common with other ion channels, described on p. 46. The \nnicotinic acetylcholine receptor cloned from the Torpedo \nelectric ray (Fig. 3.4),\n7 consists of a pentameric assembly \nof different subunits, of which there are four types, termed \n\u03b1, \u03b2, \u03b3 and \u03b4, each of molecular weight (M r) 40\u201358 kDa. \nThe subunits show marked sequence homology, and each \ncontains four membrane-spanning \u03b1-helices, inserted into \nthe membrane as shown in Fig. 3.4B. The pentameric structure (\u03b1\n2, \u03b2, \u03b3, \u03b4) possesses two acetylcholine binding \nsites, each lying at the interface between one of the two \u03b1 \nsubunits and its neighbour. Both must bind acetylcholine molecules for the receptor to be activated. Fig. 3.4B shows the receptor structure. Each subunit spans the membrane \nfour times, so the channel comprises no fewer than 20 \nmembrane-spanning helices surrounding a central pore.\n\u25bc\tOne\tof\tthe \ttransmembrane \thelices \t(M 2) from each of the five subunits \nforms the lining of the ion channel (see Fig. 3.4). The five M 2 helices \nthat form the pore are sharply kinked inwards halfway through the \nmembrane, forming a constriction. When acetylcholine molecules \nbind, a conformation change occurs in the extracellular part of the receptor, which twists the \u03b1 subunits, causing the kinked M\n2 segments \nto swivel out of the way, thus opening the channel. The channel \nlining contains a series of anionic residues, making the channel \nselectively permeable to cations (primarily Na+ and K+, although some \ntypes of nicotinic receptor are permeable to Ca2+ as well).\nThe use of site-directed mutagenesis, which enables short regions, or single residues, of the amino acid sequence to be altered, has shown that a mutation of a critical residue in the M\n2 helix changes \nthe channel from being cation permeable (hence excitatory in the \ncontext of synaptic function) to being anion permeable (typical of \nreceptors \tfor\tinhibitory \ttransmitters \tsuch\tas\tGABA\tand\tglycine).\tOther\t\nmutations affect properties such as gating and desensitisation of \nligand-gated channels.\nOther\tligand-gated \tion \tchannels, \tsuch \tas \tglutamate \treceptors \t(see \t\nCh. 39) and P2X receptors (see Chs 17 and 40), whose structures are shown in Fig. 3.5, have a different architecture. Ionotropic glutamate \nreceptors are tetrameric and the pore is built from loops rather than \ntransmembrane helices, in common with many other (non-ligand-gated) ion channels (see Fig. 3.20). P2X receptors are trimeric and each subunit \nhas only two transmembrane domains (North, 2002). The nicotinic \nreceptor and other cys-loop receptors are pentamers with two agonist binding sites on each receptor. Binding of one", "start_char_idx": 0, "end_char_idx": 3269, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3ce57e86-632b-4989-9dca-7e777ecd5a48": {"__data__": {"id_": "3ce57e86-632b-4989-9dca-7e777ecd5a48", "embedding": null, "metadata": {"page_label": "34", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5d4fab5-43ca-4deb-9c4c-591c001796a8", "node_type": null, "metadata": {"page_label": "34", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c739c4acd66605f91be348560c2308ecf0e36ce1f66d6596f2825aec4a55f245"}, "2": {"node_id": "c325d348-aca5-4088-84fc-79fbc7bb1b57", "node_type": null, "metadata": {"page_label": "34", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9b44552559f053e2ecff7c6def746ba2ed3fafdfb659a89c1b2715ad5a600a13"}}, "hash": "06718980834506961c7772e681eaacfca6907fb5e8d26427adb08df2336fb235", "text": "are pentamers with two agonist binding sites on each receptor. Binding of one agonist molecule to \none site increases the affinity of binding at the other site (positive \ncooperativity) and both sites need to be occupied for the receptor to \nbe activated and the channel to open. Some ionotropic glutamate \nreceptors have as many as four agonist binding sites and P2X receptors have three, but they appear to open when two agonist molecules are \nbound.\tOnce \tagain \twe \trealise \tthat \tthe \tsimple \tmodel \tof \treceptor \t\nA\nACh\nAChAChACh\u03b1\n\u03b1\n\u03b3\u03b1\u03b2\u03b4\u03b1\u03b2\u03b4\nExterior\nMembrane\nCytosol\n\u03b1-Helices forming gate6 nm\n3 nm\n2 nm\nPore ~0.7 nm\ndiameter\nB\nFig. 3.4 Structure of the nicotinic acetylcholine receptor \n(a typical ligand-gated ion channel). (A) Schematic diagram in \nside view (upper) and plan view (lower). The five receptor \nsubunits (\u03b1 2, \u03b2, \u03b3, \u03b4) form a cluster surrounding a central \ntransmembrane pore, the lining of which is formed by the M 2 \nhelical segments of each subunit. These contain a \npreponderance of negatively charged amino acids, which makes the pore cation selective. There are two acetylcholine binding sites in the extracellular portion of the receptor, at the interface between the \u03b1 and the adjoining subunits. When acetylcholine \nbinds, the kinked \u03b1-helices either straighten out or swing out of \nthe way, thus opening the channel pore. (B) High-resolution image showing revised arrangement of intracellular domains. (Panel [A] based on Unwin, N., 1993. Nicotinic acetylcholine receptor at 9\u00c5 resolution. J. Mol. Biol. 229, 1101\u20131124, and Unwin, N., 1995. Acetylcholine receptor channel imaged in the open state. Nature 373, 37\u201343; panel [B] reproduced with permission from Unwin, N., 2005. Refined structure of the nicotinic acetylcholine receptor at 4\u00c5 resolution. J. Mol. Biol. 346(4), 967\u2013989.)\n7In early studies the Torpedo electric ray was used to isolate and purify \nthe nicotinic receptor as it expresses a very high density of nicotinic \nreceptors on its electroplaques. We now realise that the subunit \ncompositions of the mammalian neuromuscular (Ch. 14) and neuronal (Chs 14 and 40) nicotinic receptors are different from that of the \nTorpedo but here we focus on the Torpedo receptor to keep it simple.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3192, "end_char_idx": 5907, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "06ed5854-dea8-4204-bd5c-dc1c943afe6c": {"__data__": {"id_": "06ed5854-dea8-4204-bd5c-dc1c943afe6c", "embedding": null, "metadata": {"page_label": "35", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "55c91041-228c-4727-9678-2d870c3dfe37", "node_type": null, "metadata": {"page_label": "35", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8dfb66b9d7976f45f28f5757fef11fbd9fd7d0befe221f78ff8b6643d49b8cf6"}, "3": {"node_id": "df6268ff-7dc2-46a1-9385-63e1a97ed69e", "node_type": null, "metadata": {"page_label": "35", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cab922fbfbf6df9e38b7c4d73b878fa34021fbe9c03de1bdaf78f70241286f7a"}}, "hash": "9e1b3a274a253146029d7567f7552ecbecb6f52d289cab9fa3a9b0bff6580218", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n29activation shown in Fig. 2.1 is an oversimplification as it only con -\nsidered one agonist molecule binding to produce a response. For two \nor more agonist molecules binding, more complex mathematical \nmodels are needed (see Colquhoun, 2006).\nTHE\u2003GATING \u2003MECHANISM\nReceptors of this type control the fastest synaptic events \nin the nervous system, in which a neurotransmitter acts \non the postsynaptic membrane of a nerve or muscle cell \nand transiently increases its permeability to particular ions. Most excitatory neurotransmitters, such as acetylcholine \nat the neuromuscular junction (Ch. 14) or glutamate in the \ncentral nervous system (Ch. 39), cause an increase in Na\n+ \nand K+ permeability and in some instances Ca2+ permeability. \nAt negative membrane potentials this results in a net inward \ncurrent carried mainly by Na+, which depolarises the cell \nand increases the probability that it will generate an action potential. The action of the transmitter reaches a peak in \na fraction of a millisecond, and usually decays within a few milliseconds. The sheer speed of this response implies \nthat the coupling between the receptor and the ion channel \nis a direct one, and the molecular structure of the receptor\u2013channel complex (see earlier) agrees with this. In contrast \nto other receptor families, no intermediate biochemical steps \nare involved in the transduction process.\n\u25bc The patch clamp recording technique , devised by Neher and Sakmann, \nallows the very small current flowing through a single ion channel \nto be measured directly (Fig. 3.6). The patch clamp technique provides \na view, rare in biology, of the physiological behaviour of individual protein molecules in real time, and has given many new insights into \nthe gating reactions and permeability characteristics of both ligand-\ngated channels and voltage-gated channels. The magnitude of the single channel conductance confirms that permeation occurs through \na physical pore through the membrane, because the ion flow is too \nlarge (about 10\n7 ions per second) to be compatible with a carrier \nmechanism. The channel conductance produced by different agonists \nis the same, whereas the mean channel lifetime varies. The ligand\u2013\nreceptor interaction scheme shown in Chapter 2 is a useful model for ion-channel gating. The conformation R*, representing the open \nstate of the ion channel, is thought to be the same for all agonists, \naccounting for the finding that the channel conductance does not vary. Kinetically, the mean open time is determined mainly by the \nclosing rate constant, \u03b1, and this varies from one drug to another. \nAs explained in Chapter 2 (see Fig. 2.1), an agonist of high efficacy \nthat activates a large proportion of the receptors that it occupies will N\nCCalcium release type\nN\nCN\nCIonotropic\nglutamate type\n(pentameric assembly) (tetrameric assembly) (tetrameric assembly)Example: IP 3R, RyR\n(trimeric assembly)Examples: NMDA Examples: nAChR, GABA A,\n5-HT 3Cys-loop type\nExample: P2XRP2X type\nFig. 3.5 Molecular architecture of ligand-gated ion channels. Red and blue rectangles represent membrane-spanning \u03b1-helices and \nblue hairpins represent the P loop pore-forming regions. 5-HT 3, 5-hydroxytryptamine type 3 receptor; GABA A, GABA type A receptor; I P3R, \ninositol trisphosphate receptor; nAChR, nicotinic acetylcholine receptor; NMDA, N-methyl-D-aspartatic acid receptor; P2XR, purine P2X \nreceptor; RyR, ryanodine receptor. \nbe characterised by", "start_char_idx": 0, "end_char_idx": 3509, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "df6268ff-7dc2-46a1-9385-63e1a97ed69e": {"__data__": {"id_": "df6268ff-7dc2-46a1-9385-63e1a97ed69e", "embedding": null, "metadata": {"page_label": "35", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "55c91041-228c-4727-9678-2d870c3dfe37", "node_type": null, "metadata": {"page_label": "35", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8dfb66b9d7976f45f28f5757fef11fbd9fd7d0befe221f78ff8b6643d49b8cf6"}, "2": {"node_id": "06ed5854-dea8-4204-bd5c-dc1c943afe6c", "node_type": null, "metadata": {"page_label": "35", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e1b3a274a253146029d7567f7552ecbecb6f52d289cab9fa3a9b0bff6580218"}}, "hash": "cab922fbfbf6df9e38b7c4d73b878fa34021fbe9c03de1bdaf78f70241286f7a", "text": "\nreceptor; RyR, ryanodine receptor. \nbe characterised by \u03b2/\u03b1 \u226b 1, whereas for a drug of low efficacy \u03b2/\u03b1 \nhas a lower value.\nAt some ligand-gated ion channels the situation is more complicated \nbecause different agonists may cause individual channels to open to \none or more of several distinct conductance levels (see Fig. 3.6B). \nThis implies that there is more than one R* conformation. Furthermore, desensitisation of ligand-gated ion channels (see Ch. 2) also involves \none or more additional agonist-induced conformational states. These \nfindings necessitate some elaboration of the simple scheme in which only a single open state, R*, is represented, and are an example of \nthe way in which the actual behaviour of receptors makes our theoreti -\ncal models look a little threadbare.\nLigand-gated ion channels \n\u2022\tThese\tare \tsometimes \tcalled \tionotropic \treceptors.\n\u2022\tThey\tare \tinvolved \tmainly \tin \tfast \tsynaptic \ttransmission.\n\u2022\tThere\tare \tseveral \tstructural \tfamilies, \tthe \tcommonest \t\nbeing heteromeric assemblies of four or five subunits, \nwith transmembrane helices arranged around a central aqueous channel.\n\u2022\tLigand\tbinding \tand \tchannel \topening \toccur \ton \ta \t\nmillisecond timescale.\n\u2022\tExamples \tinclude \tthe \tnicotinic \tacetylcholine, \tGABA \t\ntype A (GABA A), glutamate (e.g. N-methyl-D-aspartatic \nacid receptor [NMDA]) and ATP (P2X) receptors.\nTYPE 2: G PROTEIN\u2013COUPLED RECEPTORS\nGPCRs constitute the commonest single class of targets for \ntherapeutic drugs. The GPCR family comprises many of \nthe receptors that are familiar to pharmacologists, such as \nmuscarinic AChRs, adrenoceptors, dopamine receptors, 5-HT (serotonin) receptors, receptors for many peptides, \npurine receptors and many others, including the chemo-\nreceptors involved in olfaction and pheromone detection, and also many \u2018orphans\u2019 (see Fredriksson & Schi\u00f6th, 2005). \nFor most of these, pharmacological and molecular studies \nhave revealed a variety of subtypes. All have the charac -\nteristic heptahelical structure (see Fig. 3.3B).\nMany neurotransmitters, apart from peptides, can interact \nwith both GPCRs and ligand-gated channels, allowing the mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3453, "end_char_idx": 6073, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "981d003f-d847-46c2-ad6d-69f608dcb9da": {"__data__": {"id_": "981d003f-d847-46c2-ad6d-69f608dcb9da", "embedding": null, "metadata": {"page_label": "36", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "527c6d2f-0cab-4005-b34e-3c682253eb52", "node_type": null, "metadata": {"page_label": "36", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "abc951c5d68f83213119ba822ca232ca4f21c69dfbb53b56b14f61cea4b46f7e"}, "3": {"node_id": "6fb0c097-7282-4629-8011-94a8a0990350", "node_type": null, "metadata": {"page_label": "36", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f6ddc38ac426284b63682fee720f1702887e84e8f02396f268bce23b52b1667"}}, "hash": "d6c1aa41a68765499f52e110045b10f5a0bcbcef0e2fb981d719cf8af34e1e1e", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n30biology caught up very rapidly with pharmacology, and \nwith the sequencing of the human genome the amino acid \nsequence of all the GPCRs hitherto identified by their \npharmacological properties was revealed, as was the struc -\nture of many novel GPCRs. More recently the difficulties \nof crystallising GPCRs have been overcome, allowing the \nuse of the powerful technique of X-ray crystallography to study the three-dimensional molecular structure of these \nreceptors in detail (Fig. 3.7) (Zhang et al., 2015). Also, \ncomputational molecular docking and nuclear magnetic resonance (NMR) methods have been developed to study \nligand binding and subsequent conformational changes \nassociated with activation (see Sounier et al., 2015). This \nis starting to provide important information on agonist- \nand antagonist-bound receptor conformations as well as \nreceptor\u2013G protein interactions. From such studies we are \ngaining a clearer picture of the mechanism of activation of GPCRs and the factors determining agonist efficacy, as well \nas having a better basis for designing new GPCR ligands.\nGPCRs consist of a single polypeptide chain, usually of \n350\u2013400 amino acid residues, but in some cases up to 1100 residues. The general anatomy is shown in Fig. 3.3B. Their \ncharacteristic structure comprises seven transmembrane \u03b1-helices, similar to those of the ion channels discussed previously, with an extracellular N-terminal domain of \nvarying length, and an intracellular C-terminal domain.\nGPCRs are divided into three main classes \u2013 A, B and \nC (Table 3.2). There is considerable sequence homology between the members of one class, but little between dif -\nferent classes. They share the same seven transmembrane \nhelix (heptahelical) structure, but differ in other respects, \nprincipally in the length of the extracellular N-terminus \nand the location of the agonist binding domain. Class A is by far the largest, comprising most monoamine, neuropep -\ntide and chemokine receptors. Class B includes receptors for some other peptides, such as calcitonin and glucagon. Class C is the smallest, its main members being the 10 ms3 pA\n20 ms2 pA0\n1\n2\n18 pS\n38 pS\nNumber of open channelsConductance statesNicotinic acetylcholine channel openings\nNMDA channel openingsA\nB\nFig. 3.6 Single channel openings recorded by the patch \nclamp technique. (A) Acetylcholine-operated ion channels at \nthe frog motor endplate. The pipette, which was applied tightly \nto the surface of the membrane, contained 10 \u00b5mol/L\tACh. \tThe \t\ndownward deflections show the currents flowing through single \nion channels in the small patch of membrane under the pipette tip. Towards the end of the record, two channels can be seen to open with a discrete step from the first to the second. (B) Single-channel N-methyl-D-aspartic acid receptor (NMDA) \nreceptor currents recorded from cerebellar neurons in the outside-out patch conformation. NMDA was added to the outside of the patch to activate the channel. The channel opens to multiple conductance levels. In (B) the openings to the higher conductance level and the subsequent closings are smooth, indicating that one channel is opening (two channels would not be expected to open and close simultaneously) whereas in (A) there are discrete steps indicating two channels. (Panel [A] courtesy D. Colquhoun and D.C. Ogden; panel [B] reproduced with permission from Cull-Candy, S.G. & Usowicz, M.M., 1987. Nature 325, 525\u2013528.)Cell exteriorPositive allosteri", "start_char_idx": 0, "end_char_idx": 3516, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6fb0c097-7282-4629-8011-94a8a0990350": {"__data__": {"id_": "6fb0c097-7282-4629-8011-94a8a0990350", "embedding": null, "metadata": {"page_label": "36", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "527c6d2f-0cab-4005-b34e-3c682253eb52", "node_type": null, "metadata": {"page_label": "36", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "abc951c5d68f83213119ba822ca232ca4f21c69dfbb53b56b14f61cea4b46f7e"}, "2": {"node_id": "981d003f-d847-46c2-ad6d-69f608dcb9da", "node_type": null, "metadata": {"page_label": "36", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6c1aa41a68765499f52e110045b10f5a0bcbcef0e2fb981d719cf8af34e1e1e"}}, "hash": "0f6ddc38ac426284b63682fee720f1702887e84e8f02396f268bce23b52b1667", "text": "1987. Nature 325, 525\u2013528.)Cell exteriorPositive allosteri c\nmodulator\nAgonistMembrane\nCell interior\nFig. 3.7 Structure of the M 2 muscarinic receptor. High-\nresolution image showing the conformation of the M 2 muscarinic \nreceptor bound with both an agonist (orthosteric) and a positive \nallosteric modulator. The brown cylinders represent the \ntransmembrane domains. The full extent of the N- and \nC-terminal domains and the third intracellular loop are not \nshown. (Courtesy A. Christopoulos.)\n8Examples of promiscuity are increasing, however. Steroid hormones, \nnormally faithful to nuclear receptors, make the occasional pass at ion \nchannels and GPCRs, and some eicosanoids act on nuclear receptors as \nwell as GPCRs. Nature is quite open-minded, although such examples are liable to make pharmacologists frown and students despair.same molecule to produce fast (through ligand-gated ion \nchannels) and relatively slow (through GPCRs) effects. \nIndividual peptide hormones, however, generally act either \non GPCRs or on kinase-linked receptors (see later), but rarely on both, and a similar choosiness applies to the many \nligands that act on nuclear receptors.\n8\nMOLECULAR \u2003STRUCTURE\nIn 1986 the first pharmacologically relevant GPCR, the \u03b22 \nadrenoceptor (Ch. 15), was cloned. Thereafter molecular mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3458, "end_char_idx": 5245, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "89e46253-0a75-48a5-84f2-167cdd23d5b7": {"__data__": {"id_": "89e46253-0a75-48a5-84f2-167cdd23d5b7", "embedding": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fb79c280-38f0-4153-958c-ae079cb40282", "node_type": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1814f66775cc437e9fcb32d3df0e77ad98b03631bc264c069f0c0a9099c06cfa"}, "3": {"node_id": "5e330533-63cb-4e93-9b12-994ab7f3ae66", "node_type": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "64ff8ab5985b815f6af30f6a8630c5fc04db5ef170e3f194c6f2e5144424647f"}}, "hash": "58f84643d2d0530f689d0613e77b49719256b077d7a008eaf434b645262cb42d", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n31PROTEINASE-ACTIVATED \u2003RECEPTORS12\n\u25bc Although activation of GPCRs is normally the consequence of a dif -\nfusible agonist, it can be the result of proteinase activation. Four types \nof protease-activated receptors (PARs) have been identified (see review \nby Ramachandran et al., 2012). Many proteinases, such as thrombin (a \nproteinase involved in the blood-clotting cascade; see Ch. 25), activate \nPARs by snipping off the end of the extracellular N-terminal tail of \nthe receptor (Fig. 3.8) to expose five or six N-terminal residues that \nbind to receptor domains in the extracellular loops, functioning as a \u2018tethered agonist\u2019. Receptors of this type occur in many tissues and \nthey appear to play a role in inflammation and other responses to \ntissue damage where tissue proteinases are released. A PAR molecule can be activated only once, because the cleavage cannot be reversed, \nand thus continuous resynthesis of the receptor protein is necessary. \nInactivation occurs by a further proteolytic cleavage that frees the \ntethered ligand, or by desensitisation, involving phosphorylation (see \nFig. 3.8), after which the receptor is internalised and degraded, to be replaced by newly synthesised protein.metabotropic glutamate and GABA receptors, and the \nCa2+-sensing receptors.9\n\u25bc The understanding of the function of receptors of this type owes \nmuch to studies of a closely related protein, rhodopsin, which is \nresponsible for transduction in retinal rods. This protein is abundant \nin the retina, and much easier to study than receptor proteins (which \nare anything but abundant); it is built on an identical plan to that shown in Fig. 3.3B and also produces a response in the rod (hyperpo -\nlarisation, associated with inhibition of Na\n+ conductance) through a \nmechanism involving a G protein (see p. 32, Fig. 3.9). The most obvious \ndifference is that a photon, rather than an agonist molecule, produces \nthe response. In effect, rhodopsin can be regarded as incorporating its own inbuilt agonist molecule, namely retinal, which isomerises from \nthe trans (inactive) to the cis (active) form when it absorbs a photon.\nFor small molecules, such as noradrenaline (norepinephrine) \nand acetylcholine, the ligand-binding domain of class A \nreceptors is buried in the cleft between the \u03b1-helical segments \nwithin the membrane (see Figs 3.3B and 3.7), similar to the \nslot occupied by retinal in the rhodopsin molecule.10 Peptide \nligands, such as substance P (Ch. 19), bind more superficially \nto the extracellular loops, as shown in Fig. 3.3B. From crystal \nstructures and single-site mutagenesis experiments, it is possible to map the ligand-binding domain of these receptors. \nRecent advances in computational molecular docking of \nligands into the ligand\u2013receptor-binding domain have made it possible to design novel synthetic ligands based primarily \non knowledge of the receptor structure (see Manglik et al., \n2016) \u2013 an important milestone in drug development, which has relied up to now mainly on the structure of endogenous \nmediators (such as histamine) or plant alkaloids (such as \nmorphine) for its chemical inspiration.\n11\n11In the past many lead compounds have come from screening huge \nchemical libraries (see Ch. 60). No inspiration was required, just robust \nassays, large computers and efficient robotics. Now with the generation \nof crystal structures we have moved to a more sophisticated age in drug", "start_char_idx": 0, "end_char_idx": 3478, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5e330533-63cb-4e93-9b12-994ab7f3ae66": {"__data__": {"id_": "5e330533-63cb-4e93-9b12-994ab7f3ae66", "embedding": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fb79c280-38f0-4153-958c-ae079cb40282", "node_type": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1814f66775cc437e9fcb32d3df0e77ad98b03631bc264c069f0c0a9099c06cfa"}, "2": {"node_id": "89e46253-0a75-48a5-84f2-167cdd23d5b7", "node_type": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "58f84643d2d0530f689d0613e77b49719256b077d7a008eaf434b645262cb42d"}, "3": {"node_id": "2c7fdf7b-a6e2-4be3-8b01-08cbc46c2979", "node_type": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "32601e5eac72f7465a5ee4c915811b0cb97d8e53e6eb323f947bc84fe7c685b3"}}, "hash": "64ff8ab5985b815f6af30f6a8630c5fc04db5ef170e3f194c6f2e5144424647f", "text": "\nof crystal structures we have moved to a more sophisticated age in drug discovery.9The Ca2+-sensing receptor (see Conigrave et al., 2000) is an unusual \nGPCR that is activated not by conventional mediators, but by extracellular Ca\n2+ in the range of 1\u201310 mmol/L \u2013 an extremely low \naffinity in comparison with other GPCR agonists. It is expressed by cells of the parathyroid gland, and serves to regulate the extracellular Ca\n2+ \nconcentration by controlling parathyroid hormone secretion (Ch. 37). \nThis homeostatic mechanism is quite distinct from the mechanisms for \nregulating intracellular Ca2+, discussed in Chapter 4.\n10Hydrophilic small molecules access their ligand-binding domain from \nthe extracellular space down the water-filled cleft, however for highly \nlipophilic molecules such as those activating the cannabinoid CB 1 and \nlysophospholipid S1P 1 receptors access appears to be through a \nmembrane-embedded access channel in the side of the receptor.Table 3.2 Main G protein\u2013coupled receptor classesa,b\nClass ReceptorsbStructural features\nA: rhodopsin family The largest group. Receptors for most amine \nneurotransmitters, many neuropeptides, purines, prostanoids, cannabinoids, etc.Short extracellular (N-terminal) tail.Ligand binds to transmembrane helices (amines) or to extracellular loops (peptides)\nB: secretin/glucagon receptor familyReceptors for peptide hormones, including secretin, glucagon, calcitoninIntermediate extracellular tail incorporating ligand-binding domain\nC: metabotropic glutamate receptor/calcium sensor familySmall group. Metabotropic glutamate receptors, GABA\nB receptors, Ca2+-sensing receptorsLong extracellular tail incorporating ligand-binding domain\naOther classes include frizzled G protein\u2013coupled receptors (GPCRs), adhesion GPCRs and receptors for pheromones.\nbFor full lists, see .\nG protein\u2013coupled receptors \n\u2022\tThese\tare \tsometimes \tcalled \tmetabotropic \tor \tseven-\ntransmembrane-domain (7-TDM) receptors.\n\u2022\tStructures \tcomprise \tseven \tmembrane-spanning \t\n\u03b1-helices.\n\u2022\tThe\tG\tprotein \tis \ta \tmembrane \tprotein \tcomprising \tthree \t\nsubunits (\u03b1, \u03b2, \u03b3), the \u03b1 subunit possessing GTPase \nactivity.\n\u2022\tThe\tG\tprotein \tinteracts \twith \ta \tbinding \tpocket \ton \tthe \t\nintracellular surface of the receptor.\n\u2022\tWhen\tthe \tG \tprotein \tbinds \tto \tan \tagonist-occupied \t\nreceptor, the \u03b1 subunit binds GTP, dissociates and is \nthen free to activate an effector (e.g. a membrane enzyme). In some cases, the \u03b2\u03b3 subunit is the activator \nspecies.\n\u2022\tActivation \tof \tthe \teffector \tis \tterminated \twhen \tthe \tbound \t\nGTP molecule is hydrolysed, which allows the \u03b1 \nsubunit to recombine with \u03b2\u03b3.\n\u2022\tThere\tare \tseveral \ttypes \tof \tG \tprotein, \twhich \tinteract \t\nwith different receptors and control different effectors.\n\u2022\tExamples \tinclude \tmuscarinic \tacetylcholine \treceptors, \t\nadrenoceptors, neuropeptide and chemokine receptors, and proteinase-activated receptors.\n12These receptors were formerly called protease-activated receptors.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3419, "end_char_idx": 6598, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2c7fdf7b-a6e2-4be3-8b01-08cbc46c2979": {"__data__": {"id_": "2c7fdf7b-a6e2-4be3-8b01-08cbc46c2979", "embedding": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fb79c280-38f0-4153-958c-ae079cb40282", "node_type": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1814f66775cc437e9fcb32d3df0e77ad98b03631bc264c069f0c0a9099c06cfa"}, "2": {"node_id": "5e330533-63cb-4e93-9b12-994ab7f3ae66", "node_type": null, "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "64ff8ab5985b815f6af30f6a8630c5fc04db5ef170e3f194c6f2e5144424647f"}}, "hash": "32601e5eac72f7465a5ee4c915811b0cb97d8e53e6eb323f947bc84fe7c685b3", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6611, "end_char_idx": 6962, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "17223ed0-8791-44f3-a9a7-b6fc5c0545c6": {"__data__": {"id_": "17223ed0-8791-44f3-a9a7-b6fc5c0545c6", "embedding": null, "metadata": {"page_label": "38", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f09c85dc-6142-46ba-8ddc-c342c8587af8", "node_type": null, "metadata": {"page_label": "38", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eeca4e888bbc7579470e7ebcffe007d38013aef8217a1ea56a48bc16738229cd"}}, "hash": "eeca4e888bbc7579470e7ebcffe007d38013aef8217a1ea56a48bc16738229cd", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n32ACTIVE DESENSITISEDN\nCleavage by thrombin\nINACTIVENNTethered agonist\nPhosphorylationReleased\nfragment\nPN\nFig. 3.8 Activation of a proteinase-activated receptor by cleavage of the N-terminal extracellular domain. Inactivation occurs by \nphosphorylation. Recovery requires resynthesis of the receptor. \nG\u2003PROTEINS \u2003AND \u2003THEIR \u2003ROLE\nG proteins comprise a family of membrane-resident proteins \nwhose function is to respond to GPCR activation and pass \non the message inside the cell to the effector systems that \ngenerate a cellular response. They represent the level of middle management in the organisational hierarchy, \nintervening between the receptors \u2013 choosy mandarins, \nalert to the faintest whiff of their preferred chemical \u2013 and \nthe\teffector \tenzymes \tor \tion \tchannels \t\u2013 \tthe \tblue-collar \tbrigade\t\nthat gets the job done without needing to know which hormone authorised the process. They are the go-between Receptor\nGDP GDP\nGDP\nP+GTP\nGTPResting state\nTarget proteins\nactivated\u03b2\u03b3\u03b1\u03b2\u03b3\n\u03b2\u03b3\u03b1\u03b2\u03b3\u03b1Target\n1Target\n2\nTarget\n2Receptor occupied by agonist\nInactive Inactive\nActive Active Active ActiveInactive Inactive\nGTP hydrolysedTarget\n1Target\n2\nTarget\n1Target\n2\u03b1\nTarget\n1\nFig. 3.9 The function of the G protein. The G protein consists of three subunits ( \u03b1, \u03b2, \u03b3), which are anchored to the membrane through \nattached lipid residues. Coupling of the \u03b1 subunit to an agonist-occupied receptor causes the bound GDP to exchange with intracellular \nGTP; the \u03b1\u2013GTP complex then dissociates from the receptor and from the \u03b2\u03b3 complex, and interacts with a target protein (target 1, which \nmay be an enzyme, such as adenylyl cyclase or phospholipase C). The \u03b2\u03b3 complex also activates a target protein (target 2, which may be \nan ion channel or a kinase). The GTPase activity of the \u03b1 subunit is increased when the target protein is bound, leading to hydrolysis of the \nbound GTP to GDP, whereupon the \u03b1 subunit reunites with \u03b2\u03b3. \nproteins, but were actually called G proteins because of their interaction with the guanine nucleotides, GTP and \nGDP. For more detailed information on the structure and \nfunctions of G proteins, see reviews by Milligan and Kostenis \n(2006),\tand \tOldham \tand \tHamm \t(2008). \tG \tproteins \tconsist \t\nof three subunits: \u03b1, \u03b2 and \u03b3 (Fig. 3.9). Guanine nucleotides \nbind to the \u03b1\tsubunit,\twhich\thas\tenzymic\t(GTPase) \tactivity,\t\ncatalysing the conversion of GTP to GDP. The \u03b2 and \u03b3 \nsubunits remain together as a \u03b2\u03b3 complex. The \u2018\u03b3\u2019 subunit \nis anchored to the membrane through a fatty acid chain, coupled to the G protein through a reaction known as prenylation . In the \u2018resting\u2019 state (see Fig. 3.9), the G protein mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3156, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c86dad7a-35a1-462c-bb53-b7f3e54921fc": {"__data__": {"id_": "c86dad7a-35a1-462c-bb53-b7f3e54921fc", "embedding": null, "metadata": {"page_label": "39", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fa9b5a90-45f5-4956-9716-f57f56afa41f", "node_type": null, "metadata": {"page_label": "39", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a10506e84c91914e296409283e66a665e5b9b5e244e28fb9c81a7cef747891b3"}, "3": {"node_id": "883f004b-be84-454b-8906-3bccc985c7ad", "node_type": null, "metadata": {"page_label": "39", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c5da70180a96fce60606bd74c8abda6d93608ae9de15123f01d213575474dc4"}}, "hash": "45509241ac958b0f6ed00d2e7a31b58d06da1656b08e961d29d5a1fe42b9781f", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n33Signalling is terminated when the hydrolysis of GTP to \nGDP occurs through the inherent GTPase activity of the \u03b1 \nsubunit. The resulting \u03b1\u2013GDP then dissociates from the \neffector, and reunites with \u03b2\u03b3, completing the cycle.\n\u25bc Attachment of the \u03b1 subunit to an effector molecule actually \nincreases its GTPase activity, the magnitude of this increase being \ndifferent for different types of effector. Because GTP hydrolysis is \nthe step that terminates the ability of the \u03b1 subunit to produce its \neffect, regulation of its GTPase activity by the effector protein means \nthat the activation of the effector tends to be self-limiting. In addition, \nthere is a family of about 20 cellular proteins, regulators of G protein signalling (RGS) proteins (see review by Sj\u00f6gren, 2017), that possess \na conserved sequence that binds specifically to \u03b1 subunits to increase \ngreatly their GTPase activity, so hastening the hydrolysis of GTP and inactivating the complex. RGS proteins thus exert an inhibitory effect \non G protein signalling, a mechanism that is thought to have a regula -\ntory function in many situations.\nDifferent GPCRs couple to different G proteins and thus \nproduce distinct cellular responses. For example, M 2 mus -\ncarinic acetylcholine receptors (mAChRs) and \u03b21 adrenocep -\ntors, both of which occur in cardiac muscle cells, produce \nopposite functional effects (Chs 14 and 15). Four main classes \nof G protein (G s, G i, G o and G q) are of pharmacological \nimportance (Table 3.3). These differ primarily in the \u03b1 \nsubunit they contain.13 G proteins show selectivity with exists as an \u03b1 \u03b2\u03b3 trimer, which may or may not be precoupled \nto the receptor, with GDP occupying the site on the \u03b1 \nsubunit. When a GPCR is activated by an agonist this induces small changes in residues around the ligand-binding \npocket that translate to larger rearrangements of the \nintracellular regions of the receptor that open a cavity on the intracellular side of the receptor into which the G protein \ncan bind, resulting in a high-affinity interaction of \u03b1\u03b2\u03b3 and \nthe receptor. This agonist-induced interaction of \u03b1\u03b2\u03b3 with \nthe receptor occurs within about 50 ms, causing the bound \nGDP to dissociate and to be replaced with GTP (GDP\u2013GTP \nexchange), which in turn causes dissociation of the G protein \ntrimer, releasing \u03b1\u2013GTP from the \u03b2\u03b3 subunits; these are \nthe \u2018active\u2019 forms of the G protein, which diffuse in the \nmembrane \tand \tcan \tassociate \twith \tvarious \tenzymes \tand \t\nion channels, causing activation of the target (see Fig. 3.9). \nIt was originally thought that only the \u03b1 subunit had a \nsignalling function, the \u03b2\u03b3 complex serving merely as a chaperone to keep the flighty \u03b1 subunits out of range of \nthe various effector proteins that they might otherwise \nexcite. However, the \u03b2\u03b3 complexes actually make assigna-\ntions of their own, and control effectors in much the same \nway as the \u03b1 subunits. Association of \u03b1 or \u03b2 \u03b3 subunits with \ntarget\tenzymes \tor \tchannels \tcan \tcause \teither \tactivation \tor \t\ninhibition, depending on which G protein is involved (see Table 3.3). G protein activation results in amplification, \nbecause a single agonist\u2013receptor complex can activate \nseveral G protein molecules in turn, and each of these can \nremain\tassociated \twith \ttheir \teffector \tenzyme \tfor \tlong \tenough\t\nto produce many molecules of product. The product (see later) is often a \u2018second messenger\u2019, and further amplification \noccurs before the final", "start_char_idx": 0, "end_char_idx": 3508, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "883f004b-be84-454b-8906-3bccc985c7ad": {"__data__": {"id_": "883f004b-be84-454b-8906-3bccc985c7ad", "embedding": null, "metadata": {"page_label": "39", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fa9b5a90-45f5-4956-9716-f57f56afa41f", "node_type": null, "metadata": {"page_label": "39", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a10506e84c91914e296409283e66a665e5b9b5e244e28fb9c81a7cef747891b3"}, "2": {"node_id": "c86dad7a-35a1-462c-bb53-b7f3e54921fc", "node_type": null, "metadata": {"page_label": "39", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "45509241ac958b0f6ed00d2e7a31b58d06da1656b08e961d29d5a1fe42b9781f"}}, "hash": "2c5da70180a96fce60606bd74c8abda6d93608ae9de15123f01d213575474dc4", "text": "\u2018second messenger\u2019, and further amplification \noccurs before the final cellular response is produced. Table 3.3 The main G protein subtypes and their functionsa\nSubtypes Main effectors Notes\nG\u03b1 subunitsb\nG\u03b1 s Stimulates adenylyl cyclase, causing increased cAMP formation Activated by cholera toxin, which \nblocks GTPase activity, thus preventing inactivation\nG\u03b1\ni Inhibits adenylyl cyclase, decreasing cAMP formation Blocked by pertussis toxin, which prevents dissociation of \u03b1\u03b2\u03b3 complex\nG\u03b1\no ? Limited effects of \u03b1 subunit (effects mainly due to \u03b2\u03b3 subunits) Blocked by pertussis toxin. Occurs mainly in nervous system\nG\u03b1\nq Activates phospholipase C, increasing production of second messengers inositol trisphosphate and diacylglycerol (see pp. 36\u201338) thus releasing Ca\n2++ from intracellular stores and activating protein kinase C (PKC)\nG\u03b1 12/13 Activates Rho and thus Rho kinase\nG\u03b2\u03b3 subunits\nActivate potassium channelsInhibit voltage-gated calcium channelsActivate GPCR kinases (GRKs, pp. 38\u201339)Activate mitogen-activated protein kinase cascadeInteract with some forms of adenylyl cyclase and with phospholipase C \u03b2Many \u03b2\u03b3 isoforms identified, but \nspecific functions are not yet known\naThis table lists only those isoforms of major pharmacological significance. Many more have been identified, some of which play roles in \nolfaction, taste, visual transduction and other physiological functions (see Offermanns, 2003).\nbInitially the subscripts \u2018s\u2019 and \u2018i\u2019 were used to denote stimulatory and inhibitory actions on adenylyl cyclase but, subsequently, the terms \nused, \u2018q\u2019 and \u201812/13\u2019, have little logic behind their use.GPCR, G protein\u2013coupled receptor.\n13In humans there are 21 known subtypes of G\u03b1, 6 of G\u03b2 and 12 of G\u03b3, \nproviding, in theory, about 1500 variants of the trimer. We know little \nabout the role of different \u03b1, \u03b2 and \u03b3 subtypes, but it would be rash to \nassume that the variations are functionally irrelevant. By now, you will \nbe unsurprised (even if somewhat bemused) by such a display of \nmolecular heterogeneity, for it is the way of evolution.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3438, "end_char_idx": 5988, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "67218dc5-1ac9-4edf-b257-efbe9c55ec10": {"__data__": {"id_": "67218dc5-1ac9-4edf-b257-efbe9c55ec10", "embedding": null, "metadata": {"page_label": "40", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ccc1653-eb1f-438a-b0c8-acaea70e7dce", "node_type": null, "metadata": {"page_label": "40", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b28276972a03df9dcd6ba70d3bd261c3e0c6697b91c7caed76b1a926b915e942"}, "3": {"node_id": "deffb9e2-e741-4349-9ef8-d7776a00adb5", "node_type": null, "metadata": {"page_label": "40", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "356c657828fb8f5cd52ed58c98185d21162de0426a77b42934d2bd0e44f154a3"}}, "hash": "c0c07d0372fd0b939db2529f2df608ee538ee60bc5239e27afe75995b7c4ef60", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n34introduced the concept of second messengers in signal \ntransduction. cAMP is a nucleotide synthesised within the \ncell\tfrom\tATP\tby\tthe\taction\tof\ta\tmembrane-bound \tenzyme,\t\nadenylyl cyclase. It is produced continuously and inactivated by hydrolysis to 5 \u2032\n-AMP\tby\tthe\taction\tof\ta\tfamily\tof\tenzymes\t\nknown as phosphodiesterases (PDEs). Many different drugs, hormones and neurotransmitters act on GPCRs and increase \nor decrease the catalytic activity of adenylyl cyclase (see \nFig. 3.10), thus raising or lowering the concentration of cAMP within the cell. In mammalian cells there are 10 \ndifferent \tmolecular \tisoforms \tof\tthe\tenzyme,\tsome\tof\twhich\t\nrespond selectively to G\u03b1 s or G\u03b1 i.\nCyclic AMP regulates many aspects of cellular function \nincluding, \tfor \texample, \tenzymes \tinvolved \tin \tenergy \t\nmetabolism, cell division and cell differentiation, ion transport, ion channels and the contractile proteins in smooth \nmuscle. These varied effects are, however, all brought about \nby a common mechanism, namely the activation of protein kinases by cAMP (known as cyclic AMP-dependent protein \nkinases)\tin \teukaryotic \tcells. \tOne \timportant \tcyclic \tAMP-\ndependent protein kinase is protein kinase A (PKA). Protein \nkinases regulate the function of many different cellular \nproteins by controlling protein phosphorylation. Fig. 3.11 \nshows how increased cAMP production in response to \u03b2\n-adrenoceptor \tactivation \taffects \tenzymes \tinvolved \tin \t\nglycogen and fat metabolism in liver, fat and muscle cells. The result is a coordinated response in which stored energy \nin the form of glycogen and fat is made available as glucose \nto fuel muscle contraction.\nOther\texamples \tof \tregulation \tby \tPKA \tinclude \tthe \t\nincreased activity of voltage-gated calcium channels in heart muscle cells (see Ch. 22). Phosphorylation of these channels \nincreases the amount of Ca\n2+ entering the cell during the \naction potential, and thus increases the force of contraction of the heart.\nIn smooth muscle, PKA phosphorylates (thereby inactivat -\ning)\tanother \tenzyme, \tmyosin light-chain kinase, which is \nrequired for contraction. This accounts for the smooth muscle relaxation produced by many drugs that increase cAMP \nproduction in smooth muscle (see Ch. 4).\nAs mentioned earlier, receptors linked to G\ni rather than \nGs inhibit adenylyl cyclase, and thus reduce cAMP formation \nto elicit opposing responses to those receptors which activate \nGs. Examples include certain types of mAChR (e.g. the M 2 \nreceptor of cardiac muscle; see Ch. 14), \u03b12 adrenoceptors \nin smooth muscle (Ch. 15) and opioid receptors (see Ch. 43). Adenylyl cyclase can be activated directly by drugs \nsuch as forskolin, which is used experimentally to study the role of the cAMP system.\nCyclic AMP is hydrolysed within cells by PDEs, an \nimportant \ta nd\tu biquitous \tf amily\to f\te nzymes.\tT wenty-four \tTarget\nenzymeInhibitory\nreceptorStimulatory\nreceptor\nGi Gs\nRi Rs\n\u03b2\u03b3 \u03b2\u03b3\u03b1i \u03b1s\nFig. 3.10 Bidirectional control of a target enzyme, such as adenylyl cyclase by G s and G i. Heterogeneity of G proteins allows \ndifferent receptors to exert opposite effects on a target enzyme. \nrespect to both the receptors and the effectors with which they couple, having specific recognition domains in their \nstructure complementary", "start_char_idx": 0, "end_char_idx": 3321, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "deffb9e2-e741-4349-9ef8-d7776a00adb5": {"__data__": {"id_": "deffb9e2-e741-4349-9ef8-d7776a00adb5", "embedding": null, "metadata": {"page_label": "40", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ccc1653-eb1f-438a-b0c8-acaea70e7dce", "node_type": null, "metadata": {"page_label": "40", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b28276972a03df9dcd6ba70d3bd261c3e0c6697b91c7caed76b1a926b915e942"}, "2": {"node_id": "67218dc5-1ac9-4edf-b257-efbe9c55ec10", "node_type": null, "metadata": {"page_label": "40", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c0c07d0372fd0b939db2529f2df608ee538ee60bc5239e27afe75995b7c4ef60"}}, "hash": "356c657828fb8f5cd52ed58c98185d21162de0426a77b42934d2bd0e44f154a3", "text": "with which they couple, having specific recognition domains in their \nstructure complementary to specific G protein-binding \ndomains in the receptor and effector molecules. For example, G\ns and G i produce, respectively, stimulation and inhibition \nof\tthe\tenzyme \tadenylyl cyclase (Fig. 3.10).\nOne\tfunctional \tdifference \tthat \thas \tbeen \tuseful \tas \tan \t\nexperimental tool to distinguish which type of G protein is involved in different situations concerns the action of \ntwo bacterial toxins, cholera toxin and pertussis toxin (see \nTable\t3.3). \tThese \ttoxins, \twhich \tare \tenzymes, \tcatalyse \ta \t\nconjugation reaction (ADP ribosylation) on the \u03b1 subunit \nof G proteins. Cholera toxin acts only on G s, and it causes \npersistent activation. Many of the symptoms of cholera, such as the excessive secretion of fluid from the gastro-\nintestinal epithelium (leading to \u2018rice-water stools\u2019), are due to the uncontrolled activation of adenylyl cyclase that \noccurs. Pertussis toxin specifically blocks G\ni and G o by \npreventing dissociation of the G protein trimer. Pertussis toxin is released from Bordetella pertussis bacteria, which \ncause whooping cough. As with cholera toxin, the symptoms \ncaused by pertussis toxin are related to its effects on G \nproteins, but in this case by inhibiting G\ni and G o rather \nthan activating G s and leading to changes in respiratory \ntract secretion and a distinctive cough rather than the copious diarrhoea of cholera.\nTARGETS \u2003FOR \u2003G \u2003PROTEINS\nThe main targets for G proteins, through which GPCRs \ncontrol different aspects of cell function (see Table 3.3), are:\n\u2022\tadenylyl cyclase ,\tthe\tenzyme \tresponsible \tfor \tcAMP \t\nformation;\n\u2022\tphospholipase C ,\tthe\tenzyme \tresponsible \tfor \tinositol \t\nphosphate and diacylglycerol (DAG) formation;\n\u2022\tion channels, particularly calcium and potassium \nchannels;\n\u2022\tRho A/Rho kinase, a system that regulates the activity \nof many signalling pathways controlling cell \ngrowth, proliferation and motility, smooth muscle \ncontraction, etc.;\n\u2022\tmitogen-activated protein kinase (MAP kinase), a system \nthat controls many cell functions, including cell \ndivision and is also a target of several kinase-linked receptors.\nThe adenylyl cyclase/cAMP system\nThe discovery by Sutherland and his colleagues of the role of cAMP (cyclic 3 \u2032,5\u2032-adenosine monophosphate) as an \nintracellular mediator demolished at a stroke the barriers that existed between biochemistry and pharmacology, and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3228, "end_char_idx": 6163, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "49225b95-f6e1-433a-a90c-dcf5b8772f49": {"__data__": {"id_": "49225b95-f6e1-433a-a90c-dcf5b8772f49", "embedding": null, "metadata": {"page_label": "41", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "451fb778-e702-4947-afe1-25513cc65c11", "node_type": null, "metadata": {"page_label": "41", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10bdb5c995eb575525723b9dba1fe3bd0e110a81ab0439f099cc607e078e7b8c"}, "3": {"node_id": "ced54c58-bb38-457c-8d4e-2be835d6b5e9", "node_type": null, "metadata": {"page_label": "41", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e6b4c9dbd80b9de10c7128e9b61486af0bbd2d2acfd42cb790210634eb49eaf"}}, "hash": "591cf6c5c2d4b63b671a37d9ff86bf70e6b14b8559387c5ee03c6e4ab42b2790", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n35by Hokin and Hokin, whose recondite interests centred \non the mechanism of salt secretion by the nasal glands \nof seabirds. They found that secretion was accompanied \nby increased turnover of a minor class of membrane phospholipids known as phosphoinositides (collectively \nknown as PIs; Fig. 3.12). Subsequently, Michell and Berridge \nfound that many hormones that produce an increase in free intracellular Ca\n2+ concentration (which include, for example, \nmuscarinic agonists and \u03b1-adrenoceptor agonists acting \non smooth muscle and salivary glands) also increase PI turnover. It was later found that one particular member of the PI family, namely phosphatidylinositol (4,5) bis -\nphosphate (PIP\n2), which has additional phosphate groups \nattached to the inositol ring, plays a key role. PIP 2 is the \nsubstrate \tfor \ta \tmembrane-bound \tenzyme, \tphospholipase \t\nC\u03b2 (PLC\u03b2), which splits it into DAG and inositol (1,4,5) \ntrisphosphate (IP 3; Fig. 3.13), both of which function as second \nmessengers as discussed later (p. 36). The activation of \nPLC\u03b2 by various agonists is mediated through a G protein \n(Gq, see Table 3.3). After cleavage of PIP 2, the status quo \nis restored, as shown in Fig. 3.13, DAG being phospho-\nrylated to form phosphatidic acid (PA), while the IP 3 is PDE subtypes exist, of which some are more selective for cAMP, while others are more selective for cGMP. Most \nare weakly inhibited by drugs such as methylxanthines (e.g. theophylline and caffeine; see Chs 29 and 49). \nRoflumilast (used to treat chronic obstructive pulmonary \ndisease\t[COPD]; \tCh. \t29) \tis \tselective \tfor \tPDE 4B, expressed \nin inflammatory cells; milrinone (a positive inotrope that \nmakes the heart beat harder and is sometimes used for symptoms in patients awaiting heart transplantation; Ch. 22) is selective for PDE\n2A, which is expressed in heart muscle; \nsildenafil (better known as Viagra; Ch. 36) is selective for \nPDE 5A, and consequently enhances the vasodilator effects \nof\tnitric\toxide \t(NO) \tand \tdrugs \tthat \trelease \tNO, \twhose \t\neffects are mediated by cGMP (see Ch. 21). The similarity \nof some of the actions of these drugs to those of sympatho -\nmimetic amines (Ch. 15) probably reflects their common property of increasing the intracellular concentration \nof cAMP.\nThe phospholipase C/inositol phosphate system\nThe phosphoinositide system, an important intracellular \nsecond messenger system, was first discovered in the 1950s Lipase (active)ATP \nADPIncreased lipolysis\nATP \nADPReduced glycogen synthesis\nATP \nADPATP \nADPPhosphorylase\nkinase (active)\nPhosphorylase a\n(active)ATP \nADPIncreased glycogen breakdown\nGlycogen\nGlucose 1-phosphateGlycogen synthase\n(inactive)GProtein kinase\n(active)Protein kinase\n(inactive)Lipase (inactive)\nGlycogen synthase\n(active)\nPhosphorylase\nkinase (inactive)\nPhosphorylase b\n(inactive)ACATP \ncAMP\nAgonist\nR\nFig. 3.11 Regulation of energy metabolism by cAMP. AC, adenylyl cyclase. mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3031, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ced54c58-bb38-457c-8d4e-2be835d6b5e9": {"__data__": {"id_": "ced54c58-bb38-457c-8d4e-2be835d6b5e9", "embedding": null, "metadata": {"page_label": "41", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "451fb778-e702-4947-afe1-25513cc65c11", "node_type": null, "metadata": {"page_label": "41", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10bdb5c995eb575525723b9dba1fe3bd0e110a81ab0439f099cc607e078e7b8c"}, "2": {"node_id": "49225b95-f6e1-433a-a90c-dcf5b8772f49", "node_type": null, "metadata": {"page_label": "41", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "591cf6c5c2d4b63b671a37d9ff86bf70e6b14b8559387c5ee03c6e4ab42b2790"}}, "hash": "4e6b4c9dbd80b9de10c7128e9b61486af0bbd2d2acfd42cb790210634eb49eaf", "text": "cyclase. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2975, "end_char_idx": 3463, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bf837ad2-e0c9-478a-ad5e-2f9c1f0607ae": {"__data__": {"id_": "bf837ad2-e0c9-478a-ad5e-2f9c1f0607ae", "embedding": null, "metadata": {"page_label": "42", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3adf4295-e6b7-447d-928f-4c0250af866e", "node_type": null, "metadata": {"page_label": "42", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "73d728d3bd2998ec5a24d56ce3068e75fbef8df0164e3ab43de7665306f079b5"}, "3": {"node_id": "42025fea-f86a-4f9f-bc20-b74e98f5ff23", "node_type": null, "metadata": {"page_label": "42", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b39ba53148905b43ccf0289b7a2e991fe6a6e29866129e40cb6c8179111a2db9"}}, "hash": "2d0694d94bbc3326068cd099c8d72fc2263b9a20ca6861e537b5fefbe7522ed9", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n36by phorbol esters (highly irritant, tumour-promoting com -\npounds produced by certain plants), which have been \nextremely \tuseful\tin\tstudying \tthe\tfunctions \tof\tPKC.\tOne\tof\t\nthe subtypes is activated by the lipid mediator arachidonic \nacid (see Ch. 18) generated by the action of phospholipase \nA2 on membrane phospholipids, so PKC activation can \nalso\toccur \twith \tagonists \tthat \tactivate \tthis \tenzyme. \tThe \t\nvarious PKC isoforms, like the tyrosine kinases discussed \nlater (p. 40), act on many different functional proteins, such \nas\tion\tchannels, \treceptors, \tenzymes \t(including \tother \t\nkinases), transcription factors and cytoskeletal proteins. Protein phosphorylation by kinases plays a central role in \nsignal transduction, and controls many different aspects \nof cell function. The DAG\u2013PKC link provides a mechanism whereby GPCRs can mobilise this army of control freaks.\nIon channels as targets for G proteins\nAnother major function of GPCRs is to control ion channel function directly by mechanisms that do not involve second \nmessengers such as cAMP or inositol phosphates. Direct \nG protein\u2013channel interaction, through the \u03b2\u03b3 subunits of G\ni and G o proteins, appears to be a general mechanism for \ncontrolling K+ and Ca2+ channels. In cardiac muscle, for \nexample, mAChRs enhance K+ permeability in this way \n(thus hyperpolarising the cells and inhibiting electrical \nactivity; see Ch. 22). Similar mechanisms operate in neurons, \nwhere many inhibitory drugs, such as opioid analgesics, reduce excitability by opening certain K\n+ channels \u2013 known \nas G protein-activated inwardly rectifying K+ channels \n(GIRK) \u2013 or by inhibiting voltage-activated N and P/Q \ntype Ca2+ channels, thus reducing neurotransmitter release \n(see Chs 4 and 43).\nThe Rho/Rho kinase system\n\u25bc This signal transduction pathway (see Bishop & Hall, 2000) is \nactivated by certain GPCRs (and also by non-GPCR mechanisms), \nwhich couple to G proteins of the G 12/13 type. The free G protein \u03b1 \nsubunit interacts with a guanosine nucleotide exchange factor , which \nfacilitates GDP\u2013GTP exchange at another GTPase, Rho. Rho\u2013GDP, the resting form, is inactive, but when GDP\u2013GTP exchange occurs, Rho is activated, and in turn activates Rho kinase. Rho kinase \nphosphorylates many substrate proteins and controls a wide variety \nof cellular functions, including smooth muscle contraction and proliferation, cell movement and migration, angiogenesis and synaptic \nremodelling. By enhancing hypoxia-induced pulmonary artery \nvasoconstriction, activation of Rho kinase is thought to be important \nin the pathogenesis of pulmonary hypertension (see Ch. 23). Specific \nRho kinase inhibitors are in development for several clinical indications including glaucoma \u2013 an area to watch.\nThe MAP kinase system\n\u25bc The MAP kinase system involves several signal transduction \npathways (Fig. 3.15) that are activated not only by various cytokines and growth factors acting on kinase-linked receptors (see p. 42, Fig. \n3.17), but also by ligands activating GPCRs. The coupling of GPCRs \nto different families of MAP kinases can involve G protein \u03b1 and \u03b2\u03b3 \nsubunits as well as Src and arrestins \u2013 proteins also involved in GPCR \ndesensitisation (see p. 38). The MAP kinase system controls many processes involved in gene expression, cell division, apoptosis and", "start_char_idx": 0, "end_char_idx": 3362, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "42025fea-f86a-4f9f-bc20-b74e98f5ff23": {"__data__": {"id_": "42025fea-f86a-4f9f-bc20-b74e98f5ff23", "embedding": null, "metadata": {"page_label": "42", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3adf4295-e6b7-447d-928f-4c0250af866e", "node_type": null, "metadata": {"page_label": "42", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "73d728d3bd2998ec5a24d56ce3068e75fbef8df0164e3ab43de7665306f079b5"}, "2": {"node_id": "bf837ad2-e0c9-478a-ad5e-2f9c1f0607ae", "node_type": null, "metadata": {"page_label": "42", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2d0694d94bbc3326068cd099c8d72fc2263b9a20ca6861e537b5fefbe7522ed9"}}, "hash": "b39ba53148905b43ccf0289b7a2e991fe6a6e29866129e40cb6c8179111a2db9", "text": "system controls many processes involved in gene expression, cell division, apoptosis and tissue regeneration.dephosphorylated and then recoupled with PA to form \nPIP 2 once again.14 Lithium, an agent used in psychiatry \n(see Ch. 48), blocks this recycling pathway (see Fig. 3.13).\nInositol phosphates and intracellular calcium\nInositol (1,4,5) trisphosphate (IP 3) is a water-soluble mediator \nthat is released into the cytosol and acts on a specific receptor \n\u2013 the IP 3 receptor \u2013 which is a ligand-gated calcium channel \npresent on the membrane of the endoplasmic reticulum (see Fig. 3.5). The main role of IP\n3, described in more detail \nin Chapter 4, is to control the release of Ca2+ from intracellular \nstores. Because many drug and hormone effects involve intracellular Ca\n2+, this pathway is particularly important.\nDiacylglycerol and protein kinase C\nDAG is produced, as well as IP 3, whenever receptor-induced \nPI hydrolysis occurs. The main effect of DAG is to activate \na protein kinase, protein kinase C (PKC), which catalyses \nthe phosphorylation of several intracellular proteins. DAG, unlike the inositol phosphates, is highly lipophilic and \nremains within the membrane. It binds to a specific site on \nthe\tPKC \tmolecule, \tcausing \tthe \tenzyme \tto \tmigrate \tfrom \t\nthe cytosol to the cell membrane, thereby becoming acti -\nvated. There are at least 10 different mammalian PKC subtypes, which have distinct cellular distributions and \nphosphorylate different proteins. Several are activated by DAG and raised intracellular Ca\n2+, both of which are \nproduced by activation of GPCRs.15 PKCs are also activated \n14Alternative abbreviations for these mediators are PtdIns (PI), PtdIns \n(4,5)-P 2 (PIP 2), Ins (1,4,5)-P 3 (IP 3).6\n5\n4321 OH\nOHHO\nPPPC C CO O\nO\nI(1,4,5)P3PIP2DAG\nPA\nArachidonic acid\nFatty acid\nPLA2\nPLC\nPLD\nFig. 3.12 Structure of phosphatidylinositol bisphosphate \n(PIP 2), showing sites of cleavage by different \nphospholipases to produce active mediators. Cleavage \nby\tphospholipase \tA2 \t(PLA 2) yields arachidonic acid. Cleavage by \nphospholipase \tC \t(PLC) \tyields \tinositol \ttrisphosphate \t(I(1,4,5)P 3) \nand diacylglycerol (DAG). PA, phosphatidic acid; PLD, \nphospholipase D. \n15PKCs were originally named as Ca2+-dependent protein kinases (PKC), \nas opposed to cAMP-dependent PKA. Although later subtypes were \nfound not to be Ca2+-dependent, the PKC name has stuck.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3274, "end_char_idx": 6155, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8804fc0e-7ad8-4afa-b2e2-9c376aa2f67b": {"__data__": {"id_": "8804fc0e-7ad8-4afa-b2e2-9c376aa2f67b", "embedding": null, "metadata": {"page_label": "43", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ae696e19-2785-410e-89de-6e9aa91929d0", "node_type": null, "metadata": {"page_label": "43", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ab77dda4d5d2b145949f263801cd321ccd9dea9f5db0838239f8c45091773715"}}, "hash": "ab77dda4d5d2b145949f263801cd321ccd9dea9f5db0838239f8c45091773715", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n37Kinases\nKinase\nPhosphatasesInositol\n1-phosphatase\nP\nP\nP\nI(1,3,4)P3InositolActivation of\nprotein kinase C\nRelease ofintracellular Ca\n2+\n? Ca2+ entry\nthrough membraneDAG\nOHPIP2\nPPPPI\nP\nPhosphatidic acid\nP\nIPP\nI(1,4,5)P3P\nPP\nI(1,3,4,5)P4P\nP\nPPPhospholipase CReceptor\nInhibited\nby Li+\nFig. 3.13 The phosphatidylinositol (PI) cycle. Receptor-mediated activation of phospholipase C results in the cleavage of \nphosphatidylinositol bisphosphate (PIP 2), forming diacylglycerol (DAG) (which activates protein kinase C) and inositol trisphosphate (IP 3) \n(which releases intracellular Ca2+). The role of inositol tetraphosphate (IP 4), which is formed from IP 3 and other inositol phosphates, is \nunclear, but it may facilitate Ca2+ entry through the plasma membrane. IP 3 is inactivated by dephosphorylation to inositol. DAG is converted \nto phosphatidic acid, and these two products are used to regenerate PI and PIP 2. \nEffectors controlled by G proteins \nTwo key second messenger pathways are controlled by \nreceptors via G proteins:\n\u2022\tAdenylyl \tcyclase/cAMP:\n\u2013 can be activated or inhibited by pharmacological ligands, \ndepending on the nature of the receptor and G protein;\n\u2013 adenylyl cyclase catalyses formation of the intracellular \nmessenger cAMP;\n\u2013 cAMP activates protein kinases such as protein kinase \nA (PKA) that control cell function in many different ways by causing phosphorylation of various enzymes, carriers and other proteins.\n\u2022\tPhospholipase \tC/inositol \ttrisphosphate \t(IP3)/diacylglycerol \n(DAG):\n\u2013 catalyses the formation of two intracellular \nmessengers, IP 3 and DAG, from membrane \nphospholipid;\n\u2013 IP3 acts to increase free cytosolic Ca2+ by releasing \nCa2+ from intracellular compartments\u2013 increased free Ca2+ initiates many events, including \ncontraction, secretion, enzyme activation and membrane hyperpolarisation;\n\u2013 DAG activates various protein kinase C (PKC) \nisoforms, which control many cellular functions by phosphorylating a variety of proteins.\nReceptor-linked G proteins also control:\n\u2022\tIon\tchannels:\n\u2013 opening potassium channels, resulting in membrane \nhyperpolarisation;\n\u2013 inhibiting calcium channels, thus reducing \nneurotransmitter release.\n\u2022\tPhospholipase \tA2 (and thus the formation of arachidonic \nacid and eicosanoids).The main postulated roles of GPCRs in controlling \nenzymes and ion channels are summarised in Fig. 3.14.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2890, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "74ff3fd6-58c1-472f-94ea-c63599cdee26": {"__data__": {"id_": "74ff3fd6-58c1-472f-94ea-c63599cdee26", "embedding": null, "metadata": {"page_label": "44", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1bd461c7-3a1d-465e-90b5-a08f35001db6", "node_type": null, "metadata": {"page_label": "44", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e989d9ee149b0495e24c41d6c15c4671c548849a3504595125b9d91614768cb"}}, "hash": "4e989d9ee149b0495e24c41d6c15c4671c548849a3504595125b9d91614768cb", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n38ARRPP PP\nARRPP\nRAF1 ASK1\nMKK3/6 MKK4/7 MEK1\np38 JNK1\u20133 ERK1/2SrcGRK\nERKA\nAAAA\nAA\nARR\nJNK3PPA\nARRERKPPAA\nAltered gene expressionEndocytosisArrestin coupling to MAP kinases B Receptor coupling to MAP kinasesA\nFig. 3.15 G protein\u2013coupled receptor (GPCR) activation of mitogen-activated protein (MAP) kinase cascade. (A) Sequential \nactivation of the multiple components of the MAP kinase cascade. GPCR activation of MAP kinases can involve G \u03b1 and \u03b2\u03b3 subunits (not \nshown).\t(B) \tActivation \tof \tERK \tand \tJNK3 \tthrough \tinteraction \twith \tarrestins \t(\u03b2ARR).\tActivation \tof \tERK \tcan \toccur \teither \tat \tthe \tplasma \t\nmembrane involving Src, or by direct activation after internalisation of the receptor/arrestin complex. ARR, arrestin; GRK, G protein\u2013coupled \nreceptor kinase. Target\nenzymes\nSecondmessengers\nProtein\nkinases\nEffectorsEnzymes,\ntransport proteins, etc.Contractile\nproteinsIon\nchannelsReleased\nas local\nhormonesAA DAG IP3 cAMP cGMP\nPKG PKA PKCEicosanoids \u2191[Ca2+]iGuanylyl\ncyclaseAdenylyl\ncyclasePhospholipase CReceptors G proteins\nFig. 3.14 G protein and second messenger control of cellular effector systems. Not shown in this diagram are signalling pathways \nwhere arrestins, rather than G proteins, link G protein\u2013coupled receptors to downstream events (see text and Fig. 3.15). AA, arachidonic \nacid; DAG, diacylglycerol; IP3, inositol trisphosphate. \nFURTHER \u2003DEVELOPMENTS \u2003IN \u2003GPCR \u2003BIOLOGY\n\u25bc B y the early 1990s, we thought we had more or less got the measure \nof GPCR function, as described previously. Since then, the plot has \nthickened, and further developments have necessitated a substantial \noverhaul of the basic model.\nGPCR desensitisation\n\u25bc As described in Chapter 2, desensitisation is a feature of most \nGPCRs, and the mechanisms underlying it have been extensively \nstudied. Homologous desensitisation is restricted to the receptors activated by the desensitising agonist, while heterologous desensitisation affects \nother GPCRs in addition. Two main processes are involved (see Kelly \net al., 2008):\n\u2022\treceptor \tphosphorylation\n\u2022\treceptor \tinternalisation \t(endocytosis)\nThe sequence of GPCRs includes certain residues (serine \nand threonine), mainly in the C-terminal cytoplasmic tail, \nwhich can be phosphorylated by specific GPCR kinases \n(GRKs) and by kinases such as PKA and PKC.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2837, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1993df21-3ed9-42ad-a120-a7037b4690bc": {"__data__": {"id_": "1993df21-3ed9-42ad-a120-a7037b4690bc", "embedding": null, "metadata": {"page_label": "45", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8d5c07a6-34f2-489d-b907-da3e36d9c70d", "node_type": null, "metadata": {"page_label": "45", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20a910464bf2ba4316f3f539df3e8518162ec5a1416709b924ded4063ea00493"}, "3": {"node_id": "579f30f0-7e31-4a68-b681-c7918a138c4c", "node_type": null, "metadata": {"page_label": "45", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a994ef263b7f381663bf8e660e6b5b582e31960b90a386d156b7ad3a6ba8cc9"}}, "hash": "2f13d1275bcce5ca06c59d79106a6668f94cff0d24b616bc83e0a96f779e831b", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n39the GABA B receptor. Two subtypes of this GPCR exist, encoded by \ndifferent genes, and the functional receptor consists of a heterodimer \nof the two (see Ch. 39). A similar situation arises with G protein\u2013\ncoupled\tglutamate \treceptors. \tOddly, \talthough \tthe \tGABA B dimer \nhas two potential agonist binding sites, one on each subunit, only one is functional and signalling is transmitted through the dimer \nto the other receptor in the dimer which couples to the G protein \n(see Fig. 39.9).\nOther\tGPCRs \tare \tfunctional \tas \tmonomers \tbut \tit \tnow \tseems \tlikely \tthat\t\nmost, if not all, GPCRs can exist as either homomeric or heteromeric \noligomers (i.e. dimers or larger oligomers) (Ferr\u00e9 et al., 2015). Within \nthe opioid receptor family (see Ch. 43), the \u00b5 receptor was crystallised \nas a dimer and stable and functional heterodimers of \u043a and \u03b4 receptors, \nwhose pharmacological properties differ from those of either parent, have been created in cell lines. More diverse GPCR combinations have also been found, such as that between dopamine (D\n2) and somatostatin \nreceptors, on which both ligands act with increased potency. Roaming \neven further afield in search of functional assignations, the dopamine \nreceptor D 5 can couple directly with a ligand-gated ion channel, the \nGABA A receptor, inhibiting the function of the latter without the \nintervention of any G protein (Liu et al., 2000). These interactions have \nso far been studied mainly in engineered cell lines, but they also occur in native cells. Functional dimeric complexes between angiotensin \n(AT\n1) and bradykinin (B 2) receptors occur in human platelets and \nshow greater sensitivity to angiotensin than \u2018pure\u2019 AT 1 receptors \n(AbdAlla et al., 2001). In women suffering from pregnancy-related \nhypertension (pre-eclamptic toxaemia), the number of these dimers \nincreases due to increased expression of B 2 receptors, resulting \u2013 \nparadoxically \u2013 in increased sensitivity to the vasoconstrictor action of \nangiotensin.\nIt is too early to say what impact this newly discovered versatility \nof GPCRs in linking up with other receptors to form functional \ncombinations will have on conventional pharmacology and thera-peutics, but it could be considerable.On\treceptor\tactivation \tGRK2\tand\tGRK3\tare\trecruited \tto\t\nthe plasma membrane by binding to free G protein \u03b2\u03b3 \nsubunits. GRKs then phosphorylate the receptors in their \nactivated (i.e. agonist-bound) state. The phosphorylated \nreceptor serves as a binding site for arrestins, intracellular proteins that block the interaction between the receptor \nand the G proteins producing a selective homologous \ndesensitisation. Arrestin binding also targets the receptor \nfor endocytosis in clathrin-coated pits (Fig. 3.16). The \ninternalised receptor can then either be dephosphorylated \nand reinserted into the plasma membrane ( resensitisation) \nor trafficked to lysosomes for degradation ( inactivation). \nThis type of desensitisation seems to occur with most GPCRs \nbut with subtle differences that fascinate the aficionados.\nPhosphorylation by PKA and PKC at residues different \nfrom those targeted by GRKs generally leads to impaired coupling between the activated receptor and the G protein, \nso the agonist effect is reduced. This can give rise to either homologous or heterologous desensitisation, depending \non whether or not receptors other than that", "start_char_idx": 0, "end_char_idx": 3431, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "579f30f0-7e31-4a68-b681-c7918a138c4c": {"__data__": {"id_": "579f30f0-7e31-4a68-b681-c7918a138c4c", "embedding": null, "metadata": {"page_label": "45", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8d5c07a6-34f2-489d-b907-da3e36d9c70d", "node_type": null, "metadata": {"page_label": "45", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20a910464bf2ba4316f3f539df3e8518162ec5a1416709b924ded4063ea00493"}, "2": {"node_id": "1993df21-3ed9-42ad-a120-a7037b4690bc", "node_type": null, "metadata": {"page_label": "45", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f13d1275bcce5ca06c59d79106a6668f94cff0d24b616bc83e0a96f779e831b"}}, "hash": "8a994ef263b7f381663bf8e660e6b5b582e31960b90a386d156b7ad3a6ba8cc9", "text": "heterologous desensitisation, depending \non whether or not receptors other than that for the desensitis -\ning agonist are simultaneously phosphorylated by the \nkinases, some of which are not very selective. Receptors \nphosphorylated by second messenger kinases are probably \nnot internalised and are reactivated by dephosphorylation by phosphatases when the agonist is removed.\nGPCR oligomerisation\n\u25bc The earlier view that GPCRs exist and function as monomeric \nproteins (in contrast to ion channels, which generally comprise \nmultimeric complexes; see p. 28) was first overturned by work on \u03b1\u03b2\u03b3 \u03b2\u03b3\nARRARR\nPP2A\nPP2AClathrin-coated pit formation\nInternalisationReceptor desensitisation\nReinsertion\nRecycling\nLysosomal\ndegradation\nDephosphorylationARRGRKA\nPP\nPP GDPA\nEA\nA Dyn Dyn\nDyn\nARR\nPPARRA\nP\nP\nA\nA\nPPA\nA\nP\nPP\nPP\nFig. 3.16 Desensitisation and trafficking of G protein\u2013coupled receptors (GPCRs). On prolonged agonist activation of the GPCR, \nselective GPCR kinases (GRKs) are recruited to the plasma membrane and phosphorylate the receptor. Arrestin (ARR) then binds and \ntraffics the GPCR to clathrin-coated pits for subsequent internalisation into endosomes in a dynamin-dependent process. The GPCR is then dephosphorylated by a phosphatase (PP2A) and either recycled back to the plasma membrane or trafficked to lysosomes for degradation. Dyn, dynamin; GRK, G protein\u2013coupled receptor kinase; PP2A, phosphatase 2A. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3347, "end_char_idx": 5247, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9b3017bb-1606-4f91-92c3-e153c1ef8b62": {"__data__": {"id_": "9b3017bb-1606-4f91-92c3-e153c1ef8b62", "embedding": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "38eaefc4-4af9-4117-9d60-ed3eb7437b0e", "node_type": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8d3a9d5038bc0f9ae76fee5c136aa0a79164f4ad73f416fd788de020650a5f4"}, "3": {"node_id": "1a868faf-2a57-476a-ad57-512a4a15071c", "node_type": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a15e893ae8c56129a116fc8f979326c72e022afd69f1ffaa174008836d67461d"}}, "hash": "d16ecddc78529f0f322e0e9dd31944601aca02abd48e94e64bdd158ea8ce492f", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n40In summary, the simple dogma that has underpinned much \nof our understanding of GPCRs, namely, one GPCR gene \n\u2013 one GPCR protein \u2013 one functional GPCR \u2013 one G protein \n\u2013 one response, is showing distinct signs of wear. In particular:\n\u2022\tone\tgene, \tthrough \talternative \tsplicing, \tRNA \t \nediting, etc., can give rise to more than one receptor \nprotein;\n\u2022\tone\tGPCR \tprotein \tcan \tassociate \twith \tothers, \tor \twith \t\nother proteins such as RAMPs, to produce more than \none type of functional receptor;\n\u2022\tdifferent \tagonists \tmay \taffect \ta \treceptor \tin \tdifferent \t\nways and elicit qualitatively different responses;\n\u2022\tthe\tsignal \ttransduction \tpathway \tfrom \t\u2018GPCR\u2019 \tdoes \t\nnot invariably require G proteins, and there can be cross-talk with tyrosine kinase-linked receptors.\nGPCRs are evidently versatile and adventurous molecules around which much modern pharmacology revolves, and nobody imagines that we have reached the end of the story.\nTYPE 3: KINASE-LINKED AND \nRELATED RECEPTORS\nThese membrane receptors are quite different in structure and function from ligand-gated channels and GPCRs. They \nare activated by a wide variety of protein mediators, includ -\ning growth factors and cytokines (see Ch. 19), and hormones \nsuch as insulin (see Ch. 32) and leptin (Ch. 33), whose \neffects are exerted mainly at the level of gene transcription. \nMost of these receptors are large proteins consisting of a single chain of up to 1000 residues, with a single membrane-\nspanning helical region, linking a large extracellular \nligand-binding domain to an intracellular domain of variable \nsize\tand\tfunction. \tThe\tbasic\tstructure \tis\tshown\tin\tFig.\t3.3C,\t\nbut\tmany\tvariants\texist\t(see\tlater).\tOver\t100\tsuch\treceptors \t\nhave been cloned, and many structural variations exist. For more detail, see the review by Hubbard & Miller (2007). \nThese receptors play a major role in controlling cell division, \nintermediary metabolism, growth, differentiation, inflam-mation, tissue repair, apoptosis and immune responses, \ndiscussed further in Chapters 6 and 19.\nThe main types are as follows:\nReceptor tyrosine kinases (RTKs). These receptors have \nthe basic structure shown in Fig. 3.17A, incorporating a tyrosine kinase moiety in the intracellular region. They \ninclude receptors for many growth factors, such as epider -\nmal growth factor and nerve growth factor , and also the \ngroup of TLRs that recognise bacterial lipopolysaccharides \nand play an important role in the body\u2019s reaction to infection (see Ch. 7). The insulin receptor (see Ch. 32) also belongs \nto the RTK class, although it has a more complex dimeric \nstructure, and links indirectly to intracellular tyrosine kinases.\nReceptor serine/threonine kinases. This smaller class is \nsimilar in structure to RTKs but they phosphorylate serine \nand/or threonine residues rather than tyrosine. The main \nexample is the receptor for transforming growth factor \n(TGF).\nCytokine receptors. These receptors (Fig. 3.17B) lack \nintrinsic\tenzyme \tactivity. \tWhen \toccupied, \tthey \tactivate \t\nvarious tyrosine kinases, such as Jak (the Janus kinase). Ligands for these receptors include cytokines such as \ninterferons and colony-stimulating factors involved in \nimmunological responses as well as cell growth and \ndifferentiation.Constitutively active", "start_char_idx": 0, "end_char_idx": 3336, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1a868faf-2a57-476a-ad57-512a4a15071c": {"__data__": {"id_": "1a868faf-2a57-476a-ad57-512a4a15071c", "embedding": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "38eaefc4-4af9-4117-9d60-ed3eb7437b0e", "node_type": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8d3a9d5038bc0f9ae76fee5c136aa0a79164f4ad73f416fd788de020650a5f4"}, "2": {"node_id": "9b3017bb-1606-4f91-92c3-e153c1ef8b62", "node_type": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d16ecddc78529f0f322e0e9dd31944601aca02abd48e94e64bdd158ea8ce492f"}, "3": {"node_id": "4ead5dd9-7818-4f6c-8607-943feb02bf8a", "node_type": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b83323a3d3f9ad366029402b7c0ad886fbcde9e7ce2e6bfaba5198a28d3c0a86"}}, "hash": "a15e893ae8c56129a116fc8f979326c72e022afd69f1ffaa174008836d67461d", "text": "responses as well as cell growth and \ndifferentiation.Constitutively active receptors\n\u25bc GPCRs may be constitutively (i.e. spontaneously) active in the \nabsence of any agonist (see Ch. 2 and review by Costa & Cotecchia, \n2005). This was first shown for \u03b4 opioid receptors (see Ch. 43). There \nare now many other examples of native GPCRs that show constitutive activity when studied in vitro. The histamine H\n3 receptor also shows \nconstitutive activity in vivo, and this may prove to be a quite general \nphenomenon. It means that inverse agonists (see Ch. 2), which suppress \nthis basal activity, may exert effects distinct from those of neutral antagonists, which block agonist effects without affecting basal \nactivity.\nAgonist specificity\n\u25bc It was thought that the linkage of a particular GPCR to a particular \nsignal transduction pathway depends mainly on the structure of the \nreceptor, which confers specificity for a particular G protein, from \nwhich the rest of the signal transduction pathway follows. This would \nimply, in line with the two-state model discussed in Chapter 2, that all agonists acting on a particular receptor stabilise the same activated \n(R*) state and should activate the same signal transduction pathway, \nand produce the same type of cellular response. It is now clear that this is an oversimplification. In many cases, for example, with agonists \nacting on angiotensin receptors, or with inverse agonists on \u03b2 \nadrenoceptors, the cellular effects are qualitatively different with different ligands, implying the existence of more than one \u2013 probably \nmany \u2013 R* states (sometimes referred to as biased agonism; see Ch. 2). \nBinding of arrestins to GPCRs initiates MAP kinase signalling, such \nthat agonists that induce GRK/arrestin \u2018desensitisation\u2019 will terminate \nsome GPCR signalling but may also activate signalling through arrestins that may continue even after the receptor/arrestin complex \nhas been internalised (see Fig. 3.15).\nBiased agonism has profound implications \u2013 indeed heretical to many \npharmacologists, who are accustomed to thinking of agonists in terms \nof their affinity and efficacy, and nothing else; it has added a new dimension to the way in which we think about drug efficacy and \nspecificity (see Kenakin and Christopoulos, 2013).\nReceptor activity-modifying proteins\n\u25bc Receptor activity-modifying proteins (RAMPs) are a family of \nmembrane proteins that associate with some GPCRs and alter their \nfunctional characteristics. They were discovered in 1998 when it was \nfound that the functionally active receptor for the neuropeptide \ncalcitonin gene-related peptide (CGRP) (see Chs 16 and 19) consisted of \na complex of a GPCR \u2013 called calcitonin receptor-like receptor (CRLR) \n\u2013 that by itself lacked activity, with another membrane protein \n(RAMP1). More surprisingly, CRLR when coupled with another RAMP (RAMP2) showed a quite different pharmacology, being activated \nby an unrelated peptide, adrenomedulin. In other words, the agonist \nspecificity is conferred by the associated RAMP as well as by the \nGPCR itself. More RAMPs have emerged, and so far nearly all \nthe examples involve Class B peptide receptors (see Table 3.2), the \ncalcium-sensing receptor being an exception. RAMPs are an example \nof how protein\u2013protein interactions influence the pharmacological \nbehaviour of the receptors in a highly selective way and may be novel \ntargets for drug development (Sexton et al., 2012).\nG protein\u2013independent signalling\n\u25bc In using the term G protein\u2013coupled receptor to describe the class \nof receptors characterised by their heptahelical structure, we are \nfollowing conventional textbook dogma but neglecting the fact that \nG proteins", "start_char_idx": 3270, "end_char_idx": 6977, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4ead5dd9-7818-4f6c-8607-943feb02bf8a": {"__data__": {"id_": "4ead5dd9-7818-4f6c-8607-943feb02bf8a", "embedding": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "38eaefc4-4af9-4117-9d60-ed3eb7437b0e", "node_type": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8d3a9d5038bc0f9ae76fee5c136aa0a79164f4ad73f416fd788de020650a5f4"}, "2": {"node_id": "1a868faf-2a57-476a-ad57-512a4a15071c", "node_type": null, "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a15e893ae8c56129a116fc8f979326c72e022afd69f1ffaa174008836d67461d"}}, "hash": "b83323a3d3f9ad366029402b7c0ad886fbcde9e7ce2e6bfaba5198a28d3c0a86", "text": "conventional textbook dogma but neglecting the fact that \nG proteins are not the only link between GPCRs and the various effector systems that they regulate. In this context, signalling mediated \nthrough arrestins bound to the receptor (see p. 36), rather than through \nG\tproteins, \tis \timportant \t(see \treviews \tby \tPierce \t& \tLefkowitz, \t2001; \t\nDelcourt et al., 2007). Arrestins can act as an intermediary for GPCR \nactivation of the MAP kinase cascade (see Fig. 3.15B).\nThere are many examples where the various \u2018adapter proteins\u2019 that \nlink receptors of the tyrosine kinase type to their effectors (see p. 42) \ncan\talso\tinteract \twith \tGPCRs \t(see \tBrzostowski \t& \tKimmel, \t2001), \t\nallowing the same effector systems to be regulated by receptors of either type.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6976, "end_char_idx": 8223, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "12fab41d-e2b8-406e-bc4d-6c6d6e1f35bd": {"__data__": {"id_": "12fab41d-e2b8-406e-bc4d-6c6d6e1f35bd", "embedding": null, "metadata": {"page_label": "47", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "44e7e96e-e9ab-43cd-9165-93344bdf02da", "node_type": null, "metadata": {"page_label": "47", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91de9081c471635f1aef0c2e3f5390d9f5c1991111088d6fdc741b0713e91457"}}, "hash": "91de9081c471635f1aef0c2e3f5390d9f5c1991111088d6fdc741b0713e91457", "text": "3 How dRuGS ACt: moLECuLAR ASPECtS\n41Growth\nfactor\nReceptor\ndomain\nTransmembrane\n\u03b1 helix\nTyrosine kinase\ndomain\nTyrosine\nresidueConformation\nchange\nDimerisationTyrosine\nautophosphorylation\nBinding of SH2-domain\nprotein (Grb2)GDPActivation of Ras\nGDP/GTP exchange\nMEMBRANEPhosphorylation\nof Grb2\nPP\nGrb2GTPActivation\nRaf\nMek\nMAP kinase\nVarious transcription\nfactorsPhosphorylation\nPhosphorylation\nPhosphorylation\nNUCLEUSPP P\nGrb2\nGene transcriptionRas\nKINASE\nCASCADE\nDimerisation\nConformation change\nactivation of JakPhosphorylation of receptor\n+ JakCytokine\nJak Jak JakPP\nPPJak Jak\nNUCLEUSMEMBRANE\nP\nP Stat StatStatBinding and\nphosphorylation\nof SH2-domain\nprotein (Stat)Dimerisation\nof Stat\nGene transcriptionA\nB\nFig. 3.17 Transduction mechanisms of kinase-linked receptors. The first step following agonist binding is dimerisation, which leads \nto autophosphorylation of the intracellular domain of each receptor. SH2-domain proteins then bind to the phosphorylated receptor and are \nthemselves phosphorylated. Two well-characterised pathways are shown: (A) the growth factor (Ras/Raf/mitogen-activated protein [MAP] \nkinase) pathway (see also Ch. 6). Grb2 can also be phosphorylated but this negatively regulates its signalling. (B) Simplified scheme of the \ncytokine (Jak/Stat) pathway (see also Ch. 19). Some cytokine receptors may pre-exist as dimers rather than dimerise on cytokine binding. \nSeveral other pathways exist, and these phosphorylation cascades interact with components of G protein systems. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1995, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0831e61c-0bf5-4352-a669-03f46ef7140d": {"__data__": {"id_": "0831e61c-0bf5-4352-a669-03f46ef7140d", "embedding": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c12437f5-afce-4ef2-b43f-56eb7100a2b6", "node_type": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dfa9fa35d4c3773bd6b324c5759cda65d1287e8087c75487f54c64bde6b73965"}, "3": {"node_id": "aef0bbb6-6a34-4a8d-b9d1-8c44a38f9f24", "node_type": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44d6edf60fce1cb805a329f6b74052aa52388b5ce8ce3f9834e01e662dd5aa07"}}, "hash": "b2b362be1ec51dc9d89872a4b5d6dcf0ad754cd4bcde478025914d865090d954", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n42Kinase-linked receptors \n\u2022\tReceptors \tfor \tvarious \tgrowth \tfactors \tincorporate \t\ntyrosine kinase in their intracellular domain.\n\u2022\tCytokine \treceptors \thave \tan \tintracellular \tdomain \tthat \t\nbinds and activates cytosolic kinases when the \nreceptor is occupied.\n\u2022\tThe\treceptors \tall \tshare \ta \tcommon \tarchitecture, \twith \ta \t\nlarge extracellular ligand-binding domain connected via a single membrane-spanning helix to the intracellular domain.\n\u2022\tSignal\ttransduction \tgenerally \tinvolves \tdimerisation \tof \t\nreceptors, followed by autophosphorylation of tyrosine residues. The phosphotyrosine residues act as acceptors for the SH2 domains of a variety of \nintracellular proteins, thereby allowing control of many \ncell functions.\n\u2022\tThey\tare \tinvolved \tmainly \tin \tevents \tcontrolling \tcell \t\ngrowth and differentiation, and act indirectly by regulating gene transcription.\n\u2022\tTwo\timportant \tpathways \tare:\n\u2013 the Ras/Raf/mitogen-activated protein (MAP) kinase \npathway, which is important in cell division, growth and differentiation\n\u2013 the Jak/Stat pathway activated by many cytokines, \nwhich controls the synthesis and release of many inflammatory mediators.\n16v-Src is a gene found in Rous sarcoma virus that encodes a tyrosine \nkinase which causes sarcoma (a malignant tumour) in chickens \u2013 it was \nfound to have a closely related sequence to the chicken\u2019s own gene \ntermed c-Src (for cellular rather than viral Src). This was the first oncogene to be discovered, in 1979.17Protein kinase B was named to fill in the gap between protein kinase \nA (cAMP-dependent) and protein kinase C (Ca2+-dependent). As you \ncan see, nomenclature is highly imaginative!PROTEIN \u2003PHOSPHORYLATION \u2003AND \u2003KINASE \u2003\u2003\nCASCADE \u2003MECHANISMS\nProtein phosphorylation (see Cohen, 2002) is a key mecha -\nnism\tfor\tcontrolling \tthe\tfunction\tof\tproteins\t(e.g.\tenzymes, \t\nion channels, receptors, transport proteins) involved in \nregulating cellular processes. Phosphorylation and dephos -\nphorylation are accomplished by kinases and phosphatases, \nrespectively \t\u2013\tenzymes, \tof\twhich\tseveral\thundred \tsubtypes \t\nare represented in the human genome \u2013 which are them -\nselves subject to regulation dependent on their phosphoryla -\ntion status. Much effort is currently being invested in mapping the complex interactions between signalling molecules that are involved in drug effects and pathophysi -\nological processes such as oncogenesis, neurodegeneration, inflammation and much else. Here we can present only a few pharmacologically relevant aspects of what has become \nan enormous subject.\nIn many cases, ligand binding to the receptor leads to \ndimerisation. The association of the two intracellular kinase \ndomains allows a mutual autophosphorylation of intra -\ncellular tyrosine residues to occur. The phosphorylated tyrosine residues then serve as high-affinity docking sites for other intracellular proteins that form the next stage in \nthe\tsignal \ttransduction \tcascade. \tOne \timportant \tgroup \tof \t\nsuch proteins is known as the SH2 domain proteins (standing \nfor Src homology, because they were first identified in the \nSrc oncogene product).16 These possess a highly conserved sequence of about 100 amino acids, forming a recognition site for the phosphotyrosine residues of the receptor. Individual SH2 domain proteins, of which many", "start_char_idx": 0, "end_char_idx": 3349, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aef0bbb6-6a34-4a8d-b9d1-8c44a38f9f24": {"__data__": {"id_": "aef0bbb6-6a34-4a8d-b9d1-8c44a38f9f24", "embedding": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c12437f5-afce-4ef2-b43f-56eb7100a2b6", "node_type": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dfa9fa35d4c3773bd6b324c5759cda65d1287e8087c75487f54c64bde6b73965"}, "2": {"node_id": "0831e61c-0bf5-4352-a669-03f46ef7140d", "node_type": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2b362be1ec51dc9d89872a4b5d6dcf0ad754cd4bcde478025914d865090d954"}, "3": {"node_id": "99937a63-52ed-4da4-8cf8-f7ff7a3da181", "node_type": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b7f4068a32cd4088c3115f2c8a7d8e7a4aa3b8510fbff3a895994c4b8b8fa27"}}, "hash": "44d6edf60fce1cb805a329f6b74052aa52388b5ce8ce3f9834e01e662dd5aa07", "text": "residues of the receptor. Individual SH2 domain proteins, of which many are now \nknown, bind selectively to particular receptors, so the pattern \nof events triggered by particular growth factors is highly specific. The mechanism is summarised in Fig. 3.17.\nWhat happens when the SH2 domain protein binds to \nthe phosphorylated receptor varies greatly according to the receptor that is involved; many SH2 domain proteins are \nenzymes, \tsuch \tas \tprotein \tkinases \tor \tphospholipases. \tSome\t\ngrowth factors activate a specific subtype of phospholipase C (PLC\u03b3 ), thereby causing phospholipid breakdown, IP\n3 \nformation and Ca2+\trelease\t(see\tp.\t35).\tOther\tSH2-containing \t\nproteins couple phosphotyrosine-containing proteins with a variety of other functional proteins, including many that \nare involved in the control of cell division and differentiation. \nThe end result is to activate or inhibit, by phosphorylation, a variety of transcription factors that migrate to the nucleus \nand suppress or induce the expression of particular genes. \nFor more detail, see Jin and Pawson (2012). Nuclear factor \nkappa B (NF\u03baB) is a transcription factor that plays a key role \nin multiple disorders including inflammation and cancer \n(see Chs 18 and 57; Karin et al., 2004). It is normally present \nin the cytosol, complexed with an inhibitor (I \u03baB). Phospho-\nrylation of I \u03baB occurs when a specific kinase (IKK) is activated \nin response to various inflammatory cytokines and GPCR agonists. This results in dissociation of I \u03baB from NF\u03ba B and \nmigration of NF\u03ba B to the nucleus, where it switches on \nvarious proinflammatory and anti-apoptotic genes.\n\u25bc Two well-defined signal transduction pathways are summarised \nin Fig. 3.17 . The Ras/Raf pathway mediates the effect of many growth \nfactors and mitogens. Ras, which is a proto-oncogene product, functions \nlike a G protein, and conveys the signal (by GDP/GTP exchange) \nfrom the SH2-domain protein, Grb. Activation of Ras in turn activates Raf, which is the first of a sequence of three serine/threonine kinases, \neach of which phosphorylates, and activates, the next in line. The \nlast of these, MAP kinase (which is also activated by GPCRs, see earlier), phosphorylates one or more transcription factors that initiate \ngene expression, resulting in a variety of cellular responses, including \ncell division. This three-tiered MAP kinase cascade forms part of \nmany intracellular signalling pathways involved in a wide variety \nof disease processes, including malignancy, inflammation, neurode-generation, atherosclerosis and much else. The kinases form a large \nfamily, with different subtypes serving specific roles. They are thought \nto represent an important target for future therapeutic drugs. Many cancers are associated with mutations in the genes coding for proteins \ninvolved in this cascade, leading to activation of the cascade in the \nabsence of the growth factor signal (see Chs 6 and 57). For more details, see the review by Avruch (2007).\nA second pathway, the Jak/Stat pathway (see Fig. 3.17B), is involved \nin responses to many cytokines. Dimerisation of these receptors occurs \nwhen the cytokine binds, and this attracts a cytosolic tyrosine kinase \nunit (Jak) to associate with, and phosphorylate, the receptor dimer. Jaks belong to a family of proteins, different members having specificity for \ndifferent cytokine receptors. Among the targets for phosphorylation by \nJak are a family of transcription factors (Stats). These are SH2-domain proteins that bind to the", "start_char_idx": 3289, "end_char_idx": 6821, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "99937a63-52ed-4da4-8cf8-f7ff7a3da181": {"__data__": {"id_": "99937a63-52ed-4da4-8cf8-f7ff7a3da181", "embedding": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c12437f5-afce-4ef2-b43f-56eb7100a2b6", "node_type": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dfa9fa35d4c3773bd6b324c5759cda65d1287e8087c75487f54c64bde6b73965"}, "2": {"node_id": "aef0bbb6-6a34-4a8d-b9d1-8c44a38f9f24", "node_type": null, "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44d6edf60fce1cb805a329f6b74052aa52388b5ce8ce3f9834e01e662dd5aa07"}}, "hash": "6b7f4068a32cd4088c3115f2c8a7d8e7a4aa3b8510fbff3a895994c4b8b8fa27", "text": "transcription factors (Stats). These are SH2-domain proteins that bind to the phosphotyrosine groups on the receptor\u2013Jak \ncomplex, and are themselves phosphorylated. Thus activated, Stat \nmigrates to the nucleus and activates gene expression.\nOther\timportant \tmechanisms \tcentre \ton \tphosphatidylinositol-3 kinase \n(PI 3\tkinases, \tsee \tVanhaesebroeck \tet \tal., \t1997), \ta \tubiquitous \tenzyme \t\nfamily that is activated both by GPCRs and RTKs and attaches a phosphate group to position 3 of PIP\n2 to form PIP 3.\tOther\tprotein \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6805, "end_char_idx": 7810, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5d234af6-0d0b-4a8a-92ef-c7378fab12a3": {"__data__": {"id_": "5d234af6-0d0b-4a8a-92ef-c7378fab12a3", "embedding": null, "metadata": {"page_label": "49", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c924bd17-b0ee-4b91-b2ba-0b773b7e150e", "node_type": null, "metadata": {"page_label": "49", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e0c225ac19bf2baea2ff1305201febeb20344ba2bf41a973d2a7549d1b4bd0cd"}, "3": {"node_id": "7e29db77-cad8-422f-9bed-9dc06aab329d", "node_type": null, "metadata": {"page_label": "49", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "49fc4829736a931107a72b82b938746494cf26d6851a4ed2542aee0aca99fea2"}}, "hash": "083ad210cd861ce0b3e3a7eef7166dd41ca39680a8616e9c73ae3952e550e31c", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n43kinases, particularly protein kinase B (PKB,17 also known as Akt), \nhave recognition sites for PIP 3 and are thus activated, controlling a \nwide variety of cellular functions, including apoptosis, differentiation, \nproliferation \tand\ttrafficking. \tAkt\talso\tcauses\tNO\tsynthase \tactivation \t\nin the vascular endothelium (see Ch. 21).\nRecent work on signal transduction pathways has produced a bewilder -\ning profusion of molecular detail, often couched in a jargon that is apt \nto deter the faint-hearted. Perseverance will be rewarded, however, \nfor there is no doubt that important new drugs, particularly in the \nareas of inflammation, immunology and cancer, will come from the targeting of these proteins. A breakthrough in the treatment of chronic \nmyeloid leukaemia was achieved with the introduction of the first \nexplicitly-designed kinase inhibitor, imatinib, a drug that inhibits a \nspecific tyrosine kinase involved in the pathogenesis of the disease \n(see Ch. 57).\nFig. 3.18 illustrates the central role of protein kinases in \nsignal transduction pathways in a highly simplified and \nschematic way. Many, if not all, of the proteins involved, \nincluding the receptors and the kinases themselves, are substrates for kinases, so there are many mechanisms for \nfeedback and cross-talk between the various signalling \npathways. Given that there are over 500 protein kinases, and similarly large numbers of receptors and other signalling \nmolecules, the network of interactions can look bewilder-\ningly complex. Dissecting out the details has become a major theme in cell biology. For pharmacologists, the idea of a simple connection between receptor and response, \nwhich guided thinking throughout the 20th century, is \nundoubtedly crumbling, although it will take some time before the complexities of signalling pathways are assimi-\nlated into a new way of thinking about drug action.\n.,1$6(\u0003&$6&$'(6\n7$5*(7\u00033527(,16IP3\nCa2+ cAMP\nEnzymes ReceptorsIon\nchannelsTransportersTranscription\nfactorsContractile\nproteinsSecretory\nmechanisms\n5(63216(6\nPhysiological\nresponsesImmune\nresponsesApoptosisMalignant\ntransformationGrowth DifferentiationcGMP Auto-\nphosphorylationDAG\n*5.V 3.$ 3.& &D0\nNLQDVHV3.*GC-linked\nreceptorsKinase-linked\nreceptorsGPCRs\nFig. 3.18 Central role of kinase cascades in signal transduction. Kinase cascades (e.g. those shown in Fig. 3.15) are activated by G \nprotein\u2013coupled receptors (GPCRs), either directly or via different second messengers, by receptors that generate cGMP, or by kinase-\nlinked receptors. The kinase cascades regulate various target proteins, which in turn produce a wide variety of short- and long-term effects. CaM kinase, Ca\n2+/calmodulin-dependent kinase; DAG, diacylglycerol; GC, guanylyl cyclase; GRK, GPCR kinase; IP3, inositol trisphosphate; \nPKA, cAMP-dependent protein kinase; PKC, protein kinase C; PKG, cGMP-dependent protein kinase. Protein phosphorylation in signal \ntransduction \n\u2022\tMany\treceptor-mediated \tevents \tinvolve \tprotein \t\nphosphorylation, which controls the functional and \nbinding properties of intracellular proteins.\n\u2022\tReceptor-linked \ttyrosine \tkinases, \tcyclic \tnucleotide-\nactivated tyrosine kinases and intracellular serine/threonine kinases comprise a \u2018kinase cascade\u2019 mechanism that", "start_char_idx": 0, "end_char_idx": 3311, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7e29db77-cad8-422f-9bed-9dc06aab329d": {"__data__": {"id_": "7e29db77-cad8-422f-9bed-9dc06aab329d", "embedding": null, "metadata": {"page_label": "49", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c924bd17-b0ee-4b91-b2ba-0b773b7e150e", "node_type": null, "metadata": {"page_label": "49", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e0c225ac19bf2baea2ff1305201febeb20344ba2bf41a973d2a7549d1b4bd0cd"}, "2": {"node_id": "5d234af6-0d0b-4a8a-92ef-c7378fab12a3", "node_type": null, "metadata": {"page_label": "49", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "083ad210cd861ce0b3e3a7eef7166dd41ca39680a8616e9c73ae3952e550e31c"}}, "hash": "49fc4829736a931107a72b82b938746494cf26d6851a4ed2542aee0aca99fea2", "text": "kinases comprise a \u2018kinase cascade\u2019 mechanism that leads to amplification of receptor-\nmediated events.\n\u2022\tThere\tare \tmany \tkinases, \twith \tdiffering \tsubstrate \t\nspecificities, allowing specificity in the pathways \nactivated by different hormones.\n\u2022\tDesensitisation \tof \tG \tprotein\u2013coupled \treceptors \toccurs \t\nas a result of phosphorylation by specific receptor kinases, causing the receptor to become non-functional and to be internalised.\n\u2022\tThere\tis \ta \tlarge \tfamily \tof \tphosphatases \tthat \tact \tto \t\ndephosphorylate proteins and thus reverse the effects of kinases.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3261, "end_char_idx": 4311, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "97a71d97-b388-4830-9410-864ea5d13243": {"__data__": {"id_": "97a71d97-b388-4830-9410-864ea5d13243", "embedding": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8e356bc3-c376-4fa1-a0a4-966abcd841cb", "node_type": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aabf2398d5a78e77377e4b4c4c30f35f5610b5e145d94d4c251faa150efd7146"}, "3": {"node_id": "112f01dd-d54b-4512-8d7e-5ec87902f102", "node_type": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8309b7b5d90dbe0b6d5ac8957052e2bd6752e008308d382a100213924b2b612"}}, "hash": "b65302f1b20586645485d0cf3be64fc326b540201f8f5e32058ac61cb7a29a5a", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n44signalling, but many bind their ligands with low affinity \nand probably act as metabolic (e.g. lipid) sensors. They \nare thus crucial links between our dietary and metabolic \nstatus and the expression of genes that regulate the metabolism and disposition of lipids. NRs also regulate \nexpression \tof \tmany \tdrug-metabolising \tenzymes \tand \t \ntransporters.\nSTRUCTURE \u2003OF \u2003NUCLEAR \u2003RECEPTORS\n\u25bc All NRs are monomeric proteins of 50\u2013100 kDa, which share a \nbroadly similar structural design (see Fig. 3.19 and Bourguet et al., \n2000, for further details). The N-terminal domain displays the most \nheterogeneity. It harbours the activation function 1 (AF1) site that binds \nto other cell-specific transcription factors in a ligand-independent \nway and modifies the binding or regulatory capacity of the receptor itself. In the presence of the ligand, it synergises with AF2 to produce \nthe fully active complex. Alternative splicing of genes may yield several receptor isoforms, each with slightly different N-terminal regions. The core domain of the receptor is highly conserved and \nconsists of the structure responsible for DNA recognition and \nbinding. At the molecular level, this comprises two zinc fingers \u2013 \ncysteine- (or cystine-/histidine-) rich loops in the amino acid chain \nthat\tare\theld \tin \ta \tparticular \tconformation \tby \tzinc \tions. \tThe \tmain \t\nfunction of this portion of the molecule is to recognise and bind to the hormone response elements (HREs) located in the genes that \nare regulated by this family of receptors, but it also plays a part in \nregulating receptor dimerisation which is crucial to the function of \nmost NRs.\nIt is the highly flexible hinge region in the molecule that allows it to \ndimerise with other NRs and regulates the intracellular trafficking \nof the receptor. This can produce molecular complexes with diverse \nconfigurations, able to interact differently with DNA. Finally, the C-terminal domain contains the ligand-binding module and is specific \nto each class of receptor, although structurally highly conserved. It is also important in dimerisation and binding co-activator and co-repressor proteins (see later). The AF2 region is important in ligand-\ndependent activation and is generally highly conserved, although it \nis absent in Rev-erbA\u03b1 and Rev-erbA\u03b2, NRs that regulate metabolism \n(and also function as part of a circadian molecular clock mechanism). \nAlso located near the C-terminal are motifs that contain nuclear \nlocalisation signals and others that may, in the case of some receptors, \nbind accessory heat shock and other proteins.\nCONTROL \u2003OF \u2003GENE \u2003TRANSCRIPTION\n\u25bc HREs are short (usually 4\u20136 base pairs) sequences of DNA to \nwhich the NRs bind to modify gene transcription. They are generally \npresent symmetrically in pairs or half-sites, although these may be \narranged together in different ways (e.g. simple repeats or inverted \nrepeats ). Each NR exhibits a preference for a particular consensus sequence \nand the nucleotide spacing between them, but because of the family \nhomology, they share a close similarity. In the nucleus, the AF1 and \nAF2 domains of the ligand-bound receptor recruit large complexes of other proteins including co-activators or co-repressors to modify \ngene\texpression. \tSome \tof \tthese \tco-activators \tare \tenzymes \tinvolved \t\nin chromatin remodelling, such as histone acetylase/deacetylase which, \ntogether\twith \tother \tenzymes, \tregulate \tthe \tunravelling \tof \tthe \tDNA \t\nto\tf acilitate", "start_char_idx": 0, "end_char_idx": 3527, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "112f01dd-d54b-4512-8d7e-5ec87902f102": {"__data__": {"id_": "112f01dd-d54b-4512-8d7e-5ec87902f102", "embedding": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8e356bc3-c376-4fa1-a0a4-966abcd841cb", "node_type": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aabf2398d5a78e77377e4b4c4c30f35f5610b5e145d94d4c251faa150efd7146"}, "2": {"node_id": "97a71d97-b388-4830-9410-864ea5d13243", "node_type": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b65302f1b20586645485d0cf3be64fc326b540201f8f5e32058ac61cb7a29a5a"}, "3": {"node_id": "a8465211-371b-40cc-8ec5-1ce636927049", "node_type": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67ba43bd65444a5ab5482050b74591a0e5123a7fc3701e515121056776756dd0"}}, "hash": "a8309b7b5d90dbe0b6d5ac8957052e2bd6752e008308d382a100213924b2b612", "text": "\tthe \tunravelling \tof \tthe \tDNA \t\nto\tf acilitate \ta ccess\tb y\tp olymerase \te nzymes\ta nd\th ence\tg ene\tt ranscrip -\ntion. Co-repressor complexes are recruited by some receptors and \ncomprise histone deacetylase and other factors that cause the chromatin \nto become tightly packed, preventing further transcriptional activation. The case of the constitutive androstane receptor (CAR, see later) is \nparticularly interesting: like some G proteins described earlier in this chapter, CAR can form a constitutively active complex that is termi -\nnated when it binds its ligand. The mechanisms of negative gene \nregulation by NRs are particularly complex (see Santos et al., 2011 \nfor a good account of this phenomenon). In addition to agonists, NRs can also be targeted by competitive antagonists, which prevent \noccupation of the binding site by the endogenous ligand or by inverse \nagonists (or antagonists), which sterically prevent the binding of co-activator factors, thus reducing the constitutive activity of these TYPE 4: NUCLEAR RECEPTORS\nBy the 1970s, it was clear that receptors for steroid hormones \nsuch as oestrogen and the glucocorticoids (Chs. 36 and 34) \nwere present in the cytoplasm of cells and translocated \ninto the nucleus after binding with their steroid partner. \nOther\thormones, \tsuch \tas \tthe \tthyroid \thormone \tT3 (Ch. 35) \nand the fat-soluble vitamins D and A (retinoic acid), were \nfound to act in a similar fashion. Comparisons of gene and \nprotein sequence data led to the recognition that these receptors were members of a much larger family of related \nproteins. We now know these as the nuclear receptor (NR) \nfamily.\nAs well as NRs such as the glucocorticoid and retinoic \nacid receptor, whose ligands are well characterised, this family includes a great many (~40%) orphan receptors \u2013 \nreceptors with no known well-defined ligands (see earlier). The first of these to be described, in the 1990s, was the \nretinoid X receptor (RXR), a receptor cloned on the basis of \nits similarity with the vitamin A receptor, and which was \nsubsequently found to bind the vitamin A derivative 9- cis-\nretinoic acid. This event triggered intense interest in the NR field and, during the intervening years, specific binding partners have been characterised for many NRs (\u2018adopted \norphans\u2019, e.g. RXR) although in the case of many others \n(\u2018true orphans\u2019) these have yet to be identified \u2013 or perhaps do not exist as such, as one possible function of these \nreceptors is their \u2018promiscuous\u2019 ability to bind to many \nrelated compounds (such as dietary factors) with low affinity.\nUnlike the other receptors described in this chapter, NRs \ncan interact with DNA directly, and can be regarded as ligand-activated transcription factors that produce their effects \nby modifying gene transcription. Through this mechanism \nthey can control the transcription and expression of many \ngenes and proteins so, as it might be imagined, they are key players in regulating metabolic, developmental and \nother critical physiological processes. Another unique \nproperty is that NRs are not generally embedded in mem -\nbranes like GPCRs or ion channels, but are present in other \ncompartments of the cell. Some, such as the steroid receptors, \nwhich are predominately located in the cytoplasm, are activated by their ligand and translocate from the cytoplasm \nto the nucleus, while others, such as the RXR, probably \ndwell mainly within the nuclear compartment. Having said this, there is increasing evidence for the existence of small \npools of some NRs, such as oestrogen and glucocorticoid \nreceptors (ER and", "start_char_idx": 3486, "end_char_idx": 7096, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a8465211-371b-40cc-8ec5-1ce636927049": {"__data__": {"id_": "a8465211-371b-40cc-8ec5-1ce636927049", "embedding": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8e356bc3-c376-4fa1-a0a4-966abcd841cb", "node_type": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aabf2398d5a78e77377e4b4c4c30f35f5610b5e145d94d4c251faa150efd7146"}, "2": {"node_id": "112f01dd-d54b-4512-8d7e-5ec87902f102", "node_type": null, "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8309b7b5d90dbe0b6d5ac8957052e2bd6752e008308d382a100213924b2b612"}}, "hash": "67ba43bd65444a5ab5482050b74591a0e5123a7fc3701e515121056776756dd0", "text": "such as oestrogen and glucocorticoid \nreceptors (ER and GR) at the plasma membrane and in organelles such as the mitochondria (Levin and Hammes, \n2016), where they can act directly on other targets such as \nprotein kinases to bring about immediate biological actions.\nThe NR superfamily probably evolved from a single \ndistant evolutionary ancestral gene by duplication and other events. In man, there are at least 48 members, but more proteins may arise through alternative splicing events. While this represents a rather small proportion \nof all receptors (less than 10% of the total number of \nGPCRs), the NRs are very important drug targets (Burris \net al., 2013), being responsible for the biological effects of \napproximately 10%\u201315% of all prescription drugs. They can recognise an extraordinarily diverse group of substances \n(mostly small hydrophobic molecules), which may exhibit \nfull or partial agonist, antagonist or inverse agonist activ -\nity. Some NRs which bind their ligands with high affinity \n(e.g. ER and GR) are involved predominantly in endocrine mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7083, "end_char_idx": 8632, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "94871800-d70c-4425-8ece-cb3a0ff5e33c": {"__data__": {"id_": "94871800-d70c-4425-8ece-cb3a0ff5e33c", "embedding": null, "metadata": {"page_label": "51", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e0b0730-73a6-4f06-9a87-27c43e8dbb7c", "node_type": null, "metadata": {"page_label": "51", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "015f6af8cfdcb00b4de21d01fed66fa78c5ba6ec0231307dd7c2d7c79881c8bd"}, "3": {"node_id": "99fc101d-0c81-4986-9a02-520c9ffdd24d", "node_type": null, "metadata": {"page_label": "51", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "360d24059a0208edf16bf2e980baff8200abe1c2e35223ac29b91c202b4eab04"}}, "hash": "d0c76e1dcac8f20f052ee57701e91917322b9e46e7a3c9f7fb3afd3df6cf8a4d", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n45AF1 DBD Hinge LBD AF2 C\nC\nAC\nNN\nLA B\nFig. 3.19 Schematic diagram of a nuclear receptor. A greatly simplified diagram of the functional topology of a nuclear receptor (the \noestrogen receptor is picked as an example). A schematic diagram shows the various regions of the receptor including the DNA-binding \ndomain (DBD). Below is a diagram illustrating, in the corresponding colours, the configuration of the liganded receptor showing its binding \nto\thormone \tresponse \telements \t(HREs) \ton \tDNA. \tIn \tpanel \tA, \tthe \tligand \t(L) \tis \tbound \tin \tthe \tligand-binding \tdomain \t(LBD) \tand \tthis \tenables \tthe \t\nC-terminal \tAF2 \tregion \tto \tbind \tto \tthe \tLBD. \tIn \tturn, \tthis \tallows \tthe \tbinding \tof \ta \tco-activator \tprotein \tat \tthe \tLBD \t(only \ta \tpartial \tstructure \t\nshown),\twhich \tallows \tgene \ttranscription \tto \tproceed. \tIn \tpanel \tB, \tan \tantagonist \t(A) \tis \tbound \tto \tthe \tLBD. \tThis \tsterically \tinhibits \tthe \tbinding \tof \t\nAF2 and thus the attachment of the co-activator protein. Most nuclear receptors operate as dimers but only a monomer is shown here for \nclarity. (Based largely upon Shiau et al., 1998.) Cylindrical structures represent regions of \u03b1-helical protein structure.\nreceptors. A very interesting development is the identification of \nselective receptor modulators (e.g. selective oestrogen receptor \nmodulators - SERMs) which, by altering the binding of co-activator \nand co-repressor proteins, have agonist activity in some tissues and antagonist activities in others.\nCLASSIFICATION \u2003OF \u2003NUCLEAR \u2003RECEPTORS\nNRs are usually classified into subfamilies according to \ntheir phylogeny. For our purposes, however, it is more \nuseful to classify them on the basis of their molecular action \ninto two main classes (I and II), and two other minor groups of receptors (III, IV).\nClass I consists largely of endocrine steroid receptors, \nincluding the GRs and mineralocorticoid receptors (MRs), as well as the oestrogen, progesterone and androgen recep -\ntors (ER, PR and AR, respectively). The hormones (e.g. glucocorticoids) recognised by these receptors generally act in a negative feedback fashion to control biological events (see Ch. 34 for more details). In the absence of \ntheir ligand, these NRs are predominantly located in the \ncytoplasm, complexed with heat shock and other proteins, and possibly reversibly attached to the cytoskeleton or \nother intracellular structures. Following diffusion (or pos -\nsibly transportation) into the cell from the blood, ligands \nbind their NR partner with high affinity. These liganded \nreceptors generally form homodimers and translocate to \nthe nucleus, where they can transactivate or transrepress \ngenes\tby \tbinding \tto \t\u2018positive\u2019 \tor \t\u2018negative\u2019 \tHREs. \tOnce \t\nbound, the NR recruits other proteins to form complexes that promote transcription of multiple genes. For example, \nit is estimated that the activated GR itself can regulate transcription of ~1% of the genome either directly or \nindirectly.\nClass II NRs function in a slightly different way. Their \nligands are generally lipids or other metabolites already \npresent to some extent within the cell. This group includes \nthe peroxisome proliferator-activated receptor (PPAR) that \nrecognises fatty acids; the liver oxysterol receptor", "start_char_idx": 0, "end_char_idx": 3317, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "99fc101d-0c81-4986-9a02-520c9ffdd24d": {"__data__": {"id_": "99fc101d-0c81-4986-9a02-520c9ffdd24d", "embedding": null, "metadata": {"page_label": "51", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e0b0730-73a6-4f06-9a87-27c43e8dbb7c", "node_type": null, "metadata": {"page_label": "51", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "015f6af8cfdcb00b4de21d01fed66fa78c5ba6ec0231307dd7c2d7c79881c8bd"}, "2": {"node_id": "94871800-d70c-4425-8ece-cb3a0ff5e33c", "node_type": null, "metadata": {"page_label": "51", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0c76e1dcac8f20f052ee57701e91917322b9e46e7a3c9f7fb3afd3df6cf8a4d"}}, "hash": "360d24059a0208edf16bf2e980baff8200abe1c2e35223ac29b91c202b4eab04", "text": "that \nrecognises fatty acids; the liver oxysterol receptor (LXR) that \nrecognises and acts as a cholesterol sensor, the farnesoid \n(bile acid) receptor (FXR), a xenobiotic receptor (SXR; in rodents \nthe PXR) that recognises a great many foreign substances, \nincluding therapeutic drugs, and the CAR , which not only \nrecognises the steroid androstane but also some drugs such as phenobarbital (see Ch. 46). Indeed, PXR and CAR are \nakin to airport security guards who alert the bomb disposal \nsquad when suspicious luggage is found. When they \nsense foreign molecules (xenobiotics), they induce drug-\nmetabolising \tenzymes \tsuch\tas\tCYP3A\t(which\tis\tresponsible \t\nfor metabolising about 60% of all prescription drugs; see \nCh. 10 and di Masi et al., 2009). They also bind some \nprostaglandins and non-steroidal drugs, as well as the \nantidiabetic thiazolidinediones (see Ch. 32) and fibrates \n(see Ch. 24).\nUnlike the receptors in class I, these NRs almost always \noperate as heterodimers together with RXR, the retinoid X \nreceptor. Two types of heterodimer may then be formed: \na non-permissive heterodimer, which can be activated only \nby the RXR ligand itself, and the permissive heterodimer, \nwhich can be activated either by retinoic acid itself or by its partner\u2019s ligand. Class II NRs are generally bound to co-repressor proteins. These dissociate when the ligand binds and allows recruitment of co-activator proteins mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3259, "end_char_idx": 5167, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d8bce2db-f94a-42cb-9666-25e8f7b0d907": {"__data__": {"id_": "d8bce2db-f94a-42cb-9666-25e8f7b0d907", "embedding": null, "metadata": {"page_label": "52", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bda4286b-5944-419d-9879-4f1d143ea96e", "node_type": null, "metadata": {"page_label": "52", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ca60acfe54830d953d0ca87abb5509cba581311e6c76ae2d4de703dfcfdab00"}, "3": {"node_id": "9f6edab8-468a-4b75-8fbc-83a6d00d4f8b", "node_type": null, "metadata": {"page_label": "52", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53dbfcb5838364485de5fb15f8cc33a4b1105b73bcba80d3cfb19370581f64fd"}}, "hash": "f3a2acad7a558c68c0e861a31cc6cfa550e5a5ca63d24ee56fe57d90fe49b34d", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n46and hence changes in gene transcription. They tend to \nmediate positive feedback effects (e.g. occupation of the \nreceptor amplifies rather than inhibits a particular biological \nevent).\nClass III NRs are very similar to Class I in the sense that \nthey form homodimers, but they can bind to HREs, which \ndo not have an inverted repeat sequence. Class IV NRs may function as monomers or dimers but only bind to one \nHRE half site. Many of the remaining orphan receptors \nbelong to these latter classes.\nThe discussion here must be taken only as a broad guide \nto the action of NRs, as many other types of interaction \nhave also been discovered. For example, some of these \nreceptors may bring about non-genomic \u2013 or even genomic \u2013 actions by directly interacting with factors in the cytosol, \nor they may be covalently modified by phosphorylation \nor by protein\u2013protein interactions with other transcription factors such that their function is altered (see Falkenstein \net al., 2000).\nTable 3.4 summarises the properties of some common \nNRs of importance to pharmacologists.\nION CHANNELS AS DRUG TARGETS\nWe have discussed ligand-gated ion channels as one of the four main types of drug receptor. There are many other \ntypes of ion channel that represent important drug targets, \neven though they are not generally classified as \u2018receptors\u2019 Table 3.4 Some common pharmacologically significant nuclear receptors\nReceptor \nname Abbreviation Ligand Drugs LocationLigand bindingMechanism of action\nType I\nAndrogen AR Testosterone All natural and synthetic \nglucocorticoids (Ch. 34), mineralocorticoids (Ch. 30) and sex steroids (Ch. 36) together with their antagonists (e.g. raloxifene, 4-hydroxy-tamoxifen and mifepristone).Cytosolic HomodimersTranslocation to nucleus. Binding to HREs with two half-sites with an inverted sequence. Recruitment of co-activators, transcription factors and other proteins.Oestrogen ER\u03b1, \u03b2 17\u03b2-oestradiol\nGlucocorticoid GR\u03b1 Cortisol, corticosterone\nProgesterone PR Progesterone\nMineralocorticoid MR Aldosterone\nType II\nRetinoid X RXR \u03b1,\u03b2,\u03b3 9-cis-retinoic \nacidRetinoid drugs (Ch. 28)\nNuclearHeterodimers often with RXRBinding to HREs with two half-sites with an inverted or simple repeat sequence. Complexed with co-repressors, which are displaced following ligand binding, allowing the binding of co- activatorsRetinoic acid RAR \u03b1,\u03b2,\u03b3 Vitamin A\nThyroid hormone TR \u03b1,\u03b2 T3, T4 Thyroid hormone drugs (Ch. 35)\nPeroxisome proliferatorPPAR \u03b1,\u03b2,\u03b3,\u03b4 Fatty acids, prostaglandinsRosiglitazone, pioglitazone (Ch. 32)\nConstitutive androstaneCAR AndrostaneStimulation of CYP synthesis and alteration of drug metabolism (Ch. 10)Pregnane X PXR Xenobiotics\nOnly examples from Classes I and II are included.\nNuclear receptors \n\u2022\tA\tfamily \tof \t48 \tsoluble \treceptors \tthat \tsense \tlipid \tand \t\nhormonal signals and modulate gene transcription.\n\u2022\tTheir\tligands \tare \tmany \tand \tvaried, \tincluding \tsteroid \t\ndrugs and hormone, thyroid hormones, vitamins A and \nD, various lipids and xenobiotics\n\u2022\tThere\tare \ttwo \tmain \tcategories:\n\u2013 Class I nuclear receptors (NRs) are present in the \ncytoplasm, form homodimers in the presence of their ligand, and migrate to the nucleus. Their ligands are", "start_char_idx": 0, "end_char_idx": 3236, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9f6edab8-468a-4b75-8fbc-83a6d00d4f8b": {"__data__": {"id_": "9f6edab8-468a-4b75-8fbc-83a6d00d4f8b", "embedding": null, "metadata": {"page_label": "52", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bda4286b-5944-419d-9879-4f1d143ea96e", "node_type": null, "metadata": {"page_label": "52", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ca60acfe54830d953d0ca87abb5509cba581311e6c76ae2d4de703dfcfdab00"}, "2": {"node_id": "d8bce2db-f94a-42cb-9666-25e8f7b0d907", "node_type": null, "metadata": {"page_label": "52", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3a2acad7a558c68c0e861a31cc6cfa550e5a5ca63d24ee56fe57d90fe49b34d"}}, "hash": "53dbfcb5838364485de5fb15f8cc33a4b1105b73bcba80d3cfb19370581f64fd", "text": "presence of their ligand, and migrate to the nucleus. Their ligands are mainly endocrine in nature (e.g. steroid \nhormones);\n\u2013 Class II NRs are generally constitutively present in \nthe nucleus and form heterodimers with the retinoid \nX receptor. Their ligands are usually lipids (e.g. the fatty acids).\n\u2022\tThe\tliganded \treceptor \tcomplexes \tinitiate \tchanges \tin \t\ngene transcription by binding to hormone response elements in gene promoters and recruiting co-activator or co-repressor factors.\n\u2022\tThe\treceptor \tfamily \tis \tthe \ttarget \tof \tapproximately \t10% \t\nof prescription drugs, and the enzymes that it \nregulates\taffect \tthe \tpharmacokinetics \tof \tsome \t60% \tof \t\nall prescription drugs.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3165, "end_char_idx": 4336, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9aa5bedc-2a7f-420e-8a06-1cdc4a39bf30": {"__data__": {"id_": "9aa5bedc-2a7f-420e-8a06-1cdc4a39bf30", "embedding": null, "metadata": {"page_label": "53", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f2fc5f8b-f676-4a81-b59a-ab8873e8286c", "node_type": null, "metadata": {"page_label": "53", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c297022260f4fc235cb6f5f673e54fdc91dc2e82fabf5857480e8e3f24cc4f18"}, "3": {"node_id": "598c42f8-ac09-4e8e-82a6-3a25ed5b4618", "node_type": null, "metadata": {"page_label": "53", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdccc5691a156ab368f1639a57c27f11034b84f7428f8eadc1bc0c6b4532e8e5"}}, "hash": "50ddce286d22a00e3a88545b552d68be3d86db6d47c744b8d406bbc37190f602", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n47they underlie the mechanism of membrane excitability (see \nCh. 4). The most important channels in this group are \nselective sodium, potassium or calcium channels.\nCommonly, the channel opening (activation) induced \nby membrane depolarisation is short lasting, even if the depolarisation is maintained. This is because, with some \nchannels, the initial activation of the channels is followed by a slower process of inactivation.\nThe role of voltage-gated channels in the generation of \naction potentials and in controlling other cell functions is described in Chapter 4.\nLIGAND-GATED \u2003CHANNELS\nThese (see Fig. 3.5) are activated by binding of a chemical ligand to a site on the channel molecule. Fast neurotransmit -\nters, such as glutamate, acetylcholine, GABA, 5-HT and ATP (see Chs 14, 16, 17 and 39) act in this way, binding to sites on the outside of the membrane. In addition, there \nare also ligand-gated ion channels that do not respond to \nneurotransmitters but to changes in their local environment. For example, the TRPV1 channel on sensory nerves that \nmediates the pain-producing effect of the chilli pepper \ningredient capsaicin responds to extracellular protons when tissue pH falls, as occurs in inflamed tissue, as well as to the physical stimulus, heat (see Ch. 43).\nSome ligand-gated channels in the plasma membrane \nrespond to intracellular rather than extracellular signals, the most important being the following:\n\u2022\tCalcium-activated \tpotassium \tchannels, \twhich \toccur \tin \t\nmost cells and open, thus hyperpolarising the cell, when [Ca\n2+]i increases.\n\u2022\tCalcium-activated \tchloride \tchannels, \twidely \texpressed \t\nin excitable and non-excitable cells where they are involved in diverse functions such as epithelial \nsecretion of electrolytes and water, sensory \ntransduction, regulation of neuronal and cardiac excitability and regulation of vascular tone.\n\u2022\tATP-sensitive \tpotassium \tchannels, \twhich \topen \twhen \t\nthe intracellular ATP concentration falls because the cell is short of energy. These channels, which are quite \ndistinct from those mediating the excitatory effects of \nextracellular ATP, occur in many nerve and muscle cells, and also in insulin-secreting cells (see Ch. 32), \nwhere they are part of the mechanism linking insulin \nsecretion to blood glucose concentration.\nOther\texamples \tof \tcell \tmembrane \tchannels \tthat \trespond \t\nto intracellular ligands include arachidonic acid-sensitive potassium channels and DAG-sensitive calcium channels, \nwhose functions are not well understood.\nCALCIUM \u2003RELEASE \u2003CHANNELS\nThe main ones, IP 3 and ryanodine receptors (see Ch. 4), \nare a special class of ligand-gated calcium channels that are present on the endoplasmic or sarcoplasmic reticulum \nrather than the plasma membrane and control the release of Ca\n2+ from intracellular stores. Ca2+ can also be released \nfrom lysosomal stores by nicotinic acid adenine dinucleotide \nphosphate, which activates two-pore domain calcium \nchannels.\nSTORE-OPERATED \u2003CALCIUM \u2003CHANNELS\nWhen the intracellular Ca2+ stores are depleted, \u2018store-\noperated\u2019 \tchannels \t(SOCs) \tin \tthe \tplasma \tmembrane \topen \t\nto allow Ca2+ entry. The mechanism by which this linkage because they are not the immediate targets of fast neuro-transmitters, but drugs can act upon them to alter their ability to open and close.\n18\nHere we discuss the structure and function of ion channels \nat the molecular level; their role as", "start_char_idx": 0, "end_char_idx": 3471, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "598c42f8-ac09-4e8e-82a6-3a25ed5b4618": {"__data__": {"id_": "598c42f8-ac09-4e8e-82a6-3a25ed5b4618", "embedding": null, "metadata": {"page_label": "53", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f2fc5f8b-f676-4a81-b59a-ab8873e8286c", "node_type": null, "metadata": {"page_label": "53", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c297022260f4fc235cb6f5f673e54fdc91dc2e82fabf5857480e8e3f24cc4f18"}, "2": {"node_id": "9aa5bedc-2a7f-420e-8a06-1cdc4a39bf30", "node_type": null, "metadata": {"page_label": "53", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50ddce286d22a00e3a88545b552d68be3d86db6d47c744b8d406bbc37190f602"}}, "hash": "cdccc5691a156ab368f1639a57c27f11034b84f7428f8eadc1bc0c6b4532e8e5", "text": "the structure and function of ion channels \nat the molecular level; their role as regulators of cell function \nis described in Chapter 4.\nIons are unable to penetrate the lipid bilayer of the cell \nmembrane, and can get across only with the help of membrane-spanning proteins in the form of channels or \ntransporters. The concept of ion channels was developed in the 1950s on the basis of electrophysiological studies on \nthe mechanism of membrane excitation (see Ch. 4). Elec -\ntrophysiology, particularly the voltage clamp technique, \nremains an essential tool for studying the physiological \nand pharmacological properties of ion channels. Since the \nmid-1980s, when the first ion channels were cloned by \nNuma in Japan, much has been learned about the structure and function of these complex molecules. The use of patch \nclamp recording, which allows the behaviour of individual \nchannels to be studied in real time, has been particularly valuable in distinguishing channels on the basis of their \nconductance and gating characteristics. Accounts by Hille \n(2001), Ashcroft (2000) and Catterall (2000) give background information.\nIon channels consist of protein molecules designed to \nform water-filled pores that span the membrane, and can switch between open and closed states. The rate and direc -\ntion of ion movement through the pore is governed by the electrochemical gradient for the ion in question, which is a function of its concentration on either side of the mem-\nbrane, and of the membrane potential. Ion channels are \ncharacterised by:\n\u2022\ttheir\tselectivity \tfor \tparticular \tion \tspecies, \tdetermined \t\nby\tthe\tsize \tof \tthe \tpore \tand \tthe \tnature \tof \tits \tlining;\n\u2022\ttheir\tgating \tproperties \t(i.e. \tthe \tnature \tof \tthe \tstimulus \t\nthat controls the transition between open and closed states of the channel);\n\u2022\ttheir\tmolecular \tarchitecture.\nION SELECTIVITY\nChannels are generally either cation selective or anion selective. The main cation-selective channels are selective \nfor Na\n+, Ca2+ or K+, or non-selective and permeable to all \nthree. Anion channels are mainly permeable to Cl\u2212, although \nother types also occur. The effect of modulation of ion channels on cell function is discussed in Chapter 4.\nGATING\nVOLTAGE-GATED \u2003CHANNELS\nIn the main these channels open when the cell membrane \nis depolarised.19 They form a very important group because \n18In truth, the distinction between ligand-gated channels and other ion \nchannels is an arbitrary one. In grouping ligand-gated channels with \nother types of receptor in this book, we are respecting the historical \ntradition established by Langley and others, who first defined receptors in the context of the action of acetylcholine at the neuromuscular \njunction. The advance of molecular biology may force us to reconsider \nthis semantic issue in the future, but for now we make no apology for upholding the pharmacological tradition.\n19There is always an exception to the rule! The members of the HCN \nfamily of potassium channels found in neurons and cardiac muscle cells \nare activated by hyperpolarisation.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3390, "end_char_idx": 6955, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "75da4d16-b915-40a7-866c-9f15077ede58": {"__data__": {"id_": "75da4d16-b915-40a7-866c-9f15077ede58", "embedding": null, "metadata": {"page_label": "54", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fe6a6dfc-6763-448e-a127-155f43e5db8f", "node_type": null, "metadata": {"page_label": "54", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29ca6fecfead4e0dc8f7934d63eaf1594146ab9dd29963ea239ca1f0c7b9615b"}, "3": {"node_id": "fa614868-bbc4-4fb8-9f49-b0bd067419c5", "node_type": null, "metadata": {"page_label": "54", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dfa9c328f044a3026674fe2805ca599c7c960015e927e3ca58b45c94709f7d8e"}}, "hash": "ae5eef329a126df4e8dcdc874b37a1cc56802e53122b2768635409ac4d459a49", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n48a\nCATION\nCHANNELS\nVOLTAGE-GATED \nSODIUM AND \nCALCIUM \nCHANNELS\nN CN C\nExamples: Voltage-gated\nK+ channels, TRP channels\n(tetrame ric assembly)N C\nExamples: Inward-rectifying\nK+ channelsa, ASICb,\nENaCb\n(atetrameric or btrimeric assembly)N C\nExamples: Resting K+ \nchannels\n(dimeric assembly)A\nB\nFig. 3.20 Molecular architecture of ion channels. Red and blue rectangles represent membrane-spanning \u03b1-helices. Blue hairpins are \npore loop (P) domains, present in many channels, blue rectangles being the pore-forming regions of the membrane-spanning \u03b1-helices. \nCross-shaded rectangles represent the voltage-sensing regions of voltage-gated channels. The green symbol represents the inactivating \nparticle of voltage-gated sodium channels. Further information on ion channels is given in Chapter 4. ASIC, acid-sensing ion channel; \nENaC, epithelial sodium channel; TRP, transient receptor potential channel. \n20The human genome encodes more than 70 distinct potassium channel \nsubtypes \u2013 either a nightmare or a golden opportunity for the \npharmacologist, depending on one\u2019s perspective.occurs involves interaction of a Ca2+-sensor protein in the \nendoplasmic reticulum membrane with a dedicated Ca2+ \nchannel in the plasma membrane (see Stathopulos & Ikura, \n2017). In response to GPCRs that elicit Ca2+ release, the \nopening of these channels allows the cytosolic free Ca2+ \nconcentration, [Ca2+]i, to remain elevated even when the \nintracellular stores are running low, and also provides \na route through which the stores can be replenished \n(see Ch. 4).\nMOLECULAR ARCHITECTURE OF ION CHANNELS\n\u25bc I on channels are large and elaborate molecules. Their characteristic \nstructural motifs have been revealed as knowledge of their sequence \nand structure has accumulated since the mid-1980s, when the first \nvoltage-gated sodium channel was cloned. The main structural \nsubtypes are shown in Fig. 3.20. All consist of several (often four) domains, which are similar or identical to each other, organised either \nas an oligomeric array of separate subunits, or as one large protein. \nEach subunit or domain contains a bundle of two to six membrane-spanning helices.\nVoltage-gated channels generally include one transmembrane helix \nthat contains an abundance of basic (i.e. positively charged) amino \nacids. When the membrane is depolarised, so that the interior of the \ncell becomes less negative, this region \u2013 the voltage sensor \u2013 moves slightly towards the outer surface of the membrane, which has the \neffect\tof\topening \tthe \tchannel \t(see \tBezanilla, \t2008). \tMany \tvoltage-\nactivated channels also show inactivation, which happens when an \nintracellular appendage of the channel protein moves to plug the \nchannel from the inside. Voltage-gated sodium and calcium channels are remarkable in that the whole structure with four six-helix domains \nconsists of a single huge protein molecule, the domains being linked together by intracellular loops of varying length (see Fig. 3.20B). \nPotassium channels comprise the most numerous and heterogeneous \nclass.\n20 Voltage-gated potassium channels resemble sodium channels, \nexcept that they are made up of four subunits rather than a single \nlong chain. The class of potassium channels known as \u2018inward rectifier \nchannels\u2019 because of their biophysical properties has the", "start_char_idx": 0, "end_char_idx": 3359, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fa614868-bbc4-4fb8-9f49-b0bd067419c5": {"__data__": {"id_": "fa614868-bbc4-4fb8-9f49-b0bd067419c5", "embedding": null, "metadata": {"page_label": "54", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fe6a6dfc-6763-448e-a127-155f43e5db8f", "node_type": null, "metadata": {"page_label": "54", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29ca6fecfead4e0dc8f7934d63eaf1594146ab9dd29963ea239ca1f0c7b9615b"}, "2": {"node_id": "75da4d16-b915-40a7-866c-9f15077ede58", "node_type": null, "metadata": {"page_label": "54", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ae5eef329a126df4e8dcdc874b37a1cc56802e53122b2768635409ac4d459a49"}}, "hash": "dfa9c328f044a3026674fe2805ca599c7c960015e927e3ca58b45c94709f7d8e", "text": "as \u2018inward rectifier \nchannels\u2019 because of their biophysical properties has the two-helix structure shown in Fig. 3.20A, whereas others are classed as \u2018two-pore \ndomain\u2019 channels, because each subunit contains two P loops.\nThe various architectural motifs shown in Fig. 3.20 only scrape the \nsurface of the molecular diversity of ion channels. In all cases, the \nindividual subunits come in several molecular varieties, and these can unite in different combinations to form functional channels as \nhetero-oligomers (as distinct from homo-oligomers built from identical \nsubunits). Furthermore, the channel-forming structures described are usually associated with other membrane proteins, which significantly \naffect their functional properties. For example, the ATP-gated potas -\nsium channel exists in association with the sulfonylurea receptor (SUR), \nand it is through this linkage that various drugs (including antidiabetic drugs of the sulfonylurea class; see Ch. 32) regulate the channel. \nGood progress is being made in understanding the relation between \nmolecular structure and ion channel function, but we still have only \na fragmentary understanding of the physiological role of many of these channels. Many important drugs exert their effects by influencing \nchannel function, either directly or indirectly.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3280, "end_char_idx": 5079, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f6770141-7143-4232-9d58-a5407559fc8d": {"__data__": {"id_": "f6770141-7143-4232-9d58-a5407559fc8d", "embedding": null, "metadata": {"page_label": "55", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d20a21e8-617f-4acf-96e9-5767a390d0f3", "node_type": null, "metadata": {"page_label": "55", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc83766bc0b13b699f93048e22a15ccfdacc0bbc923f87ffa4a3482aab298192"}, "3": {"node_id": "44dbac68-49ef-4c9a-8b6f-5866bd6d36f1", "node_type": null, "metadata": {"page_label": "55", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "32a327124c17430691d25fa9752f5957aa1570b7c506ce5b0ccc15ddc0e81c04"}}, "hash": "8b633401c58e36327233f93168884ad173caead87f841ef7ac02fa263b658d7e", "text": "3 How d RuGS AC t: mo LEC u LAR ASPEC t S\n49to\tdrug\ttargets \t other \tth an \t receptors \t (ion \t channels, \t enzymes, \t\ntransporters, etc.) where adaptive changes in expression \nand function follow long-term drug administration, result -\ning, for example, in resistance to certain anticancer drugs (Ch. 57).\nRECEPTORS AND DISEASE\nIncreasing understanding of receptor function in molecular terms has revealed a number of disease states directly linked \nto receptor malfunction. The principal mechanisms involved \nare:\n\u2022\tautoantibodies \tdirected \tagainst \treceptor \tproteins;\n\u2022\tmutations \tin \tgenes \tencoding \treceptors, \tion \tchannels \t\nand proteins involved in signal transduction.\nAn example of the former is myasthenia gravis (see Ch. 14), \na disease of the neuromuscular junction due to autoantibod -\nies that inactivate nicotinic acetylcholine receptors. Autoan -\ntibodies can also mimic the effects of agonists, as in many \ncases of thyroid hypersecretion, caused by activation of \nthyrotropin receptors (Ch. 35).\nInherited mutations of genes encoding GPCRs account \nfor various disease states (see Stoy & Gurevich, 2015). Mutated vasopressin and adrenocorticotrophic hormone \nreceptors (see Chs 30 and 34) can result in resistance to \nthese hormones. Receptor mutations can result in activation \nof\teffector \tmechanisms \tin \tthe \tabsence \tof \tagonists. \tOne \tof \t\nthese involves the receptor for thyrotropin, producing \ncontinuous oversecretion of thyroid hormone; another PHARMACOLOGY OF ION CHANNELS\n\u25bc Many drugs and physiological mediators described in this book \nexert their effects by altering the behaviour of ion channels.\nThe gating and permeation of both voltage-gated and ligand-gated \nion channels is modulated by many factors, including the following.\n\u2022\tLigands that bind directly to various sites on the channel protein. \nThese include a variety of drugs and toxins that act in different ways, for example by blocking the channel or by affecting the \ngating process, thereby either facilitating or inhibiting the \nopening of the channel.\n\u2022\tMediators and drugs that act indirectly, mainly by activation of GPCRs. The latter produce their effects mainly by affecting the state of phosphorylation of individual amino acids located on \nthe intracellular region of the channel protein. As described \nabove, this modulation involves the production of second messengers that activate protein kinases. The opening of the \nchannel may be facilitated or inhibited, depending on which \nresidues are phosphorylated. Drugs such as \u03b2-adrenoceptor \nagonists (Ch. 15) affect calcium and potassium channel function \nin this way, producing a wide variety of cellular effects.\n\u2022\tIntracellular signals, particularly Ca\n2+ and nucleotides such as ATP \nand GTP (see Ch. 4). Many ion channels possess binding sites for \nthese intracellular mediators. Increased [Ca2+]i opens certain \ntypes of potassium and chloride channels, and inactivates voltage-gated calcium channels. As described in Chapter 4, \n[Ca\n2+]i is itself affected by the function of ion channels and \nGPCRs. Intracellular ATP binds to and closes a family of \npotassium channels known as the ATP-gated potassium \nchannels (see Ch. 32) that are also sensitive to sulfonylurea drugs. Intracellular cyclic nucleotides, cAMP and cGMP, activate \nchannels permeable to either calcium and sodium ions or to \npotassium ions.\nFig. 3.21 summarises the main sites and mechanisms by which drugs affect voltage-gated sodium channels, a typical example", "start_char_idx": 0, "end_char_idx": 3499, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "44dbac68-49ef-4c9a-8b6f-5866bd6d36f1": {"__data__": {"id_": "44dbac68-49ef-4c9a-8b6f-5866bd6d36f1", "embedding": null, "metadata": {"page_label": "55", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d20a21e8-617f-4acf-96e9-5767a390d0f3", "node_type": null, "metadata": {"page_label": "55", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc83766bc0b13b699f93048e22a15ccfdacc0bbc923f87ffa4a3482aab298192"}, "2": {"node_id": "f6770141-7143-4232-9d58-a5407559fc8d", "node_type": null, "metadata": {"page_label": "55", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b633401c58e36327233f93168884ad173caead87f841ef7ac02fa263b658d7e"}}, "hash": "32a327124c17430691d25fa9752f5957aa1570b7c506ce5b0ccc15ddc0e81c04", "text": "by which drugs affect voltage-gated sodium channels, a typical example of this type of drug target.\nCONTROL OF RECEPTOR EXPRESSION\nReceptor proteins are synthesised by the cells that express \nthem, and the level of expression is itself controlled, via \nthe pathways discussed previously, by receptor-mediated \nevents. We can no longer think of the receptors as the fixed elements in cellular control systems, responding to changes \nin the concentration of ligands, and initiating effects through \nthe signal transduction pathway \u2013 they are themselves subject to regulation. Short-term regulation of receptor \nfunction generally occurs through desensitisation , as discussed \nearlier. Long-term regulation occurs through an increase or \ndecrease of receptor expression . Examples of this type of control \ninclude the proliferation of various postsynaptic receptors after denervation (see Ch. 13), the up-regulation of various \nG protein\u2013coupled and cytokine receptors in response to inflammation (see Ch. 18), and the induction of growth \nfactor receptors by certain tumour viruses (see Ch. 6). \nLong-term drug treatment invariably induces adaptive responses, which, particularly with drugs that act on the \ncentral nervous system, can limit their effectiveness as in \nopioid tolerance (see Ch. 43) or can be the basis for thera -\npeutic efficacy. In the latter instance this may take the form \nof a very slow onset of the therapeutic effect (e.g. with \nantidepressant drugs; see Ch. 48). It is likely that changes in receptor expression, secondary to the immediate action \nof the drug, are involved in delayed effects of this sort \u2013 a \nkind of \u2018secondary pharmacology\u2019, the importance of which is only now becoming clearer. The same principles apply GPCRs\nSecond messengers\nPKA\nPKC\nPhosphorylationTetrodotoxin\nSaxitoxin\nConotoxins\nBLOCK OF\nINACTIVATION\nVeratridine\nBatrachotoxin\nScorpion toxins\nDDT, pyrethroids\nCHANNEL\nBLOCK\nLocal anaesthetics\nAntiepileptic drugs\n(e.g. phenytoin)\nAntidysrhythmic drugs\n(e.g. disopyramide)ALTERED\nGATING\nGPCR ligandsCHANNEL\nBLOCK\nFig. 3.21 Drug-binding domains of voltage-gated sodium \nchannels (see Ch. 44). The multiplicity of different binding sites \nand effects appears to be typical of many ion channels. DDT, \nDichlorodiphenyltrichloroethane (dicophane, a well-known \ninsecticide); GPCR, G protein\u2013coupled receptor; PKA, protein \nkinase A; PKC, protein kinase C. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3429, "end_char_idx": 6312, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a5628738-a1be-43f8-ae8d-c0a46b6d639c": {"__data__": {"id_": "a5628738-a1be-43f8-ae8d-c0a46b6d639c", "embedding": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2cd795c4-1b50-49a8-ba49-8c8057d21a6a", "node_type": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d6644bc783947e7294e79a7f64c3a070a6b2036ae7c5feda747e97505501870"}, "3": {"node_id": "072a0792-c6aa-455d-8a5b-c45ea9db4163", "node_type": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5205cd22c27c03c9d58f8a3785b5b64809cf30bc93b8ec7fe2bffa9c83c8452f"}}, "hash": "be5c2852c68884d42adf6f5901101a262641fd15b72ae66e2e659a68bcf2ceaf", "text": "3 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n50their function give rise to some forms of idiopathic epilepsy \n(see Ch. 46 and Poduri & Lowenstein, 2011).\nGiven the fact that the NR family of receptors plays a \nkey part in the regulation and coordination of growth, development and organogenesis, reproduction, the immune \nsystem and many other fundamental biological processes, \nit is not surprising that many illnesses are associated with malfunctioning of the NR system. Such conditions include \ninflammation, cancer, diabetes, cardiovascular disease, \nobesity and reproductive disorders (see Kersten et al., 2000; \nMurphy & Holder, 2000).\nResearch on genetic polymorphisms affecting recep-\ntors, signalling molecules, ion channels and effector \nenzymes \tis \tcontinuing \tapace, \tand \tit \tis \texpected \tthat \ta \t\nclearer understanding of the variability between indi -\nviduals in their disease susceptibility and response to therapeutic drugs (see Ch. 58) will result, in the foreseeable \nfuture.involves the receptor for luteinising hormone and results \nin precocious puberty. Adrenoceptor polymorphisms are common in humans, and recent studies suggest that certain \nmutations of the \u03b2\n2 adrenoceptor, although they do not \ndirectly cause disease, are associated with a reduced efficacy of \u03b2-adrenoceptor agonists in treating asthma (Ch. 29) and \na poor prognosis in patients with cardiac failure, potentially \nthrough constitutively active mutations that render receptors \nactive in the absence of any agonists (Ch. 22). Mutations in G proteins can also cause disease (see Spiegel & Weinstein, \n2004). For example, mutations of a particular G \u03b1 subunit \ncause one form of hypoparathyroidism, while mutations of a G\u03b2 subunit result in hypertension. Many cancers are associated with mutations of the genes encoding growth factor receptors, kinases and other proteins involved in \nsignal transduction (see Ch. 6).\nMutations in ligand-gated ion channels (GABA\nA and \nnicotinic) and other ion channels (Na+ and K+) that alter \nREFERENCES AND FURTHER READING\nGeneral\nIUPHAR/BPS. Guide to Pharmacology. www.guidetopharmacology \n.org/. (Comprehensive catalogue of molecular and pharmacological \nproperties of known receptor and ion channels \u2013 also transporters and some \nenzymes involved in signal transduction)\nNelson, N., 1998. The family of Na+/Cl\u2212 neurotransmitter transporters. \nJ. Neurochem. 71, 1785\u20131803. (Review article describing the molecular \ncharacteristics of the different families of neurotransporters)\nIon channels\nAshcroft, F.M., 2000. Ion Channels and Disease. Academic Press, \nLondon. (A useful textbook covering all aspects of ion channel physiology and its relevance to disease, with a lot of pharmacological information for \ngood measure)\nBezanilla, \tF., \t2008. \tHow \tmembrane \tproteins \tsense \tvoltage. \tNat. \tRev. \t\nMol. Cell Biol. 9, 323\u2013332. (Review of recent studies of how membrane proteins respond to changes in transmembrane potential)\nCatterall, W.A., 2000. From ionic currents to molecular mechanisms: the \nstructure and function of voltage-gated sodium channels. Neuron 26, 13\u201325. (General review of sodium channel structure, function and \npharmacology)\nColquhoun, D., 2006. Agonist-activated ion channels. Br. J. Pharmacol. \n147, S17\u2013S26. (Review article discussing the relationship between agonist binding and channel opening)\nHalliwell, R.F., 2007. A short history of the rise of the molecular \npharmacology of ionotropic drug receptors.", "start_char_idx": 0, "end_char_idx": 3463, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "072a0792-c6aa-455d-8a5b-c45ea9db4163": {"__data__": {"id_": "072a0792-c6aa-455d-8a5b-c45ea9db4163", "embedding": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2cd795c4-1b50-49a8-ba49-8c8057d21a6a", "node_type": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d6644bc783947e7294e79a7f64c3a070a6b2036ae7c5feda747e97505501870"}, "2": {"node_id": "a5628738-a1be-43f8-ae8d-c0a46b6d639c", "node_type": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be5c2852c68884d42adf6f5901101a262641fd15b72ae66e2e659a68bcf2ceaf"}, "3": {"node_id": "57ba2a49-3d32-45b7-84c7-5c86193ba66a", "node_type": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e1538eaacb4e10c10405a877cf8a36189c997980ef1d79c6ca7bbf7bfc7b223"}}, "hash": "5205cd22c27c03c9d58f8a3785b5b64809cf30bc93b8ec7fe2bffa9c83c8452f", "text": "of the rise of the molecular \npharmacology of ionotropic drug receptors. Trends Pharmacol. Sci. 28, 214\u2013219. (Good account of the main discoveries in this active field)\nHille, B., 2001. Ionic Channels of Excitable Membranes. Sinauer \nAssociates, Sunderland. (A clear and detailed account of the basic principles of ion channels, with emphasis on their biophysical \nproperties)\nNorth, R.A., 2002. Molecular physiology of P2X receptors. Physiol. Rev. \n82, 1013\u20131067. (Encyclopedic review of P2X receptor structure and function)\nPoduri, A., Lowenstein, D., 2011. Epilepsy genetics\u2014past, present, and \nfuture.\tCurr. \tOpin. \tGenet. \tDev. \t21, \t325\u2013332.\nStathopulos, P.B., Ikura, M., 2017. Store operated calcium entry: From \nconcept to structural mechanisms. Cell Calcium 63, 3\u20137.\nG protein\u2013coupled receptors\nAbdAlla, S., Lother, H., El Massiery, A., Quitterer, U., 2001. Increased \nAT 1 receptor heterodimers in preeclampsia mediate enhanced \nangiotensin II responsiveness. Nat. Med. 7, 1003\u20131009. (The first \ninstance of disturbed GPCR heterodimerisation in relation to human \ndisease)\nAdams,\tM.N., \tRamachandran, \tR., \tYau, \tM.K., \tet \tal., \t2011. \tStructure, \t\nfunction and pathophysiology of protease activated receptors. Pharmacol. Ther. 130, 248\u2013282. (Extensive review of the topic)\nAudet, M., Bouvier, M., 2012. Restructuring G protein-coupled receptor \nactivation. Cell 151, 14\u201323. (Review of recent developments related to G protein-coupled receptor crystallisation)Conigrave, A.D., Quinn, S.J., Brown, E.M., 2000. Cooperative \nmulti-modal sensing and therapeutic implications of the \nextracellular Ca\n2+-sensing receptor. Trends Pharmacol. Sci. 21, \n401\u2013407. (Short account of the Ca2+-sensing receptor, an anomalous type of \nGPCR)\nCosta, T., Cotecchia, S., 2005. Historical review: negative efficacy and \nthe constitutive activity of G protein-coupled receptors. Trends Pharmacol. Sci. 26, 618\u2013624. (A clear and thoughtful review of ideas \nrelating to constitutive receptor activation and inverse agonists)\nFerr\u00e9, S., Casad\u00f3, V., Devi, L.A., et al., 2015. G protein-coupled receptor \noligomerization \trevisited: \tfunctional \tand \tpharmacological \t\nperspectives. Pharmacol. Rev. 66, 413\u2013434. (Comprehensive review of \nGPCR olgomerisation and the implications for pharmacology and cellular \nsignalling)\nFredriksson, R., Schi\u00f6th, H.B., 2005. The repertoire of G protein-coupled \nreceptors in fully sequenced genomes. Mol. Pharmacol. 67, 1414\u20131425. (Estimation of the number of GPCR genes in different species \u2013 nearly 500 \nmore in mouse than in human!)\nKelly, E., Bailey, C.P., Henderson, G., 2008. Agonist-selective \nmechanisms \tof \tGPCR \tdesensitization. \tBr. \tJ. \tPharmacol. \t153 \t \n(Suppl. 1), S379\u2013S388. (Short review of main mechanisms of GPCR \ndesensitisation)\nKenakin, T., Christopoulos, A., 2013. Signalling bias in new drug \ndiscovery: detection, quantification and therapeutic impact. Nat. Rev. Drug Discov. 12, 205\u2013216. (Detailed discussion of the difficulties in", "start_char_idx": 3402, "end_char_idx": 6385, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "57ba2a49-3d32-45b7-84c7-5c86193ba66a": {"__data__": {"id_": "57ba2a49-3d32-45b7-84c7-5c86193ba66a", "embedding": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2cd795c4-1b50-49a8-ba49-8c8057d21a6a", "node_type": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d6644bc783947e7294e79a7f64c3a070a6b2036ae7c5feda747e97505501870"}, "2": {"node_id": "072a0792-c6aa-455d-8a5b-c45ea9db4163", "node_type": null, "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5205cd22c27c03c9d58f8a3785b5b64809cf30bc93b8ec7fe2bffa9c83c8452f"}}, "hash": "9e1538eaacb4e10c10405a877cf8a36189c997980ef1d79c6ca7bbf7bfc7b223", "text": "Drug Discov. 12, 205\u2013216. (Detailed discussion of the difficulties in \nmeasuring agonist efficacy and bias)\nLiu, F., Wan, Q., Pristupa, Z., et al., 2000. Direct protein\u2013protein \ncoupling enables cross-talk between dopamine D 5 and \u03b3-aminobutyric \nacid A receptors. Nature 403, 274\u2013280. (The first demonstration of direct \ncoupling of a GPCR with an ion channel. Look, no G protein!)\nManglik, A., Lin, H., Aryal, D.K., et al., 2016. Structure-based discovery \nof opioid analgesics with reduced side effects. Nature 537, 185\u2013190. \n(Exciting report of the use of computational molecular modelling in the \ndesign of a new opioid receptor agonist)\nMilligan, G., Kostenis, E., 2006. Heterotrimeric G proteins: a short \nhistory. Br. J. Pharmacol. 147 (Suppl. 1), 46\u201355.\nOffermanns, \tS., \t2003. \tG \tproteins \tas \ttransducers \tin \ttransmembrane \t\nsignalling. Prog. Biophys. Mol. Biol. 83, 101\u2013130. (Detailed review of G \nprotein subtypes and their function in signal transduction)\nOldham, \tW.M., \tHamm, \tH.E., \t2008. \tHeterotrimeric \tG \tprotein \tactivation \t\nby G protein-coupled receptors. Nat. Rev. Mol. Cell Biol. 9, 60\u201371. (Useful review of the structure and function of G proteins)\nPierce,\tK.L., \tLefkowitz, \tR.J., \t2001. \tClassical \tand \tnew \troles \tof \t\u03b2-arrestins \nin the regulation of G protein-coupled receptors. Nat. Rev. Neurosci. \n2, 727\u2013733. (Good review of non-G protein-mediated signalling of GPCRs \nthrough arrestin)\nRamachandran, R., Noorbakhsh, F., defea, K., Hollenberg, M.D., 2012. \nTargeting proteinase-activated receptors: therapeutic potential and challenges. Nat. Rev. Drug Discov. 11, 69\u201386.\nSexton, P.M., Poyner, D.R., Simms, J., Christopoulos, A., Hay, D.L., \n2012. RAMPs as drug targets. Adv. Exp. Med. Biol. 744, 61\u201374.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6378, "end_char_idx": 8599, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bbedbda5-035a-4f18-a208-9fd4b05ba83b": {"__data__": {"id_": "bbedbda5-035a-4f18-a208-9fd4b05ba83b", "embedding": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1efe8edc-b934-4ff4-9ce5-4a7955a007cb", "node_type": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "17b905c858b4a395b1376443957db4e2484c6ab592ade6ca2a37a047281f36c0"}, "3": {"node_id": "7c088bfd-965f-46a0-8780-029a2f750d19", "node_type": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f9d3f24aae687af7e130874b6188a20a9b5918d8f90508a261e3d0d450e52562"}}, "hash": "bd32290808311533f08c2c0087bbd42748848d9dde48e1bbc132910d1bb95a34", "text": "3 How dRuGS ACt: moLECuLAR ASPECtS\n51Jin, J., Pawson, T., 2012. Modular evolution of phosphorylation-based \nsignalling systems. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 367, \n2540\u20132555. ( Informative review on receptor kinase signalling )\nKarin,\tM.,\tYamamoto,\t Y.,\tWang,\tM.,\t2004.\tThe\tIKK-NF \u03baB system: a \ntreasure trove for drug development. Nat. Rev. Drug Discov. 3, 17\u201326. \n(Describes the transcription factor NF \u03baB, which plays a key role in \ninflammation, and its control by kinase cascades )\nNuclear receptors\nBourguet, W., Germain, P., Gronemeyer, H., 2000. Nuclear receptor \nligand-binding domains: three-dimensional structures, molecular \ninteractions and pharmacological implications. Trends Pharmacol. Sci. \n21, 381\u2013388. ( Accessible review concentrating on distinction between \nagonist and antagonist effects at the molecular level )\nBurris,\tT.P.,\tSolt,\tL.A.,\tWang,\tY.,\tet\tal.,\t2013.\tNuclear\t receptors\t and\ttheir\t\nselective pharmacologic modulators. Pharmacol. Rev. 65, 710\u2013778. ( A \nvery comprehensive account of the action of drugs at nuclear receptors. Not \nlight reading, but worthwhile if you really want to dig deeply into this \nfascinating subject )\nEvans, R.M., Mangelsdorf, D.J., 2014. Nuclear receptors, RXR, and the \nbig bang. Cell 157, 255\u2013266. ( Easy-to-read review of nuclear receptors \nfocusing on the key role that RXR plays in many crucial physiological \nsignalling systems. Contains a lot of useful background material on nuclear \nreceptors and their history )\nFalkenstein, E., Tillmann, H.C., Christ, M., Feuring, M., Wehling, M., \n2000. Multiple actions of steroid hormones \u2013 a focus on rapid \nnon-genomic effects. Pharm. Rev. 52, 513\u2013553. ( Comprehensive review \narticle describing the \u2018non-classical\u2019 effects of steroids )\nGermain, P., Staels, B., Dacquet, C., Spedding, M., Laudet, V., 2006. \nOverview\t of\tnomenclature\t of\tnuclear\treceptors.\t Pharmacol.\t Rev.\t58,\t\n685\u2013704. ( Comprehensive and authoritative review that deals with receptor \nbiology as well as nomenclature. Recommended )\nKersten, S., Desvergne, B., Wahli, W., 2000. Roles of PPARs in health \nand disease. Nature 405, 421\u2013424. ( General review of an important class \nof nuclear receptors )\ndi\tMasi,\tA.,\tDe\tMarinis,\t E.,\tAscenzi,\t P.,\tMarino,\t M.,\t2009.\tNuclear\t\nreceptors CAR and PXR: molecular, functional, and biomedical \naspects. Mol. Aspects Med. 30, 297\u2013343. ( A very comprehensive account \nof the role played by these nuclear receptors in xenobiotic metabolism but \nalso contains some useful general background information on the receptor \nfamily )\nLevin, E.R., Hammes, S.R., 2016. Nuclear receptors outside the nucleus: \nextranuclear signalling by steroid receptors. Nat. Rev. Mol. Cell Biol. \n17, 783\u2013797. ( This paper reviews the increasing evidence that some of the \nkey effects of steroids are mediated by populations of nuclear receptors \noutside the nucleus and describes the often rather complex networks through \nwhich they bring about these effects )\nMurphy, G.J., Holder, J.C., 2000. PPAR- \u03b3 agonists: therapeutic role in", "start_char_idx": 0, "end_char_idx": 3042, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7c088bfd-965f-46a0-8780-029a2f750d19": {"__data__": {"id_": "7c088bfd-965f-46a0-8780-029a2f750d19", "embedding": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1efe8edc-b934-4ff4-9ce5-4a7955a007cb", "node_type": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "17b905c858b4a395b1376443957db4e2484c6ab592ade6ca2a37a047281f36c0"}, "2": {"node_id": "bbedbda5-035a-4f18-a208-9fd4b05ba83b", "node_type": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bd32290808311533f08c2c0087bbd42748848d9dde48e1bbc132910d1bb95a34"}, "3": {"node_id": "50f06179-9a8b-423c-9216-b66bc76ceb07", "node_type": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "470a3afb117a6dcb02140a82258afd5d81250c41eb1ffb296c72e576f64dfe19"}}, "hash": "f9d3f24aae687af7e130874b6188a20a9b5918d8f90508a261e3d0d450e52562", "text": "Holder, J.C., 2000. PPAR- \u03b3 agonists: therapeutic role in \ndiabetes, inflammation and cancer. Trends Pharmacol. Sci. 21, \n469\u2013474. ( Account of the emerging importance of nuclear receptors of the \nPPAR family as therapeutic targets )\nSantos, G.M., Fairall, L., Schwabe, J.W.R., 2011. Negative regulation by \nnuclear receptors: a plethora of mechanisms. Trends Endocrinol. \nMetab. 22, 87\u201393. ( A very accessible and well written introduction to a very \ncomplex subject. Highly recommended )\nShiau, A.K., Barstad, D., Loria, P.M., et al., 1998. The structural basis of \nestrogen receptor/coactivator recognition and the antagonism of this \ninteraction by tamoxifen. Cell 95, 927\u2013937.Simonds, W.F., 1999. G protein regulation of adenylate cyclase. Trends \nPharmacol. Sci. 20, 66\u201372. ( Review of mechanisms by which G proteins \naffect adenylyl cyclase at the level of molecular structure )\nSj\u00f6gren, B., 2017. The evolution of regulators of G protein signalling \nproteins as drug targets \u2013 20 years in the making: IUPHAR Review \n21. Br. J. Pharmacol. 174, 427\u2013437. ( Useful description of how RGS \nproteins function and their potential as drug targets )\nSounier, R., Mas, C., Steyaert, J., et al., 2015. Propagation of \nconformational changes during \u00b5-opioid receptor activation. Nature \n524, 375\u2013378. ( Describes the use of NMR to study conformational changes \nin a GPCR upon agonist activation )\nSpiegel, A.M., Weinstein, L.S., 2004. Inherited diseases involving G \nproteins and G protein-coupled receptors. Annu. Rev. Med. 55, 27\u201339. \n(Short review article )\nStoy, H., Gurevich, V.V., 2015. How genetic errors in GPCRs affect their \nfunction: Possible therapeutic strategies. Genes Dis. 2, 108\u2013132. \n(Extensive review with many examples of GPCR mutations associated with \ndisease )\nXie, G.X., Palmer, P.P., 2007. How regulators of G protein signalling \nachieve selective regulation. J. Mol. Biol. 366, 349\u2013365. ( General review \nabout RGS proteins and how they work )\nZhang, D., Zhao, Q., Wu, B., 2015. Structural studies of G \nprotein-coupled receptors. Mol. Cells 38, 836\u2013842. ( Informative review of \nGPCR crystal structures )\nSignal transduction\nAvruch, J., 2007. MAP kinase pathways: the first twenty years. Biochim. \nBiophys. Acta 1773, 1150\u20131160. ( Short general review. One of a series of \narticles on MAP kinases in this issue )\nBishop, A.L., Hall, R.A., 2000. Rho-GTPases and their effector proteins. \nBiochem. J. 348, 241\u2013255. ( General review article on the Rho/Rho kinase \nsystem and the various pathways and functions that it controls )\nBrzostowski,\t J.A.,\tKimmel,\t A.R.,\t2001.\tSignaling\t at\tzero\tG:\tG\t\nprotein-independent functions for 7TM receptors. Trends Biochem. \nSci. 26, 291\u2013297. ( Review of evidence for GPCR signalling that does not \ninvolve G proteins, thus conflicting with the orthodox dogma )\nVanhaesebroeck, B., Leevers, S.J., Panayotou, G., Waterfield, M.D., 1997. \nPhosphoinositide 3-kinases: a conserved family of signal transducers. \nTrends Biochem.", "start_char_idx": 2994, "end_char_idx": 5974, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "50f06179-9a8b-423c-9216-b66bc76ceb07": {"__data__": {"id_": "50f06179-9a8b-423c-9216-b66bc76ceb07", "embedding": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1efe8edc-b934-4ff4-9ce5-4a7955a007cb", "node_type": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "17b905c858b4a395b1376443957db4e2484c6ab592ade6ca2a37a047281f36c0"}, "2": {"node_id": "7c088bfd-965f-46a0-8780-029a2f750d19", "node_type": null, "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f9d3f24aae687af7e130874b6188a20a9b5918d8f90508a261e3d0d450e52562"}}, "hash": "470a3afb117a6dcb02140a82258afd5d81250c41eb1ffb296c72e576f64dfe19", "text": "a conserved family of signal transducers. \nTrends Biochem. Sci. 22, 267\u2013272. ( Review by the group that discovered \nPI-3 kinases, summarising the multiple roles of this signal transduction \nmechanism \u2013 much expanded since 1997 )\nKinase-linked receptors\nCohen, P., 2002. Protein kinases \u2013 the major drug targets of the \ntwenty-first century. Nat. Rev. Drug Discov. 1, 309\u2013315. ( General \nreview on pharmacological aspects of protein kinases )\nCook,\tD.N.,\tPisetsky,\t D.S.,\tSchwartz,\t D.A.,\t2004.\tToll-like\t receptors\t in\t\nthe pathogenesis of human disease. Nat. Immunol. 5, 975\u2013979. ( Review \nemphasising the role of this class of receptor tyrosine kinases in many human \ndisease states )\nDelcourt, N., Bockaert, J., Marin, P., 2007. GPCR-jacking: from a new \nroute in RTK signalling to a new concept in GPCR activation. Trends \nPharmacol. Sci. 28, 602\u2013607. ( Gives examples of \u2018cross-talk\u2019 between GPCR \nand RTK signalling pathways )\nHubbard, S.R., Miller, W.T., 2007. Receptor tyrosine kinases: \nmechanisms\t of\tactivation\t and\tsignaling.\t Curr.\tOpin.\tCell\tBiol.\t19,\t\n117\u2013123 ( Reviews recent structural results showing mechanism of RTK \ndimerisation and signalling )\nIhle, J.N., 1995. Cytokine receptor signalling. Nature 377, 591\u2013594.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5965, "end_char_idx": 7679, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "20658aac-1419-47ef-8c02-64898af730b3": {"__data__": {"id_": "20658aac-1419-47ef-8c02-64898af730b3", "embedding": null, "metadata": {"page_label": "58", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "84310896-2912-4cf4-89cb-e43712dcd9d8", "node_type": null, "metadata": {"page_label": "58", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e053a53d27cfe7ae627af391d4b0dc2796ecc866c2c095f403528aabe6433578"}, "3": {"node_id": "73521a5b-44d3-43cf-baeb-45d75aae8882", "node_type": null, "metadata": {"page_label": "58", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4348b4cffee44f3508ac6e020675657097cc95d1ba80f4743f2b48484a53503d"}}, "hash": "3b3ab8dcafe1ce6d175581899e9d71f2d3944c6f9a1acd37686a743bc4d6d7b5", "text": "52\nHow drugs act: cellular \naspects \u2013 excitation, \ncontraction and secretion4 GENERAL PRINCIPLES SECTION 1 \nOVERVIEW\nThe link between a drug interacting with a molecular \ntarget and its effect at the pathophysiological level, \nsuch as a change in blood glucose concentration or \nthe shrinkage of a tumour, involves events at the cellular level. Whatever their specialised physiological \nfunction, cells generally share much the same rep -\nertoire of signalling mechanisms. In the next four \nchapters, we describe the parts of this repertoire \nthat are of particular significance in understanding \ndrug action at the cellular level. In this chapter, we describe mechanisms that operate mainly over a \nshort timescale (milliseconds to hours), particularly \nexcitation, contraction and secretion, which account for many physiological responses; Chapter 5 looks at \nhow biopharmaceuticals and gene therapy may alter the cell\u2019s chemical behaviours to have their desired effects; Chapter 6 deals with the slower processes \n(generally days to months), including cell division, growth, differentiation and cell death, that determine the body\u2019s structure and constitution; Chapter 7 \ndescribes host defence mechanisms.\nThe short-term regulation of cell function depends \nmainly on the following components and mechanisms, \nwhich regulate, or are regulated by, the free concentra -\ntion of Ca\n2+ in the cytosol, [Ca2+]i:\n\u2022 ion channels and transporters in the plasma \nmembrane\n\u2022 the storage and release of Ca2+ by intracellular \norganelles\n\u2022 Ca2+-dependent regulation of a variety of functional \nproteins, including enzymes, contractile proteins and \nvesicle proteins\nMore detailed coverage of the topics presented in \nthis chapter can be found in Berridge (2014) and \nKandel et al. (2012) .\nBecause [Ca2+]i plays such a key role in cell function, \na wide variety of drug effects result from interference \nwith one or more of these mechanisms. Knowledge \nof the molecular and cellular details is extensive, and here we focus on the aspects that help to explain \ndrug effects.\nREGULATION OF INTRACELLULAR \nCALCIUM\nEver since the famous accident in 1882 by Sidney Ringer\u2019s \ntechnician, which showed that using tap water rather than \ndistilled water to make up the bathing solution for isolated frog hearts would allow them to carry on contracting, the \nrole of Ca2+ as a major regulator of cell function has never \nbeen in question. Many drugs and physiological mechanisms \noperate, directly or indirectly, by influencing [Ca2+]i. Here \nwe consider the main ways in which it is regulated, and later we describe some of the ways in which [Ca\n2+]i controls \ncell function. Details of the molecular components and drug targets are presented in Chapter 3, and descriptions of drug \neffects on integrated physiological function are given in later chapters.\nThe study of Ca\n2+ regulation took a big step forward in \nthe 1970s with the development of optical techniques based \non the Ca2+-sensitive photoprotein aequorin , and fluorescent \ndyes such as Fura-2, which, for the first time, allowed free \n[Ca2+]i to be continuously monitored in living cells with a \nhigh level of temporal and spatial resolution.\nMost of the Ca2+ in a resting cell is sequestered in orga-\nnelles, particularly the endoplasmic or sarcoplasmic reticulum \n(ER or SR) and the mitochondria, and the free [Ca2+]i is \nkept to a low level, about 100 nmol/L. The Ca2+ concentra -\ntion in extracellular fluid, [Ca2+]o, is about 2.4 mmol/L, so \nthere is a large concentration gradient favouring Ca2+ entry. \n[Ca2+]i is", "start_char_idx": 0, "end_char_idx": 3581, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "73521a5b-44d3-43cf-baeb-45d75aae8882": {"__data__": {"id_": "73521a5b-44d3-43cf-baeb-45d75aae8882", "embedding": null, "metadata": {"page_label": "58", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "84310896-2912-4cf4-89cb-e43712dcd9d8", "node_type": null, "metadata": {"page_label": "58", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e053a53d27cfe7ae627af391d4b0dc2796ecc866c2c095f403528aabe6433578"}, "2": {"node_id": "20658aac-1419-47ef-8c02-64898af730b3", "node_type": null, "metadata": {"page_label": "58", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b3ab8dcafe1ce6d175581899e9d71f2d3944c6f9a1acd37686a743bc4d6d7b5"}}, "hash": "4348b4cffee44f3508ac6e020675657097cc95d1ba80f4743f2b48484a53503d", "text": "concentration gradient favouring Ca2+ entry. \n[Ca2+]i is kept low (a) by the operation of active transport \nmechanisms that eject cytosolic Ca2+ through the plasma \nmembrane and pump it into the ER, and (b) by the normally low Ca\n2+ permeability of the plasma and ER membranes. \nRegulation of [Ca2+]i involves three main mechanisms:\n\u2022\tcontrol \tof \tCa2+ entry\n\u2022\tcontrol \tof \tCa2+ extrusion\n\u2022\texchange \tof \tCa2+ between the cytosol and the \nintracellular stores\nThese mechanisms are described in more detail later and \nare summarised in Fig. 4.1.\nCALCIUM ENTRY MECHANISMS\nThere are four main routes by which Ca2+ enters cells across \nthe plasma membrane:\n\u2022\tvoltage-gated \tcalcium \tchannels\n\u2022\tligand-gated \tcalcium \tchannels\n\u2022\tstore-operated \tcalcium \tchannels \t(SOCs)\n\u2022\tNa+\u2013Ca2+ exchange (can operate in either direction; see \nCalcium extrusion mechanisms, p. 55)\nVOLTAGE-GATED CALCIUM CHANNELS\nThe pioneering work of Hodgkin and Huxley on the ionic basis of the nerve action potential (see pp. 56\u201358) identified \nvoltage-dependent \tNa+ and K+ conductances as the main \nparticipants. It was later found that some invertebrate \nnerve and muscle cells could produce action potentials \nthat depended on Ca2+\trather\tthan \tNa+, and it was then \nfound that vertebrate cells also possess voltage-activated \ncalcium channels capable of allowing substantial amounts mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3525, "end_char_idx": 5359, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f1fb16e4-d2af-4364-8b94-b9c440f2b97d": {"__data__": {"id_": "f1fb16e4-d2af-4364-8b94-b9c440f2b97d", "embedding": null, "metadata": {"page_label": "59", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1b199d19-5066-4fa6-8bf0-139cea942264", "node_type": null, "metadata": {"page_label": "59", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39e02c09059731d38ab32d17809fc97324183b4a8d6c3e82782e8330ebe3df7e"}, "3": {"node_id": "b42b8e16-fcbe-41aa-b2c9-22e7957a2659", "node_type": null, "metadata": {"page_label": "59", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4fee46a5762b32899126db47387a209976788b5bbefa44b90521395b67e810a0"}}, "hash": "08608cac1d345485ab05bcde50cee40130ad0ed6d224d20e688bd407df46dfa8", "text": "4 How d RuGS AC t: CELL u LAR ASPEC t S \u2013 E x CI t A t I o N , C o N t RAC t I o N AN d SECRE t I o N \n53\u03b11, see Fig. 3.20) occurs in at least 10 molecular subtypes, and \nassociates with other subunits ( \u03b2, \u03b3 and two subunits from \nthe same gene, \u03b1 2\u03b4, linked by a disulfide bond) that also \nexist in different subtypes to form the functional channel. \nDifferent combinations of these subunits give rise to the \ndifferent physiological subtypes2. In general, L channels are \nparticularly important in regulating contraction of cardiac \nand\tsmooth \tmuscle \t(see \tp. \t64), \tand \tN \tchannels \t(and \talso \t\nP/Q) are involved in neurotransmitter and hormone release, while T channels mediate Ca\n2+ entry into neurons around \nthe resting membrane potential and can control the rate \nof repolarisation of neurons and cardiac cells as well as \nvarious Ca2+-dependent functions such as regulation of \nother channels, enzymes, etc. Clinically used drugs that \nact directly on some forms of calcium channel include the \ngroup of \u2018Ca2+ antagonists\u2019 consisting of dihydropyridines \n(e.g. nifedipine), verapamil and diltiazem (used for their of Ca2+ to enter the cell when the membrane is depolarised. \nThese voltage-gated channels are highly selective for Ca2+ \n(although they also conduct Ba2+ ions, which are often used \nas a substitute in electrophysiological experiments), and do \nnot\tconduct\tNa+ or K+; they are ubiquitous in excitable cells \nand cause Ca2+ to enter the cell whenever the membrane is \ndepolarised, for example by a conducted action potential.\nA combination of electrophysiological and pharmacological \ncriteria have revealed five distinct subtypes of voltage-gated \ncalcium\tchannels: \tL, \tT, \tN, \tP/Q \tand \tR1. The subtypes vary \nwith respect to their activation and inactivation kinetics, their \nvoltage threshold for activation, their conductance and their \nsensitivity to blocking agents, as summarised in Table 4.1. The molecular basis for this heterogeneity has been worked \nout in some detail. The main pore-forming subunit (termed SOC LGC\nEndoplasmic reticulum Lysosome\nPlasma membraneVGCCCa2+\nCa2+\nCa2+Ca2+Na+\nH+NAADPATP PMCA\nSERCATPC1/2GPCRsIP3\nIP3R RyR Ca\nsensorNCXDepolarisation\nAgonists\nATPAgonists\n(e.g. glutamate, ATP)\nStore depletion signal\nFig. 4.1 Regulation of intracellular calcium. The main routes of transfer of Ca2+ into, and out of, the cytosol, endoplasmic reticulum \n(ER) and lysosomal structures are shown for a typical cell (see text for details). Black arrows: routes into the cytosol. Blue arrows : routes \nout of the cytosol. Red arrows : regulatory mechanisms. The state of the ER store of Ca2+ is monitored by the sensor protein Stim1, which \ninteracts directly with the store-operated calcium channel (SOC) to promote Ca2+ entry when the ER store is depleted. Normally, [Ca2+]i is \nregulated to about 10\u22127 mol/L in a \u2018resting\u2019 cell. Mitochondria (not shown) also function as Ca2+ storage organelles but release Ca2+ only \nunder pathological conditions, such as ischaemia (see pp. 55\u201356). There is recent evidence for a lysosomal store of Ca2+, activated by the \nsecond messenger nicotinic acid adenine dinucleotide phosphate (NAADP) through a two-pore domain", "start_char_idx": 0, "end_char_idx": 3207, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b42b8e16-fcbe-41aa-b2c9-22e7957a2659": {"__data__": {"id_": "b42b8e16-fcbe-41aa-b2c9-22e7957a2659", "embedding": null, "metadata": {"page_label": "59", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1b199d19-5066-4fa6-8bf0-139cea942264", "node_type": null, "metadata": {"page_label": "59", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39e02c09059731d38ab32d17809fc97324183b4a8d6c3e82782e8330ebe3df7e"}, "2": {"node_id": "f1fb16e4-d2af-4364-8b94-b9c440f2b97d", "node_type": null, "metadata": {"page_label": "59", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "08608cac1d345485ab05bcde50cee40130ad0ed6d224d20e688bd407df46dfa8"}}, "hash": "4fee46a5762b32899126db47387a209976788b5bbefa44b90521395b67e810a0", "text": "adenine dinucleotide phosphate (NAADP) through a two-pore domain calcium channel (TPC). GPCR, G \nprotein\u2013coupled receptor; IP 3, inositol trisphosphate; IP3R, inositol trisphosphate receptor; LGC, ligand-gated cation channel; NCX, \nNa+\u2013Ca2+ exchange transporter; PMCA, plasma membrane Ca2+-ATPase; RyR, ryanodine receptor; SERCA, sarcoplasmic/endoplasmic \nreticulum ATPase; VGCC, voltage-gated calcium channel. \n1P and Q are so similar that they usually get lumped together. The \nterminology is less than poetic: L stands for long-lasting; T stands for \ntransient;\tN\tstands \tfor \tneither long-lasting nor transient. Although P \nstands for Purkinje \u2013 this type of channel was first observed in cerebellar Purkinje cells \u2013 it continued the alphabetical sequence \n(missing \tout \tO \tof \tcourse) \tand \tso \tthe \tnext \tdiscovered \twere \ttermed \tQ \t\nand R.2Readers interested in knowing more about the subunit composition of \ndifferent voltage-gated calcium channels should consult the Guide to Pharmacology at mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3143, "end_char_idx": 4701, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b21a42a2-26aa-47a0-bd18-dce7cd721184": {"__data__": {"id_": "b21a42a2-26aa-47a0-bd18-dce7cd721184", "embedding": null, "metadata": {"page_label": "60", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d23970fe-0999-4f8c-87f3-4fb36487aa58", "node_type": null, "metadata": {"page_label": "60", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d975dc3bd129736880fd0beee72ed3b64a68ec1696ed0c6052fe83de7566e5a4"}, "3": {"node_id": "6118958b-c6eb-46c3-ad6d-f7c1428d2c58", "node_type": null, "metadata": {"page_label": "60", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ae02dad64009600a0f2539c1dcd2813789d28f7045a9268b52f4fc299dff6607"}}, "hash": "c0dea40421cd3f859ae735ead6396a160b94248c2f6c8ce3351c044d399f4fcf", "text": "4 SECTION 1 GENERAL PRINCIPLES\n54permeability to Ca2+ and is a major contributor to Ca2+ \nuptake by postsynaptic neurons (and also glial cells) in the \ncentral nervous system. Activation of this receptor can \nreadily cause so much Ca2+ entry that the cell dies, mainly \nthrough activation of Ca2+-dependent proteases but also \nby triggering apoptosis (see Ch. 6). This mechanism, termed \nexcitotoxicity , probably plays a part in various neurodegen -\nerative disorders (see Ch. 41).\nFor many years, there was dispute about the existence \nof \u2018receptor-operated channels\u2019 in smooth muscle, respond -\ning directly to mediators such as adrenaline (epinephrine), \nacetylcholine \tand \thistamine. \tNow \tit \tseems \tthat \tthe \tP2X \t\nreceptor (see Ch. 3), activated by ATP, is the only example of a true ligand-gated channel in smooth muscle, and this cardiovascular effects; see Chs 22 and 23), and gabapentin \nand pregabalin (used to treat epilepsy, pain and anxiety; \nsee Chs 43, 45 and 46). Many drugs affect calcium channels indirectly by acting on G protein\u2013coupled receptors (see Ch. 3). A number of toxins act selectively on one or other \ntype of calcium channel (see Table 4.1), and these are used \nas experimental tools.\nLIGAND-GATED CHANNELS\nMost ligand-gated cation channels (see Ch. 3) that are activated by excitatory neurotransmitters are relatively \nnon-selective, and conduct Ca\n2+ ions as well as other cations. \nMost important in this respect is the glutamate receptor of \nthe\tNMDA \ttype \t(Ch. \t39), \twhich \thas \ta \tparticularly \thigh \tTable 4.1 Types and functions of Ca2+ channels\nGated by Main types Characteristics Location and function Drug effects\nVoltage L High activation \nthresholdSlow inactivationPlasma membrane of many cellsMain Ca\n2+ source for \ncontraction in smooth \nand cardiac muscleBlocked by dihydropyridines, verapamil, \ndiltiazem; and calciseptine (peptide from \nsnake venom)\nActivated by BayK 8644\nPhosphorylation by PKA (e.g. following \u03b21 \nadrenoceptor activation) increases channel opening\nN Low activation thresholdSlow inactivationMain Ca\n2+ source for \ntransmitter release by nerve terminalsBlocked by \u03c9-conotoxin GV1A (component of Conus snail venom) and ziconotide (marketed preparation of \u03c9-conotoxin used to control pain) (Ch. 43)\nT Low activation thresholdFast inactivationWidely distributedImportant in cardiac pacemaker and atria (role in dysrhythmias), also neuronal firing patternsBlocked by mibefradil\nP/Q Low activation thresholdSlow inactivationNerve terminalsTransmitter releaseBlocked by \u03c9-agatoxin-4A (component of funnel-web spider venom)\nR Low threshold Neurons and dendrites Blocked by low concentrations of SNX-482 (a toxin from a member of the tarantula family) Fast inactivation Control of firing patterns\nIP\n3 IP3 receptor Activated by binding of IP\n3 and \nCa2+Located in endoplasmic/sarcoplasmic reticulumMediates Ca\n2+ release \nproduced by GPCR \nactivationNot directly targeted by drugs\nSome experimental blocking agents known\nResponds to GPCR agonists and antagonists \nin many cells\nCa2+Ryanodine receptorDirectly activated in skeletal muscle via dihydropyridine receptor of T-tubules. Activated by Ca\n2+ \nin cardiac muscleLocated in endoplasmic/sarcoplasmic reticulum.Pathway for Ca\n2+ release \nin striated muscleActivated by caffeine and ATP in the presence of", "start_char_idx": 0, "end_char_idx": 3329, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6118958b-c6eb-46c3-ad6d-f7c1428d2c58": {"__data__": {"id_": "6118958b-c6eb-46c3-ad6d-f7c1428d2c58", "embedding": null, "metadata": {"page_label": "60", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d23970fe-0999-4f8c-87f3-4fb36487aa58", "node_type": null, "metadata": {"page_label": "60", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d975dc3bd129736880fd0beee72ed3b64a68ec1696ed0c6052fe83de7566e5a4"}, "2": {"node_id": "b21a42a2-26aa-47a0-bd18-dce7cd721184", "node_type": null, "metadata": {"page_label": "60", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c0dea40421cd3f859ae735ead6396a160b94248c2f6c8ce3351c044d399f4fcf"}}, "hash": "ae02dad64009600a0f2539c1dcd2813789d28f7045a9268b52f4fc299dff6607", "text": "\nin striated muscleActivated by caffeine and ATP in the presence of Ca\n2+\nRyanodine both activates (low concentrations) and closes (high concentrations) the channel. Also closed by Mg\n2+, K+ channel blockers and \ndantroleneMutations may lead to drug-induced \nmalignant hypothermia, sudden cardiac death and central core disease\nStore depletionStore-operated channelsActivated by sensor protein that monitors level of ER Ca\n2+ storesLocated in plasma membraneActivated indirectly by agents that deplete intracellular stores (e.g. GPCR agonists, thapsigargin)Not directly targeted by drugs\nER, endoplasmic reticulum; GPCR, G protein\u2013coupled receptor; IP\n3, inositol trisphosphate; PKA, protein kinase A.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3262, "end_char_idx": 4442, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e2a48ae5-d595-4bc6-bab4-660263bddf37": {"__data__": {"id_": "e2a48ae5-d595-4bc6-bab4-660263bddf37", "embedding": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f4c94c80-ba1c-4d5b-bf82-182cb5b20b06", "node_type": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "98358b133409bf20e24a3e5409773cde13f28e1a24df6c7f2d2ccd3a2ade1275"}, "3": {"node_id": "7a141031-702a-4fcc-9d00-a7497cff1a2c", "node_type": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "45dcdc6aa7e94d81f4782ca2df0f65afaba307ce55de48055c8c64f1daad7ba0"}}, "hash": "904ee0b9584aefe504981d50b3ef24d9175928b777bb01c77346565e4b21dee2", "text": "4 How d RuGS AC t: CELL u LAR ASPEC t S \u2013 E x CI t A t I o N , C o N t RAC t I o N AN d SECRE t I o N \n55\u2022\tRyanodine receptors (RyR) are so called because they \nwere first identified through the specific blocking \naction of the plant alkaloid ryanodine. There are three \nisoforms \u2013 RyR1\u20133 (Van Petegem, 2012), which are expressed in many different cell types. RyR1 is highly \nexpressed in skeletal muscle, RyR2 in the heart and \nRyR3 in brain neurons. In skeletal muscle, RyRs on the SR are physically coupled to dihydropyridine \nreceptors on the T-tubules (see Fig. 4.9); this coupling \nresults in rapid Ca\n2+ release following the action \npotential in the muscle fibre. In other muscle types, \nRyRs respond to Ca2+ that enters the cell through \nmembrane calcium channels by a mechanism known as calcium-induced calcium release (CICR).\nThe functions of IP\n3Rs and RyRs are modulated by a variety \nof other intracellular signals (see Berridge, 2016; Van Petegem, 2012), which affect the magnitude and spatiotem -\nporal patterning of Ca\n2+ signals. Fluorescence imaging \ntechniques have revealed a remarkable level of complexity of Ca\n2+ signals, and much remains to be discovered about \nthe importance of this patterning in relation to physiological and pharmacological mechanisms. The Ca\n2+ sensitivity of \nRyRs is increased by caffeine, causing Ca2+ release from \nthe SR even at resting levels of [Ca2+]i. This is used experi -\nmentally but rarely happens in humans, because the other pharmacological effects of caffeine (see Ch. 49) occur at \nmuch lower doses. The blocking effect of dantrolene, a compound related to ryanodine, is used therapeutically to \nrelieve muscle spasm in the rare condition of malignant \nhyperthermia (see Ch. 42), which is associated with inherited \nabnormalities in the RyR protein.\nA typical [Ca\n2+]i signal resulting from activation of a \nGq\u2013coupled receptor is shown in Fig. 4.2A. The response produced in the absence of extracellular Ca\n2+ represents \nrelease from intracellular stores. The larger and more prolonged response when extracellular Ca\n2+ is present shows \nthe\tcontribution \tof \tSOC-mediated \tCa2+ entry. The various \npositive and negative feedback mechanisms that regulate [Ca\n2+]i give rise to a variety of temporal and spatial oscil -\nlatory patterns (Fig. 4.2B) that are responsible for spontane -\nous rhythmic activity in smooth muscle and nerve cells \n(see Berridge, 2008).\nOTHER SECOND MESSENGERS\n\u25bc Two intracellular metabolites, cyclic ADP-ribose (cADPR) and \nnicotinic\tacid\tadenine\tdinucleotide \tphosphate \t(NAADP) \tformed\tfrom\t\nthe\tubiquitous \t coenzymes \t nicotinamide \t adenine \t dinucleotide \t(NAD)\t\nand\tNAD \tphosphate, \talso \taffect \tCa2+ signalling (see Morgan et al., \n2015; Parrington et al., 2015). cADPR acts by increasing the sensitivity \nof RyRs to Ca2+, thus increasing the \u2018gain\u2019 of the CICR effect, whereas \nNAADP\thas\tbeen\tproposed \tto\trelease\tCa2+ from lysosomes by activat -\ning two-pore domain calcium channels (Fig. 4.1).\nThe levels of these messengers in mammalian cells may be regulated \nmainly in response to changes in the metabolic status of the cell, \nalthough the details are not yet clear. Abnormal Ca2+ signalling is \ninvolved in many pathophysiological", "start_char_idx": 0, "end_char_idx": 3245, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a141031-702a-4fcc-9d00-a7497cff1a2c": {"__data__": {"id_": "7a141031-702a-4fcc-9d00-a7497cff1a2c", "embedding": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f4c94c80-ba1c-4d5b-bf82-182cb5b20b06", "node_type": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "98358b133409bf20e24a3e5409773cde13f28e1a24df6c7f2d2ccd3a2ade1275"}, "2": {"node_id": "e2a48ae5-d595-4bc6-bab4-660263bddf37", "node_type": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "904ee0b9584aefe504981d50b3ef24d9175928b777bb01c77346565e4b21dee2"}, "3": {"node_id": "3993c164-af7b-4d42-9ccb-e446b2cce491", "node_type": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "74a9df1b207d624c568f58d461ec0749f826534fe1b51bab82b5930bc6c9dd8f"}}, "hash": "45dcdc6aa7e94d81f4782ca2df0f65afaba307ce55de48055c8c64f1daad7ba0", "text": "are not yet clear. Abnormal Ca2+ signalling is \ninvolved in many pathophysiological conditions, such as ischaemic cell death, endocrine disorders and cardiac dysrhythmias, where \nthe\troles \tof \tcADPR \tand \tNAADP, \tand \ttheir \tinteraction \twith \tother \t\nmechanisms that regulate [Ca2+]i, are the subject of much current \nwork.\nTHE ROLE OF MITOCHONDRIA\n\u25bc Under normal conditions, mitochondria accumulate Ca2+ passively \nas a result of the intramitochondrial potential, which is strongly negative with respect to the cytosol. This negativity is maintained constitutes an important route of entry for Ca2+. As men -\ntioned above, many mediators acting on G protein\u2013coupled \nreceptors affect Ca2+ entry indirectly, mainly by regulating \nvoltage-gated calcium channels or potassium channels.\nSTORE-OPERATED CALCIUM CHANNELS (SOCS)\nSOCs\tare\tvery\tlow-conductance \tchannels \tthat\toccur\tin\tthe\t\nplasma membrane and open to allow entry when the ER \nstores are depleted, but are not sensitive to cytosolic [Ca2+]i. \nThe linkage between the ER and the plasma membrane \ninvolves a Ca2+-sensor protein ( Stim1) in the ER membrane, \nwhich connects directly to the channel protein ( Orai1) in \nthe plasma membrane. Depletion of ER Ca2+ causes Stim1 \nto accumulate at junctions between the ER and the plasma \nmembrane \twhere \tit \ttraps \tand \tactivates \tOrai1 \tresulting \tin \t\nCa2+ entry (see Prakriya & Lewis, 2015).\nLike the ER and SR channels, these channels can serve \nto amplify the rise in [Ca2+]i resulting from Ca2+ release \nfrom the stores. So far, only experimental compounds are known to block these channels, but efforts are being made \nto develop specific blocking agents for therapeutic use as relaxants of smooth muscle.\nCALCIUM EXTRUSION MECHANISMS\nActive transport of Ca2+ outwards across the plasma \nmembrane, and inwards across the membranes of the ER \nor SR, depends on the activity of distinct Ca2+-dependent \nATPases,3\tsimilar\tto \tthe \tNa+/K+-dependent ATPase that \npumps\tNa+ out of the cell in exchange for K+. Thapsigargin \n(derived from a Mediterranean plant, Thapsia garganica) \nspecifically blocks the ER pump, causing loss of Ca2+ from \nthe ER. It is a useful experimental tool but has no therapeutic significance.\nCalcium\tis\talso\textruded \tfrom\tcells\tin\texchange \tfor\tNa+, \nby\tNa+\u2013Ca2+\texchange. \tThe \texchanger \ttransfers \tthree \tNa+ \nions for one Ca2+, and therefore produces a net depolarising \ncurrent when it is extruding Ca2+. The energy for Ca2+ \nextrusion \tcomes\tfrom\tthe\telectrochemical \tgradient\tfor\tNa+, \nnot directly from ATP hydrolysis. This means that a reduc -\ntion\tin\tthe \tNa+\tconcentration \tgradient \tresulting \tfrom \tNa+ \nentry will reduce Ca2+ extrusion by the exchanger, causing \na secondary rise in [Ca2+]i, a mechanism that is particularly \nimportant in cardiac muscle (see Ch. 22). Digoxin (derived \nfrom the Digitalis \tor\t\u2018Foxglove\u2019 \tplant), \twhich \tinhibits \tNa+ \nextrusion, acts on cardiac muscle in this way (Ch. 22), causing [Ca\n2+]i to increase.\nCALCIUM RELEASE MECHANISMS\nThere are two main types of calcium channel in the ER \nand SR membrane, which play an", "start_char_idx": 3174, "end_char_idx": 6274, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3993c164-af7b-4d42-9ccb-e446b2cce491": {"__data__": {"id_": "3993c164-af7b-4d42-9ccb-e446b2cce491", "embedding": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f4c94c80-ba1c-4d5b-bf82-182cb5b20b06", "node_type": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "98358b133409bf20e24a3e5409773cde13f28e1a24df6c7f2d2ccd3a2ade1275"}, "2": {"node_id": "7a141031-702a-4fcc-9d00-a7497cff1a2c", "node_type": null, "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "45dcdc6aa7e94d81f4782ca2df0f65afaba307ce55de48055c8c64f1daad7ba0"}}, "hash": "74a9df1b207d624c568f58d461ec0749f826534fe1b51bab82b5930bc6c9dd8f", "text": "two main types of calcium channel in the ER \nand SR membrane, which play an important part in control -\nling the release of Ca2+ from these stores.\n\u2022\tThe\tinositol trisphosphate receptor (IP 3R) is activated by \ninositol trisphosphate (IP 3), a second messenger \nproduced by the action of many ligands on G protein\u2013\ncoupled receptors (see Ch. 3). IP 3R is a ligand-gated \nion channel, although its molecular structure differs from that of ligand-gated channels in the plasma \nmembrane (see Berridge, 2016). This is the main mechanism by which activation of Gq\u2013coupled \nreceptors causes an increase in [Ca\n2+]i.\n3These pumps have been likened to Sisyphus, condemned endlessly to \npush a stone up a hill (also consuming ATP, no doubt), only for it to \nroll down again.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6271, "end_char_idx": 7515, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b079a0ff-8e6f-4fc9-a6a3-a3eadb315236": {"__data__": {"id_": "b079a0ff-8e6f-4fc9-a6a3-a3eadb315236", "embedding": null, "metadata": {"page_label": "62", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce7ca287-7bae-4d73-9e1b-53e2877c19dc", "node_type": null, "metadata": {"page_label": "62", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ae6a176bbb09bc53d5e1d0d40071de0d199e911071587c27cf5d85b352abb6b"}, "3": {"node_id": "3dbd165f-0d69-4e7d-a7ff-f2fa5fd30754", "node_type": null, "metadata": {"page_label": "62", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d45b8dcaff63cd58790ead2b134ede5b102d13f9e23c996f5a352630b756ec2"}}, "hash": "dd3f99a425dddd2bc55f65af87297e419a4be971f0be35cd97740c5b8467f654", "text": "4 SECTION 1 GENERAL PRINCIPLES\n56by active extrusion of protons, and is lost \u2013 thus releasing Ca2+ into \nthe cytosol \u2013 if the cell runs short of ATP, for example under conditions \nof hypoxia. This only happens in extremis , and the resulting Ca2+ \nrelease contributes to the cytotoxicity associated with severe metabolic \ndisturbance. Cell death resulting from brain ischaemia or coronary \nischaemia (see Chs 22 and 41) involves this mechanism, along with \nothers that contribute to an excessive rise in [Ca2+]i.\nCALMODULIN\nCalcium exerts its control over cell functions by virtue of \nits ability to regulate the activity of many different proteins, \nincluding enzymes (particularly kinases and phosphatases), \nchannels, transporters, transcription factors, synaptic vesicle \nproteins and many others either by binding directly to \nthese proteins or through a Ca2+-binding protein that serves \nas an intermediate between Ca2+ and the regulated functional \nprotein, the best known such binding protein being the \nubiquitous calmodulin . This regulates at least 40 different \nfunctional proteins \u2013 indeed a powerful fixer. Calmodulin \nis a dumbbell-shaped protein with a globular domain at \neither end, each with two Ca2+ binding sites. When all are \noccupied, the protein undergoes a conformational change, \nexposing a \u2018sticky\u2019 hydrophobic domain that lures many \nproteins into association, thereby affecting their functional \nproperties.\nEXCITATION\nExcitability describes the ability of a cell to show a regenera -\ntive all-or-nothing electrical response to depolarisation of \nits membrane, this membrane response being known as Fig. 4.2 (A) Increase in intracellular free calcium concentration in response to receptor activation. The records were obtained from a \nsingle rat sensory neuron grown in tissue culture. The cells were loaded with the fluorescent Ca2+ indicator Fura-2, and the signal from a \nsingle cell monitored with a fluorescence microscope. A brief exposure to the peptide bradykinin, which causes excitation of sensory \nneurons (see Ch. 43), causes a transient increase in [Ca2+]i from the resting value of about 150 nmol/L. When Ca2+ is removed from the \nextracellular solution, the bradykinin-induced increase in [Ca2+]i is still present but is smaller and briefer. The response in the absence of \nextracellular Ca2+ represents the release of stored intracellular Ca2+ resulting from the intracellular production of inositol trisphosphate. The \ndifference between this and the larger response when Ca2+ is present extracellularly is believed to represent Ca2+ entry through store-\noperated ion channels in the cell membrane. (Figure kindly provided by G. M. Burgess and A. Forbes, Novartis Institute for Medical \nResearch.) (B) Spontaneous intracellular calcium oscillations in pacemaker cells from the rabbit urethra that regulate the rhythmic \ncontractions of the smooth muscle. The signals cease when external Ca2+ is removed, showing that activation of membrane Ca2+ channels \nis involved in the mechanism. (From McHale, N., et al., 2006. J. Physiol. 570, 23\u201328.)1 min\nNormal extracellular [Ca2+]\nZero extracellular [Ca2+]1.0\n0.8\n0.6\n0.4\n0.2\n0\nBradykinin 30 nmol/LIntracellular [Ca2+] (\u00b5mol/L)A\nTime (min)0 mM Ca2+\n2\n1\n0[Ca2+] arbitrary units\n01234B\nCalcium regulation \nIntracellular Ca2+ concentration, [Ca2+]i, is critically \nimportant as a regulator of cell function.\n\u2022\tIntracellular\t", "start_char_idx": 0, "end_char_idx": 3415, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3dbd165f-0d69-4e7d-a7ff-f2fa5fd30754": {"__data__": {"id_": "3dbd165f-0d69-4e7d-a7ff-f2fa5fd30754", "embedding": null, "metadata": {"page_label": "62", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce7ca287-7bae-4d73-9e1b-53e2877c19dc", "node_type": null, "metadata": {"page_label": "62", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ae6a176bbb09bc53d5e1d0d40071de0d199e911071587c27cf5d85b352abb6b"}, "2": {"node_id": "b079a0ff-8e6f-4fc9-a6a3-a3eadb315236", "node_type": null, "metadata": {"page_label": "62", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd3f99a425dddd2bc55f65af87297e419a4be971f0be35cd97740c5b8467f654"}}, "hash": "9d45b8dcaff63cd58790ead2b134ede5b102d13f9e23c996f5a352630b756ec2", "text": "is critically \nimportant as a regulator of cell function.\n\u2022\tIntracellular\t Ca2+ is determined by (a) Ca2+ entry; (b) \nCa2+ extrusion; and (c) Ca2+ exchange between the \ncytosol, endoplasmic or sarcoplasmic reticulum (ER, \nSR), lysosomes and mitochondria.\n\u2022\tCalcium\t entry\toccurs\tby\tvarious\troutes,\tincluding\t\nvoltage- and ligand-gated calcium channels and \nNa+\u2013Ca2+ exchange.\n\u2022\tCalcium\t extrusion\t depends\tmainly\ton\tan\tATP-driven\t\nCa2+ pump.\n\u2022\tCalcium\t ions\tare\tactively\ttaken\tup\tand\tstored\tby\tthe\t\nER/SR, from which they are released in response to \nvarious stimuli.\n\u2022\tCalcium\t ions\tare\treleased\tfrom\tER/SR\tstores\tby\t(a)\t\nthe second messenger inositol trisphosphate (IP 3) \nacting on IP 3 receptors; or (b) increased [Ca2+]i itself \nacting on ryanodine receptors, a mechanism known as \nCa2+-induced Ca2+ release.\n\u2022\tOther\tsecond\tmessengers,\t cyclic\tADP-ribose\t and\t\nnicotinic acid dinucleotide phosphate, also promote \nthe release of Ca2+ from Ca2+ stores.\n\u2022\tDepletion\t of\tER/SR\tCa2+ stores promotes Ca2+ entry \nthrough the plasma membrane, via store-operated \nchannels.\n\u2022\tCalcium\t ions\taffect\tmany\taspects\tof\tcell\tfunction\tby\t\nbinding to proteins such as calmodulin, which in turn \nbind other proteins and regulate their function.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3341, "end_char_idx": 5051, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b1c398c3-af7f-44f7-9bf4-a14c6bdbe12b": {"__data__": {"id_": "b1c398c3-af7f-44f7-9bf4-a14c6bdbe12b", "embedding": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc268ea8-3541-4a54-9ea3-4ec4ef175355", "node_type": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9272ab85e40c4aa6c8580acf76d8620fad159a3417d785d01857def9a764b004"}, "3": {"node_id": "e4416dfc-d69f-4b0a-8375-6a316fb4ffcd", "node_type": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87470f32138918f9115ba8208d5ff385be9adfd079ffb1c04c3a0174bc1194a8"}}, "hash": "e2088e5b48a397adc415a6c92874e2eff9be167dbaba64c2483a78e8caa94e8e", "text": "4 How d RuGS AC t: CELL u LAR ASPEC t S \u2013 E x CI t A t I o N , C o N t RAC t I o N AN d SECRE t I o N \n57permeability causes an inward (depolarising) current of \nNa+ ions, whereas an increase in K+ permeability causes \nan outward (repolarising) current. The separability of these \ntwo currents can be most clearly demonstrated by the use \nof drugs blocking sodium and potassium channels, as shown in Fig. 4.4. During the physiological initiation or \npropagation of a nerve impulse, the first event is a small \ndepolarisation of the membrane, produced either by trans -\nmitter action or by the approach of an action potential \npassing along the axon. This opens sodium channels, \nallowing \tan \tinward \tcurrent \tof \tNa+ ions to flow, which \ndepolarises the membrane still further. The process is thus \na\tregenerative \tone, \tand \tthe \tincrease \tin \tNa+ permeability \nis enough to bring the membrane potential towards E Na. \nThe\tincreased \tNa+ conductance is transient, because the \nchannels inactivate rapidly and the membrane returns to its \nresting state.\nIn many types of cell, including most nerve cells, repo -\nlarisation is assisted by the opening of voltage-dependent K\n+ channels. These function in much the same way as sodium \nchannels, but their activation kinetics are about 10 times slower and they do not inactivate appreciably. This means \nthat the potassium channels open later than the sodium channels, contributing to the rapid termination of the action \npotential and to the after-hyperpolarisation that follows \nthe depolarising phase. The behaviour of the sodium and an action potential. It is a characteristic of most neurons and muscle cells (including skeletal, cardiac and smooth muscle) and of many endocrine gland cells. In neurons \nand muscle cells, the ability of the action potential, once \ninitiated, to propagate to all parts of the cell membrane, and often to spread to neighbouring cells, explains the \nimportance of membrane excitation in intra- and intercellular \nsignalling. In the nervous system and in skeletal muscle, action potential propagation is the mechanism responsible \nfor communication over long distances at high speed, \nindispensable for large, fast-moving creatures. In cardiac and smooth muscle, as well as in some central neurons, spontaneous rhythmic activity occurs. In gland cells, the \naction potential, where it occurs, serves to amplify the signal \nthat causes the cell to secrete. In each type of tissue, the properties of the excitation process reflect the special \ncharacteristics of the ion channels that underlie the process. \nThe molecular nature of ion channels, and their importance as drug targets, is considered in Chapter 3; here we discuss \nthe cellular processes that depend primarily on ion channel \nfunction. For more detail, see Hille (2001).\nTHE \u2018RESTING\u2019 CELL\nThe resting cell is not resting at all but very busy controlling the state of its interior, and it requires a continuous supply \nof energy to do so. In relation to the topics discussed in \nthis chapter, the following characteristics are especially important:\n\u2022\tmembrane \tpotential\n\u2022\tpermeability \tof \tthe \tplasma \tmembrane \tto \tdifferent \tions\n\u2022\tintracellular \tion \tconcentrations, \tespecially \t[Ca2+]i\nUnder resting conditions, all cells maintain a negative internal potential between about \u221230 and \u2212\n80 mV, depending \non the cell type. This arises because (a) the membrane is \nrelatively \timpermeable \tto\tNa+,\tand\t(b)\tNa+ ions are actively \nextruded from the cell in exchange for K+ ions by an energy-\ndependent \ttransporter,", "start_char_idx": 0, "end_char_idx": 3567, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e4416dfc-d69f-4b0a-8375-6a316fb4ffcd": {"__data__": {"id_": "e4416dfc-d69f-4b0a-8375-6a316fb4ffcd", "embedding": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc268ea8-3541-4a54-9ea3-4ec4ef175355", "node_type": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9272ab85e40c4aa6c8580acf76d8620fad159a3417d785d01857def9a764b004"}, "2": {"node_id": "b1c398c3-af7f-44f7-9bf4-a14c6bdbe12b", "node_type": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2088e5b48a397adc415a6c92874e2eff9be167dbaba64c2483a78e8caa94e8e"}, "3": {"node_id": "0bf45a48-f030-497a-a8ed-60882a4ad3b8", "node_type": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7c078dea43f9bbb42b7d9764f016973bdeffa1425ba98bd116597142d6819895"}}, "hash": "87470f32138918f9115ba8208d5ff385be9adfd079ffb1c04c3a0174bc1194a8", "text": "from the cell in exchange for K+ ions by an energy-\ndependent \ttransporter, \tthe\tNa+\tpump\t(or\tNa+\u2013K+-ATPase). \nThe result is that the intracellular K+ concentration, [K+]i, \nis\thigher, \tand \t[Na+]i is lower, than the respective extracellular \nconcentrations. In many cells, other ions, particularly Cl\u2212, \nare also actively transported and unequally distributed \nacross the membrane. In many cases (e.g. in neurons), the \nmembrane permeability to K+ is relatively high, and the \nmembrane potential settles at a value of \u221260 to \u2212 80 mV, \nclose to the equilibrium potential for K+ (Fig. 4.3). In other \ncells (e.g. smooth muscle), anions play a larger part, and \nthe membrane potential is generally lower ( \u221230 to \u221250 mV) \nand less dependent on K+.\nELECTRICAL AND IONIC EVENTS UNDERLYING \nTHE ACTION POTENTIAL\nOur\tpresent \tunderstanding \tof \telectrical \texcitability \trests \t\nfirmly on the work of Hodgkin, Huxley and Katz on squid \naxons, published in 1949\u20131952. Their experiments (see Katz, \n1966) revealed the existence of voltage-gated ion channels (see pp. 60\u201361) and showed that the action potential is generated by the interplay of two processes:\n1.\tA\trapid, \ttransient \tincrease \tin \tNa+ permeability that \noccurs when the membrane is depolarised beyond \nabout \u221250 mV.\n2. A slower, sustained increase in K+ permeability.\nBecause\tof \tthe \tinequality \tof \tNa+ and K+ concentrations \non\tthe\ttwo \tsides \tof \tthe \tmembrane, \tan \tincrease \tin \tNa+ Ca2+\npumpNa+/K+\npump\u2018Resting\u2019\npotassium\nchannels\nNa+\u2013Ca2+\nexchange\nNa+Na+K+K+\nATPATP\nCa2+CYTOSOL\nCa2+Na+ 12mmol/L\nK+ 150 mmol/L\nCa2+ 0.1\u00b5mol/L\nCl\u22125 mmol/L+60 mV\n\u221290 mV\n+120 mV\n\u221290 mV\n\u221260 mV145 mmol/ L\n2.4 mmol/L\n2 mmol/L125 mmol/\nLIntracellular Equilibrium potential Extracellula r\nFig. 4.3 Simplified diagram showing the ionic balance of a \ntypical \u2018resting\u2019 cell. The main transport mechanisms that \nmaintain the ionic gradients across the plasma membrane are \nthe ATP-driven Na+\u2013K+ and Ca2+ pumps and the Na+\u2013Ca2+ \nexchange transporter. The membrane is relatively permeable to \nK+, because some types of potassium channel are open at rest, \nbut impermeable to other cations. The unequal ion \nconcentrations on either side of the membrane give rise to the \u2018equilibrium potentials\u2019 shown. The resting membrane potential, typically about \u2212\n60 mV but differing between different cell types, \nis determined by the equilibrium potentials and the permeabilities of the various ions involved, and by the \u2018electrogenic\u2019 effect of the transporters. For simplicity, anions and other ions, such as protons, are not shown, although these play an important role in many cell types. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3504, "end_char_idx": 6459, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0bf45a48-f030-497a-a8ed-60882a4ad3b8": {"__data__": {"id_": "0bf45a48-f030-497a-a8ed-60882a4ad3b8", "embedding": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc268ea8-3541-4a54-9ea3-4ec4ef175355", "node_type": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9272ab85e40c4aa6c8580acf76d8620fad159a3417d785d01857def9a764b004"}, "2": {"node_id": "e4416dfc-d69f-4b0a-8375-6a316fb4ffcd", "node_type": null, "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87470f32138918f9115ba8208d5ff385be9adfd079ffb1c04c3a0174bc1194a8"}}, "hash": "7c078dea43f9bbb42b7d9764f016973bdeffa1425ba98bd116597142d6819895", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6476, "end_char_idx": 6667, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d501622b-b7b0-448e-b8d0-dc51c10c963e": {"__data__": {"id_": "d501622b-b7b0-448e-b8d0-dc51c10c963e", "embedding": null, "metadata": {"page_label": "64", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1e7984c-51a3-4d80-8eff-e2d4ae60ca4e", "node_type": null, "metadata": {"page_label": "64", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79b796d44340054fde20e31cfd89463d0bd8c19a0064ff1258e563593ee07f47"}, "3": {"node_id": "45f1da4c-d5db-4178-aa88-c971df6ba348", "node_type": null, "metadata": {"page_label": "64", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "589e8a10c880e0276c86da49358fbe10fd5ff15245ea856d4af0526765cd4bed"}}, "hash": "5b16bc296754d6418619507862f78fb7b4e7bf11d2718c478e15f581036a225e", "text": "4 SECTION 1 GENERAL PRINCIPLES\n58through voltage-gated calcium channels plays a key role \nin intracellular signalling, as described on pp. 52\u201356.\nCHANNEL FUNCTION\nThe discharge patterns of excitable cells vary greatly. Skeletal muscle fibres are quiescent unless stimulated by the arrival \nof a nerve impulse at the neuromuscular junction. Cardiac \nmuscle fibres discharge spontaneously at a regular rate \n(see\tCh.\t22).\tNeurons \tmay\tbe\tnormally \tsilent,\tor\tthey\tmay\t\ndischarge spontaneously, either regularly or in bursts; smooth muscle cells show a similar variety of firing patterns. \nThe frequency at which different cells normally discharge \naction potentials also varies greatly, from 100 Hz or more \nfor fast-conducting neurons, down to about 1 Hz for cardiac \nmuscle cells. These very pronounced functional variations \nreflect the different characteristics of the ion channels \nexpressed in different cell types. Rhythmic fluctuations of \n[Ca2+]i underlie the distinct firing patterns that occur in \ndifferent types of cell (see Berridge, 2016).\nDrugs that alter channel characteristics, either by interact-\ning directly with the channel itself or indirectly through second messengers, affect the function of many organ \nsystems, including the nervous, cardiovascular, endocrine, \nrespiratory and reproductive systems, and are a frequent theme in this book. Here we describe some of the key \nmechanisms involved in the regulation of excitable cells.\nIn general, action potentials are initiated by membrane \ncurrents that cause depolarisation of the cell. These currents \nmay be produced by synaptic activity, by an action potential \napproaching from another part of the cell, by a sensory \nstimulus or by spontaneous pacemaker activity. The tendency \nof such currents to initiate an action potential is governed \nby the excitability of the cell, which depends mainly on the \nstate of (a) the voltage-gated sodium and/or calcium chan -\nnels, and (b) the potassium channels of the resting mem -\nbrane. Anything that increases the number of available sodium or calcium channels, or reduces their activation threshold, will tend to increase excitability, whereas increas -\ning the resting K\n+ conductance reduces it. Agents that do \nthe reverse, by blocking channels or interfering with their \nopening, will have the opposite effect. Some examples are \nshown in Figs 4.6 and 4.7. Inherited mutations of channel proteins are responsible for a wide variety of neurological \nand other genetic disorders (see Imbrici et al., 2016).\nUSE DEPENDENCE AND VOLTAGE DEPENDENCE\n\u25bc Voltage-gated channels can exist in three functional states (Fig. \n4.8): resting (the closed state that prevails at the normal resting \npotential), activated (the open state favoured by brief depolarisation) \nand inactivated (the blocked state resulting from a trapdoor-like \nocclusion of the open channel by a floppy intracellular appendage \nof the channel protein). After the action potential has passed, many \nsodium channels are in the inactivated state; after the membrane \npotential returns to its resting value, the inactivated channels take time to revert to the resting state and thus become available for \nactivation once more. In the meantime, the membrane is temporarily \nrefractory. Each action potential causes the channels to cycle through \nthese states. The duration of the refractory period determines the \nmaximum frequency at which action potentials can occur. Drugs that block sodium channels, such as local anaesthetics (Ch. 44), antidys -\nrhythmic drugs (Ch. 22) and antiepileptic drugs (Ch. 46), commonly show a selective affinity for one or other of these functional states of the channel, and in their presence the", "start_char_idx": 0, "end_char_idx": 3718, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "45f1da4c-d5db-4178-aa88-c971df6ba348": {"__data__": {"id_": "45f1da4c-d5db-4178-aa88-c971df6ba348", "embedding": null, "metadata": {"page_label": "64", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1e7984c-51a3-4d80-8eff-e2d4ae60ca4e", "node_type": null, "metadata": {"page_label": "64", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79b796d44340054fde20e31cfd89463d0bd8c19a0064ff1258e563593ee07f47"}, "2": {"node_id": "d501622b-b7b0-448e-b8d0-dc51c10c963e", "node_type": null, "metadata": {"page_label": "64", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5b16bc296754d6418619507862f78fb7b4e7bf11d2718c478e15f581036a225e"}}, "hash": "589e8a10c880e0276c86da49358fbe10fd5ff15245ea856d4af0526765cd4bed", "text": "affinity for one or other of these functional states of the channel, and in their presence the proportion of channels in the \nhigh-affinity \tstate \tis \tincreased. \tOf \tparticular \timportance \tare \tdrugs \t\nthat bind most strongly to the inactivated state of the channel and thus favour the adoption of this state, prolonging the refractory period \nand reducing the maximum frequency at which action potentials can potassium channels during an action potential is shown \nin Fig. 4.5.\nThe foregoing account, based on Hodgkin and Huxley\u2019s \nwork\t65 \tyears \tago, \tinvolves \tonly \tNa+ and K+ channels. \nSubsequently (see Hille, 2001), voltage-gated calcium chan -\nnels (see Fig. 4.1) were discovered. These function in basically the same way as sodium channels, if on a slightly slower timescale; they contribute to action potential genera -\ntion in many cells, particularly cardiac and smooth muscle cells, but also in neurons and secretory cells. Ca\n2+ entry Time (ms) Time (ms)\n20 15 10 5 0 10 5 0 \n\u221210\n\u2212100 01010Current (nA)\nCurrent (nA)\nTEA TTXControl ControlA B\nC D\nFig. 4.4 Separation of sodium and potassium currents in \nthe nerve membrane. Voltage clamp records from the node of \nRanvier of a single frog nerve fibre. At time 0, the membrane \npotential was stepped to a depolarised level, ranging from \n\u221260 mV (lower trace in each series) to +60 mV (upper trace in \neach series) in 15-mV steps. (A and B) Control records from two fibres. (C) Effect of tetrodotoxin (TTX), which abolishes Na\n+ \ncurrents. (D) Effect of tetraethylammonium (TEA), which abolishes K\n+ currents. (From Hille, B., 1970. Ionic channels in \nnerve membranes. Prog. Biophys. Mol. Biol. 21, 1\u201332.)\n0102030\n4 3 2 1 0Time (ms)Conductance (mmho/cm2)\nEm (mV)Em\ngK\ngNa+40\n0\n\u221240\n\u221280\nFig. 4.5 Behaviour of sodium and potassium channels \nduring a conducted action potential. Rapid opening of sodium \nchannels occurs during the action potential upstroke. Delayed opening of potassium channels, and inactivation of sodium channels, causes repolarisation. E\nm, membrane potential; \ngK, membrane conductance to K+; gNa, membrane conductance \nto Na+. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3624, "end_char_idx": 6219, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1321f416-92f3-4c08-ae4e-4c0175fbcc61": {"__data__": {"id_": "1321f416-92f3-4c08-ae4e-4c0175fbcc61", "embedding": null, "metadata": {"page_label": "65", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "418c248c-21b2-42e1-9636-e911e7092d79", "node_type": null, "metadata": {"page_label": "65", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b1590e87c5e4f44181fc8f9093035c9a53e253e780ea7dbb2a0036f16a25ebd0"}}, "hash": "b1590e87c5e4f44181fc8f9093035c9a53e253e780ea7dbb2a0036f16a25ebd0", "text": "4 How dRuGS ACt: CELLuLAR ASPECtS \u2013 ExCItAtIoN, CoNtRACtIoN ANd SECREtIoN \n59Excitatory voltage-gated channels\nDepolarisation\nBatrachotoxinVeratridine\nTetrodotoxin\nLocal anaesthetics (Ch. 44)\nAntiepileptics (some, Ch. 45)Antidysrhythmics (some, Ch. 22)Na+\nCa2+Depolarisation\nBayK 8644 (some)\ncAMP (some)\nDihydropyridines (some, Ch. 23)\n\u03c9-Conotoxins (some)\nGPCR ligands (some)\nExcitatory ligand-gated channelsHyperpolarisation-activated,\ncyclic nucleotide-gated channels (HCNs)\nNEUROTRANSMITTERSMany examples\n(Chs 13, 14, 16, 38) \nLow pH \n(H+)\nAmiloride (some, Ch. 30)\nCapsaicin\nNoxious heat\nCapsazepineHyperpolarisation\ncAMP (some)\nIvabradine (Ch. 22)Na+/K+\nOTHER LIGANDSInhibitory voltage-gated channels\n'Resting' channelsDepolarisation\nTetraethylammonium4-Aminopyridine\nDendrotoxinsK+\nGPCR ligands (some)\nAnaesthetics (some, Ch. 42)\nGPCR ligands (some)K+\nCa2+-gated channels\nIncreased [Ca2+]i\nApamin (some)K+\nATP-gated channels\nSulfonylureas (Ch. 32)\nDiazoxide (Chs. 23, 32)\nInternal [ATP]iK+\nInhibitory ligand-gated channels\nGABA (Ch. 39)\nBicuculline\nPicrotoxinCl\u2212\nGlycine (Ch. 39)\nStrychnineCl\u2212EXCITATION\nINHIBITIONNa+/K+\n(and Ca2+?)\nFig. 4.6 Ion channels associated with excitatory and inhibitory membrane effects, and some of the drugs and other ligands that \naffect them. Channel openers are shown in green boxes, blocking agents and inhibitors in pink boxes. Hyperpolarisation-activated Na+/K+ \nchannels are known as hyperpolarisation-activated, cyclic nucleotide-gated channels (HCNs); H+ activated channels are known as \nacid-sensing ion channels (ASICs). GPCR, G protein\u2013coupled receptor. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2084, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fc3e45d1-e539-4a33-b465-35dcfe0f49b0": {"__data__": {"id_": "fc3e45d1-e539-4a33-b465-35dcfe0f49b0", "embedding": null, "metadata": {"page_label": "66", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ca5fd6e5-9a6a-4a42-9351-a8a2c8b95f6e", "node_type": null, "metadata": {"page_label": "66", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50c635a7f07c46278d5e3d07d4121722777486f4cf08a7ee04c755b3610324e3"}, "3": {"node_id": "fc2a8504-bbee-43c8-8db5-dfbb6cfc95d5", "node_type": null, "metadata": {"page_label": "66", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e953ec9f4be6715cf4142b63abc5feaa21e8855ffe0055c0b768f46a6f6b7c47"}}, "hash": "60c9914a11113b2752a39badfa7c42f918c17cb9dc00f0b2406c3c90459744bb", "text": "4 SECTION 1 GENERAL PRINCIPLES\n60(TTX,\tsee \tCh. \t44) \tto \tlabel \tand \tpurify \tthe \tchannel \tproteins, \t\nand subsequently to clone them. Sodium channels consist \nof a central, pore-forming \u03b1 subunit (shown in Fig. 3.20) \nand two auxiliary \u03b2\tsubunits. \tNine \t\u03b1-subunits \t(Na v1.1 \nthrough\tNa v1.9) and four \u03b2 subunits have been identified \nin mammals. The \u03b1 subunits contain four similar domains, \neach comprising six membrane-spanning helices (see Cat -\nterall\t&\tSwanson, \t2015). \tOne \tof \tthese \thelices, \tS4, \twhich \t\ncontains several basic amino acids and forms the voltage \nsensor, moves outwards, thus opening the channel, when \nthe\tmembrane \ti s \t depolarised. \t One\t of \tt he\t intracellular \t loops\t\nis designed to swing across and block the channel when S4 is displaced, thus inactivating the channel.\nIt was known from physiological studies that the sodium \nchannels of heart and skeletal muscle differ in various ways from those of neurons. In particular, cardiac sodium channels \n(and those of some sensory neurons) are relatively insensi -\ntive\tto\tTTX \tand \tslower \tin \ttheir \tkinetics, \tcompared \twith \tbe generated. This type of block is called use dependent, because the \nbinding of such drugs increases as a function of the rate of action \npotential discharge, which governs the rate at which inactivated \u2013 and \ntherefore drug-sensitive \u2013 channels are generated. This is important for some antidysrhythmic drugs (see Ch. 22) and for antiepileptic \ndrugs (Ch. 46), because high-frequency discharges can be inhibited \nwithout affecting excitability at normal frequencies. Drugs that readily block sodium channels in their resting state (e.g. local anaesthetics, \nCh. 44) prevent excitation at low as well as high frequencies.\nMost sodium channel-blocking drugs are cationic at physiological \npH and are therefore affected by the voltage gradient across the cell \nmembrane. They block the channel from the inside, so that their blocking action is favoured by depolarisation. This phenomenon, \nknown as voltage dependence, is also of relevance to the action of \nantidysrhythmic and antiepileptic drugs, because the cells that are the seat of dysrhythmias or seizure activity are generally somewhat \ndepolarised and therefore more strongly blocked than healthy cells. \nSimilar considerations apply also to drugs that block potassium or \ncalcium channels, but we know less about the importance of use and \nvoltage dependence for these than we do for sodium channels.\nSODIUM CHANNELS\nIn most excitable cells, the regenerative inward current \nthat initiates the action potential results from activation of \nvoltage-gated sodium channels. The early voltage clamp \nstudies by Hodgkin and Huxley on the squid giant axon, described on p. 57, revealed the essential functional proper -\nties of these channels. Later, advantage was taken of the potent and highly selective blocking action of tetrodotoxin Local anaesthetics\nSTX, TTXIncreased K +\nconductance\nOutward K +\ncurrentInward Na +\ncurrentIncreased Na +\nconductanceMembrane\ndepolarisation\nSodium channel\ninactivationTetraethylammonium \n4-Aminopyridine\nVeratridine,\nbatrachotoxin,\nscorpion toxin,\netc.SlowSlow\nFast\nFig. 4.7 Sites of action of drugs and toxins that affect \nchannels involved in action potential generation. Many other \nmediators affect these channels indirectly via membrane \nreceptors, through phosphorylation or altered expression. STX, \nsaxitoxin;", "start_char_idx": 0, "end_char_idx": 3430, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fc2a8504-bbee-43c8-8db5-dfbb6cfc95d5": {"__data__": {"id_": "fc2a8504-bbee-43c8-8db5-dfbb6cfc95d5", "embedding": null, "metadata": {"page_label": "66", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ca5fd6e5-9a6a-4a42-9351-a8a2c8b95f6e", "node_type": null, "metadata": {"page_label": "66", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50c635a7f07c46278d5e3d07d4121722777486f4cf08a7ee04c755b3610324e3"}, "2": {"node_id": "fc3e45d1-e539-4a33-b465-35dcfe0f49b0", "node_type": null, "metadata": {"page_label": "66", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "60c9914a11113b2752a39badfa7c42f918c17cb9dc00f0b2406c3c90459744bb"}}, "hash": "e953ec9f4be6715cf4142b63abc5feaa21e8855ffe0055c0b768f46a6f6b7c47", "text": "through phosphorylation or altered expression. STX, \nsaxitoxin; TTX, tetrodotoxin. Resting Open\nInactivatedFavoured by\ndepolarisation\nfast\nslow very\nslowInactivating\nparticle\nBlocking\ndrugNa+A\nB\nFig. 4.8 Resting, activated and inactivated states of \nvoltage-gated channels, exemplified by the sodium channel. \n(A) Membrane depolarisation causes a rapid transition from the \nresting (closed) state to the open state. The inactivating particle \n(part of the intracellular domain of the channel protein) is then \nable to block the channel. With prolonged depolarisation below \nthe threshold for opening, channels can go directly from resting \nto inactivated without opening. (B) Some blocking drugs (such \nas tetrodotoxin) block the channel from the outside like a plug, \nwhereas others (such as local anaesthetics and antiepileptic \ndrugs) enter from the inside of the cell and often show \npreference for the open or inactivated states, and thus affect the \nkinetic behaviour of the channels, with implications for their \nclinical application. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3367, "end_char_idx": 4890, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9a34710e-7bd9-4fb6-ab8b-db69789e68f3": {"__data__": {"id_": "9a34710e-7bd9-4fb6-ab8b-db69789e68f3", "embedding": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "07c80ebe-0826-4842-864f-006768ff70b0", "node_type": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "667a012fde289e9ca9c9e019d0479cc7f5605a557040b3d38f6240cd3e44a0f0"}, "3": {"node_id": "15d8d458-2b02-48f9-bf3d-7687e468f860", "node_type": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3a9a4e3031acc6deebebc2aa8ae3d16dcd290e8e8c94fb73c059358ec76435f6"}}, "hash": "ec7f2c332f3616e5fd197418d990f5668ccd046b0eaf80beb50546f0d44dcb4d", "text": "4 How d RuGS AC t: CELL u LAR ASPEC t S \u2013 E x CI t A t I o N , C o N t RAC t I o N AN d SECRE t I o N \n61them; see Ch. 32) and smooth muscle relaxant drugs, such as \nminoxidil and diazoxide, which open them (see Ch. 23).\n\u2022\tTwo-pore domain potassium channels, with four helices and two P loops. These show outward rectification and therefore exert a strong repolarising influence, opposing any tendency to \nexcitation. They may contribute to the resting K\n+ conductance in \nmany cells and are susceptible to regulation via G proteins; certain subtypes have been implicated in the action of volatile \nanaesthetics such as isoflurane (Ch. 42).\nFor more details, and information on potassium channels and the various drugs and toxins that affect them, see Jenkinson (2006) and \nAlexander et al. (2015).\nInherited abnormalities of potassium channels (channelo -\npathies) contribute to a rapidly growing number of cardiac, \nneurological and other diseases. These include the long QT \nsyndrome associated with mutations in cardiac voltage-gated \npotassium channels, causing episodes of ventricular arrest that can result in sudden death. Drug-induced prolongation \nof the QT interval is an unwanted side effect of several \ndrugs (see Ch 22), including methadone and various \nantipsychotic \tagents. \tNowadays, \tnew \tdrugs \tare \tscreened \t\nfor this property at an early stage in the development process (see Ch. 60). Certain familial types of deafness and epilepsy \nare associated with mutations in voltage-gated potassium \nchannels (Imbrici et al., 2016).most neuronal sodium channels. This is explained by the \nrelative insensitivity of some \u03b1\tsubunits \t(Na v1.5,\tNa v1.8 \nand\tNa v1.9) to tetrodotoxin. Changes in the level of expres -\nsion of some sodium channel subunits is thought to underlie \nthe hyperexcitability of sensory neurons in different types \nof neuropathic pain (see Ch. 43).\nIn addition to channel-blocking compounds such as \ntetrodotoxin, other compounds affect sodium channel gating. For example, the plant alkaloid veratridine and the frog \nskin poison batrachotoxin cause persistent activation, while \nvarious scorpion toxins prevent inactivation, mechanisms resulting in enhanced neuronal excitability.\nPOTASSIUM CHANNELS\nIn a typical resting cell (see p. 57, Fig. 4.3), the membrane is selectively permeable to K\n+ and the membrane potential \n(about \u221260 mV) is somewhat positive to the K+ equilibrium \n(about \u221290 mV). This resting permeability comes about \nbecause some potassium channels are open. If more potas -\nsium channels open, the membrane hyperpolarises and \nthe cell is inhibited, whereas the opposite happens if \npotassium channels close. As well as affecting excitability in this way, potassium channels also play an important \nrole in regulating the duration of the action potential and \nthe temporal patterning of action potential discharges; altogether, these channels play a central role in regulating \ncell function. As mentioned in Chapter 3, the number and \nvariety of potassium channel subtypes is extraordinary, implying that evolution has been driven by the scope for biological advantage to be gained from subtle variations \nin the functional properties of these channels. A recent \nr\u00e9sum\u00e9 lists over 60 different pore-forming subunits, plus another 20 or so auxiliary subunits. An impressive evolution -\nary display, maybe, but hard going for most of us.\n\u25bc Potassium channels fall into three main classes (Table 4.2),4 of \nwhich the structures are shown in Fig.", "start_char_idx": 0, "end_char_idx": 3509, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "15d8d458-2b02-48f9-bf3d-7687e468f860": {"__data__": {"id_": "15d8d458-2b02-48f9-bf3d-7687e468f860", "embedding": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "07c80ebe-0826-4842-864f-006768ff70b0", "node_type": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "667a012fde289e9ca9c9e019d0479cc7f5605a557040b3d38f6240cd3e44a0f0"}, "2": {"node_id": "9a34710e-7bd9-4fb6-ab8b-db69789e68f3", "node_type": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ec7f2c332f3616e5fd197418d990f5668ccd046b0eaf80beb50546f0d44dcb4d"}, "3": {"node_id": "85df5f9b-266c-4ae7-bcf8-a28d0b66ee30", "node_type": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8eadf7129a130c34f8f39508edfe3a420af65282ef2b8fb8be6e657ff5d12a46"}}, "hash": "3a9a4e3031acc6deebebc2aa8ae3d16dcd290e8e8c94fb73c059358ec76435f6", "text": "main classes (Table 4.2),4 of \nwhich the structures are shown in Fig. 3.20.\n\u2022\tVoltage-gated potassium channels, which possess six \nmembrane-spanning helices, one of which serves as the voltage \nsensor, causing the channel to open when the membrane is \ndepolarised. Included in this group are channels of the shaker family, accounting for most of the voltage-gated K\n+ currents \nfamiliar to electrophysiologists, and others such as Ca2+-\nactivated potassium channels and two subtypes that are \nimportant in the heart, HERG and LQT channels. Many of these \nchannels are blocked by drugs such as tetraethylammonium and 4-aminopyridine.\n\u2022\tInwardly rectifying potassium channels, so called because they allow K\n+ to pass inwards much more readily than outwards. \nThese have two membrane-spanning helices and a single \npore-forming loop (P loop). These channels are regulated by \ninteraction with G proteins (see Ch. 3) and mediate the inhibitory effects of many agonists acting on G protein\u2013coupled \nreceptors. Certain types are important in the heart, particularly \nin regulating the duration of the cardiac action potential (Ch. 22); others are the target for the action of sulfonylureas \n(antidiabetic drugs that stimulate insulin secretion by blocking \n4Potassium channel terminology is confusing, to put it mildly. \nElectrophysiologists have named K+ currents prosaically on the basis of \ntheir functional properties (I KV, IKCa, IKATP, IKIR, etc.); geneticists have \nnamed genes somewhat fancifully according to the phenotypes \nassociated with mutations (\u2018shaker\u2019, \u2018ether-a-go-go\u2019, etc.), while \nmolecular biologists have introduced a rational but unmemorable \nnomenclature \ton \tthe \tbasis \tof \tsequence \tdata \t(KCNK, \tKCNQ, \tetc., \twith\t\nnumerical suffixes). The rest of us must make what we can of the unlovely jargon of labels such as HERG (which \u2013 don\u2019t blink \u2013 stands for \n\u2018Human Ether-a-go-go Related Gene\u2019), TWIK, TREK and TASK.Ion channels and electrical \nexcitability \n\u2022\tExcitable \tcells \tgenerate \tan \tall-or-nothing \taction \t\npotential in response to membrane depolarisation. This \noccurs in most neurons and muscle cells, and in some gland cells. The ionic basis and time course of the \nresponse varies between tissues.\n\u2022\tThe\tregenerative \tresponse \tresults \tfrom \tthe \t\ndepolarising current associated with opening of \nvoltage-gated cation channels (mainly Na+ and Ca2+). It \nis terminated by inactivation of these channels accompanied by opening of K\n+ channels.\n\u2022\tThese\tvoltage-gated \tchannels \texist \tin \tmany \tmolecular \t\nvarieties, with specific functions in different types of cell.\n\u2022\tThe\tmembrane \tof \tthe \t\u2018resting\u2019 \tcell \tis \trelatively \t\npermeable to K+ but impermeable to Na+ and Ca2+. \nDrugs or mediators that open K+ channels reduce \nmembrane excitability, as do inhibitors of Na+ or Ca2+ \nchannel function. Blocking K+ channels or activating \nNa+ or Ca2+ channels increases excitability.\n\u2022\tCardiac \tmuscle \tcells, \tsome \tneurons \tand \tsome \t\nsmooth muscle cells generate spontaneous action potentials whose amplitude, rate and rhythm are affected by drugs that affect ion channel function.\nMUSCLE CONTRACTION\nEffects of drugs on the contractile machinery of smooth \nmuscle are the basis of many therapeutic applications, for \nsmooth muscle is an important component of most \nphysiological systems, including blood vessels and the", "start_char_idx": 3452, "end_char_idx": 6809, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "85df5f9b-266c-4ae7-bcf8-a28d0b66ee30": {"__data__": {"id_": "85df5f9b-266c-4ae7-bcf8-a28d0b66ee30", "embedding": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "07c80ebe-0826-4842-864f-006768ff70b0", "node_type": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "667a012fde289e9ca9c9e019d0479cc7f5605a557040b3d38f6240cd3e44a0f0"}, "2": {"node_id": "15d8d458-2b02-48f9-bf3d-7687e468f860", "node_type": null, "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3a9a4e3031acc6deebebc2aa8ae3d16dcd290e8e8c94fb73c059358ec76435f6"}}, "hash": "8eadf7129a130c34f8f39508edfe3a420af65282ef2b8fb8be6e657ff5d12a46", "text": "muscle is an important component of most \nphysiological systems, including blood vessels and the gastrointestinal, respiratory and urinary tracts. For many \ndecades, smooth muscle pharmacology with its trademark mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6771, "end_char_idx": 7462, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e4c25c41-12d3-445f-b38a-2b515d7806d6": {"__data__": {"id_": "e4c25c41-12d3-445f-b38a-2b515d7806d6", "embedding": null, "metadata": {"page_label": "68", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "52a1ce83-0aa5-40f5-a784-d828a084fd3d", "node_type": null, "metadata": {"page_label": "68", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2961fe5dd777b10d8befe8c103398daaa6e85170f8df364102f0cab49af1d71d"}, "3": {"node_id": "75b8c2fe-a448-4d39-81d5-00e7ec5e839c", "node_type": null, "metadata": {"page_label": "68", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c54a33a8c5adb1046a171c6c5dc2ac2f661240e7f8b88d3f1c8facf013746604"}}, "hash": "31d541ed7df83e2217edd621644817e220d96dbece0092ab8aa46e51d6c09fbb", "text": "4 SECTION 1 GENERAL PRINCIPLES\n62action potential of the plasma membrane depends on \nvoltage-gated sodium channels, as in most nerve cells, and \npropagates rapidly from its site of origin, the motor endplate \n(see Ch. 14), to the rest of the fibre. The T-tubule membrane contains voltage-gated calcium channels termed dihydro -\npyridine receptors (DHPRs),\n5 that respond to membrane \ndepolarisation conducted passively along the T-tubule when \nthe plasma membrane is invaded by an action potential. \nDHPRs are located extremely close to RyRs (see Ch. 3) in the adjacent SR membrane and activation of these RyRs \ncauses release of Ca\n2+ from the SR. Direct coupling between \nthe DHPRs of the T-tubule and the RyRs of the SR (as technology \u2013 the isolated organ bath \u2013 held the centre of \nthe pharmacological stage, and neither the subject nor the technology shows any sign of flagging, even though the \nstage has become much more crowded. Cardiac and skeletal \nmuscle contractility are also the targets of important drug effects.\nAlthough in each case the basic molecular basis of contrac -\ntion is similar, namely an interaction between actin and myosin, fuelled by ATP and initiated by an increase in \n[Ca\n2+]i, there are differences between these three kinds of \nmuscle that account for their different responsiveness to drugs and chemical mediators.\nThese differences (Fig. 4.9) involve (a) the linkage between \nmembrane events and increase in [Ca\n2+]i, and (b) the \nmechanism by which [Ca2+]i regulates contraction.\nSKELETAL MUSCLE\nSkeletal muscle possesses an array of transverse T-tubules \nextending into the cell from the plasma membrane. The Table 4.2 Types and functions of K+ channels\nStructural \nclassaFunctional subtypes\nbFunctions Drug effects Notes\nVoltage-gated \n(6T, 1P)Voltage-gated K\n+ channelsAction potential repolarisationBlocked by tetraethylammonium, 4-aminopyridineSubtypes in the heart include HERG and LQT channels, which are involved in congenital and drug-induced dysrhythmiasOther subtypes may be involved in inherited forms of epilepsyLimits maximum firing frequencyCertain subtypes blocked by dendrotoxins (from mamba snake venom)\nCa\n2+-activated \nK+ channelsInhibition following stimuli which increase [Ca\n2+]iCertain subtypes blocked by apamin (from bee venom), and charybdotoxin (from scorpion venom)Important in many excitable tissues to limit repetitive discharges, also in secretory cells\nInward rectifying (2T, 1P)G protein-activatedMediate effects of Gi/Go-coupled GPCRs which cause inhibition by increasing K\n+ conductanceGPCR agonists and antagonistsSome are blocked by tertiapin (from honey bee venom)Other inward rectifying K\n+ channels important \nin kidney\nATP-sensitive Found in many cellsChannels open when [ATP] is low, causing inhibitionImportant in control of insulin secretion in the pancreasAssociation of one subtype with the sulfonylurea receptor (SUR) results in modulation by sulfonylureas (e.g. glibenclamide) which close channel, and by K\n+ \nchannel openers (e.g. diazoxide, minoxidil) which relax smooth muscle\nTwo-pore domain (4T, 2P)Several subtypes identified (TWIK, TRAAK, TREK, TASK, etc.)Most are voltage-insensitive; some are normally open and contribute to the \u2018resting\u2019 K\n+ conductance\nModulated by GPCRsCertain subtypes are activated by volatile anaesthetics", "start_char_idx": 0, "end_char_idx": 3329, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "75b8c2fe-a448-4d39-81d5-00e7ec5e839c": {"__data__": {"id_": "75b8c2fe-a448-4d39-81d5-00e7ec5e839c", "embedding": null, "metadata": {"page_label": "68", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "52a1ce83-0aa5-40f5-a784-d828a084fd3d", "node_type": null, "metadata": {"page_label": "68", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2961fe5dd777b10d8befe8c103398daaa6e85170f8df364102f0cab49af1d71d"}, "2": {"node_id": "e4c25c41-12d3-445f-b38a-2b515d7806d6", "node_type": null, "metadata": {"page_label": "68", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "31d541ed7df83e2217edd621644817e220d96dbece0092ab8aa46e51d6c09fbb"}}, "hash": "c54a33a8c5adb1046a171c6c5dc2ac2f661240e7f8b88d3f1c8facf013746604", "text": "conductance\nModulated by GPCRsCertain subtypes are activated by volatile anaesthetics (e.g. isoflurane)No selective blocking agentsThe nomenclature is misleading, especially when they are incorrectly referred to as two-pore channels\naK+ channel structures (see Fig. 3.20) are defined according to the number of transmembrane helices (T) and the number of pore-forming \nloops (P) in each \u03b1 subunit. Functional channels contain several subunits (often four) which may be identical or different, and they are often \nassociated with accessory ( \u03b2) subunits.\nbWithin each functional subtype, several molecular variants have been identified, often restricted to particular cells and tissues. The \nphysiological and pharmacological significance of this heterogeneity is not yet understood.GPCR, G protein\u2013coupled receptor.\n5Although these are, to all intents and purposes, just a form of L-type \ncalcium channel the term dihydropyridine receptor (DHPR) is used to \nreflect that they are not identical to the L-type channels in neurons and \ncardiac muscle.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3244, "end_char_idx": 4771, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a324f98f-e2c6-49a5-9c50-6fffde1c6d78": {"__data__": {"id_": "a324f98f-e2c6-49a5-9c50-6fffde1c6d78", "embedding": null, "metadata": {"page_label": "69", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f238dff4-b098-41bf-b79c-3024d1e49d07", "node_type": null, "metadata": {"page_label": "69", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f229cc11448d182834b2ea6168cc9a926c8404dfcf914ec150d18fd21d35c9a"}, "3": {"node_id": "a12cbc3e-66e9-44c6-854e-0d653bad8073", "node_type": null, "metadata": {"page_label": "69", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "267c0f0f788d82529ca32950f501aa06832311b178e63c23bd95b61a5096e165"}}, "hash": "dfa52a85c7f2d147e387ad0a8ee6c3ba5f3cb54d219d3ff7f612380ad1f50e98", "text": "4 How d RuGS AC t: CELL u LAR ASPEC t S \u2013 E x CI t A t I o N , C o N t RAC t I o N AN d SECRE t I o N \n63Conducted action potential (fast)\nRyRNaC\nSRL-type CaC\nT-TUBULE Ca2+\nTroponin Ca2+-troponin\nCONTRACTIONCa2+\nSRCa2+\nCa2+L-type CaC\nIP3RCa2+\nMLCK\nMyosin Myosin-P\nCONTRACTIONCaM Ca2+\u2013 CaMLigand-gated CaCAgonists\nGPCR\nIP3Skeletal muscle Cardiac muscle\nSmooth musclePLASMA\nMEMBRANEConducted action potential (slow)\nRyR\nRyRNaC\nSRL-type CaC\nT-TUBULE\nCa2+\nTroponin Ca2+-troponin\nCONTRACTIONCa2+Ca2+ Ca2+PLASMA\nMEMBRANE\nPLASMA\nMEMBRANEA B\nC\nFig. 4.9 Comparison of excitation\u2013contraction coupling in (A) skeletal muscle, (B) cardiac muscle and (C) smooth muscle. \nSkeletal and cardiac muscle differ mainly in the mechanism by which membrane depolarisation is coupled to Ca2+ release. The calcium \nchannel (CaC) and ryanodine receptor (RyR) are very closely positioned in both types of muscle. In cardiac muscle, Ca2+ entry via voltage-\ngated calcium channels initiates Ca2+ release through activation of the Ca2+-sensitive RyRs, whereas in skeletal muscle the sarcolemmal \ncalcium channels activate the RyRs through a voltage-dependent physical interaction. The control of intracellular Ca2+ in smooth muscle \ncells may vary depending upon the type of smooth muscle. In general terms, smooth muscle contraction is largely dependent upon inositol \ntrisphosphate (IP 3)-induced Ca2+ release from SR stores through IP 3 receptors (IP 3R). Smooth muscle contraction can also be produced \neither by Ca2+ entry through voltage- or ligand-gated calcium channels. The mechanism by which Ca2+ activates contraction is different, \nand operates more slowly, in smooth muscle compared with in skeletal or cardiac muscle. CaC, calcium channel; CaM, calmodulin; GPCR, \nG protein\u2013coupled receptor; MLCK, myosin light-chain kinase; NaC, voltage-gated sodium channel; RyR, ryanodine receptor; SR, \nsarcoplasmic reticulum. \nshown in Fig. 4.9) causes the opening of the RyRs on \nmembrane depolarisation. Through this link, depolarisation \nrapidly activates the RyRs, releasing a short puff of Ca2+ \nfrom the SR into the sarcoplasm. The Ca2+ binds to troponin, \na protein that normally blocks the interaction between actin and myosin. When Ca\n2+ binds, troponin moves out of the way and allows the contractile machinery to operate. Ca2+ \nrelease is rapid and brief, and the muscle responds with a short-lasting \u2018twitch\u2019 response. This is a relatively fast and \ndirect mechanism compared with the arrangement in cardiac and smooth muscle (see later), and consequently less \nsusceptible to pharmacological modulation.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2946, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a12cbc3e-66e9-44c6-854e-0d653bad8073": {"__data__": {"id_": "a12cbc3e-66e9-44c6-854e-0d653bad8073", "embedding": null, "metadata": {"page_label": "69", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f238dff4-b098-41bf-b79c-3024d1e49d07", "node_type": null, "metadata": {"page_label": "69", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f229cc11448d182834b2ea6168cc9a926c8404dfcf914ec150d18fd21d35c9a"}, "2": {"node_id": "a324f98f-e2c6-49a5-9c50-6fffde1c6d78", "node_type": null, "metadata": {"page_label": "69", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dfa52a85c7f2d147e387ad0a8ee6c3ba5f3cb54d219d3ff7f612380ad1f50e98"}}, "hash": "267c0f0f788d82529ca32950f501aa06832311b178e63c23bd95b61a5096e165", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2899, "end_char_idx": 3074, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0ad8b8c7-1960-4345-8c86-e2b1f4f9164e": {"__data__": {"id_": "0ad8b8c7-1960-4345-8c86-e2b1f4f9164e", "embedding": null, "metadata": {"page_label": "70", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "af558226-ca59-4531-b13d-0c3483f85ce0", "node_type": null, "metadata": {"page_label": "70", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "685bcb33d9e115b070a62c5b7d07307676a4431082b02cdbc185d3618b266e0c"}, "3": {"node_id": "c52bca6c-3938-42be-b9fb-731c57141b58", "node_type": null, "metadata": {"page_label": "70", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f42d73b99d548425448cbb1f9debaaa4ce835426968fb4e92415a2d17bb0999"}}, "hash": "b8088265ecd8e1ed1d108e731c7e2f9323c7206c8b9b2be6d317df66c033b937", "text": "4 SECTION 1 GENERAL PRINCIPLES\n64mediated through G protein\u2013coupled receptors or through \nguanylyl cyclase-linked receptors act in this way. Fig. 4.10 \nsummarises the main mechanisms by which drugs control smooth muscle contraction. The complexity of these control mechanisms and interactions explains why pharmacologists \nhave been entranced for so long by smooth muscle. Many \ntherapeutic drugs work by contracting or relaxing smooth muscle, particularly those affecting the cardiovascular, \nrespiratory and gastrointestinal systems, as discussed in \nlater chapters, where details of specific drugs and their physiological effects are given.CARDIAC MUSCLE\nCardiac muscle differs from skeletal muscle in several important respects. The nature of the cardiac action potential, \nthe ionic mechanisms underlying its inherent rhythmicity \nand the effects of drugs on the rate and rhythm of the heart are described in Chapter 22. The cardiac action potential \nvaries in its configuration in different parts of the heart, \nbut commonly shows a plateau lasting several hundred milliseconds following the initial rapid depolarisation. \nT-tubules in cardiac muscle contain L-type calcium channels, \nwhich open during this plateau and allow Ca\n2+ to enter. \nThis Ca2+ entry acts on RyRs (a different molecular type \nfrom those of skeletal muscle) to release Ca2+ from the SR \n(see Fig. 4.9). With minor differences, the subsequent \nmechanism by which Ca2+ activates the contractile machinery \nis the same as in skeletal muscle. Ca2+-induced Ca2+ release \nvia RyRs may play a role in some forms of cardiac arrhyth -\nmia. Mutations of RyRs are implicated in various disorders \nof skeletal and cardiac muscle function (see Priori & \nNapolitano, \t2005).\nSMOOTH MUSCLE\nThe properties of smooth muscle vary considerably in different organs, and the mechanisms linking membrane \nevents and contraction are correspondingly variable and \nmore complex than in other kinds of muscle. Spontaneous rhythmic activity occurs in many organs, by mechanisms \nproducing oscillations of [Ca\n2+]i (see Fig. 4.2B). The action \npotential of smooth muscle is generally a rather lazy and vague affair compared with the more military behaviour \nof skeletal and cardiac muscle, and it propagates through the tissue much more slowly and uncertainly. The action \npotential is, in most cases, generated by L-type calcium \nchannels rather than by voltage-gated sodium channels, and this is one important route of Ca\n2+ entry. In addition, \nmany\tsmooth \tmuscle \tcells \tpossess \tP2X \treceptors, \tligand-\ngated cation channels, which allow Ca2+ entry when activated \nby ATP released from autonomic nerves (see Ch. 13). Smooth \nmuscle cells also store Ca2+ in the ER, from which it can \nbe released when the IP 3R is activated (see Ch. 3). IP 3 is \ngenerated by activation of many types of G protein\u2013coupled receptor. Thus in contrast to skeletal and cardiac muscle, \nCa\n2+ release and contraction can occur in smooth muscle \nwhen such receptors are activated without necessarily \ninvolving depolarisation and Ca2+ entry through the plasma \nmembrane. RyRs are also present in many smooth muscle cells and calcium-induced Ca\n2+ release via these channels \nmay play a role in generating muscle contraction (see Fig. 4.9) or couple to plasma membrane calcium-activated K\n+ \nchannels resulting in cell hyperpolarisation, thereby reducing Ca\n2+ entry through voltage-gated calcium channels (Fig. \n4.10).\nThe contractile machinery of smooth muscle is activated \nwhen the myosin light chain undergoes phosphorylation, \ncausing it", "start_char_idx": 0, "end_char_idx": 3583, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c52bca6c-3938-42be-b9fb-731c57141b58": {"__data__": {"id_": "c52bca6c-3938-42be-b9fb-731c57141b58", "embedding": null, "metadata": {"page_label": "70", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "af558226-ca59-4531-b13d-0c3483f85ce0", "node_type": null, "metadata": {"page_label": "70", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "685bcb33d9e115b070a62c5b7d07307676a4431082b02cdbc185d3618b266e0c"}, "2": {"node_id": "0ad8b8c7-1960-4345-8c86-e2b1f4f9164e", "node_type": null, "metadata": {"page_label": "70", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8088265ecd8e1ed1d108e731c7e2f9323c7206c8b9b2be6d317df66c033b937"}}, "hash": "2f42d73b99d548425448cbb1f9debaaa4ce835426968fb4e92415a2d17bb0999", "text": "the myosin light chain undergoes phosphorylation, \ncausing it to become detached from the actin filaments. This phosphorylation is catalysed by a kinase, myosin light-\nchain kinase (MLCK), which is activated when it binds to \nCa\n2+\u2013calmodulin (see p. 56, Fig. 4.9). A second enzyme, \nmyosin phosphatase , reverses the phosphorylation and causes \nrelaxation. The activity of MLCK and myosin phosphatase thus exerts a balanced effect, promoting contraction and relaxation, respectively. Both enzymes are regulated by \ncyclic nucleotides (cAMP and cGMP; see Ch. 3), and many \ndrugs that cause smooth muscle contraction or relaxation Muscle contraction \n\u2022\tMuscle\tcontraction \toccurs \tin \tresponse \tto \ta \trise \tin \t\n[Ca2+]i.\n\u2022\tIn\tskeletal \tmuscle, \tdepolarisation \tcauses \trapid \tCa2+ \nrelease from the sarcoplasmic reticulum (SR); in \ncardiac muscle, Ca2+ enters through voltage-gated \nchannels, and this initial entry triggers further release from the SR; in smooth muscle, the Ca\n2+ signal is due \npartly to Ca2+ entry and partly to inositol trisphosphate \n(IP3)-mediated release from the SR.\n\u2022\tIn\tsmooth \tmuscle, \tcontraction \tcan \toccur \twithout \t\naction potentials, for example, when agonists at G protein\u2013coupled receptors lead to IP\n3 formation.\n\u2022\tActivation \tof \tthe \tcontractile \tmachinery \tin \tsmooth \t\nmuscle involves phosphorylation of the myosin light chain, a mechanism that is regulated by a variety of second messenger systems.\n6Carrier-mediated release can also occur with neurotransmitters that are \nstored in vesicles but is quantitatively less significant than exocytosis.RELEASE OF CHEMICAL MEDIATORS\nMuch of pharmacology is based on interference with the \nbody\u2019s own chemical mediators, particularly neurotransmit -\nters, hormones and inflammatory mediators. Here we discuss some of the common mechanisms involved in the release of such mediators, and it will come as no surprise \nthat Ca\n2+ plays a central role. Drugs and other agents that \naffect the various control mechanisms that regulate [Ca2+]i \nwill therefore also affect mediator release, and this accounts for many of the physiological effects that they produce.\nChemical mediators that are released from cells fall into \ntwo main groups (Fig. 4.11):\n\u2022\tMediators \tthat \tare \tpreformed \tand \tpackaged \tin \tstorage \t\nvesicles \u2013 sometimes called storage granules \u2013 from \nwhich they are released by exocytosis. This large group \ncomprises all the conventional neurotransmitters and \nneuromodulators (see Chs 13 and 38), and many hormones. It also includes secreted proteins such as \ncytokines and various growth factors (Ch. 19).\n\u2022\tMediators \tthat \tare \tproduced \ton \tdemand \tand \tare \t\nreleased by diffusion or by membrane carriers.6 This \ngroup includes nitric oxide (Ch. 21) and many lipid mediators (e.g. prostanoids, Ch. 18) and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3521, "end_char_idx": 6811, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e858fa5d-087d-4fef-b323-51e5f9df874e": {"__data__": {"id_": "e858fa5d-087d-4fef-b323-51e5f9df874e", "embedding": null, "metadata": {"page_label": "71", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "26046351-e663-453b-88d0-38bd5f628dc4", "node_type": null, "metadata": {"page_label": "71", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad7de4e75dba19ce5f39aa8f0dab86364ccd0c1faa2b205d518dc5edeecd3dad"}, "3": {"node_id": "6be9cdb6-1f8c-4c02-9257-f29af674cd27", "node_type": null, "metadata": {"page_label": "71", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4803adafc83cdf5f9c60777b891ff64d776f4288ccca29e875bfe80471047965"}}, "hash": "73bd80063696619b8b4d7072ff9d8659ca2078b5d37654980d8d696319d56021", "text": "4 How d RuGS AC t: CELL u LAR ASPEC t S \u2013 E x CI t A t I o N , C o N t RAC t I o N AN d SECRE t I o N \n65or quanta, each representing the contents of a single vesicle. \nThe first evidence for this came from the work of Katz and \nhis colleagues in the 1950s, who recorded spontaneous \n\u2018miniature endplate potentials\u2019 at the frog neuromuscular junction, and showed that each resulted from the spontane -\nous release of a packet of the transmitter, acetylcholine. They also showed that release evoked by nerve stimulation occurred by the synchronous release of several hundred \nsuch quanta and was highly dependent on the presence of \nCa\n2+ in the bathing solution. Unequivocal evidence that \nthe quanta represented vesicles releasing their contents by \nexocytosis came from electron microscopic studies, in which \nthe tissue was rapidly frozen in mid-release, revealing vesicles in the process of extrusion, and from elegant \nelectrophysiological measurements showing that membrane \ncapacitance (reflecting the area of the presynaptic membrane) increased in a stepwise manner as each vesicle fused and \nthen gradually returned as the vesicle membrane was \nrecovered from the surface. There is also biochemical evidence showing that, in addition to the transmitter, other constituents of the vesicles are released at the same time.\n\u25bc In nerve terminals specialised for fast synaptic transmission, Ca2+ \nenters\tthrough \tvoltage-gated \tcalcium \tchannels, \tmainly \tof \tthe \tN \tand \t\nP/Q type (see p. 52 and Table 4.1), and the synaptic vesicles are \n\u2018docked\u2019 at active zones \u2013 specialised regions of the presynaptic IP3PLCK+\nGC\nGCAC\nPDE\nPKG PKAcAMP cGMP\nCONTRACTION[Ca2+]i Ca2+ releaseDEPOLARISATION HYPERPOLARISATIONCa2+Ca2+Na+ATP\nANP NOCalcium channel\nblockersPotassium-channel\nactivatorsAgonists\nadenosine\nb-agonists\nprostaglandins\netc.Agonists\nnoradrenaline\nhistamine\nangiotensin\netc.CONTRACTION RELAXATION\nSMOOTH MUSCLE CELL12 34 56\n7\n8PDE\ninhibitors\nFig. 4.10 Mechanisms controlling smooth muscle contraction and relaxation. 1. G protein\u2013coupled receptors for excitatory agonists, \nmainly regulating inositol trisphosphate formation and calcium channel function. 2. Voltage-gated calcium channels. 3. P2X receptor for \nATP (ligand-gated cation channel). 4. Potassium channels. 5. G protein\u2013coupled receptors for inhibitory agonists, mainly regulating cAMP \nformation and potassium and calcium channel function. 6. Receptor for atrial natriuretic peptide (ANP), coupled directly to guanylyl cyclase \n(GC). 7. Soluble GC, activated by nitric oxide (NO). 8. Phosphodiesterase (PDE), the main route of inactivation of cAMP and cGMP. AC, \nadenylyl cyclase; PKA, protein kinase A; PKG, protein kinase G; PLC, phospholipase C. \nendocannabinoids (Ch. 20), which are released from \nthe postsynaptic cell to act retrogradely on nerve \nterminals.\nCalcium ions play a key role in both cases, because a rise in [Ca\n2+]i initiates exocytosis and is also the main activator \nof the enzymes responsible for the synthesis of diffusible mediators.\nIn addition to mediators that are released from cells, \nsome are formed from precursors in the plasma, two important examples being kinins (Ch. 19) and angiotensin \n(Ch.", "start_char_idx": 0, "end_char_idx": 3205, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6be9cdb6-1f8c-4c02-9257-f29af674cd27": {"__data__": {"id_": "6be9cdb6-1f8c-4c02-9257-f29af674cd27", "embedding": null, "metadata": {"page_label": "71", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "26046351-e663-453b-88d0-38bd5f628dc4", "node_type": null, "metadata": {"page_label": "71", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad7de4e75dba19ce5f39aa8f0dab86364ccd0c1faa2b205d518dc5edeecd3dad"}, "2": {"node_id": "e858fa5d-087d-4fef-b323-51e5f9df874e", "node_type": null, "metadata": {"page_label": "71", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "73bd80063696619b8b4d7072ff9d8659ca2078b5d37654980d8d696319d56021"}}, "hash": "4803adafc83cdf5f9c60777b891ff64d776f4288ccca29e875bfe80471047965", "text": "important examples being kinins (Ch. 19) and angiotensin \n(Ch. 23), which are peptides produced by protease-mediated \ncleavage of circulating proteins.\nEXOCYTOSIS\nExocytosis, occurring in response to an increase of [Ca2+]i, \nis the principal mechanism of transmitter release (see Fig. \n4.11) in the peripheral and central nervous systems, as well \nas in endocrine cells and mast cells. The secretion of enzymes and other proteins by gastrointestinal and exocrine glands \nand by vascular endothelial cells is also basically similar. \nExocytosis (see Thorn et al., 2016) involves fusion between \nthe membrane of synaptic vesicles and the inner surface \nof the plasma membrane. The vesicles are preloaded with \nstored transmitter, and release occurs in discrete packets, mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3143, "end_char_idx": 4392, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "61b0b080-e377-47c7-b286-3303de4844bb": {"__data__": {"id_": "61b0b080-e377-47c7-b286-3303de4844bb", "embedding": null, "metadata": {"page_label": "72", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2b64243f-9d69-4c90-ab25-aaeb96bf5432", "node_type": null, "metadata": {"page_label": "72", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b243674f5a7d7bf2f2cd8cfccca902876de69e71771243d3cd03d1247b64758"}, "3": {"node_id": "e733db96-f024-4ecc-a12e-4b740af790d4", "node_type": null, "metadata": {"page_label": "72", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ec84f17b050e4400bdd0d70570b3cc17ba8921fd18b1e2ab60de766a5283011"}}, "hash": "bc499473ff509c2fe0595638e6419fd07648e04b1894fa29bf1d5dfb06906195", "text": "4 SECTION 1 GENERAL PRINCIPLES\n66Having undergone exocytosis, the empty vesicle7 is recaptured by \nendocytosis and returns to the interior of the terminal, where it fuses \nwith the larger endosomal membrane. The endosome buds off new \nvesicles, which take up transmitter from the cytosol by means of specific transport proteins and are again docked on the presynaptic \nmembrane. This sequence, which typically takes several minutes, is \ncontrolled by various trafficking proteins associated with the plasma membrane and the vesicles, as well as cytosolic proteins. So far, there \nare few examples of drugs that affect transmitter release by interacting \nwith synaptic proteins, although the botulinum neurotoxins (see Ch. \n14)\tproduce \ttheir \teffects \tby \tproteolytic \tcleavage \tof \tSNARE \tproteins.\nNON-VESICULAR RELEASE MECHANISMS\nIf this neat and tidy picture of transmitter packets ready \nand waiting to pop obediently out of the cell in response \nto a puff of Ca2+ seems a little too good to be true, rest \nassured that the picture is not quite so simple. Acetylcholine, noradrenaline (norepinephrine) and other mediators can \nleak out of nerve endings from the cytosolic compartment, independently of vesicle fusion, by utilising carriers in the \nplasma membrane (see Fig. 4.11 ). Drugs such as ampheta -\nmines, which release amines from central and peripheral \nnerve terminals (see Chs 15 and 40), do so by displacing the endogenous amine from storage vesicles into the cytosol, \nwhence it escapes via the monoamine transporter in the plasma membrane, a mechanism that does not depend on Ca\n2+.8\nNitric\toxide \t(see \tCh. \t21), \tarachidonic \tacid \tmetabolites \t\n(e.g. prostaglandins; Ch. 18) and endocannabinoids (see membrane from which exocytosis occurs, situated close to the relevant \ncalcium channels and opposite receptor-rich zones of the postsynaptic \nmembrane. Elsewhere, where speed is less critical, Ca2+ may come \nfrom intracellular stores and the spatial organisation of active zones is less clear. It is common for secretory cells, including neurons, to \nrelease more than one mediator (for example, a \u2018fast\u2019 transmitter such as glutamate and a \u2018slow\u2019 transmitter such as a neuropeptide) from \ndifferent vesicle pools (see Ch. 13). The fast transmitter vesicles are \nlocated close to active zones, while the slow transmitter vesicles are further away. Release of the fast transmitter, because of the tight \nspatial organisation, occurs as soon as the neighbouring calcium \nchannels open, before the Ca\n2+ has a chance to diffuse throughout \nthe terminal, whereas release of the slow transmitter requires the \nCa2+ to diffuse more widely. As a result, release of fast transmitters \noccurs impulse by impulse, even at low stimulation frequencies, whereas release of slow transmitters builds up only at higher stimula -\ntion frequencies. The release rates of the two therefore depend critically \non the frequency and patterning of firing of the presynaptic neuron \n(Fig. 4.12). In non-excitable cells (e.g. most exocrine and endocrine \nglands), the slow mechanism predominates and is activated mainly by Ca\n2+ release from intracellular stores.\nCalcium causes exocytosis by binding to the vesicle-bound protein synaptotagmin , and this favours association between a second vesicle-\nbound protein, synaptobrevin, and a related protein, synaptotaxin, on \nthe inner surface of the plasma membrane. This association brings the vesicle membrane into close apposition with the plasma membrane,", "start_char_idx": 0, "end_char_idx": 3506, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e733db96-f024-4ecc-a12e-4b740af790d4": {"__data__": {"id_": "e733db96-f024-4ecc-a12e-4b740af790d4", "embedding": null, "metadata": {"page_label": "72", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2b64243f-9d69-4c90-ab25-aaeb96bf5432", "node_type": null, "metadata": {"page_label": "72", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b243674f5a7d7bf2f2cd8cfccca902876de69e71771243d3cd03d1247b64758"}, "2": {"node_id": "61b0b080-e377-47c7-b286-3303de4844bb", "node_type": null, "metadata": {"page_label": "72", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc499473ff509c2fe0595638e6419fd07648e04b1894fa29bf1d5dfb06906195"}}, "hash": "2ec84f17b050e4400bdd0d70570b3cc17ba8921fd18b1e2ab60de766a5283011", "text": "brings the vesicle membrane into close apposition with the plasma membrane, causing membrane fusion. This group of proteins, known collectively \nas\tSNAREs, \tplays \ta \tkey \trole \tin \texocytosis.ENDOSOME\nEXOCYTOSISAA\nPG\nPGNO\nNOTT\nTT\nNOS PLA2PL Arg\nDIFFUSIONEndocytosisSynaptic\nvesicle\ncycleLoading\nDockingCARRIER-\nMEDIATED\nRELEASE \nT\nTCa2+\nFig. 4.11 Role of exocytosis, carrier-mediated transport \nand diffusion in mediator release. The main mechanism of \nrelease of monoamine and peptide mediators is Ca2+-mediated \nexocytosis, but carrier-mediated release from the cytosol also \noccurs. T represents a typical amine transmitter, such as noradrenaline (norepinephrine) or 5-hydroxytryptamine. Nitric oxide (NO) and prostaglandins (PGs) are released by diffusion as soon as they are formed, from arginine (Arg) and arachidonic acid (AA), respectively, through the action of Ca\n2+-activated \nenzymes, nitric oxide synthase (NOS) and phospholipase A 2 \n(PLA 2) (see Chs 18 and 21 for more details). Brief localised\npulses\nNo release Slow diffuse build-up\nand decayBrief localised\npulsesFast transmitter\n(e.g. glutamate)\nSlow transmitter\n(e.g. neuropeptide)\nLow-frequency\nimpulsesHigh-frequency\nimpulses\nFig. 4.12 Time course and frequency dependence of the \nrelease of \u2018fast\u2019 and \u2018slow\u2019 transmitters. Fast transmitters (e.g. \nglutamate) are stored in synaptic vesicles that are \u2018docked\u2019 close to voltage-gated calcium channels in the membrane of the nerve terminal and are released in a short burst when the membrane is depolarised (e.g. by an action potential). Slow transmitters (e.g. neuropeptides) are stored in separate vesicles further from the membrane. Release is slower, because they must first migrate to the membrane, and occurs only when [Ca\n2+]i builds up sufficiently. \n7The vesicle contents may not always discharge completely. Instead, \nvesicles may fuse transiently with the cell membrane and release only \npart of their contents before becoming disconnected (termed kiss-and-\nrun exocytosis).\n8Some cheeses may have high levels of the trace amino acid tyramine, \nwhich can act akin to amphetamines and release noradrenaline \n(particularly \tin \tthose \tbeing \ttreated \twith \tmonoamine \toxidase \t(MAO) \t\ninhibitors, see Ch. 48) giving a dramatic sympathetic episode known as \na \u2018cheese effect\u2019.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3431, "end_char_idx": 6219, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2e476019-922d-43d1-8436-9d911b6e2775": {"__data__": {"id_": "2e476019-922d-43d1-8436-9d911b6e2775", "embedding": null, "metadata": {"page_label": "73", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "af9152c4-0a69-4bf3-8852-570c8faa5663", "node_type": null, "metadata": {"page_label": "73", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01ca8210fbf05837e751167fbc282afb28a48221f5b3c2513dc500a6b87002c1"}, "3": {"node_id": "a2d83870-e4f0-4c06-bf17-b67d4b2dca51", "node_type": null, "metadata": {"page_label": "73", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f8eea9957ad47493d12ff7212d56281ac6033ddef692fccdcf5d16b508036cef"}}, "hash": "f4582fccbf462f7d7916e5f8a65cf2def879945ef982507bad766722e1bd74a7", "text": "4 How d RuGS AC t: CELL u LAR ASPEC t S \u2013 E x CI t A t I o N , C o N t RAC t I o N AN d SECRE t I o N \n67gene\texpression \t(see\tCh.\t3),\tand\tcauses\tan\tincrease\tin\tENaC\t\nexpression, \tthereby \tincreasing \tthe \trate \tof \tNa+ and fluid \ntransport. \tENaCs\tare\tselectively \tblocked\tby\tcertain\tdiuretic\t\ndrugs, notably amiloride (see Ch. 30), a compound that is \nwidely\tused \tto \tstudy \tthe \tfunctioning \tof \tENaCs \tin \tother \t\nsituations.\nChloride transport is particularly important in the airways \nand gastrointestinal tract. In the airways it is essential for Ch. 20) are important examples of mediators that are \nreleased from the cytosol by diffusion across the membrane \nor by carrier-mediated extrusion, rather than by exocytosis. The mediators are not stored but escape from the cell as \nsoon as they are synthesised. In each case, the synthetic \nenzyme(s) is activated by Ca\n2+, and the moment-to-moment \ncontrol of the rate of synthesis depends on [Ca2+]i. This \nkind of release is necessarily slower than the classic exo -\ncytotic mechanism, but in the case of nitric oxide is fast enough for it to function as a true transmitter (see Fig. 13.5 and Ch. 21).\nMediator release\n\u2022\tMost\tchemical \tmediators \tare \tpackaged \tinto \tstorage \t\nvesicles and released by exocytosis. Some are not \nstored but synthesised on demand and released by diffusion or the operation of membrane carriers.\n\u2022\tExocytosis \toccurs \tin \tresponse \tto \tincreased \t[Ca2+]i as a \nresult of a Ca2+-mediated interaction between proteins \nof the synaptic vesicle and the plasma membrane, causing the membranes to fuse.\n\u2022\tAfter\treleasing \ttheir \tcontents, \tvesicles \tare \trecycled \tand \t\nreloaded with transmitter.\n\u2022\tMany\tsecretory \tcells \tcontain \tmore \tthan \tone \ttype \tof \t\nvesicle, loaded with different mediators and secreted independently.\n\u2022\tStored\tmediators \t(e.g. \tneurotransmitters) \tmay \tbe \t\nreleased directly from the cytosol independently of Ca\n2+ and exocytosis, by drugs that interact with \nmembrane transport mechanisms.\n\u2022\tNon-stored \tmediators, \tsuch \tas \tprostanoids, \tnitric \t\noxide and endocannabinoids are released by increased [Ca\n2+]i, which activates the enzymes responsible for \ntheir synthesis.Na+Na+Na+\nNa+\nK+K+\nK+K+\nK+K+Amiloride\nLUMENENaC\nPotassium\nchannelsPotassium\nchannels\nPotassiumchannelsNa\n+/K+\npump\nNa+/K+\npump\nNa+Na+\nNa+K+\nK+\nLUMENEXTRACELLULAR\nCOMPARTMENT\nEXTRACELLULAR\nCOMPARTMENTCFTR\nNa+/Cl\u2212\nco-transporterCl\u2212\u2013HCO 3\u2212\nexchange\nCl\u2212Cl\u2212\nCl\u2212\nCl\u2212HCO3\u2212ATP\nATPA\nB\nFig. 4.13 Generalised mechanisms of epithelial ion \ntransport. Such mechanisms are important in renal tubules (see \nCh. 30 for more details) and in many other situations, such as the gastrointestinal and respiratory tracts. The exact mechanism may vary from tissue to tissue depending upon channel and pump expression and location. (A) Sodium transport. A special type of epithelial sodium channel (ENaC) controls entry of Na\n+ \ninto the cell from the lumenal surface, the", "start_char_idx": 0, "end_char_idx": 2940, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a2d83870-e4f0-4c06-bf17-b67d4b2dca51": {"__data__": {"id_": "a2d83870-e4f0-4c06-bf17-b67d4b2dca51", "embedding": null, "metadata": {"page_label": "73", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "af9152c4-0a69-4bf3-8852-570c8faa5663", "node_type": null, "metadata": {"page_label": "73", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01ca8210fbf05837e751167fbc282afb28a48221f5b3c2513dc500a6b87002c1"}, "2": {"node_id": "2e476019-922d-43d1-8436-9d911b6e2775", "node_type": null, "metadata": {"page_label": "73", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4582fccbf462f7d7916e5f8a65cf2def879945ef982507bad766722e1bd74a7"}}, "hash": "f8eea9957ad47493d12ff7212d56281ac6033ddef692fccdcf5d16b508036cef", "text": "controls entry of Na\n+ \ninto the cell from the lumenal surface, the Na+ being actively \npumped out at the apical surface by the Na+\u2013K+ exchange \npump. K+ moves passively via potassium channels. (B) Chloride \ntransport. Cl\u2212 leaves the cell via a special membrane channel, \nthe cystic fibrosis transmembrane conductance regulator (CFTR), after entering the cell either from the apical surface via the Na\n+/Cl\u2212 co-transporter, or at the lumenal surface via the Cl\u2212/\nHCO 3\u2212 co-transporter. EPITHELIAL ION TRANSPORT\nFluid-secreting epithelia include the renal tubule, salivary \nglands, gastrointestinal tract and airways epithelia. In each \ncase, epithelial cells are arranged in sheets separating the \ninterior (blood-perfused) compartment from the exterior lumen compartment, into which, or from which, secretion \ntakes place. Fluid secretion involves two main mechanisms, \nwhich often co-exist in the same cell and indeed interact with each other. The two mechanisms (Fig. 4.13) are concerned, \nrespectively, \twith \tNa+ transport and Cl\u2212 transport.\nIn\tthe\tcase \tof \tNa+ transport, secretion occurs because \nNa+ enters the cell passively at one end and is pumped out \nactively at the other, with water following passively. Critical \nto this mechanism is a class of highly regulated epithelial \nsodium\tchannels \t(ENaCs) \tthat \tallow \tNa+ entry.\nENaCs\t(see \tHanukoglu \t& \tHanukoglu, \t2016) \tare \twidely \t\nexpressed, not only in epithelial cells but also in neurons \nand other excitable cells, where their function is largely \nunknown. They are regulated mainly by aldosterone, a \nhormone produced by the adrenal cortex that enhances Na\n+ reabsorption by the kidney (see Ch. 30). Aldosterone, \nlike other steroid hormones, exerts its effects by regulating mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2873, "end_char_idx": 5102, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2ebb7c5b-5c02-4d96-899b-956f0e7ea3d8": {"__data__": {"id_": "2ebb7c5b-5c02-4d96-899b-956f0e7ea3d8", "embedding": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "63c747f6-b5df-47ec-ace9-7a918c5f5033", "node_type": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dcdb04ab85e2884690b96e88fa2791e3e19760a557aed1afa1f15bea38d9c203"}, "3": {"node_id": "cbe6c204-b872-45d2-9935-e111795d69f2", "node_type": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c906b4bcb965c2f0084344f7552a510470b83443a94a0314124d2f172f42bf3e"}}, "hash": "082465a31e03af06d1641ce9ff045d7a7695ca526c2e9fbd9bef7489d5151bb7", "text": "4 SECTION 1 GENERAL PRINCIPLES\n68is increased (see Ch. 18). Activation of G protein\u2013coupled \nreceptors, which cause release of Ca2+, also stimulates secre -\ntion, possibly also by activating CFTR. Many examples of \ntherapeutic drugs that affect epithelial secretion by activating \nor blocking G protein\u2013coupled receptors appear in later chapters.fluid secretion, whereas in the colon it mediates fluid reabsorption, the difference being due to the different arrangement of various transporters and channels with \nrespect to the polarity of the cells. The simplified diagram \nin Fig. 4.13B represents the situation in the pancreas, where secretion depends on Cl\n\u2212 transport. The key molecule in \nCl\u2212 transport is the cystic fibrosis transmembrane conductance \nregulator (CFTR), so named because early studies on the \ninherited disorder cystic fibrosis showed it to be associated \nwith impaired Cl\u2212 conductance in the membrane of secretory \nepithelial cells, and the CFTR gene, identified through \npainstaking genetic linkage studies and isolated in 1989, \nwas found to encode a Cl\u2212-conducting ion channel. Severe \nphysiological consequences follow from CFTR mutations \nand the resulting impairment of secretion, particularly in \nthe airways but also in many other systems, such as sweat glands and pancreas. Studies on the disease-associated \nmutations of the CFTR gene have revealed much about \nthe molecular mechanisms involved in Cl\n\u2212 transport ( Wang \net al., 2014).\nBoth\tNa+ and Cl\u2212 transport are regulated by intracellular \nmessengers, notably by Ca2+ and cAMP, the latter exert-\ning its effects by activating protein kinases and thereby \ncausing phosphorylation of channels and transporters. CFTR \nitself is activated by cAMP. In the gastrointestinal tract, increased cAMP formation causes a large increase in the \nrate of fluid secretion, an effect that leads to the copious \ndiarrhoea produced by cholera infection (see Ch. 3) and by inflammatory conditions in which prostaglandin formation Epithelial ion transport \n\u2022\tMany\tepithelia \t(e.g. \trenal \ttubules, \texocrine \tglands \tand \t\nairways) are specialised to transport specific ions.\n\u2022\tThis\ttype \tof \ttransport \tdepends \ton \ta \tspecial \tclass \tof \t\nepithelial sodium channels (ENaCs) which allow Na+ \nentry into the cell at one surface, coupled to active \nextrusion of Na+, or exchange for another ion, from the \nopposite surface.\n\u2022\tAnion\ttransport \tdepends \ton \ta \tspecific \tchloride \t\nchannel (the cystic fibrosis transmembrane conductance regulator [CFTR]), mutations of which result in cystic fibrosis.\n\u2022\tThe\tactivity \tof \tchannels, \tpumps \tand \texchange \t\ntransporters is regulated by various second messengers and nuclear receptors, which control the transport of ions in specific ways.\nREFERENCES AND FURTHER READING\nGeneral references\nAlexander, S.P., Catterall, W.A., Kelly, E., et al., 2015. The concise guide \nto pharmacology 2015/16: Voltage-gated ion channels. Br. J. \nPharmacol. 172, 5904\u20135941. (Contains a brief description of a range of ion \nchannels and the drugs that interact with them)\nBerridge, M.J., 2014. Cell Signalling Biology. Portland Press. \ndoi:10.1042/csb0001002. (Free ebook available online at www.cellsignallingbiology.org; a regularly updated resource that covers \nvarious aspects of cell signalling in a highly readable format)\nKandel, E.R., Schwartz, J.H., Jessell, T.M., Siegelbaum, S.A.,", "start_char_idx": 0, "end_char_idx": 3390, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cbe6c204-b872-45d2-9935-e111795d69f2": {"__data__": {"id_": "cbe6c204-b872-45d2-9935-e111795d69f2", "embedding": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "63c747f6-b5df-47ec-ace9-7a918c5f5033", "node_type": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dcdb04ab85e2884690b96e88fa2791e3e19760a557aed1afa1f15bea38d9c203"}, "2": {"node_id": "2ebb7c5b-5c02-4d96-899b-956f0e7ea3d8", "node_type": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "082465a31e03af06d1641ce9ff045d7a7695ca526c2e9fbd9bef7489d5151bb7"}, "3": {"node_id": "60dbb3c5-7e9c-48db-b3f2-6613968aa704", "node_type": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e1b0ce40ed3a4eacddecb15cbb65cbaaa85fbb0b302f733732222aac6ab9dfe"}}, "hash": "c906b4bcb965c2f0084344f7552a510470b83443a94a0314124d2f172f42bf3e", "text": "J.H., Jessell, T.M., Siegelbaum, S.A., Hudspeth, \nA.J.,\t2012. \tPrinciples \tof \tNeural \tScience. \tMcGraw-Hill, \tNew \tYork. \t\n(Excellent, well-written textbook of neuroscience)\nKatz,\tB.,\t1966. \tNerve, \tMuscle \tand \tSynapse. \tMcGraw\u2013Hill, \tNew \tYork. \t(A \nclassic account of the ground-breaking electrophysiological experiments that \nestablished the basis of nerve and muscle function)\nBerridge, M.J., 2016. The inositol trisphosphate/calcium signaling \npathway in health and disease. Physiol. Rev. 96, 1261\u20131296. (Clear and readable up-to-date account of the mechanisms and versatility of calcium \nsignaling and how it may be altered in disease states)\nMorgan, \tA.J., \tDavis, \tL.C., \tRuas, \tM., \tGalione, \tA., \t2015. \tTPC: \tthe \tNAADP \t\ndiscovery channel? Biochem. Soc. Trans. 43, 384\u2013389. (Interesting discussion of this controversial topic from the laboratory of one of the main \nprotagonists)\nParrington, J., Lear, P., Hachem, A., 2015. Calcium signals regulated by \nNAADP \tand \ttwo-pore \tchannels\u2013their \trole \tin \tdevelopment, \t\ndifferentiation and cancer. Int. J. Dev. Biol. 59, 341\u2013355. (Review of the \npotential pathophysiological importance)\nPrakriya, M., Lewis, R.S., 2015. Store-operated calcium channels. \nPhysiol. Rev. 95, 1383\u20131436. (Comprehensive review of this topic)\nExcitation and ion channels\nCatterall, W.A., Swanson, T.M., 2015. Structural basis for pharmacology \nof voltage-gated sodium and calcium channels. Mol. Pharmacol. 88, \n141\u2013150. (Useful, authoritative review article)Hille, B., 2001. Ionic Channels of Excitable Membranes. Sinauer Associates, \nSunderland. (Still probably the best, clear and detailed account of the basic \nprinciples of ion channels, with emphasis on their biophysical properties)\nImbrici, P., Liantonio, A., Camerino, G.M., et al., 2016. Therapeutic \napproaches to genetic ion channelopathies and perspectives in drug discovery. Front. Pharmacol. 7, 121. (Detailed review of the importance of \nchannelopathies in multiple disorders)\nJenkinson, D.H., 2006. Potassium channels \u2013 multiplicity and challenges. \nBr. J. Pharmacol. 147 (Suppl. 1), 63\u201371. (Useful short article on the many types of K\n+ channel)\nMuscle contraction\nBerridge, M.J., 2008. Smooth muscle cell calcium activation mechanisms. \nJ. Physiol. 586, 5047\u20135061. (Excellent review article describing the various mechanisms by which calcium signals control activity in different types of \nsmooth muscle \u2013 complicated but clear)\nPriori,\tS.G., \tNapolitano, \tC., \t2005. \tCardiac \tand \tskeletal \tmuscle \tdisorders \t\ncaused by mutations in the intracellular Ca2+ release channels. J. Clin. \nInvest. 115, 2033\u20132038. (Focuses on RyR mutations in various inherited \ndiseases)\nVan Petegem, F., 2012. Ryanodine receptors: structure and function. \nJ. Biol. Chem. 287 (31), 31624\u201331632.\nSecretion and exocytosis\nHanukoglu, \tI., \tHanukoglu, \tA., \t2016. \tEpithelial \tsodium \tchannel \t(ENaC) \t\nfamily: phylogeny, structure-function, tissue distribution, and \nassociated inherited diseases. Gene 579, 95\u2013132. (Extensive review of the", "start_char_idx": 3357, "end_char_idx": 6383, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "60dbb3c5-7e9c-48db-b3f2-6613968aa704": {"__data__": {"id_": "60dbb3c5-7e9c-48db-b3f2-6613968aa704", "embedding": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "63c747f6-b5df-47ec-ace9-7a918c5f5033", "node_type": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dcdb04ab85e2884690b96e88fa2791e3e19760a557aed1afa1f15bea38d9c203"}, "2": {"node_id": "cbe6c204-b872-45d2-9935-e111795d69f2", "node_type": null, "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c906b4bcb965c2f0084344f7552a510470b83443a94a0314124d2f172f42bf3e"}}, "hash": "9e1b0ce40ed3a4eacddecb15cbb65cbaaa85fbb0b302f733732222aac6ab9dfe", "text": "inherited diseases. Gene 579, 95\u2013132. (Extensive review of the \nfunction and importance of these channels in health and disease)\nThorn, P., Zorec, R., Rettig, J., Keating, D.J., 2016. Exocytosis in \nnon-neuronal \tcells. \tJ. \tNeurochem. \t137, \t849\u2013859.\nWang,\tY., \tWrennall, \tJ.A., \tCai, \tZ., \tLi, \tH., \tSheppard, \tD.N., \t2014. \t\nUnderstanding how cystic fibrosis mutations disrupt CFTR function: \nfrom single molecules to animal models. Int. J. Biochem. Cell Biol. 52, \n47\u201357.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6355, "end_char_idx": 7309, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "660de627-9f06-4a09-8d20-c603e6a07086": {"__data__": {"id_": "660de627-9f06-4a09-8d20-c603e6a07086", "embedding": null, "metadata": {"page_label": "75", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "51d6ccbe-5663-422f-a1af-c24e3bbd7b12", "node_type": null, "metadata": {"page_label": "75", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d84adfabc623b5af903635d4eb7d29e5fbbc7aa7e859d3bbb253718638af0fec"}, "3": {"node_id": "77a37bd5-b1cb-4d79-9ecc-908838dc3440", "node_type": null, "metadata": {"page_label": "75", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "676a7fb7eb70f5d1b4f1b52c5b621e47b5c969992d7edd0e20238772a5682570"}}, "hash": "644787f24caf11ad30b64f900d90b5413db2c39a0f5b3e6290b34658af2b4043", "text": "69\nHow drugs act: biopharmaceuticals \nand gene therapy 5 GENERAL PRINCIPLES SECTION 1 \nOVERVIEW\nIn this chapter, we discuss the properties of a group \nof therapeutic agents known collectively as biop-\nharmaceuticals. These are relatively recent additions to our therapeutic armoury, but they have already made a major impact on treatment of diseases such \nas rheumatoid arthritis and cancer. The number of \nbiopharmaceuticals approved for clinical use is growing and the sector will assume more significance in the \nfuture. In this chapter, we first introduce protein- and \noligonucleotide-based biopharmaceuticals, highlight the major differences with \u2018conventional\u2019 small molecule \ndrugs and explain how they are manufactured, how \nthey work and how they are metabolised. We then introduce the central concepts of gene therapy , discuss \nthe promise and problems associated with this thera -\npeutic modality and highlight some limited successes.\nINTRODUCTION\nThis chapter deals with the general pharmacological \ncharacteristics of protein and nucleic acid-based pharma-\nceuticals produced using genetic engineering techniques \n(i.e. biotechnology, as distinct from synthetic chemistry). Such agents currently account for 20%\u201325% of new registra -\ntions, and are increasingly important therapeutically. Individual agents are discussed in later chapters.\n\u25bc Annoyingly for authors of textbooks and their readers, there is \nno consensus on what actually constitutes a \u2018biopharmaceutical\u2019 as \nopposed to a conventional drug. An apparently obvious distinguishing \nfeature is whether it is predominately \u2018chemical\u2019 in nature (like almost \nall the small molecule drugs in this book) or of \u2018biological\u2019 origin (like insulin or growth hormone, for example). Unfortunately, this \nsimplistic distinction breaks down rather quickly when we consider \nthat some \u2018small molecule\u2019 drugs (such as morphine or penicillin) \nare plant or fungal products whilst other \u2018biological molecules\u2019 such \nas short peptides or antisense oligonucleotides are produced by \nsynthetic organic chemistry techniques.\nA further problem is the stance adopted by the main drug regulatory \nagencies. The FDA and their European counterparts use slightly different definitions when classifying \u2018biopharmaceuticals\u2019 and this \nhas profound effects on the companies that manufacture them, affecting \ntheir regulatory obligations, their business models, patent filings, investment funding and even public relations. As one commentator \n(Rader, 2008) put it, \u2018The result is a Babel-like situation with termi-\nnological chaos and anarchy confounding communication, comparative \nand industry analyses, understanding and regulation\u2019.\nTo simplify the situation, we will adopt a largely pragmatic defini -\ntion in this chapter; there is no doubt that biopharmaceuticals\n1 are \ndifferent in many respects from conventional small molecule drugs (including their pharmacology) and we will use these as our criteria \nfor distinguishing between them. We will begin with a discussion \nof protein and oligonucleotide biopharmaceuticals.\nPROTEIN AND OLIGONUCLEOTIDE \nBIOPHARMACEUTICALS\nThe use of proteins as therapeutic agents is not a novel \nidea; insulin, extracted from animal pancreas tissue (Ch. \n32), and human growth hormone, extracted at one time \nfrom human cadaver pituitary glands (Ch. 34), were among the first therapeutic proteins to be used and, for many \nyears, such purified extracts provided the only option for \ntreating protein hormone deficiency disorders. However, there were problems. Technical difficulties in extraction of \nthe hormone from tissue often led to disappointing yields. \nAdministration of animal hormones (e.g. pig insulin) to humans could evoke an immune response and there was another insidious danger \u2013", "start_char_idx": 0, "end_char_idx": 3785, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "77a37bd5-b1cb-4d79-9ecc-908838dc3440": {"__data__": {"id_": "77a37bd5-b1cb-4d79-9ecc-908838dc3440", "embedding": null, "metadata": {"page_label": "75", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "51d6ccbe-5663-422f-a1af-c24e3bbd7b12", "node_type": null, "metadata": {"page_label": "75", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d84adfabc623b5af903635d4eb7d29e5fbbc7aa7e859d3bbb253718638af0fec"}, "2": {"node_id": "660de627-9f06-4a09-8d20-c603e6a07086", "node_type": null, "metadata": {"page_label": "75", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "644787f24caf11ad30b64f900d90b5413db2c39a0f5b3e6290b34658af2b4043"}}, "hash": "676a7fb7eb70f5d1b4f1b52c5b621e47b5c969992d7edd0e20238772a5682570", "text": "insulin) to humans could evoke an immune response and there was another insidious danger \u2013 transmission of infectious agents \nacross species or between people. This was highlighted in \nthe 1970s, when cases of Creutzfeldt\u2013Jakob disease (see Ch. \n41) were seen in patients treated with human growth \nhormone obtained from cadavers. This serious problem \nwas later traced to contamination of the donor pituitary glands with infectious prions (Ch. 41). The advent of \u2018genetic \nengineering\u2019 techniques offered a new way to deal with these perennial problems.\n1There is a tiresome terminological issue here too: such drugs are often \nknown simply as \u2018biologics\u2019, but this term is also used to refer to any \nbiological reagents (e.g. antibody-based laboratory tests, plasma \nexpanders and so on).Biopharmaceuticals and gene \ntherapy: definition and \npotential uses\n\u2022\tBiopharmaceuticals \tinclude\tproteins \tand \tantibodies \t\n(and\toligonucleotides) \tused \tas \tdrugs:\n\u2013\tFirst-generation \tbiopharmaceuticals \tare \tmainly \t\ncopies\tof\tendogenous \tproteins \tor \tantibodies, \t\nproduced\tby \trecombinant \tDNA \ttechnology.\n\u2013\tSecond-generation \tbiopharmaceuticals \thave \tbeen \t\n\u2018engineered\u2019 \tto \timprove \tthe \tperformance \tof \tthe \t\nprotein,\tantibody \tor \tantisense \tagent.\n\u2022\tApplications:\n\u2013\ttherapeutic \tmonoclonal \tantibodies\n\u2013\trecombinant \thormones\n\u2013\tcontrolling \tgene \texpression \t(oligonucleotides)\n\u2022\tGene therapy \tis\tthe\taddition \tof \tgenetic \tmaterial \tto \t\ncells\tto\tprevent, \talleviate \tor \tcure \tdisease.\n\u2022\tPotential \tapplications:\n\u2013\tradical\tcure \tof \tmonogenic \tdiseases \t(e.g. \tcystic \t\nfibrosis,\thaemoglobinopathies);\n\u2013\tamelioration \tof \tdiseases \twith \tor \twithout \ta \tgenetic \t\ncomponent, \tincluding \tmany \tmalignant, \t\nneurodegenerative \tand \tinfectious \tdiseases.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3695, "end_char_idx": 5936, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dd83b3d6-0dc5-4331-b408-de3d1604f5c9": {"__data__": {"id_": "dd83b3d6-0dc5-4331-b408-de3d1604f5c9", "embedding": null, "metadata": {"page_label": "76", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "94517a50-09a8-4f34-a390-5cb644cfd387", "node_type": null, "metadata": {"page_label": "76", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "76ca3962db434583a4c219a9499ed9ba1569f19a9cc1884e897aa12fef71ab29"}, "3": {"node_id": "2c273a64-bc09-4cd9-a649-fb4e64491e1a", "node_type": null, "metadata": {"page_label": "76", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d9ef90a2757ccb3331218638b057bd7851932518702bdd0c4bd2880fd9c4b18"}}, "hash": "6c44824656835cf4aaca924cf7e084b781efa601d87264869323092cd1520f56", "text": "5 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n70Production methods\n\u25bc There are several problems associated with the manufacture of \nany type of recombinant protein, and one of the most pressing is the \nchoice of expression system. Many recombinant proteins are expressed \nin bacterial systems (Escherichia coli, for example), which is useful \nbecause cultures grow quickly and are generally easy to manipulate. Disadvantages include the fact that the product may contain bacte -\nrial endotoxins, which must be removed before administration to patients, and also that bacterial cells differ from mammalian cells in patterns of post-translational processing (e.g. glycosylation) of proteins, \nwhich may affect the protein\u2019s biological action. To circumvent these problems, mammalian (e.g. Chinese hamster ovary [CHO]) \ncells can also be used as expression systems, although such cells \nrequire more careful culture, grow more slowly than bacteria and produce less product, all of which contributes to the cost of the \nfinal medicine.\nA number of emergent technologies are set to transform the produc -\ntion process. The use of plants to produce recombinant proteins has \nattracted considerable interest (see Melnik & Stoger, 2013). Several \nspecies have shown promise, including the tobacco plant. Human \ngenes of interest can readily be transfected into the plant using \ntobacco mosaic virus as a vector; the crop grows rapidly (yields a high biomass ) and offers a number of other advantages. Edible plants PROTEINS AND POLYPEPTIDES\nThe biopharmaceuticals in use today are generally classified \nas first- or second-generation agents. First-generation \nbiopharmaceuticals are usually straightforward copies of human hormones or other proteins, prepared by transfecting \nthe human gene into a suitable expression system (a cell line \nthat produces the protein in good yield), harvesting and purifying the recombinant protein for use as a drug. The first \nagent to be produced in this way was recombinant human \ninsulin in 1982.\nSecond-generation biopharmaceuticals are those that \nhave been engineered; that is to say, either the gene has \nbeen deliberately altered prior to transfection such that the structure of the recombinant protein is changed, or \nsome alteration is made to the purified end product. Such changes are generally made to improve some aspect of \nthe protein\u2019s activity profile. Human recombinant insulins \ndesigned to act faster or last longer were among the first in this class to be marketed; Table 5.1 contains other \nexamples.\nTable 5.1 Some examples of biopharmaceuticals\nClass Type Biopharmaceutical Change Target IndicationReason for \nchange\nFirst \ngenerationProtein Human insulin None Insulin receptor Diabetes N/A\nProtein Human growth hormoneNone Growth hormone receptor (agonist)Pituitary dwarfism, \nTurner\u2019s syndromeN/A\nSecond generationProtein Insulin AA sequence Insulin receptor Diabetes Faster acting hormone\nProtein Interferon analogue AA sequence Viral replication Viral infection Superior antiviral activity\nProtein Glucocerebrosidase enzymeCarbohydrate residueGlucocerebrosides Gaucher\u2019s disease Promotes phagocytic uptake\nProtein Erythropoietin analogueCarbohydrate residueErythropoietin receptorAnaemia Prolongs half-life\nProtein Human growth hormoneAA sequence, prosthetic groupGrowth hormone receptor (antagonist)Acromegaly Converts agonist into antagonist with long duration of action\nProtein Adalimumab\naHumanised mAbTumour necrosis factorRheumatoid disease Persists in circulation\nProtein Omalizumab Humanised mAbIgE IgE-mediated \nasthmaPersists in circulation\nAntisense", "start_char_idx": 0, "end_char_idx": 3610, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2c273a64-bc09-4cd9-a649-fb4e64491e1a": {"__data__": {"id_": "2c273a64-bc09-4cd9-a649-fb4e64491e1a", "embedding": null, "metadata": {"page_label": "76", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "94517a50-09a8-4f34-a390-5cb644cfd387", "node_type": null, "metadata": {"page_label": "76", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "76ca3962db434583a4c219a9499ed9ba1569f19a9cc1884e897aa12fef71ab29"}, "2": {"node_id": "dd83b3d6-0dc5-4331-b408-de3d1604f5c9", "node_type": null, "metadata": {"page_label": "76", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c44824656835cf4aaca924cf7e084b781efa601d87264869323092cd1520f56"}}, "hash": "8d9ef90a2757ccb3331218638b057bd7851932518702bdd0c4bd2880fd9c4b18", "text": "IgE-mediated \nasthmaPersists in circulation\nAntisense oligonucleotideMipomersin Modified nucleotidesApolipoprotein B geneFamilial \nhypercholesteraemiaStability\nAntisense oligonucleotideEteplirsen Modified nucleotidesDystrophin gene Duchenne muscular \ndystrophyStability\nAntisenseoligonucleotideNusinersen Modified nucleotidesSurvival motor neuron protein (SMN 1)Spinal muscular \natrophyStability\naTherapeutic \tmonoclonal \tantibody \tnames \tall \tend \tin \t\u2018-mab\u2019, \tprefixed \tby \tan \tindication \tof \ttheir \tspecies \tnature: \t-umab \t(human), \t-omab \t\n(mouse),\t-ximab \t(chimera), \t-zumab \t(humanised).\nAA,\tamino\tacids; \tIgE,\timmunoglobulin \tE; \tmAb,\tmonoclonal \tantibody.\n(Source:\tWalsh, \t2004; \tThe \tBritish \tNational \tFormulary; \tand \tothers.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3557, "end_char_idx": 4775, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "80d3b47c-56bf-4f17-80b8-03191e5a16a2": {"__data__": {"id_": "80d3b47c-56bf-4f17-80b8-03191e5a16a2", "embedding": null, "metadata": {"page_label": "77", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "108ae145-5d6c-4074-b880-a88e2125df39", "node_type": null, "metadata": {"page_label": "77", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c7d1a3ad5f0942db919297fdeb721d6f476dbca5e1a5deca120a35e2ba78bfb5"}, "3": {"node_id": "0b93104a-fbb9-434d-8e24-3279ef3937c1", "node_type": null, "metadata": {"page_label": "77", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7d9f1367a16433f61c99075485da801f9b8b84d3dbc1124171fb64f39844a159"}}, "hash": "9cbc1e39714cde3f44bf5e048b0e1d86f935ad4b174d2dba43a9ad2fc7c71316", "text": "5 How d RuGS AC t: b I o PHAR m ACE ut ICALS AN d GENE t HERAP y\n71Milstein and K\u00f6hler2 discovered a method of producing \nfrom immunised mice an immortalised hybridoma , a fusion \nof one particular lymphocytic clone with an immortalised \ntumour cell. This furnished a method of producing mono-\nclonal antibodies (mAbs) \u2013 a single species of monovalent \nantibody \u2013 at high abundance in vitro. The hybridoma cell \nline could be retained and expanded indefinitely while preserving the integrity of its product.\nmAbs can be classified into first- or second-generation \nreagents along similar lines to the other therapeutic proteins discussed above. First-generation mAbs were simply murine monoclonals (or fragments thereof) but had several draw -\nbacks. As mouse proteins, they provoked an immune response in 50%\u201375% of all human recipients, had a short half-life in the human circulation and were unable to activate \nhuman complement.\nMost of these problems can now be surmounted by using \neither chimeric or humanised mAbs. These two terms refer \nto the degree to which they have been engineered. Fig. 5.1 \nshows how this is done; the antibody molecule consists of \na constant domain (Fc) and the antibody-binding domain \n(Fab), with hypervariable regions that recognise and bind to the antigen in question. The genes for chimeric mAbs are engineered to contain the cDNA of the murine Fab \ndomain coupled with the human Fc domain sequences. This such as lettuce and bananas could be used to produce some orally \nactive proteins, such as vaccines, which could then be consumed \ndirectly without the need for prior purification. Several such proteins \nhave already been produced in plants, and have entered clinical trials \n(Kwon et al., 2013).\nAnother technology that could dramatically increase the yield of human recombinant proteins is the use of transgenic cattle. A dairy \ncow can produce some 10,000 litres of milk per year, and recombinant \nproteins introduced into the genome and under the control of promoters that regulate production of other milk proteins, can generate yields \nas high as 1 g/L (see Brink et al., 2000).\nEngineered proteins\nThere are several ways in which proteins can be altered \nprior to expression. Alteration of the nucleotide sequence \nof the coding gene can be used to change single amino \nacids or, indeed, whole regions of the polypeptide chain. There are good reasons why it may be an advantage to \nengineer proteins in this way. These include:\n\u2022\tmodification \tof \tpharmacokinetic \tproperties\n\u2022\tcreation \tof \tnovel \tfusion or other proteins\n\u2022\treducing \timmunogenicity, \tfor \texample, \tby \thumanising \nthe protein\nIt is often useful to modify the pharmacokinetic properties \nof recombinant proteins. Changes in the structure of human insulin, for example, provided a form of the hormone that \ndid not self-associate during storage and was thus faster \nacting and easier to manage. The half-life of proteins in the blood can often be extended by PEGylation (see Ch. \n11), the addition of polyethylene glycol to the molecule. This post-translational engineering approach has been applied \nto some human hormones, such as recombinant growth \nhormone, interferons and others. This is not merely a \nconvenience to patients; it also reduces the overall cost of the treatment, an important factor in the adoption of this \ntype of therapy.\nFusion proteins comprise two or more proteins engineered \nto be expressed as one single polypeptide chain, sometimes joined by a short linker. An example is etanercept, an \nanti-inflammatory drug", "start_char_idx": 0, "end_char_idx": 3571, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0b93104a-fbb9-434d-8e24-3279ef3937c1": {"__data__": {"id_": "0b93104a-fbb9-434d-8e24-3279ef3937c1", "embedding": null, "metadata": {"page_label": "77", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "108ae145-5d6c-4074-b880-a88e2125df39", "node_type": null, "metadata": {"page_label": "77", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c7d1a3ad5f0942db919297fdeb721d6f476dbca5e1a5deca120a35e2ba78bfb5"}, "2": {"node_id": "80d3b47c-56bf-4f17-80b8-03191e5a16a2", "node_type": null, "metadata": {"page_label": "77", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9cbc1e39714cde3f44bf5e048b0e1d86f935ad4b174d2dba43a9ad2fc7c71316"}}, "hash": "7d9f1367a16433f61c99075485da801f9b8b84d3dbc1124171fb64f39844a159", "text": "by a short linker. An example is etanercept, an \nanti-inflammatory drug used in the treatment of rheumatoid \narthritis and other conditions (see Ch. 27). Etanercept consists of the ligand-binding domain taken from the tumour \nnecrosis factor (TNF) receptor, joined to the Fc domain of \na human immunoglobulin G antibody. The receptor moiety sequesters endogenous TNF ligand in a complexed inactive \nform, while the immunoglobulin increases persistence of \nthe drug in the blood. Reduction of immunogenicity through bioengineering is discussed later.\nMONOCLONAL ANTIBODIES\nAlthough antisera preparations can be used to confer passive \nimmunity , there are a number of inherent disadvantages that \nlimit their utility. Conventionally, antisera are produced from the blood of immunised humans or animals. Antise -\nrum containing high levels of specific antibodies (e.g. to \ntetanus toxin or snake venom) is prepared from the plasma \nand this can then be used therapeutically to neutralise pathogens or other dangerous substances in the blood of \nthe patient.\nSuch preparations are comprised of polyclonal antibodies \n\u2013 that is, a polyvalent mixture of antibodies from all the \nplasma cell clones that reacted to that particular antigen. \nThe actual composition and efficacy of these varies over \ntime, and obviously there is a limit to how much plasma can be collected on any one occasion. However, in 1975, \n2They won the 1984 Nobel Prize for Physiology or Medicine for this \nwork.Light chains\nHinge regionVariabl e\nregionHypervariable\nregion\nComplement\nfixation region\nHeavy chains\nFC regionDisulfide\nbonds\nFig. 5.1\tProduction of engineered \u2018chimeric\u2019 and \n\u2018humanised\u2019 monoclonal antibodies. \tThe\tY-shaped \tantibody \t\nmolecule\tconsists \tof \ttwo \tmain \tdomains: \tthe \tFc \t(constant) \t\ndomain\tand \tthe \tFab \t(antigen-binding) \tdomain. \tAt \tthe \ttip \tof \tthe \t\nFab\tregions \t(on \tthe \tarms \tof \tthe \t\u2018Y\u2019) \tare \tthe \thypervariable \t\nregions\tthat \tactually \tbind \tthe \tantigen. \tChimeric \tantibodies \tare \t\nproduced\tby \treplacing \tthe \tmurine \tFc \tregion \twith \tits \thuman \t\nequivalent \tby \taltering \tand \tsplicing \tthe \tgene. \tFor \thumanised \t\nantibodies, \tonly \tthe \tmurine \thypervariable \tregions \tare \tretained, \t\nthe\tremainder \tof \tthe \tmolecule \tbeing \thuman \tin \torigin. \t(After \t\nWalsh,\t2004.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3500, "end_char_idx": 6274, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b71a1de9-8fe6-4722-8cba-09eb8459e6c7": {"__data__": {"id_": "b71a1de9-8fe6-4722-8cba-09eb8459e6c7", "embedding": null, "metadata": {"page_label": "78", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4cff3ca7-6f2e-4b4e-a82f-460d650acd71", "node_type": null, "metadata": {"page_label": "78", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "08dc250cfd3654bf286c7d44b59fe66663c4d232114ad16c24ebda8812790386"}, "3": {"node_id": "8e4eeac6-2e5e-4b1b-b326-d0971d61e8b5", "node_type": null, "metadata": {"page_label": "78", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1639f4502d09f13614451b77707fd8a80c4c39da9caaf8260de1b99a35381838"}}, "hash": "d66e792ab42cb8bd360fc8b3ddff65aeb4572b644f33e433bd123116582e63bf", "text": "5 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n72are ubiquitous in biological fluids, enzyme-resistant meth-\nylphosphorate , phosphothiorate or other analogues have been \ndeveloped.\nFollowing parenteral administration, such oligomers \ndistribute widely throughout the body (although not to \nthe CNS) and work in part by interfering with the transcrip -\ntion of mRNA and in part by stimulating its breakdown \nby ribonuclease H. Mipomersen, the first ever licensed \nantisense therapeutic (2013), is a phosphothiorate analogue that suppresses the expression of apolipoprotein B, acts through this mechanism. It can be used to treat a rare form of hypercholesterolaemia (Fig. 5.2). Another oligonucleotide \ndrug recently (2016) approved by the FDA, etiplersen, \ntargets a specific region of the dystrophin gene that is mutated \nin Duchenne muscular dystrophy, changing the reading frame and causing the faulty exon to be removed, with the \nresult that the final translated product is a partially func -\ntional version of the protein.\nAfter a slow start with only two agents actually reaching \nthe market prior to 2017, at the time of writing, several candidate drugs are being tested for use in the treatment \nof viral diseases including HIV, cytomegalovirus and \nhaemorrhagic virus infections as well as cancer, spinal muscular atrophy and other disorders.\nA related approach (see Castanatto & Rossi, 2009), which \nprovides more efficient gene silencing than antisense oli -\ngonucleotides, is the use of short interfering RNA (siRNA),\n3 \nwhereby short lengths of double-stranded RNA recruit an \nenzyme complex, known as RISC ( RNA-I nduced Silencing \nComplex), which selectively degrades the corresponding +20\n0\n2468 10 12 14 16Placebo\n200 mg/wk\n400 mg/wk\nWeeksMean % change from baseline\nTreatment18 20 22 24\u221220\n\u221240\n\u221260\n\u221280\nFig. 5.2\tUsing antisense oligonucleotides to correct mild-moderate hyperlipidaemia. \tThe\tantisense \toligonucleotide \tmipomersen \t\nwas\tadministered \tto \t50 \tpatients \tfor \t13 \tweeks. \tThe \tdata \tshows \tthe \tmean \treduction \tin \tlow-density \tlipoprotein \t(LDL) \tcholesterol \texpressed \t\nin\tpercentage \tterms \tfrom \tthe \tbaseline \treadings \tat \tday \t1 \twith \tdoses \tof \t200 \tmg/week \t(red)\tand\t400\tmg/week \t(blue)\tcompared \twith \ta \t\nplacebo\t(black).\tThe\treduction \tin \texpression \tof \tapolipoprotein \tB \tcaused \tby \tthe \tdrug \texactly \tparalleled \tthe \tLDL \tcholesterol \tdata. \tAfter \t\ndiscontinuation \tof \tthe \ttreatment \t(indicated \tby \tdotted \tline) \tthe \tblood \tlevels \tshowed \tsigns \tof \treturning \tto \tbaseline \tvalues, \tbut \twere \tstill \t\ndepressed \tby \t20%\u201330% \tat \tthe \tconclusion \tof \tthe \tstudy \tat \tthese \tdoses \t(Redrawn \tfrom \tGeary \tet \tal., \t2015).\n3Discovered when plant scientists found, to their surprise, that \nintroducing RNA which encoded the colour-producing enzyme in \npetunias made the flowers less colourful, not more so. Subsequently \nsiRNA has emerged as an important physiological mechanism for controlling gene expression and was recognised by the award in 2006 of \nthe Nobel Prize to Craig Mello and Andrew Fire.greatly (around five-fold) extends the plasma half-life \nbecause whilst most plasma proteins turn over quite rapidly \nimmunoglobulins are an exception (it is easy to see why \nthis provides a selective advantage to the host).", "start_char_idx": 0, "end_char_idx": 3277, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e4eeac6-2e5e-4b1b-b326-d0971d61e8b5": {"__data__": {"id_": "8e4eeac6-2e5e-4b1b-b326-d0971d61e8b5", "embedding": null, "metadata": {"page_label": "78", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4cff3ca7-6f2e-4b4e-a82f-460d650acd71", "node_type": null, "metadata": {"page_label": "78", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "08dc250cfd3654bf286c7d44b59fe66663c4d232114ad16c24ebda8812790386"}, "2": {"node_id": "b71a1de9-8fe6-4722-8cba-09eb8459e6c7", "node_type": null, "metadata": {"page_label": "78", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d66e792ab42cb8bd360fc8b3ddff65aeb4572b644f33e433bd123116582e63bf"}}, "hash": "1639f4502d09f13614451b77707fd8a80c4c39da9caaf8260de1b99a35381838", "text": "(it is easy to see why \nthis provides a selective advantage to the host). Incorpora -\ntion of human Fc sequences also improves the functionality \nof the antibody in human medicine. A further development \n(and now the preferred approach) is to replace the entire Fc and Fab region with the human equivalent with the \nexception of the hypervariable regions, giving a molecule \nwhich, while essentially human in nature, contains just the minimal murine antibody-binding sites. The anticancer monoclonal Herceptin (trastuzumab; see Ch. 57) is an \nexample of such an antibody, and some others (together with an explanation of the tongue-twisting nomenclature system) are given in Table 5.1.\nOLIGONUCLEOTIDES\nWe turn next to another type of biopharmaceutical, this time based upon oligonucleotide structures. These offer \nan alternative way of modifying genetic material that is \nfar less problematic than delivering entire genes (see later). Amongst the most useful approaches is the use of antisense \noligonucleotides. These are short oligonucleotides that are complementary to part of a gene or gene product that one wishes to modify or suppress. The oligomer needs to be \nat least 15 bases long to confer specificity and tight binding \nto its target sequence (most antisense oligos are 15\u201325 mers). These snippets of genetic material can be designed to suppress the expression of a harmful gene either by forming \na triplex (three-stranded helix) with a regulatory component \nof chromosomal DNA, or by complexing a region of mRNA as a duplex. Unlike entire gene constructs, oligonucleotides \ncan cross plasma and nuclear membranes by endocytosis \nas well as by direct diffusion, despite their molecular size and charge. To avoid destruction by nucleotidases which mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3204, "end_char_idx": 5445, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2f073e4a-5b9f-47c3-ba13-e3bb7fda1b54": {"__data__": {"id_": "2f073e4a-5b9f-47c3-ba13-e3bb7fda1b54", "embedding": null, "metadata": {"page_label": "79", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7dd86da5-b6d8-4e80-b3f2-9382a9be9efd", "node_type": null, "metadata": {"page_label": "79", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "adfdeb6ccb84e384f5ae0520e33be6d43f34fffea498e22d96f48e1e80c55e5f"}, "3": {"node_id": "67b7fe86-1304-494b-80ed-995fac1dfd97", "node_type": null, "metadata": {"page_label": "79", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3436e695d741d6549533f398aa2d4f4019d4ac6d1f822751dc93889bc4b1cf7a"}}, "hash": "ca1cf99411be9b5631237ced194b8d79c977f3ef050d1f45613148cf663a1aa9", "text": "5 How d RuGS AC t: b I o PHAR m ACE ut ICALS AN d GENE t HERAP y\n73entry biologics (SEBs) or follow-on biologics (FOBs), may be \nbioequivalents (i.e. drugs that are interchangeable with, and \ntherapeutically equivalent to, the original preparation); more often, while still therapeutically effective, they have different clinical properties.\n5 However, each requires sepa -\nrate regulatory approval.\nAnother manufacturing issue concerns the number of \nsteps required to prepare biopharmaceuticals. With chemi -\ncal synthesis, one can assess the exact purity of the final \nproduct, but preparations of biopharmaceuticals may not \nbe homogenous and could contain mixtures of different glycoforms of the protein or possibly bacterial proteins \nor endotoxins. This means that there is a requirement for \ngreatly enhanced quality control and this obviously has profound implications for ease of manufacture and final cost (Revers & Furzcon, 2010).\nSome actions of biopharmaceuticals resemble those of \nconventional drugs: for example, insulin or growth hormone have identical actions to the native hormone. But there are \ndifferences too. Some mAbs immunoneutralise unwanted \nsubstances: for example, infliximab directly neutralises the \ncytokine TNF to produce its therapeutic effect. However, \nanother mAb, rituximab, binds to CD20 on lymphocytes \nand causes actual destruction of the cells to diminish an unwanted immune response. Ibritumomab tiuxetan also \nbinds CD20, but delivers \n90Y to kill the cells.\nBecause of these different modes of action, the relationship \nbetween dose and effect, so beloved of pharmacologists, is much less clear cut. Agoram (2009) highlights some of the problems. In the case of mAbs, high-affinity binding is usual \n(sometimes a mixture of specific and non-specific binding), \nslow on- and off-rates are common and the mAb may be internalised, thus modifying its target cell. Dose\u2013response \nrelationships are sometimes bell-shaped or U-shaped. \nHuman recombinant erythropoietin has a bell-shaped dose\u2013response and, in the case of many mAbs, there is a single optimal dose at which effective immunoneutralisation mRNA produced by the cell, thereby blocking expression. These silencing RNA sequences can also be efficiently \nproduced in a cell infected with a virus that is engineered \nto express the right sequence. Clinical trials of siRNA therapeutics are in progress.\nPHARMACOLOGY OF PROTEIN AND \nOLIGONUCLEOTIDE PHARMACEUTICALS\nThere are important differences between the pharmacological \nproperties of protein and oligonucleotide biopharmaceuticals \nand those of conventional small molecule drugs (Table 5.2), \nattributable in part to their difference in molecular mass. Most conventional drugs have molecular masses of less \nthan 1000 and are usually less than 500 \u2013 in fact, it is thought \nthat this factor is important in achieving optimal distribution in the body and for the biological activity of the drug. In \ncontrast, even the smallest protein biopharmaceutical, \ninsulin, has a molecular mass of almost 6000. Antibodies usually weigh in at about 150,000 and oligonucleotides about 2000\u20133000. Their size obviously affects the absorption \nand bioavailability of biopharmaceuticals.\nAnother distinguishing factor is a consequence of their \nproduction. Conventional drugs and short oligonucleotides are produced by total (occasionally partial) chemical \nsynthesis, with identical characteristics wherever the compound is made. However, this is not the case with \nmany protein-based biopharmaceuticals. The gene expres -\nsion system used to produce therapeutically active proteins \ndiffers from one company to another \u2013 deliberately so in \nmost cases because, unlike genes themselves, proprietary \ngene constructs and expression systems can be", "start_char_idx": 0, "end_char_idx": 3788, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "67b7fe86-1304-494b-80ed-995fac1dfd97": {"__data__": {"id_": "67b7fe86-1304-494b-80ed-995fac1dfd97", "embedding": null, "metadata": {"page_label": "79", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7dd86da5-b6d8-4e80-b3f2-9382a9be9efd", "node_type": null, "metadata": {"page_label": "79", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "adfdeb6ccb84e384f5ae0520e33be6d43f34fffea498e22d96f48e1e80c55e5f"}, "2": {"node_id": "2f073e4a-5b9f-47c3-ba13-e3bb7fda1b54", "node_type": null, "metadata": {"page_label": "79", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca1cf99411be9b5631237ced194b8d79c977f3ef050d1f45613148cf663a1aa9"}}, "hash": "3436e695d741d6549533f398aa2d4f4019d4ac6d1f822751dc93889bc4b1cf7a", "text": "genes themselves, proprietary \ngene constructs and expression systems can be patented, enabling pharma to protect its intellectual property. Each \nexpression system produces a slightly different product in \nterms of its purity, post-translational modifications and protein \u2018fingerprint\u2019\n4. This has important consequences for \ndrug regulation, because unlike synthetic small molecule \ndrugs, each biopharmaceutical is unique and a common \nsaying in the biotech industry is that \u2018the product is the process\u2019. Compared to the first-in-the-field drug, subsequent Table 5.2 Differences between biopharmaceuticals and conventional small molecule drugs\nProperty Conventional drug Biopharmaceutical\nSize Generally <500 kDa (102)Generally >5000 kDa (103), e.g. oligonucleotides, \n103; small proteins 103\u2013104; mAbs 105; genes >106.\nSynthesis Easy to synthesise identical batchesMost biopharmaceuticals are unique (except small \npeptides and short oligonucleotides which can be synthesised chemically)\nRelationship between dose and effectUsually a predictable relationship between dose and effectComplex mechanisms of action, usually high-affinity binding, slow on- and off-rates, unusual shaped D/R curves\nPharmacokineticsOften oral administration, variable absorption and bioavailability, phase 1 and phase 2 metabolism, excretion of drug in urine or faecesUsually parenteral administration, bioavailability high, long half-life, atypical biodistribution and removal mechanisms\nToxicology and adverse effectsVariable, possible drug interactionsImmunogenicity, few drug interactions, generally fewer adverse effects\n4This \u2018biological variation\u2019 using cells to produce a drug is obviously \nnot inherent in more exact medicinal chemistry processes.5More bewildering terminology: biosimilars are generic drugs with a \nsimilar function to the original but with different pharmacology or \ntoxicology; biobetters are generic drugs with a similar function to the \noriginal but with superior pharmacology or toxicology.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3712, "end_char_idx": 6195, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "71756b83-15c6-4b11-a53f-3a44c5cf2148": {"__data__": {"id_": "71756b83-15c6-4b11-a53f-3a44c5cf2148", "embedding": null, "metadata": {"page_label": "80", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e424bc1d-fd47-4aaf-883b-7a0fcfd34468", "node_type": null, "metadata": {"page_label": "80", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e07de946062fee6255c74c4f8b95986ca5f05a204abfa1a92b46f4240f4d9dcb"}, "3": {"node_id": "d1b053bb-6836-436f-8e37-d3d00175c02d", "node_type": null, "metadata": {"page_label": "80", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "26dbdf2f27e2459a32ae1a297044122f527e7454e5d5530714a0e29ae4e3c6f4"}}, "hash": "67907e7cad55204cfd54769c08f0f7c574ddc7326dfc76ba1bd2b9ce89d6cc16", "text": "5 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n74can inactivate single targets with an extraordinary degree \nof precision. Ironically, this can cause major problems when \ntesting these drugs.\n\u25bc In 2006, for example, a UK clinical trial of a new mAb (TGN 1412) \ndesigned to activate T cells (see Ch. 7) and thus treat B-cell lymphocytic \nleukaemia went badly wrong. All six participants became severely \nill following a \u2018cytokine storm\u2019 and suffered lasting damage. The \nincident provoked wide media publicity7 and, while the subsequent \ninvestigation blamed an \u2018unpredictable\u2019 biological reaction, it caused \nmany to think hard about how such trials should be conducted in the \nfuture (see Muller & Brennan, 2009). Highly specific reagents, such as monoclonals intended for human use, pose particular problems as they \nmay not cross-react with the corresponding proteins of other species, \nthus evading detection in the usual preclinical animal safety screens. It may be the case that \u2018surrogate\u2019 mAbs which are species-specific \nwill have to be developed to test in animal models of the disease.\nGENE THERAPY\nAstonishingly, the first study to demonstrate the theoretical \nfeasibility of gene transfer took place in 1944 when Avery \nand his colleagues showed that a virulence factor could be \ntransferred between two strains of pneumococcus and identified the factor as (what we now call) DNA, which \nwas not even recognised at that time as the genetic material. \nFollowing the molecular biology revolution in the 1980s however, the significance of this experiment became clear \nand the notion that one could replace faulty or missing \ngenes became a thrilling \u2013 if distant \u2013 prospect. Despite the high hopes and intensive research efforts in the interven -\ning years, the full potential of gene therapy is still unrealised. \nHowever, the idea commands such appeal that vast \nresources (both public and private) have been committed to its development. There are several reasons why it is so \nattractive. First, it is a (deceptively) simple approach to a \nradical cure of single-gene diseases such as cystic fibrosis \nand the haemoglobinopathies , which are collectively respon -\nsible for much misery throughout the world. Second, many other more common conditions, including malignant, neurodegenerative and infectious diseases, have a large \ngenetic component. Conventional treatment of such disor -\nders is (as readers of later chapters will appreciate) far \nfrom ideal, so the promise of a completely new approach \nhas enormous allure.occurs, instead of the proportional effects that we are more \naccustomed to when dealing with small molecule drugs. In \nthe case of oligonucleotides, there are also several different \nmechanisms of action, as we saw previously.\nThe differences in the nature and size of most biophar-\nmaceuticals when compared with conventional drugs also have implications for their pharmacokinetic properties. Because proteins do not usually survive oral administration, \nmost are administered subcutaneously, intramuscularly or \nintravenously and so bioavailability is typically high compared with many small molecule drugs, often in the region of 80%\u2013100%. But, except in the case of intravenous \nadministration, absorption from the injection site is usually \nslow and the time taken to achieve attain the T\nmax reflects \nthis. Once in the circulation however, the half-life is typically \nlong. Because antibodies bind to their target with high \naffinity, the volume of distribution is often small, but transcellular and unusual trafficking may redistribute the \ndrug to other tissues (Zhao et al., 2012). A comparison of \nthe pharmacokinetics of conventional small molecule drugs with several biopharmaceuticals is shown in Table 5.3.\nBiopharmaceuticals are not", "start_char_idx": 0, "end_char_idx": 3777, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d1b053bb-6836-436f-8e37-d3d00175c02d": {"__data__": {"id_": "d1b053bb-6836-436f-8e37-d3d00175c02d", "embedding": null, "metadata": {"page_label": "80", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e424bc1d-fd47-4aaf-883b-7a0fcfd34468", "node_type": null, "metadata": {"page_label": "80", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e07de946062fee6255c74c4f8b95986ca5f05a204abfa1a92b46f4240f4d9dcb"}, "2": {"node_id": "71756b83-15c6-4b11-a53f-3a44c5cf2148", "node_type": null, "metadata": {"page_label": "80", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67907e7cad55204cfd54769c08f0f7c574ddc7326dfc76ba1bd2b9ce89d6cc16"}}, "hash": "26dbdf2f27e2459a32ae1a297044122f527e7454e5d5530714a0e29ae4e3c6f4", "text": "is shown in Table 5.3.\nBiopharmaceuticals are not removed from the body \nfollowing metabolic transformation and excretion of the type described in Chapter 10 and indeed, some antibodies \ncan persist in the circulation for weeks. Instead, uptake of \nlarge biopharmaceuticals by the lymphatic system is the usual first step, followed by lysosomal degradation. \nHowever, some \u2018small\u2019 ( <\n69 kDa) mAbs may be eliminated \ndirectly by the kidney. Immunogenicity is an issue that \nplagued early development of proteins as drugs and whilst \nthis has been largely overcome by \u2018humanisation\u2019 of antibod -\nies and proteins, it is still important because it alters the \npharmacokinetic properties of the drug ( Richter et al ., 1999) \nby increasing its clearance from the circulation.\nDrug interactions are less of an issue with biopharma -\nceuticals, as are general toxicity problems and adverse side \neffects, an advantage that is reflected in their relatively rapid approval by regulatory agencies. In part, this is due \nto their extraordinary specificity. In fact, few drugs come \ncloser to the idea of a \u2018magic bullet\u2019\n6 than biopharmaceuticals \nwhich, because of the specificity of the immune system, Table 5.3 A comparison of pharmacokinetics between two conventional small molecule drugs and some \nbiopharmaceuticals\nType Drug RouteaDosing frequency Tmax T1/2 Bioavailability V\nConventional drug 20 mg simvastatin p.o. 1 per day 0.7 h 1.5 h <5% 215 L/kg\n75 mg indometacin p.o. 1\u20132 per day 2\u20133 h 2\u20133 h >90% 1.0 L/kg\nBiopharmaceutical 25 mg etanercept i.m. 1\u20132 per week 69 h 102 h 58% 6\u201311 L/kg\n40 mg adalimumab i.m. 1 per 2 weeks 131 h 10\u201320 days 64% 4.7\u20136.0 L/kg\n75 mg omalizumab i.m. 1 per month 7\u20138 days 26 days 62% 5.5 L/kg\naRoute\tof\tadministration: \ti.m.,\tintramuscular; \tp.o.,\tby\tmouth. \tAll \tdata \tapproximated \tfrom \tinformation \tfrom \tmanufacturers.\nTmax,\ttime\tto\tmaximum \tplasma \tconcentration; \tt1/2,\thalf-life;\tV,\tvolume\tof \tdistribution.\n6It was Weber\u2019s opera, Der Freisch\u00fctz (The Sharpshooter, 1821), that \nintroduced the idea of a \u2018magic bullet\u2019 which, once fired, always found \nits mark. Ehrlich liked the idea and thought that it was a good \ndescription of a highly specific drug. The term, and the concept, has haunted our discipline ever since.7One tabloid headline read: \u2018We saw human guinea pigs explode\u2019 \n(quoted by Stobbart et al., 2007).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3728, "end_char_idx": 6569, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e6b36480-6c67-4d9f-b718-1199955fd4c7": {"__data__": {"id_": "e6b36480-6c67-4d9f-b718-1199955fd4c7", "embedding": null, "metadata": {"page_label": "81", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e9e8e560-f979-4eb6-83a1-5313ac7253ba", "node_type": null, "metadata": {"page_label": "81", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e50fb8b7a772a8883011e5c36e91b8a987c96517b5e40289c334d83bc71e4e4b"}, "3": {"node_id": "c8e1887c-e273-439d-8d38-b0c41e39e83d", "node_type": null, "metadata": {"page_label": "81", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43398a9c8dd43c38d9392638a99becf324536ac10e5df3e810dae6b46dafc6ee"}}, "hash": "47d97a8b95b80faab1f9bb3634aa98443055934284a47d82e2b5b7a8f04b13ee", "text": "5 How d RuGS AC t: b I o PHAR m ACE ut ICALS AN d GENE t HERAP y\n75\u2022\tthe\tcapacity of the system (e.g. how much DNA it can \ncarry);\n\u2022\tthe\ttransfection efficiency (its ability to enter and \nbecome utilised by cells);\n\u2022\tthe\tlifetime of the transfected material (determined by \nthe lifetime of the targeted cells);\n\u2022\tthe\tsafety issue, especially important in the case of viral \ndelivery systems.\nVarious approaches have been developed (Table 5.4) in an \nattempt to produce the optimal system.\nThere are two main gene therapy strategies. Using the \nin vivo technique, the vector containing the therapeutic \ngene is injected into the patient, either intravenously (in \nwhich case some form of organ or tissue targeting is required) or directly into the target tissue (e.g. the retina). \nWhen using the ex vivo strategy, cells are removed from \nthe patient (e.g. stem cells from bone marrow or circulating blood, or myoblasts from a biopsy of striated muscle), and \ntreated with the vector in the laboratory. The genetically \naltered cells are injected back into the patient they came from, thus avoiding any immune rejection (autologous \nrather than allogenic).\nAn ideal vector should be safe, highly efficient (i.e. insert \nthe therapeutic gene into a high proportion of target cells and under control of the appropriate promoter) and selective \nin that it should lead to expression of the therapeutic protein \nin the target cells but not to the expression of other viral \nproteins. Ideally, and provided that the cell into which it is inserted is itself long-lived, the vector should cause persistent expression, avoiding the need for repeated treat -\nment. The latter consideration can be a problem in some \ntissues. In the autosomal recessive disorder cystic fibrosis, \nfor example, the airway epithelium malfunctions because \nit lacks a membrane Cl\n\u2212 transporter known as the cystic \nfibrosis transport regulator (CFTR). Epithelial cells in the \nairways are continuously dying and being replaced, so \neven if the unmutated CFTR gene could be stably transfected into the epithelium, there would still be a periodic need \nfor further treatment unless the gene could be inserted into \nthe progenitor (stem) cells. Similar problems are anticipated in other cells that turn over continuously, such as gastro -\nintestinal epithelium and skin.The gurus are emphatic that \u2018the conceptual part of the \ngene therapy revolution has indeed occurred \u2026\u2019 \u2013 so where are the therapies? The devil, of course, is in the detail: in this case, the details of:\n\u2022\tpharmacokinetics: delivery of the gene to the interior of \nappropriate target cells (especially those in the CNS);\n\u2022\tpharmacodynamics: the controlled expression of the \ngene in question;\n\u2022\tsafety;\n\u2022\tclinical efficacy and long-term practicability.\nThere is a broad consensus that the Weismann barrier\n8 should \nnot be breached and so a moratorium has been agreed on making alterations to the DNA of germ cells (which could \ninfluence future generations) and gene therapy trials have focused on somatic cells only.\nHere we focus first on the main problems and approaches \nbeing used to transform gene therapy into useful medicines, and conclude with a final section on the limited success \nachieved so far.\nGENE DELIVERY\nThe transfer of large sections of recombinant nucleic acid \ninto target cells is critical to the success of gene therapy. In \nthe words of one commentator (Galun, quoted in Bender, \n2016), \u2018Gene therapy is actually three things: delivery, delivery and delivery\u2019. To overcome this first and most \nfundamental hurdle, techniques borrowed from viruses, \nwhich are masters of the sort of molecular hijacking that is required to introduce functional genes into", "start_char_idx": 0, "end_char_idx": 3718, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c8e1887c-e273-439d-8d38-b0c41e39e83d": {"__data__": {"id_": "c8e1887c-e273-439d-8d38-b0c41e39e83d", "embedding": null, "metadata": {"page_label": "81", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e9e8e560-f979-4eb6-83a1-5313ac7253ba", "node_type": null, "metadata": {"page_label": "81", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e50fb8b7a772a8883011e5c36e91b8a987c96517b5e40289c334d83bc71e4e4b"}, "2": {"node_id": "e6b36480-6c67-4d9f-b718-1199955fd4c7", "node_type": null, "metadata": {"page_label": "81", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "47d97a8b95b80faab1f9bb3634aa98443055934284a47d82e2b5b7a8f04b13ee"}}, "hash": "43398a9c8dd43c38d9392638a99becf324536ac10e5df3e810dae6b46dafc6ee", "text": "of the sort of molecular hijacking that is required to introduce functional genes into mammalian \ncells, are often used in gene therapy research. The constructs \nmust pass from the extracellular space across the plasma and nuclear membranes, and be incorporated into the chro -\nmosomes. Because DNA is negatively charged and single \ngenes have molecular weights around 10\n4 times greater \nthan conventional drugs, the problem is of a different order from the equivalent stage of routine drug development.\nThere are several important considerations in choosing \na gene delivery system; these include:Table 5.4 Characteristics of some delivery systems for gene therapy\nVector Advantages Disadvantages Utilisation of systema\nLiposomes Virus-free, cheap to \nproduceLow efficiency, sometimes cytotoxic 6%\nDNA cassettes Virus-free Low efficiency, expression temporary 18%\nHerpes simplex virus type IHighly infective, persistent expressionNo integration with host DNA, cytotoxic, difficult to handle3%\nAdenovirus Highly infective in epitheliaImmunogenic and transient, requires \nrepeated administration23%\nAdeno-associated virus Stable Low capacity 5%\nRetrovirus Efficient, permanent Low capacity, unstable, must integrate \ninto host DNA, requires dividing cells22%\naThe\tapproximate \tpercentage \tof \ttrials \temploying \tthis \ttype \tof \tdelivery \tsystem. \t(After \tWolf \t& \tJenkins, \t2002; \tand \twith \tdata \tfrom \tWirth \tet \tal., \t\n2013.)\n8Named after August Weismann (1834\u20131914), who formulated the \nconcept that inheritance utilises only germ, and not somatic, cells.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3632, "end_char_idx": 5671, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4e53dd9b-f7a0-470f-84d4-dccac2fb1920": {"__data__": {"id_": "4e53dd9b-f7a0-470f-84d4-dccac2fb1920", "embedding": null, "metadata": {"page_label": "82", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc55bab8-9e1f-4036-bccb-51c5a9e78738", "node_type": null, "metadata": {"page_label": "82", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3768a0355c2fa358eb84fce803fdf69d43ad2dc01e4bf9ce609cd398f7458ffd"}, "3": {"node_id": "eebda1a3-1672-41cb-b512-dc71a8e092b5", "node_type": null, "metadata": {"page_label": "82", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "36e54d6daa4658f38deaa66ceb917c2ef8b65843fd84b44c28513eae868fb97e"}}, "hash": "fc489b4e9909ba86d0a2c30e4a29403b21399795325cea30e2ab14f711a3be29", "text": "5 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n76systemically but would target only the desired cell population. An \nexample of this approach with a lentivirus (a type of retrovirus) is \nthe substitution of the envelope protein of a non-pathogenic vector (e.g. mouse leukaemia virus) with the envelope protein of human vesicular stomatitis virus, to specifically target human epithelial cells.\nMost retrovirus vectors are unable to penetrate the nuclear envelope, \nand because this dissolves during cell division, they only infect dividing \ncells rather than non-dividing cells (such as adult neurons).\nAdenovirus\n\u25bc Adenovirus vectors are popular because of the high transgene \nexpression that can be achieved. They transfer genes to the nucleus of the host cell, but (unlike retroviruses) these are not inserted into \nthe host genome and so do not produce effects that outlast the lifetime of the transfected cell. This property also obviates the risk of disturbing \nthe function of other cellular genes and the theoretical risks of car -\ncinogenicity and germ cell transfection. Because of these favourable \nproperties, adenovirus vectors have been used for in vivo gene therapy. \nEngineered deletions in the viral genome render it unable to replicate \nor cause widespread infection in the host while at the same time \ncreating space in the viral genome for the therapeutic transgene to \nbe inserted.\nOne of the first adenoviral vectors lacked part of a growth-controlling \nregion called E\n1, while incorporating the desired transgene. This vector \ngave excellent results, demonstrating gene transfer to cell lines and animal models of disease, but it proved disappointing as a treatment \nfor cystic fibrosis in human trials. Low doses (administered by aerosol to patients with this disease) produced only a very low-efficiency \ntransfer, whereas higher doses caused inflammation, a host immune \nresponse and short-lived gene expression. Furthermore, treatment VIRAL \u2003VECTORS\nMany contemporary gene delivery strategies aim to capi -\ntalise on the capacity of viruses to subvert the transcriptional \nmachinery of the cells they infect and their ability (in some \ncases) to fuse with the host genome. While seemingly simple, there remain substantial practical problems with this viral \nvector approach. As viruses have evolved the means to invade human cells, so humans have evolved immune responses and other protective countermeasures. Although \nlimiting in some respects, this is not all bad news from the \npoint of view of safety. As many of the viruses used for vectors are pathogenic, they are usually modified such that they are \u2018replication defective\u2019 to avoid toxicity.\nRetroviruses\n\u25bc If introduced into stem cells, retroviral vectors have long-lasting \neffects because they are incorporated into, and replicate along with, \nhost DNA, and so the \u2018therapeutic\u2019 gene is passed down to each \ndaughter cell during division. Against this, the retroviral integrase \ninserts the construct into chromosomes randomly, so it may cause \ndamage. Also, retroviruses could infect germ or non-target cells and \nproduce undesired effects if administered in vivo. For this reason, retroviruses have been used mainly for ex vivo gene therapy. The \nlife cycle of naturally occurring retroviruses may be exploited to \ncreate useful vectors for gene therapy (Fig. 5.3).\nMany viruses are equipped to infect specific cell types, though not \nnecessarily the target cell of interest. It is possible to alter the retroviral envelope to alter specificity, such that the vector could be administered \nNUCLEUSRNAEnhancer-promoter\nTransfection\nEnv\nFactor IX proteinInfection\nGag", "start_char_idx": 0, "end_char_idx": 3644, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "eebda1a3-1672-41cb-b512-dc71a8e092b5": {"__data__": {"id_": "eebda1a3-1672-41cb-b512-dc71a8e092b5", "embedding": null, "metadata": {"page_label": "82", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc55bab8-9e1f-4036-bccb-51c5a9e78738", "node_type": null, "metadata": {"page_label": "82", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3768a0355c2fa358eb84fce803fdf69d43ad2dc01e4bf9ce609cd398f7458ffd"}, "2": {"node_id": "4e53dd9b-f7a0-470f-84d4-dccac2fb1920", "node_type": null, "metadata": {"page_label": "82", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc489b4e9909ba86d0a2c30e4a29403b21399795325cea30e2ab14f711a3be29"}}, "hash": "36e54d6daa4658f38deaa66ceb917c2ef8b65843fd84b44c28513eae868fb97e", "text": "IX proteinInfection\nGag Polba\nPACKAGING\nCELLTransgene\nTARGET\nCELLCYTOPLASMReverse\ntranscriptasec\ndViral RNA\nIntegration\nHost DNANUCLEUS\nTranslationRNA\u2013DNA hybrid\nSecretionDouble-stranded DNA\neLTR LTR Factor IX\u03a8\nFig. 5.3\tStrategy for making retroviral vectors. \tThe\ttransgene \t(the \texample \tshows \tthe \tgene \tfor \tfactor \tIX) \tin \ta \tvector \tbackbone \tis \t\nintroduced \t(a)\tinto\ta\tpackaging \tcell, \twhere \tit \tis \tintegrated \tinto \ta \tchromosome \tin \tthe \tnucleus, \tand \t(b)\ttranscribed \tto \tmake \tvector \tmRNA, \t\nwhich\tis\tpackaged \tinto \tthe \tretroviral \tvector \tand \tshed \tfrom \tthe \tpackaging \tcell. \tIt \tthen \tinfects \tthe \ttarget \tcell \t(c).\tVirally\tencoded \treverse \t\ntranscriptase \t(d)\tconverts\tvector \tRNA \tinto \tan \tRNA\u2013DNA \thybrid, \tand \tthen \tinto \tdouble-stranded \tDNA, \twhich \tis \tintegrated \t(e)\tinto\tthe\t\ngenome\tof \tthe \ttarget \tcell. \tIt \tcan \tthen \tbe \ttranscribed \tand \ttranslated \tto \tmake \t(in \tthis \tcase) \tfactor \tIX \tprotein. \t\u2018Env\u2019, \tGag\u2019 \tand \t\u2018Pol\u2019 \trepresent \t\ncomponents \tof \tthe \tretroviral \tvector. \tLTR,\tlong\tterminal \trepeat. \t(Redrawn \tfrom \tVerma \t& \tSomia, \t1997.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3621, "end_char_idx": 5198, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "50ecf123-c78c-4203-92c4-d7aebfadfb77": {"__data__": {"id_": "50ecf123-c78c-4203-92c4-d7aebfadfb77", "embedding": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "434e4647-fa83-4200-a0b5-f1d974b88edf", "node_type": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce99bcb01a3ab399e892cb46439fbe59d29a48f882df7e28ade49e4f5768af78"}, "3": {"node_id": "0ef2d212-1dff-4d79-96f9-7237559920b8", "node_type": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6eadaa0a962c6f9ac72752e19cbad1bb652154093dd4aee2c2cd2b125827aae3"}}, "hash": "61afa4d3b35ccc2e6515304c1d9eac5862087539bc75b212dba0a8867ba6a2b0", "text": "5 How d RuGS AC t: b I o PHAR m ACE ut ICALS AN d GENE t HERAP y\n77demands an appropriate balance of normal \u03b1- and \u03b2-globin \nchain synthesis to be effective, and for this, and many other \npotential applications, precisely controlled gene expression \nis essential.\n\u25bc It has not yet proved possible to control transgenes precisely in \nhuman recipients, but there are techniques that may eventually enable \nus to achieve this goal. One hinges on the use of an inducible expression \nsystem. This is a fairly standard laboratory technique whereby the \ninserted gene also includes a doxycycline-inducible promoter such \nthat expression of the gene can be switched on or off by treatment \nwith, or withdrawal of, doxycycline.\nThe control of transfected genes is important in gene targeting as \nwell. By splicing the gene of interest with a tissue-specific promoter, \nit should be possible to restrict expression of the gene to the target tissue. Such an approach has been used in the design of gene therapy \nconstructs for use in ovarian cancer, the cells of which express several \nproteins at high abundance, including the proteinase inhibitor SLP1. In combination with the SLP1 promoter, plasmids carrying various \ngenes were successfully and selectively expressed in ovarian cancer \ncell lines (Wolf & Jenkins, 2002).\nSAFETY AND SOCIETAL ISSUES\nExperiments or protocols involving the transfer of genetic \nmaterial tend to provoke deep unease in some sectors of \nsociety \u2013 witness the genetically modified (GM) crop debate \n(and see Freier et al., 2014). Partly, this may be traced to \nignorance or prejudice but it is nevertheless a problem that \ncan hinder the introduction of new agents. Societal issues \naside, the technique does raise a number of specific concerns \nthat generally relate to the use of viral vectors. These are usually selected because they are non-pathogenic, or modi -\nfied to render them innocuous, but there is a concern that such agents might still acquire virulence during use. Retroviruses, which insert randomly into host DNA, could \ndamage the genome and interfere with the protective \nmechanisms that normally regulate the cell cycle (see Ch. 6), and if they happen to disrupt essential cellular functions, this could increase the risk of malignancy.\n9\nAnother problem is that immunogenic viral proteins may \nelicit an inflammatory response, and this could be harmful \nin some situations (e.g. in the airways of patients with \ncystic fibrosis). Initial clinical experience was reassuring, but the death of Jesse Gelsinger, an 18-year-old volunteer \nin a gene therapy trial for the non-fatal disease ornithine \ndecarboxylase deficiency (which can be controlled, albeit \ntediously, by diet and drugs anyway), led to the appreciation \nthat safety concerns related to immune-mediated responses \nto vectors are very real (see Marshall, 1999).\nTHERAPEUTIC APPLICATIONS\nDespite the plethora of technical problems and safety concerns, there have been some encouraging successes and \ninterest \u2013 and confidence \u2013 in the area is still very strong \nwith some 3000 new publications appearing each year.could not be repeated because of the appearance, in the circulation, \nof neutralising antibodies. This has led to attempts to manipulate \nadenoviral vectors to mutate or remove the genes that are most strongly \nimmunogenic.\nOther viral vectors\n\u25bc Other potential viral vectors under investigation include adeno- \nassociated virus, herpes virus and disabled versions of human immuno -\ndeficiency virus (HIV). Adeno-associated virus associates with host DNA \nbut is not activated unless the cell is infected with an adenovirus. It is \nless immunogenic than other vectors but is difficult to mass produce \nand cannot", "start_char_idx": 0, "end_char_idx": 3731, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0ef2d212-1dff-4d79-96f9-7237559920b8": {"__data__": {"id_": "0ef2d212-1dff-4d79-96f9-7237559920b8", "embedding": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "434e4647-fa83-4200-a0b5-f1d974b88edf", "node_type": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce99bcb01a3ab399e892cb46439fbe59d29a48f882df7e28ade49e4f5768af78"}, "2": {"node_id": "50ecf123-c78c-4203-92c4-d7aebfadfb77", "node_type": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61afa4d3b35ccc2e6515304c1d9eac5862087539bc75b212dba0a8867ba6a2b0"}, "3": {"node_id": "f573ffa9-5fdf-4ab7-95a0-fa0facec9195", "node_type": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c8637a6a9cae7eb1eee9279e9ea616db76c960b10941ec7cf9950592b363163"}}, "hash": "6eadaa0a962c6f9ac72752e19cbad1bb652154093dd4aee2c2cd2b125827aae3", "text": "immunogenic than other vectors but is difficult to mass produce \nand cannot be used to carry large transgenes. Herpes virus does not associate with host DNA but is very long lived in nervous tissue (so \ncould have a specific application in treating neurological disease). \nHIV, unlike most other retroviruses, can infect non-dividing cells such as neurons. It is possible to remove the genes from HIV that \ncontrol replication and substitute other genes. Alternatively, it may \nprove possible to transfer to other non-pathogenic retroviruses those \ngenes that permit HIV to penetrate the nuclear envelope.\nNON-VIRAL \u2003VECTORS\nTo reduce the problems associated with viral vectors, a \nvariety of other substances have been used to deliver genes \nand other material. These are often collectively known as \nnanocarriers. The list includes the following (but see also \nXu et al., 2014):\nLiposomes\n\u25bc Non-viral vectors include a variant of liposomes (Ch. 9). Plasmids \n(diameter up to approximately 2 \u00b5m) are too big to package in regular \nliposomes (diameter 0.025\u20130.1 \u00b5m), but larger particles can be made \nfrom positively charged lipids (\u2018lipoplexes\u2019), which interact with both \nnegatively charged cell membranes and DNA, improving delivery \ninto the cell nucleus and incorporation into the host chromosome. Such particles have been used to deliver the genes for HLA-B7, \ninterleukin-2 and CFTR. They are much less efficient than viruses, \nand attempts are currently under way to improve this by incorporating various viral signal proteins (membrane fusion proteins, for example) \nin their outer coat. Direct injection of these complexes into solid \ntumours (e.g. melanoma, breast, kidney and colon cancers) can, \nhowever, achieve high local concentrations within the tumour.\nMicrospheres\n\u25bc Bio degradable microspheres made from polyanhydride co-polymers \nof fumaric and sebacic acids (see Ch. 9) can be loaded with plasmid \nDNA. A plasmid with bacterial \u03b2-galactosidase activity formulated \nin this way and given by mouth to rats has resulted in systemic absorption and expression of the bacterial enzyme in the rat liver, raising the possibility of oral gene therapy.\nPlasmid DNA\n\u25bc Surprisingly, plasmid DNA itself (\u2018naked DNA\u2019) enters the nucleus \nof some cells and is expressed, albeit much less efficiently than when it is packaged in a vector. Such DNA carries no risk of viral replication \nand is not usually immunogenic, but it cannot be targeted precisely. \nThere is considerable interest in the possibility of using naked DNA for vaccines, which has several theoretical advantages and numerous \ntrials are using the technique (Liu, 2011).\nCONTROLLING GENE EXPRESSION\nTo realise the full potential of gene therapy, it is not enough \nto transfer the gene selectively to the desired target cells \nand maintain acceptable expression of its product \u2013 difficult \nthough these goals are. It is also essential that the activity of the gene is controlled. Historically, it was the realisation \nof the magnitude of this task that diverted attention from \nthe haemoglobinopathies (which were the first projected targets of gene therapy). Correction of these disorders 9This risk is more than a theoretical possibility; several children treated \nfor severe combined immunodeficiency (SCID) with a retrovirus vector \ndeveloped a leukaemia-like illness (Woods et al., 2006). The retroviral \nvector was shown to have inserted itself into a gene called LMO-2, \nmutations of which are associated with childhood cancers.mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3668, "end_char_idx": 7228, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f573ffa9-5fdf-4ab7-95a0-fa0facec9195": {"__data__": {"id_": "f573ffa9-5fdf-4ab7-95a0-fa0facec9195", "embedding": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "434e4647-fa83-4200-a0b5-f1d974b88edf", "node_type": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce99bcb01a3ab399e892cb46439fbe59d29a48f882df7e28ade49e4f5768af78"}, "2": {"node_id": "0ef2d212-1dff-4d79-96f9-7237559920b8", "node_type": null, "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6eadaa0a962c6f9ac72752e19cbad1bb652154093dd4aee2c2cd2b125827aae3"}}, "hash": "4c8637a6a9cae7eb1eee9279e9ea616db76c960b10941ec7cf9950592b363163", "text": "childhood cancers.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7227, "end_char_idx": 7724, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "204ac2cb-39aa-4912-8979-ce7c6734b259": {"__data__": {"id_": "204ac2cb-39aa-4912-8979-ce7c6734b259", "embedding": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "559cf4ab-e4c0-442f-a93e-93177a9709cd", "node_type": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e144c7d99240e41897b666bf6f1f857203bcd903e3aaf1f1f3fdaf2377e76e74"}, "3": {"node_id": "92705424-bcd9-454f-bba8-10b20c7d5f29", "node_type": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b39682871a76bb48bcf45988ebff1b412b12f4ac9843b9dc5a105f27285b630d"}}, "hash": "ed38a2b67860a01686d87191cc82e972166efd6a232cd720dc27e8f30d02e497", "text": "5 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n78no successful gene therapy using CRISPR-Cas9 has been \napproved for therapeutic use, but several human trials are \nunderway11, and are very close to getting this therapy into the \nclinic.\n\u25bc Target diseases eliciting interest from companies specialising in \ngene therapy applications include:\nSingle-Gene Defects\nSingle-gene ( monogenic ), often rare, disorders, were the obvious starting \npoint for gene therapy trials and haemoglobinopathies were the first \nprojected targets, but early attempts (in the 1980s) were put \u2018on hold\u2019 \nbecause of the problem (mentioned previously) of controlling precisely \nthe expression of the genes encoding the different polypeptide chains \nof the haemoglobin molecule. Recent trials have proved encouraging \nin the treatment of thalassaemia (the commonest monogenic disease) and sickle cell disease (see Rai & Malik, 2016) although no products \nhave yet been approved.\nAnother early target was cystic fibrosis, but progress here has been \ndisappointing (see Kim et al., 2016 for details) largely because of the \nbiological barriers that must be penetrated. There have been other \nsuccesses though. For example, X-linked chronic granulomatous disease \nhas been successfully treated using a retroviral technique to deliver a functional version of the mutated NADPH oxidase protein (Ott \net al., 2006 and Fig. 5.4) and a form of inherited blindness, Leber\u2019s \ncongenital amaurosis , associated with a mutation in a gene that produces \nretinal pigment, has been rectified using an adeno-associated virus \nvector bearing a cDNA coding for the intact gene (Maguire et al., \n2009). Several other ocular conditions also seem to be promising \ncandidates for gene therapy approaches (see Borras, 2017; Boye et al ., \n2013). Williams and Thrasher (2014) have reviewed the general According to a recent reviewer (Tani, 2016) 2210 gene \ntherapy trials had been approved by regulatory agencies \naround the world by 2015, with six gene therapies already \napproved by a limited number of countries. The first was Gendicine , a treatment for replacing the faulty p53 protein \ncausing head and neck cancer, which was licensed in China in 2003. The European Medicines Agency granted its first license for a gene therapy product, Glybera, in 2012\n10. This \nis an adeno-associated virus construct that delivers a correct \ncopy of lipoprotein lipase to patients lacking this enzyme \n(a very rare disorder that causes severe pancreatitis) and in 2016, Strimvelis was also approved in Europe. This is \nan ex vivo gene therapy approach to replace adenosine \ndeaminase which is absent in children with a rare (~15 patients per year in Europe) type of SCID. At the time of \nwriting, no gene therapy-based therapeutics had been \napproved in the United States although intense interest continues.\nRecently, a system of gene editing originally discovered \nin bacteria is promising to transform gene therapy (garner -\ning nearly 7000 publications over the last few years). This bears the rather complex name of Clustered Regulatory \nInterspersed Short Palindromic Repeats (CRISPR) and can \ntarget nucleases (notably Cas9) to precisely edit genes of \ninterest. Viruses can deliver the CRISPR-Cas9 components, \nthereby acting as delivery vehicles for the biochemical \nmachinery required to repair faulty genes in humans (see \nfor example, Gori et al., 2015; Gee et al., 2017). To date, \n11Allogenic transplants in childhood leukaemias, autologous immune \ncell PD-1 knock-out in lung cancer patients, and OCT4\u2019s role in human \nembryo development are all", "start_char_idx": 0, "end_char_idx": 3596, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "92705424-bcd9-454f-bba8-10b20c7d5f29": {"__data__": {"id_": "92705424-bcd9-454f-bba8-10b20c7d5f29", "embedding": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "559cf4ab-e4c0-442f-a93e-93177a9709cd", "node_type": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e144c7d99240e41897b666bf6f1f857203bcd903e3aaf1f1f3fdaf2377e76e74"}, "2": {"node_id": "204ac2cb-39aa-4912-8979-ce7c6734b259", "node_type": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed38a2b67860a01686d87191cc82e972166efd6a232cd720dc27e8f30d02e497"}, "3": {"node_id": "e2af8eeb-4d89-4996-8c4c-8536a1967da5", "node_type": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "071a098e7c8b18de5d39d87136cb75a787e86416268f6bbebe175afce2c7f42d"}}, "hash": "b39682871a76bb48bcf45988ebff1b412b12f4ac9843b9dc5a105f27285b630d", "text": "patients, and OCT4\u2019s role in human \nembryo development are all recent examples of breakthroughs using \nCRISPR-Cas9 in human cells.10With an annual cost of at least US$1 million per treatment, Glybera \nhas been called the most expensive medicine in the world. No wonder \nthat only one patient has been treated so far! (see Regolado, 2016)Gene delivery and expression \n\u2022\tGene\tdelivery \tis \tthe \tmain \thurdle \tto \tpractical \tgene \t\ntherapy.\n\u2022\tRecombinant \tgenes \tare \ttransferred \tusing \ta \tvector,\toften\t\na\tsuitably\tmodified \tvirus.\n\u2022\tThere\tare \ttwo \tmain \tstrategies \tfor \tdelivering \tgenes \tinto \t\npatients:\n\u2013\tin vivo\tinjection\tof \tthe \tvector \tdirectly \tinto \tthe \tpatient \t\n(e.g.\tinto\ta \tmalignant \ttumour);\n\u2013\tex vivo\ttreatment \tof \tcells \tfrom \tthe \tpatient \t(e.g. \tstem \t\ncells\tfrom \tmarrow \tor \tcirculating \tblood), \twhich \tare \tthen \t\nreturned\tto \tthe \tpatient.\n\u2022\tAn\tideal \tvector \tshould \tbe \tsafe, \tefficient, \tselective \tand \t\nproduce\tlong-lasting \texpression \tof \tthe \ttherapeutic \tgene.\n\u2022\tViral\tvectors \tinclude \tretroviruses, \tadenoviruses, \tadeno-\nassociated \tvirus, \therpesvirus \tand \tdisabled \tHIV:\n\u2013\tRetroviruses \tinfect\tmany \tdifferent \ttypes \tof \tdividing \t\ncells\tand\tbecome \tincorporated \trandomly \tinto \thost \t\nDNA.\n\u2013\tAdenoviruses \tare\tgenetically \tmodified \tto \tprevent \t\nreplication \tand \taccommodate \tthe \ttherapeutic \t\ntransgene. \tThey \ttransfer \tgenes \tto \tthe \tnucleus \tbut \tnot \t\nto\tthe\tgenome \tof \tthe \thost \tcell. \tProblems \tinclude \ta \tstrong\thost \timmune \tresponse, \tinflammation \tand \t\nshort-lived \texpression. \tTreatment \tcan \tbe \t\ncompromised \tby \tneutralising \tantibodies.\n\u2013\tAdeno-associated virus \tassociates \twith \thost \tDNA \tand \t\nis\tnon-immunogenic \tbut \tis \thard \tto \tmass \tproduce \tand \t\nhas\ta\tsmall \tcapacity.\n\u2013\tHerpesvirus \tdoes \tnot \tassociate \twith \thost \tDNA \tbut \t\npersists\tin \tnervous \ttissue \tand \tmay \tbe \tuseful \tin \ttreating \t\nneurological \tdisease.\n\u2013\tDisabled \tversions \tof \tHIV \tdiffer \tfrom \tmost \tother \t\nretroviruses \tin \tthat \tthey \tinfect \tnon-dividing \tcells, \t\nincluding\tneurons.\n\u2022\tNon-viral \tvectors \tinclude:\n\u2013\ta\tvariant \tof \tliposomes, \tmade \tusing \tpositively \tcharged \t\nlipids\tand\tcalled \t\u2018lipoplexes\u2019;\n\u2013\tbiodegradable \tmicrospheres, \twhich \tmay", "start_char_idx": 3544, "end_char_idx": 5755, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e2af8eeb-4d89-4996-8c4c-8536a1967da5": {"__data__": {"id_": "e2af8eeb-4d89-4996-8c4c-8536a1967da5", "embedding": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "559cf4ab-e4c0-442f-a93e-93177a9709cd", "node_type": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e144c7d99240e41897b666bf6f1f857203bcd903e3aaf1f1f3fdaf2377e76e74"}, "2": {"node_id": "92705424-bcd9-454f-bba8-10b20c7d5f29", "node_type": null, "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b39682871a76bb48bcf45988ebff1b412b12f4ac9843b9dc5a105f27285b630d"}}, "hash": "071a098e7c8b18de5d39d87136cb75a787e86416268f6bbebe175afce2c7f42d", "text": "\toffer \torally \t\nactive\tgene \ttherapy;\n\u2013\tplasmid \tDNA \t(\u2018naked \tDNA\u2019), \twhich \tcan \tbe \tused \tas \ta \t\nvaccine.\n\u2022\tA\ttetracycline-inducible expression system \tor\tsimilar \t\ntechnique \tcan \tcontrol \tthe \tactivity \tof \tthe \ttherapeutic \t\ngene.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5809, "end_char_idx": 6526, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e6fa2d4e-8b95-4ee2-b0dd-7e7304c2b52e": {"__data__": {"id_": "e6fa2d4e-8b95-4ee2-b0dd-7e7304c2b52e", "embedding": null, "metadata": {"page_label": "85", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "86b6e004-dea7-44e1-81d2-98aff8b89b51", "node_type": null, "metadata": {"page_label": "85", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51398e0b79d09bbeb5a7a34dcc2c17655afe08f197c6e298d5b51a6b5cecc2b3"}, "3": {"node_id": "eeb87108-8f11-4858-abe3-b766017ff050", "node_type": null, "metadata": {"page_label": "85", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e9c0f359e25cc757d9f2878eb4409fc32195b6a12059f4ff8635ae8ac2e54f57"}}, "hash": "9da97c6b92292ac43afa182ff10809ebf940427707cc28a6a4cd7db876d0d37a", "text": "5 How d RuGS AC t: b I o PHAR m ACE ut ICALS AN d GENE t HERAP y\n79\u2022\ttagging \tcancer \tcells \twith \tgenes \texpressing \tproteins \tthat \trender \t\nmalignant cells more visible to the immune system (e.g. for \nantigens such as HLA-B7 or cytokines such as \ngranulocyte-macrophage colony-stimulating factor and \ninterleukin-2).\n\u2022\tRecent \tprogress \tin \tresearch \tin \tsome \tof \tthese \tareas \thas \tbeen \t\nreviewed by Gilham et al. (2015).\nGene Therapy and Infectious Disease\nIn addition to DNA vaccines mentioned previously, there is consider -\nable interest in the potential of gene therapy for HIV and other viral \ninfections. The aim is to render stem cells (which differentiate into \nimmune cells) resistant to HIV before they mature. For an account \nof the strategies under investigation, see Chung et al. (2013).\nGene Therapy and Cardiovascular Disease\nGene therapy trials for treating cardiovascular diseases are reviewed \nby Bradshaw and Baker (2013). Vascular gene transfer is attractive not least because cardiologists and vascular surgeons routinely \nperform invasive studies that offer the opportunity to administer \ngene therapy vectors ex vivo (e.g. to a blood vessel that has been removed to use as an autograft) or locally in vivo (e.g. by injection \nthrough a catheter directly into a diseased coronary or femoral \nartery). The nature of many vascular disorders, such as restenosis following angioplasty (stretching a narrowed artery using a balloon \nthat can be inflated via a catheter), is such that transient gene \nexpression might be all that is required therapeutically. Exten -\nsion of vein graft patency by gene therapy approaches has been \nreviewed by Chandiwal et al. (2005). This seems to be a promising \narea (see Hammond & McKirnan, 2001; Ghosh et al., 2008) although \nHammer and Steiner (2013) concluded that most trials had proved \ndisappointing.\nCONCLUDING REMARKS\nWhilst protein and oligonucleotide biopharmaceuticals \nshare some of the characteristics of other drugs described \nin this book, the same cannot be said for gene therapy. Is \na gene a drug? Is a virus a drug? You could argue that it satisfies the broad definition that we posited in on page 1 problems associated with gene therapy in the treatment of monogenic \nimmunodeficiency diseases.\nCancer\nGene therapy for cancer and related diseases currently comprise almost \n70% of gene therapy trials. Several therapeutic approaches (see Barar \n& Omidi, 2012) are under investigation, including:\n\u2022\trestoring \t\u2018protective\u2019 \tproteins, \tsuch \tas \tthe \ttumour \tsuppressor \t\ngene (see Ch. 6);\n\u2022\tinactivating \toncogene \texpression \t(e.g. \tby \tusing \ta \tretroviral \t\nvector bearing an antisense transcript RNA to the K-Ras oncogene);\n\u2022\tdelivering \ta \tgene \tto \tmalignant \tcells \tthat \trenders \tthem \t \nsensitive to cytotoxic drugs (e.g. thymidylate kinase, \nwhich activates ganciclovir) \u2013 the so-called \u2018suicide gene\u2019 \napproach;\n\u2022\tdelivery \tof \tproteins \tto \thealthy \thost \tcells, \twhich, \tfor \texample, \t\nrenders them resistant to chemotherapy (e.g. addition of the multidrug resistance channel to bone marrow cells ex vivo);Days after transplantationT-cellsGranulocytes70\n60\n5040302010\n0Percent of gene-modified cells\n20 120 220 320 420 520\nFig. 5.4\tCorrecting an inherited defect", "start_char_idx": 0, "end_char_idx": 3265, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "eeb87108-8f11-4858-abe3-b766017ff050": {"__data__": {"id_": "eeb87108-8f11-4858-abe3-b766017ff050", "embedding": null, "metadata": {"page_label": "85", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "86b6e004-dea7-44e1-81d2-98aff8b89b51", "node_type": null, "metadata": {"page_label": "85", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51398e0b79d09bbeb5a7a34dcc2c17655afe08f197c6e298d5b51a6b5cecc2b3"}, "2": {"node_id": "e6fa2d4e-8b95-4ee2-b0dd-7e7304c2b52e", "node_type": null, "metadata": {"page_label": "85", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9da97c6b92292ac43afa182ff10809ebf940427707cc28a6a4cd7db876d0d37a"}}, "hash": "e9c0f359e25cc757d9f2878eb4409fc32195b6a12059f4ff8635ae8ac2e54f57", "text": "120 220 320 420 520\nFig. 5.4\tCorrecting an inherited defect using gene therapy. \tIn\tthis\tclinical \ttrial, \ttwo \tpatients \twith \tX-linked \tchronic \tgranulomatous \t\ndisease\twere \ttransfused \twith \tGM\u2013CSF \t(Granulocyte-Macrophage \tColony \tStimulating \tFactor)-treated \tperipheral \tblood \tcells \tthat \thad \tbeen \t\ngenetically \tmodified \twith \ta \tretroviral \tvector \tbearing \tthe \tintact \tgp91phox \tgene\t(\u2018in\tvitro \tprotocol\u2019 \t\u2013 \tsee \ttext). \tThe \tgraph \tshows \tthat \tthe \t\nnumber\tof \tgene-modified \tperipheral \tblood \tleukocytes \tremained \thigh \tfor \twell \tover \ta \tyear \tand \tthis \twas \taccompanied \tby \tgood \tlevels \tof \t\nsuperoxide \tproduction \tin \tthese \tcells \t\u2013 \ta \tclinical \t\u2018cure\u2019. \t(Data \tredrawn \tfrom \tOtt \tet \tal., \t2006.)\nSafety issues for gene therapy\n\u2022\tThere\tare \tthose \tsafety \tconcerns \tthat \tare \tspecific \tto \t\nany\tparticular \ttherapy \t(e.g. \tpolycythaemia \tfrom \t\noverexpression \tof \terythropoietin )\tand\talso \tadditional \t\ngeneral\tconcerns \trelating, \tfor \texample, \tto \tthe \tnature \tof \t\nthe\tvectors \tused.\n\u2022\tViral\tvectors:\n\u2013\tmight\tacquire \tvirulence \tduring \tuse\n\u2013\tcontain\tviral \tproteins, \twhich \tmay \tbe \timmunogenic\n\u2013\tcan\telicit \tan \tinflammatory \tresponse\n\u2013\tcould\tdamage \tthe \thost \tgenome \tand \tinterfere \twith \t\nthe\tcell\tcycle, \tprovoking \tmalignancy.\n\u2022\tThe\tlimited \tclinical \texperience \tto \tdate \thas \tnot \tso \tfar \t\nprovided\tevidence \tof \tinsurmountable \tproblems.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3206, "end_char_idx": 5077, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "da3a9b5e-f56b-4e04-8b43-ce3cc7064725": {"__data__": {"id_": "da3a9b5e-f56b-4e04-8b43-ce3cc7064725", "embedding": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d297ec2d-4538-404c-96f1-606872d0d47b", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "954970a9a3955853d34a81b7204f045f21126126c03108bf1d3e1b247279eb74"}, "3": {"node_id": "7694f525-45e1-4751-9afc-f2c6ac2abfd1", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39f018b53966c60a3623778b65c8ad306c3eff4f736a55aa9a1cc1b7890873b9"}}, "hash": "21352836d88a0276d247ad9641c78d18903e59d6a09c07a50197221929b1dc91", "text": "5 SECTION 1 \u2003\u2003GENERAL PRINCIPLES\n80gene itself. And how do you assess the dose of a \u2018drug\u2019 that \nis self-replicating? Having said that, we make no apologies \nfor including gene therapy in this section. There is little \ndoubt that it will become a major therapeutic modality in \nthe future and that physicians and pharmacologists alike \nwill be called on to assess and comment on the biological \neffects produced.of this book in that \u2018administration to a living organism \nproduces a biological effect\u2019, but it does not seem sensible \nto discuss the pharmacology of gene therapy as such and \nmost would consider it beyond the scope of the subject. A \ngene has no inherent pharmacodynamic or pharmacoki -\nnetic properties, most of the toxicity and adverse effects \nmentioned here are due to the vector or carrier and not the \nREFERENCES AND FURTHER READING\nGeneral reviews on biopharmaceuticals, gene therapy \nand utilities\nAgoram, B.M., 2009. Use of pharmacokinetic/ pharmacodynamic \nmodelling for starting dose selection in first-in-human trials of \nhigh-risk biologics. Br. J. Clin. Pharmacol. 67, 153\u2013160. ( Interesting \nreview of the PK problems of biopharmaceuticals )\nBender, E., 2016. Gene therapy: Industrial strength. Nature 537, S57\u2013S59. \n(Short commentary on recent progress )\nBrink, M.F., Bishop, M.D., Pieper, F.R., 2000. Developing efficient \nstrategies for the generation of transgenic cattle which produce \nbiopharmaceuticals in milk. Theriogenology 53, 139\u2013148. ( A bit \nspecialised, as it focuses mainly on the husbandry of transgenic cattle, but \ninteresting nonetheless )\nCastanatto, D., Rossi, J.J., 2009. The promises and pitfalls of RNA-\ninterference-based therapeutics. Nature 457, 426\u2013433. ( Useful review of \nthe mechanism, current status and potential applications of RNAi as a \nmeans of controlling gene expression )\nGuttmacher, A.E., Collins, F.S., 2002. Genomic medicine: a primer. N. \nEngl. J. Med. 347, 1512\u20131520. ( First in a series on genomic medicine )\nKwon, K.C., Verma, D., Singh, N.D., Herzog, R., Daniell, H., 2013. Oral \ndelivery of human biopharmaceuticals, autoantigens and vaccine \nantigens bioencapsulated in plant cells. Adv. Drug Deliv. Rev. 65, \n782\u2013799. ( The title is self-explanatory )\nLiu, M.A., 2011. DNA vaccines: an historical perspective and view to \nthe future. Immunol. Rev. 239, 62\u201384.\nMelnik, S., Stoger, E., 2013. Green factories for biopharmaceuticals. \nCurr. Med. Chem. 20, 1038\u20131046. ( Another paper on the use of plants to \nproduce biologics )\nRader, R.A., 2008. (Re)defining biopharmaceutical. Nat. Biotechnol. 26, \n743\u2013751. ( Short commentary dealing with the vexed problem of defining \nwhat biopharmaceuticals are )\nRegolado, A., 2016. The world\u2019s most expensive medicine is a bust. MIT \nTechnology Review. May issue.\nRevers, L., Furczon, E., 2010. An introduction to biologics and \nbiosimilars. Part II: Subsequent entry biologics: biosame or \nbiodifferent? Can. Pharm. J. 143, 184\u2013191. ( Useful review on regulatory \nissues surrounding the introduction of follow-on biopharmaceuticals )\nTani, K., 2016. Current status of ex vivo gene therapy for hematological \ndisorders: a review of clinical trials in Japan around the world. Int.", "start_char_idx": 0, "end_char_idx": 3199, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7694f525-45e1-4751-9afc-f2c6ac2abfd1": {"__data__": {"id_": "7694f525-45e1-4751-9afc-f2c6ac2abfd1", "embedding": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d297ec2d-4538-404c-96f1-606872d0d47b", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "954970a9a3955853d34a81b7204f045f21126126c03108bf1d3e1b247279eb74"}, "2": {"node_id": "da3a9b5e-f56b-4e04-8b43-ce3cc7064725", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "21352836d88a0276d247ad9641c78d18903e59d6a09c07a50197221929b1dc91"}, "3": {"node_id": "6db0efd6-ca6b-410f-a658-a94572f9b686", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "66c2351995d02416f37b8909fd084fb450519db983f90c7dc0cd59afcc0d2429"}}, "hash": "39f018b53966c60a3623778b65c8ad306c3eff4f736a55aa9a1cc1b7890873b9", "text": "hematological \ndisorders: a review of clinical trials in Japan around the world. Int. J. \nHematol. 104, 42\u201372.\nVerma, I.M., Somia, N., 1997. Gene therapy \u2013 promises, problems and \nprospects. Nature 389, 239\u2013242. ( The authors, from the Salk Institute, \ndescribe the principle of inserting corrective genetic material into cells to \nalleviate disease, the practical obstacles to this and the hopes that better \ndelivery systems will overcome them )\nWalsh, G., 2004. Second-generation biopharmaceuticals. Eur. J. Pharm. \nBiopharm. 58, 185\u2013196. ( Excellent overview of therapeutic proteins and \nantibodies; some good tables and figures )\nWirth, T., Parker, N., Yla-Herttuala, S., 2013. History of gene therapy. \nGene 525, 162\u2013169. ( An excellent review of the area from its very \nbeginnings. Highly recommended )\nXu, H., Li, Z., Si, J., 2014. Nanocarriers in gene therapy: a review. J. \nBiomed. Nanotechnol. 10, 3483\u20133507.\nZhao, L., Ren, T.H., Wang, D.D., 2012. Clinical pharmacology \nconsiderations in biologics development. Acta Pharmacol. Sin. 33, \n1339\u20131347. ( Review article stressing the differences between conventional \ndrugs and biopharmaceuticals. Good place to start reading )\nProblems\nCheck, E., 2002. A tragic setback. Nature 420, 116\u2013118. ( News feature \ndescribing efforts to explain the mechanism underlying a leukaemia-like \nillness in a child previously cured of SCID by gene therapy )Freire, J.E., Medeiros, S.C., Lopes Neto, A.V., et al., 2014. Bioethical \nconflicts of gene therapy: a brief critical review. Rev. Assoc. Med. \nBras. (1992) 60, 520\u2013524. ( The title is self-explanatory. Easy to read )\nKim, N., Duncan, G.A., Hanes, J., Suk, J.S., 2016. Barriers to inhaled \ngene therapy of obstructive lung diseases: A review. J. Control. \nRelease 240, 465\u2013488. ( Describes the rather disappointing results obtained \nin the cystic fibrosis trials. See also Pickett et al., 2013 below )\nHammer, A., Steiner, S., 2013. Gene therapy for therapeutic \nangiogenesis in peripheral arterial disease - a systematic review and \nmeta-analysis of randomized, controlled trials. Vasa 42, 331\u2013339.\nMarshall, E., 1999. Gene therapy death prompts review of adenovirus \nvector. Science 286, 2244\u20132245. ( Deals with the tragic \u2018Gelsinger affair\u2019 )\nMuller, P.Y., Brennan, F.R., 2009. Safety assessment and dose selection \nfor first-in-human clinical trials with immunomodulatory monoclonal \nantibodies. Clin. Pharmacol. Ther. 85, 247\u2013258. ( A sober and, at times, \nrather technical assessment of the safety procedures required for the \n\u2018first-in-man\u2019 testing of therapeutic monoclonals. Written in the wake of the \nTGN 1412 affair )\nRichter, W.F., Gallati, H., Schiller, C.D., 1999. Animal pharmacokinetics \nof the tumor necrosis factor receptor-immunoglobulin fusion protein \nlenercept and their extrapolation to humans. Drug Metab. Dispos. 27, \n21\u201325.\nStobbart, L., Murtagh, M.J., Rapley, T., et al., 2007. We saw human \nguinea pigs explode. BMJ 334, 566\u2013567. ( Analysis of the, often grotesque, \npress coverage of the above clinical trial", "start_char_idx": 3127, "end_char_idx": 6165, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6db0efd6-ca6b-410f-a658-a94572f9b686": {"__data__": {"id_": "6db0efd6-ca6b-410f-a658-a94572f9b686", "embedding": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d297ec2d-4538-404c-96f1-606872d0d47b", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "954970a9a3955853d34a81b7204f045f21126126c03108bf1d3e1b247279eb74"}, "2": {"node_id": "7694f525-45e1-4751-9afc-f2c6ac2abfd1", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39f018b53966c60a3623778b65c8ad306c3eff4f736a55aa9a1cc1b7890873b9"}, "3": {"node_id": "8e903659-1ebe-4383-b213-3480babebe5c", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "65bf42f0c5fafc28ce1a2ed05b4b45c9e4988c103e43c31957c57d9ea66894ee"}}, "hash": "66c2351995d02416f37b8909fd084fb450519db983f90c7dc0cd59afcc0d2429", "text": "( Analysis of the, often grotesque, \npress coverage of the above clinical trial )\nWoods, N.B., Bottero, V., Schmidt, M., von Kalle, C., Verma, I.M., 2006. \nGene therapy: therapeutic gene causing lymphoma. Nature 440, 1123.\nWilliams, D.A., Thrasher, A.J., 2014. Concise review: lessons learned \nfrom clinical trials of gene therapy in monogenic immunodeficiency \ndiseases. Stem Cells Transl. Med. 3, 636\u2013642.\nTherapeutic uses\nBarar, J., Omidi, Y., 2012. Translational approaches towards cancer gene \ntherapy: hurdles and hopes. Bioimpacts 2, 127\u2013143.\nBorras, T., 2017. The pathway from genes to gene therapy in glaucoma: \na review of possibilities for using genes as glaucoma drugs. Asia Pac. \nJ. Ophthalmol. (Phila.) 6, 80\u201393.\nBoye, S.E., Boye, S.L., Lewin, A.S., Hauswirth, W.W., 2013. A \ncomprehensive review of retinal gene therapy. Mol. Ther. 21, 509\u2013519.\nBradshaw, A.C., Baker, A.H., 2013. Gene therapy for cardiovascular \ndisease: perspectives and potential. Vasc. Pharm. 58, 174\u2013181.\nChandiwal, A., Balasubramanian, V., Baldwin, Z.K., Conte, M.S., \nSchwartz, L.B., 2005. Gene therapy for the extension of vein graft \npatency: a review. Vasc. Endovasc. Surg. 39, 1\u201314.\nChung, J., DiGiusto, D.L., Rossi, J.J., 2013. Combinatorial RNA-based \ngene therapy for the treatment of HIV/AIDS. Expert Opin. Biol. Ther. \n13 (3), 437\u2013445. ( Review on prophylactic gene therapy approaches for HIV )\nGee, P., Xu, H., Hotta, A., 2017. Cellular reprogramming, genome \nediting, and alternative CRISPR Cas9 technologies for precise gene \ntherapy of Duchenne muscular dystrophy. Stem Cells Int. 2017, \n8765154. ( A rather technical paper but gives a good idea of the power of the \ntechnique )\nGeary, R.S., Baker, B.F., Crooke, S.T., 2015. Clinical and preclinical \npharmacokinetics and pharmacodynamics of mipomersen \n(KynamroR): a second-generation antisense oligonucleotide inhibitor \nof apolipoprotein B. Clin. Pharmacokinet. 54, 133\u2013146.\nGhosh, R., Walsh, S.R., Tang, T.Y., Noorani, A., Hayes, P.D., 2008. Gene \ntherapy as a novel therapeutic option in the treatment of peripheral \nvascular disease: systematic review and meta-analysis. Int. J. Clin. \nPract. 62, 1383\u20131390.\nGori, J.L., Hsu, P.D., Maeder, M.L., Shen, S., Welstead, G.G., Bumcrot, \nD., 2015. Delivery and specificity of CRISPR-Cas9 genome editing mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6172, "end_char_idx": 8938, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e903659-1ebe-4383-b213-3480babebe5c": {"__data__": {"id_": "8e903659-1ebe-4383-b213-3480babebe5c", "embedding": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d297ec2d-4538-404c-96f1-606872d0d47b", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "954970a9a3955853d34a81b7204f045f21126126c03108bf1d3e1b247279eb74"}, "2": {"node_id": "6db0efd6-ca6b-410f-a658-a94572f9b686", "node_type": null, "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "66c2351995d02416f37b8909fd084fb450519db983f90c7dc0cd59afcc0d2429"}}, "hash": "65bf42f0c5fafc28ce1a2ed05b4b45c9e4988c103e43c31957c57d9ea66894ee", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 8958, "end_char_idx": 9021, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f5bf7544-62a2-448d-9760-64f4d5152a05": {"__data__": {"id_": "f5bf7544-62a2-448d-9760-64f4d5152a05", "embedding": null, "metadata": {"page_label": "87", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5ee4cec0-21cb-469f-85bd-0eee0c52b017", "node_type": null, "metadata": {"page_label": "87", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a77c8a3425cba8b57d23212584af302ef6fbc246e6157fbd7d3f207682ed3332"}}, "hash": "a77c8a3425cba8b57d23212584af302ef6fbc246e6157fbd7d3f207682ed3332", "text": "5 How dRuGS ACt: bIoPHARmACEutICALS ANd GENE tHERAPy\n81by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat. \nMed. 12, 401\u2013409. ( Clinical trial of gene therapy to correct hereditary \nneutrophil dysfunction )\nRai, P., Malik, P., 2016. Gene therapy for hemoglobin disorders - a \nmini-review. J. Rare Dis. Res. Treat. 1, 25\u201331.\nPrickett, M., Jain, M., 2013. Gene therapy in cystic fibrosis. Transl. Res. \n161, 255\u2013264. ( Cystic fibrosis was one of the first monogenic disorders \nidentified as a candidate for gene therapy. This review explains how and why \nthings haven\u2019t quite worked out the way it was hoped. See also Kim et al., \n2016, above )\nWolf, J.K., Jenkins, A.D., 2002. Gene therapy for ovarian cancer \n(review). Int. J. Oncol. 21, 461\u2013468. ( Excellent review and broad \nintroduction to gene therapy in general )technologies for human gene therapy. Hum. Gene Ther. 26, \n443\u2013451.\nHammond, H.K., McKirnan, M.D., 2001. Angiogenic gene therapy for \nheart disease: a review of animal studies and clinical trials. \nCardiovasc. Res. 49, 561\u2013567. ( Comprehensive review spanning animal \nand human trials of gene therapy for myocardial ischaemia )\nMaguire, A.M., High, K.A., Auricchio, A., et al., 2009. Age-dependent \neffects of RPE65 gene therapy for Leber\u2019s congenital amaurosis: a \nphase 1 dose-escalation trial. Lancet 374, 1597\u20131605.\nNathwani, A.C., Davidoff, A.M., Linch, D.C., 2005. A review of gene \ntherapy for haematological disorders. Br. J. Haematol. 128, 3\u201317. ( The \ntitle is self-explanantory; easy to read and comprehensive in scope )\nOtt, M.G., Schmidt, M., Schwarzwaelder, K., et al., 2006. Correction of \nX-linked chronic granulomatous disease by gene therapy, augmented mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2179, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "394e5e7b-0379-432e-906d-653e37a19629": {"__data__": {"id_": "394e5e7b-0379-432e-906d-653e37a19629", "embedding": null, "metadata": {"page_label": "88", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d4adfd5d-0b7e-4e02-8aa2-661e574d4604", "node_type": null, "metadata": {"page_label": "88", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "49680ae71dc24f3db570b67abaec49930e61cec0454f684e097d5b2675f495d7"}, "3": {"node_id": "8e335c04-0570-4fce-8c29-3a3329f355fd", "node_type": null, "metadata": {"page_label": "88", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c5d1d413af6c9f88542eea3e339b6c1345b8aa53251e7ce97e7ece89de9f2fa"}}, "hash": "0f3a6702153ab401eab1f8709e63226563fecf86d2887403d4f7da96782ed757", "text": "82\nCell proliferation, apoptosis, \nrepair and regeneration6 GENERAL PRINCIPLES SECTION 1\nOVERVIEW\nAbout 10 billion new cells are created daily in US \nthrough cell division and this must be counterbalanced \nby the elimination of a similar number from the body \nin an ordered manner. This chapter explains how this homeostasis is managed. We deal with the life \nand death of the cell \u2013 the processes of replication, \nproliferation, apoptosis, repair and regeneration and how these relate to the actions of drugs. We begin \nwith cell replication. We explain how stimulation by \ngrowth factors causes cells to divide and then consider the interaction of these cells with the extracellular \nmatrix (ECM) which regulates further cell proliferation. \nWe describe the crucial phenomenon of apoptosis (the programmed series of events that lead to cell \ndeath), outlining the changes that occur in a cell that \nis preparing to die and the intracellular pathways that culminate in its demise. We explain how these \nprocesses relate to the repair of damaged tissue, to \nthe possibility of its regeneration and whether there is scope for modulating this with novel drugs.\nCELL PROLIFERATION\nCell proliferation is, of course, a fundamental biological \nevent. It is integral to many physiological and pathological \nprocesses including growth, healing, repair, hypertrophy, \nhyperplasia and the development of tumours. Because cells need oxygen and nutrients to survive, angiogenesis (the \ndevelopment of new blood vessels) necessarily accompanies many of these processes.\nProliferating cells go through what is termed the cell cycle , \nduring which they replicate all their components and then divide into two identical daughter cells.\n1 The process is \ntightly regulated by signalling pathways, including receptor \ntyrosine kinases or receptor-linked kinases and the mitogen-\nactivated protein kinase (MAP kinase) cascade (see Ch. 3). In all cases, the pathways eventually lead to transcription \nof the genes that control the cell cycle.\nTHE CELL CYCLE\nIn the adult, few cells divide repeatedly and most remain \nin a quiescent phase outside the cycle in the phase termed \nG0 (Fig. 6.1). Some cells such as neurons and skeletal muscle \ncells spend all their lifetime in G 0 whereas others being \nmore stem cell\u2013like in phenotype, including bone marrow cells and the epithelium of the gastrointestinal tract, divide \ndaily.\nThe cell cycle is an ordered sequential series of phases \n(see Fig. 6.1). These are known as S (Synthesis), M (Mitosis) and G (Gap between S or M phases), and they always occur \nin this order:\n\u2022\tG\n1: (Gap1) preparation for DNA synthesis\n\u2022\tS:\t(Synthesis) \tDNA \tsynthesis \tand \tchromosome \t\nduplication of the parental cell\n\u2022\tG 2: (Gap2) preparation for division\n\u2022\tM:\t(Mitosis) \tdivision \tinto \ttwo \tidentical \tdaughter \tcells.\nIn cells that are dividing continuously, G 1, S and G 2 comprise \ninterphase \u2013 the phase between one mitosis and the next.\nCell division requires the controlled timing of the critical \nS phase and M phases. Entry into each of these phases is \ntightly regulated at check points (restriction points) at the \nstart of the S and M phases. Any DNA damage stops the cycle at one or other of these check points to allow repair and thus maintain the integrity of our DNA sequence in \neach cell. This process is critical for the maintenance of \ngenetic stability. Failure of the check points to stop the cycle when it is appropriate to do so leads to genetic instability, which is a hallmark of cancer.\n2\nQuiescent (G 0) cells enter G 1 after exposure to chemical \nmediators, some of which are associated with damage. For \nexample, a wound can stimulate a quiescent skin cell to \ndivide, thus repairing the", "start_char_idx": 0, "end_char_idx": 3731, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e335c04-0570-4fce-8c29-3a3329f355fd": {"__data__": {"id_": "8e335c04-0570-4fce-8c29-3a3329f355fd", "embedding": null, "metadata": {"page_label": "88", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d4adfd5d-0b7e-4e02-8aa2-661e574d4604", "node_type": null, "metadata": {"page_label": "88", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "49680ae71dc24f3db570b67abaec49930e61cec0454f684e097d5b2675f495d7"}, "2": {"node_id": "394e5e7b-0379-432e-906d-653e37a19629", "node_type": null, "metadata": {"page_label": "88", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f3a6702153ab401eab1f8709e63226563fecf86d2887403d4f7da96782ed757"}}, "hash": "4c5d1d413af6c9f88542eea3e339b6c1345b8aa53251e7ce97e7ece89de9f2fa", "text": "wound can stimulate a quiescent skin cell to \ndivide, thus repairing the lesion. The impetus for a cell to enter the cycle (i.e. to move from G\n0 into G 1) may be growth \nfactors acting on growth factor receptors, though the action \nof other types of ligands on G protein\u2013coupled receptors \n(see Ch. 3) can also initiate the process.\nGrowth factors stimulate the synthesis of both positive \nregulators of the cell cycle that control the changes necessary for cell division and negative regulators that counterbalance the positive regulators. The maintenance of normal cell \nnumbers in tissues and organs requires a balance between \nthe positive and the negative regulatory signals. Apoptosis\n3 \nalso controls cell numbers.\nPOSITIVE REGULATORS OF THE CELL CYCLE\nThe cycle begins when a growth factor acts on a quiescent cell, provoking it to divide. Growth factors stimulate \n1Not strictly identical in the case of stem cells, as one differentiates and \nthe other remains stem.2The main daily job of our immune system is to detect and destroy cells \nwhich have genetic instability, which may become cancerous if missed. \nThis immuno-surveillance gets rid of thousands of incorrectly divided \nor dangerously damaged cells each day. Occasionally, our immune system will encounter a foreign body such as a virus or bacteria, and \nwill then \u2018moonlight\u2019 on that job for a while too.\n3The term is originally a Greek word that describes the falling of leaves \nor petals from plants. Termed in 1972 by Professor James Cormack of Aberdeen University\u2019s Greek Department, the second \u2018p\u2019 is silent \u2013 APE \noh TOE sis. \nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3659, "end_char_idx": 5743, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "665b91f5-954f-4060-9645-adeb2ec558b7": {"__data__": {"id_": "665b91f5-954f-4060-9645-adeb2ec558b7", "embedding": null, "metadata": {"page_label": "89", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "16dfa785-0672-479a-86a6-891c7f7daeff", "node_type": null, "metadata": {"page_label": "89", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdc382eea32d337da4cc27f96db7437972a3f65573b47784f3a95a4f1d8deb22"}, "3": {"node_id": "33a968f1-05fc-4285-b813-0f4254798fcc", "node_type": null, "metadata": {"page_label": "89", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d34aa02a9af4e3225b130904ffc01c49acdd558f05fc9d0a3cf0110f68e70b0"}}, "hash": "6c0cde10943c70330df0f98d8649fa0e0810c8e46e37b97f6680b0fa15d8708b", "text": "6 CELL PR o LI f ERA t I o N , AP o P to SIS , REPAIR AN d REGENERA t I o N\n83The activity of these cyclin/cdk complexes is negatively \nmodulated at one or other of the two check points. In \nquiescent G 0 cells, cyclin D is present in low concentration, \nand an important regulatory protein \u2013 the Rb protein5 is \nhypophosphorylated. This restrains the cell cycle at check point 1 by inhibiting the expression of several proteins \ncritical for further cycle progression. The Rb protein accom -\nplishes this restraint by binding to transcription factors and \npreventing them from promoting expression of the genes \nthat code for proteins needed for DNA replication during S phase (such as cyclins E and A, DNA polymerase, thymidine \nkinase and dihydrofolate reductase). This configuration is \nmaintained until a cell is instructed to divide.\n\u2022\tGrowth \tfactor \taction \ton \ta \tcell \tin \tG0 propels it into G 1, \nwhich prepares the cell for S phase. The concentration \nof cyclin D increases and the cyclin D/cdk complex \nphosphorylates and activates the proteins required for DNA replication.\n\u2022\tIn\tmid-G 1, the cyclin D/cdk complex phosphorylates \nthe Rb protein, releasing a transcription factor that \nactivates the genes for the components essential for \nthe next phase \u2013 DNA synthesis. The action of the cyclin E/cdk complex is necessary for transition from \nG\n1, past check point 1, into S phase.\n\u2022\tOnce\tinto \tS \tphase, \tthe \tprocesses \tthat \thave \tbeen \tset \tin \t\nmotion cannot be reversed and the cell is committed \nto DNA replication and mitosis. Cyclin E/cdk and \ncyclin A/cdk regulate progress through S phase, \nphosphorylating and thus activating the proteins/enzymes involved in DNA synthesis.\n\u2022\tIn\tG2 phase, the cell, which now has double the \nnumber of chromosomes, produces the messenger \nRNAs and proteins needed to duplicate all other \ncellular components for allocation to the two daughter cells.\n\u2022\tCyclin \tA/cdk \tand \tcyclin \tB/cdk \tcomplexes \tare \tactive \t\nduring G 2 phase and are necessary for entry into M \nphase, i.e. for passing check point 2. The presence of \ncyclin B/cdk complexes in the nucleus is required for \nmitosis to commence.\nMitosis occurs in four stages:\n\u2022\tProphase. The duplicated chromosomes (which are at \nthis point a tangled mass in the nucleus) condense, \neach now consisting of two daughter chromatids (the \noriginal chromosome and an identical copy). These are released into the cytoplasm as the nuclear membrane disintegrates.\n\u2022\tMetaphase. The chromosomes are aligned at the equator of the cell (see Fig. 6.3).\n\u2022\tAnaphase. A specialised cytoskeletal device, the mitotic \napparatus, captures the chromosomes and draws them to opposite poles of the dividing cell (see Fig. 6.3).\n\u2022\tTelophase. A nuclear membrane forms round each set \nof chromosomes. Finally, the cytoplasm divides \nbetween the two forming daughter cells. The last step in mitosis is cytokinesis, where the plasma membrane \nbetween each daughter cell is pinched-off and split.\n6 production of two families of proteins, namely cyclins and \nserine/threonine protein kinases called cyclin-dependent \nkinases (cdks), coded for by the delayed response genes. The \ncdks sequentially phosphorylate various enzymes \u2013 activat -\ning some and inhibiting others \u2013 to coordinate the progres -\nsion of the cell through the cycle.\nEach cdk is inactive and must bind to a cyclin partner, \nbefore it can", "start_char_idx": 0, "end_char_idx": 3392, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "33a968f1-05fc-4285-b813-0f4254798fcc": {"__data__": {"id_": "33a968f1-05fc-4285-b813-0f4254798fcc", "embedding": null, "metadata": {"page_label": "89", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "16dfa785-0672-479a-86a6-891c7f7daeff", "node_type": null, "metadata": {"page_label": "89", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdc382eea32d337da4cc27f96db7437972a3f65573b47784f3a95a4f1d8deb22"}, "2": {"node_id": "665b91f5-954f-4060-9645-adeb2ec558b7", "node_type": null, "metadata": {"page_label": "89", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c0cde10943c70330df0f98d8649fa0e0810c8e46e37b97f6680b0fa15d8708b"}}, "hash": "5d34aa02a9af4e3225b130904ffc01c49acdd558f05fc9d0a3cf0110f68e70b0", "text": "cdk is inactive and must bind to a cyclin partner, \nbefore it can phosphorylate its target protein(s). After the phosphorylation event the cyclin is degraded (Fig. 6.2) by \nthe ubiquitin/protease system . Here, several enzymes sequen -\ntially add small molecules of ubiquitin to the cyclin. The \nresulting ubiquitin polymer acts as an \u2018address label\u2019 that \ndirects the cyclin to the proteasome where it is degraded.\nThere are eight main groups of cyclins. According to the \n\u2018classical model\u2019 of the cell cycle (see Satyanarayana & \nKaldis, 2009), those of principal importance in the control of the cycle are cyclins A, B, D and E. Each cyclin is associ -\nated with, and activates, a particular cdk. Cyclin A activates cdks 1 and 2; cyclin B, cdk 1; cyclin D, cdks 4 and 6; and cyclin E, cdk 2. Precise timing of each step is essential and \nmany cycle proteins are degraded after they have carried \nout their functions.\n4\n The actions of the cyclin/cdk complexes throughout the \ncell cycle are depicted in Fig. 6.3.G2\nM\nG0\nG1S\nCheck point 1Check point 2\nFig. 6.1 The main phases of the cell cycle of dividing \ncells. \nCyclin\nADPcdk cdk cdk Cyclin\nSubstrate\nSubstratePATPA B C\nFig. 6.2 Schematic representation of the activation of a \ncyclin-dependent kinase (cdk). (A) An inactive cdk. (B) The \ninactive cdk binds to a cyclin and is activated; it can now phosphorylate a specific protein substrate (e.g. an enzyme). \n(C) After the phosphorylating event, the cyclin is degraded. \n4This sequencing ensures that cells cycle in one direction only, i.e. \nthere\u2019s no point dividing before you made two identical copies of your \nchromosome set. That would be asking for trouble, and disease.5So named because mutations of the Rb gene are associated with \nretinoblastoma tumours.\n6IPMATC \u2013 the whole cell cycle processes and order are summed up in \nthis acronym for Interphase, Prophase, Metaphase, Anaphase, Telophase and Cytokinesis.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3327, "end_char_idx": 5736, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c8fdbccc-951b-4ec9-8d7e-e2ad63f1d7c5": {"__data__": {"id_": "c8fdbccc-951b-4ec9-8d7e-e2ad63f1d7c5", "embedding": null, "metadata": {"page_label": "90", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d261d037-7e9b-49a5-9063-4f252be69392", "node_type": null, "metadata": {"page_label": "90", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f679b348d8c184dad5811ec3155d870c83ed54d4b3f6e7c791fe8b6285da9a91"}, "3": {"node_id": "26a399e1-a739-43e7-a787-b9c338334543", "node_type": null, "metadata": {"page_label": "90", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69630df97977415322bcfc49b28aea1f926401728a9b4923dad144cb0c672846"}}, "hash": "5bdcbf84bebada9499f0f8ea6874c78641961482f48ce4f5c4b05b5e4d93e5a4", "text": "6 SECTION 1 GENERAL PRINCIPLES\n84following DNA damage, the protein accumulates and \nactivates the transcription of several genes, one of which \ncodes for p21. Protein p21 inactivates cyclin/cdk complexes, \nthus Rb phosphorylation is prevented, and it becomes hypophosphorylated (below normal phosphorylation levels). \nThis causes arrest of the cycle at check point 1, allowing \nDNA repair to take place. If the repair is successful, the cycle proceeds past check point 1 into S phase. If the repair \nis unsuccessful, the p53 gene triggers apoptosis or cell \nsuicide.\n7\nInhibition of the cycle at check point 2\nDNA damage can arrest the cycle at check point 2, but \nthe mechanisms involved are poorly understood. Inhibi -\ntion of the accumulation of cyclin B/cdk complex in the nucleus seems to be a factor. For more detail on the control of the cell cycle, see section on microRNAs (p. 88) and \nSwanton (2004).Each daughter cell will be in G\n0 phase and will remain \nthere unless stimulated into G 1 phase once more, as \ndescribed earlier.\nDuring metaphase, the cyclin A and B complexes phos-\nphorylate cytoskeletal proteins, nuclear histones and \npossibly components of the spindle (the microtubules along which the chromatids are pulled during metaphase).\nNEGATIVE REGULATORS OF THE CELL CYCLE\nOne of the main negative regulators is the Rb protein, which restrains the cell cycle while it is hypophosphorylated.\nInhibitors of the cdks also serve as negative regulators, \ntheir main action being at check points. There are two known families of inhibitors: the CIP family (cdk inhibitory proteins, \nalso termed KIP or kinase inhibitory proteins) \u2013 proteins p21, p27 and p57; and the Ink family (inhibitors of kinases) \n\u2013 proteins p16, p19 and p15.\nProtein p21 is a good example of the role of a cyclin/\ncdk inhibitor. It is under the control of the p53 gene \u2013 a \nparticularly important negative regulator which is relevant in carcinogenesis \u2013 that operates at check point 1.\nInhibition of the cycle at check point 1\nThe p53 gene has been called the \u2018guardian of the genome\u2019. \nIt codes for the p53 protein, a transcription factor found \nin only low concentrations in normal healthy cells. However, Metaphase\nAnaphase\nDaughter cellsG2\nM\nG0\nG1S\nCheck point 1Check point 2\nRb acts as a brake here, keeping the cell in G1 by \ninhibiting the genes necessary for the entry into S phase; \nphosphorylation by the cdks releases the brake. The p53 protein stops the cycle here if there has been DNA damageGrowth factor actionB + cdk 2 \nA + cdks 1 & 2 \nD + cdks 4 & 6 \nE + cdk 2 cdk inhibitors\nCell during G 1Cell during G 2\nFig. 6.3 Schematic diagram of the cell cycle, showing the role of the cyclin/cyclin-dependent kinase (cdk) complexes. The \nprocesses outlined in the cycle occur inside a cell such as the one shown in Fig. 6.4. A quiescent cell (in G 0 phase), when stimulated to \ndivide by growth factors, is propelled into G 1 phase and prepares for DNA synthesis. Progress through the cycle is determined by \nsequential action of the cyclin/cdk complexes \u2013 depicted here by coloured arrows , the arrows being given the names of the relevant \ncyclins: D, E, A and B. The cdks are given next to the relevant cyclins. The thickness of each arrow represents the intensity of the cdk \naction at that point in the cycle. The activity of the cdks is regulated by cdk inhibitors. If there is DNA damage, the products of the tumour suppressor gene p53 arrest the cycle at check", "start_char_idx": 0, "end_char_idx": 3474, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "26a399e1-a739-43e7-a787-b9c338334543": {"__data__": {"id_": "26a399e1-a739-43e7-a787-b9c338334543", "embedding": null, "metadata": {"page_label": "90", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d261d037-7e9b-49a5-9063-4f252be69392", "node_type": null, "metadata": {"page_label": "90", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f679b348d8c184dad5811ec3155d870c83ed54d4b3f6e7c791fe8b6285da9a91"}, "2": {"node_id": "c8fdbccc-951b-4ec9-8d7e-e2ad63f1d7c5", "node_type": null, "metadata": {"page_label": "90", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5bdcbf84bebada9499f0f8ea6874c78641961482f48ce4f5c4b05b5e4d93e5a4"}}, "hash": "69630df97977415322bcfc49b28aea1f926401728a9b4923dad144cb0c672846", "text": "the products of the tumour suppressor gene p53 arrest the cycle at check point 1, allowing for repair. If repair fails, apoptosis (see Fig. 6.5) is initiated. The state of the \nchromosomes is shown schematically in each G phase \u2013 as a single pair in G\n1, and each duplicated and forming two daughter chromatids \nin G 2. Some changes that occur during mitosis (metaphase, anaphase) are shown in a subsidiary circle. After the mitotic division, the \ndaughter cells may enter G 1 or G 0 phase. Rb, retinoblastoma gene. \n7Thus p53 is the guardian of the genome by preventing any \nunrepairable errors or genomic instability that occur in a cell from \npassing on to daughter cells. Another healthy cell will have to step in \nand replace the p53-destroyed cell. It is better for an organism to kill off less than perfect cells than to have any error whatsoever kept for future \ngenerations \u2013 \u2018the needs of the many outweigh the needs of the few\u2019 as \nSpock would say.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3402, "end_char_idx": 4840, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cbfd69db-9482-4d09-a11c-73769cfd00f4": {"__data__": {"id_": "cbfd69db-9482-4d09-a11c-73769cfd00f4", "embedding": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "53d9a10f-24c1-47b3-ace5-020773733807", "node_type": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a48f98f8e23f58cff21e8bd1e808bcf6a27e87fdccc955c5c4a60058504cd326"}, "3": {"node_id": "2b34b785-a141-4655-a90d-7eab6e8e8f74", "node_type": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef8b8c3c021f65e682fcad6aadc859ce641d4d1fda661b81f93aec7f31c1f097"}}, "hash": "67eeb27405a8158c363a81364b9095d04e6941d8d7c573061d2944f8c7998d33", "text": "6 CELL PR o LI f ERA t I o N , AP o P to SIS , REPAIR AN d REGENERA t I o N\n85to the matrix. Adhesive proteins link the various \nelements of the matrix together and also form links \nbetween the cells and the matrix through cell surface \nintegrins.\nOther proteins in the ECM are thrombospondin and osteo-\npontin, which are not structural elements but modulate cell\u2013matrix interactions and repair processes. The production \nof the ECM components is regulated by growth factors, \nparticularly TGF-\u03b2.\n\u25bc The ECM is a target for drug action. Both beneficial and adverse \neffects have been reported. Thus glucocorticoids decrease collagen \nsynthesis in chronic inflammation and cyclo-oxygenase (COX)-2 \ninhibitors can modify fibrotic processes through a proposed action \non TGF-\u03b2. Statins can decrease fibrosis by inhibiting angiotensin-\ninduced connective tissue growth factor production (Rup\u00e9rez et al., \n2007) and reducing MMP expression. This may contribute to their \neffects in cardiovascular diseases (Tousoulis et al., 2010). The adverse \nactions of some drugs attributable to an effect on the ECM include the osteoporosis and skin thinning caused by glucocorticoids (discussed \nin J\u00e4rvel\u00e4inen et al., 2009). The ECM is also an important target in \nthe search for new drugs that regulate tissue repair.\nTHE ROLE OF INTEGRINS\n\u25bc Integrins are transmembrane kinase-linked receptors (see Ch. 3) \ncomprising \u03b1 and \u03b2 subunits. Interaction with the ECM elements \n(e.g. fibronectin) triggers various cell responses, such as cytoskeletal \nrearrangement (not considered here) and co-regulation of growth \nfactor function.\nIntracellular signalling by both growth factor receptors and integrins \nis important for optimal cell proliferation (Fig. 6.4). Following integrin stimulation an adapter protein and an enzyme (focal adhesion kinase), \nactivate the kinase cascade that comprises the growth factor signalling \npathway. There is extensive cross-talk between the integrin and growth factor pathways (Streuli & Akhtar, 2009). Autophosphorylation of \ngrowth factor receptors (Ch. 3) is enhanced by integrin activation \nand integrin-mediated adhesion to the ECM (see Fig. 6.4) not only suppresses the concentrations of cdk inhibitors, but is required for \nthe expression of cyclins A and D, and therefore for the progression \nof the cell cycle. Furthermore, integrin activation inhibits apoptosis (see later), further facilitating growth factor action (see reviews by \nGahmberg et al., 2009 and Barczyk et al., 2010).\nSeveral monoclonal antibodies are targeted at integrins, \nincluding natalizumab , used to treat multiple sclerosis and \nabciximab, an antithrombotic (Ch. 25).\nTHE ROLE OF MATRIX METALLOPROTEINASES\n\u25bc Degradation of the ECM by metalloproteinases is necessary for \ntissue growth, repair and remodelling. When growth factors stimulate a cell to enter the cell cycle, they also stimulate the secretion of metal -\nloproteinases (as inactive precursors), which then sculpt the matrix, producing the local changes necessary to accommodate the increased cell numbers. Metalloproteinases in turn release growth factors from \nthe ECM and, in some cases (e.g. interleukin [IL]-1 \u03b2), process them \nfrom precursor to their active form. The action of these enzymes is \nregulated by tissue inhibitors of metalloproteinases (TIMPS), which \nare also secreted by local cells.\nIn addition to their physiological function, metalloproteinases are \ninvolved in the tissue destruction that accompanies various diseases, \nsuch as", "start_char_idx": 0, "end_char_idx": 3517, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2b34b785-a141-4655-a90d-7eab6e8e8f74": {"__data__": {"id_": "2b34b785-a141-4655-a90d-7eab6e8e8f74", "embedding": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "53d9a10f-24c1-47b3-ace5-020773733807", "node_type": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a48f98f8e23f58cff21e8bd1e808bcf6a27e87fdccc955c5c4a60058504cd326"}, "2": {"node_id": "cbfd69db-9482-4d09-a11c-73769cfd00f4", "node_type": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67eeb27405a8158c363a81364b9095d04e6941d8d7c573061d2944f8c7998d33"}, "3": {"node_id": "a1c19f9e-d8ba-40b5-b6c7-73212c24b656", "node_type": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a47c969113d424bc61088cc2619fc740691e535bd610b9b36e3fa9776703fe15"}}, "hash": "ef8b8c3c021f65e682fcad6aadc859ce641d4d1fda661b81f93aec7f31c1f097", "text": "\ninvolved in the tissue destruction that accompanies various diseases, \nsuch as rheumatoid arthritis, osteoarthritis, periodontitis, macular degeneration and myocardial restenosis. They also have a critical \nrole in the growth, invasion and metastasis of tumours (Clark et al., \n2008; Marastoni et al., 2008; Jackson et al., 2017). Because of this, much \neffort has gone into developing synthetic MMP inhibitors for treating cancers and inflammatory disorders, although clinical trials so far \nhave shown limited efficacy and significant adverse effects (see Gialeli \net al., 2011). Doxycycline, an antibiotic, also inhibits MMPs, and is \nused experimentally for this purpose.INTERACTIONS BETWEEN CELLS, GROWTH \nFACTORS AND THE EXTRACELLULAR MATRIX\nCell proliferation is regulated by the integrated interplay \nbetween growth factors, cells, the ECM and the matrix \nmetalloproteinases (MMPs). The ECM is secreted by the \ncells and provides a supportive framework. It also pro -\nfoundly influences cell behaviour by signalling through \nthe cell\u2019s integrins (proteins on a cell\u2019s extracellular surface \nthat sense the ECM and signal to the cell what environment it is in or the neighbours it has). Matrix expression by cells \nis regulated by growth factors and cytokines (see Verrecchia \n& Mauviel, 2007; J\u00e4rvel\u00e4inen et al., 2009). The activity of \nsome growth factors is, in turn, determined by the matrix, \nbecause they are sequestered by matrix components and \nreleased by proteinases (e.g. MMPs) secreted by the cells.\nThe action of growth factors acting through receptor \ntyrosine kinases or receptor-coupled kinases (see Ch. 3) is a fundamental part of these processes. Important examples \ninclude fibroblast growth factor (FGF), epidermal growth factor \n(EGF), platelet-dependent growth factor (PDGF), vascular \nendothelial growth factor (VEGF) and transforming growth \nfactor (TGF)-\u03b2.\nThe main components of the ECM are:\n\u2022\tFibre-forming \telements, \te.g. \tcollagen species (the main \nproteins of the matrix) and elastin.\n\u2022\tNon-fibre-forming \telements, \te.g. \tproteoglycans, \t\nglycoproteins and adhesive proteins such as fibronectin. Proteoglycans have a growth-regulating \nrole, in part by functioning as a reservoir of \nsequestered growth factors. Other elements are associated with the cell surface, where they bind cells The cell cycle \n\u2022\tThe\tterm \tcell cycle refers to the sequence of events \nthat take place within a cell as it prepares for division. \nThe quiescent or resting state is called G 0.\n\u2022\tGrowth \tfactor \taction \tstimulates \ta \tcell \tin \tG0 to enter \nthe cycle.\n\u2022\tThe\tphases \tof \tthe \tcell \tcycle \tare:\n\u2013 G1: preparation for DNA synthesis\n\u2013 S: DNA synthesis\n\u2013 G2: preparation for division\n\u2013 M, mitosis: division into two daughter cells\n\u2022\tIn\tG0 phase, a hypophosphorylated protein, coded for \nby the Rb gene, arrests the cycle by inhibiting \nexpression of critical factors necessary for DNA \nreplication.\n\u2022\tProgress \tthrough \tthe \tcycle \tis \tcontrolled \tby \tspecific \t\nkinases (cyclin-dependent kinases; cdks) that are \nactivated by binding to specific proteins termed cyclins.\n\u2022\tFour\tmain \tcyclins \tD, \tE, \tA \tand \tB, \ttogether \twith \ttheir \t\ncdk complexes drive the cycle; cyclin D/cdk also releases the Rb protein-mediated inhibition.There are protein inhibitors of cdks in the cell. Protein \np21 is particularly important; it is", "start_char_idx": 3449, "end_char_idx": 6809, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a1c19f9e-d8ba-40b5-b6c7-73212c24b656": {"__data__": {"id_": "a1c19f9e-d8ba-40b5-b6c7-73212c24b656", "embedding": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "53d9a10f-24c1-47b3-ace5-020773733807", "node_type": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a48f98f8e23f58cff21e8bd1e808bcf6a27e87fdccc955c5c4a60058504cd326"}, "2": {"node_id": "2b34b785-a141-4655-a90d-7eab6e8e8f74", "node_type": null, "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef8b8c3c021f65e682fcad6aadc859ce641d4d1fda661b81f93aec7f31c1f097"}}, "hash": "a47c969113d424bc61088cc2619fc740691e535bd610b9b36e3fa9776703fe15", "text": "of cdks in the cell. Protein \np21 is particularly important; it is expressed when DNA damage triggers transcription of gene p53 and arrests \nthe cycle at check point 1.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6812, "end_char_idx": 7459, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "87c27c3f-8226-457b-a1e0-c82ec89056b5": {"__data__": {"id_": "87c27c3f-8226-457b-a1e0-c82ec89056b5", "embedding": null, "metadata": {"page_label": "92", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eadbe98b-2eb5-4a80-a5e0-93f91acdd6a8", "node_type": null, "metadata": {"page_label": "92", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "63ce2c52f3e9228cd1449d47dd285237f4763083c486a4cb4464efcba333dafa"}, "3": {"node_id": "a466e41a-8c86-4653-9e99-592680d38d81", "node_type": null, "metadata": {"page_label": "92", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d5c254628d7ff079448599820de9c1f3e39796a59450d8d3d34aa3870e23c0f2"}}, "hash": "8e3e5d28f986f69b4125e60791505708499b396d3a53f3e889b13aae9754baa0", "text": "6 SECTION 1 GENERAL PRINCIPLES\n86A monoclonal antibody, bevacizumab, which neutralises \nVEGF, is used as adjunct treatment for various cancers (see \nCh. 57), and following injection into the eye, to treat age-\nrelated macular degeneration, a condition in which retinal blood vessels over-proliferate, causing blindness.\nAPOPTOSIS AND CELL REMOVAL\nApoptosis is cell suicide. It is regulated by a built-in geneti -\ncally programmed self-destruct mechanism consisting of \na specific sequence of biochemical events. It is thus unlike \nnecrosis, which is a wholly disorganised disintegration of a damaged cells that releases substances which trigger the \ninflammatory response.\n8\nApoptosis plays an essential role in embryogenesis, \nshaping organs during development by eliminating cells that have become redundant. It is the mechanism that each \nday unobtrusively removes some 10 billion cells from the human body. It is involved in numerous physiological \nevents, including the shedding of the intestinal lining, the \ndeath of time-expired neutrophils and the turnover of tissues as the newborn infant grows to maturity. It is the basis for \nthe development of self-tolerance in the immune system \n(Ch. 7) and acts as a first-line defence against carcinogenic mutations by purging cells that could become malignant.\nDisorders of apoptosis are also implicated in the patho -\nphysiology of many conditions, including:\n\u2022\tchronic \tneurodegenerative \tdiseases \tsuch \tas \t\nAlzheimer\u2019s and Parkinson\u2019s disease and multiple sclerosis (Ch. 41);\n\u2022\tconditions \twith \tacute \ttissue \tdamage \tor \tcell \tloss, \tsuch \t\nas myocardial infarction (Ch. 22), stroke and spinal cord injury (Ch. 41);\n\u2022\tdepletion \tof \tT \tcells \tin \tHIV \tinfection \t(Ch. \t53);\n\u2022\tosteoarthritis \t(Ch. \t37);\n\u2022\thaematological \tdisease, \tsuch \tas \taplastic \tanaemia \t \n(Ch. 26);FA kinaseGrowth factors\nGrowth factor\nreceptorsPLASMA MEMBRANE\nRas\nGTP\nCytosolic\ntransducers\nNuclear\ntransducers\nCell cycle\ntransducersNUCLEUS\nEarly response genes\nDelayed reponse\ngenes\nPositive regulators ofthe cell cycle: \u2022 cyclins\n \u2022 cyclin-dependent \nkinases (cdks)Negative regulators of the cell cycle: \u2022 p53 protein\n \u2022 Rb protein\n \u2022 cdk inhibitorsCYTOSOLExtracellular\nmatrix\nIntegrins\u03b2\u03b1\nAP AP AP\nKinase 1\nKinase 2\nKinase 3\nFig. 6.4 Simplified diagram of the effect of growth factors \non a cell in G 0. The overall effect of growth factor action is the \ngeneration of the cell cycle transducers. A cell such as the one \ndepicted will then embark on G 1 phase of the cell cycle. Most \ngrowth factor receptors have integral tyrosine kinase (see Fig. 3.17). These receptors dimerise, then cross-phosphorylate their tyrosine residues. The early cytosolic transducers include proteins that bind to the phosphorylated tyrosine residues. Optimum effect requires cooperation with integrin action. Integrins (which have \u03b1 and \u03b2 subunits) connect the extracellular \nmatrix with intracellular signalling pathways and also with the cell cytoskeleton (not shown here). G protein\u2013coupled receptors can also stimulate cell proliferation, because their intracellular pathways can connect with the Ras/kinase cascade (not shown). AP, adapter protein; FA kinase, focal adhesion kinase; \nRb, retinoblastoma protein. Interactions between cells, growth \nfactors and the matrix \n\u2022\tCells\tsecrete \tthe \tcomponents \tof", "start_char_idx": 0, "end_char_idx": 3333, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a466e41a-8c86-4653-9e99-592680d38d81": {"__data__": {"id_": "a466e41a-8c86-4653-9e99-592680d38d81", "embedding": null, "metadata": {"page_label": "92", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eadbe98b-2eb5-4a80-a5e0-93f91acdd6a8", "node_type": null, "metadata": {"page_label": "92", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "63ce2c52f3e9228cd1449d47dd285237f4763083c486a4cb4464efcba333dafa"}, "2": {"node_id": "87c27c3f-8226-457b-a1e0-c82ec89056b5", "node_type": null, "metadata": {"page_label": "92", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e3e5d28f986f69b4125e60791505708499b396d3a53f3e889b13aae9754baa0"}}, "hash": "d5c254628d7ff079448599820de9c1f3e39796a59450d8d3d34aa3870e23c0f2", "text": "and the matrix \n\u2022\tCells\tsecrete \tthe \tcomponents \tof \tthe \textracellular \t\nmatrix (ECM) and become embedded in this tissue.\n\u2022\tThe\tECM \tinfluences \tthe \tgrowth \tand \tbehaviour \tof \tthe \t\ncells. It also acts as a reservoir of growth factors.\n\u2022\tIntegrins \tare \ttransmembrane \tcellular \treceptors \tthat \t\ncan interact with elements of the ECM. They modulate \ngrowth factor signalling pathways and also mediate cytoskeletal adjustments within the cell.\n\u2022\tGrowth \tfactors \tcause \tcells \tto \trelease \t\nmetalloproteinases that degrade the local matrix so that it can accommodate the increase in cell numbers.\n\u2022\tMetalloproteinases \trelease \tgrowth \tfactors \tfrom \tthe \t\nECM and can activate some that are present in precursor form.\n8There are other forms of programmed cell death (PCD) including \nautophagy and (confusingly) programmed necrosis or necroptosis. Here we \nwill focus on apoptosis, also known as \u2018Type I PCD\u2019.ANGIOGENESIS\nAngiogenesis, which normally accompanies cell prolifera -\ntion, is the formation of new capillaries from existing small \nblood vessels. Without this, new tissues (including tumours) \ncannot feed and grow. Angiogenic stimuli include cytokines and various growth factors, in particular VEGF. The \nsequence of events in angiogenesis is as follows:\n1. The basement membrane is degraded locally by \nproteinases.\n2. Endothelial cells migrate out, forming a \u2018sprout\u2019.\n3. Following these leading cells, other endothelial cells \nproliferate under the influence of VEGF.\n4. Matrix material is laid down around the new \ncapillary.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3281, "end_char_idx": 5305, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a85acdb-7a47-4aad-b529-9ac31a834f94": {"__data__": {"id_": "7a85acdb-7a47-4aad-b529-9ac31a834f94", "embedding": null, "metadata": {"page_label": "93", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fc715357-b3f5-4bbd-8935-bdefdf179b92", "node_type": null, "metadata": {"page_label": "93", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06562f80df5dc9daecb53e2e364596d9b92dfdb2729f5c6a920f53e2ffee514c"}, "3": {"node_id": "0bf3bb7c-15a8-4dc9-a81a-89a1aae3ca4a", "node_type": null, "metadata": {"page_label": "93", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9467d8bdc95555b62c889e861611a59cc3efdebf8f9f1b2bc834b71a2cc4ba5"}}, "hash": "ae3fc32abe50f596c6aab7b5263bbebbdbe8113a91c389e15372b0c6a1941ca3", "text": "6 CELL PR o LI f ERA t I o N , AP o P to SIS , REPAIR AN d REGENERA t I o N\n87\u2022\tevasion \tof \tthe \timmune \tresponse \tby \tcancer \tcells \tand \t\nresistance to cancer chemotherapy (Ch. 57);\n\u2022\tautoimmune/inflammatory \tdiseases \tsuch \tas \t\nmyasthenia gravis (Ch. 14), rheumatoid arthritis (Ch. \n27), and bronchial asthma (Ch. 29);\n\u2022\tviral\tinfections \twith \tineffective \teradication \tof \t\nvirus-infected cells (Ch. 53).\n\u25bc Apoptosis is particularly important in the regulation of the immune \nresponse and in the many conditions in which it is an underlying \ncomponent. There is evidence that T cells have a negative regulatory \npathway controlled by surface programmed cell death receptors (e.g. the \nPD-1 receptor), and that there is normally a balance between the \nstimulatory pathways triggered by antigens and this negative regula -\ntory apoptosis-inducing pathway. The balance is important in the maintenance of peripheral tolerance. A disturbance of this balance is seen in autoimmune disease, in the \u2018exhaustion\u2019 of T cells in chronic \nviral diseases such as HIV, and possibly in tumour escape from immune \ndestruction (Zha et al., 2004). Indeed PD-1 generally acts to inhibit \nT-cell receptor signalling, and PD-1 inhibitors (checkpoint inhibitors) \ncause activation of T cells, allowing them to once more recognise and \nattack the tumour (see also Ch. 57).\nApoptosis is a default response , i.e. continuous active signal -\nling by tissue-specific trophic factors, cytokines and hor -\nmones, and cell-to-cell contact factors (adhesion molecules, \nintegrins, etc.) are required for cell survival and viability. The self-destruct mechanism is automatically triggered \nunless it is actively and continuously inhibited by these \nantiapoptotic factors. Different cell types require differing sets of survival factors, which function only locally. If a \ncell strays or is dislodged from the area protected by its \nparacrine survival signals, it will die.\nWithdrawal of these survival factors \u2013 which has been \ntermed \u2018death by neglect\u2019 \u2013 is not the only pathway to \napoptosis (Fig. 6.5). The death machinery can be activated \nby ligands that stimulate death receptors and by DNA \ndamage. But it is generally accepted that cell proliferation \nprocesses and apoptosis are tightly integrated.\nMORPHOLOGICAL CHANGES IN APOPTOSIS\nAs the cell dies it \u2018rounds up\u2019, the chromatin condenses \ninto dense masses, nucleases chop up the genome into \nunusable different sized fragments (seen on a gel as DNA \n\u2018laddering\u2019), the cytoplasm shrinks and there is blebbing of the plasma membrane. Finally, mediated by a family of \nproteolytic enzymes known as caspases, the cell is trans -\nformed into a cluster of membrane-bound entities. This \ncellular \u2018corpse\u2019 displays \u2018eat me\u2019 signals, such as phos -\nphatidylserine on its surface, which are recognised by macrophages, which then phagocytose the remains. It is important that these cellular fragments are enclosed by a membrane because otherwise the release of cell constituents \ncould trigger an inflammatory reaction. An additional \nsafeguard against this is that phagocytosing macrophages release anti-inflammatory mediators such as TGF- \u03b2, \nannexin-1 and IL-10.\nTHE MAJOR PLAYERS IN APOPTOSIS\nThe repertoire of reactions in apoptosis is extremely complex and varies between species and cell types. Yet it could be \nthat the pivotal reaction(s) that lead to either cell survival", "start_char_idx": 0, "end_char_idx": 3413, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0bf3bb7c-15a8-4dc9-a81a-89a1aae3ca4a": {"__data__": {"id_": "0bf3bb7c-15a8-4dc9-a81a-89a1aae3ca4a", "embedding": null, "metadata": {"page_label": "93", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fc715357-b3f5-4bbd-8935-bdefdf179b92", "node_type": null, "metadata": {"page_label": "93", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06562f80df5dc9daecb53e2e364596d9b92dfdb2729f5c6a920f53e2ffee514c"}, "2": {"node_id": "7a85acdb-7a47-4aad-b529-9ac31a834f94", "node_type": null, "metadata": {"page_label": "93", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ae3fc32abe50f596c6aab7b5263bbebbdbe8113a91c389e15372b0c6a1941ca3"}}, "hash": "d9467d8bdc95555b62c889e861611a59cc3efdebf8f9f1b2bc834b71a2cc4ba5", "text": "could be \nthat the pivotal reaction(s) that lead to either cell survival \nor cell death are controlled by a single gene or combination of genes. If so, these genes could be desirable targets for \ndrugs used to treat many proliferative diseases.\nOnly a simple outline of apoptosis can be given here. \nPortt et al. (2011) have reviewed the whole area in detail. PLASMA MEMBRANE\nCYTOSOLFas ligands\nAdapter\nproteinDeath\ndomainsReceptor for \nsurvival factorsSurvival factors\nR\nAntiapoptotic Bcl-2\nMitochondrion\nApoptosome\nMitochondrial\npathway\nCaspase 9\nCaspase 3Caspase 8\nDeath \nreceptor \npathwayp53 protein\nProapoptotic \nmiRNAsDNA damageProapoptotic Bcl-2\nIAPsInitiates the effector\nstage: cleavage\nand inactivation of \nenzymes and\nstructural constituents, \nfragmentation of \ngenomic DNA etc.\nAPOPTOSISA trimer of TNF receptors \naka Fas/Apo-1 receptors\nFig. 6.5 A simplified diagram of the two main signalling \npathways in apoptosis. The \u2018death receptor\u2019 pathway is \nactivated when death receptors such as members of the tumour \nnecrosis factor (TNF) family are stimulated by specific death \nligands. This recruits adapter proteins that activate initiator \ncaspases (e.g. caspase 8), which in turn activate effector \ncaspases such as caspase 3. The mitochondrial pathway is \nactivated by diverse signals, one being DNA damage. In the \npresence of DNA damage that cannot be repaired, the p53 \nprotein (see text and Figs 6.3 and 6.4) activates a subpathway \nthat releases cytochrome C from the mitochondrion, with \nsubsequent involvement of the apoptosome and activation of an \ninitiator caspase, caspase 9. The apoptosome is a complex of \nprocaspase 9, cytochrome C and apoptotic-activating protease \nfactor-1 (Apaf-1). Both these pathways converge on the effector \ncaspase (e.g. caspase 3), which brings about the demise of the \ncell. The survival factor subpathway normally restrains apoptosis \nby inhibiting the mitochondrial pathway through activation of the \nantiapoptotic factor Bcl-2. The receptor labelled \u2018R\u2019 represents \nthe respective receptors for trophic factors, growth factors, \ncell-to-cell contact factors (adhesion molecules, integrins), etc. \nContinuous stimulation of these receptors is necessary for cell \nsurvival/proliferation. If this pathway is non-functional (shown in \ngrey), this antiapoptotic drive is withdrawn. IAP, inhibitor of \napoptosis. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3341, "end_char_idx": 6189, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "47354fed-9314-4ef0-abb4-58b1f19543fb": {"__data__": {"id_": "47354fed-9314-4ef0-abb4-58b1f19543fb", "embedding": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "74dacdf4-76e1-4b29-8462-2a1e4f1397cc", "node_type": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79d8418d6a2d9ae05262cee058cf0ebb33b438e7549ad1ab05f6004958caedcc"}, "3": {"node_id": "17284040-52b0-4567-b2cd-4d7e4d993b20", "node_type": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4cc90040a57a032359654ed28746c6849b0e89405172e41bee07a693a7a0c01"}}, "hash": "578b2512c470498d31131f267f01b662da4036e5eabdc4c8416eb1a34c760323", "text": "6 SECTION 1 GENERAL PRINCIPLES\n88promyelocytic leukaemia bodies, large complexes of proteins \nin the nucleus, participate in this task (Wyllie, 2010), \nalthough how they do so is not clear.\nRegulating the apoptotic event are the members of the \nBcl-2 protein family, a group of proteins with homologous domains allowing interactions between individual members. \nIf the cell selects the apoptotic route, the p53 protein activates p21 and proapoptotic members of the Bcl-2 family \u2013 Bid, \nBax and Bak. In addition to these proapoptotic individuals, \nthis family has antiapoptotic members (e.g. Bcl-2 itself\n11). \nThese factors compete with each other on the surface of \nthe mitochondria and the outcome depends upon the relative \ncompeting concentrations of these molecular players. In the case of a proapoptotic signal, oligomers of Bax and or \nBak form pores in the mitochondrial membrane through \nwhich proteins such as cytochrome C can leak.\nWhen released, cytochrome C complexes with a protein \ntermed Apaf-1 (apoptotic protease-activating factor-1); the pair then combining with procaspase 9 to activate it. This latter enzyme orchestrates the effector caspase pathway. The triumvirate of cytochrome C, Apaf-1 and procaspase \n9 is termed the apoptosome (see Fig. 6.5 and see Riedl & \nSalvesen, 2007). Nitric oxide (see Ch. 21) is another mediator \nthat can have proapoptotic and antiapoptotic actions.\nIn normal cells, survival factors (specified earlier) continu -\nously activate antiapoptotic mechanisms. The withdrawal of survival factors can cause death in several different ways \ndepending on the cell type. A common mechanism is tipping \nthe balance between Bcl-2 family members leading to loss of the antiapoptotic protein action, with the resultant \nunopposed action of the proapoptotic members of the Bcl-2 \nfamily of proteins (see Fig. 6.5).\nThe two main cell death pathways are connected to each \nother, in that caspase 8 in the death receptor pathway can activate the proapoptotic Bcl-2 family proteins and thus activate the mitochondrial pathway.\nMicroRNAs, the cell cycle and apoptosis\nMicroRNAs (miRNAs), discovered only around the turn of the millennium, are a family of small \u2018non-coding\u2019 RNAs \npresent within plants and animals. Coded by sections of \nthe genome found outside the normal coding sequences of genes, miRNAs negatively regulate the ribosomal transla -\ntion processes of many other genes. They are now known to inhibit the expression of genes coding for cell cycle regulation, apoptosis (see Fig. 6.5), cell differentiation and \ndevelopment (Carleton et al., 2007; Lynam-Lennon et al., \n2009). About 3% of human genes encode for miRNA and some 30% of human genes coding for proteins are regulated \nby miRNAs.\nAltered miRNA expression is now believed to be linked to \na variety of diseases, including diabetes, obesity, Alzheimer\u2019s disease, cardiovascular system diseases, inflammatory condi -\ntions and neurodegenerative diseases (Barbato et al., 2009), \nas well as carcinogenesis, metastasis and resistance to cancer \ntherapies (Wurdinger & Costa, 2007; Garzon et al., 2009). \nmiRNAs are also believed to function as oncogenes and/\nor tumour suppressor genes and to regulate T cells (Zhou \net al., 2009). Not surprisingly, miRNAs are being heralded \nas targets for new drug development for a variety of disease states (Christopher et al., 2016; Cho 2010).The major players are a family of cysteine aspartate-directed \nproteinases", "start_char_idx": 0, "end_char_idx": 3472, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "17284040-52b0-4567-b2cd-4d7e4d993b20": {"__data__": {"id_": "17284040-52b0-4567-b2cd-4d7e4d993b20", "embedding": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "74dacdf4-76e1-4b29-8462-2a1e4f1397cc", "node_type": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79d8418d6a2d9ae05262cee058cf0ebb33b438e7549ad1ab05f6004958caedcc"}, "2": {"node_id": "47354fed-9314-4ef0-abb4-58b1f19543fb", "node_type": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "578b2512c470498d31131f267f01b662da4036e5eabdc4c8416eb1a34c760323"}, "3": {"node_id": "cc8f2717-127e-4ab1-8cac-3b3f2c534a4e", "node_type": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8bf1dd8009370c0c9bf34e83ed1695679c49685afca48a177cb1f2cc32aa7321"}}, "hash": "d4cc90040a57a032359654ed28746c6849b0e89405172e41bee07a693a7a0c01", "text": "2010).The major players are a family of cysteine aspartate-directed \nproteinases (caspases) present in the cell in inactive form. \nThese undertake delicate protein surgery, selectively cleav -\ning a specific set of target proteins (enzymes, structural \ncomponents, all of which contain a characteristic motif \nrecognised by the caspases), inactivating some and activating others. A cascade of about nine different caspases is required, \nsome functioning as initiators that transmit the initial \napoptotic signals, and others being responsible for the final phase of cell death (see Fig. 6.5).\nThe \u2018executioner\u2019 caspases (e.g. caspase 3) cleave and \ninactivate cell constituents such as the DNA repair enzymes, protein kinase C, and cytoskeletal components. A DNAase is activated that cuts genomic DNA between the nucle -\nosomes, generating DNA fragments of approximately 180 base pairs.\nHowever, not all caspases are death-mediating enzymes; \nsome have a role in the processing and activating of cytokines (e.g. caspase 8 is active in processing the inflam -\nmatory cytokines IL-1 and IL-18).\nBesides the caspases, another pathway can be triggered \nby apoptotic initiating factor (AIF), a protein released from \nmitochondria that enters the nucleus and triggers cell \nsuicide.\nPATHWAYS TO APOPTOSIS\nThere are two main routes to cell death: stimulation of \ndeath receptors by external ligands (the extrinsic pathway) \nand an internal mitochondrial pathway. Both routes activate \ninitiator caspases and converge on a final common effector caspase pathway.\nTHE EXTRINSIC PATHWAY\nLurking in the plasma membrane of most cell types are members of the tumour necrosis factor receptor (TNFR) \nsuperfamily (also known as Fas receptors), which function \nas \u2018death receptors\u2019 (see Fig. 6.5). Important family members include TNFR-1 and CD95 (also known as Fas ligands or \nApo-1), but there are many others (e.g. PD-1, a death \nreceptor that can be induced on activated T cells, as dis -\ncussed previously).\nEach receptor has a \u2018death domain\u2019 in its cytoplasmic \ntail. Stimulation of the receptors by a ligand such as tumour necrosis factor (TNF\n9) itself or TRAIL10 causes them to \ntrimerise and recruit an adapter protein that binds to their \ndeath domains. The resulting complex activates caspase 8 \n(and probably caspase 10), which in turn activate the effector caspases (see Fig. 6.5).\nThe mitochondrial pathway\nThis pathway can be triggered by DNA damage or by withdrawal of cell survival factors or other factors. In some \nway, the cell can \u2018audit\u2019 such damage and decide whether \nto initiate the apoptotic pathway. It is possible that \n9Tumour necrosis factor was first thought to be secreted by bacteria, \nsince it was known that infected tumours would sometimes recede and \nbe cured. This \u2018bacterial-secreted\u2019 tumour killing factor was discovered to \nbe TNF, released instead from our macrophages responding to the bacterial infection. A side effect of the TNF was to kill the tumour, \nhence its name. TNF is also known as cachexin, the agent responsible for \nmuscle apoptosis and wastage in cancer patients.\n10TRAIL is tumour necrosis factor-\u03b1\u2013related apoptosis-inducing ligand, \nof course; what else? See Janssen et al. (2005) for discussion of a role of \nTRAIL. PD-L1, a ligand for the PD-1 receptor, is found on all haemopoietic cells and many other tissues.11Another brake on cell death is a family of", "start_char_idx": 3402, "end_char_idx": 6807, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cc8f2717-127e-4ab1-8cac-3b3f2c534a4e": {"__data__": {"id_": "cc8f2717-127e-4ab1-8cac-3b3f2c534a4e", "embedding": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "74dacdf4-76e1-4b29-8462-2a1e4f1397cc", "node_type": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79d8418d6a2d9ae05262cee058cf0ebb33b438e7549ad1ab05f6004958caedcc"}, "2": {"node_id": "17284040-52b0-4567-b2cd-4d7e4d993b20", "node_type": null, "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4cc90040a57a032359654ed28746c6849b0e89405172e41bee07a693a7a0c01"}}, "hash": "8bf1dd8009370c0c9bf34e83ed1695679c49685afca48a177cb1f2cc32aa7321", "text": "cells and many other tissues.11Another brake on cell death is a family of caspase-inhibiting proteins \ncalled IAPs (inhibitors of apoptosis proteins).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6805, "end_char_idx": 7434, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a5eec967-4b60-456a-8190-2627fdf9b687": {"__data__": {"id_": "a5eec967-4b60-456a-8190-2627fdf9b687", "embedding": null, "metadata": {"page_label": "95", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7d4dda25-30a4-49b6-9927-6b71e5c7ec19", "node_type": null, "metadata": {"page_label": "95", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4d7ea15689601112aa63da0c5ac46252567d3b376a26a456c0d380b1aad73c78"}, "3": {"node_id": "4e8f41a4-33d7-4c82-bac7-c69d81978d21", "node_type": null, "metadata": {"page_label": "95", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06b0e072b8375f353ec300dc28ad0782e9345a36da244060fb5c71a5b4010f39"}}, "hash": "458318872dcef8662e50ccd8d045a341aa2d94bede2f6bcac68cad0620288fed", "text": "6 CELL PR o LI f ERA t I o N , AP o P to SIS , REPAIR AN d REGENERA t I o N\n89REPAIR AND HEALING\nRepair occurs when tissues are damaged or lost. It is also \nimplicated in the resolution of the local inflammatory \nreaction to a pathogen or chemical irritant. In some instances, \ndamage or tissue loss can lead to regeneration, which is \ndifferent from repair and is considered below.\nThere is considerable overlap between the mechanisms \nactivated in inflammation and repair. Both entail an ordered series of events including cell migration, angiogenesis, \nproliferation of connective tissue cells, synthesis of ECM \nand finally remodelling \u2013 all coordinated by the growth factors and cytokines that are appropriate for the particular \ntissue involved. TGF-\u03b2 is a key regulator of several of these \nprocesses.\n12Apoptosis \n\u2022\tApoptosis \tis \tprogrammed \tcell \tdeath. \tIt \tis \tan \tessential \t\nbiological process and critical, for example, \nembryogenesis and tissue homeostasis.\n\u2022\tApoptosis \tdepends \tupon \ta \tcascade \tof \tproteinases \t\ncalled caspases. Two sets of initiator caspases converge on a set of effector caspases, which bring about the apoptotic event.\n\u2022\tTwo\tmain \tpathways \tactivate \tthe \teffector \tcaspases: \t\nthe death receptor pathway and the mitochondrial pathway.\n\u2013 Stimulation of the tumour necrosis factor receptor \nfamily initiates the death receptor pathway. The main initiator is caspase 8.\n\u2013 The mitochondrial pathway is activated by internal \nfactors such as DNA damage, which results in transcription of gene p53. The p53 protein activates \na subpathway that releases cytochrome C from the \nmitochondrion. This, in turn, complexes with protein \nApaf-1 and together they activate initiator caspase 9.\n\u2022\tIn\tundamaged \tcells, \tsurvival \tfactors \t(cytokines, \t\nhormones, cell-to-cell contact factors) continuously activate antiapoptotic mechanisms. Withdrawal of survival factors causes cell death through the \nmitochondrial pathway.\n\u2022\tThe\teffector \tcaspases \t(e.g. \tcaspase \t3) \tinitiate \ta \t\ncascade of proteases that cleave cell constituents, \nDNA, cytoskeletal components, enzymes, etc. This reduces the cell to a cluster of membrane-bound \nentities that are eventually phagocytosed by \nmacrophages.Repair, healing and regeneration \n\u2022\tRepair\tand \thealing \toccurs \twhen \ttissues \tare \tdamaged. \t\nIt\tis\ta\tcommon \tsequel \tto \tinflammation. \tConnective \t\ntissue cells, white blood cells and blood vessels are commonly involved.\n\u2022\tRegeneration \tis \tthe \treplacement \tof \tthe \ttissue \tor \torgan \t\nthat has been damaged or lost. It depends upon the presence of a pool of primitive stem cells that have the potential to develop into any cell in the body. \nComplete regeneration of a tissue or organ is rare in \nmammals. The more rapid repair processes \u2013 often accompanied by scarring \u2013 usually make good the damage. This may be an evolutionary trade-off in \nmammals for the lost power of regeneration.\n\u2022\tHowever, \tit \tmight \tbe \tpossible \tto \tactivate \tregenerative \t\npathways in mammals \u2013 at least to some extent and in \nsome organs.\n12Next time you cut yourself, have a look at the scar exactly a week \nlater. It may be that almost all signs of the scar have nearly vanished. \nThis impressive biological process (bleeding, scabbing, scarring, wound \nhealing) in a week is thanks to growth factors from the scab stimulating epithelial and endothelial stem cells into action to remodel and match", "start_char_idx": 0, "end_char_idx": 3409, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4e8f41a4-33d7-4c82-bac7-c69d81978d21": {"__data__": {"id_": "4e8f41a4-33d7-4c82-bac7-c69d81978d21", "embedding": null, "metadata": {"page_label": "95", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7d4dda25-30a4-49b6-9927-6b71e5c7ec19", "node_type": null, "metadata": {"page_label": "95", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4d7ea15689601112aa63da0c5ac46252567d3b376a26a456c0d380b1aad73c78"}, "2": {"node_id": "a5eec967-4b60-456a-8190-2627fdf9b687", "node_type": null, "metadata": {"page_label": "95", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "458318872dcef8662e50ccd8d045a341aa2d94bede2f6bcac68cad0620288fed"}}, "hash": "06b0e072b8375f353ec300dc28ad0782e9345a36da244060fb5c71a5b4010f39", "text": "stimulating epithelial and endothelial stem cells into action to remodel and match \nwhat was damaged \u2013 even down to replicating a fingerprint.PATHOPHYSIOLOGICAL IMPLICATIONS\nAs mentioned before, cell proliferation and apoptosis are \ninvolved in many physiological and pathological processes. \nThese are:\n\u2022\tthe\tgrowth \tof \ttissues \tand \torgans \tin \tthe \tembryo \tand \t\nlater during development;\n\u2022\tthe\treplenishment \tof \tlost \tor \ttime-expired \tcells \tsuch \tas \t\nleukocytes, gut epithelium and uterine endometrium;\n\u2022\timmunological \tresponses, \tincluding \tdevelopment \tof \t\nimmunological tolerance to host proteins;\n\u2022\trepair\tand \thealing \tafter \tinjury \tor \tinflammation;\n\u2022\tthe\thyperplasia \t(increase \tin \tcell \tnumber \tand \tin \t\nconnective tissue) associated with chronic \ninflammatory, hypersensitivity and autoimmune \ndiseases (Ch. 7);\n\u2022\tthe\tgrowth, \tinvasion \tand \tmetastasis \tof \ttumours \t \n(Ch. 57);\n\u2022\tregeneration \tof \ttissues.\nThe role of cell proliferation and apoptosis in the first two \nprocesses listed is self-evident and needs no further \ncomment. Their involvement in immune tolerance is dis -\ncussed briefly above but the other processes require further \ndiscussion.HYPERPLASIA\nHyperplasia (cell proliferation and matrix expansion) is a hallmark of chronic inflammatory and autoimmune diseases \nsuch as rheumatoid arthritis (Chs 7 and 27), psoriasis, \nchronic ulcers and chronic obstructive lung disease. It also underlies the bronchial hyper-reactivity of chronic asthma \n(Ch. 29) and glomerular nephritis.\nCell proliferation and apoptotic events are also implicated \nin atherosclerosis (Ch. 24), restenosis and myocardial repair after infarction (Ch. 22).\nTHE GROWTH, INVASION AND METASTASIS \nOF TUMOURS\nGrowth factor signalling systems, antiapoptotic pathways \nand cell cycle controllers are of increasing interest as \ntargets for novel approaches to the treatment of cancer. See \nChapter 57.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3327, "end_char_idx": 5715, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "187ee27d-98c1-482c-80ca-647f549bed5e": {"__data__": {"id_": "187ee27d-98c1-482c-80ca-647f549bed5e", "embedding": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e98604d1-26a7-42b0-95a4-202faba70a45", "node_type": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "629c42087e364be3ab09fa9ec1db13331806cfd8a0aa07ea1fd630d52c6cb83c"}, "3": {"node_id": "a37761b4-3cd9-4542-bf1e-1b2b8edf5bf9", "node_type": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "710c8361c0d3c46ff0c30353a91327fffddd2c1ecb450865f6d280963ea4ad73"}}, "hash": "132258a49ebbd375ba5cd6a3197891916d2b93e40a38df8cc71e2cb06e9d5a1a", "text": "6 SECTION 1 GENERAL PRINCIPLES\n90\u25bc Where are the relevant stem cells that could be coaxed into \nregenerative service? Various possibilities are being vigorously \ninvestigated and in some cases tested clinically. These include:\n\u2022\tES\tcells \t(limited \tavailability \tand \tserious \tethical \tissues)\n\u2022\tbone\tmarrow-derived \tmesenchymal \tstem \tcells \t(Zhang \tet \tal., \t\n2017)\n\u2022\tmuscle-derived \tstem \tcells \t(Kelc \tet \tal., \t2013)\n\u2022\thuman-induced \tpluripotent \tstem \tcells \t(Nishikawa \tet \tal., \t2008)\n\u2022\ttissue-resident \tprogenitor \tcells.\nFor a tissue such as the liver to regenerate, local tissue-\nspecific stem cells must be stimulated by growth factors \nto enter the cell cycle and to proliferate. Other essential \nprocesses include those already discussed such as angio -\ngenesis, activation of MMPs and interaction between the \nmatrix and fibronectin to link all the new elements together. \nThe concomitant replacement of components of the lost connective tissue (fibroblasts, macrophages, etc.) would \nalso be necessary.\nBecause most tissues do not regenerate spontaneously, \nmechanisms that could restore regenerative ability could \nbe of immense therapeutic value. Stem cell therapy has \nbecome an attractive prospect for treating all manner of \ndiseases, ranging from erectile dysfunction and urinary incontinence to heart disease and neurodegeneration. Animal \nstudies have confirmed that this is a potentially rewarding \narea although routine stem cell therapy in humans is still a distant prospect. The literature is daunting but the fol -\nlowing examples provide an insight into the obstacles and aspirations of the field: repair of damaged heart muscle (Ch. 22; see Lovell & Mathur, 2011), repair of retinal \ndegeneration (Ong & da Cruz, 2012), stroke (Banerjee et al., \n2011) and replacement of insulin-secreting cells to treat \ntype 1 diabetes mellitus (Ch. 32; Voltarelli et al., 2007).\nTHERAPEUTIC PROSPECTS\nTheoretically, all the processes described in this chapter could constitute useful targets for new drug development. \nBelow, we list those approaches that are proving or are \nlikely to prove fruitful.\nAPOPTOTIC MECHANISMS\nCompounds that could modify apoptosis are being inten -\nsively investigated (Melnikova & Golden, 2004; MacFarlane, \n2009). Here we can only outline some of the more important approaches.\nDrugs that promote apoptosis by various mechanisms \nwere heralded as a potential new approach to cancer treat -\nment, and are actively being studied, though none has yet been approved for clinical use. Potential proapoptotic \ntherapeutic approaches need to be targeted precisely to \nthe diseased tissue to avoid the obvious risks of damaging other tissues. Examples include the following:\n\u2022\tAn\tantisense \tcompound \tagainst \tBcl-2 \t(oblimersen) is \nbeing tested for chronic lymphocytic leukaemia.\n\u2022\tObatoclax, and Navitoclax are small molecule \ninhibitors of Bcl-2 action, being tested for treating haematological malignancies. For details see \nMacFarlane (2009).\n\u2022\tMicroRNA \ttechnology \tcould \talso \tbe \tused \tto \tpromote \t\napoptosis (see Fig. 6.5).\n\u2022\tMonoclonal \tagonist \tantibodies \tto \tthe \tdeath \treceptor \t\nligand TRAIL (e.g. lexatumumab) are undergoing STEM CELLS AND REGENERATION\nRegeneration of tissue replaces that lost following damage \nor disease and allows restoration of function. Many animals \n(e.g. amphibians) have impressive regenerative powers and \ncan even", "start_char_idx": 0, "end_char_idx": 3409, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a37761b4-3cd9-4542-bf1e-1b2b8edf5bf9": {"__data__": {"id_": "a37761b4-3cd9-4542-bf1e-1b2b8edf5bf9", "embedding": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e98604d1-26a7-42b0-95a4-202faba70a45", "node_type": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "629c42087e364be3ab09fa9ec1db13331806cfd8a0aa07ea1fd630d52c6cb83c"}, "2": {"node_id": "187ee27d-98c1-482c-80ca-647f549bed5e", "node_type": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "132258a49ebbd375ba5cd6a3197891916d2b93e40a38df8cc71e2cb06e9d5a1a"}, "3": {"node_id": "80ecd270-f1bf-4e90-b31b-e671b78c62e3", "node_type": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ba5472a830c56faaacd1d36388030131e6bd09212dd58ee280433bf89b5a992"}}, "hash": "710c8361c0d3c46ff0c30353a91327fffddd2c1ecb450865f6d280963ea4ad73", "text": "amphibians) have impressive regenerative powers and \ncan even regrow an entire organ such as a limb or a tail. The essential process is the activation of stem cells \u2013 a pool \nof undifferentiated cells that have the potential to develop into any of the more specialised cells in the body \u2013 \u2018toti -\npotent\u2019 or \u2018pluripotent\u2019 cells (Slack, 2014; Burgess, 2016). \nNot only do amphibians have a plentiful supply of these \nprimitive cells but many of their more specialised cells can de-differentiate, becoming stem cells again. These can then \nmultiply and retrace the fetal developmental pathways that \ngenerated the organ, by differentiating into the various cell \ntypes needed to replace the missing structure.\nHowever, during evolution, mammals have lost this \nability in all but a few tissues. Blood cells, intestinal epi -\nthelium and the outer layers of the skin are replaced continu -\nously throughout life but there is a low turnover and \nreplacement of cells in organs such as liver, kidney and \nbone. This \u2018physiological renewal\u2019 is effected by local tissue-specific stem cells.\nAlmost alone among mammalian organs, the liver has \nsignificant ability to replace itself. It can regenerate to its original size in a remarkably short time, provided that at \nleast 25% has been left intact.\n13 The mature parenchymal \nliver cells participate in this process as well as all the other cellular components of the liver.\nIt is necessary to distinguish embryonic stem cells (ES cells) \nfrom adult stem cells (AS cells) and progenitor cells. ES cells \nare the true pluripotent cells of the embryo that can dif -\nferentiate into any other cell type. AS cells have a more \nrestricted capability, whereas progenitor cells are able to \ndifferentiate only into a single cell type. ES cells are absent \nin the adult mammal, but AS cells are present, although they are few in number. In mammals, tissue or organ damage (with the exception of the liver, mentioned previ -\nously) normally leads to repair, rather than regeneration.\nUntil recently, it was assumed that this was (with a few \nexceptions) an unalterable situation, but recent work has \nsuggested that it might be possible to activate the regenera -\ntive pathways in mammals \u2013 at least to some extent and in \nsome organs. For this to happen, it is necessary to encourage \nsome stem cells to proliferate, develop and differentiate \nat the relevant sites; or \u2013 and this is a rather more remote prospect in humans \u2013 to persuade some local specialised \ncells to de-differentiate. This can occur in some mammals \nunder special circumstances. However, it may be that repair \nis the Janus face of regeneration, being an evolutionary trade-off in mammals for the lost power of regeneration\n.14\n13There is an account of liver regeneration in Greek mythology. \nPrometheus stole the secret of fire from Zeus and gave it to mankind. \nTo punish him, Zeus had him shackled to a crag in the Caucasus and \nevery day an eagle tore at his flesh and devoured much of his liver. During the night, however, it regenerated and in the morning was \nwhole again. The legend doesn\u2019t say whether the requisite 25% was left \nafter the eagle had had its fill, and the regeneration described seems unrealistically fast \u2013 rat liver takes 2 weeks or more to get back to the \noriginal size after 66% hepatectomy.\n14Bovine myosatellite stem cells have been used to grow burgers in the \nlab (a slightly vegetarian alternative). The fact that one burger can cost up to \u00a3250,000 to make may mean that only professional footballers can \nafford them for now.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3356, "end_char_idx": 7052, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "80ecd270-f1bf-4e90-b31b-e671b78c62e3": {"__data__": {"id_": "80ecd270-f1bf-4e90-b31b-e671b78c62e3", "embedding": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e98604d1-26a7-42b0-95a4-202faba70a45", "node_type": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "629c42087e364be3ab09fa9ec1db13331806cfd8a0aa07ea1fd630d52c6cb83c"}, "2": {"node_id": "a37761b4-3cd9-4542-bf1e-1b2b8edf5bf9", "node_type": null, "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "710c8361c0d3c46ff0c30353a91327fffddd2c1ecb450865f6d280963ea4ad73"}}, "hash": "3ba5472a830c56faaacd1d36388030131e6bd09212dd58ee280433bf89b5a992", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7075, "end_char_idx": 7458, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e8cbcf2b-c54e-4b64-9f23-05d9337395f5": {"__data__": {"id_": "e8cbcf2b-c54e-4b64-9f23-05d9337395f5", "embedding": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a73ccbb6-470f-4e3e-beb5-6c73ce8d3361", "node_type": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3c1b1e760fd1e2c858a3ae12f1a64198acc693fe872ab90caa0ab6a6547f9b9"}, "3": {"node_id": "568924d6-2905-4a31-8c52-0b0143f4ae64", "node_type": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79bc5659c6864a8d6d02bf6ce4935324d9e8fd0b86e817338967b40f0ed397ef"}}, "hash": "b49cd2426bc6732477e39890b615bffe19c34a41f1ef328ad7c8c6a336458e9b", "text": "6 CELL PR o LI f ERA t I o N , AP o P to SIS , REPAIR AN d REGENERA t I o N\n91clinical trials for treatment of solid tumours and \nlymphomas (MacFarlane, 2009).\n\u2022\tBortezomib, which inhibits the proteasome, is available for the treatment of selected cancers. It causes the build-up of Bax, an apoptotic promoter \nprotein of the Bcl-2 family that acts by inhibiting \nantiapoptotic Bcl-2. Bortezomib acts partly by inhibiting NF-\u03baB action (see Ch. 3).\n\u2022\tOne\tof \tthe \tmost \tcancer-specific \tgenes \tcodes \tfor \tan \t\nendogenous caspase inhibitor, survivin. This occurs in high concentrations in certain tumours and a small \nmolecule suppressor of survivin is in clinical trial \n(Giaccone & Rajan, 2009), the objective being to induce cancer cell suicide.\nInhibiting apoptosis might prevent or treat a wide range of common degenerative disorders. Unfortunately, success \nin developing such inhibitors for clinical use has so far \nproved elusive and a number have been found to lack efficacy in clinical trials. Current areas of interest include \nthe following:\n\u2022\tBlocking \tthe \tPD-1 \tdeath \treceptor \twith \ta \ttargeted \t\nantibody (such as Nivolumab) is a potentially fruitful \nnew avenue to explore for the treatment of HIV, \nhepatitis B and hepatitis C infections, as well as other \nchronic infections and some cancers that express the ligand for PD-1 (Trivedi et al., 2015).\n\u2022\tSeveral \tcaspase \tinhibitors \tare \tunder \tinvestigation \tfor \t\ntreating myocardial infarction, stroke, liver disease, organ transplantation and sepsis. Emricasan is one \nsuch candidate undergoing trials in patients requiring \nliver transplants.ANGIOGENESIS AND METALLOPROTEINASES\nThe search for clinically useful anti-angiogenic drugs and MMP inhibitors is continuing, but has not so far been \nsuccessful. At present, only one new drug has been approved \nfor use in cancer treatment: bevacizumab, a monoclonal antibody that neutralises VEGF, which is also used to treat \nage-related macular degeneration, a disease also associated \nwith excessive proliferation of retinal blood vessels.\nCELL CYCLE REGULATION\nThe main endogenous positive regulators of the cell cycle are the cdks. Several small molecules that inhibit cdks by targeting the ATP-binding sites of these kinases have been developed; an example is flavopiridol, currently in clinical \ntrials, which inhibits all the cdks, causing arrest of the cell \ncycle; it also promotes apoptosis, has anti-angiogenic \nproperties and can induce differentiation (Dickson & Schwartz, 2009).\nSome compounds affect upstream pathways for cdk \nactivation and may find a use in cancer treatment. Examples are perifosine (although its future is uncertain at the \nmoment) and lovastatin (a cholesterol-lowering drug, see \nCh. 24, which may also have anticancer properties).\nBortezomib , a boronate compound, covalently binds the \nproteasome, inhibiting the degradation of proapoptotic proteins. It is used in treating multiple myeloma (see Ch. 57).\nOf the various components of the growth factor signalling \npathway, receptor tyrosine kinases, the Ras protein and cytoplasmic kinases have been the subjects of most interest. \nKinase inhibitors recently introduced for cancer treatment include imatinib, gefitinib lapatinib, sunitinib and erlo-\ntinib (see Ch. 57).\nREFERENCES AND FURTHER READING\nCell cycle and apoptosis (general)\nAshkenasi, A., 2002. Targeting death and decoy", "start_char_idx": 0, "end_char_idx": 3388, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "568924d6-2905-4a31-8c52-0b0143f4ae64": {"__data__": {"id_": "568924d6-2905-4a31-8c52-0b0143f4ae64", "embedding": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a73ccbb6-470f-4e3e-beb5-6c73ce8d3361", "node_type": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3c1b1e760fd1e2c858a3ae12f1a64198acc693fe872ab90caa0ab6a6547f9b9"}, "2": {"node_id": "e8cbcf2b-c54e-4b64-9f23-05d9337395f5", "node_type": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b49cd2426bc6732477e39890b615bffe19c34a41f1ef328ad7c8c6a336458e9b"}, "3": {"node_id": "27b3c26c-acb4-497b-863d-70058ea96e70", "node_type": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f1af1cedc1815ff7751e94824a63370161b84f0180f7d182376066ecee0bcc54"}}, "hash": "79bc5659c6864a8d6d02bf6ce4935324d9e8fd0b86e817338967b40f0ed397ef", "text": "(general)\nAshkenasi, A., 2002. Targeting death and decoy receptors of the tumour \nnecrosis receptor superfamily. Nat. Rev. Cancer 2, 420\u2013429. (Exemplary \nreview, comprehensive; good diagrams)\nAslan, J.E., Thomas, G., 2009. Death by committee: organellar trafficking \nand communication in apoptosis. Traffic 10, 1390\u20131404.\nBarbato, C., Ruberti, F., Cogoni, C., 2009. Searching for MIND: \nmicroRNAs in neurodegenerative diseases. J. Biomed. Biotechnol. \n2009, 871313.\nCarleton, M., Cleary, M.C., Linsley, P.S., 2007. MicroRNAs and cell \ncycle regulation. Cell Cycle 6, 2127\u20132132. (Describes how specific microRNAs act to control cell cycle check points)\nCho, W.C., 2010. MicroRNAs: potential biomarkers for cancer diagnosis, \nprognosis and targets for therapy. Int. J. Biochem. Cell Biol. 42, 1273\u20131281.\nChristopher, A.F., Kaur, R.P., Kaur, G., Kaur, A., Gupta, V., Bansal, P., \n2016. MicroRNA therapeutics: Discovering novel targets and developing specific therapy. Perspectives Clin. Res. 7, 68\u201374.\nCummings, J., Ward, T., Ranson, M., Dive, C., 2004. Apoptosis \npathway-targeted drugs \u2013 from the bench to the clinic. Biochim. Biophys. Acta 1705, 53\u201366. (Good review discussing \u2013 in the context of \nanticancer drug development \u2013 Bcl-2 proteins, IAPs, growth factors, tyrosine \nkinase inhibitors and assays for apoptosis-inducing drugs)\nDanial, N.N., Korsmeyer, S.J., 2004. Cell death: critical control points. \nCell 116, 205\u2013219. (Definitive review of the biology and control of apoptosis; includes evidence from C. elegans, Drosophila and mammals)\nDickson, M.A., Schwartz, G.K., 2009. Development of cell-cycle \ninhibitors for cancer therapy. Curr. Oncol. 16, 36\u201343. (Discusses drugs that target the cell cycle that have entered clinical trials)\nElmore, S., 2007. Apoptosis: a review of programmed cell death. \nToxicol. Pathol. 35, 495\u2013516. (A general overview of apoptosis, including structural changes, biochemistry and the role of apoptosis in health and \ndisease)\nGarzon, R., Calin, G.A., Croce, C.M., 2009. MicroRNAs in cancer. Annu. \nRev. Med. 60, 167\u2013179.\nGiaccone, G., Rajan, A., 2009. Met amplification and HSP90 inhibitors. \nCell Cycle 8, 2682.\nJanssen, E.M., Droin, N.M., Lemmens, E.E., 2005. CD4\n+ T-cell-help \ncontrols CD4+ T cell memory via TRAIL-mediated activation-induced \ncell death. Nature 434, 88\u201392. (Control of TRAIL expression could explain the role of CD4\n+ T cells in CD8+ T-cell function)\nLynam-Lennon, N., Maher, S.M., Reynolds, J.V., 2009. The roles of \nmicroRNAs in cancer and apoptosis. Biol. Rev. 84, 55\u201371. (Detailed \nreview of the role of microRNAs in cell proliferation and cell death and their potential roles as oncogenes and tumour suppressor genes)\nMacFarlane, M., 2009. Cell death pathways \u2013 potential therapeutic \ntargets. Xenobiotica 39, 616\u2013624. (Excellent up-to-date review with table of agents in early clinical trial)\nMelnikova, A., Golden, J., 2004. Apoptosis-targeting", "start_char_idx": 3339, "end_char_idx": 6254, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "27b3c26c-acb4-497b-863d-70058ea96e70": {"__data__": {"id_": "27b3c26c-acb4-497b-863d-70058ea96e70", "embedding": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a73ccbb6-470f-4e3e-beb5-6c73ce8d3361", "node_type": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3c1b1e760fd1e2c858a3ae12f1a64198acc693fe872ab90caa0ab6a6547f9b9"}, "2": {"node_id": "568924d6-2905-4a31-8c52-0b0143f4ae64", "node_type": null, "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79bc5659c6864a8d6d02bf6ce4935324d9e8fd0b86e817338967b40f0ed397ef"}}, "hash": "f1af1cedc1815ff7751e94824a63370161b84f0180f7d182376066ecee0bcc54", "text": "A., Golden, J., 2004. Apoptosis-targeting therapies. Nat. Rev. \nDrug Discov. 3, 905\u2013906. (Crisp overview)\nOuyang, L., Shi, Z., Zhao, S., et al., 2012. Programmed cell death \npathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif. 45, 487\u2013498. (A wide-ranging review \ndealing with all types of programmed cell death in cancer cells)\nPortt, L., Norman, G., Clapp, C., Greenwood, M., Greenwood, M.T., \n2011. Anti-apoptosis and cell survival: a review. Biochim. Biophys. Acta 1813, 238\u2013259. (A very detailed review which deals with both pro- \nand antiapoptotic mechanisms as well as other types of programmed cell death)\nRiedl, S.J., Salvesen, G.S., 2007. The apoptosome: signalling platform of \ncell death. Nat. Rev. Mol. Cell Biol. 8, 405\u2013413. (Discusses the formation \nof the apoptosome and the activation of its effector, caspase 9)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6263, "end_char_idx": 7611, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6215427a-e93d-4249-bc71-a21e3c7ee940": {"__data__": {"id_": "6215427a-e93d-4249-bc71-a21e3c7ee940", "embedding": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e9033864-b226-45f2-80f2-bc671d10b6e8", "node_type": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3fa92e81eb36a2955fddb13b3589a29860d3c8b9daebc6639e5aebddd00acfef"}, "3": {"node_id": "16645623-0e18-49af-8343-6576d44c69e2", "node_type": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "074380d96cfeed5af6f1e5e3ea586012791fecb06dc99c4f8a1f043602060a80"}}, "hash": "ac6d9c84383420beee6aff500c7fa4b9ca6c5a3401985aac74ed030537ec43ae", "text": "6 SECTION 1 GENERAL PRINCIPLES\n92Res. 49, 203\u2013206. ( Crisp analysis of the ECM and its role in cell survival, \ngrowth and proliferation )\nRup\u00e9rez, M., Rodrigues-Diez, R., Blanco-Colio, L.M., et al., 2007. \nHMG-CoA reductase inhibitors decrease angiotensin II-induced \nvascular fibrosis: role of RhoA/ROCK and MAPK pathways. \nHypertension 50, 377\u2013383.\nStreuli, C.H., Akhtar, N., 2009. Signal co-operation between integrins \nand other receptor systems. Biochem. J. 418, 491\u2013506. ( Deals with \nintegrin interaction with growth factors to regulate angiogenesis, their \ninterplay with tyrosine kinases and with cytokine receptors )\nVerrecchia, F., Mauviel, A., 2007. Transforming growth factor-beta and \nfibrosis. World J. Gastroenterol. 13, 3056\u20133062.\nStem cells, regeneration and repair\nAldhous, P., 2008. How stem cell advances will transform medicine. \nNew Scientist 2654, 40\u201343. ( Clear, simple article )\nBanerjee, S., Williamson, D., Habib, N., Gordon, M., Chataway, J., 2011. \nHuman stem cell therapy in ischaemic stroke: a review. Age. Ageing \n40, 7\u201313.\nBurgess, R., 2016. Stem Cells: A Short Course. Wiley-Blackwell. ISBN: \n978-1-118-43919-7.\nGaetani, R., Barile, L., Forte, E., et al., 2009. New perspectives to repair a \nbroken heart. Cardiovasc. Hematol. Agents Med. Chem. 7, 91\u2013107. \n(Discusses sources of cardiomyogenic cells and their potential for diseased or \ninjured myocardium )\nKelc, R., Trapecar, M., Vogrin, M., Cencic, A., 2013. Skeletal \nmuscle-derived cell cultures as potent models in regenerative \nmedicine research. Muscle Nerve 47, 477\u2013482.\nLovell, M.J., Mathur, A., 2011. Republished review: cardiac stem cell \ntherapy: progress from the bench to bedside. Postgrad. Med. J. 87, \n558\u2013564. ( Useful review on the state of cardiac stem cell therapy \nhighlighting the problems as well as the potential. Easy to read )\nNature Reviews Drug Discovery, 2006. Vol. 5 (August) has a series of \narticles on nerve regeneration. ( The articles \u2018highlight recent progress in \nknowledge of the molecular, cellular and circuitry level responses to injuries \nto the adult mammalian CNS, with a view to understanding the underlying \nmechanism that will enable the development of appropriate therapeutic \nstrategies\u2019 )\nNishikawa, S., Goldstein, R.A., Nierras, C.R., 2008. The promise of \nhuman induced pluripotent stem cells for research and therapy. Nat. \nRev. Mol. Cell Biol. 9, 725\u2013729. ( Induced pluripotent stem cells [iPS] are \nhuman somatic cells that have reprogrammed to be pluripotent )\nOng, J.M., da Cruz, L., 2012. A review and update on the current status \nof stem cell therapy and the retina. Br. Med. Bull. 102, 133\u2013146. ( Easy \nto read review )\nRosenthal, N., 2003. Prometheus\u2019s vulture and the stem-cell promise. N. \nEngl. J. Med. 349, 267\u2013286. ( Excellent article on the problem of \nregeneration of tissues and organs )\nSlack, J.M.W., 2014. Genes. A Very Short Introduction. Oxford \nUniversity Press. ISBN: 9780199603381.\nVoltarelli, J.C., Couri, C.E., Stracieri, A.B., et al.,", "start_char_idx": 0, "end_char_idx": 3003, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "16645623-0e18-49af-8343-6576d44c69e2": {"__data__": {"id_": "16645623-0e18-49af-8343-6576d44c69e2", "embedding": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e9033864-b226-45f2-80f2-bc671d10b6e8", "node_type": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3fa92e81eb36a2955fddb13b3589a29860d3c8b9daebc6639e5aebddd00acfef"}, "2": {"node_id": "6215427a-e93d-4249-bc71-a21e3c7ee940", "node_type": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ac6d9c84383420beee6aff500c7fa4b9ca6c5a3401985aac74ed030537ec43ae"}, "3": {"node_id": "3b82a1cf-427f-4829-9589-efae4df36d73", "node_type": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c051879a3bf7bc270aa2315188871cc74ff72b82ae31a89e5582eab975a963c"}}, "hash": "074380d96cfeed5af6f1e5e3ea586012791fecb06dc99c4f8a1f043602060a80", "text": "Couri, C.E., Stracieri, A.B., et al., 2007. Autologous \nnonmyeloablative hematopoietic stem cell transplantation in newly \ndiagnosed type 1 diabetes mellitus. JAMA 297, 1568\u20131576. ( Successful \nearly trial of stem cell transplantation )\nZhang, X., Bendeck, M.P., Simmons, C.A., Santerre, J.P., 2017. Deriving \nvascular smooth muscle cells from mesenchymal stromal cells: \nevolving differentiation strategies and current understanding of their \nmechanisms. Biomaterials 145, 9\u201322.\nWilson, C., 2003. The regeneration game. New Scientist 179, 2414\u20132427. \n(Very readable article on the possibility of regeneration of mammalian tissues \nand organs )Riedl, S.J., Shi, Y., 2004. Molecular mechanisms of caspase regulation \nduring apoptosis. Nat. Rev. Mol. Cell Biol. 5, 897\u2013905. ( Systematic \nreview )\nSatyanarayana, A., Kaldis, P., 2009. Mammalian cell-cycle regulation: \nseveral Cdks, numerous cyclins and diverse compensatory \nmechanisms. Oncogene 28, 2925\u20132939. ( Summarises the results of gene \nknockout experiments which point to the ability of the cell to compensate for \nthe loss of most cyclins. Interesting review for those who want to delve \ndeeper into the subject )\nSwanton, C., 2004. Cell-cycle targeted therapies. Lancet 5, 27\u201336. \n(Definitive review of the protein families controlling the cell cycle, their \nalterations in malignancy and their potential as targets for new drugs )\nTousoulis, D., Andreou, I., Tentolouris, C., et al., 2010. Comparative \neffects of rosuvastatin and allopurinol on circulating levels of matrix \nmetalloproteinases in patients with chronic heart failure. Int. J. \nCardiol. 145, 438\u2013443.\nTrivedi, M.S., Hoffner, B., Winkelmann, J.L., Abbott, M.E., Hamid, O., \nCarvajal, R.D., 2015. Programmed death 1 immune checkpoint \ninhibitors. Clin. Adv. Hematol. Oncol. 13, 858\u2013868. ( Review that \nappraises the recent work on reversing T cell exhaustion )\nWurdinger, T., Costa, F.F., 2007. Molecular therapy in the microRNA \nera. Pharmacogenomics J. 7, 297\u2013304.\nWyllie, A.H., 2010. \u2018Where, O death, is thy sting?\u2019 A brief review of \napoptosis biology. Mol. Neurobiol. 42, 4\u20139. ( A short and very accessible \nreview by one of the founders of the field. Highly recommended )\nYang, B.F., Lu, Y.J., Wang, Z.G., 2009. MicroRNAs and apoptosis: \nimplications in molecular therapy of human disease. Clin. Exp. \nPharmacol. Physiol. 36, 951\u2013960. ( Comprehensive review of the \napotosis-regulating miRNAs and apoptotic cell death )\nZha, Y., Blank, C., Gajewski, T.F., 2004. Negative regulation of T-cell \nfunction by PD-1. Crit. Rev. Immunol. 24, 229\u2013237. ( Article on the \nbalance between stimulatory and inhibitory signalling and its relevance to \nself-tolerance and the pathogenesis of autoimmune diseases )\nZhou, L., Seo, K.H., Wong, H.K., Mi, Q.S., 2009. MicroRNAs and \nimmune regulatory T cells. Int. Immunopharmacol. 9, 524\u2013527.\nIntegrins, extracellular matrix, metalloproteinases and \nangiogenesis\nBarczyk, M., Carracedo, S.,", "start_char_idx": 2972, "end_char_idx": 5923, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3b82a1cf-427f-4829-9589-efae4df36d73": {"__data__": {"id_": "3b82a1cf-427f-4829-9589-efae4df36d73", "embedding": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e9033864-b226-45f2-80f2-bc671d10b6e8", "node_type": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3fa92e81eb36a2955fddb13b3589a29860d3c8b9daebc6639e5aebddd00acfef"}, "2": {"node_id": "16645623-0e18-49af-8343-6576d44c69e2", "node_type": null, "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "074380d96cfeed5af6f1e5e3ea586012791fecb06dc99c4f8a1f043602060a80"}}, "hash": "4c051879a3bf7bc270aa2315188871cc74ff72b82ae31a89e5582eab975a963c", "text": "and \nangiogenesis\nBarczyk, M., Carracedo, S., Gullberg, D., 2010. Integrins. Cell Tissue \nRes. 339, 269\u2013280.\nClark, I.M., Swingler, T.E., Sampieri, C.L., Edwards, D.R., 2008. The \nregulation of matrix metalloproteinases and their inhibitors. Int. J. \nBiochem. Cell Biol. 40, 1362\u20131378.\nGialeli, C., Theocharis, A.D., Karamanos, N.K., 2011. Roles of matrix \nmetalloproteinases in cancer progression and their pharmacological \ntargeting. FEBS J. 278, 16\u201327. ( Somewhat discouraging review of clinical \ntrials data with MMP inhibitors )\nGahmberg, C.G., Fagerholm, S.C., Nurmi, S.M., et al., 2009. Regulation \nof integrin activity and signalling. Biochim. Biophys. Acta 1790, \n431\u2013444. ( Crisp review of the control of cell signalling by integrins )\nJackson, H.W., Defamie, V., Waterhouse, P., Khokha, R., 2017. TIMPs: \nversatile extracellular regulators in cancer. Nat. Rev. Cancer 17, 38\u201353. \n(Thorough review of the roles of TIMPs, ADAMs and MMPs in cancer )\nJ\u00e4rvel\u00e4inen, H., Sainio, A., Koulu, M., Wight, T.N., Penttinen, R., 2009. \nExtracellular matrix molecules: potential targets in pharmacotherapy. \nPharmacol. Rev. 61, 198\u2013223. ( Comprehensive review of the role of the \nextracellular matrix [ECM] in the cellular events involved in proliferation \nand differentiation with discussion of the ECM as a potential target for new \ndrug development )\nMarastoni, S., Ligresti, G., Lorenzon, E., Colombatti, A., Mongiat, M., \n2008. Extracellular matrix: a matter of life and death. Connect. Tissue mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5910, "end_char_idx": 7884, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "805c864d-0d56-4773-9ff5-7a885e35dd84": {"__data__": {"id_": "805c864d-0d56-4773-9ff5-7a885e35dd84", "embedding": null, "metadata": {"page_label": "99", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "be206d83-2285-4564-adec-859ecb1853ec", "node_type": null, "metadata": {"page_label": "99", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "508cd0cbc68bfe128f09d7981754f98e7b4007df40b55a9f57667e2a037b9611"}, "3": {"node_id": "d4e7d1a6-939a-4ec1-81cd-1611ca8adc95", "node_type": null, "metadata": {"page_label": "99", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0d5965e1517f3ec09dcec302e0c836787e9d6c7cddb705c9b7920d467648985e"}}, "hash": "dbde67810bd58abaf00ba5119eba611bb0e7a594c1cfdc638ff6a0ebf836a6a7", "text": "93\nCellular mechanisms: host defence 7 GENERAL PRINCIPLES SECTION 1 \nOVERVIEW\nEveryone has experienced an inflammatory episode \nat some time or other, and will be familiar with the \ncharacteristic symptoms such as redness, swelling, heat, \npain and loss of function at the site of injury sometimes accompanied by fever and malaise. Inflammatory \nmediators are considered separately in Chapters 18 \nand 19; here we focus on the cellular players involved \nin the host defence response and explain the bare bones of this crucial and sophisticated mechanism. \nUnderstanding these cellular responses and their func -\ntions provides an essential basis for understanding \nthe actions of anti-inflammatory and immunosuppres -\nsant drugs \u2013 a major class of therapeutic agents with \nmultiple clinical applications (see Ch. 27).\nINTRODUCTION\nAll living creatures are born into a world that poses a \nconstant challenge to their physical well-being and survival. \nEvolution, which has equipped us with homeostatic systems \nthat maintain a stable internal environment in the face of changing external temperatures and fluctuating supplies \nof food and water, has also provided us with mechanisms \nfor combating the ever-present threat of infection and for promoting healing and restoration of normal function in \nthe event of injury. In mammals, this function is subserved \nby the innate and acquired (or adaptive) immune systems, \nworking together with a variety of mediators and mecha -\nnisms which, when deployed collectively, give rise to what \nwe term the inflammatory response . Generally, this acts to \nprotect us, but occasionally it goes awry, leading to a \nspectrum of autoimmune and inflammatory diseases which \nrequire drug therapy to restore order.\nThe main functions of this host inflammatory response \nthen, are defence and repair \u2013 in other words, nothing less than the on-going biosecurity and survival of the organism. \nImmunodeficiency due, for example, to genetic causes (e.g. leukocyte adhesion deficiency ), infection with organisms such \nas HIV, radiation overexposure or immunosuppressant drugs, is usually a life-threatening condition.\nLike airport security systems in the mundane world, the \nbody has the cellular and molecular equivalents of guards, identity checks, alarm systems and a communication network with which to summon back-up when required. \nIt also has access to an astonishing data bank that stores \nprecise molecular details of previous illegal intruders and prevents them from returning. This host response has two main components, which work hand-in-hand. These are:\n\u2022\tThe\tinnate, \u2018non-adaptive\u2019 response. This developed \nearly in evolution and is present in virtually all organisms. In fact, some of the key mammalian gene families and other components were first identified in \nplants and insects. This is the first line of defence.\n\u2022\tThe\tadaptive immune response. This appeared much \nlater in evolutionary terms and is found only in vertebrates. It provides the physical basis for our \nimmunological \u2018memory\u2019 and is the second, and supremely effective, line of defence.\n1One immunologist described the innate immune response as the \norganism\u2019s \u2018knee jerk\u2019 response to infection; it is an excellent \ndescription.The inflammatory response \n\u2022\tThe\tinflammatory \tresponse \toccurs \tin \ttissues \tfollowing \t\ninjury\tor\texposure \tto \ta \tpathogen \tor \tother \tnoxious \t\nsubstance.\n\u2022\tIt\tusually \thas \ttwo \tcomponents: \tan \tinnate\tnon-adaptive \t\nresponse\tand \tan \tadaptive\t(acquired \tor \tspecific) \t\nimmunological \tresponse.\n\u2022\tThese\treactions \tare \tgenerally \tprotective, \tbut \tif \t\ninappropriately \tdeployed \tthey \tare \tdeleterious.\n\u2022\tThe\tnormal \toutcome \tof \tthe \tresponse \tis \thealing \twith \tor \t\nwithout\tscarring; \talternatively, \tif", "start_char_idx": 0, "end_char_idx": 3759, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d4e7d1a6-939a-4ec1-81cd-1611ca8adc95": {"__data__": {"id_": "d4e7d1a6-939a-4ec1-81cd-1611ca8adc95", "embedding": null, "metadata": {"page_label": "99", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "be206d83-2285-4564-adec-859ecb1853ec", "node_type": null, "metadata": {"page_label": "99", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "508cd0cbc68bfe128f09d7981754f98e7b4007df40b55a9f57667e2a037b9611"}, "2": {"node_id": "805c864d-0d56-4773-9ff5-7a885e35dd84", "node_type": null, "metadata": {"page_label": "99", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dbde67810bd58abaf00ba5119eba611bb0e7a594c1cfdc638ff6a0ebf836a6a7"}}, "hash": "0d5965e1517f3ec09dcec302e0c836787e9d6c7cddb705c9b7920d467648985e", "text": "\thealing \twith \tor \t\nwithout\tscarring; \talternatively, \tif \tthe \tunderlying \tcause \t\npersists,\tchronic \tinflammation \tresults.\n\u2022\tMany\tof \tthe \tdiseases \tthat \trequire \tdrug \ttreatment \t\ninvolve\tinflammation. \tUnderstanding \tthe \taction \tand \t\nuse\tof\tanti-inflammatory \tand \timmunosuppressive \t\ndrugs\tnecessitates \tunderstanding \tthe \tinflammatory \t\nreaction.\nTHE INNATE IMMUNE RESPONSE\nMucosal epithelial tissues, which are exposed to the external \nenvironment, constantly secrete antibacterial proteins such \nas defensins together with a type of \u2018all purpose\u2019 immuno -\nglobulin (Ig)A as a sort of pre-emptive defensive strategy, \nbut elsewhere the innate response is activated immediately \nfollowing infection or injury.1\nPATTERN RECOGNITION\nOne of the most important functions of any security system \nis the ability to establish identity. How does an organism \ndecide whether a cell or stray molecule is a bona fide citizen \nor an unwanted and potentially dangerous intruder? In \nthe case of the innate response this is achieved through a \nnetwork of pattern recognition receptors (PRRs). They recognise mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3701, "end_char_idx": 5288, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3f23568d-d209-43ff-8a7a-09a1396bd307": {"__data__": {"id_": "3f23568d-d209-43ff-8a7a-09a1396bd307", "embedding": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "551b6a42-8c74-4f54-a581-ae3f30d66d91", "node_type": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67474c7e8dc9dc67f3cf721b20d8197e0e56771d286ac7bf7ce85bb5c358033d"}, "3": {"node_id": "384e0a9b-7528-485a-8fb3-f5a94502198a", "node_type": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "802fc83d78fb7e19602d965927d9068c5bf9b88c70aa2fff7dbfce32b523b87e"}}, "hash": "e0e5fe794ef7b2e5de6162e4b74f33d5982c4eb2127cc9a4b35f1df4edfcdc00", "text": "7 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n94Humans have a repertoire of 10 TLRs but some other \nanimals have more. Structurally, they are transmembrane \nglycoproteins belonging to the receptor tyrosine kinase family \n(see Ch. 3). Phylogenetically they are highly conserved. \nUnlike the antigen receptors on T and B cells that develop \nand change through life, endowing each lymphocyte clone \nwith a structurally unique receptor (see later), TLRs are encoded for by discrete genes in the host DNA. Table 7.1 \nlists these receptors and the chief pathogenic products they \nrecognise, where these are known. There are two main types of TLR, located respectively on the cell surface and in endosomes. The latter type generally recognises pathogen \nRNA/DNA (presumably because they appear in phago -\nsomes), while the former recognises other pathogen \ncomponents such as cell wall material, endotoxin, etc. Some \nTLRs also recognise damage associated molecular patterns \n(DAMPs), substances released when host cells are damaged \n(e.g. heat shock proteins) thus providing an additional way \nof monitoring internal damage.\nHow a single family of receptors can recognise such a \nwide spectrum of different chemicals is a molecular mystery. Some act together (e.g. TLR 1, 2 and 6), in other cases they \nsolve the problem by recruiting additional \u2018accessory\u2019 proteins that modulate their binding properties (e.g. TLR \n4). When activated, Toll receptors dimerise and initiate \ncomplex signalling pathways that activate genes coding for proteins and factors crucial to the deployment or \nmodulation of the inflammatory response, many of which \nwe will discuss further. Interestingly from the pharm -\nacological viewpoint, TLR 7 also recognises some synthetic antiviral compounds such as imidazoquinolones . The ability \nof these drugs to provoke TLR activation probably underlies their clinical effectiveness (see Ch. 53).\nTLRs are strategically located on \u2018sentinel\u2019 cells \u2013 those \nlikely to come into early contact with invaders. These include macrophages as well as mast cells and (crucially) \ndendritic cells, which are especially abundant in skin and \nother inside\u2013outside interfaces, as well as some intestinal \nepithelial cells that are exposed to pathogens in the food \nthat we eat. Genetic defects in the TLR system have been \nobserved. These can lead to an inability to mount an effective \nhost defence response or sometimes to a constitutively active \ninflammatory response.\nHaving outlined how \u2018non-self\u2019 pathogens are detected \nby the innate immune system, we can now describe the events that follow the \u2018raising of the alarm\u2019.\nRESPONSES \u2003TO \u2003PATTERN \u2003RECOGNITION\nVascular events\nInteraction of a PAMP with TLRs triggers the sentinel cells to respond by producing a range of pro-inflammatory \npolypeptides called cytokines, including tumour necrosis factor \n(TNF) -\u03b1 and interleukin (IL)-1. The maturation and processing \nof IL-1 (and some other cytokines) is managed by inflam-\nmasomes, intracellular multiprotein complexes that vary \naccording to the type of inflammatory stimulus. The inflammasome thus initiates a precisely tailored inflam -\nmatory response appropriate to the situation (see Yang \net al., 2015, for a recent overview).\nAlso released, either as a direct consequence of tissue \ndamage or following cytokine stimulation, are lower \nmolecular-weight inflammatory mediators (such as prostaglandins and histamine). These act on the vascular endothelial cells of the postcapillary venules, causing expres -\nsion of adhesion molecules on the intimal surface and an The innate immune response \n\u2022\tThe\tinnate \tresponse \toccurs \timmediately \ton \tinjury \tor \t\ninfection.\tIt", "start_char_idx": 0, "end_char_idx": 3679, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "384e0a9b-7528-485a-8fb3-f5a94502198a": {"__data__": {"id_": "384e0a9b-7528-485a-8fb3-f5a94502198a", "embedding": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "551b6a42-8c74-4f54-a581-ae3f30d66d91", "node_type": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67474c7e8dc9dc67f3cf721b20d8197e0e56771d286ac7bf7ce85bb5c358033d"}, "2": {"node_id": "3f23568d-d209-43ff-8a7a-09a1396bd307", "node_type": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e0e5fe794ef7b2e5de6162e4b74f33d5982c4eb2127cc9a4b35f1df4edfcdc00"}, "3": {"node_id": "16d2ca7b-ecf9-4bfc-897c-41753862c9c7", "node_type": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69658da6d38676de3f4db5cb001407a00f07c968309704ea018a9336cfec3c3c"}}, "hash": "802fc83d78fb7e19602d965927d9068c5bf9b88c70aa2fff7dbfce32b523b87e", "text": "\toccurs \timmediately \ton \tinjury \tor \t\ninfection.\tIt \tcomprises \tvascular \tand \tcellular \telements. \t\nMediators \tgenerated \tby \tcells \tor \tfrom \tplasma \tmodify \t\nand\tregulate \tthe \tmagnitude \tof \tthe \tresponse.\n\u2022\tUtilising \tToll \tand \tother \trecognition \treceptors, \tsentinel \t\ncells\tin\tbody \ttissues, \tsuch \tas \tmacrophages, \tmast \tand \t\ndendritic\tcells \tdetect \tspecific \tpathogen-associated \t\nmolecular\tpatterns. \tThis \ttriggers \tthe \trelease \tof \t\ncytokines, \tparticularly \tinterleukin \t(IL)-1 \tand \ttumour \t\nnecrosis\tfactor \t(TNF)- \u03b1,\tas\twell\tas \tvarious \t\nchemokines.\n\u2022\tIL-1\tand \tTNF- \u03b1\tact\ton\tlocal \tpostcapillary \tvenular \t\nendothelial \tcells, \tcausing:\n\u2013\tvasodilatation \tand \tfluid \texudation\n\u2013\texpression \tof \tadhesion \tmolecules \ton \tthe \tcell \t\nsurfaces\n\u2022\tExudate \tcontains \tenzyme \tcascades \tthat \tgenerate \t\nbradykinin \t(from \tkininogen), \tand \tC5a \tand \tC3a \t(from \t\ncomplement). \tComplement \tactivation \tlyses \tbacteria.\n\u2022\tC5a\tand \tC3a \tstimulate \tmast \tcells \tto \trelease \thistamine, \t\nwhich\tdilates \tlocal \tarterioles.\n\u2022\tTissue\tdamage \tand \tcytokines \trelease \tprostaglandins \t\nPGI 2\tand\tPGE 2\t(vasodilators) \tand \tleukotriene \t(LT)B 4\t(a\t\nchemotaxin).\n\u2022\tCytokines \tstimulate \tsynthesis \tof \tvasodilator \tnitric \t\noxide,\twhich \tincreases \tvascular \tpermeability.\n\u2022\tUsing\tadhesion \tmolecules, \tleukocytes \troll \ton, \tadhere \t\nto\tand\tfinally \tmigrate \tthrough \tactivated \tvascular \t\nendothelium \ttowards \tthe \tpathogen \t(attracted \tby \t\nchemokines, \tIL-8, \tC5a, \tand \tLTB 4),\twhere\t\nphagocytosis \tand \tbacterial \tkilling \ttakes \tplace.\n2The name, which loosely translates from German as \u2018Great!\u2019 or \n\u2018Eureka!\u2019, has remained firmly attached to the family. Discovered in \nfruit fly experiments, Christiane N\u00fcsslein-Volhard exclaimed \u2018Das ist ja \ntoll!\u2019 The name has stuck since then.pathogen-associated molecular patterns (PAMPs) \u2013 common \nproducts produced by bacteria, fungi, parasites and viruses, \nwhich they cannot readily change to evade detection. PRRs \ninclude G protein\u2013coupled receptors such as the FPR (formyl peptide receptor) family that recognises N-formylated \npeptides characteristic of bacterial protein synthesis (and \nliberated from damaged mitochondria too), and cytoplasmic receptors such as the NOD-like receptors (Nucleotide-binding \nOligomerization Domain-like receptors) \u2013 a large family \nof intracellular proteins that can recognise fragments of bacterial proteoglycan, as well as several other families of molecules.\nAmong the best-studied of these PRRs are the Toll-like \nreceptors\n (TLRs: see Jimenez et al., 2016,", "start_char_idx": 3633, "end_char_idx": 6192, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "16d2ca7b-ecf9-4bfc-897c-41753862c9c7": {"__data__": {"id_": "16d2ca7b-ecf9-4bfc-897c-41753862c9c7", "embedding": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "551b6a42-8c74-4f54-a581-ae3f30d66d91", "node_type": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67474c7e8dc9dc67f3cf721b20d8197e0e56771d286ac7bf7ce85bb5c358033d"}, "2": {"node_id": "384e0a9b-7528-485a-8fb3-f5a94502198a", "node_type": null, "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "802fc83d78fb7e19602d965927d9068c5bf9b88c70aa2fff7dbfce32b523b87e"}}, "hash": "69658da6d38676de3f4db5cb001407a00f07c968309704ea018a9336cfec3c3c", "text": "for a recent review). \nThe Toll2 gene was first identified in Drosophila in the mid-\n1990s. Analogous genes were soon found in vertebrates \nand it was quickly established that as a family, their main \njob was to detect highly conserved components in pathogens and to signal their presence to both arms of the immune \nsystem.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6240, "end_char_idx": 7045, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1e42e95b-f727-4728-b563-22d63a48d735": {"__data__": {"id_": "1e42e95b-f727-4728-b563-22d63a48d735", "embedding": null, "metadata": {"page_label": "101", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5b2b54a-7b6a-43d2-bc9a-109d23b4a347", "node_type": null, "metadata": {"page_label": "101", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff1f211f4e04ee4444a0ec2c9b9d7af8712a7a8d961b46ba5846dd7de242a903"}, "3": {"node_id": "e44672d9-e397-4d81-96ee-c638d48479ba", "node_type": null, "metadata": {"page_label": "101", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "31f904146b9d137b34d4e533fe081025157c793674fd41f2251cc3b36e33f8d9"}}, "hash": "43eba12f8316fe8152dfca0b66a647a5901fb872bc19814fbd66d353e6b8cba4", "text": "7 CELLuLAR mEChANIS mS: ho St dEfENCE\n95pathway of activation is termed the alternative pathway (see Fig. 7.1) \nas opposed to the classic pathway, which is dealt with later. One of \nthe main events is the enzymatic splitting of C3, giving rise to various \npeptides, one of which, C3a (termed an anaphylatoxin), stimulates \nmast cells to secrete further chemical mediators and can also directly \nstimulate smooth muscle, while C3b (termed an opsonin) attaches to \nthe surface of a microorganism, facilitating ingestion by phagocytes. \nC5a, generated enzymatically from C5, also releases mediators from \nmast cells and is a powerful chemotactic attractant and activator of \nleukocytes.\nThe final components in the sequence, complement-derived mediators \n(C5 to C9), coalesce to form a membrane attack complex that can attach \nto certain bacterial membranes, leading to lysis. Complement can \ntherefore mediate the destruction of invading bacteria or damage \nmulticellular parasites; however, it may sometimes cause injury to the host. The principal enzymes of the coagulation and fibrinolytic \ncascades, thrombin and plasmin, can also activate the cascade by \nhydrolysing C3, as can enzymes released from leukocytes.\nThe coagulation system and the fibrinolytic system are described in \nChapter 25. Factor XII is activated to XIIa (e.g. by collagen), and the \nend product, fibrin, laid down during a host\u2013pathogen interaction, \nmay also serve to limit the extent of the infection. Thrombin is \nadditionally involved in the activation of the kinin (see Fig. 7.1) and, indirectly, the fibrinolytic systems (see Ch. 25).\nThe kinin system is another enzyme cascade relevant to inflammation. \nIt yields several pro-inflammatory and pain-producing mediators, in \nparticular bradykinin (see Fig. 7.1).\nEventually, the exudate drains through the lymphatics to \nlocal lymph nodes or lymphoid tissue, where the products \nof the invading microorganism trigger the adaptive phase \nof the response.increase in vascular permeability (which allows immune cells to pass from the blood to the affected tissue).\nLeukocytes adhere to the endothelial cells through \ninteractions between their cell surface integrins and adhe -\nsion molecules on endothelial cells, and this halts their flow through the microcirculation. They are then able to \nmigrate out of the vessels, attracted by chemotaxins gener-\nated by the microorganisms themselves or as a result of \ntheir interaction with the tissues. Polypeptide chemokines \nreleased during TLR activation play an important part in this. (Cytokines and chemokines are considered separately \nin Ch. 19.)\nThe initial vascular events also include dilatation of the \nsmall arterioles, resulting in increased blood flow. This is followed by a slowing (and sometimes a cessation) of blood \nflow and an increase in the permeability of the postcapillary \nvenules allowing exudation of fluid. This vasodilatation is brought about by mediators, including histamine, prosta-glandin (PG)E\n2 and PGI 2 (prostacyclin) released from injured \ncells, some of which act together with cytokines to increase \nvascular permeability.\nThe resulting fluid exudate contains the components for \nfour proteolytic enzyme cascades: the complement system, \nthe coagulation system, the fibrinolytic system and the kinin \nsystem (Fig. 7.1). The components of these cascades are \ninactive proteases that are activated by cleavage, each \nactivated component then activating the next.\n\u25bc The complement system comprises nine major components, designated \nC1 to C9. Activation of the cascade is", "start_char_idx": 0, "end_char_idx": 3583, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e44672d9-e397-4d81-96ee-c638d48479ba": {"__data__": {"id_": "e44672d9-e397-4d81-96ee-c638d48479ba", "embedding": null, "metadata": {"page_label": "101", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5b2b54a-7b6a-43d2-bc9a-109d23b4a347", "node_type": null, "metadata": {"page_label": "101", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff1f211f4e04ee4444a0ec2c9b9d7af8712a7a8d961b46ba5846dd7de242a903"}, "2": {"node_id": "1e42e95b-f727-4728-b563-22d63a48d735", "node_type": null, "metadata": {"page_label": "101", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43eba12f8316fe8152dfca0b66a647a5901fb872bc19814fbd66d353e6b8cba4"}}, "hash": "31f904146b9d137b34d4e533fe081025157c793674fd41f2251cc3b36e33f8d9", "text": "major components, designated \nC1 to C9. Activation of the cascade is initiated by substances derived \nfrom microorganisms, such as yeast cell walls or endotoxins. This Table 7.1 The human toll-like receptor (TLR) family of pattern recognition receptors (PRRs)\nPRRPathogen or endogenous \nproduct recognised Ligand Sites of expression Location\nTLR 2 (usually acting \ntogether with TLR 1 , \nTLR 6 and possiblyTLR 10)Bacteria (Gm pos)MycoplasmaParasitesYeastDamaged host cellsLipoproteinsLipoteichoic acidGPI anchorsCell wall carbohydratesHeat shock proteinsMonocyte/macrophagesSome dendritic cellsB lymphocytesMast cells\nSurface\nTLR 4\naBacteria (Gm neg)VirusDamaged host cellsLipopolysaccharideSome viral proteinsHeat shock proteinsFibrinogenHyaluronic acidMonocyte/macrophagesSome dendritic cellsMast cellsIntestinal epithelium\nTLR 5 Bacteria FlagellinMonocyte/macrophagesSome dendritic cellsIntestinal epithelium\nTLR 3 Virus Viral dsRNADendritic cellsB lymphocytes\nIntracellular (endosomal)TLR 7 VirusViral ssRNASome synthetic drugsMonocyte/macrophages\nTLR 8 Virus Viral ssRNA Mast cells\nTLR 9 BacteriaBacterial CpG containing Bacterial DNASelf DNAB lymphocytes\naOperates\tin \tconjunction \twith \tMD-2 \t(lymphocyte \tantigen \t96, \ta \tlipopolysaccharide \tbinding \tprotein).\nCpG DNA, \tunmethylated \tCG \tdinucleotide; \tGm neg/pos, \tGram-negative/positive \t(bacteria); \tGPI,\tglycosylphosphatidylinositol \tanchoring \t\nproteins;\tssRNA,\tsingle-stranded \tRNA; \tdsRNA,\tdouble-stranded \tRNA.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3515, "end_char_idx": 5472, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "146f0be5-66ac-4746-b4a3-32e81d5c18e3": {"__data__": {"id_": "146f0be5-66ac-4746-b4a3-32e81d5c18e3", "embedding": null, "metadata": {"page_label": "102", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e46b303c-f250-46c9-be33-0eea50e6a1c7", "node_type": null, "metadata": {"page_label": "102", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "22c896fa41559bc3452f4b07c53a4316bf1730acf0e92aac9a7119552e5ec0d3"}, "3": {"node_id": "5bb9fdc9-f998-4edd-abde-f843da32e42c", "node_type": null, "metadata": {"page_label": "102", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1b2b56c422c6634e202ef5012b48a72e794df95712364c62c35f7ad331620f9c"}}, "hash": "4699ba465a57d38f469939576f7e72019575d87ce86bf2f901bb12df07f5821b", "text": "7 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n96whereas others, such as C5a, are produced locally or in \nsome cases released (e.g. chemokines such as IL-8), from \nnearby cells such as macrophages.\nNeutrophils can engulf, kill and digest microorganisms. \nTogether with eosinophils, they have surface receptors for C3b, which acts as an opsonin that forms a link between \nneutrophil and invading bacterium (an even more effective link may be made by antibodies.) Neutrophils kill micro -\norganisms by internalising them into internal vacuoles. An NADPH oxidase enzyme on the leukocyte surface regulates ion transport such that the pH of the normally acidic vacuole is raised and optimal enzymatic digestion of the organism \nby neutral proteases can occur. Toxic oxygen radicals are \nalso produced by this enzyme but it is now believed that these are less important in microbial killing (see Segal, 2016). \nHowever, if the neutrophil is inappropriately activated, \nthese biochemical weapons may be turned inadvertently on the host\u2019s tissues, causing damage. When neutrophils \nhave exhausted their potential, they undergo apoptosis \nand are cleared by phagocytic macrophages. It is this mass of live and apoptotic neutrophils that constitutes \u2018pus\u2019.\nMast cells\nImportant \u2018sentinel\u2019 cells that express TLRs, mast cells also \nhave surface receptors both for IgE and for the complement-\nderived anaphylatoxins C3a and C5a. Ligands acting at these Cellular events\nOf the cells involved in inflammation, some (e.g. vascular endothelial cells, mast cells, dendritic cells and tissue \nmacrophages) are normally present in tissues, while other \nactively motile cells (e.g. leukocytes) gain access from the circulating blood.\nPolymorphonuclear leukocytes\nNeutrophil polymorphs \u2013 the \u2018shock troops\u2019 of inflammation \n\u2013 are the first blood leukocytes to enter an infected or \ndamaged tissue (Fig. 7.2). The whole process is cleverly choreographed: under direct observation, the neutrophils may be seen first to roll along the activated endothelium, \nthen to adhere and finally to migrate out of the blood vessel \nand into the extravascular space. This process is regulated by the successive activation of different families of adhesion \nmolecules (selectins, intercellular adhesion molecule [ICAM] \nand integrins) on the inflamed endothelium that engage \ncorresponding counter-ligands on the neutrophil, capturing \nit as it rolls along the surface, stabilising its interaction \nwith the endothelial cells and enabling it to migrate out of the vessel (using a further adhesion molecule termed \nPECAM, Platelet Endothelial Cell Adhesion Molecule). The \nneutrophil is attracted to the invading pathogen by chemicals \ntermed chemotaxins, some of which (such as the tripeptide \nformyl-Met-Leu-Phe) are released by the microorganism, COAGULATION\nCASCADECOMPLEMENT\nCASCADE\nFIBRINOLYTIC\nCASCADE\nKININ\nCASCADEPlasma fibrinogen Fibrin\nPlasma\n\u03b1-globulinThrombin\nPlasmin\nKallikreinXIIa\nBradykinin C3a\n(Vasodilator; increases vascular \npermeability; spasmogen; causes pain; generates eicosanoids; stimulates endothelial NO synthesis)Classical \npathwayAlternative \npathway\nC3\nC3b(Releases histamine;spasmogen)\nC3b\n(Opsonin)\nC5a\n(Chemotaxin; activates \nphagocytic cells; releases histamine)C1 C2 C4POSTCAPILLARY", "start_char_idx": 0, "end_char_idx": 3272, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5bb9fdc9-f998-4edd-abde-f843da32e42c": {"__data__": {"id_": "5bb9fdc9-f998-4edd-abde-f843da32e42c", "embedding": null, "metadata": {"page_label": "102", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e46b303c-f250-46c9-be33-0eea50e6a1c7", "node_type": null, "metadata": {"page_label": "102", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "22c896fa41559bc3452f4b07c53a4316bf1730acf0e92aac9a7119552e5ec0d3"}, "2": {"node_id": "146f0be5-66ac-4746-b4a3-32e81d5c18e3", "node_type": null, "metadata": {"page_label": "102", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4699ba465a57d38f469939576f7e72019575d87ce86bf2f901bb12df07f5821b"}}, "hash": "1b2b56c422c6634e202ef5012b48a72e794df95712364c62c35f7ad331620f9c", "text": "cells; releases histamine)C1 C2 C4POSTCAPILLARY VENULENeutral proteases from\nphagocytic cells\n(Lysis of bacteria)C5,6,7,8,9\nFig. 7.1\tFour\tenzyme \tcascades \tare \tactivated \twhen \tplasma \tleaks \tout \tinto \tthe \ttissues \tas \ta \tresult \tof \tthe \tincreased \tvascular \tpermeability \tof \t\ninflammation. \tFactors \tcausing \texudation \tare \tdepicted \tin \tFig. \t7.2. \tMediators \tgenerated \tare \tshown \tin \tred-bordered boxes .\tComplement \t\ncomponents \tare \tindicated \tby \tC1, \tC2, \tetc. \tWhen \tplasmin \tis \tformed, \tit \ttends \tto \tincrease \tkinin \tformation \tand \tdecrease \tthe \tcoagulation \t\ncascade.\tXIIa, \tFactor \tXIIa, \tsee \ttext. \t(Adapted \tfrom \tDale, \tM.M., \tForeman, \tJ.C., \tFan, \tT-P. \t(eds), \t1994. \tTextbook \tof \tImmunopharmacology. \t\n3rd\ted.\tBlackwell \tScientific, \tOxford.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3225, "end_char_idx": 4479, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "21438291-6488-4938-979a-c45500b1e757": {"__data__": {"id_": "21438291-6488-4938-979a-c45500b1e757", "embedding": null, "metadata": {"page_label": "103", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c56fba1-1eb6-4331-9f3f-7dbd63bc1109", "node_type": null, "metadata": {"page_label": "103", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "62a29ec129141a6156719031de6ace712a1996010eb19b71fb757c1be920dd0e"}, "3": {"node_id": "2c1514f1-777e-439c-90a5-d38c34e58a25", "node_type": null, "metadata": {"page_label": "103", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d79a5e43180db8ddad7566330334202f3c64a546e0dd41164fe8f52ba8112921"}}, "hash": "535fba51517d30120feae4b93ac45f02f01bb31144f6a2e0df18c3680a031095", "text": "7 CELLuLAR mEChANIS mS: ho St dEfENCE\n97enough, stands for Monocyte Chemoattractant Protein-1) \nand RANTES (which very unreasonably stands for Regulated \non Activation Normal T cell Expressed and Secreted; \nimmunological nomenclature has excelled itself here!).\nOnce in tissues, blood monocytes differentiate into \nmacrophages .4 The newly differentiated cell may acquire an \nM1 or an M2 phenotype, depending upon the types of \ncytokines it secretes. The former is generally regarded as \na pro-inflammatory cell, whereas the latter is probably more involved in tissue repair and healing (although this simplistic \ndistinction is currently a subject of debate: see Martinez & \nGordon, 2014). Macrophages therefore have a remarkable range of abilities, being not only a jack-of-all-trades but \nalso a master of many.\nActivation of monocyte/macrophage TLRs stimulates the \ngeneration and release of chemokines and other cytokines \nthat act on vascular endothelial cells, attract other leukocytes \nto the area and give rise to systemic manifestations of the receptors trigger mediator release, as does direct physical damage. One of the main substances released is histamine; \nothers include heparin, leukotrienes, PGD\n2, platelet-activating \nfactor (PAF), nerve growth factor and some interleukins and \nproteases. Unusually, mast cells have preformed packets of cytokines that they can release instantaneously (by Ca\n2+-mediated exocytosis, Ch. 4) when stimulated. This \nmakes them extremely effective triggers of the inflammatory \nresponse.\nMonocytes/macrophages\nMonocytes follow polymorphs into inflammatory lesions \nafter a delay (sometimes several hours). Adhesion to endothelium and migration into the tissue follow a similar \npattern of adhesive molecule binding to that seen with \nneutrophils, although monocyte chemotaxis utilises addi-tional chemokines, such as MCP-1\n3 (which, reasonably \nCapture Rolling Arrest Adhesion CrawlingTranscellularMigration\nMigrated cell\nin tissue\nPathogensParacellularLeukocytes\nin blood\nEndothelial cell\nPericyteBasement membrane\nconnective tissue\nFig. 7.2\tSimplified diagram of the events leading up to polymorphonuclear leukocyte (PMN) migration in a local acute \ninflammatory reaction. \tIn\tresponse \tto \tactivation \tof \tpattern \trecognition \treceptors, \ttissue \tmacrophages \trelease \tthe \tpro-inflammatory \t\ncytokines\tinterleukin \t(IL)-1 \tand \ttumour \tnecrosis \tfactor \t(TNF)- \u03b1.\tThese\tact \ton \tthe \tendothelial \tcells \tof \tpostcapillary \tvenules, \tcausing \t\nexudation \tof \tfluid \tand \texpression \tof \tadhesion \tfactors \tthat \trecognise \tcounter-ligands \ton \tblood-borne \tneutrophils. \tFree \tflowing \tneutrophils \tin \t\nthe\tblood\tare \tfirst \t\u2018captured\u2019 \tby \tselectins\ton\tactivated \tendothelial \tcells. \tThese \tcells \tthen \troll \talong \tthe \tendothelium \tbefore \ttheir \tprogress \tis \t\narrested\tby \tthe \taction \tof \tintegrins\tand\tthey\tadhere \tto \tthe \tvessel \twall. \tThe \tactivated \tcells \tthen \t\u2018crawl\u2019 \talong \tthe \tendothelium \tuntil \tthey \tfind \t\na\tsuitable\tsite \tfor \ttransmigration. \tIn \ta \tminority \tof \tcases, \tneutrophils \tcan \tactually \tmove \tthrough \tendothelial \tcells \t(transcellular transmigration )\t\nbut\tthey\tmainly \tmigrate", "start_char_idx": 0, "end_char_idx": 3176, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2c1514f1-777e-439c-90a5-d38c34e58a25": {"__data__": {"id_": "2c1514f1-777e-439c-90a5-d38c34e58a25", "embedding": null, "metadata": {"page_label": "103", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c56fba1-1eb6-4331-9f3f-7dbd63bc1109", "node_type": null, "metadata": {"page_label": "103", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "62a29ec129141a6156719031de6ace712a1996010eb19b71fb757c1be920dd0e"}, "2": {"node_id": "21438291-6488-4938-979a-c45500b1e757", "node_type": null, "metadata": {"page_label": "103", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "535fba51517d30120feae4b93ac45f02f01bb31144f6a2e0df18c3680a031095"}}, "hash": "d79a5e43180db8ddad7566330334202f3c64a546e0dd41164fe8f52ba8112921", "text": "\tthrough \tthe \tjunction \tbetween \tendothelial \tcells \t(paracellular transmigration ).\tFurther\tadhesion \tmolecules \tthen \tguide \t\nthe\tcell\tthrough \tthe \tgaps. \tThe \tmigrating \tcells \tmust \talso \tmigrate \tthrough \tgaps \tin \tthe \tlayer \tof \tpericytes \t(contractile \tcells) \tthat \tsurround \tthe \t\nvenules\tas \twell \tas \tthe \tbasement \tmembrane \t(comprised \tof \tconnective \ttissue). \tChemotactic \tgradients \tformed \tby \tthe \trelease \tof \tsubstances \t\nreleased\tby \tor \tfrom \tthe \tpathogen \tguide \tthe \tcell \tto \tits \ttarget \twhere \tit \tcan \tkill \tand/or \tphagocytose \tthe \tinvader. \tNeutrophils \tcharacteristically \t\ndie\tafter\tthis \tevent, \tin \twhich \tcase \tthey \tenter \tapoptosis \tand \tare \tphagocytosed \tby \tmacrophages, \tresolving \tthe \tinflammatory \tevent. \tPhoto \ninset:\tPhotomicrograph \tof \ta \tnormal, \tun-inflamed \tmicrocirculation \tin \tthe \tmesenteric \tbed \tof \tmouse \t(left-hand panel) \tand\tfollowing \ta \tperiod \tof \t\ninflammation \t(right-hand panel). \tThe\tarrows \tindicate \tneutrophils \tadhering \tto \tthe \tendothelium \tas \twell \tas \tsome \tthat \thave \talready \t\ntransmigrated. \t(Diagram \tmodified \tfrom \tNourshargh \tet \tal., \t2010. \tPicture \tcourtesy \tDrs \tS. \tYazid, \tG. \tLeoni \tand \tD. \tCooper.)\n3Human immunodeficiency virus-1 binds to the surface CD4 \nglycoprotein on monocytes/macrophages but is able to penetrate the \ncell only after binding also to MCP-1 and RANTES receptors. This is a \ncase where the innate immune system inadvertently aids the enemy.4Literally \u2018big eaters\u2019, compared with neutrophils, originally called \nmicrophages or \u2018little eaters\u2019.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3177, "end_char_idx": 5220, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7ef0d6f6-d4a2-46cf-9e96-2754e4d778b0": {"__data__": {"id_": "7ef0d6f6-d4a2-46cf-9e96-2754e4d778b0", "embedding": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4a9cf1f1-aa36-41ec-96f6-75b2f6345c1e", "node_type": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c67bbe9378a4972661d26ba063a25e39298c67b002d48424591f5e4be5150853"}, "3": {"node_id": "c8234730-0c36-4cd1-bed0-9af7c1cc54d5", "node_type": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bdc770d94d619132812337baf19f64dbda634a60fa6e74bb2abbf393eca08619"}}, "hash": "e79d0058c16afb2c6a215d95605d9d429a0798b0f68d9757d24476c0a1f2942d", "text": "7 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n98and PAF, they can generate free radicals and pro-\ninflammatory cationic proteins. Platelet-derived growth \nfactor contributes to the repair processes that follow inflam -\nmatory responses or damage to blood vessels.\nNatural killer cells\nNatural killer (NK) cells are a specialised type of lympho -\ncyte. In an unusual twist to the receptor concept, NK cells \nkill targets (e.g. virus-infected or tumour cells) that lack \nligands for inhibitory receptors on the NK cells themselves. These ligands are known as major histocompatibility complex \n(MHC) molecules, and any cells lacking these become a \ntarget for NK-cell attack, a strategy sometimes called the \n\u2018mother turkey strategy\u2019.\n5 MHC proteins are expressed on \nthe surface of most host cells and, in simple terms, are \nspecific for that individual, enabling the NK cells to avoid \ndamaging their host\u2019s cells. NK cells have other functions: they are equipped with Fc receptors and, in the presence \nof antibodies directed against a target cell, they can kill the \ncell by antibody-dependent cellular cytotoxicity.\nTHE ADAPTIVE IMMUNE RESPONSE\nThe adaptive response provides the cellular basis for an \u2018immunological memory\u2019. It provides a more powerful \ndefence than the innate response, as well as being highly \nspecific for the invading pathogen. Here we will provide only a simplified outline, stressing those aspects relevant \nfor an understanding of drug action; for more detailed \ncoverage, see textbooks in the References and Further Reading section at the end of this chapter.\nThe key cells are the lymphocytes\n6. These are long-lived \ncells derived from precursor stem cells within the bone \nmarrow. Following release into the blood and maturation, \nthey dwell in the lymphoid tissues such as the lymph nodes and spleen. Here, they are poised to detect, intercept and \nidentify foreign proteins presented to them by antigen-\npresenting cells (APCs) such as the macrophage or the \ndendritic cells. The three main groups of lymphocytes are:\n\u2022\tB cells, which mature in the bone marrow. They are \nresponsible for antibody production, i.e. the humoral immune response.\n\u2022\tT cells, which mature in the thymus. They are important in the induction phase of the immune response and in cell-mediated immune reactions.\n\u2022\tNK cells. These are really part of the innate system. They are activated by interferons and release cytotoxic granules that destroy target cells identified as \u2018foreign\u2019 \nor abnormal.\n\u25bc Fig. 7.3 shows how these cells arise. APCs ingest and process \nantigen (A\u2013D) and present fragments to naive, uncommitted CD4 T \ncells in conjunction with MHC class II molecules, or to naive CD8 T inflammatory response such as fever (many of these inflam -\nmatory mediators have pyrogenic properties). Macrophages engulf tissue debris and dead cells, as well as phagocytosing \nand killing most (but unfortunately not all) microorganisms. They also play an important part in antigen presentation. \nWhen stimulated by glucocorticoids, macrophages also secrete annexin 1 (a potent anti-inflammatory polypeptide; \nsee Ch. 34), which controls the development of the local \ninflammatory reaction helping to limit any collateral \ndamage.\nDendritic cells\nThese are present in many tissues, especially those that \nsubserve a barrier function (e.g. the skin, where they are sometimes referred to as Langerhans cells after their discov -\nerer). As a key \u2018sentinel cell\u2019 they can detect the presence of pathogens and when thus activated they can migrate into lymphoid tissue, where they play an crucial part in \nantigen presentation.\nEosinophils\nThese cells have similar capacities to neutrophils", "start_char_idx": 0, "end_char_idx": 3680, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c8234730-0c36-4cd1-bed0-9af7c1cc54d5": {"__data__": {"id_": "c8234730-0c36-4cd1-bed0-9af7c1cc54d5", "embedding": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4a9cf1f1-aa36-41ec-96f6-75b2f6345c1e", "node_type": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c67bbe9378a4972661d26ba063a25e39298c67b002d48424591f5e4be5150853"}, "2": {"node_id": "7ef0d6f6-d4a2-46cf-9e96-2754e4d778b0", "node_type": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e79d0058c16afb2c6a215d95605d9d429a0798b0f68d9757d24476c0a1f2942d"}, "3": {"node_id": "b5f3147f-c55b-44f2-9fde-14cadaf87ece", "node_type": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f7d9228a78edc178e1a82007c49a9cd80239863c9d4cc25627c866613813bedf"}}, "hash": "bdc770d94d619132812337baf19f64dbda634a60fa6e74bb2abbf393eca08619", "text": "cells have similar capacities to neutrophils but, like \nmast cells, are also \u2018armed\u2019 with a battery of substances stored in their granules, which, when released, kill multi-\ncellular parasites (e.g. helminths). These include eosinophil \ncationic protein, a peroxidase enzyme, the eosinophil major \nbasic protein and a neurotoxin . The eosinophil is considered \nby many to be of primary importance in the pathogenesis of the late phase of asthma where, it is suggested, secreted granule proteins cause damage to bronchiolar epithelium (see Fig. 29.4).\nBasophils\nBasophils are very similar in many respects to mast cells. \nExcept in certain inflammatory diseases, such as viral \ninfections and myeloproliferative disorders, the basophil content of the tissues is generally tiny and in health they \nform only <0.1% of circulating white blood cells.\nVascular endothelial cells\nVascular endothelial cells (see also Chs 23 and 24), originally \nconsidered as passive lining cells, are now known to play an active part in inflammation. Small arteriole endothelial \ncells secrete nitric oxide (NO), causing relaxation of the \nunderlying smooth muscle (see Ch. 21), vasodilatation and increased delivery of plasma and blood cells to the inflamed \narea. The endothelial cells of the postcapillary venules \nregulate plasma exudation and thus the delivery of plasma-derived mediators (see Fig. 7.1). Vascular endothelial cells express several adhesion molecules (the ICAM and selectin \nfamilies; see Fig. 7.2), as well as a variety of receptors, \nincluding those for histamine, acetylcholine and IL-1. In addition to NO, the cells can synthesise and release the \nvasodilator agents PGI\n2 and PGE 2, the vasoconstrictor agent \nendothelin, plasminogen activator, PAF and several cytokines. Endothelial cells also participate in the angio -\ngenesis that occurs during inflammatory resolution, chronic \ninflammation and cancer (see Chs 6, 7 and 57).\nPlatelets\nPlatelets are involved primarily in coagulation and throm -\nbotic phenomena (see Ch. 25) but also play a part in inflammation. They have low-affinity receptors for IgE, and may contribute to the first phase of allergic asthma (Fig. 29.1). In addition to generating thromboxane (TX)A\n2 5Richard Dawkins in River Out of Eden, citing the zoologist Schliedt, \nexplains that the \u2018rule of thumb a mother turkey uses to recognise nest \nrobbers is a dismayingly brusque one; in the vicinity of the nest, attack \nanything that moves unless it makes a noise like a baby turkey\u2019.\n6White blood cells (WBC) or leukocytes in blood are mostly neutrophils \n(50%\u201360%) or lymphocytes (20%\u201340%), with the rest being monocytes \n(3%\u20137%), eosinophils (1%\u20135%) and less than 1% basophils. The WBC \ncount in a healthy adult is in the range 3.5\u201311 million per mL of blood \u2013 higher values may indicate chronic bacterial or viral infection; lower \nlevels occur in anaemia or in immunosuppressed individuals (e.g. when \nundergoing treatment with chemotherapeutic drugs [see Ch. 57]).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3642, "end_char_idx": 6991, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b5f3147f-c55b-44f2-9fde-14cadaf87ece": {"__data__": {"id_": "b5f3147f-c55b-44f2-9fde-14cadaf87ece", "embedding": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4a9cf1f1-aa36-41ec-96f6-75b2f6345c1e", "node_type": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c67bbe9378a4972661d26ba063a25e39298c67b002d48424591f5e4be5150853"}, "2": {"node_id": "c8234730-0c36-4cd1-bed0-9af7c1cc54d5", "node_type": null, "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bdc770d94d619132812337baf19f64dbda634a60fa6e74bb2abbf393eca08619"}}, "hash": "f7d9228a78edc178e1a82007c49a9cd80239863c9d4cc25627c866613813bedf", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6983, "end_char_idx": 7158, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "367c3e8d-383d-4363-bc47-d6c9b9f85985": {"__data__": {"id_": "367c3e8d-383d-4363-bc47-d6c9b9f85985", "embedding": null, "metadata": {"page_label": "105", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8bbd8faf-a3ab-4288-8e90-26e5345469c4", "node_type": null, "metadata": {"page_label": "105", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b5d705f5c1ec99f522ac5fef9a87135579747284c8e73b26e2e01fcd1f68dd76"}, "3": {"node_id": "6a2f82e6-d943-4338-b1d2-07151d328d7d", "node_type": null, "metadata": {"page_label": "105", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2005a129f65291253185a5d005eacc3464578ad0a0909610f497700c81ab0936"}}, "hash": "f0519700dc1747b86fa067cbaca05234cdec8b67747dae030d3ebbd14ea2cf33", "text": "7 CELLuLAR mEChANISmS: hoSt dEfENCE\n99T and B lymphocytes express antigen-specific receptors \nthat recognise and react with virtually all foreign proteins \nand polysaccharides that we are likely to encounter during \nour lifetime. This receptor repertoire is generated randomly \nand so could recognise \u2018self\u2019 proteins as well as foreign \nantigens, with devastating results. However, tolerance to \nself-antigens is acquired during fetal life by apoptotic \ndeletion of T-cell clones in the thymus that recognise the \nhost\u2019s own tissues. Dendritic cells and macrophages involved \nin the innate response also have a role in preventing harmful \nimmune reactions against the host\u2019s own cells.\nThe adaptive immune response occurs in two phases, \ntermed the induction phase and the effector phase .\nTHE INDUCTION PHASE\nDuring the induction phase, antigen is \u2018presented\u2019 to T \ncells in the lymph nodes by macrophages or large dendritic \ncells. This antigen may constitute part of an invading \npathogen (e.g. the coat of a bacterium) or be released by \nsuch an organism (e.g. a bacterial toxin), or it may be a \nvaccine, an environmental agent such as pollen, an insect \nbite, a foodstuff or a substance introduced experimentally \nto study the immune response (e.g. the injection of egg \nalbumin into the guinea pig). APCs ingest and proteolytically \n\u2018process\u2019 the antigen and once they reach local lymph nodes, \nthey \u2018present\u2019 the fragments on their surface to lymphocytes cells in conjunction with MHC class I molecules, thus \u2018arming\u2019 them. \nThe armed CD4+ T cells synthesise and express IL-2 receptors and \nrelease this cytokine, which stimulates the cells by autocrine action, \ncausing generation and proliferation of T-helper zero (Th0) cells. \nAutocrine cytokines (e.g. IL-4) cause differentiation of some Th0 cells \nto give Th2 cells, which are responsible for the development of \nantibody-mediated immune responses. These Th2 (and sometimes \nTh1) cells cooperate with and activate B cells to proliferate and give \nrise eventually to memory B cells (MB) and plasma cells (P), which \nsecrete antibodies. The T cells that aid B cells in this way are referred \nto as TFH (follicular homing) cells. Further stimulation by autocrine \ncytokines (e.g. IL-2,6) cause proliferation of Th0 cells to give Th1, \nTh17 or iTreg cells. Th1 and Th17 cells secrete cytokines that activate \nmacrophages (responsible for some cell-mediated immune reactions). \niTreg (inducible Treg derived from Th0 precursors) and nTreg (natu -\nrally occurring Treg matured in the thymus) cells restrain and inhibit \nthe development of the immune response, thus preventing auto -\nimmunity and excessive immune activation. The armed CD8+ T cells \n(E) also synthesise and express IL-2 receptors and release IL-2, which \nstimulates the cells by autocrine action to proliferate and give rise to \ncytotoxic T cells (TC). These can kill virally infected cells. IL-2 secreted \nby CD4+ cells also plays a part in stimulating CD8+ cells to proliferate. \nNote that the \u2018effector phase\u2019 depicted above relates to the \u2018protective\u2019 \naction of the immune response. When the response is inappropriately \ndeployed \u2013 as in chronic inflammatory conditions such as rheumatoid \narthritis \u2013 the Th1/Th17 component of the immune response is \ndominant and the activated macrophages release IL-1 and TNF- \u03b1, \nwhich in turn trigger the release of the chemokines and inflammatory \ncytokines that play a major role in the", "start_char_idx": 0, "end_char_idx": 3457, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6a2f82e6-d943-4338-b1d2-07151d328d7d": {"__data__": {"id_": "6a2f82e6-d943-4338-b1d2-07151d328d7d", "embedding": null, "metadata": {"page_label": "105", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8bbd8faf-a3ab-4288-8e90-26e5345469c4", "node_type": null, "metadata": {"page_label": "105", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b5d705f5c1ec99f522ac5fef9a87135579747284c8e73b26e2e01fcd1f68dd76"}, "2": {"node_id": "367c3e8d-383d-4363-bc47-d6c9b9f85985", "node_type": null, "metadata": {"page_label": "105", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0519700dc1747b86fa067cbaca05234cdec8b67747dae030d3ebbd14ea2cf33"}}, "hash": "2005a129f65291253185a5d005eacc3464578ad0a0909610f497700c81ab0936", "text": "release of the chemokines and inflammatory \ncytokines that play a major role in the pathology of the disease.PCell-mediated\nimmunity:\nactivation of\nmacrophages\nCell-mediated\nimmunity:\nkills virally\ninfected cellsAntibody-mediated\nimmunityRestrain immune\nreactionsAntigen\nCD4\nTh1\nTh17\nTh17Th0\nTh0Th0\niTreg\nnTregMTCD8\nTC\nTC\nMB B\nPMHCAPC\nIL-2\nIL-2IL-2\nTGF-\u03b2,\nIL-6, IL-21\nIL-4TGF-\u03b2,\nIL-10IL-2E AB CD\nFoxP3Th1\nTh17\nTh2\nFig. 7.3\tSimplified diagram of the induction and effector phases of lymphocyte activation. \tSee\ttext\tfor\tdetails.\t MT,\tmemory\tT\tcell;\t\nMB,\tmemory\tB\tcell;\tTC,\tcytotoxic\t T\tcell;\tP,\tplasma\tcell;\tTreg,\tregulatory\t T\tcell.\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3374, "end_char_idx": 4486, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "18248a49-7cbd-4016-8c8b-3f9b47164ea5": {"__data__": {"id_": "18248a49-7cbd-4016-8c8b-3f9b47164ea5", "embedding": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "68e269cf-0e6e-4866-a060-0b7508b0d38c", "node_type": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "777f3ea3e5178cb79dda68f384ac44bee97babc56ae5249ae7ac2be652c18cd3"}, "3": {"node_id": "3572ad87-1e37-491c-b38d-beaf82d9e0f0", "node_type": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d72f709a610ded93960e9b7b24b6d0b4d46887d1f43cf5c62a3ed66251d057b1"}}, "hash": "bc1c5f2befbc8f2c23369e5cd910c209d9c0e6e7cf73bd0661b40b4568b653ee", "text": "7 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n100\u2022\tUncommitted \t(naive) \tCD4+ T-helper (Th) lymphocytes, \nor T-helper precursor (Thp) cells, in association with \nclass II MHC molecules (see Fig. 7.4).\n\u2022\tNaive\tCD8+ T lymphocytes in association with class I \nMHC molecules.7\nActivation of a T cell by an APC requires that several \n\u2018identification\u2019 and \u2018authentication\u2019 signals pass between \nthe two cells at this \u2018immune synapse\u2019 (see Fig. 7.4; see \nMedzhitov & Janeway, 2000). After activation, the T cells \nboth generate IL-2 and acquire IL-2 receptors. IL-2 has an \nautocrine8 action, stimulating proliferation and giving rise \nto a clone of T cells, termed Th0 cells, which, depending \non the prevailing cytokine milieu, give rise to different \nsubsets of armed helper cells. There are four major types of these \u2018helper cells\u2019, each of which generates a characteristic \ncytokine profile, possesses a unique surface marker profile \nand has a different role in disease. These characteristics are summarised in Table 7.2. Some potent anti-inflammatory \ndrugs block the IL-2 receptor, thus preventing lymphocyte \nproliferation (see Ch. 27).\nKnowledge of the relationship between T-cell subsets, \ntheir respective cytokine profiles and pathological conditions \ncan be used to manipulate the immune responses for disease \nprevention and treatment. There are already many experi -\nmental models in which modulation of the Th1/Th2 balance \nwith recombinant cytokines or cytokine antagonists alters \nthe outcome of the disease.\nTHE EFFECTOR PHASE\nDuring the effector phase, the activated B and T lymphocytes differentiate either into plasma cells or into memory cells. \nThe B plasma cells produce specific antibodies, which are \neffective in the extracellular fluid, but which cannot neu -\ntralise pathogens within cells. T-cell-mediated immune \nmechanisms overcome this problem by activating mac -\nrophages or directly killing virus-infected host cells. \nAntigen-sensitive memory cells are formed when the clone \nof lymphocytes that are programmed to respond to an antigen is greatly expanded after the first contact with the organism. They allow a greatly accelerated and more effective response to subsequent antigen exposure. In some \ncases, the response is so rapid and efficient that, after one \nexposure, the pathogen can never gain a foothold again. Vaccination and immunisation procedures make use of \nthis invaluable phenomenon.\nTHE\u2003ANTIBODY-MEDIATED \u2003(HUMORAL) \u2003RESPONSE\nThere are five main classes of antibody \u2013 IgG, IgM, IgE, \nIgA and IgD \u2013 which differ from each other in certain \nstructural respects. All are \u03b3-globulins (immunoglobulins), \nwhich both recognise and interact specifically with antigens \n(i.e. proteins or polysaccharides foreign to the host), as \nwell as activating one or more further components of the \nhost\u2019s defence systems.\nin combination with various MHC molecules. This is fol -\nlowed by complex interactions of those T cells with B cells and other T cells (Fig. 7.4). Two types of lymphocytes \u2018attend\u2019 APCs. They are generally distinguished by the presence, on their surface, of CD4 or CD8 receptors. These are co-\nreceptors that cooperate with the main antigen-specific receptors in antigen recognition. Macrophages also carry surface CD4 proteins.\nThe two types of lymphocyte involved in the adaptive \nresponse are:The adaptive response \n\u2022\tThe\tadaptive \t(specific, \tacquired) \timmunological \t\nresponse\tboosts", "start_char_idx": 0, "end_char_idx": 3430, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3572ad87-1e37-491c-b38d-beaf82d9e0f0": {"__data__": {"id_": "3572ad87-1e37-491c-b38d-beaf82d9e0f0", "embedding": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "68e269cf-0e6e-4866-a060-0b7508b0d38c", "node_type": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "777f3ea3e5178cb79dda68f384ac44bee97babc56ae5249ae7ac2be652c18cd3"}, "2": {"node_id": "18248a49-7cbd-4016-8c8b-3f9b47164ea5", "node_type": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc1c5f2befbc8f2c23369e5cd910c209d9c0e6e7cf73bd0661b40b4568b653ee"}, "3": {"node_id": "e9b6b475-f705-4d1c-8d1c-db4f72afdc1a", "node_type": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f8e99f31b7582d303fc6312a5797a4d432cf397bbbe275bc00a370a78227b810"}}, "hash": "d72f709a610ded93960e9b7b24b6d0b4d46887d1f43cf5c62a3ed66251d057b1", "text": "\t(specific, \tacquired) \timmunological \t\nresponse\tboosts \tthe \teffectiveness \tof \tthe \tinnate \t\nresponses. \tIt \thas \ttwo \tphases, \tthe \tinduction \tphase \tand \t\nthe\teffector \tphase, \tthe \tlatter \tconsisting \tof \t(i) \tantibody-\nmediated\tand \t(ii) \tcell-mediated \tcomponents.\n\u2022\tDuring\tthe \tinduction phase ,\tnaive\tT\tcells \tbearing \teither \t\nthe\tCD4\tor \tthe \tCD8 \tco-receptors \tare \tpresented \twith \t\nantigen,\ttriggering \tproliferation:\n\u2013\tCD8-bearing \tT \tcells \tdevelop \tinto \tcytotoxic \tT \tcells \t\nthat\tcan\tkill \tvirally \tinfected \tcells\n\u2013\tCD4-bearing \tT-helper \t(Th) \tcells \tare \tstimulated \tby \t\ndifferent\tcytokines \tto \tdevelop \tinto \tTh1, \tTh2, \tTh17 \tor \t\nTreg\tcells\n\u2013\tTh1\tcells\tdevelop \tinto \tcells \tthat \trelease \tcytokines \t\nthat\tactivate \tmacrophages; \tthese \tcells, \talong \twith \t\ncytotoxic\tT \tcells, \tcontrol \tcell-mediated \tresponses\n\u2013\tTh2\tcells\tcontrol \tantibody-mediated \tresponses \tby \t\nstimulating \tB \tcells \tto \tproliferate, \tgiving \trise \tto \t\nantibody-secreting \tplasma \tcells \tand \tmemory \tcells\n\u2013\tTh17\tcells\tare\tsimilar \tto \tTh1 \tcells \tand \tare \timportant \t\nin\tsome\thuman \tdiseases \tsuch \tas \trheumatoid \t\narthritis\n\u2013\tTreg\tcells\trestrain \tthe \tdevelopment \tof \tthe \timmune \t\nresponse.\n\u2022\tThe\teffector \tphase \tutilises \tboth \tantibody- \tand \t\ncell-mediated \tresponses.\n\u2022\tAntibodies \tprovide:\n\u2013\tmore\tselective \tcomplement \tactivation\n\u2013\tmore\teffective \tpathogen \tphagocytosis\n\u2013\tmore\teffective \tattachment \tto \tmulticellular \tparasites, \t\nfacilitating \ttheir \tdestruction\n\u2013\tdirect\tneutralisation \tof \tsome \tviruses \tand \tof \tsome \t\nbacterial\ttoxins.\n\u2022\tCell-mediated \treactions \tprovide:\n\u2013\tCD8+\tcytotoxic \tT \tcells \tthat \tkill \tvirus-infected \tcells\n\u2013\tcytokine-releasing \tCD4+\tT\tcells\tthat \tenable \t\nmacrophages \tto \tkill \tintracellular \tpathogens \tsuch \tas \t\nthe\ttubercle \tbacillus\n\u2013\tmemory \tcells \tprimed \tto \treact \trapidly \tto \ta \tknown \t\nantigen\n\u2013\thelp\tfor \tB-cell \tactivation.\n\u2022\tInappropriately \tdeployed \timmune \treactions \tare \ttermed \t\nhypersensitivity reactions.\n\u2022\tAnti-inflammatory \tand \timmunosuppressive \tdrugs \tare \t\nused\twhen \tthe \tnormally \tprotective \tinflammatory \tand/or \t\nimmune\tresponses \tescape \tcontrol.\n7The main reason that it is difficult to transplant organs such as kidneys \nfrom one person to another is that their respective MHC molecules are \ndifferent. Lymphocytes in the recipient will react to non-self (", "start_char_idx": 3379, "end_char_idx": 5729, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e9b6b475-f705-4d1c-8d1c-db4f72afdc1a": {"__data__": {"id_": "e9b6b475-f705-4d1c-8d1c-db4f72afdc1a", "embedding": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "68e269cf-0e6e-4866-a060-0b7508b0d38c", "node_type": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "777f3ea3e5178cb79dda68f384ac44bee97babc56ae5249ae7ac2be652c18cd3"}, "2": {"node_id": "3572ad87-1e37-491c-b38d-beaf82d9e0f0", "node_type": null, "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d72f709a610ded93960e9b7b24b6d0b4d46887d1f43cf5c62a3ed66251d057b1"}}, "hash": "f8e99f31b7582d303fc6312a5797a4d432cf397bbbe275bc00a370a78227b810", "text": "allogenic) \nMHC molecules in the donor tissue, which is then likely to be rejected \nby a rapid and powerful immunological reaction.\n8In \u2018autocrine\u2019 signalling the mediator acts on the cell that released it. In \n\u2018paracrine\u2019 signalling, the mediator acts on neighbouring cells, whilst in \n\u2018juxtacrine\u2019 signalling, it acts on cells in direct contact.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5782, "end_char_idx": 6608, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "97fa29ab-e644-4f9f-b4da-b4ed2569dd9c": {"__data__": {"id_": "97fa29ab-e644-4f9f-b4da-b4ed2569dd9c", "embedding": null, "metadata": {"page_label": "107", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "61e96006-6546-4a6b-b2ad-c7bebffc2675", "node_type": null, "metadata": {"page_label": "107", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8ed4136e9034b6713e2950521a29a80a40b38427b48fe3362dec072945d52ea0"}, "3": {"node_id": "6b1f4e28-5122-4077-89d7-358f01817061", "node_type": null, "metadata": {"page_label": "107", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "471de5b8e4a4381a93c2fc3978ae89162773b5ebafdaead57714d54b12cb840c"}}, "hash": "92cc6d38b554ddb109d62d2ea1055013ba075e9a5a86ae58b46dee7b9c61cafa", "text": "7 CELLuLAR mEChANIS mS: ho St dEfENCE\n101APC\nT\nCD4Co-stimulatory signalAntigen-presenting cell\n(APC)Antigenic peptide\nMHC II\nCD4+ T cell\nCD4 coreceptor\nChemokine receptorB7 CD28AB\nFig. 7.4\tThe activation of a T cell by an antigen-presenting cell (APC). \t(A)\tThe\tAPC \tencounters \ta \tforeign \tprotein \tand \tthis \tis \t\nproteolytically \tprocessed \tinto \tpeptide \tfragments. \tThe \tactivation \tprocess \tthen \tinvolves \tthree \tstages: \t(i) \tInteraction \tbetween \tthe \tcomplex \tof \t\npathogen-derived \tantigen \tpeptide \tfragments \twith \tmajor \thistocompatibility \tcomplex \t(MHC) \tclass \tII \tand \tthe \tantigen-specific \treceptor \ton \tthe \t\nT\tcell;\t(B)\t(ii) \tInteraction \tbetween \tthe \tCD4 \tco-receptor \ton \tthe \tT \tcell \tand \tan \tMHC \tmolecule \ton \tthe \tAPC; \t(iii) \tThe \tB7 \tprotein \ton \tthe \tAPC \tcell \t\nsurface\tbinds \tto \tCD28 \ton \tthe \tT \tcell \tproviding \ta \tco-stimulatory \tsignal. \tThe \tCD4 \tco-receptor, \ttogether \twith \ta \tT-cell \tchemokine \treceptor, \t\nconstitute \tthe \tmain \tbinding \tsites \tfor \tthe \tHIV \tvirus \t(see \tFig. \t53.3). \t\nTable 7.2 Lymphocyte subsets, their role in host defence and relationship to inflammatory disease\nSubset Cytokine trigger Main role in adaptive responseMain \ncytokines produced Role in disease\nTh0 IL-2 Precursor cells for further differentiation \u2014 \u2014\nTh1 IL-2\u2018Cell-mediated immunity\u2019\n\u2022\tCytokines \treleased \tfrom \tthese \tcells: \tactivate \t\nmacrophages to phagocytose and kill \nmicroorganisms and kill tumour cells; drive proliferation and maturation of the clone into cytotoxic T cells that kill virally infected host \ncells; reciprocally inhibit Th2 cell maturationIFN-\u03b3, IL-2 and TNF- \u03b1Insulin-dependent diabetes mellitus (Ch. 32), multiple sclerosis, Helicobacter \npylori-induced peptic ulcer (Ch. 31), aplastic anaemia (Ch. 26) and rheumatoid arthritis (Ch. 27).Allograft rejection\nTh2 IL-4\u2018Humoral immunity\u2019\n\u2022\tCytokines \treleased \tfrom \tthese \tcells: \tstimulate \t\nB cells to proliferate and mature into plasma cells producing antibodies; enhance differentiation and activation of eosinophils and reciprocally inhibit Th1/Th17-cell functions. For this reason, they are often thought of as having a predominately anti-inflammatory action.IL-4, IL-5, TGF-\u03b2,IL-10 and IL-13Asthma (Ch. 29) and allergy.AIDS progression is associated with loss of Th1 cells and is facilitated by Th2 responses\nTh17TGF-\u03b2, IL-6 and IL-21A specialised type of Th1 cell IL-17The response to infection, organ-specific immune responses and in the pathogenesis of diseases such as rheumatoid arthritis and multiple sclerosis\nTreg\naIL-10 and TGF- \u03b2 \nor FOX P3Matured in the thymusRestraining the immune response, preventing autoimmunity and curtailing potentially damaging inflammatory responsesIL-10 and TGF-\u03b2Failure of this mechanism can provoke excessive inflammation\naTwo\tpopulations \tare \tcommonly", "start_char_idx": 0, "end_char_idx": 2810, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6b1f4e28-5122-4077-89d7-358f01817061": {"__data__": {"id_": "6b1f4e28-5122-4077-89d7-358f01817061", "embedding": null, "metadata": {"page_label": "107", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "61e96006-6546-4a6b-b2ad-c7bebffc2675", "node_type": null, "metadata": {"page_label": "107", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8ed4136e9034b6713e2950521a29a80a40b38427b48fe3362dec072945d52ea0"}, "2": {"node_id": "97fa29ab-e644-4f9f-b4da-b4ed2569dd9c", "node_type": null, "metadata": {"page_label": "107", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92cc6d38b554ddb109d62d2ea1055013ba075e9a5a86ae58b46dee7b9c61cafa"}}, "hash": "471de5b8e4a4381a93c2fc3978ae89162773b5ebafdaead57714d54b12cb840c", "text": "\tencountered: \tinducible \t(iTreg) \tand \tnaturally \toccurring \tTreg \tcells \t(nTreg).\nIFN,\tinterferon; \tIL,\tinterleukin; \tTGF,\ttransforming \tgrowth \tfactor; \tTNF,\ttumour\tnecrosis \tfactor.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2811, "end_char_idx": 3475, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f62be533-76cf-4ab3-b573-a3c186e5ca17": {"__data__": {"id_": "f62be533-76cf-4ab3-b573-a3c186e5ca17", "embedding": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d220d9c1-4db6-4622-bd32-d93bcc8e3a95", "node_type": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0210bdfee56849bab1ed6e8e24b02c1ddf00d4e7d0a87769e14f10dd2d62fd50"}, "3": {"node_id": "3f049968-6296-4c50-b57c-3839feedb368", "node_type": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e67c35c918c7a24ef855657a1de9ad0489a3bc4906e9cc935fa4caa8975a03db"}}, "hash": "ed6239fabe3221824d17c3d7e66fbddab0fba8ec0d5993a0209787d97e717b07", "text": "7 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n102Antibody molecules can form a link between parasite and \nthe host\u2019s white cells (in this case, eosinophils), which are \nthen able to damage or kill the parasite. NK cells in conjunc -\ntion with Fc receptors can also kill antibody-coated target \ncells (an example of antibody-dependent cell-mediated cytotoxic -\nity; ADCC).\nAntibodies and mast cells or basophils\nMast cells and basophils have receptors for IgE, a particular form of antibody that can attach (\u2018fix\u2019) to their cell mem -\nbranes. When this cell-fixed antibody reacts with an antigen, an entire panoply of pharmacologically active mediators is secreted. This very complex reaction is found widely \nthroughout the animal kingdom and presumably confers \nclear survival value to the host. Having said that, its precise biological significance is not always entirely clear, although \nit may be of importance in association with eosinophil \nactivity as a defence against parasitic worms. When inap-propriately triggered by substances not inherently damaging to the host, it is implicated in certain types of allergic reaction \nand seemingly contributes more to illness than to survival \nin the modern world.\nTHE\u2003CELL-MEDIATED \u2003IMMUNE \u2003RESPONSE\nCytotoxic T cells (derived from CD8+ cells) and inflammatory \n(cytokine-releasing) Th1 cells are attracted to inflammatory \nsites in a similar manner to neutrophils and macrophages, \nand are involved in cell-mediated responses (see Fig. 7.3).\nCytotoxic T cells\nArmed cytotoxic T cells kill intracellular microorganisms such as viruses. When a virus infects a mammalian cell, there \nare two aspects to the resulting defensive response. The first \nstep is the expression on the cell surface of peptides derived from the pathogen in association with MHC molecules. The \nsecond step is the recognition of the peptide\u2013MHC complex \nby specific receptors on cytotoxic (CD8\n+) T cells (Fig. 7.4 \nshows a similar process for a CD4+ T cell). The cytotoxic \nT cells then destroy virus-infected cells by programming \nthem to undergo apoptosis. Cooperation with macrophages \nmay be required for killing to occur.\nMacrophage activating CD4+ Th1 cells\nSome pathogens (e.g. Mycobacteria, Listeria) survive and \nactually multiply within macrophages after ingestion. Armed \nCD4+ Th1 cells release cytokines that activate macrophages \nto kill these intracellular pathogens. Th1 cells also recruit macrophages by releasing cytokines that act on vascular \nendothelial cells (e.g. TNF- \u03b1) and chemokines (e.g. mac-\nrophage chemotactic factor-1; MCP-1) that attract the mac -\nrophages to the sites of infection.\nA complex of microorganism-derived peptides plus MHC \nmolecules is expressed on the macrophage surface and is \nrecognised by cytokine-releasing Th1 cells, which then \ngenerate cytokines that enable the macrophage to deploy its killing mechanisms. Activated macrophages (with or without intracellular pathogens) are veritable factories for \nthe production of chemical mediators: they can generate \nand secrete not only many cytokines but also toxic oxygen metabolites and neutral proteases that kill extracellular \norganisms (e.g. Pneumocystis jiroveci and helminths), comple -\nment components, eicosanoids, NO, a fibroblast-stimulating \nfactor, pyrogens and the \u2018tissue factor\u2019 that initiates the \nextrinsic pathway of the coagulation cascade (Ch. 25), as \nwell as various other coagulation", "start_char_idx": 0, "end_char_idx": 3418, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3f049968-6296-4c50-b57c-3839feedb368": {"__data__": {"id_": "3f049968-6296-4c50-b57c-3839feedb368", "embedding": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d220d9c1-4db6-4622-bd32-d93bcc8e3a95", "node_type": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0210bdfee56849bab1ed6e8e24b02c1ddf00d4e7d0a87769e14f10dd2d62fd50"}, "2": {"node_id": "f62be533-76cf-4ab3-b573-a3c186e5ca17", "node_type": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed6239fabe3221824d17c3d7e66fbddab0fba8ec0d5993a0209787d97e717b07"}, "3": {"node_id": "30159b04-274f-4061-904d-93ad66743365", "node_type": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa94b26b484a26c98a77a2fc4e84d45a3464a6e3d48e8129d1fbb11664b3e089"}}, "hash": "e67c35c918c7a24ef855657a1de9ad0489a3bc4906e9cc935fa4caa8975a03db", "text": "coagulation cascade (Ch. 25), as \nwell as various other coagulation factors. It is primarily 9Mainly boys: \u2018Bruton\u2019s agammaglobulinaemia\u2019 is caused by a defect in \na tyrosine kinase (BTK) coded on the X chromosome (Col. Bruton was \nchief of paediatrics at the Walter Reid army hospital). BTKs promote \nleukocyte survival and proliferation and BTK inhibitors are proving useful in treating certain leukaemias (see Ch. 57).\u25bc An antibody is a Y-shaped protein molecule (see Ch. 5) in which \nthe arms of the Y (the Antigen Binding Fragment - Fab portion) include \na variable recognition site for specific antigens, and the invariable \nstem of the Y (the \u2018 Constant\u2019 Fc portion) activates host defences. The \nB cells that are responsible for antibody production recognise foreign \nmolecules by means of surface receptors that are similar to the \nimmunoglobulin that the B-cell clone will eventually produce. \nMammals harbour a vast number of B-cell clones that produce different antibodies with recognition sites for different antigens.\nThe induction of antibody-mediated responses varies with \nthe type of antigen. With most antigens, a cooperative \nprocess between Th2 cells and B cells is generally necessary \nto produce a response. B cells can also present antigen to T cells which then release cytokines that act further on the \nB cell. The anti-inflammatory glucocorticoids (see Chs 27 \nand 34) and the immunosuppressive drug ciclosporin (see \nCh. 27) affect the molecular events crucial to induction. \nThe cytotoxic immunosuppressive drugs (see Ch. 27) inhibit \nthe proliferation of both B and T cells. Eicosanoids may play a part in controlling these processes as prostaglandins of the E series can inhibit lymphocyte proliferation, probably \nby inhibiting the release of IL-2.\nAs you might guess, the ability to make antibodies has \nhuge survival value; children born without this ability\n9 \nsuffer repeated infections such as pneumonia, skin infections and tonsillitis. Before the days of antibiotics, they died in \nearly childhood, and even today they require regular replacement therapy with immunoglobulin. Apart from \ntheir ability to neutralise pathogens, antibodies can boost \nthe effectiveness and specificity of the host\u2019s defence reaction in several ways.\nAntibodies and complement\nFormation of the antigen\u2013antibody complex exposes a binding site for complement on the Fc domain. This activates \nthe complement sequence and sets in train its attendant \nbiological effects (see Fig. 7.1). This route to C3 activation (the classic pathway) provides an especially selective way \nof activating complement in response to a particular pathogen, because the antigen\u2013antibody reaction that initi -\nates it is not only a highly specific recognition event, but \nalso occurs in close association with the pathogen. The lytic \nproperty of complement can be used therapeutically: monoclonal antibodies (mAbs) and complement together can be used to rid bone marrow of cancer cells as an adjunct \nto chemotherapy or radiotherapy (see Ch. 57).\nAntibodies and the phagocytosis of bacteria\nWhen antibodies are attached to their antigens on micro -\norganisms by their Fab portions, the Fc domain is exposed. Phagocytic cells (neutrophils and macrophages) express \nsurface receptors for these projecting Fc portions, which serve as a very specific link between microorganism and \nphagocyte.\nAntibodies and cellular toxicity\nIn some cases, for example, with parasitic worms, the \ninvader may be too large to be ingested by phagocytes. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3361, "end_char_idx": 6953, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "30159b04-274f-4061-904d-93ad66743365": {"__data__": {"id_": "30159b04-274f-4061-904d-93ad66743365", "embedding": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d220d9c1-4db6-4622-bd32-d93bcc8e3a95", "node_type": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0210bdfee56849bab1ed6e8e24b02c1ddf00d4e7d0a87769e14f10dd2d62fd50"}, "2": {"node_id": "3f049968-6296-4c50-b57c-3839feedb368", "node_type": null, "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e67c35c918c7a24ef855657a1de9ad0489a3bc4906e9cc935fa4caa8975a03db"}}, "hash": "aa94b26b484a26c98a77a2fc4e84d45a3464a6e3d48e8129d1fbb11664b3e089", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6948, "end_char_idx": 7427, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "51e43c99-0a46-4d0c-af97-b06e6437dc61": {"__data__": {"id_": "51e43c99-0a46-4d0c-af97-b06e6437dc61", "embedding": null, "metadata": {"page_label": "109", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c0a25662-8abf-4d2a-8ce9-85ac3dfb02ff", "node_type": null, "metadata": {"page_label": "109", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16f82a37b1095b0064fbf7c32c099cf1749472d004af3868d0e0db7c11587a4c"}, "3": {"node_id": "6e500db8-f5b5-44a4-a660-78ed2205831b", "node_type": null, "metadata": {"page_label": "109", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "81116835aee4beb2d3e9d495ff73191f8ab399753dc02ee11ee757bb868f956a"}}, "hash": "5ff3bed2577a0750826a28206d5ff70be856c7111f09211b3c57f1aacb728d73", "text": "7 CELLuLAR mEChANIS mS: ho St dEfENCE\n103to stress, releases cortisol from the adrenal glands. \nThis hormone plays a crucial role in regulating \nimmune function at all levels, hence the use of \nglucocorticoid drugs in the treatment of inflammatory disease. This topic is explored fully in Chapters 27 \nand 34.\n\u2022\tThe CNS. Surprisingly, cytokines such as IL-1 can \nsignal the development of an inflammatory response \ndirectly to the brain through receptors on the vagus \nnerve. This may elicit an \u2018inflammatory reflex\u2019 and trigger activation of a cholinergic anti-inflammatory pathway. See Tracey (2002) and Sternberg (2006) for \ninteresting discussions of this topic.\n\u2022\tThe autonomic nervous system. Both the sympathetic \nand parasympathetic systems can modulate the \ndevelopment of the inflammatory response. Generally \nspeaking, their influence is anti-inflammatory. Receptors for noradrenaline and acetylcholine are \nfound on macrophages and many other cells involved \nin the immune response although the origins of these ligands are unclear. Opioid receptors are also found \non inflammatory cells and they also have multiple \neffects on many aspects of the inflammatory response \n(Liang et al., 2016).\n\u2022\tPeripheral sensory neurons. Some sensory neurons release inflammatory neuropeptides when \nappropriately stimulated. These neurons are fine \nafferents (capsaicin-sensitive C and A\u03b4 fibres; see Ch. 43) with specific receptors at their peripheral \nterminals. Kinins, 5-hydroxytryptamine (5-HT) and \nother chemical mediators generated during inflammation act on these receptors, stimulating the \nrelease of neuropeptides such as the tachykinins \n(neurokinin A, substance P) and calcitonin gene-related peptide (CGRP), which have pro-inflammatory or algesic actions. The \nneuropeptides are considered further in Chapter 19.\nUNWANTED INFLAMMATORY AND \nIMMUNE RESPONSES\nThe immune response has to strike a delicate balance. \nAccording to one school of thought, an infection-proof \nimmune system would be a possibility but would come at \na serious cost to the host. With many millions of potential antigenic sites in the host, such a \u2018super-immune\u2019 system \nwould be some 1000 times more likely to attack the host \nitself, triggering autoimmune disease . It is not uncommon to \nencounter patients in whom exposure to ordinarily innocu -\nous substances such as pollen or peanuts inadvertently activates the immune system. When this happens, the ensuing inflammation itself inflicts self-harm \u2013 either acutely as in (for example) anaphylaxis, or chronically in (for \nexample) asthma or rheumatoid arthritis. In either case, \nanti-inflammatory or immunosuppressive therapy may be required.\n\u25bc Unwanted immune responses, termed allergic or hypersensitivity \nreactions, are generally classified into four types.\nType I hypersensitivity\n\u25bc Also called immediate or anaphylactic hypersensitivity (often known \nsimply as \u2018allergy\u2019), type I hypersensitivity occurs in individuals who \npredominantly exhibit a Th2 rather than a Th1 response to antigen. \nIn these individuals, substances that are not inherently noxious (such as grass pollen, house dust mites, certain foodstuffs or drugs, animal the cell-mediated reaction that is ultimately responsible \nfor allograft rejection. Macrophages are also important in \ncoordinating the repair processes that must occur for \ninflammation to resolve.\nThe specific cell-mediated or humoral immunological \nresponse is superimposed on the innate non-specific vascular and cellular reactions described previously, making them \nnot only markedly more effective but much more selective for particular pathogens.\nThe general events of the inflammatory and hypersensitiv -\nity reactions specified above vary in some", "start_char_idx": 0, "end_char_idx": 3741, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6e500db8-f5b5-44a4-a660-78ed2205831b": {"__data__": {"id_": "6e500db8-f5b5-44a4-a660-78ed2205831b", "embedding": null, "metadata": {"page_label": "109", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c0a25662-8abf-4d2a-8ce9-85ac3dfb02ff", "node_type": null, "metadata": {"page_label": "109", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16f82a37b1095b0064fbf7c32c099cf1749472d004af3868d0e0db7c11587a4c"}, "2": {"node_id": "51e43c99-0a46-4d0c-af97-b06e6437dc61", "node_type": null, "metadata": {"page_label": "109", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5ff3bed2577a0750826a28206d5ff70be856c7111f09211b3c57f1aacb728d73"}}, "hash": "81116835aee4beb2d3e9d495ff73191f8ab399753dc02ee11ee757bb868f956a", "text": "of the inflammatory and hypersensitiv -\nity reactions specified above vary in some tissues. For example, in the airway inflammation of asthma, eosinophils and neuropeptides play a particularly significant role (see \nCh. 29). In central nervous system (CNS) inflammation, \nthere is less neutrophil infiltration and monocyte influx is delayed, possibly because of lack of adhesion molecule \nexpression on CNS vascular endothelium and deficient \ngeneration of chemokines. It has long been known that some tissues \u2013 the CNS parenchyma, the anterior chamber \nof the eye and the testis \u2013 are immunologically privileged \nsites, in that a foreign antigen introduced directly does not \nprovoke an immune reaction (which could be very disad -\nvantageous to the host)\n10. However, introduction elsewhere \nof an antigen already in the CNS parenchyma will trigger \nthe development of immune/inflammatory responses in \nthe CNS.\nSYSTEMIC RESPONSES IN \nINFLAMMATION\nIn addition to the local changes in an inflammatory site, \nthere are commonly more general systemic manifestations of \ninflammatory disease. Typically, these could include fever, \nan increase in blood leukocytes and the release from the liver of acute-phase proteins . These include C-reactive protein, \n\u03b1\n2-macroglobulin, fibrinogen, \u03b11-antitrypsin, serum amyloid \nA and some complement components. While the function \nof many of these components is still a matter of conjecture, \nmany seem to have some antimicrobial actions. C-reactive protein, for example, binds to some microorganisms, and \nthe resulting complex activates complement. Other proteins \nscavenge iron (an essential nutrient for invading organisms) or block proteases, perhaps protecting the host against the \nworst excesses of the inflammatory response.\nTHE ROLE OF THE NERVOUS SYSTEM \nIN INFLAMMATION\nIt has become clear in recent years that the central, autonomic \nand peripheral nervous systems all play an important part \nin the regulation of the inflammatory response. This occurs \nat various levels:\n\u2022\tThe neuroendocrine system. Adrenocorticotrophic \nhormone (ACTH), released from the anterior pituitary \ngland in response to endogenous circadian rhythm or \n10Cold sore sufferers can blame this phenomenon for their misery \u2013 \nherpes simplex virus resides in the facial nervous tissue and becomes \nactivated following stress or environmental stimuli, for example, \nexposure to the sun. The virus can reside in the CNS tissue for a whole lifetime from infancy, stubbornly resistant to the attempts of our \nimmune cells to remove it. It can be transmitted to the baby from a \ncarrier via a kiss, before the infant\u2019s immune system can eliminate the virus (usually by 6 months old). Bonnie babies are destined to suffer \nforever more.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3659, "end_char_idx": 6894, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "27c7d407-6407-46bf-b75a-a1c1a2281449": {"__data__": {"id_": "27c7d407-6407-46bf-b75a-a1c1a2281449", "embedding": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6fb17d2d-d89b-4543-888b-bd06572ac85c", "node_type": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43011236b6fb5bc7a993c1432de09d768ac4f45782173960d044cea600de5ff0"}, "3": {"node_id": "cf0734f3-dc0b-4bcc-9971-c1b36bb93ff5", "node_type": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0bf3efafef6ee037ccb4d0add37e690f2ddc330ab8e49cddeb423357775895b"}}, "hash": "90c9c836e0e0af11a507f696bdd46be96f568c5cc96a1b94266d777aa67c6aab", "text": "7 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n104drugs or industrial chemicals (see Ch. 58), where the chemical (termed \na hapten) combines with proteins in the skin to form the \u2018foreign\u2019 \nsubstance that evokes the cell-mediated immune response (see Fig. 7.3).\nIn essence, inappropriately deployed T-cell activity underlies \nall types of hypersensitivity, initiating types I, II and III, \nand being involved in both the initiation and the effector \nphase in type IV. These reactions are the basis of the clinically important group of autoimmune diseases.\n12 \nImmunosuppressive drugs (Ch. 27) and/or glucocorticoids \n(Ch. 34) are routinely employed to treat such disorders.\nTHE OUTCOME OF THE \nINFLAMMATORY RESPONSE\nIt is important not to lose sight of the fact that the inflam -\nmatory response is a defence mechanism and not a disease per se. Its role is to restore normal structure and function \nto the infected or damaged tissue and, in the vast majority of cases, this is what occurs. The healing and resolution \nphase of the inflammatory response is an active process \nand does not simply \u2018happen\u2019 in the absence of further inflammation. It is now clear that resolution involves its \nown unique palette of mediators and cytokines (including \nvarious growth factors, annexin A1, lipoxins, resolvins and IL-10; see Ch. 19) to terminate residual inflammation and to promote remodelling and repair of damaged tissue.\nIn some cases, healing will be complete, but if there has \nbeen marked damage, repair is usually necessary and this may result in scarring. If the pathogen persists, it is enclosed \nby the host in a fibrous capsule \u2018prison\u2019 to prevent any \nfurther damage. Alternatively, the acute inflammatory response may transform into a chronic inflammatory \nresponse. This is a slow, smouldering reaction that can \ncontinue indefinitely, destroying tissue and promoting local proliferation of cells and connective tissue. The principal \ncell types found in areas of chronic inflammation are \nmononuclear cells and abnormal macrophage-derived cells. During healing or chronic inflammation, growth factors \ntrigger angiogenesis and cause fibroblasts to lay down \nfibrous tissue. Infection by some microorganisms, such as syphilis, tuberculosis and leprosy, bear the characteristic \nhallmarks of chronic inflammation from the start. The \ncellular and mediator components of this type of inflam-mation are also seen in many, if not most, chronic auto -\nimmune and hypersensitivity diseases, and are important \ntargets for drug action.fur and so on) provoke the production of antibodies of the IgE type.11 \nThese fix on mast cells, in the lung, and also to eosinophils. Subsequent \ncontact with the problematic substance causes the release of histamine, \nPAF, eicosanoids and cytokines. The effects may be localised to the nose (hay fever), the bronchial tree (the initial phase of asthma), the \nskin (urticaria) or the gastrointestinal tract. In some cases, the reaction \nis more generalised and produces anaphylactic shock, which can be \nsevere and life-threatening. Some important unwanted effects of drugs \ninclude anaphylactic hypersensitivity responses (see Ch. 58).\nType II hypersensitivity\n\u25bc Also called antibody-dependent cytotoxic hypersensitivity , type II \nhypersensitivity occurs when the mechanisms outlined above are directed against cells within the host that are (or appear to be) foreign. \nFor example, host cells or proteins altered by drugs are sometimes mistaken by the immune system for foreign organisms and evoke \nantibody formation. The antigen\u2013antibody reaction triggers comple -\nment activation (and its sequelae) and may promote attack by NK \ncells. Examples include", "start_char_idx": 0, "end_char_idx": 3684, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cf0734f3-dc0b-4bcc-9971-c1b36bb93ff5": {"__data__": {"id_": "cf0734f3-dc0b-4bcc-9971-c1b36bb93ff5", "embedding": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6fb17d2d-d89b-4543-888b-bd06572ac85c", "node_type": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43011236b6fb5bc7a993c1432de09d768ac4f45782173960d044cea600de5ff0"}, "2": {"node_id": "27c7d407-6407-46bf-b75a-a1c1a2281449", "node_type": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "90c9c836e0e0af11a507f696bdd46be96f568c5cc96a1b94266d777aa67c6aab"}, "3": {"node_id": "32466f12-adc5-4721-81c7-f1c21cce22f7", "node_type": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e465dde23876f61c44c8a4cd123763d5d02226ab6ec8f8bee117015562b3c351"}}, "hash": "b0bf3efafef6ee037ccb4d0add37e690f2ddc330ab8e49cddeb423357775895b", "text": "activation (and its sequelae) and may promote attack by NK \ncells. Examples include alteration by drugs of neutrophils, leading \nto agranulocytosis (see Ch. 57), or of platelets, leading to thrombocytopenic \npurpura (Ch. 25). These type II reactions are also implicated in some types of autoimmune thyroiditis (e.g. Hashimoto\u2019s disease; see Ch. 35).\nType III hypersensitivity\n\u25bc Also called complex-mediated hypersensitivity , type III hypersensitivity \noccurs when antibodies react with soluble antigens. The antigen\u2013\nantibody complexes can activate complement or attach to mast cells \nand stimulate the release of inflammatory mediators.\nAn experimental example of this is the Arthus reaction that occurs if \na foreign protein is injected subcutaneously into a rabbit or guinea \npig with high pre-existing circulating concentrations of antibody. \nWithin 3\u20138 hours the area becomes red and swollen because the \nantigen\u2013antibody complexes precipitate in small blood vessels and activate complement. Neutrophils are attracted and activated (by \nC5a) to generate toxic oxygen species and to secrete enzymes.\nMast cells are also stimulated by C3a to release mediators. Damage \ncaused by this process is involved in serum sickness, which occurs \nwhen antigen persists in the blood after sensitisation, causing a severe \nreaction, as in the response to mouldy hay (known as farmer\u2019s lung), \nand in certain types of autoimmune kidney and arterial disease. Type III hypersensitivity is also implicated in lupus erythematosus (a chronic, \nautoimmune inflammatory disease).\nType IV hypersensitivity\n\u25bc The prototype of type IV hypersensitivity (also known as cell-\nmediated or delayed hypersensitivity) is the tuberculin reaction, a local \ninflammatory response seen when proteins derived from cultures of \nthe tubercle bacillus are injected into the skin of a person who has been sensitised by a previous infection or immunisation. An \u2018inappropri -\nate\u2019 cell-mediated immune response is stimulated, accompanied by infiltration of mononuclear cells and the release of various cytokines. Cell-mediated hypersensitivity is also the basis of the reaction seen \nin some other infections (e.g. mumps and measles), as well as with \nmosquito and tick bites. It is also important in the skin reactions to \n12Leukaemias are more likely in individuals who haven\u2019t been regularly \nexposed to infectious agents throughout their lives. Our immune \nsystems have evolved to fight invaders \u2013 if our world is too sterile and \nour immune system unchallenged, then it is more likely to turn on itself predisposing us to cancerous pre-leukaemic cells (Cornwall, 2015). \nDairy farmers who drink unpasteurized milk and breath farm air, suffer \nless from asthma and other autoimmune disorders (Kaiser, 2015).11Such individuals are said to be \u2018atopic\u2019, from a Greek word meaning \n\u2018out of place\u2019.\nREFERENCES AND FURTHER READING\nThe innate and adaptive responses\nAbbas, A.K., Murphy, K.M., Sher, A., 1996. Functional diversity of \nhelper lymphocytes. Nature 383, 787\u2013793. (Excellent review, helpful \ndiagrams; commendable coverage of Th1 and Th2 cells and their respective \ncytokine subsets)\nAdams, D.H., Lloyd, A.R., 1997. Chemokines: leukocyte recruitment \nand activation cytokines. Lancet 349, 490\u2013495. (Commendable review)Cornwall, W., 2015. Study may explain mysterious cancer\u2013day care \nconnection. Science doi:10.1126/science.aac4614. http://www.sciencemag.org/news/2015/05/study-may-explain-mysterious-cancer-day-care-connection.\nDelves,", "start_char_idx": 3614, "end_char_idx": 7123, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "32466f12-adc5-4721-81c7-f1c21cce22f7": {"__data__": {"id_": "32466f12-adc5-4721-81c7-f1c21cce22f7", "embedding": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6fb17d2d-d89b-4543-888b-bd06572ac85c", "node_type": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43011236b6fb5bc7a993c1432de09d768ac4f45782173960d044cea600de5ff0"}, "2": {"node_id": "cf0734f3-dc0b-4bcc-9971-c1b36bb93ff5", "node_type": null, "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0bf3efafef6ee037ccb4d0add37e690f2ddc330ab8e49cddeb423357775895b"}}, "hash": "e465dde23876f61c44c8a4cd123763d5d02226ab6ec8f8bee117015562b3c351", "text": "P.J., Roitt, I.M., 2000. The immune system. N. Engl. J. Med. 343, \n37\u201349, 108\u2013117. (A good overview of the immune system \u2013 a mini-textbook of major areas in immunology; colourful three-dimensional figures)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7195, "end_char_idx": 7879, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9e369014-bac7-4a98-b93f-7cdc5d1d14b0": {"__data__": {"id_": "9e369014-bac7-4a98-b93f-7cdc5d1d14b0", "embedding": null, "metadata": {"page_label": "111", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3751be59-962a-4bae-b8b7-e42e4059c160", "node_type": null, "metadata": {"page_label": "111", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb6175c52e78a46a007f3ec6cdebf7ea550b4c45cdb2eba63ea4fbae6ec4f799"}, "3": {"node_id": "3b6cddd5-bffe-456e-9217-a4cbbc33ed78", "node_type": null, "metadata": {"page_label": "111", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "88a7646027c9e69d482db3367157bf5245efe42ab5f6372c9b884136498e0024"}}, "hash": "8271f2047d760c7af6b44a25c2b4b67805be71fe2651e41ea17cd9a8eac64ab4", "text": "7 CELLuLAR mEChANIS mS: ho St dEfENCE\n105interstitium. Nature Rev. Mol. Cell Biol. 11, 366\u2013378. (Excellent review \nof leukocyte mechanisms of transmigration through blood vessels. Contains \nexcellent diagrams. Recommended)\nParkin, J., Cohen, B., 2001. An overview of the immune system. Lancet \n357, 1777\u20131789. (A competent, straightforward review covering the role of the immune system in recognising, repelling and eradicating pathogens and \nin reacting against molecules foreign to the body)\nSegal, A.W., 2016. NADPH oxidases as electrochemical generators to \nproduce ion fluxes and turgor in fungi, plants and humans. Open Biol. 6, 1\u201315. (Very good review of the role of neutrophil killing mechanisms which suggests a new paradigm for understanding their microbiocidal \nactions. Very good diagrams)\nSternberg, E.M., 2006. Neural regulation of innate immunity: a \ncoordinated nonspecific host response to pathogens. Nat. Rev. Immunol. 6, 318\u2013328. (This paper and the paper by Tracey (below) are both \nexcellent and easy-to-read reviews covering the role of the CNS in inflammation. Some good diagrams)\nStrowig, T., Henao-Mejia, J., Elinav, E., Flavell, R., 2012. Inflammasomes \nin health and disease. Nature 481, 278\u2013286. (Excellent, comprehensive review if you want to keep up to date in this area)\nTracey, K.J., 2002. The inflammatory reflex. Nature 420, 853\u2013859.Wills-Karp, M., Santeliz, J., Karp, C.L., 2001. The germless theory of \nallergic diseases. Nat. Rev. Immunol. 1, 69\u201375. (Discusses the hypothesis \nthat early childhood infections inhibit the tendency to develop allergic \ndisease)\nYang, C.A., Chiang, B.L., 2015. Inflammasomes and human \nautoimmunity: a comprehensive review. J. Autoimmun. 61, 1\u20138.\nBooks\nDawkins, R., 1995. River out of Eden, first ed. Weidenfeld & Nicholson, \nLondon.\nMurphy, K.M., Travers, P., Walport, M., 2011. Janeway\u2019s \nImmunobiology, eighth ed. Taylor & Francis, London. (A classic textbook, updated and available as an e-book also. Excellent diagrams )\nNijkamp, F.P., Parnham, M. (Eds.), 2011. Principles of \nImmunopharmacology, third ed. Birkhauser, Basle. (A popular textbook that covers most of the topics in more depth than is possible in this book. \nWell written and illustrated. Recommended)\nSerhan, C., Ward, P.A., Gilroy, D.W. (Eds.), 2010. Fundamentals of \nInflammation. Cambridge University Press, New York. (A different type of textbook. Individual topics are written by appropriate experts and \ncombined into a single volume. An authoritative and comprehensive volume that provides access to cutting-edge thinking in the field. \nRecommended)Gabay, C., Kushner, I., 1999. Acute phase proteins and other systemic \nresponses to inflammation. N. Engl. J. Med. 340, 448\u2013454. (Lists the \nacute-phase proteins and outlines the mechanisms controlling their synthesis and release)\nJimenez-Dalmaroni, M.J., Gerswhin, M.E., Adamopoulos, I.E., 2016. The \ncritical role of toll-like receptors\u2013From microbial recognition to autoimmunity: a comprehensive review. Autoimmun. Rev. 15, 1\u20138. \n(Whilst it focusses on bone destruction, this has a good overview of the TLR", "start_char_idx": 0, "end_char_idx": 3104, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3b6cddd5-bffe-456e-9217-a4cbbc33ed78": {"__data__": {"id_": "3b6cddd5-bffe-456e-9217-a4cbbc33ed78", "embedding": null, "metadata": {"page_label": "111", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3751be59-962a-4bae-b8b7-e42e4059c160", "node_type": null, "metadata": {"page_label": "111", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb6175c52e78a46a007f3ec6cdebf7ea550b4c45cdb2eba63ea4fbae6ec4f799"}, "2": {"node_id": "9e369014-bac7-4a98-b93f-7cdc5d1d14b0", "node_type": null, "metadata": {"page_label": "111", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8271f2047d760c7af6b44a25c2b4b67805be71fe2651e41ea17cd9a8eac64ab4"}}, "hash": "88a7646027c9e69d482db3367157bf5245efe42ab5f6372c9b884136498e0024", "text": "it focusses on bone destruction, this has a good overview of the TLR \nfamily)\nKaiser, J., 2015. Dirty farm air may ward off asthma in children. Science \ndoi:10.1126/science.aad1700. http://www.sciencemag.org/news/2015/09/dirty-farm-air-may-ward-asthma-children.\nKennedy, M.A., 2010. A brief review of the basics of immunology: the \ninnate and adaptive response. Vet. Clin. North Am. Small Anim. Pract. 40, 369\u2013379. (Actually written for vets, this little review is an easy-to-read introduction to the subject)\nKay, A.B., 2001. Allergic diseases and their treatment. N. Engl. J. Med. \n344, 30\u201337, 109\u2013113. (Covers atopy and Th2 cells, the role of Th2 cytokines in allergies, IgE, the main types of allergy and new therapeutic approaches)\nLiang, X., Liu, R., Chen, C., Ji, F., Li, T., 2016. Opioid system modulates \nthe immune function: a review. Transl. Perioper. Pain Med. 1, 5\u201313.\nMackay, C.R., Lanzavecchia, A., Sallusto, F., 1999. Chemoattractant \nreceptors and immune responses. Immunologist 7, 112\u2013118. (Masterly short review covering the role of chemoattractants in orchestrating immune responses \u2013 both the innate reaction and the Th1 and Th2 responses)\nMartinez, F.O., Gordon, S., 2014. The M1 and M2 paradigm of \nmacrophage activation: time for reassessment. F1000Prime Rep. 6, 13. (For those who want to dig a bit deeper into macrophage biology. Some very \ngood diagrams)\nMedzhitov, R., 2001. Toll-like receptors and innate immunity. Nat. Rev. \nImmunol. 1, 135\u2013145. (Excellent review of the role of Toll-like receptors in (a) the detection of microbial infection, and (b) the activation of innate \nnon-adaptive responses, which in turn lead to antigen-specific adaptive responses)\nMedzhitov, R., Janeway, C., 2000. Innate immunity. N. Engl. J. Med. \n343, 338\u2013344. (Outstandingly clear coverage of the mechanisms involved in innate immunity and its significance for the adaptive immune response)\nMills, K.H., 2008. Induction, function and regulation of IL-17-producing \nT cells. Eur. J. Immunol. 38, 2636\u20132649. (This paper covers the biology of Th17 cells \u2013 a relatively recent addition to our understanding of Th biology. \nAccessible and has good diagrams)\nMurphy, P.M., 2001. Viral exploitation and subversion of the immune \nsystem through chemokine mimicry. Nat. Immunol. 2, 116\u2013122. (Excellent description of viral/immune system interaction)\nNourshargh, S., Hordijk, P.L., Sixt, M., 2010. Breaching multiple \nbarriers: leukocyte motility through venular walls and the mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3036, "end_char_idx": 5996, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9ee187eb-ec86-449a-ba82-a2b55c476a9c": {"__data__": {"id_": "9ee187eb-ec86-449a-ba82-a2b55c476a9c", "embedding": null, "metadata": {"page_label": "112", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5a81b037-d520-4060-9e08-e8c70195cf07", "node_type": null, "metadata": {"page_label": "112", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5b56bfd314c40ea09aa2dd18f967563cff1fcd81b61b7ae494e844694407ab64"}, "3": {"node_id": "92fc4f0b-0c1d-4f7a-97e1-77c35513ea8f", "node_type": null, "metadata": {"page_label": "112", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5eb4de60b8264e6ff6e2f1f9af1a68e889724b2d2724296ff268f53791e4b08c"}}, "hash": "7e8e678a3a0aaa4d80a69b78a8c3123d6fcc836d9d6ef8576923d44d7c23294a", "text": "106\nMethod and measurement \nin pharmacology8 GENERAL PRINCIPLES SECTION 1 \nOVERVIEW\nWe emphasised in Chapters 2 to 5 that drugs, being \nmolecules, produce their effects by interacting with \nother molecules. This interaction can lead to effects \nat all levels of biological organisation, from molecules to human populations.\n1\nGaddum, a pioneering pharmacologist, commented \nin 1942: \u2018A branch of science comes of age when it \nbecomes quantitative.\u2019 In this chapter, we cover the \nprinciples of metrication at the various organisational levels, ranging from laboratory methods to clinical \ntrials. Assessment of drug action at the population \nlevel is the concern of pharmacoepidemiology and pharmacoeconomics (see Ch. 1), disciplines that are \nbeyond the scope of this book.\nWe consider first the general principles of bioassay \nand its extension to studies in human beings; we \ndescribe the development of animal models to bridge \nthe predictive gap between animal physiology and human disease; we next discuss aspects of clinical \ntrials used to evaluate therapeutic efficacy in a clinical \nsetting; finally, we consider the principles of balancing benefit and risk. Experimental design and statistical \nanalysis are central to the interpretation of all types \nof pharmacological data. Kirkwood and Sterne (2003) \nprovide an excellent introduction.\nBIOASSAY\nBioassay, defined as the estimation of the concentration or \npotency of a substance by measurement of the biological \nresponse that it produces, has played a key role in the \ndevelopment of pharmacology. Quantitation of drug effects by bioassay is necessary to compare the properties of dif -\nferent substances, or the same substance under different circumstances. It is used:\n\u2022\tto\tmeasure \tthe \tpharmacological \tactivity \tof \tnew \tor \t\nchemically undefined substances;\n\u2022\tto\tinvestigate \tthe \tfunction \tof \tendogenous \tmediators;\n\u2022\tto\tmeasure \tdrug \ttoxicity \tand \tunwanted \teffects.\n\u25bc Bioassay plays a key role in the development of new drugs, dis -\ncussed in Chapter 60.\nThe use of bioassay to measure the concentration of drugs and other \nactive substances in the blood or other body fluids \u2013 once an important \ntechnology \u2013 has now been largely replaced by analytical chemistry \ntechniques.Many hormones and chemical mediators have been discovered by the biological effects that they produce. For example, the ability of extracts of the posterior lobe of the pituitary to produce a rise in \nblood pressure and a contraction of the uterus was observed at the \nbeginning of the 20th century. Quantitative assay procedures based \non these actions enabled a standard preparation of the extract to \nbe established by international agreement in 1935. By use of these assays, it was shown that two distinct peptides \u2013 vasopressin and \noxytocin \u2013 were responsible, and they were eventually identified \nand synthesised in 1953. Biological assay had already revealed much \nabout the synthesis, storage and release of the hormones, and was \nessential for their purification and identification. Nowadays, it does not take 50 years of laborious bioassays to identify new hormones \nbefore they are chemically characterised,\n2 but bioassay still plays \na key role. The recent growth of biopharmaceuticals (see Ch. 5) as \nregistered therapeutic agents has relied on bioassay techniques and \nthe establishment of standard preparations. Biopharmaceuticals, whether derived from natural sources (e.g. monoclonal antibodies, \nvaccines) or by recombinant DNA technology (e.g. erythropoietin), \ntend to vary from batch to batch, and need to be standardised with respect to their biological activity. Varying glycosylation patterns, \nfor example, which are not detected by", "start_char_idx": 0, "end_char_idx": 3717, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "92fc4f0b-0c1d-4f7a-97e1-77c35513ea8f": {"__data__": {"id_": "92fc4f0b-0c1d-4f7a-97e1-77c35513ea8f", "embedding": null, "metadata": {"page_label": "112", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5a81b037-d520-4060-9e08-e8c70195cf07", "node_type": null, "metadata": {"page_label": "112", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5b56bfd314c40ea09aa2dd18f967563cff1fcd81b61b7ae494e844694407ab64"}, "2": {"node_id": "9ee187eb-ec86-449a-ba82-a2b55c476a9c", "node_type": null, "metadata": {"page_label": "112", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e8e678a3a0aaa4d80a69b78a8c3123d6fcc836d9d6ef8576923d44d7c23294a"}}, "hash": "5eb4de60b8264e6ff6e2f1f9af1a68e889724b2d2724296ff268f53791e4b08c", "text": "Varying glycosylation patterns, \nfor example, which are not detected by immunoassay techniques, \nmay affect biological activity.\nBIOLOGICAL TEST SYSTEMS\nNowadays, an important use of bioassay is to provide \ninformation that will predict the effect of the drug in the \nclinical situation (where the aim is to improve function in \npatients suffering from the effects of disease). The choice of laboratory test systems (in vitro and in vivo \u2018models\u2019) \nthat provide this predictive link is an important aspect of \nquantitative pharmacology.\nBy the 1960s, pharmacologists had become adept at using \nisolated organs and laboratory animals (usually under anaesthesia) for quantitative experiments, and had devel -\noped the principles of bioassay to allow reliable measure -\nments to be made with these sometimes difficult and \nunpredictable test systems.\nBioassays on different test systems may be run in parallel \nto reveal the profile of activity of an unknown mediator. Vane and his colleagues studied the generation and destruc -\ntion of endogenous active substances such as prostanoids \n(see Ch. 18) in blood by the technique of cascade superfusion , \nmeasuring contraction or relaxation of a series of different smooth muscle test preparations chosen to differentiate between different active constituents of the sample. This \ntechnique has been invaluable in studying the production \nand fate of short-lived mediators such as thromboxane, prostacyclin and nitric oxide (Chs 18 and 21).\nThese \u2018traditional\u2019 assay systems address drug action at \nthe physiological level \u2013 roughly, the mid-range of the organisational hierarchy shown in Fig. 8.1. Extension of \n2In 1988, a Japanese group (Yanagisawa et al., 1988) described in a single \nremarkable paper the bioassay, purification, chemical analysis, synthesis \nand DNA cloning of a new vascular peptide, endothelin (Ch. 23).1Consider the effect of cocaine on organised crime, of organophosphate \n\u2018nerve gases\u2019 on the stability of dictatorships or of anaesthetics on the \nfeasibility of surgical procedures for examples of molecular interactions \nthat affect the behaviour of populations and societies.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3646, "end_char_idx": 6275, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "59bd06a0-aa11-4def-9921-ee34102df027": {"__data__": {"id_": "59bd06a0-aa11-4def-9921-ee34102df027", "embedding": null, "metadata": {"page_label": "113", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d6c3a031-06c5-4854-9c91-907910d0077c", "node_type": null, "metadata": {"page_label": "113", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "846895d1b574852ea5f33e78124d40303150304485af8cd6c5ca08b4ef97f770"}, "3": {"node_id": "c20bf026-294c-4ec9-b83a-2ed178b9c05a", "node_type": null, "metadata": {"page_label": "113", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a3bc041c06ef5f926f5deecdb3e463ad9ba4c7569a4a94440c75db3d9ad756f5"}}, "hash": "765ef2fbdef1ac0707f0b92a460b207af6e08728ce74943563f2ec584e17b2d9", "text": "8 MEthod AN d MEAS u REMEN t IN P h ARMAC o L o G y \n107These approaches have important implications for \nbasic understanding of drug action, and for drug design, \nbut the need remains for measurement of drug effects \nat the physiological and clinical level \u2013 the focus of \nthis chapter.\nBridging the gap between events at the molecular level \nand at the physiological and therapeutic levels presents difficulties, because human illness cannot, in many cases, \nbe accurately reproduced in experimental animals. The use \nof transgenic animals to model human disease is discussed in more detail later.\nGENERAL PRINCIPLES OF BIOASSAY\nTHE USE OF STANDARDS\nJ.H. Burn wrote in 1950: \u2018Pharmacologists today strain at \nthe king\u2019s arm, but they swallow the frog, rat and mouse, \nnot to mention the guinea pig and the pigeon.\u2019 He was \nreferring to the fact that the \u2018king\u2019s arm\u2019 had been long the range in both directions, towards the molecular and towards the clinical, has taken place since. Binding assays (Ch. 3) and the use of engineered cell lines expressing normal \nand mutated receptors and signalling molecules are now \nwidely used. Techniques based on X-ray crystallography, nuclear magnetic resonance spectroscopy and fluorescence signals have thrown much new light on drug action at the \nmolecular level (see reviews by Lohse et al., 2012; Nygaard \net al., 2013), and allow, for the first time, measurement as \nwell as detection of the initial molecular events. Indeed, the range of techniques for analysing drug effects at the \nmolecular and cellular levels is now very impressive and \nexpanding rapidly. An example (Fig. 8.2) is the use of fluorescence-activated cell sorting (FACS) to measure the \neffect of a corticosteroid on the expression of a cell surface \nmarker protein by human blood monocytes. Quantitative cellular assays of this kind are now widely used in \npharmacology.Level of biological \norganisationTest system\n(examples)Response measures\n(example relating to \nanalgesia)Methods\nIndividualFamily\nHuman\nvolunteerPatient\nNormal healthy \nsubjects\nRat, mouse, \nprimate, etc.\nCNSSubjective pain intensity \nand threshold\nBehavioural responses to \nnoxious and non-noxious \nstimuli\nReflex responses to \nnoxious stimuliClinical \npharmacology\nPhysiological\nCellular\nMolecularPopulation & society\nPhysiological system\nSpinal cord Synaptic responses in \ndorsal hornTissue & organ\nSpinal cord \nneuronsMembrane responses\nTransfected cell \nlinesSecond messenger \nresponsesCell\nSubstance P \n(NK-1) receptorBinding studies on \ncloned receptor \nexpressed in cell linesMoleculeSocioeconomic \ngroup\nPatients\u2019 family \nmembers\nPatients undergoing \nmedical treatmentImpact on healthcare \ncosts, social costs, \ndisability costs,\ndisease prevalence\nImpact on relationships, \njob prospects, suicide risk\nPain relief, improvement \nof disability, etc.Pharmaco- \neconomics,\npharmaco- \nepidemiology\nSocial \nmedicine\nClinical trials\nExperimental \nanimal\nClinical Socioeconomic\nDRUG\nACTION\nLaboratory methods\nFig. 8.1 Levels of biological organisation and types of pharmacological measurement. CNS, central nervous system; \nNK-1, neurokinin-1. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3443, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c20bf026-294c-4ec9-b83a-2ed178b9c05a": {"__data__": {"id_": "c20bf026-294c-4ec9-b83a-2ed178b9c05a", "embedding": null, "metadata": {"page_label": "113", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d6c3a031-06c5-4854-9c91-907910d0077c", "node_type": null, "metadata": {"page_label": "113", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "846895d1b574852ea5f33e78124d40303150304485af8cd6c5ca08b4ef97f770"}, "2": {"node_id": "59bd06a0-aa11-4def-9921-ee34102df027", "node_type": null, "metadata": {"page_label": "113", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "765ef2fbdef1ac0707f0b92a460b207af6e08728ce74943563f2ec584e17b2d9"}}, "hash": "a3bc041c06ef5f926f5deecdb3e463ad9ba4c7569a4a94440c75db3d9ad756f5", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3396, "end_char_idx": 3619, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d7c314f0-62d2-432e-9725-42387dd8d28d": {"__data__": {"id_": "d7c314f0-62d2-432e-9725-42387dd8d28d", "embedding": null, "metadata": {"page_label": "114", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d98ce27f-6b62-4e0f-8dce-defa0068d651", "node_type": null, "metadata": {"page_label": "114", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b25d412abfa3dcec0d9baeeb4ad95d35424751d4770d4c7a75fb7beaea198315"}, "3": {"node_id": "2d50a8b4-06d0-4f74-a1f9-2cae801d95bf", "node_type": null, "metadata": {"page_label": "114", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6fe2d3af84e20df9acc0cb0ce87df20f7a2e3fa480319d489064ba5d43a19d52"}}, "hash": "7e13aedc2e7c17dfe0470985359dad89ea74ded070f40d2b2cd902b1c0895b03", "text": "8 SECTION 1 GENERAL PRINCIPLES\n108the pigeon test. Biological assays are therefore designed to \nmeasure the relative potency of two preparations, usually a \nstandard and an unknown. Maintaining stable preparations \nof various hormones, antisera and other biological materials as reference standards is the task of the UK National Board \nfor Biological Standards Control.\nTHE DESIGN OF BIOASSAYS\n\u25bc Given the aim of comparing the activity of two preparations, a \nstandard (S) and an unknown (U), on a particular preparation, a \nbioassay must provide an estimate of the dose or concentration of \nU that will produce the same biological effect as that of a known \ndose or concentration of S. As Fig. 8.3 shows, provided that the log dose\u2013effect curves for S and U are parallel, the ratio, M, of \nequiactive doses will not depend on the magnitude of response chosen. Thus M provides an estimate of the potency ratio of the two preparations. A comparison of the magnitude of the effects \nproduced by equal doses of S and U does not provide an estimate of M \n(see Fig. 8.3).since abandoned as a standard measure of length, whereas \ndrug activity continued to be defined in terms of dose \nneeded to cause, say, vomiting of a pigeon or cardiac arrest \nin a mouse. A plethora of \u2018pigeon units\u2019, \u2018mouse units\u2019 and the like, which no two laboratories could agree on, con-\ntaminated the literature.\n3 Even if two laboratories cannot \nagree \u2013 because their pigeons differ \u2013 on the activity in pigeon units of the same sample of an active substance, \nthey should nonetheless be able to agree that preparation X is, say, 3.5 times as active as standard preparation Y on \n10.0\n7.5\n5.02.5\n0\n10\n\u20131010\u2013810\u2013910\u2013710\u2013610\u2013510\u20134\nConcentration of steroid (M)LaserAnalyserFlow cell in\nFACS machine37\u00b0C 8 h 4\u00b0C 4\u00b0CFITC-equivalent sites per cell \u00d7 104A\nEFBC D\nHydrocortisone\nControlPrednisoneDexamethasoneGlucocorticoids\nadded to cellsFluorescent-tagged\nantibodies added to cellsFixative added\nto cells\nFig. 8.2 Measuring the effect of glucocorticoid drugs on cell surface receptor expression using FACS (fluorescence-activated \ncell sorting). FACS technology enables the detection and measurement of fluorescent-tagged antibodies attached to structures on \nindividual cells. In this experiment the effect of three glucocorticoids is tested on the expression of a cell surface haemoglobin scavenger \nreceptor (CD 163). (A) Human monocytes were isolated from human venous blood and (B) incubated for 8 h alone or with various \nconcentrations of the glucocorticoids dexamethasone, prednisone or hydrocortisone (see Chs 27 and 34). (C) The cells were then placed \non ice and incubated with fluorescent-tagged antibodies to the receptor. (D) The cells were then fixed, washed and (E) subjected to FACS \nanalysis. In this technique, cells flow through a small tube and are individually scanned by a laser. The reflected light is analysed using a series of filters (so that different coloured fluorescent tags can be used) and the data collected as fluorescence intensity units, compared \nwith a standard (FITC) and expressed as \u2018FITC equivalents\u2019 to produce the final results (F), which can be plotted as a conventional \nlog-concentration curve. (Data courtesy N. Goulding.)\n3More picturesque examples of absolute units of the kind that Burn \nwould have frowned on are the PHI and the mHelen. PHI, cited by \nColquhoun (1971), stands for", "start_char_idx": 0, "end_char_idx": 3409, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2d50a8b4-06d0-4f74-a1f9-2cae801d95bf": {"__data__": {"id_": "2d50a8b4-06d0-4f74-a1f9-2cae801d95bf", "embedding": null, "metadata": {"page_label": "114", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d98ce27f-6b62-4e0f-8dce-defa0068d651", "node_type": null, "metadata": {"page_label": "114", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b25d412abfa3dcec0d9baeeb4ad95d35424751d4770d4c7a75fb7beaea198315"}, "2": {"node_id": "d7c314f0-62d2-432e-9725-42387dd8d28d", "node_type": null, "metadata": {"page_label": "114", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e13aedc2e7c17dfe0470985359dad89ea74ded070f40d2b2cd902b1c0895b03"}}, "hash": "6fe2d3af84e20df9acc0cb0ce87df20f7a2e3fa480319d489064ba5d43a19d52", "text": "mHelen. PHI, cited by \nColquhoun (1971), stands for \u2018purity in heart index\u2019 and measures the \nability of a virgin pure-in-heart to transform, under appropriate conditions, a he-goat into a youth of surpassing beauty. The mHelen is \na unit of beauty, 1 mHelen being sufficient to launch one ship.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3358, "end_char_idx": 4132, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0a478be9-4dbd-4e52-a1f1-52c85936bc0c": {"__data__": {"id_": "0a478be9-4dbd-4e52-a1f1-52c85936bc0c", "embedding": null, "metadata": {"page_label": "115", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7414a4ad-2973-49f5-87cf-33c0d38fd0bb", "node_type": null, "metadata": {"page_label": "115", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c448df0edc8c70a5808e90da4d9fe7abd35f24f22d15c6e7b3bb60de74c0ac23"}, "3": {"node_id": "dcdae60e-44eb-4939-b839-7753c102748f", "node_type": null, "metadata": {"page_label": "115", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "645614c0e2d47e7189c20804b12a443b82f8e0c9db3a95d5111b44b7cc6b8619"}}, "hash": "07ff2429a5b3681b0bb973284109a3ff8716834abbb104251bfb8db8a35df5de", "text": "8 MEthod AN d MEAS u REMEN t IN P h ARMAC o L o G y \n1093 2 1 0Unknown \nStandard \n0100Response (% maximal)A2\nA1\nlog Mlog M\nlog10 volume administered (\u00b5L)\nFig. 8.3 Comparison of the potency of unknown and \nstandard by bioassay. Note that comparing the magnitude of \nresponses produced by the same dose (i.e. volume) of standard and unknown gives no quantitative estimate of their relative potency. (The differences, A\n1 and A 2, depend on the dose \nchosen.) Comparison of equieffective doses of standard and unknown gives a valid measure of their relative potencies. Because the lines are parallel, the magnitude of the effect chosen for the comparison is immaterial; i.e. log M is the same \nat all points on the curves. 4\n4\n3\n32\n21\n1\nDose (mg)Codeine Morphine\n240 120 60 30 16 8Potency ratio = 136\n420Pain relief score\nFig. 8.4 Assay of morphine and codeine as analgesics in \nhumans. Each of four patients (numbered 1\u20134) was given, on \nsuccessive occasions in random order, four different treatments \n(high and low morphine, and high and low codeine) by \nintramuscular injection, and the subjective pain relief score \ncalculated for each. The calculated regression lines gave a \npotency ratio estimate of 13 for the two drugs. (After Houde, \nR.W. et al., 1965. In: Analgetics. Academic Press, New York.)\nBioassay \n\u2022\tBioassay \tis \tthe \tmeasurement \tof \tpotency \tof \ta \tdrug \tor \t\nunknown mediator from the magnitude of the \nbiological effect that it produces.\n\u2022\tBioassay \tnormally \tinvolves \tcomparison \tof \tthe \tunknown \t\npreparation with a standard. Estimates that are not based on comparison with standards are liable to vary from laboratory to laboratory.\n\u2022\tComparisons \tare \tbest \tmade \ton \tthe \tbasis \tof \tdose\u2013\nresponse curves, which allow estimates of the equiactive concentrations of unknown and standard to be used as a basis for the potency comparison. \nParallel line assays follow this principle.\n\u2022\tThe\tbiological \tresponse \tmay \tbe \tquantal (the \nproportion of tests in which a given all-or-nothing \neffect is produced) or graded. Different statistical \nprocedures are appropriate in each case.\n\u2022\tDifferent \tapproaches \tto \tmetrication \tapply \taccording \tto \t\nthe level of biological organisation at which the drug effect needs to be measured. Approaches range through molecular and chemical techniques, in vitro \nand in vivo animal studies and clinical studies on \nvolunteers and patients, to measurement of effects at the socioeconomic level.The main problem with all types of bioassay is that of biological \nvariation, and the design of bioassays is aimed at:\n\u2022\tminimising \tvariation\n\u2022\tavoiding \tsystematic \terrors \tresulting \tfrom \tvariation\n\u2022\testimation \tof \tthe \tlimits \tof \terror \tof \tthe \tassay \tresult.\nCommonly, comparisons are based on analysis of dose\u2013response curves , \nfrom which the matching doses of S and U are calculated. The use \nof a logarithmic dose scale means that the curves for S and U will \nnormally be parallel, and the potency ratio ( M) is estimated from the \nhorizontal distance between the two curves (see Fig. 8.3). Assays of \nthis type are known as parallel line assays, the minimal design being \nthe 2 + 2 assay, in which two doses of standard (S 1 and S 2) and two \nof unknown (U 1 and U 2) are used. The doses are chosen to give \nresponses lying on the linear part of the log dose\u2013response curve, and are given", "start_char_idx": 0, "end_char_idx": 3362, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dcdae60e-44eb-4939-b839-7753c102748f": {"__data__": {"id_": "dcdae60e-44eb-4939-b839-7753c102748f", "embedding": null, "metadata": {"page_label": "115", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7414a4ad-2973-49f5-87cf-33c0d38fd0bb", "node_type": null, "metadata": {"page_label": "115", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c448df0edc8c70a5808e90da4d9fe7abd35f24f22d15c6e7b3bb60de74c0ac23"}, "2": {"node_id": "0a478be9-4dbd-4e52-a1f1-52c85936bc0c", "node_type": null, "metadata": {"page_label": "115", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07ff2429a5b3681b0bb973284109a3ff8716834abbb104251bfb8db8a35df5de"}}, "hash": "645614c0e2d47e7189c20804b12a443b82f8e0c9db3a95d5111b44b7cc6b8619", "text": "\nresponses lying on the linear part of the log dose\u2013response curve, and are given repeatedly in randomised order, providing an inherent \nmeasure of the variability of the test system, which can be used, by means of straightforward statistical analysis, to estimate the confidence \nlimits of the final result.\nA simple example of an experiment to compare two analgesic drugs, \nmorphine and codeine (see Ch. 43) in humans, based on a modified \n2 + 2 design is shown in Fig. 8.4. Each of the four doses was given \non different occasions to each of the four subjects, the order being randomised and both subject and observer being unaware of the dose \ngiven. Subjective pain relief was assessed by a trained observer, and the results showed morphine to be 13 times as potent as codeine. This, of \ncourse, does not prove its superiority, but merely shows that a smaller \ndose is needed to produce the same effect. Such a measurement is, however, an essential preliminary to assessing the relative therapeutic \nmerits of the two drugs, for any comparison of other factors, such as \nside effects, duration of action, tolerance or dependence, needs to be \ndone on the basis of doses that are equiactive as analgesics.\nProblems arise if the two log dose\u2013response curves are not parallel, \nor if the maximal responses differ, which can happen if the mechanism \nof action of the two drugs differs, or if one is a partial agonist (see \nCh. 2). In this case it is not possible to define the relative potencies of S and U unambiguously in terms of a simple ratio and the experi -\nmenter must then face up to the fact that the comparison requires measurement of more than a single dimension of potency.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3281, "end_char_idx": 5447, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c2d01b2c-63cb-4081-9429-1ef20d9144b1": {"__data__": {"id_": "c2d01b2c-63cb-4081-9429-1ef20d9144b1", "embedding": null, "metadata": {"page_label": "116", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73608b1a-2275-407d-83bf-dc322a0bacc3", "node_type": null, "metadata": {"page_label": "116", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6faba28a4364f2a0d72f2d2a3e5af76e6a48132fdcd19bfdaef1233dd0682fc1"}, "3": {"node_id": "51bcb4b4-7b56-4f41-a3d7-75a43d49355e", "node_type": null, "metadata": {"page_label": "116", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce0047cd7a522165915bbd922aaadcd47dadc78b5fc111af0e31114164d934ce"}}, "hash": "92e65c4b6ee8ece189190966d45ba4604c39d3520d6f927667a94757e119b7a4", "text": "8 SECTION 1 GENERAL PRINCIPLES\n110the brain, rather than other potential mechanisms that \nneed to be targeted if drug discovery is to move on to \naddress new targets.\nGENETIC AND TRANSGENIC ANIMAL MODELS\nNowadays, genetic approaches are increasingly used as an \nadjunct to conventional physiological and pharmacological \napproaches to disease modelling.ANIMAL MODELS OF DISEASE\nThere are many examples where simple intuitive models \npredict with fair accuracy therapeutic efficacy in humans. \nFerrets vomit when placed in swaying cages, and drugs \nthat prevent this are also found to relieve motion sickness and other types of nausea in humans. Irritant chemicals \ninjected into rats\u2019 paws cause them to become swollen and \ntender, and this model predicts very well the efficacy of drugs used for symptomatic relief in inflammatory condi -\ntions such as rheumatoid arthritis in humans. As discussed elsewhere in this book, models for many important disor -\nders, such as epilepsy, diabetes, hypertension and gastric ulceration, based on knowledge of the physiology of the \ncondition, are available, and have been used successfully \nto produce new drugs, even though their success in predict -\ning therapeutic efficacy is far from perfect.\n4\nIdeally, an animal model should resemble the human \ndisease in the following ways:\n1. similar pathophysiological phenotype ( face validity)\n2. similar causation ( construct validity)\n3. similar response to treatment ( predictive validity)\nIn practice, there are many difficulties, and the shortcomings \nof animal models are one of the main roadblocks on the \nroute from basic medical science to improvements in therapy. The difficulties include the following.\n\u2022\tMany\tdiseases, \tparticularly \tin \tpsychiatry, \tare \tdefined \t\nby phenomena in humans that are difficult or impossible to observe in animals, which rules out face \nvalidity. As far as we know, mania or delusions have \nno counterpart in rats, nor does anything resembling a migraine attack or autism. Pathophysiological \nsimilarity is also inapplicable to conditions such as \ndepression or anxiety disorders, where no clear brain pathology has been defined.\n\u2022\tThe\t\u2018cause\u2019 \tof \tmany \thuman \tdiseases \tis \tcomplex \tor \t\nunknown. To achieve construct validity for many degenerative diseases (e.g. Alzheimer\u2019s disease, \nosteoarthritis, Parkinson\u2019s disease), we need to model \nthe upstream (causative) factors rather than the downstream (symptomatic) features of the disease, \nalthough the latter are the basis of most of the simple \nphysiological models used hitherto. The inflammatory pain model mentioned earlier lacks construct validity \nfor rheumatoid arthritis, which is an autoimmune \ndisease.\n\u2022\tRelying \ton \tresponse \tto \ttreatment \tas \ta \ttest \tof \t\npredictive validity carries the risk that drugs acting by novel mechanisms could be missed, because the \nmodel will have been selected on the basis of its \nresponsiveness to known drugs. With schizophrenia (Ch. 47), for example, it is clear that dopamine \nantagonists are effective, and many of the models \nused are designed to assess dopamine antagonism in Animal models \n\u2022\tAnimal\tmodels \tof \tdisease \tare \timportant \tfor \t\ninvestigating pathogenesis and for the discovery of \nnew therapeutic agents. Animal models generally reproduce imperfectly only certain aspects of human \ndisease states. Models of psychiatric illness are \nparticularly problematic.\n\u2022\tTransgenic \tanimals \tare \tproduced \tby \tintroducing \t\nmutations into the germ cells of animals (usually mice), which allow new genes to be introduced (\u2018knock-ins\u2019) or existing genes to be inactivated (\u2018knockouts\u2019) or \nmutated in a stable strain of", "start_char_idx": 0, "end_char_idx": 3663, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "51bcb4b4-7b56-4f41-a3d7-75a43d49355e": {"__data__": {"id_": "51bcb4b4-7b56-4f41-a3d7-75a43d49355e", "embedding": null, "metadata": {"page_label": "116", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73608b1a-2275-407d-83bf-dc322a0bacc3", "node_type": null, "metadata": {"page_label": "116", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6faba28a4364f2a0d72f2d2a3e5af76e6a48132fdcd19bfdaef1233dd0682fc1"}, "2": {"node_id": "c2d01b2c-63cb-4081-9429-1ef20d9144b1", "node_type": null, "metadata": {"page_label": "116", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92e65c4b6ee8ece189190966d45ba4604c39d3520d6f927667a94757e119b7a4"}}, "hash": "ce0047cd7a522165915bbd922aaadcd47dadc78b5fc111af0e31114164d934ce", "text": "(\u2018knockouts\u2019) or \nmutated in a stable strain of animals.\n\u2022\tTransgenic \tanimals \tare \twidely \tused \tto \tdevelop \tdisease \t\nmodels for drug testing. Many such models are now \navailable.\n\u2022\tThe\tinduced \tmutation \toperates \tthroughout \tthe \t\ndevelopment and lifetime of the animal, and may be lethal. Techniques of conditional mutagenesis allow the abnormal gene to be switched on or off at a chosen \ntime.\n4There have been many examples of drugs that were highly effective in \nexperimental animals (e.g. in reducing brain damage following cerebral \nischaemia) but ineffective in humans (stroke victims). Similarly, \nsubstance P antagonists (Ch. 19) are effective in animal tests for analgesia, but they proved inactive when tested in humans. How many \nerrors in the opposite direction may have occurred we shall never \nknow, because such drugs will never have been tested in humans.By selective breeding, it is possible to obtain pure animal \nstrains with characteristics closely resembling certain human \ndiseases. Genetic models of this kind include spontaneously \nhypertensive rats, genetically obese mice, epilepsy-prone dogs and mice, rats with deficient vasopressin secretion, and \nmany other examples. In many cases, the genes responsible \nhave not been identified.\n\u25bc The obese mouse, which arose from a spontaneous mutation in a \nmouse-breeding facility, is one of the most widely used models for \nthe study of obesity and type 2 diabetes (see Ch. 32). The phenotype \nresults from inactivation of the leptin gene, and shows good face \nvalidity (high food intake, gross obesity, impaired blood glucose \nregulation, vascular complications \u2013 features characteristic of human \nobesity) and good predictive validity (responding to pharmacological \nintervention similarly to humans), but poor construct validity, since most obese humans are not leptin deficient.\nGenetic manipulation of the germline to generate transgenic \nanimals\t(see\tRudolph \t&\tMoehler, \t1999;\tOffermanns \t&\tHein,\t\n2004) is important as a means of generating animal models \nthat replicate human disease and are expected to be predic -\ntive of therapeutic drug effects in humans. This versatile technology, first reported in 1980, can be used in many different ways, for example:\n\u2022\tto\tinactivate \tindividual \tgenes, \tor \tmutate \tthem \tto \t\npathological forms\n\u2022\tto\tintroduce \tnew \t(e.g. \thuman) \tgenesmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3616, "end_char_idx": 6462, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0a8de0ea-68ac-49aa-bd9b-c9b386294b44": {"__data__": {"id_": "0a8de0ea-68ac-49aa-bd9b-c9b386294b44", "embedding": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2ef94ce3-f862-4939-965f-6fba3393fe3e", "node_type": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "78703643423ace4145afe3f1384eb31b3f37a7b625095529d02a94c8922b0391"}, "3": {"node_id": "b68fa49c-5164-49d7-ad4e-7018c64ed0c7", "node_type": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed3ae626974632ad6d30e13bc34fd904dd610e6757e6e91faa4474872c84425e"}}, "hash": "26d845d85cc8f25caa606e0a186074990339fa2f22b8acf2ecba3f3b7ed816a0", "text": "8 MEthod AN d MEAS u REMEN t IN P h ARMAC o L o G y \n111Ethics committees associated with all medical research \ncentres tightly control the type of experiment that can be \ndone, weighing up not only safety and ethical issues, but \nalso the scientific importance of the proposed study. At the other end of the spectrum of experimentation on humans \nare formal clinical trials, often involving thousands of \npatients, aimed at answering specific questions regarding \nthe efficacy and safety of new drugs.\nCLINICAL TRIALS\nClinical trials are an important and highly specialised form of biological assay, designed specifically to measure thera -\npeutic efficacy and detect adverse effects. The need to use patients undergoing treatment for experimental purposes raises serious ethical considerations, and imposes many \nrestrictions. Here, we discuss some of the basic principles \ninvolved in clinical trials; the role of such trials in the course of drug development is described in Chapter 60.\nA clinical trial is a method for comparing objectively, by \na prospective study, the results of two or more therapeutic procedures. For new drugs, this is carried out during phases II and III of clinical development (Ch. 60). It is important \nto realise that, until about 60 years ago, methods of treatment \nwere chosen on the basis of clinical impression and personal experience rather than objective testing.\n6 Although many \ndrugs, with undoubted effectiveness, remain in use without \never having been subjected to a controlled clinical trial, \nany new drug is now required to have been tested in this way before being licensed for clinical use.\n7\nOn\tthe\tother \thand, \tdigitalis (see Ch. 22) was used for \n200 years to treat cardiac failure before a controlled trial \nshowed it to be of very limited value except in a particular \ntype of patient.\nAn introduction to the principles and organisation of \nclinical trials is given by Hackshaw (2009). A clinical trial aims to compare the response of a test group of patients receiving a new treatment (A) with that of a control group \nreceiving an existing \u2018standard\u2019 treatment (B). Treatment \nA might be a new drug or a new combination of existing drugs, or any other kind of therapeutic intervention, such as a surgical operation, a diet, physiotherapy and so on. \nThe standard against which it is judged (treatment B) might \nbe a drug or non-drug treatment that is in current clinical practice, or (if there is no currently available effective \ntreatment), a placebo or no treatment at all.\nThe use of controls is crucial in clinical trials. Claims of \ntherapeutic efficacy based on reports that, for example, 16 \u2022\tto\toverexpress \tgenes \tby \tinserting \tadditional \tcopies\n\u2022\tto\tallow \tgene \texpression \tto \tbe \tcontrolled \tby \tthe \t\nexperimenter5\nCurrently, most transgenic technologies are applicable in \nmice\tbut \tmuch \tmore \tdifficult \tin \tother \tmammals. \tOther \t\nvertebrates (e.g. zebrafish) and invertebrates (Drosophila, \nCaenorhabditis elegans ) are increasingly used for drug screen -\ning purposes.\nExamples of such models include transgenic mice that \noverexpress mutated forms of the amyloid precursor protein \nor presenilins, which are important in the pathogenesis of \nAlzheimer\u2019s disease (see Ch. 41). When they are a few months old, these mice develop pathological lesions and \ncognitive changes resembling Alzheimer\u2019s disease, and \nprovide very useful models with which to test possible new therapeutic approaches. Another neurodegenerative condition, Parkinson\u2019s disease (Ch. 41), has been modelled \nin transgenic mice that overexpress synuclein, a protein \nfound in the brain inclusions that are characteristic of the \ndisease. Transgenic mice with mutations in tumour sup -\npressor genes and oncogenes (see Ch. 6) are widely", "start_char_idx": 0, "end_char_idx": 3787, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b68fa49c-5164-49d7-ad4e-7018c64ed0c7": {"__data__": {"id_": "b68fa49c-5164-49d7-ad4e-7018c64ed0c7", "embedding": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2ef94ce3-f862-4939-965f-6fba3393fe3e", "node_type": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "78703643423ace4145afe3f1384eb31b3f37a7b625095529d02a94c8922b0391"}, "2": {"node_id": "0a8de0ea-68ac-49aa-bd9b-c9b386294b44", "node_type": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "26d845d85cc8f25caa606e0a186074990339fa2f22b8acf2ecba3f3b7ed816a0"}, "3": {"node_id": "649a4a46-132b-44a2-aebf-5503a2fa6b2b", "node_type": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc6f9919efeb6a93956a62a0cb4ea8845a68ec6dccf5dfe17d329ef8e0c5b80b"}}, "hash": "ed3ae626974632ad6d30e13bc34fd904dd610e6757e6e91faa4474872c84425e", "text": "-\npressor genes and oncogenes (see Ch. 6) are widely used as models for human cancers. Mice in which the gene for a particular adenosine receptor subtype has been inactivated \nshow distinct behavioural and cardiovascular abnormalities, \nsuch as increased aggression, reduced response to noxious stimuli and raised blood pressure. These findings serve to \npinpoint the physiological role of this receptor, whose \nfunction was hitherto unknown, and to suggest new ways in which agonists or antagonists for these receptors might \nbe developed for therapeutic use (e.g. to reduce aggressive \nbehaviour or to treat hypertension). Transgenic mice can, however, be misleading in relation to human disease. For \nexample, the gene defect responsible for causing cystic \nfibrosis (a disease affecting mainly the lungs in humans), when reproduced in mice, causes a disorder that mainly affects the intestine.\nPHARMACOLOGICAL STUDIES \nIN HUMANS\nStudies involving human subjects range from experimental pharmacodynamic or pharmacokinetic investigations to \nformal clinical trials. Non-invasive recording methods, such \nas functional magnetic resonance imaging\n\t(FMRI)\tto\tmeasure \t\nregional blood flow in the brain (a surrogate for neuronal activity) and ultrasonography to measure cardiac performance, \nhave greatly extended the range of what is possible. The scientific principles underlying experimental work in humans designed (for example) to check whether mecha -\nnisms that operate in other species also apply to humans, or to take advantage of the much broader response capabili -\nties of a person compared with a rat, are the same as for \nanimals, but the ethical and safety issues are paramount. 6Not exclusively. James Lind conducted a controlled trial in 1753 on 12 \nmariners, which showed that oranges and lemons offered protection \nagainst scurvy. However, 40 years passed before the British Navy acted \non his advice, and a further century before the US Navy did.\n7It is fashionable in some quarters to argue that to require evidence of \nefficacy of therapeutic procedures in the form of a controlled trial runs \ncounter to the doctrines of \u2018holistic\u2019 medicine. This is a fundamentally \nantiscientific view, for science advances only by generating predictions from hypotheses and by subjecting the predictions to experimental test. \n\u2018Alternative\u2019 medical procedures, such as homeopathy, aromatherapy, \nacupuncture or \u2018detox\u2019, have rarely been so tested, and where they have, they generally lack efficacy. Standing up for the scientific \napproach is the evidence-based medicine\n movement (see Sackett et al., \n1996), which sets out strict criteria for assessing therapeutic efficacy, \nbased on randomised controlled clinical trials, and urges scepticism \nabout therapeutic doctrines whose efficacy has not been so \ndemonstrated.5With conventional transgenic technology, the genetic abnormality is \nexpressed throughout development, sometimes proving lethal or \ncausing major developmental abnormalities. Conditional transgenesis (see \nRistevski, \t2005), \tallows \tthe \tmodified \tgene \tto \tremain \tunexpressed \tuntil \t\ntriggered by the administration of a chemical promoter (e.g. the \ntetracycline analogue, doxycycline, in the most widely used Cre-Lox \nconditional system). This avoids the complications of developmental \neffects and long-term adaptations, and may allow adult disease to be modelled more accurately.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3744, "end_char_idx": 7465, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "649a4a46-132b-44a2-aebf-5503a2fa6b2b": {"__data__": {"id_": "649a4a46-132b-44a2-aebf-5503a2fa6b2b", "embedding": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2ef94ce3-f862-4939-965f-6fba3393fe3e", "node_type": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "78703643423ace4145afe3f1384eb31b3f37a7b625095529d02a94c8922b0391"}, "2": {"node_id": "b68fa49c-5164-49d7-ad4e-7018c64ed0c7", "node_type": null, "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed3ae626974632ad6d30e13bc34fd904dd610e6757e6e91faa4474872c84425e"}}, "hash": "bc6f9919efeb6a93956a62a0cb4ea8845a68ec6dccf5dfe17d329ef8e0c5b80b", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7462, "end_char_idx": 7685, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e07d054-f586-4c94-aabe-70f055a2d80e": {"__data__": {"id_": "8e07d054-f586-4c94-aabe-70f055a2d80e", "embedding": null, "metadata": {"page_label": "118", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "86ee8e7a-f7ad-4ddd-b510-ec59e90e8715", "node_type": null, "metadata": {"page_label": "118", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "26e2d58453b66e35b992b318a19c7a30069a0fbc3949074f3672d2ff1a8a68dc"}, "3": {"node_id": "79660338-0c5a-4587-a6b0-d46c545e65f3", "node_type": null, "metadata": {"page_label": "118", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9fe84baf26a52bef4475b407b599240c3637e294176c3be28047e8133065e200"}}, "hash": "2816605a37efcdecda077f830631019c972a163f021ca98e737e3a380839e3b8", "text": "8 SECTION 1 GENERAL PRINCIPLES\n112complicated, time-consuming and expensive than that of \nany\tlaboratory-based \tassay. \tObservational \tstudies \tmay \t\ntherefore be more practical or appropriate for assessing \nrare adverse effects where large sample sizes and long-term \nfollow-up are needed.\nAVOIDANCE OF BIAS\nThere are three main strategies that aim to minimise bias \nin clinical trials, namely:\n1. randomisation\n2. the double-blind technique\n3. rigorous follow-up and ascertainment of outcomes\nIf two treatments, A and B, are being compared on a series of selected patients, the simplest form of randomisation is \nto allocate each patient to A or B by reference to a series \nof random numbers, toss of a coin, or even drawing lots. In a properly randomised trial, neither the patient nor the \ninvestigator should have any influence on which treatment \nthe\tpatient\twill\tend\tup\treceiving. \tOne\tdifficulty, \tparticularly \t\nif the groups are small, is that the two groups may turn out \nto be ill-matched with respect to characteristics such as age, \nsex or disease severity. Stratified randomisation avoids the \ndifficulty by dividing the subjects into age, sex, severity, or \nother categories, random allocation to A or B being used \nwithin each category. It is possible to treat two or more \ncharacteristics of the trial population in this way, but the number of strata can quickly become large, and the process is \nself-defeating when the number of subjects in each becomes \ntoo small. As well as avoiding error resulting from imbalance of groups assigned to A and B, stratification can also allow more sophisticated conclusions to be reached. B might, for \nexample, prove to be better than A in a particular group of \npatients even if it is not significantly better overall.out of 20 patients receiving drug X got better within 2 weeks are of no value (particularly so with minor illnesses \nthat are self-resolving), without a knowledge of how 20 \npatients receiving a different treatment, or none at all, would have fared. In a parallel-group design, the controls are \nprovided by a separate group of patients from those receiv -\ning the test treatment, but sometimes a crossover design is \npossible in which the same patients are switched from test to control treatment or vice versa, and the results compared. \nRandomisation \tis \tessential \tto \tavoid \tbias \tin \tassigning \t\nindividual patients to test or control groups. Hence, the randomised controlled clinical trial is now regarded as the \nessential tool for assessing clinical efficacy of new drugs.\nConcern inevitably arises over the ethics of assigning \npatients at random to particular treatment groups (or to \nno treatment). However, the reason for setting up a trial \nis that doubt exists whether the test treatment offers greater benefit than the control treatment, and there is genuine \nclinical equipoise in treatment selection. All would agree \non the principle of informed consent,\n8 whereby each patient \nmust be told the nature and risks of the trial, and agree to \nparticipate on the basis that he or she will be randomly \nand unknowingly assigned to either the test or the control group. The regularly updated \u2018Declaration of Helsinki\u2019 sets \nout the widely accepted ground rules governing research \non human subjects.\nUnlike the kind of bioassay discussed earlier, the clinical \ntrial does not normally give any information about potency or the form of the dose\u2013response curve, but merely compares the response produced by two or more stipulated therapeutic regimens. Survival curves provide one commonly used \nmeasure. Fig. 8.5 shows rates of disease-free survival in \ntwo groups of breast cancer patients treated with conven -\ntional chemotherapy with and without the addition of paclitaxel (see Ch. 57). The divergence of the curves shows \nthat paclitaxel significantly improved the clinical response. Additional", "start_char_idx": 0, "end_char_idx": 3891, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "79660338-0c5a-4587-a6b0-d46c545e65f3": {"__data__": {"id_": "79660338-0c5a-4587-a6b0-d46c545e65f3", "embedding": null, "metadata": {"page_label": "118", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "86ee8e7a-f7ad-4ddd-b510-ec59e90e8715", "node_type": null, "metadata": {"page_label": "118", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "26e2d58453b66e35b992b318a19c7a30069a0fbc3949074f3672d2ff1a8a68dc"}, "2": {"node_id": "8e07d054-f586-4c94-aabe-70f055a2d80e", "node_type": null, "metadata": {"page_label": "118", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2816605a37efcdecda077f830631019c972a163f021ca98e737e3a380839e3b8"}}, "hash": "9fe84baf26a52bef4475b407b599240c3637e294176c3be28047e8133065e200", "text": "of the curves shows \nthat paclitaxel significantly improved the clinical response. Additional questions may be posed, such as the incidence \nand severity of side effects, or whether the treatment works \nbetter or worse in particular classes of patient, but only at the expense of added complexity and numbers of patients. \nThe investigator must decide in advance, using a proto -\ncolised approach, what dose to use and how often to give \nit, and the trial will reveal only whether the chosen regimen \nperformed better or worse than the control treatment. Unless \ndifferent doses are compared, it will not say whether increasing or decreasing the dose would have improved \nthe response.\nA considerable amount of preliminary or fundamental \nwork has to be completed prior to designing and embarking \non a clinical trial that measures patient outcomes with a \nnew drug. The basic question or hypothesis posed by a \nclinical trial is thus simpler than that addressed by most conventional bioassays. However, the organisation of clinical \ntrials, with controls against bias, is immeasurably more Months from start of treatmentStandard chemotherapy\n+ paclitaxel\nStandard chemotherapy100\n5060708090Percentage of patients surviving\n02 04 06 08 0 100\nFig. 8.5 Disease-free survival curves followed for 8 years in \nmatched groups of breast cancer patients treated with a \nstandard chemotherapy regime alone (629 patients), or with addition of paclitaxel (613 patients), showing a highly significant (p = 0.006) improvement with paclitaxel. Error bars represent \n95% confidence intervals. (Redrawn from Martin et al., 2008. \nJ. Natl. Cancer Inst. 100, 805\u2013814.)\n8Even this can be contentious, because patients who are unconscious, \ndemented or mentally ill are unable to give such consent, yet no one \nwould want to preclude trials that might offer improved therapies to \nthese needy patients. Clinical trials in children are particularly problematic but are necessary if the treatment of childhood diseases is \nto be placed on the same evidence base as is judged appropriate for \nadults. There are many examples where experience has shown that children respond differently from adults, and there is now increasing \npressure on pharmaceutical companies to perform trials in children, \ndespite the difficulties of carrying out such studies. The same concerns apply to trials in elderly patients.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3798, "end_char_idx": 6663, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "82e3bc19-dc6e-4515-811d-ea452d3e7eed": {"__data__": {"id_": "82e3bc19-dc6e-4515-811d-ea452d3e7eed", "embedding": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43bb0877-3aa2-42dd-921c-0663baf7cd22", "node_type": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db9a83f6b5ef5831abeba8d4540c9b341ffcdc9ab3c7951e46fc67c9b1e83143"}, "3": {"node_id": "5d362cd5-9435-4006-8e81-fea18d78e913", "node_type": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5dbed56e03f99a2ae09e674354b220abf54b3f16a793f6986dcf3bbff78d37e5"}}, "hash": "ddedfadc0ce4736c2c14fec30c280c3120790e0862da3a4faf256d2f557a0629", "text": "8 MEthod AN d MEAS u REMEN t IN P h ARMAC o L o G y \n113difference is found although A and B do actually differ \n(false negative). A major factor that determines the size of \nsample needed is the degree of certainty the investigator \nseeks in avoiding either type of error. The probability of incurring a type I error is expressed as the significance \nof the result. To say that A and B are different at the \np < 0.05 level of significance means that the probability \nof obtaining a false positive result (i.e. incurring a type I \nerror) is less than 1 in 20. For most purposes, this level of \nsignificance is considered acceptable as a basis for drawing \nconclusions.\nThe probability of detecting a genuine difference that \nexists between interventions, and avoiding a type II error is termed the power of the trial. We tend to regard type II \nerrors more leniently than type I errors, and it is often \nacceptable to design trials with a power of 0.8\u20130.9, which \nmeans that there is an 80%\u201390% chance of detecting a real effect. A larger sample size will confer greater power or \nability to detect any difference that exists.\nThe second factor that determines the sample size required \nis the magnitude of difference between A and B that is regarded as clinically important. For example, to detect \nthat a given treatment reduces the mortality in a certain condition by at least 10 percentage points, say from 50% \n(in the control group) to 40% (in the treated group), would \nrequire 850 subjects, assuming that we wanted to achieve a p < 0.05 level of significance and a power of 0.9. If we \nwere content only to detect a larger treatment effect of a 20-percentage point reduction in mortality (and very likely miss a reduction by 10 points), only 210 subjects would be needed. In this example, missing a real 10-point reduction \nin mortality could result in abandonment of a treatment \nthat would save 100 lives for every 1000 patients treated \u2013 an extremely serious mistake from society\u2019s point of view. \nThis simple example emphasises the need to assess clinical \nbenefit (which is often difficult to quantify) in parallel with statistical considerations (which are fairly straightforward) \nin planning trials.\n\u25bc A trial may give a significant result (of benefit or harm) before \nthe planned number of patients have been enrolled, so it is common \nfor interim analyses to be carried out at intervals (by an independ-\nent data monitoring team so that the trial team remains unaware of \nthe results). If this analysis gives a conclusive result, or if it shows \nthat continuation is unlikely to give a conclusive result (i.e. futility), \nthe trial can be terminated, thus reducing the number of subjects \ntested. In one such large-scale trial (Beta-blocker Heart Attack Trial \nResearch \tGroup, \t1982) \tof \tthe \tvalue \tof \tlong-term \ttreatment \twith \tthe \t\n\u03b2-adrenoceptor-blocking drug propranolol (Ch. 15) following heart \nattacks, the interim results showed a significant reduction in mortality, \nwhich led to the early termination of the trial. Another trial, the \nCardiac Arrhythmia Suppression Trial (CAST, Echt et al., 1991), was \nstopped because the treatment group, contrary to expectation, showed \nincreased mortality compared with placebo.\nRecently, \tt he \t tendency \th as\t been\t to \tpe rform \tv ery \t large-scale \t trials,\t to \t\nallow several different treatment protocols in various different patient groups to be compared. An example is the ALLHAT trial of various \nantihypertensive and lipid-lowering drugs to improve the outcome \nin cardiovascular disease (see Ch. 23). This ran from 1994 to 2002, cost US$130 million, and involved more than 42,000 patients in 623 \ntreatment centres, with an army of coordinators and managers to keep", "start_char_idx": 0, "end_char_idx": 3755, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5d362cd5-9435-4006-8e81-fea18d78e913": {"__data__": {"id_": "5d362cd5-9435-4006-8e81-fea18d78e913", "embedding": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43bb0877-3aa2-42dd-921c-0663baf7cd22", "node_type": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db9a83f6b5ef5831abeba8d4540c9b341ffcdc9ab3c7951e46fc67c9b1e83143"}, "2": {"node_id": "82e3bc19-dc6e-4515-811d-ea452d3e7eed", "node_type": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ddedfadc0ce4736c2c14fec30c280c3120790e0862da3a4faf256d2f557a0629"}, "3": {"node_id": "58530ce7-a72e-4210-a098-52b6add9287f", "node_type": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f2ed4d9b9aa86981d673278593139d32c0fdb7d73d6362769640d6b8c309fe5e"}}, "hash": "5dbed56e03f99a2ae09e674354b220abf54b3f16a793f6986dcf3bbff78d37e5", "text": "in 623 \ntreatment centres, with an army of coordinators and managers to keep \nit\ton\ttrack.\tOne\tof\tits\tseveral\tfar-reaching \tconclusions \twas\tthat\ta\tcheap\t\nand familiar diuretic drug in use for more than 50 years was more \neffective than more recent and expensive antihypertensive drugs.11The double-blind technique, whereby neither subject nor \ninvestigator is aware at the time of the assessment which \ntreatment is being used, is intended to minimise subjective \nbias. It has been repeatedly shown that, with the best will in the world, subjects and investigators both contribute to \nbias if they know which treatment is which. Awareness of \nthe specific trial intervention may lead to changes in clinical management, or to biased reporting and measurement of \noutcomes Although the use of a double-blind technique is \nan important safeguard this is not always possible. A dietary regimen, for example, can seldom be disguised; with drugs, pharmacological effects may reveal to patients what they \nare taking and predispose them to report accordingly.\n9 In \ngeneral, however, the double-blind procedure, with precau -\ntions if necessary to disguise such clues as the taste or \nappearance of the two drugs, is used whenever possible.10 \nIf full-blinding of participants and investigators is not \npossible, one option is to have a follow-up of outcomes \nconducted by assessors who are unaware of the treatments being used.\nHigh-quality clinical trials have pre-specified follow-up \ntime points where outcomes are measured in a defined manner. Study results may be incomplete and potentially \nbiased if patients drop out of the study or fail to attend \nfollow-up because the intervention did not improve their symptoms. Inadequate follow-up or missing data means that important outcomes (such as serious adverse events) \nmay not have been detected.\nTHE SIZE OF THE SAMPLE\nBoth ethical and financial considerations dictate that the \ntrial should involve the minimum number of subjects, \nand much statistical thought has gone into the problem \nof deciding in advance how many subjects will be required to produce a useful \u2013 and statistically meaningful \u2013 result \n(a power calculation). The results of a trial cannot be \nabsolutely conclusive, because it is based on a sample \nof patients (selected on the basis of specific eligibility \ncriteria), and there is always a chance that the sample \nwas atypical of the population from which it came. Thus, the trial findings may not be generalisable to the routine \nclinical practice.\nJudgements on the appropriate sample size should be \nbased on whether the aim is to demonstrate that two treat -\nments are equivalent (e.g. new treatment is non-inferior to \nthe one that is currently in use), or whether the aim is to \ndemonstrate a significant difference between interventions. Two types of erroneous conclusion are possible, referred \nto as type I and type II errors . A type I error occurs if the \nresults show a difference between A and B when none \nactually exists (false positive). A type II error occurs if no \n11Though without much impact so far on prescribing habits, owing to \nthe marketing muscle of pharmaceutical companies.9The distinction between a true pharmacological response and a \nbeneficial clinical effect produced by the knowledge (based on the \npharmacological effects that the drug produces) that an active drug is \nbeing administered is not easy to draw, and we should not expect a mere clinical trial to resolve such a tricky semantic issue.\n10Maintaining the blind can be problematic. In an attempt to determine \nwhether melatonin is effective in countering jet lag, a pharmacologist \ninvestigator recruited a group of fellow pharmacologists attending a congress in Australia, providing them with unlabelled capsules of melatonin or placebo, with a jet lag questionnaire to fill in when they \narrived. Some of them (one of the authors included), with analytical \nresources easily to hand, opened the capsules and consigned them to the bin on finding that they contained placebo.", "start_char_idx": 3692, "end_char_idx": 7740, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "58530ce7-a72e-4210-a098-52b6add9287f": {"__data__": {"id_": "58530ce7-a72e-4210-a098-52b6add9287f", "embedding": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43bb0877-3aa2-42dd-921c-0663baf7cd22", "node_type": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db9a83f6b5ef5831abeba8d4540c9b341ffcdc9ab3c7951e46fc67c9b1e83143"}, "2": {"node_id": "5d362cd5-9435-4006-8e81-fea18d78e913", "node_type": null, "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5dbed56e03f99a2ae09e674354b220abf54b3f16a793f6986dcf3bbff78d37e5"}}, "hash": "f2ed4d9b9aa86981d673278593139d32c0fdb7d73d6362769640d6b8c309fe5e", "text": "opened the capsules and consigned them to the bin on finding that they contained placebo. Pharmacologists are \nonly human.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7715, "end_char_idx": 8316, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e2d337a9-b7d2-4667-bc33-ea5aec3cf1fc": {"__data__": {"id_": "e2d337a9-b7d2-4667-bc33-ea5aec3cf1fc", "embedding": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f6caa8d2-6666-48c1-ab16-6076128dd297", "node_type": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b4344be1d61d81388910ae59b1f0f83390d50ec4a521edf75967a1c8e6ed513"}, "3": {"node_id": "40dc5499-34ca-488f-a98e-28f1b2fbc130", "node_type": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46adfef1cea3f874dbcad41774c7ee5beffe53baae231ee1836cb4f802a7e2f9"}}, "hash": "1883c8aaefbc580fd0e9160fc43f9682dc945e034a99ce3b02f2857dfa7726ae", "text": "8 SECTION 1 GENERAL PRINCIPLES\n114The risks of placebo therapies should not be underestimated. The \nuse of active medicines may be delayed. The necessary element of \ndeception14 risks undermining the confidence of patients in the integrity \nof doctors. A state of \u2018therapy dependence\u2019 may be produced in people who are not ill, because there is no way of assessing whether a patient \nstill \u2018needs\u2019 the placebo.\nMETA-ANALYSIS\n\u25bc It is possible, using statistical techniques, to combine the data \nobtained in several individual trials (provided each has been conducted according to a randomised design) in order to gain greater power \nand significance. This procedure, known as meta-analysis or overview \nanalysis, can be very useful in arriving at a conclusion on the basis of several published trials, of which some claimed superiority of the \ntest treatment over the control while others did not. As an objective \nprocedure with defined study selection and quality assessment criteria, it is certainly preferable to the \u2018take your pick\u2019 approach to \nconclusion-forming adopted by most human beings when confronted \nwith contradictory data. It has several drawbacks, however (see Naylor, \n1997), the main ones being susceptibility to selective reporting of results and \u2018publication bias\u2019, because negative studies (or unfavour -\nable findings) are less likely to be published than positive studies, \npartly because they are considered less interesting or, more seriously, \nbecause publication would harm the business of the pharmaceutical company that performed the trial.\n15 Double counting, caused by the \nsame data being incorporated into more than one trial report, is another \nproblem.\nThe published clinical trials literature contains reports of many trials \nthat are poorly designed and unreliable. The Cochrane Collaboration \n() sifts carefully through the literature and produces systematic reviews that collate and combine data only from \ntrials (of drugs and other therapeutic interventions) that meet strict quality criteria. About 7000 such \u2018gold-standard\u2019 summaries are available, and provide the most reliable evaluation of trials data on \na wide range of therapeutic drugs.\nBALANCING BENEFIT AND RISK\nTHERAPEUTIC INDEX\n\u25bc The concept of therapeutic index aims to provide a measure of \nthe margin of safety of a drug, by drawing attention to the relationship \nbetween the effective and toxic doses:\nTherapeutic inde xL DE D = 50 50\nwhere LD 50 is the dose that is lethal in 50% of the population, and \nED 50\tis\tthe\tdose \tthat \tis \t\u2018effective\u2019 \tin \t50%. \tObviously, \tit \tcan \tonly \tbe \t\nmeasured in animals, and it is not a useful guide to the safety of a drug in clinical use for several reasons:\n\u2022\tLD\n50 does not reflect the incidence of adverse effects in the \ntherapeutic setting.16\n\u2022\tED 50 depends on what measure of effectiveness is used. For \nexample, the ED 50 for aspirin used for a mild headache is much \nlower than for aspirin as an antirheumatic drug.\n\u2022\tBoth\tefficacy \tand \ttoxicity \tare \tsubject \tto \tindividual \tvariation. \t\nIndividual differences in the effective dose or the toxic dose of a \ndrug makes it inherently less predictable, and therefore less safe, \nalthough this is not reflected in the therapeutic index.CLINICAL OUTCOME MEASURES\nThe measurement of clinical outcome can be a complicated \nbusiness, and is becoming increasingly so as society becomes \nmore preoccupied with assessing the efficacy of therapeutic \nprocedures in terms of improved length and quality of life, and societal and economic benefit. Various scales for assess -\ning \u2018health-related quality of life\u2019 have been devised and \ntested\t(see \tWalley \t& \tHaycocks,", "start_char_idx": 0, "end_char_idx": 3692, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "40dc5499-34ca-488f-a98e-28f1b2fbc130": {"__data__": {"id_": "40dc5499-34ca-488f-a98e-28f1b2fbc130", "embedding": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f6caa8d2-6666-48c1-ab16-6076128dd297", "node_type": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b4344be1d61d81388910ae59b1f0f83390d50ec4a521edf75967a1c8e6ed513"}, "2": {"node_id": "e2d337a9-b7d2-4667-bc33-ea5aec3cf1fc", "node_type": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1883c8aaefbc580fd0e9160fc43f9682dc945e034a99ce3b02f2857dfa7726ae"}, "3": {"node_id": "43e9f679-a6f4-4c0d-9ce6-041be89dad5b", "node_type": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a11fdc96a8891fd813a8e49deca5fb5a122913b2ad6a7e788c2a4d7e382a3dce"}}, "hash": "46adfef1cea3f874dbcad41774c7ee5beffe53baae231ee1836cb4f802a7e2f9", "text": "have been devised and \ntested\t(see \tWalley \t& \tHaycocks, \t1997); \tthese \tmay \tbe \tcom -\nbined with measures of life expectancy to arrive at the \nmeasure \u2018quality-adjusted life years\u2019 (QALYs) as an overall \nmeasure of therapeutic efficacy, which attempts to combine both survival time and relief from suffering in assessing overall benefit.\n12 In planning clinical trials, it is necessary \nto decide the purpose of the trial in advance, and to define \nthe outcome measures accordingly, particularly in light of \nthe modern-day emphasis on outcomes that are important to patients.\nMeasuring long-term patient benefit may take years, so \nobjective clinical effects, such as lowering of blood pressure, improved airways conductance or change in white cell \ncount are often used as trial outcome measures. These \nsurrogate markers reflect pathophysiological changes of which \nthe patient is most likely unaware. In many cases such changes correlate well with clinical outcome as it affects \nthe patient; not always, though. In the CAST trial (see \npreviously), anti-arrhythmic drugs were found to suppress certain ventricular arrhythmias (the surrogate marker), but \nto increase\n\tsudden\tcardiac \tdeaths. \tRegulatory \tauthorities \t\nare therefore rightly cautious about accepting surrogate \nend points as a measure of actual patient benefit.\nPLACEBOS\n\u25bc A placebo is a dummy medicine containing no active ingredient \n(or alternatively, a dummy surgical procedure, diet or other kind \nof therapeutic intervention), which the patient believes is (or could \nbe, in the context of a controlled trial) the real thing. The \u2018placebo \nresponse\u2019 (see review by Enck et al., 2013) is widely believed to be a \npowerful therapeutic effect,13 producing a significant beneficial effect \nin about one-third of patients. While many clinical trials include a placebo group that shows improvement, few have compared this \ngroup directly with untreated controls, particularly where the natural history of the disease is symptom resolution without any intervention. \nThe role of placebo is a topic of major debate, with some arguing \nthat placebo has limited effect, except perhaps in trials involving \npain\tor\tnausea \t(Hr\u00f3bjartsson \t& \tG\u00f8tzsche, \t2010), \twhilst \tothers \thave \t\nreported clinically meaningful effects with placebo (Howick et al, \n2013). There are also growing numbers of pragmatic trials where the new treatment is compared against \u2018standard or usual\u2019 care, \nrather than the rather artificial construct of a placebo dummy pill \nthat does not represent what the patient would actually receive in \nclinical practice.\n12As may be imagined, trading off duration and quality of life raises \nissues about which many of us feel decidedly squeamish. Not so \neconomists, however. They approach the problem by asking such \nquestions as: \u2018How many years of life would you be prepared to sacrifice in order to live the rest of your life free of the disability you \nare\tcurrently \texperiencing?\u2019 \tOr, \teven \tmore \tdisturbingly: \t\u2018If, \tgiven \tyour \t\npresent condition, you could gamble on surviving free of disability for your normal lifespan, or (if you lose the gamble) dying immediately, \nwhat odds would you accept?\u2019 Imagine being asked this by your \ndoctor. \u2018But I only wanted something for my sore throat,\u2019 you protest weakly.\n13Its opposite, the nocebo effect, describes the adverse effects reported \nwith dummy medicines.14Surprisingly, deception may not even be necessary. Kaptchuk et al. \n(2010) found that symptoms of irritable bowel syndrome were improved slightly more in patients given inert sugar pills, described as \nsuch by the physician, than in patients given no pills. The effect was, \nhowever, small, and the patients were", "start_char_idx": 3644, "end_char_idx": 7367, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "43e9f679-a6f4-4c0d-9ce6-041be89dad5b": {"__data__": {"id_": "43e9f679-a6f4-4c0d-9ce6-041be89dad5b", "embedding": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f6caa8d2-6666-48c1-ab16-6076128dd297", "node_type": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b4344be1d61d81388910ae59b1f0f83390d50ec4a521edf75967a1c8e6ed513"}, "2": {"node_id": "40dc5499-34ca-488f-a98e-28f1b2fbc130", "node_type": null, "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46adfef1cea3f874dbcad41774c7ee5beffe53baae231ee1836cb4f802a7e2f9"}}, "hash": "a11fdc96a8891fd813a8e49deca5fb5a122913b2ad6a7e788c2a4d7e382a3dce", "text": "given no pills. The effect was, \nhowever, small, and the patients were encouraged to think that the pills might engage \u2018mind-body healing processes\u2019.\n15To reduce this bias, measures are now in place to ensure that most \nclinical trials are registered and the results publicly disclosed.\n16Ironically, thalidomide \u2013 probably the most harmful drug ever \nmarketed \u2013 was promoted specifically on the basis of its exceptionally \nhigh therapeutic index (i.e. it killed rats only when given in extremely \nlarge doses).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7346, "end_char_idx": 8336, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c90978d2-af98-4a92-bcc4-2a97d8478c5f": {"__data__": {"id_": "c90978d2-af98-4a92-bcc4-2a97d8478c5f", "embedding": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bebbe97a-6ba0-45c7-9d6b-033a087e73fe", "node_type": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "701c010412ddb13be2e967244e4ee0ab8280b49c14baf8bddc8bf8c271bab6b8"}, "3": {"node_id": "96567bcd-6ad0-4113-a1fc-a83b8a89f947", "node_type": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5dd149cd5b13138326f99b2e2db9e652bc2067799ca4ebc2325f55bd44355744"}}, "hash": "49da404c905c4b82c55a3ec8c3c0887d76547f28a4e7ab2c72c21e1e248a102e", "text": "8 MEthod ANd MEASuREMENt IN PhARMACoLoGy \n115OTHER MEASURES OF BENEFIT AND RISK\n\u25bc Alternative ways of quantifying the benefits and risks of drugs \nin\tclinical\tuse\thave\treceived\t much\tattention.\t One\tuseful\tapproach\t is\t\nto estimate from clinical trial data the proportion of test and control \npatients who will experience (A) a defined level of clinical benefit \n(e.g. survival beyond 2 years, pain relief to a certain predetermined \nlevel, slowing of cognitive decline by a given amount) and (B) adverse \neffects of defined degree. These estimates of proportions of patients \nshowing beneficial or harmful reactions can be expressed as number \nneeded to treat (NNT; i.e. the number of patients who need to be \ntreated in order for one to show the given effect, whether beneficial \nor adverse). For example, in a recent study of pain relief by antidepres -\nsant drugs compared with placebo, the findings were: for benefit (a \ndefined level of pain relief), NNT = 3; for minor unwanted effects, \nNNT = 3; for major adverse effects, NNT = 22. Thus of 100 patients \ntreated with the drug, on average 33 will experience pain relief, 33 \nwill experience minor unwanted effects, and 4 or 5 will experience \nmajor adverse effects, information that is helpful in guiding therapeutic \nchoices.\tOne\tadvantage\tof\tthis\ttype\tof\tanalysis\tis\tthat\tit\tcan\ttake\tinto \t\naccount the underlying disease severity in quantifying benefit. Thus \nif drug A halves the mortality of an often fatal disease (reducing it \nfrom 50% to 25%, say), the NNT to save one life is 4; if drug B halves \nthe mortality of a rarely fatal disease (reducing it from 5% to 2.5%, \nsay), the NNT to save one life is 40. Notwithstanding other considera -\ntions, drug A is judged to be more valuable than drug B, even though \nboth reduce mortality by one-half. Furthermore, the clinician must \nrealise that to save one life with drug B, 40 patients must be exposed \nto a risk of adverse effects, whereas only four are exposed for each \nlife saved with drug A.Clinical trials \n\u2022\tA\tclinical\ttrial\tis\ta\tspecial\ttype\tof\tbioassay\tdone\tto\t\ncompare the clinical efficacy of a new drug or \nprocedure with that of a known drug or procedure (or \na placebo).\n\u2022\tAt\tits\tsimplest,\tthe\taim\tis\ta\tstraight\tcomparison\t of\t\nunknown (A) with standard (B) at a single-dose level. \nThe result may be: \u2018B better than A\u2019, \u2018B worse than A\u2019, \nor \u2018No difference detected\u2019. Efficacy, not potency, is \ncompared.\n\u2022\tTo\tavoid\tbias,\tclinical\ttrials\tshould\tbe:\n\u2013 controlled (comparison of A with B, rather than \nstudy of A alone);\n\u2013 randomised (assignment of subjects to A or B on a \nrandom basis);\n\u2013 double-blind (neither subject nor assessor knows \nwhether A or B is being used).\n\u2022\tType\tI\terrors\t(concluding\t that\tA\tis\tbetter\tthan\tB\twhen\t\nthe difference is actually due to chance) and type II \nerrors (concluding that A is not different from B \nbecause a real difference has escaped detection) can \noccur; the likelihood of either kind of error decreases \nas the methodological quality, sample size and number \nof end-point events is increased.\n\u2022\tInterim\t analysis\tof\tdata,\tcarried\tout\tby\tan\tindependent\t\ngroup, may be used as a basis for terminating a trial \nprematurely if the data are already conclusive, or if a \nclear result is unlikely to be", "start_char_idx": 0, "end_char_idx": 3270, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "96567bcd-6ad0-4113-a1fc-a83b8a89f947": {"__data__": {"id_": "96567bcd-6ad0-4113-a1fc-a83b8a89f947", "embedding": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bebbe97a-6ba0-45c7-9d6b-033a087e73fe", "node_type": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "701c010412ddb13be2e967244e4ee0ab8280b49c14baf8bddc8bf8c271bab6b8"}, "2": {"node_id": "c90978d2-af98-4a92-bcc4-2a97d8478c5f", "node_type": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "49da404c905c4b82c55a3ec8c3c0887d76547f28a4e7ab2c72c21e1e248a102e"}, "3": {"node_id": "15ae37b9-c52d-4189-9178-997cc157abb5", "node_type": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "778e6dde66541db063bda5a42385e681a3a2778e8561f4ff0fe14064b9efb4b0"}}, "hash": "5dd149cd5b13138326f99b2e2db9e652bc2067799ca4ebc2325f55bd44355744", "text": "if the data are already conclusive, or if a \nclear result is unlikely to be reached.\n\u2022\tAll\texperiments\t on\thuman\tsubjects\trequire\tapproval\tby\t\nan independent ethics committee.\n\u2022\tClinical\t trials\trequire\tvery\tcareful\tplanning\tand\t\nexecution, and are inevitably expensive.\n\u2022\tClinical\t outcome\tmeasures\t may\tcomprise:\n\u2013 physiological measures (e.g. blood pressure, liver \nfunction tests, airways function);\n\u2013 subjective assessments (e.g. pain relief, mood);\n\u2013 long-term outcome (e.g. survival or freedom from \nrecurrence);\n\u2013 overall \u2018 quality of life \u2019 measures;\n\u2013 \u2018quality-adjusted life years \u2019 (QALYs), which combine \nsurvival with quality of life.\n\u2022\tMeta-analysis\t is\ta\tstatistical\t technique\t used\tto\tpool\t\nthe data from several independent trials.Determination of risk and benefit \n\u2022\tTherapeutic index (lethal dose for 50% of the \npopulation divided by effective dose for 50%) is \nunsatisfactory as a measure of drug safety because:\n\u2013 it is based on animal toxicity data, which may not \nreflect forms of toxicity or adverse reactions that are \nimportant clinically;\n\u2013 it takes no account of idiosyncratic toxic reactions.\n\u2022\tMore\tsophisticated\t measures\t of\trisk\u2013benefit\t analysis\t\nfor drugs in clinical use are available, and include the \nnumber needed to treat (NNT) principle.\nREFERENCES AND FURTHER READING\nGeneral references\nColquhoun,\t D.,\t1971.\tLectures\t on\tBiostatistics.\t Oxford\tUniversity\t Press,\t\nOxford.\t(Standard textbook )\nKirkwood,\t B.R.,\tSterne,\tJ.A.C.,\t2003.\tMedical\t Statistics,\t second\ted.\t\nBlackwell, Malden. ( Clear introductory textbook covering statistical \nprinciples and methods )\nWalley, T., Haycocks, A., 1997. Pharmacoeconomics: basic concepts and \nterminology. Br. J. Clin. Pharmacol. 43, 343\u2013348. ( Useful introduction to \nanalytical principles that are becoming increasingly important for therapeutic \npolicy makers )\nYanagisawa, M., Kurihara, H., Kimura, S., et al., 1988. A novel potent \nvasoconstrictor peptide produced by vascular endothelial cells. \nNature 332, 411\u2013415. ( The first paper describing endothelin \u2013 a remarkably \nfull characterisation of an important new mediator )Molecular methods\nLohse, M.J., Nuber, S., Hoffmann, C., 2012. Fluorescence/\nbioluminescence resonance energy transfer techniques to study G \nprotein-coupled\t receptor\t activation\t and\tsignaling.\t Pharmacol.\t Rev.\t64,\t\n299\u2013336. ( Review of modern fluorescence-based methods for studying GPCR \nfunction )\nNygaard,\t R.,\tZou,\tY.,\tDror,\tR.O.,\tet\tal.,\t2013.\tThe\tdynamic\t process\tof\t\n\u03b2(2)-adrenergic receptor activation. Cell 152 (3), 532\u2013542. ( Review \ndemonstrating the use of modern spectroscopic techniques to measure the \neffects of ligands on receptor conformation )\nAnimal models\nOffermanns,\t S.,\tHein,\tL.\t(Eds.),\t2004.\tTransgenic\t models\tin\t\npharmacology. Handb. Exp. Pharmacol. 159. ( A comprehensive series of mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3210, "end_char_idx": 6312, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "15ae37b9-c52d-4189-9178-997cc157abb5": {"__data__": {"id_": "15ae37b9-c52d-4189-9178-997cc157abb5", "embedding": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bebbe97a-6ba0-45c7-9d6b-033a087e73fe", "node_type": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "701c010412ddb13be2e967244e4ee0ab8280b49c14baf8bddc8bf8c271bab6b8"}, "2": {"node_id": "96567bcd-6ad0-4113-a1fc-a83b8a89f947", "node_type": null, "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5dd149cd5b13138326f99b2e2db9e652bc2067799ca4ebc2325f55bd44355744"}}, "hash": "778e6dde66541db063bda5a42385e681a3a2778e8561f4ff0fe14064b9efb4b0", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6326, "end_char_idx": 6581, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "98b25184-9037-4ea5-9be9-e93b5e1a61e1": {"__data__": {"id_": "98b25184-9037-4ea5-9be9-e93b5e1a61e1", "embedding": null, "metadata": {"page_label": "122", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f36838e-a6d9-419d-a03f-fe45f488028a", "node_type": null, "metadata": {"page_label": "122", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "499e4ecd523f780d8257811907540fed04a82f7ffb0f4270b3d2c0f8dff3b29e"}, "3": {"node_id": "ad16ddb8-d426-4971-b25f-b91294818f66", "node_type": null, "metadata": {"page_label": "122", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "554572964e457ed39c33f8b1dd668be196560e1127b557a88fed9272f83dfd5a"}}, "hash": "57380efa899d9c76cfe406d9c713be81bb955b14e00a43d5d796089ab29f1765", "text": "8 SECTION 1 GENERAL PRINCIPLES\n116Drug Discov. 12, 191\u2013204. ( Comprehensive review of a slippery \nphenomenon )\nHackshaw, A., 2009. A Concise Guide to Clinical Trials. Wiley \nBlackwell. ( Short introductory textbook )\nHowick, J., Friedemann, C., Tsakok, M., et al., 2013. Are treatments \nmore effective than placebos? A systematic review and meta-analysis. \nPLoS\tONE\t8,\te62599.\nHrobjartsson, A., Gotzsche, P.C., 2010. Placebo interventions for all \nclinical\tconditions.\t Cochrane\t Database\t Syst.\tRev.\tCD003974.\nKaptchuk, T.J., Friedlander, E., Kelley, J.M., et al., 2010. Placebos \nwithout deception: a randomized controlled trial in irritable bowel \nsyndrome.\t PLoS\tONE\t5\t(12),\te15591.\t(Study showing that placebo pills \nhave a significant effect even if the patient knows that they contain no active \ningredient )\nNaylor, C.D., 1997. Meta-analysis and the meta-epidemiology of clinical \nresearch. Br. Med. J. 315, 617\u2013619. ( Thoughtful review on the strengths \nand weaknesses of meta-analysis )\nSackett,\tD.L.,\tRosenburg,\t W.M.C.,\t Muir-Gray,\t J.A.,\tet\tal.,\t1996.\t\nEvidence-based medicine: what it is and what it isn\u2019t. Br. Med. J. 312, \n71\u201372. ( Balanced account of the value of evidence-based medicine \u2013 an \nimportant recent trend in medical thinking )review articles describing transgenic mouse models used to study different \npharmacological mechanisms and disease states )\nRistevski,\t S.,\t2005.\tMaking\tbetter\ttransgenic\t models:\t conditional,\t\ntemporal, and spatial approaches. Mol. Biotechnol. 29, 153\u2013164. \n(Description of methods for controlling transgene expression )\nRudolph,\t U.,\tMoehler,\t H.,\t1999.\tGenetically\t modified\t animals\t in\t\npharmacological research: future trends. Eur. J. Pharmacol. 375, \n327\u2013337. ( Good review of uses of transgenic animals in pharmacological \nresearch, including application to disease models )\nClinical trials\nBeta-blocker\t Heart\tAttack\tTrial\tResearch\t Group,\t1982.\tA\trandomised\t\ntrial of propranolol in patients with acute myocardial infarction. 1. \nMortality results. JAMA 247, 1707\u20131714. ( A trial that was terminated \nearly when clear evidence of benefit emerged )\nEcht,\tD.S.,\tLiebson,\t P.R.,\tMitchell,\t L.B.,\tet\tal.,\t1991.\tMortality\t and\t\nmorbidity in patients receiving encainide, flecainide, or placebo. The \nCardiac Arrhythmia Suppression Trial. N. Engl. J. Med. 324, 781\u2013788. \n(Important trial showing that antiarrhythmic drugs, which were expected to \nreduce sudden deaths after a heart attack, have the opposite effect )\nEnck,\tP.,\tBigel,\tU.,\tSchedlowski,\t M.,\tRief,\tW.,\t2013.\tThe\tplacebo\t\nresponse\t in\tmedicine:\t minimize,\t maximize\t or\tpersonalize?\t Nat.\tRev.\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2922, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ad16ddb8-d426-4971-b25f-b91294818f66": {"__data__": {"id_": "ad16ddb8-d426-4971-b25f-b91294818f66", "embedding": null, "metadata": {"page_label": "122", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f36838e-a6d9-419d-a03f-fe45f488028a", "node_type": null, "metadata": {"page_label": "122", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "499e4ecd523f780d8257811907540fed04a82f7ffb0f4270b3d2c0f8dff3b29e"}, "2": {"node_id": "98b25184-9037-4ea5-9be9-e93b5e1a61e1", "node_type": null, "metadata": {"page_label": "122", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57380efa899d9c76cfe406d9c713be81bb955b14e00a43d5d796089ab29f1765"}}, "hash": "554572964e457ed39c33f8b1dd668be196560e1127b557a88fed9272f83dfd5a", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2875, "end_char_idx": 3098, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "57f670dc-b330-42e9-8869-0c404c3e7657": {"__data__": {"id_": "57f670dc-b330-42e9-8869-0c404c3e7657", "embedding": null, "metadata": {"page_label": "123", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "07ab4333-e343-4311-9c87-1a54cb27536f", "node_type": null, "metadata": {"page_label": "123", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad543b6b48f0f017a73cc458be271bdd54f958c9a1e0fb62cce43629c754c6fc"}, "3": {"node_id": "28d84a72-5738-451a-a697-3528e8c1da17", "node_type": null, "metadata": {"page_label": "123", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eb647cce6b25055cfcc7cf94dfdf5c1d9d218ecc431083e656cb2b57454e5a74"}}, "hash": "15e5356620a300a02e793994c3694be7b495ebab429af8a3707efa3a1eb3909e", "text": "117\nAbsorption and distribution \nof drugs9 GENERAL PRINCIPLES SECTION 1 \nOVERVIEW\nThe physical processes of diffusion, penetration of \nmembranes, binding to plasma protein and partition \ninto fat and other tissues underlie the absorption and \ndistribution of drugs. These processes are described, \nfollowed by more specific coverage of the process of \ndrug absorption and related practical issue of routes \nof drug administration, and of the distribution of drugs \ninto different bodily compartments. Drug interactions \ncaused by one drug altering the absorption or distribu -\ntion of another are described. There is a short final \nsection on special drug delivery systems designed to \ndeliver drugs efficiently and selectively to their sites \nof action.\nINTRODUCTION\nDrug disposition is divided into four stages designated by \nthe acronym \u2018ADME\u2019:\n\u2022\tAbsorption from the site of administration\n\u2022\tDistribution within the body\n\u2022\tMetabolism\n\u2022\tExcretion\nGeneral aspects of drug absorption and distribution are \nconsidered here, together with routes of administration. \nAbsorption and distribution of inhaled general anaesthetics \n(a special case) are described in Chapter 42. Metabolism \nand excretion are covered in Chapter 10. We begin with a \ndescription of the physical processes that underlie drug \ndisposition.\nPHYSICAL PROCESSES UNDERLYING \nDRUG DISPOSITION\nDrug molecules move around the body in two ways:\n\u2022\tbulk\tflow\t(i.e.\tin\tthe\tbloodstream,\t lymphatics\t or\t\ncerebrospinal\t fluid)\n\u2022\tdiffusion\t (i.e.\tmolecule\t by\tmolecule,\t over\tshort\t\ndistances).\nThe\tchemical\t nature\tof\ta\tdrug\tmakes\tno\tdifference\t to\tits\t\ntransfer\tby\tbulk\tflow.\tThe\tcardiovascular\tsystem\tprovides \t\na rapid long-distance distribution system. In contrast, \ndiffusional\tcharacteristics\tdiffer\tmarkedly\tbetween\tdifferent \t\ndrugs. In particular, ability to cross hydrophobic diffusion \nbarriers\tis\tstrongly\tinfluenced\tby\tlipid\tsolubility.\tAqueous \t\ndiffusion is part of the overall mechanism of drug transport, \nbecause it is this process that delivers drug molecules to \nand\tfrom\tthe\tnon-aqueous\t barriers.\t The\trate\tof\tdiffusion\tof a substance depends mainly on its molecular size, the \ndiffusion coefficient \tbeing\tinversely\tproportional\tto\tthe\tsquare \t\nroot\tof\tmolecular\t weight.\t Consequently,\t while\tlarge\t\nmolecules diffuse more slowly than small ones, the variation \nwith molecular weight is modest. Classical \u2018small molecule\u2019 \ndrugs mainly fall within the molecular weight range \n200\u20131000\t Da,\tand\tvariations\tin\taqueous\tdiffusion\trate\thave \t\nonly\ta\tsmall\teffect\ton\ttheir\toverall\tpharmacokinetic \tbehav -\niour, whereas biopharmaceuticals are typically much larger \nmolecules (Ch. 5). Thus the molecular weight of a mono -\nclonal\tantibody\t drug\tis\tapproximately\t 150\tkDa\tand\tof\ta\t\nsmall\tinterfering\t RNA\t7.5\tkDa,\tso\tdiffusion\t can\tbe\tan\t\nimportant limitation to the rate of onset of action of biop -\nharmaceutical drugs.\nFor small molecule drugs, we can treat the body as a \nseries of interconnected, well-stirred compartments, within \neach of which the drug concentration is uniform. It is \nmovement between compartments, generally involving \npenetration\t of\tnon-aqueous\t diffusion\t barriers,\t that\tdeter -\nmines where, and for how long, a drug will be present in \nthe body after it has been administered. The analysis of", "start_char_idx": 0, "end_char_idx": 3301, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "28d84a72-5738-451a-a697-3528e8c1da17": {"__data__": {"id_": "28d84a72-5738-451a-a697-3528e8c1da17", "embedding": null, "metadata": {"page_label": "123", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "07ab4333-e343-4311-9c87-1a54cb27536f", "node_type": null, "metadata": {"page_label": "123", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad543b6b48f0f017a73cc458be271bdd54f958c9a1e0fb62cce43629c754c6fc"}, "2": {"node_id": "57f670dc-b330-42e9-8869-0c404c3e7657", "node_type": null, "metadata": {"page_label": "123", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "15e5356620a300a02e793994c3694be7b495ebab429af8a3707efa3a1eb3909e"}}, "hash": "eb647cce6b25055cfcc7cf94dfdf5c1d9d218ecc431083e656cb2b57454e5a74", "text": "a drug will be present in \nthe body after it has been administered. The analysis of \ndrug movements with the help of a simple compartmental \nmodel is discussed in Chapter 11.\nTHE MOVEMENT OF DRUG MOLECULES \nACROSS CELL BARRIERS\nCell\tmembranes\t form\tthe\tbarriers\tbetween\taqueous\tcompart -\nments in the body. A single layer of membrane separates \nthe intracellular from the extracellular compartments. An \nepithelial barrier, such as the gastrointestinal mucosa or \nrenal tubule, consists of a layer of cells tightly connected \nto each other so that molecules must traverse at least two \ncell membranes (inner and outer) to pass from one side to \nthe other. The anatomical disposition and permeability of \nvascular endothelium (the cell layer that separates intra -\nvascular from extravascular compartments) varies from \none tissue to another. Gaps between endothelial cells are \npacked\twith\ta\tloose\tmatrix\tof\tproteins\t that\tact\tas\tfilters,\t\nretaining large molecules and letting smaller ones through. \nThe cut-off of molecular size is not exact: water permeates \nrapidly whereas molecules of 80,000\u2013100,000 Da permeate \nvery slowly. In some regions, especially the blood\u2013brain \nbarrier (see p. 129) of the CNS, and the placenta, there are \ntight junctions between the cells, and the endothelium is \nencased in an impermeable layer of periendothelial cells \n(pericytes ). These features prevent potentially harmful \nmolecules from penetrating to brain or fetus and have major \nconsequences\t for\tdrug\tdistribution\t and\tactivity.\nIn other organs (e.g. the liver and spleen), endothelium \nis discontinuous, allowing free passage between cells. In \nthe liver, hepatocytes form the barrier between intra- and \nextravascular\tcompartments\tand\ttake\ton\tseveral\tendothelial \t\ncell functions. Fenestrated endothelium occurs in endocrine \nglands, facilitating transfer to the bloodstream of hormones mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3218, "end_char_idx": 5585, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "37d8a102-3ccd-42af-b300-02f3ffb58675": {"__data__": {"id_": "37d8a102-3ccd-42af-b300-02f3ffb58675", "embedding": null, "metadata": {"page_label": "124", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7e9db47e-a794-457e-9cdf-c69acc8f26ce", "node_type": null, "metadata": {"page_label": "124", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e50f0dc09269277416a0655d5cc2da53b82973dbb74b14cb1f214b4f82cfcd83"}, "3": {"node_id": "3f66f6cb-0e56-4e16-a2c7-06b085ff0150", "node_type": null, "metadata": {"page_label": "124", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5488f23e8a31bb15b1b62b6eb910ddd27a359d0d3677c8205f7d4e24bc8fec3f"}}, "hash": "fc0ba0647d94aedf66b3906dbd1ca6e71394ea8f953e1505ad1aa33b63902280", "text": "9 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n118numbers and must be mobile within the membrane if rapid \npermeation is to occur. Thus, two physicochemical factors \ncontribute to P, namely solubility in the membrane (which \ncan be expressed as a partition coefficient for the substance \ndistributed \tbetween\tthe\tmembrane \tphase\tand\tthe\taqueous\t\nenvironment) and diffusivity, which is a measure of the \nmobility of molecules within the lipid and is expressed as \na diffusion coefficient. The diffusion coefficient varies only \nmodestly between conventional drugs, as noted above, so the most important determinant of membrane permeability \nfor conventional low molecular-weight drugs is the partition \ncoefficient \t(Fig.\t9.2).\tMany\tpharmacokinetic \tcharacteristics \t\nof a drug \u2013 such as rate of absorption from the gut, penetra -\ntion into different tissues and the extent of renal elimination \n\u2013\tcan\tbe\tpredicted \tfrom \tknowledge \tof \tits \tlipid \tsolubility.\nION\u2003TRAPPING\nIonisation and membrane permeability affect not only the \nrate at which drugs permeate membranes but also the \nsteady-state \tdistribution \tof\tdrug\tmolecules \tbetween\taqueous\t\ncompartments. Lipid-soluble molecules diffuse into cells where they can be metabolised (e.g. by esterases); this may \nEXTRACELLULAR\nMEMBRANE\nINTRACELLULARCarrierDiffusion\nthrough\naqueous\nchannelDiffusion\nthrough\nlipid\nFig. 9.1 Routes by which solutes can traverse cell \nmembranes. (Molecules can also cross cellular barriers by \npinocytosis.) \nConcentration of drug (A) Concentration of drug (B)C2C1\u2206Cm\n\u2206CmCompartment 1\n(extracellular)\nLow lipid solubilityHigh lipid solubilityCompartment 2\n(intracellular)Membrane\nCompartment 1\n(extracellular)Compartment 2\n(intracellular)Membrane\nC2C1A\nB\nFig. 9.2 The importance of lipid solubility in membrane \npermeation. (A) and (B) show the concentration profile in a lipid \nmembrane separating two aqueous compartments. A lipid-\nsoluble drug (A) is subject to a much larger transmembrane \nconcentration gradient (\u0394C m) than a lipid-insoluble drug (B). It \ntherefore diffuses more rapidly, even though the aqueous concentration gradient (C\n1\u2013C2) is the same in both cases. or other molecules through pores in the endothelium. \nFormation of fenestrated endothelium is controlled by a \nspecific endocrine gland-derived vascular endothelial growth \nfactor (dubbed EG-VEGF). Endothelial cells lining postcapil -\nlary\tvenules\thave\tspecialised \tfunctions \trelating\tto\tleukocyte \t\nmigration \tand \tinflammation, \tand \tthe \tsophistication \tof \tthe \t\nintercellular junction can be appreciated from the observa -\ntion\tthat \tleukocyte \tmigration \tcan \toccur \twithout \tany \t\ndetectable \tleak \tof \twater \tor \tsmall \tions \t(see \tCh. \t7).\nThere are four main ways by which small molecules \ncross cell membranes (Fig. 9.1):\n\u2022\tby\tdiffusing \tdirectly \tthrough \tthe \tlipid;\n\u2022\tby\tcombination \twith \ta \tsolute carrier (SLC) or other \nmembrane transporter;\n\u2022\tby\tdiffusing \tthrough \taqueous \tpores \tformed \tby \tspecial \t\nmembrane glycoproteins (aquaporins) that traverse the lipid;\n\u2022\tby\tpinocytosis.\nOf these routes, diffusion through lipid and", "start_char_idx": 0, "end_char_idx": 3096, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3f66f6cb-0e56-4e16-a2c7-06b085ff0150": {"__data__": {"id_": "3f66f6cb-0e56-4e16-a2c7-06b085ff0150", "embedding": null, "metadata": {"page_label": "124", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7e9db47e-a794-457e-9cdf-c69acc8f26ce", "node_type": null, "metadata": {"page_label": "124", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e50f0dc09269277416a0655d5cc2da53b82973dbb74b14cb1f214b4f82cfcd83"}, "2": {"node_id": "37d8a102-3ccd-42af-b300-02f3ffb58675", "node_type": null, "metadata": {"page_label": "124", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc0ba0647d94aedf66b3906dbd1ca6e71394ea8f953e1505ad1aa33b63902280"}}, "hash": "5488f23e8a31bb15b1b62b6eb910ddd27a359d0d3677c8205f7d4e24bc8fec3f", "text": "these routes, diffusion through lipid and carrier-mediated \ntransport are particularly important in relation to pharma-\ncokinetic \tmechanisms.\n\u25bc\tDiffusion \t through \t aquaporins \t is \t probably \t important \t in \t the \t transfer\t\nof gases such as carbon dioxide, but the pores are too small in diameter \n(about 0.4 nm) to allow most drug molecules (which usually exceed \n1\tnm\tin\tdiameter) \tto \tpass \tthrough. \tConsequently, \tdrug \tdistribution \t\nis not notably abnormal in patients with genetic diseases affecting \naquaporins. \tPinocytosis \tinvolves \tinvagination \tof \tpart \tof \tthe \tcell \t\nmembrane and the trapping within the cell of a small vesicle containing \nextracellular constituents. The vesicle contents can then be released \nwithin the cell, or extruded from its other side. This mechanism is \nimportant for the transport of some macromolecules (e.g. insulin, \nwhich crosses the blood\u2013brain barrier by this process), but not for \nsmall molecules.\nDIFFUSION \u2003THROUGH \u2003LIPID\nNon-polar molecules (in which electrons are uniformly \ndistributed) dissolve freely in membrane lipids, and con -\nsequently \tdiffuse \treadily \tacross \tcell \tmembranes. \tThe \tnumber\t\nof molecules crossing the membrane per unit area in unit time is determined by the permeability coefficient , P, and the \nconcentration \tdifference \tacross \tthe \tmembrane. \tPermeant \t\nmolecules must be present within the membrane in sufficient mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3055, "end_char_idx": 4943, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ba20c5ae-1203-4cfa-b9a1-485d621e0576": {"__data__": {"id_": "ba20c5ae-1203-4cfa-b9a1-485d621e0576", "embedding": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "304f44ed-0692-43a5-815f-e9880eb2301b", "node_type": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61901787cd1227ce8511deb326fccd03661f76338b31c6eedbacd361fe2ea204"}, "3": {"node_id": "17c15225-1113-46bc-9b68-293ee6d5761e", "node_type": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b6dcaf728b3eb8f922ded954bf9272d6260402f083e0e7982c90417b51c94a25"}}, "hash": "15b604d0c9e7073d6b6321595ae37453e5c2904fb4007d0cff880f16361156b7", "text": "9 AbSoRPtIoN AN d d IS t RI but I o N of d R u GS \n119the pH of that compartment. It is assumed that the un-\nionised species can cross the membrane, and therefore \nreaches\tan \tequal \tconcentration \tin \teach \tcompartment. \tThe \t\nionised species is assumed not to cross at all. The result is \nthat,\tat\tequilibrium, \tthe \ttotal \t(ionised \t+ un-ionised) con-\ncentration of the drug will be different in each compartment, \nwith an acidic drug being concentrated in the compartment \nwith high pH (\u2018ion trapping\u2019), and vice versa. The concentra -\ntion gradients produced by ion trapping can theoretically \nbe very large if there is a large pH difference between \ncompartments. Thus, aspirin would be concentrated more \nthan\tfour-fold \twith \trespect \tto \tplasma \tin \tan \talkaline \trenal \t\ntubule, and about 6000-fold in plasma with respect to the acidic gastric contents. Such large gradients are not achieved \nin reality for two main reasons. First, assuming total \nimpermeability of the charged species is not realistic, and even a small permeability will attenuate considerably the \nconcentration difference that can be reached. Second, body \ncompartments \trarely \tapproach \tequilibrium. \tNeither \tthe \t\ngastric\tcontents\tnor\tthe\trenal\ttubular\tfluid\tstands\tstill,\tand\t\nthe\tresulting \tbulk \tflow \tof \tdrug \tmolecules \treduces \tthe \t\nconcentration \tgradients \twell\tbelow\tthe\ttheoretical \tequilib -\nrium conditions. The pH partition mechanism nonetheless \ncorrectly \texplains \tsome \tof \tthe \tqualitative \teffects \tof \tpH \t\nchanges in different body compartments on the pharma -\ncokinetics \tof \tweakly \tacidic \tor \tbasic \tdrugs, \tparticularly \tin \t\nrelation to renal excretion and to penetration of the blood\u2013\nbrain barrier.\npH partition is not the main determinant of the site of \nabsorption of drugs from the gastrointestinal tract. This is because the enormous absorptive surface area of the villi \nand microvilli in the ileum compared with the much smaller \nabsorptive surface area in the stomach is of overriding importance. Thus absorption of an acidic drug such as \naspirin is promoted by drugs that accelerate gastric emptying \n(e.g. metoclopramide) and retarded by drugs that slow \ngastric emptying (e.g. propantheline), even though the \nacidic pH of the stomach contents favours absorption of \nweak\tacids. \tValues \tof \tpKa for some common drugs are \nshown in Fig. 9.4.\nThere\tare\tseveral\timportant \tconsequences \tof\tpH\tpartition:\n\u2022\tFree-base \ttrapping \tof \tsome \tantimalarial \tdrugs \t(e.g. \t\nchloroquine, see Ch. 55) in the acidic environment in the food vacuole of the malaria parasite contributes to \nthe disruption of the haemoglobin digestion pathway \nthat underlies their toxic effect on the parasite.\n\u2022\tUrinary \tacidification \taccelerates \texcretion \tof \tweak \t\nbases\tand \tretards \tthat \tof \tweak \tacids \t(see \tCh. \t10).\n\u2022\tUrinary \talkalinisation \thas \tthe \topposite \teffects: \tit \t\nreduces\texcretion \tof \tweak \tbases \tand \tincreases \t\nexcretion \tof \tweak \tacids.\n\u2022\tIncreasing \tplasma \tpH \t(e.g. \tby \tadministration \tof \t\nsodium\tbicarbonate) \tcauses \tweakly \tacidic \tdrugs \tto \tbe \t\nextracted from the CNS into the plasma.", "start_char_idx": 0, "end_char_idx": 3128, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "17c15225-1113-46bc-9b68-293ee6d5761e": {"__data__": {"id_": "17c15225-1113-46bc-9b68-293ee6d5761e", "embedding": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "304f44ed-0692-43a5-815f-e9880eb2301b", "node_type": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61901787cd1227ce8511deb326fccd03661f76338b31c6eedbacd361fe2ea204"}, "2": {"node_id": "ba20c5ae-1203-4cfa-b9a1-485d621e0576", "node_type": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "15b604d0c9e7073d6b6321595ae37453e5c2904fb4007d0cff880f16361156b7"}, "3": {"node_id": "1feb8d29-005a-43d0-ab32-31caf3e23a13", "node_type": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4425f0918bd2e8cc7b5130d1e14bb4d13eb2ed071e56995cdd6410a18e5ae93"}}, "hash": "b6dcaf728b3eb8f922ded954bf9272d6260402f083e0e7982c90417b51c94a25", "text": "from the CNS into the plasma. Conversely, reducing plasma pH (e.g. by administration of a \ncarbonic anhydrase inhibitor such as acetazolamide, \nsee\tCh.\t30) \tcauses \tweakly \tacidic \tdrugs \tto \tbecome \t\nconcentrated in the CNS, potentially increasing their \nneurotoxicity. \tThis \thas \tpractical \tconsequences \tin \t\nchoosing \ta \tmeans \tto \talkalinise \turine \tin \ttreating \taspirin \t\noverdose: bicarbonate and acetazolamide each increase \nurine pH and hence increase salicylate elimination, \nbut bicarbonate reduces whereas acetazolamide \nincreases distribution of salicylate to the CNS.liberate a functionally important charged (and hence \nimpermeant) \tmetabolite, \twhich \tis \tconsequently \ttrapped \t\nwithin the cell. This has been extensively exploited, notably in probing the function of intracellular mediators such as \nCa\n2+\tusing\tfluorescent \tindicators \tsuch \tas \tfura-2, \twhich \tis \t\nloaded into cells as an uncharged ester and trapped intracel -\nlularly as the charged form (see, for example, Fig. 4.2). The same approach has been used recently by pharmaceutical \nchemists \tseeking \tto \ttarget \tdrugs \t(several \tof \twhich \tare \tin \t\ndevelopment) to intracellular sites of action within mono -\ncytes and macrophages using esterase-sensitive chemical motifs conjugated to a drug such as a histone deacetylase \ninhibitor (Ch. 29). This forms a prodrug (see later, p. 131) that delivers the drug to cells of the monocyte macrophage \nlineage which selectively express human carboxylesterase-1, \nthe charged active drug product being trapped in the monocyte cytoplasm, which is its site of action (Needham \net al., 2011).\npH and ionisation\nOne important complicating factor in relation to membrane \npermeation \tis \tthat \tmany \tdrugs \tare \tweak \tacids \tor \tbases, \t\nand therefore exist in both un-ionised and ionised form, \nthe\tratio \tof \tthe \ttwo \tforms \tvarying \twith \tpH. \tFor \ta \tweak \t\nbase, B, the ionisation reaction is:\nBH BHKa +++ /horizontalharpoonextender/arrowrighttophalf/horizontalharpoonextender/horizontalharpoonextender/arrowleftbothalf/horizontalharpoonextender/horizontalharpoonextender/horizontalharpoonextender\nand the dissociation constant p Ka is given by the Henderson\u2013\nHasselbalch \tequation\npK pHBH\nBa=++\nlog[]\n[]10\nFor\ta\tweak \tacid, \tAH:\nAH AH\npK pHAH\nAK\naa/horizontalharpoonextender/arrowrighttophalf/horizontalharpoonextender/horizontalharpoonextender/arrowleftbothalf/horizontalharpoonextender/horizontalharpoonextender/horizontalharpoonextender\u2212\n\u2212++\n=+ log[]\n[]10\nIn either case, the ionised species, BH+ or A\u2212, has very low \nlipid solubility and is virtually unable to permeate mem-\nbranes except where a specific transport mechanism exists. \nThe lipid solubility of the uncharged species, B or AH, depends on the chemical nature of the drug; for many \ndrugs, the uncharged species is sufficiently lipid-soluble \nto permit rapid membrane permeation, although there are exceptions (e.g. aminoglycoside antibiotics; see Ch. 52) \nwhere even the uncharged molecule is insufficiently lipid-\nsoluble to cross membranes appreciably. This is usually because of hydrogen-bonding", "start_char_idx": 3105, "end_char_idx": 6203, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1feb8d29-005a-43d0-ab32-31caf3e23a13": {"__data__": {"id_": "1feb8d29-005a-43d0-ab32-31caf3e23a13", "embedding": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "304f44ed-0692-43a5-815f-e9880eb2301b", "node_type": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61901787cd1227ce8511deb326fccd03661f76338b31c6eedbacd361fe2ea204"}, "2": {"node_id": "17c15225-1113-46bc-9b68-293ee6d5761e", "node_type": null, "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b6dcaf728b3eb8f922ded954bf9272d6260402f083e0e7982c90417b51c94a25"}}, "hash": "f4425f0918bd2e8cc7b5130d1e14bb4d13eb2ed071e56995cdd6410a18e5ae93", "text": "This is usually because of hydrogen-bonding groups (such as hydroxyl in sugar moieties in aminoglycosides) that render the \nuncharged molecule hydrophilic.\npH partition and ion trapping\nIf a pH difference exists between body compartments, this \ncan alter the steady-state distribution of drugs that are \nweak\tacids \tor \tweak \tbases \tvia \tits \tinfluence \ton \ttheir \tionisation. \t\nFig.\t9.3\tshows \thow \ta \tweak \tacid \t(e.g. \taspirin, pK a 3.5) and \na\tweak\tbase\t(e.g.\tpethidine , pKa 8.6) would be distributed \nat\tequilibrium \tbetween\tthree\tbody\tcompartments, \tnamely\t\nplasma\t(pH \t7.4), \talkaline \turine \t(pH \t8) \tand \tgastric \tjuice \t\n(pH 3). Within each compartment, the ratio of ionised to un-ionised drug is governed by the p K\na of the drug and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6184, "end_char_idx": 7409, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6549fafe-abc1-49e3-8fa8-68332e23251b": {"__data__": {"id_": "6549fafe-abc1-49e3-8fa8-68332e23251b", "embedding": null, "metadata": {"page_label": "126", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a17dd8f2-8471-4f40-94d1-21ef60f86416", "node_type": null, "metadata": {"page_label": "126", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a590e84cfd2abe9beac44f446179080a46234f1d161bd4e094b84276b804caeb"}, "3": {"node_id": "22ef48cc-6a12-46f0-8e36-0938f530f701", "node_type": null, "metadata": {"page_label": "126", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "920b4b34265d3e80a37f3ae6ce9d8f5131eab30bf3ae8188d6d01c1a7b10f5f3"}}, "hash": "aa4be52bb5d2aa3e253b78f05d812505e4595823c73813873d901a0563b20bb5", "text": "9 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n120molecules or ions, changes conformation and releases its \ncargo on the other side of the membrane. Such systems \nmay operate purely passively, without any energy source; \nin this case, they merely facilitate the process of transmem -\nbrane\tequilibration \tof \ta \tsingle \ttransported \tspecies \tin \tthe \t\ndirection of its electrochemical gradient. The OCTs trans -\nlocate dopamine, choline and various drugs including \nvecuronium , quinine and procainamide . They are \u2018uniport -\ners\u2019 (i.e. each protein transporter molecule binds one solute \nmolecule at a time and transports it down its gradient). \nOCT2 (present in proximal renal tubules) concentrates drugs \nsuch as cisplatin (an important anticancer drug, see Ch. \n57) in these cells, resulting in its selective nephrotoxicity; \nrelated drugs (e.g. carboplatin, oxaliplatin) are not trans -\nported by OCT2 and are less nephrotoxic; competition with \ncimetidine for OCT2 offers possible protection against cisplatin nephrotoxicity (Fig. 9.5). Other SLCs are coupled \nto the electrochemical gradient of Na\n+ or other ions across \nthe\tmembrane, \tgenerated \tby \tATP-dependent \tion \tpumps \t\n(see Ch. 4); in this case, transport can occur against an \nelectrochemical gradient. It may involve exchange of one \nmolecule for another (\u2018antiport\u2019) or transport of two CARRIER-MEDIATED \u2003TRANSPORT\nMany cell membranes possess specialised transport mecha -\nnisms that regulate entry and exit of physiologically important molecules, such as sugars, amino acids, neuro -\ntransmitters and metal ions. They are broadly divided into \nSLC transporters and ATP-binding cassette (ABC) transporters . \nThe former facilitate passive movement of solutes down their electrochemical gradient, while the latter are active \npumps\tfuelled\tby\tATP.\tOver\t300\thuman\tgenes\tare\tbelieved\t\nto code these transporters, most of which act mainly on endogenous substrates, but some also transport foreign \nchemicals (\u2018xenobiotics\u2019) including drugs. The role of such \ntransporters in neurotransmitter function is discussed in Chapters 14, 15 and 38.\nOrganic cation transporters and organic \nanion transporters\nTwo structurally related SLCs of importance in drug dis -\ntribution are the organic cation transporters (OCTs) and \norganic anion transporters (OATs). The carrier molecule \nconsists of a transmembrane protein that binds one or more Pethidine\nWeak base\npKa 8.6Aspirin\nWeak acid\npKa 3.5Urine\npH 8Plasma\npH 7.4Gastric juice\npH 3\nUndissociated\nacid\nAHAnion\nA\u2212\nIonisation greatest at alkaline pH\nIonisation greatest at acid pH\nProtonated\nbase\nBH+Free\nbase B> 106\n100\n30> 400\n100\n< 0.1Relative concentration\nFig. 9.3 Theoretical partition of a weak acid (aspirin) and a weak base (pethidine) between aqueous compartments (urine, \nplasma and gastric juice) according to the pH difference between them. Numbers represent relative concentrations (total plasma \nconcentration = 100). It is assumed that the uncharged species in each case can permeate the cellular barrier separating the \ncompartments, and therefore reaches the same concentration in all three. Variations in the fractional ionisation as a function of pH give rise \nto the large total concentration differences with respect to plasma. mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3282, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "22ef48cc-6a12-46f0-8e36-0938f530f701": {"__data__": {"id_": "22ef48cc-6a12-46f0-8e36-0938f530f701", "embedding": null, "metadata": {"page_label": "126", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a17dd8f2-8471-4f40-94d1-21ef60f86416", "node_type": null, "metadata": {"page_label": "126", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a590e84cfd2abe9beac44f446179080a46234f1d161bd4e094b84276b804caeb"}, "2": {"node_id": "6549fafe-abc1-49e3-8fa8-68332e23251b", "node_type": null, "metadata": {"page_label": "126", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa4be52bb5d2aa3e253b78f05d812505e4595823c73813873d901a0563b20bb5"}}, "hash": "920b4b34265d3e80a37f3ae6ce9d8f5131eab30bf3ae8188d6d01c1a7b10f5f3", "text": "differences with respect to plasma. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3215, "end_char_idx": 3730, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "336e0deb-2a2e-47a6-8e05-9ce863c13d99": {"__data__": {"id_": "336e0deb-2a2e-47a6-8e05-9ce863c13d99", "embedding": null, "metadata": {"page_label": "127", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3906f15e-a1ac-4dc7-9c78-380be7d210c7", "node_type": null, "metadata": {"page_label": "127", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "55d946000123fee3927620403f5027a50c92aebb8b97dc35dde98e08aaa7ce2a"}, "3": {"node_id": "74d33cf4-31e3-4b3f-8391-e15925f25df2", "node_type": null, "metadata": {"page_label": "127", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29c090e2a5c68183e811b682542e4781ebf63a8382054fa2fbe934f0262c3560"}}, "hash": "e196011430e0f90bf0fd19e507fc4bb9b79e7278289b53131d3747145c4a79bc", "text": "9 AbSoRPtIoN AN d d IS t RI but I o N of d R u GS \n121class of transporters, and are responsible for multidrug \nresistance \tin \tcancer \tcells, \tmany \tof \twhich \texpress \tan \tATP-\ndependent pump with broad specificity called multidrug \nresistance protein 1 (mdr1) \u2013 see Chapter 57. This is \nexpressed in animals, fungi and bacteria and may have \nevolved\tas \ta \tdefence \tmechanism \tagainst \ttoxins. \tP-gps \tare \t\npresent in renal tubular brush border membranes, in bile \ncanaliculi, in astrocyte foot processes in brain microvessels1, \nand in the gastrointestinal tract. They play an important \npart in absorption, distribution and elimination of many \ndrugs, and are often co-located with SLC drug carriers, so that a drug that has been concentrated by, for example, an \nOAT transporter in the basolateral membrane of a renal \ntubular\tcell \tmay \tthen \tbe \tpumped \tout \tof \tthe \tcell \tby \ta \tP-gp \t\nin the lumenal membrane (see Ch. 30).\nPolymorphic \tvariation \tin \tthe \tgenes \tcoding \tSLCs \tand \t\nP-gp\tcontributes \tto\tindividual \tgenetic\tvariation \tin\trespon -\nsiveness to different drugs, and competition between drugs for the same transporter cause drug\u2013drug interactions (see \nYoshida et al., 2013 for a review). OCT1 transports several \ndrugs, including metformin (used to treat diabetes; see \nCh. 32), into hepatocytes (in contrast to OCT2 which is active in renal proximal tubular cells, see previously). \nMetformin acts partly through effects within hepatocytes. \nSingle\tnucleotide \tpolymorphisms \t(SNPs) \tthat \timpair \tthe \t\nfunction\tof\tOCT1\tinfluence \tthe\teffectiveness \tof\tmetformin \t\n(Fig.\t9.6).\tThis\tis\tbut\tone\texample\tof\tmany\tgenetic\tinfluences \t\non drug effectiveness or toxicity via altered activity of \ncarriers\tthat \tinfluence \tdrug \tdisposition. \tFurthermore, \t\ninduction or competitive inhibition of transporter molecules can occur in the presence of a second ligand that binds the \ncarrier, so there is a potential for drug interaction (see Fig. \n9.5 and Ch. 12).\nPlasma protein and tissue partition of drugs\nIn addition to the processes so far described, which govern \nthe transport of drug molecules across the barriers between \ndifferent \taqueous \tcompartments, \ttwo \tadditional \tfactors \t\nhave\ta\tmajor\tinfluence \ton\tdrug\tdistribution \tand\telimination. \t\nThese are:\n\u2022\tbinding \tto \tplasma \tproteins\n\u2022\tpartition \tinto \tbody \tfat \tand \tother \ttissues\nBINDING OF DRUGS TO PLASMA PROTEINS\nAt therapeutic concentrations in plasma, many drugs exist mainly in bound form. The fraction of drug that is unbound \nand pharmacologically active in plasma can be less than \n1%, the remainder being associated with plasma protein. Seemingly small differences in protein binding (e.g. 99.5% \nvs 99.0%) can have large effects on free drug concentration \nand drug effect. Such differences are common between human plasma and plasma from species used in preclinical \ndrug\ttesting,\tand\tmust\tbe\ttaken\tinto\taccount\twhen\testimat -\ning a suitable dose for \u2018first time in human\u2019 studies during \ndrug development. The most important plasma protein in \nrelation to drug binding is albumin, which binds many \nacidic\tdrugs\t(e.g.\twarfarin, \tnon-steroidal \tanti-inflammatory \tmolecules together in the same direction (\u2018symport\u2019). The OATs are responsible for the", "start_char_idx": 0, "end_char_idx": 3254, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "74d33cf4-31e3-4b3f-8391-e15925f25df2": {"__data__": {"id_": "74d33cf4-31e3-4b3f-8391-e15925f25df2", "embedding": null, "metadata": {"page_label": "127", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3906f15e-a1ac-4dc7-9c78-380be7d210c7", "node_type": null, "metadata": {"page_label": "127", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "55d946000123fee3927620403f5027a50c92aebb8b97dc35dde98e08aaa7ce2a"}, "2": {"node_id": "336e0deb-2a2e-47a6-8e05-9ce863c13d99", "node_type": null, "metadata": {"page_label": "127", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e196011430e0f90bf0fd19e507fc4bb9b79e7278289b53131d3747145c4a79bc"}}, "hash": "29c090e2a5c68183e811b682542e4781ebf63a8382054fa2fbe934f0262c3560", "text": "in the same direction (\u2018symport\u2019). The OATs are responsible for the renal secretion of urate, \nprostaglandins, several vitamins and p-amino hippurate, \nand for drugs such as probenecid, many antibiotics, \nantiviral, \tnon-steroidal \tanti-inflammatory \tand\tantineoplastic \t\ndrugs.\tUptake \tis \tdriven \tby \texchange \twith \tintracellular \t\ndicarboxylic acids (mainly \u03b1-ketoglutarate, \tpartly\tderived\t\nfrom cellular metabolism and partly by co-transport with \nNa+ entering cells down its concentration gradient). Meta -\nbolic\tenergy \tis \tprovided \tby \tATP \tfor \tNa+/K+ exchange. \nCarrier-mediated transport, because it involves a binding \nstep, shows the characteristic of saturation.\nCarriers\tof \tthis \ttype \tare \tubiquitous, \tand \tmany \tpharm -\nacological effects are the result of interference with them. Thus, some nerve terminals have transport mechanisms \nthat accumulate specific neurotransmitters or their precur -\nsors, and there are many examples of drugs that act by \ninhibiting these transport mechanisms (see Chs 14, 15, 38, \n48\tand\t49).\tFrom\ta\tgeneral\tpharmacokinetic \tpoint\tof\tview,\t\nhowever, the main sites where SLCs, including OCTs and \nOATs, are expressed and carrier-mediated drug transport \nis important are:\n\u2022\tthe\tblood\u2013brain \tbarrier\n\u2022\tthe\tgastrointestinal \ttract\n\u2022\tthe\trenal \ttubule\n\u2022\tthe\tbiliary \ttract\n\u2022\tthe\tplacenta\nP-glycoprotein transporters\nP-glycoproteins \t(P-gp;\tP\tfor\t\u2018permeability\u2019), \twhich\tbelong\tto\t\nthe ABC transporter superfamily, are the second important 12\n11\n10\n9\n8765432\n1Strong Weak\nStrong WeakAscorbic acid\nPhenytoi\nn\nThiopental\nPhenobarbital\nChlorothiazide\nSulphamethoxazole\nWarfarin\nMethotrexate\nAspirin Probenecid\nPenicillins\nLevodopaAcids\nChloroquine\nDesmethyl-\nimipramine\nAmphetamine\nAtropine\nHistamine\nPropranolol\nChlorpromazine\nMepyramine\nDopamine\nNoradrenaline\n(norepinephrine)\nMorphine\nErgometrine\nTrimethoprim\nChlordiazepoxide\nDiazepampKaBases\nFig. 9.4 pKa values for some acidic and basic drugs. \n1This is illustrated by strain and species differences. For example, Collie \ndogs\tlack \tthe \tmultidrug \tresistance \tgene \t(mdr1), that encodes a \nP-glycoprotein \twhich \textrudes \ttoxins \tfrom \tthe \tcerebrospinal \tfluid \t\nacross\tthe \tblood\u2013brain \tbarrier. \tThis \thas \tconsequences \tfor \tveterinary \t\nmedicine because ivermectin (an anthelminthic drug, Ch. 56) is severely \nneurotoxic in the many breeds with Collie ancestry.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3187, "end_char_idx": 6037, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "70848291-718a-4ed6-a573-6122ec5f7508": {"__data__": {"id_": "70848291-718a-4ed6-a573-6122ec5f7508", "embedding": null, "metadata": {"page_label": "128", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "caf58547-e1d0-40ae-928f-de73dfd67b76", "node_type": null, "metadata": {"page_label": "128", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "428f7ea20c8d7bdaf4ab421cfa566f98d5fc675e5e6c0ba522974956caf16c53"}, "3": {"node_id": "04f7e6b7-5cae-4129-9c2c-3c47bcf1d1b0", "node_type": null, "metadata": {"page_label": "128", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d76981885fdd94dc473ce432fbcc6c50ff5d647bf82b39eb5368e516262f90e6"}}, "hash": "dd8d3df544731c7b13c8139017caf6ef3cff21697ef54578b6626c1c823c6267", "text": "9 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n122The usual concentration of albumin in plasma is approxi -\nmately 0.6 mmol/L (4 g/100 mL). With two sites per \nalbumin molecule, the drug-binding capacity of plasma \nalbumin would therefore be about 1.2 mmol/L. For most \ndrugs,\tthe\ttotal\tplasma\tconcentration \trequired\tfor\ta\tclinical\t\neffect is much less than 1.2 mmol/L, so with usual thera -\npeutic doses the binding sites are far from saturated, and \nthe concentration bound [DS] varies nearly in direct propor -\ntion\tto\tthe \tfree \tconcentration \t[D]. \tUnder \tthese \tconditions, \t\nthe fraction bound, [DS]/([D] + [DS]), is independent of \nthe drug concentration. However, some drugs, for example, tolbutamide (see Ch. 32), act at plasma concentrations at \nwhich its binding to plasma albumin approaches saturation \n(i.e.\ton\tthe \tflat \tpart \tof \tthe \tbinding \tcurve). \tThis \tmeans \tthat \t\nincreasing the dose increases the free (pharmacologically active) concentration disproportionately. This is illustrated \nin Fig. 9.7.\nPlasma\talbumin\tbinds\tmany\tdifferent\tdrugs,\tso\tcompeti -\ntion can occur between them. If two drugs (A and B) compete drugs, sulfonamides) and a smaller number of basic drugs \n(e.g. tricyclic antidepressants and chlorpromazine). Other plasma proteins, including \u03b2-globulin and an acid glyco -\nprotein\tthat \tincreases \tin \tinflammatory \tdisease, \thave \talso \t\nbeen implicated in the binding of certain basic drugs such \nas\tquinine.\nThe amount of a drug that is bound to protein depends \non three factors:\n\u2022\tthe\tconcentration \tof \tfree \tdrug\n\u2022\tits\taffinity \tfor \tthe \tbinding \tsites\n\u2022\tthe\tconcentration \tof \tprotein\nAs a first approximation, the binding reaction can be regarded as a simple association of the drug molecules \nwith a finite population of binding sites, exactly analogous \nto drug\u2013receptor binding (see Ch. 2):\nDS DS\nfree\ndrugbindin g\nsitecomple x+/harpoonrightleft\u221240 0\n0400.6 (3)\n(3)Cisplatin\nKidney cells Liver cellsDiabetic\nkidney cellsChange in transporter activity (% control)\nApoptosis (%)\nCisplatin uptake (pg/cell)OCT1\n\u2212OCT2\n\u2212OCT2\nCisplatin \u2212 + \u2212 + + + + +\nCimetidine \u2212 \u2212 \u2212 \u2212 100 50 20 10\u00a7\n\u00a7*+OCT2\n+OCT2OCT2\nCarboplatin\n**\n*Cisplatin\nCisplatin effect\non each cell typeOxaliplatin\n0\n0\n\u22125020A\nB DC\nFig. 9.5 Human organic cation transporter 2 (OCT2) mediates cisplatin nephrotoxicity. OCT2 is expressed in kidney whereas OCT1 \nis expressed in liver. Cisplatin (100 \u00b5mol/L) influences the activity of OCT2 but not of OCT1, each expressed in a cultured cell line (A), \nwhereas the less nephrotoxic drugs carboplatin and oxaliplatin do not. Cisplatin similarly influences OCT2 activity in fresh human kidney \ntubule cells but not in fresh hepatocytes or kidney cells from diabetic patients who are less susceptible to cisplatin nephrotoxicity (B). Cisplatin accumulates in cells that express OCT2 (C) and causes cell death (D). Cimetidine competes with cisplatin for", "start_char_idx": 0, "end_char_idx": 2923, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "04f7e6b7-5cae-4129-9c2c-3c47bcf1d1b0": {"__data__": {"id_": "04f7e6b7-5cae-4129-9c2c-3c47bcf1d1b0", "embedding": null, "metadata": {"page_label": "128", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "caf58547-e1d0-40ae-928f-de73dfd67b76", "node_type": null, "metadata": {"page_label": "128", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "428f7ea20c8d7bdaf4ab421cfa566f98d5fc675e5e6c0ba522974956caf16c53"}, "2": {"node_id": "70848291-718a-4ed6-a573-6122ec5f7508", "node_type": null, "metadata": {"page_label": "128", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd8d3df544731c7b13c8139017caf6ef3cff21697ef54578b6626c1c823c6267"}}, "hash": "d76981885fdd94dc473ce432fbcc6c50ff5d647bf82b39eb5368e516262f90e6", "text": "and causes cell death (D). Cimetidine competes with cisplatin for OCT2 and concentration dependently protects against cisplatin-induced apoptosis (D) \u2013 cimetidine concentrations are in \u00b5mol/L. (Data redrawn from \nCiarimboli, G et al., 2005. Am. J. Pathol. 167, 1477\u20131484.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2858, "end_char_idx": 3610, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6c5e45ec-8e9e-44ad-b6ab-3dd70aed2f77": {"__data__": {"id_": "6c5e45ec-8e9e-44ad-b6ab-3dd70aed2f77", "embedding": null, "metadata": {"page_label": "129", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "de3c56c2-8565-4b8f-846f-d4a23aa926c2", "node_type": null, "metadata": {"page_label": "129", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea7dc542a2df5ba56a6239dc7e36fe29d15e23353ee009ab8a36f6e896b99ca8"}, "3": {"node_id": "32cbeda5-8234-42b4-a6cd-92a08fcd09ce", "node_type": null, "metadata": {"page_label": "129", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2aa9523682f24d183c1eb0804d658023761bbd26154e655a566bced98f085ce8"}}, "hash": "6896f8cf2b982ec248d4b8a8c091e8a376832ada123e52bc770c4a5db5d30f77", "text": "9 AbSoRPtIoN ANd dIStRIbutIoN of dRuGS \n123Glucose AUC (min mol/L)410\n200 150 100OCT1-reference\n50 0\nTime (min)\nOCT1-reference OCT1-variantPlasma glucose (mmol/L) Plasma glucose (mmol/L)\n0.81.6OCT1-variant\n410\n200 150 100OCT1-reference\n50**\n*\n*\n0\nTime (min)OCT1-variantA\nB\nC\nFig. 9.6 Genetic variants of organic cation transporter 1 \n(OCT1) are associated with different responses to metformin \nin healthy humans. (A) An oral glucose tolerance test (OGTT) \ngave similar plasma glucose responses in control subjects with \nonly reference OCT1 alleles versus subjects with at least one \nreduced function OCT1 allele. (B) In contrast, after metformin \ntreatment, the OGTT response was less in the same reference \nsubjects than in those with reduced function OCT1 alleles \u2013 i.e. \nthe effect of metformin was blunted in the variant-allele group. \n(C) Glucose exposure estimated by area under the glucose time \ncurves (AUC) was significantly lower in subjects with only \nreference OCT1 alleles, p = 0.004. (Data redrawn from Yan Shu, \net al., 2007. J. Clin. Invest. 117, 1422\u20131431.)Movement of drugs across cellular \nbarriers \n\u2022\tTo\ttraverse\tcellular\tbarriers\t(e.g.\tgastrointestinal\t\nmucosa, renal tubule, blood\u2013brain barrier, placenta), \ndrugs have to cross lipid membranes.\n\u2022\tDrugs\tcross\tlipid\tmembranes\t mainly\t(a)\tby\tpassive\t\ndiffusional transfer and (b) by carrier-mediated transfer.\n\u2022\tThe\tmain\tfactor\tthat\tdetermines\t the\trate\tof\tpassive\t\ndiffusional transfer across membranes is a drug\u2019s lipid \nsolubility.\n\u2022\tMany\tdrugs\tare\tweak\tacids\tor\tweak\tbases;\ttheir\tstate\t\nof ionisation varies with pH according to the \nHenderson\u2013Hasselbalch equation.\n\u2022\tWith\tweak\tacids\tor\tbases,\tonly\tthe\tuncharged\t species\t\n(the protonated form for a weak acid, the \nunprotonated form for a weak base) can diffuse across \nlipid\tmembranes;\t this\tgives\trise\tto\tpH\tpartition.\n\u2022\tpH\tpartition\tmeans\tthat\tweak\tacids\ttend\tto\t\naccumulate in compartments of relatively high pH, \nwhereas weak bases do the reverse.\n\u2022\tCarrier-mediated\t transport\t is\tmediated\t by\tsolute\t\ncarriers (SLCs), which include organic cation \ntransporters (OCTs) and organic anion transporters \n(OATs), and P-glycoproteins (P-gps) (ATP-binding \ncassette [ABC] transporters) in the renal tubule, \nblood\u2013brain barrier and gastrointestinal epithelium. \nThese are important in determining the distribution of \nmany drugs, are prone to genetic variation and are \ntargets for drug interactions.100\n50\n0800\n600\n400\n200\n0200 400 600 800FreeBound\nFree phenylbutazone concentration ( \u00b5mol/L)Bound phenylbutazone concentration (\u00b5mol/L)\nTotal phenylbutazone\nconcentration (\u00b5mol/L)\nFig. 9.7 Binding of phenylbutazone to plasma albumin. \nThe graph shows the disproportionate increase in free \nconcentration as the total concentration increases, owing to the \nbinding sites approaching saturation. (Data from Brodie,", "start_char_idx": 0, "end_char_idx": 2848, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "32cbeda5-8234-42b4-a6cd-92a08fcd09ce": {"__data__": {"id_": "32cbeda5-8234-42b4-a6cd-92a08fcd09ce", "embedding": null, "metadata": {"page_label": "129", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "de3c56c2-8565-4b8f-846f-d4a23aa926c2", "node_type": null, "metadata": {"page_label": "129", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea7dc542a2df5ba56a6239dc7e36fe29d15e23353ee009ab8a36f6e896b99ca8"}, "2": {"node_id": "6c5e45ec-8e9e-44ad-b6ab-3dd70aed2f77", "node_type": null, "metadata": {"page_label": "129", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6896f8cf2b982ec248d4b8a8c091e8a376832ada123e52bc770c4a5db5d30f77"}}, "hash": "2aa9523682f24d183c1eb0804d658023761bbd26154e655a566bced98f085ce8", "text": "increases, owing to the \nbinding sites approaching saturation. (Data from Brodie, B., \nHogben, C.A.M., 1957. J. Pharm. Pharmacol. 9, 345.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2767, "end_char_idx": 3384, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e1c1509c-e163-4887-85a5-cece63b6c7fe": {"__data__": {"id_": "e1c1509c-e163-4887-85a5-cece63b6c7fe", "embedding": null, "metadata": {"page_label": "130", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "28c18585-ff3f-40e5-931f-243e0b3cac4f", "node_type": null, "metadata": {"page_label": "130", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bb6d05288c73a6037a3c24b0c692ce88d2d795b41eba18edfed028b1f7451d39"}, "3": {"node_id": "4439160c-6fcc-470d-8274-59af86c23d8a", "node_type": null, "metadata": {"page_label": "130", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "25ed5b2e5c85b6c1f649e1f3d1e23c530832f83e44e0d314fa9dffd8fe3ddc9b"}}, "hash": "4c3f7d676a5808d7d97e5f592a9c57b7b3a606eceac0d12bcc56aca039571d80", "text": "9 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n124lipid-soluble drugs are given chronically, however, accu -\nmulation in body fat is often significant (e.g. benzodiazepines; \nCh. 45). Some drugs and environmental contaminants (such \nas insecticides), if ingested intermittently, accumulate slowly but progressively in body fat.\nFat is not the only tissue in which drugs can accumulate. \nChloroquine \u2013 an antimalarial drug (Ch. 55) \u2013 has a high \naffinity\tfor \tmelanin \tand \tis \ttaken \tup \tby \tthe \tretina, \twhich \t\nis\trich\tin \tmelanin \tgranules, \taccounting \tfor \tchloroquine\u2019s \t\nocular toxicity. Tetracyclines (Ch. 52) accumulate slowly in bones and teeth, because they have a high affinity for \ncalcium, and should not be used in children for this reason. \nVery high concentrations of amiodarone (an antidysrhyth -\nmic drug; Ch. 22) accumulate in liver and lung during \nchronic use, causing hepatitis and interstitial pulmonary \nfibrosis.\nDRUG ABSORPTION AND ROUTES OF \nADMINISTRATION\nThe main routes of drug administration and elimination \nare shown schematically in Fig. 9.8. Absorption is defined \nas the passage of a drug from its site of administration into \nthe plasma. It is important for all routes of administration except intravenous injection, where it is complete by defini -\ntion. There are instances, such as topical administration of \na\tsteroid \tcream \tto \tskin \tor \tinhalation \tof \ta \tbronchodilator \t\naerosol to treat asthma (Ch. 29), where absorption as just \ndefined\tis \tnot \trequired \tfor \tthe \tdrug \tto \tact, \tbut \tin \tmost \t\ncases the drug must enter plasma before reaching its site of action.\nThe main routes of administration are:\n\u2022\toral\t(drug \tis \tswallowed)\n\u2022\tsublingual \tor \tbuccal \t(drug \tis \tkept \tin \tcontact \twith \tthe \t\noral mucosa)\n\u2022\trectal\n\u2022\tapplication \tto \tother \tepithelial \tsurfaces \t(e.g. \tskin, \t\ncornea, vagina and nasal mucosa)\n\u2022\tinhalation\n\u2022\tinjection\n\u2022\tsubcutaneous\n\u2022\tintramuscular\n\u2022\tintravenous\n\u2022\tintrathecal\u2022\tintravitreal\nORAL ADMINISTRATION\nMost\tsmall \tmolecule \tdrugs \tare \ttaken \tby \tmouth \tand \tswal -\nlowed. Little absorption occurs until the drug enters the \nsmall intestine, although non-polar drugs applied to the \nbuccal mucosa or under the tongue are absorbed directly from the mouth (e.g. organic nitrates, Ch. 21, and buprenor -\nphine,\tCh.\t43).\tPeptides\tand\tproteins\tare\tsubject\tto\tdigestion \t\nas well as epithelial barriers, so the oral route is not generally suitable to biopharmaceuticals and despite ingenious \npharmaceutical approaches to circumvent these problems, \nsuccess\thas \tbeen \tlimited \t(Renukuntla \tet \tal., \t2013).\nDRUG \u2003ABSORPTION \u2003FROM \u2003THE \u2003INTESTINE\nFor most drugs, the mechanism of absorption is the same \nas for other epithelial barriers, namely, passive transfer at \na rate determined by the ionisation and lipid solubility of \nthe drug molecules. Fig. 9.9 shows the absorption of various Binding of drugs to plasma \nproteins \n\u2022\tPlasma\talbumin \tbinds \tmainly \tacidic \tdrugs \t\n(approximately two molecules per albumin molecule).\n\u2022\tSaturable \tbinding", "start_char_idx": 0, "end_char_idx": 3017, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4439160c-6fcc-470d-8274-59af86c23d8a": {"__data__": {"id_": "4439160c-6fcc-470d-8274-59af86c23d8a", "embedding": null, "metadata": {"page_label": "130", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "28c18585-ff3f-40e5-931f-243e0b3cac4f", "node_type": null, "metadata": {"page_label": "130", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bb6d05288c73a6037a3c24b0c692ce88d2d795b41eba18edfed028b1f7451d39"}, "2": {"node_id": "e1c1509c-e163-4887-85a5-cece63b6c7fe", "node_type": null, "metadata": {"page_label": "130", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c3f7d676a5808d7d97e5f592a9c57b7b3a606eceac0d12bcc56aca039571d80"}}, "hash": "25ed5b2e5c85b6c1f649e1f3d1e23c530832f83e44e0d314fa9dffd8fe3ddc9b", "text": "two molecules per albumin molecule).\n\u2022\tSaturable \tbinding \tcan \tlead \tto \ta \tnon-linear \trelation \t\nbetween dose and free (active) drug concentration, but \nthe effective concentration range of most therapeutic drugs is below that at which this would be important.\n\u2022\tBinding \tto \tplasma \tprotein \tis \ta \tsource \tof \tspecies \t\nvariation, important in interpreting preclinical pharmacology studies and estimating the first-in-human dose.\n\u2022\t\u03b2-Globulin and acid glycoprotein also bind some drugs.\n\u2022\tExtensive \tprotein \tbinding \tslows \tdrug \telimination \t\n(metabolism and/or glomerular filtration).\n\u2022\tCompetition \tbetween \tdrugs \tfor \tprotein \tbinding \tcan \t\nlead to clinically significant drug interactions, but this is uncommon.in this way, administration of drug B can reduce the protein \nbinding, and hence increase the free plasma concentration, \nof drug A. To do this, drug B needs to occupy an appreciable \nfraction of the binding sites. Few therapeutic drugs affect \nthe binding of other drugs because they occupy, at thera -\npeutic plasma concentrations, only a tiny fraction of the \navailable sites. Sulfonamides (Ch. 52) are an exception, \nbecause they occupy about 50% of the binding sites at \ntherapeutic concentrations and so can cause harmful effects \nby displacing other drugs or, in premature babies, bilirubin \n(see later). Much has been made of binding interactions of \nthis\tkind\tas\ta\tsource\tof\tuntoward \tdrug\tinteractions \tin\tclinical\t\nmedicine, but this type of competition is less important than was once thought (see Ch. 58).\nPARTITION INTO BODY FAT AND \nOTHER TISSUES\nFat represents a large, non-polar compartment. In practice, this is important for only a few drugs, mainly because the \neffective fat:water partition coefficient is relatively low for \nmost drugs. Morphine, for example, although lipid-soluble enough to cross the blood\u2013brain barrier, has a lipid:water \npartition \tcoefficient \tof\tonly\t0.4,\tso\tsequestration \tof\tthe\tdrug\t\nby body fat is of little importance. Thiopental, by comparison (fat:water partition coefficient approximately 10), accumu -\nlates substantially in body fat. This has important conse -\nquences\tthat \tlimit \tits \tusefulness \tas \tan \tintravenous \tanaesthetic \t\nto short-term initiation (\u2018induction\u2019) of anaesthesia, and it has been replaced by propofol even for this indication in \nmany countries (Ch. 42).\nThe second factor that limits the accumulation of drugs \nin body fat is its low blood supply \u2013 less than 2% of the \ncardiac\toutput. \tConsequently, \tdrugs \tare \tdelivered \tslowly \t\nto\tbody\tfat, \tand \tthe \ttheoretical \tequilibrium \tdistribution \t\nbetween fat and body water is delayed. For practical \npurposes, therefore, partition into body fat when drugs \nare given acutely is important only for a few highly lipid-\nsoluble drugs (e.g. general anaesthetics; Ch. 42). When mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2960, "end_char_idx": 6272, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c19ee288-4cee-4533-b6c8-b33411dd502c": {"__data__": {"id_": "c19ee288-4cee-4533-b6c8-b33411dd502c", "embedding": null, "metadata": {"page_label": "131", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "274f3b76-0c27-4757-ac3d-753baca11a28", "node_type": null, "metadata": {"page_label": "131", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "471a2f9cf7580479f98b6ba6d2d8b4d71afdeac60eebbc5b3a43ae2e45e2c1ad"}, "3": {"node_id": "e586b307-102a-49fe-9b28-b0b42cc86b3f", "node_type": null, "metadata": {"page_label": "131", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ee8abfa606f1c90f355cb18665ac570495ce2bfc142331efd940d1b0ce8ac17b"}}, "hash": "b149d2aa51a6279cf3121f598bd39600e817517abfc3ffb5818d2b56a62abd2e", "text": "9 AbSoRPtIoN ANd dIStRIbutIoN of dRuGS \n125bases are poorly absorbed from the gastrointestinal tract, \nso\tthe\tmeat\tfrom\tanimals\tkilled\tin\tthis\tway\twas\tsafe\tto\teat.\nIn some instances, intestinal drug absorption depends \non carrier-mediated transport rather than simple lipid \ndiffusion. Examples include levodopa , used in treating \nParkinson\u2019s\t disease\t(see\tCh.\t41),\twhich\tis\ttaken\tup\tby\tthe\t\ncarrier that normally transports phenylalanine, and fluo-\nrouracil (Ch. 57), a cytotoxic drug that is transported by \nthe carrier for pyrimidines (thymine and uracil). Iron is \nabsorbed via specific carriers in the epithelial cell membranes \nof jejunal mucosa, and calcium is absorbed by a vitamin \nD\u2013dependent carrier.\nFACTORS\u2003 AFFECTING\u2003 GASTROINTESTINAL\u2003 ABSORPTION\nTypically, about 75% of a drug given orally is absorbed in \n1\u20133 h, but numerous factors alter this, some physiological \nand some to do with the formulation of the drug. The main \nfactors are:\n\u2022\tgut\tcontent\t(e.g.\tfed\tvs\tfasted)\n\u2022\tgastrointestinal\t motility\n\u2022\tsplanchnic\t blood\tflow\n\u2022\tparticle\t size\tand\tformulation\n\u2022\tphysicochemical\t factors,\tincluding\t some\tdrug\t\ninteractions\n\u2022\tgenetic\t polymorphisms\t in,\tand\tdrug\u2013drug\t\ncompetition for, transporters\nThe\tinfluence\tof\tfeeding,\twhich\tinfluences\tboth\tgut\tcontent \t\nand\tsplanchnic\t blood\tflow,\tis\troutinely\t examined\t in\t\nearly phase clinical trials and prescribing advice tailored \naccordingly. Gastrointestinal motility has a large effect. weak\tacids\tand\tbases\tas\ta\tfunction\t of\tpKa. As expected, \nstrong bases of p Ka 10 or higher are poorly absorbed, as \nare strong acids of p Ka less than 3, because they are fully \nionised. The arrow poison curare used by South American \nIndians\tcontains\t quaternary\t ammonium\t compounds\t that\t\nblock\tneuromuscular\t transmission\t (Ch.\t14).\tThese\tstrong\tPLASMAUrine\nExpired\nairMilk,\nsweatFaeces Gut\nSkin\nMuscle\nCSF\nLungBreast, sweat glandsMetabolitesAbsorption and distribution Administration Elimination\nFetusKidney\nBrain\nPlacentaPortal \nsystemBile\nOral or rectal\nIntravenousPercutaneous\nIntramuscular\nInhalationIntrathecalLiver\nFig. 9.8 The main routes of drug administration and elimination. CSF, cerebrospinal fluid. Absorption (%)\n02468 10 12\npKaAcids Bases100\n50\n20\n10\n5\n2\nFig. 9.9 Absorption of drugs from the intestine, as a \nfunction of p Ka, for acids and bases. \tWeak\tacids\tand\tbases\t\nare\twell\tabsorbed;\t strong\tacids\tand\tbases\tare\tpoorly\tabsorbed.\t\n(Redrawn from Schanker, L.S. et al., 1957. J. Pharmacol. 120, \n528.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2835, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e586b307-102a-49fe-9b28-b0b42cc86b3f": {"__data__": {"id_": "e586b307-102a-49fe-9b28-b0b42cc86b3f", "embedding": null, "metadata": {"page_label": "131", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "274f3b76-0c27-4757-ac3d-753baca11a28", "node_type": null, "metadata": {"page_label": "131", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "471a2f9cf7580479f98b6ba6d2d8b4d71afdeac60eebbc5b3a43ae2e45e2c1ad"}, "2": {"node_id": "c19ee288-4cee-4533-b6c8-b33411dd502c", "node_type": null, "metadata": {"page_label": "131", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b149d2aa51a6279cf3121f598bd39600e817517abfc3ffb5818d2b56a62abd2e"}}, "hash": "ee8abfa606f1c90f355cb18665ac570495ce2bfc142331efd940d1b0ce8ac17b", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2788, "end_char_idx": 2963, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7d9a9573-b836-4d32-9785-47f49206b760": {"__data__": {"id_": "7d9a9573-b836-4d32-9785-47f49206b760", "embedding": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "63680f32-3eed-4ec6-b70e-0dc839ce1408", "node_type": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a33467342c6b384d916b6c131020903c8ad0b19cbfd74a1bfc822455aefe25d4"}, "3": {"node_id": "3134c9cf-b6f1-4efa-ba9c-fe6b7fce1478", "node_type": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e8fc039de03e43424316f9097487060a7099b71a1f290d7a06ac254dbe763da"}}, "hash": "be654b08f3b598371692155dad0cb3b3d35b2c6e53854f2be3d0d8f60e295797", "text": "9 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n126antibiotics caused by appearance of this organism in the \nbowel). Mesalazine is a formulation of 5-aminosalicylic \nacid in a pH-dependent acrylic coat that degrades in the terminal ileum and proximal colon, and is used to treat \ninflammatory \tbowel \tdisease \taffecting \tthis \tpart \tof \tthe \tgut. \t\nOlsalazine is a prodrug (see p. 131) consisting of a dimer of two molecules of 5-aminosalicylic acid that is cleaved \nby colonic bacteria in the distal bowel and is used to treat \npatients with distal colitis.\nBioavailability and bioequivalence\nTo access the systemic circulation, a drug given orally must not only penetrate the intestinal mucosa, it must also run \na gauntlet of inactivating enzymes in the gut wall and \nliver, referred to as \u2018presystemic\u2019 or \u2018first-pass\u2019 metabolism. The term bioavailability is used to indicate the fraction ( F) \nof an orally administered dose that reaches the systemic \ncirculation \tas\tintact\tdrug,\ttaking\tinto\taccount\tboth\tabsorp -\ntion and local metabolic degradation. F is measured by \ndetermining the plasma drug concentration versus time curves in a group of subjects following oral and (on a separate occasion) intravenous administration (the fraction \nabsorbed following an intravenous dose is 1 by defini -\ntion). The area under the plasma concentration time curves \n(AUC)\tprovides \tan \tintegrated \tmeasure \tof \tdrug \texposure, \t\ntaking\tinto \taccount \ttime \tas \twell \tas \tconcentration, \tand \tF \nis\testimated \tas\tAUC oral/AUC intravenous . Bioavailability is not \na characteristic solely of the drug preparation: variations in enzyme activity of gut wall or liver, in gastric pH or \nintestinal motility all affect it. Because of this, one cannot \nspeak\tstrictly\tof\tthe\tbioavailability \tof\ta\tparticular \tprepara -\ntion, but only of that preparation in a given individual on a \nparticular occasion, and F determined in a group of healthy \nvolunteer subjects may differ substantially from the value \ndetermined in patients with diseases of gastrointestinal or \ncirculatory systems.\nBioavailability relates only to the total proportion of the \ndrug that reaches the systemic circulation and neglects the rate of absorption. If a drug is completely absorbed in \n30\tmin,\tit \t will \t reach \t a \t much \t higher \t peak \t plasma \t concentra -\ntion (and have a more dramatic effect) than if it were absorbed over several hours. Regulatory authorities \u2013 which \nhave\tto\tmake \tdecisions \tabout \tthe \tlicensing \tof \tproducts \t\nthat\tare\t\u2018generic\tequivalents\u2019 \tof\tpatented \tproducts \t\u2013\trequire\t\nevidence \tof \t\u2018bioequivalence\u2019 \tbased \ton \tthe \tmaximum \t\nconcentration achieved (C max) and time between dosing \nand C max (T max)\tas\twell\tas\tAUC (0\u2013t).\tFor\tmost\tdrugs,\tAUC (0\u2013t) \nand C max\tmust\tlie \tbetween \t80% \tand \t125% \tof \ta \tmarketed \t\npreparation for the new generic product to be accepted as \nbioequivalent \t(EMEA, \t2010).\nOROMUCOSAL (SUBLINGUAL OR BUCCAL) \nADMINISTRATION\nAbsorption directly from the oral cavity is sometimes useful \nwhen\ta\trapid \tresponse \tis \trequired, \tparticularly \twhen \tthe \t\ndrug is either unstable at gastric pH or rapidly metabolised \nby the liver. Glyceryl trinitrate and buprenorphine are \nexamples of", "start_char_idx": 0, "end_char_idx": 3199, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3134c9cf-b6f1-4efa-ba9c-fe6b7fce1478": {"__data__": {"id_": "3134c9cf-b6f1-4efa-ba9c-fe6b7fce1478", "embedding": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "63680f32-3eed-4ec6-b70e-0dc839ce1408", "node_type": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a33467342c6b384d916b6c131020903c8ad0b19cbfd74a1bfc822455aefe25d4"}, "2": {"node_id": "7d9a9573-b836-4d32-9785-47f49206b760", "node_type": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be654b08f3b598371692155dad0cb3b3d35b2c6e53854f2be3d0d8f60e295797"}, "3": {"node_id": "d74c3130-78c4-4e4a-8dae-2e4a71ac002f", "node_type": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2338926e1e58a79cf5c82d4dd2580092c405e21b51093f39eb532d163cc1bc48"}}, "hash": "9e8fc039de03e43424316f9097487060a7099b71a1f290d7a06ac254dbe763da", "text": "Glyceryl trinitrate and buprenorphine are \nexamples of drugs that are often given sublingually (Chs 22 and 43, respectively). Buccal midazolam is as effective and safe as intravenous or rectal diazepam in terminating \nearly status epilepticus\n (Ch. 46) in children (Brigo et al., 2015). \nTimes from arrival in the emergency department to drug \nadministration and to seizure cessation are shortened and \nthe drug is easier to administer. Drugs absorbed from the \nmouth pass directly into the systemic circulation without Many disorders (e.g. migraine, diabetic neuropathy) cause gastric stasis and slow drug absorption. Drug treatment can also affect motility, either reducing (e.g. drugs that \nblock\tmuscarinic \treceptors; \tsee\tCh.\t14)\tor\tincreasing \tit\t(e.g.\t\nmetoclopramide , an antiemetic used in migraine to facilitate \nabsorption of analgesic). Excessively rapid movement of \ngut contents (e.g. in some forms of diarrhoea) can impair \nabsorption. Several drugs (e.g. propranolol ) reach a higher \nplasma\tc oncentration \ti f \tt hey\ta re\tt aken\ta fter \ta\tm eal,\tp robably\t\nbecause\tfood\tincreases \tsplanchnic \tblood\tflow.\tConversely, \t\nsplanchnic \tblood \tflow \tis \tgreatly \treduced \tby \thypovolae -\nmia or heart failure, with a resultant reduction of drug \nabsorption.\nParticle\tsize\tand\tformulation \thave\tmajor\teffects\ton\t absorp -\ntion.\tIn\t1971, \tpatients \tin \ta \tNew \tYork \thospital \twere \tfound \t\nto\trequire \tunusually \tlarge \tmaintenance \tdoses \tof \tdigoxin \n(Ch. 22). In a study on normal volunteers, it was found \nthat standard digoxin tablets from different manufacturers \nresulted in different plasma concentrations ( Fig. 9.10 ), even \nthough the digoxin content of the tablets was the same, \nprobably in part because of differences in particle size.\nTherapeutic drugs are formulated to produce desired \nabsorption characteristics. Capsules may be designed to remain intact for some hours after ingestion in order to \ndelay absorption, or tablets may have a resistant coating to give the same effect. In some cases, a mixture of slow- and fast-release particles is included in a capsule to produce \nrapid but sustained absorption. More elaborate pharmaceuti -\ncal systems include modified-release preparations that \npermit\tless \tfrequent \tdosing. \tSuch \tpreparations \tnot \tonly \t\npermit an increased dose interval but also reduce adverse \neffects\trelated\tto\thigh\tpeak\tplasma\tconcentrations \tfollowing \t\nadministration of a conventional formulation.\nWhen drugs are swallowed, the intention is usually that \nthey should be absorbed and cause a systemic effect, but \nthere are exceptions. Vancomycin is very poorly absorbed, \nand is administered orally to eradicate toxin-forming \nClostridium difficile from the gut lumen in patients with pseu -\ndomembranous colitis (an adverse effect of broad-spectrum \nHoursPlasma digoxin concentration (nmol/L)2\n1\n00\n12345\nFig. 9.10 Variation in oral absorption among different \nformulations of digoxin. The four curves show the mean \nplasma concentrations attained for the four preparations, each \nof which was given on separate occasions to four subjects. The large variation has caused the formulation of digoxin tablets to be standardised since this study was published. (From \nLindenbaum, \tJ. \tet \tal., \t1971. \tN \tEngl \tJ \tMed \t285, \t1344.)mebooksfree.net mebooksfree.net", "start_char_idx": 3152, "end_char_idx": 6480, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d74c3130-78c4-4e4a-8dae-2e4a71ac002f": {"__data__": {"id_": "d74c3130-78c4-4e4a-8dae-2e4a71ac002f", "embedding": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "63680f32-3eed-4ec6-b70e-0dc839ce1408", "node_type": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a33467342c6b384d916b6c131020903c8ad0b19cbfd74a1bfc822455aefe25d4"}, "2": {"node_id": "3134c9cf-b6f1-4efa-ba9c-fe6b7fce1478", "node_type": null, "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e8fc039de03e43424316f9097487060a7099b71a1f290d7a06ac254dbe763da"}}, "hash": "2338926e1e58a79cf5c82d4dd2580092c405e21b51093f39eb532d163cc1bc48", "text": "\tMed \t285, \t1344.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6479, "end_char_idx": 6976, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "02833468-9df0-4072-ac67-0d314a99792f": {"__data__": {"id_": "02833468-9df0-4072-ac67-0d314a99792f", "embedding": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6dd44b4b-033c-446a-b98b-08686acb43d1", "node_type": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d3f7c3793eddc1c4c98121593ecbbd52fd409aeeaa0997dfe5553bca425ee9b6"}, "3": {"node_id": "cc212c81-d538-4ec7-b810-ff69a2069cd2", "node_type": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "49d2745e752792632130ff99674f49819da6547143a346d1dbd6e2e75b7bd376"}}, "hash": "51587d35d6fe4152c5e87930d245326db7487c6c2fdafdb61fd10f7d5155d268", "text": "9 AbSoRPtIoN ANd dIStRIbutIoN of dRuGS \n12737).\tAbsorption\t is\tbelieved\t to\ttake\tplace\tthrough\t mucosa\t\noverlying nasal-associated lymphoid tissue. This is similar \nto\tthe\tmucosa\t overlying\t Peyer\u2019s\t patches\t in\tthe\tsmall\t\nintestine, which is also unusually permeable.\nEYE\u2003DROPS\nMany drugs are applied as eye drops, relying on absorption \nthrough the epithelium of the conjunctival sac to produce \ntheir effects. Desirable local effects within the eye can be \nachieved without causing systemic side effects; for example, \ndorzolamide is a carbonic anhydrase inhibitor that is given \nas eye drops to lower ocular pressure in patients with \nglaucoma.\tIt\tachieves\tthis\twithout\taffecting\tthe\tkidney\t(see \t\nCh. 30), thus avoiding the acidosis that is caused by oral \nadministration of acetazolamide. Some systemic absorption \nfrom the eye occurs, however, and can result in unwanted \neffects (e.g. bronchospasm in asthmatic patients using \ntimolol eye drops for glaucoma).\nADMINISTRATION\u2003 BY\u2003INHALATION\nInhalation is the route used for volatile and gaseous \nanaesthetics, the lung serving as the route of both admin -\nistration and elimination. The rapid exchange resulting \nfrom\tthe\tlarge\tsurface\tarea\tand\tblood\tflow\tmakes\tit\tpossible \t\nto achieve rapid adjustments of plasma concentration. The \npharmacokinetic\t behaviour\t of\tinhalation\t anaesthetics\t is\t\ndiscussed in Chapter 42.\nDrugs used for their effects on the lung are also given \nby inhalation, usually as an aerosol. Glucocorticoids (e.g. \nbeclometasone dipropionate ) and bronchodilators (e.g. \nsalbutamol ; Ch. 29) are given in this way to achieve high \nlocal concentrations in the lung while minimising systemic \neffects. However, drugs given by inhalation in this way \nare usually partly absorbed into the circulation, and systemic \nside effects (e.g. tremor following salbutamol) can occur. \nChemical modification of a drug may minimise such \nabsorption. For example, ipratropium , a muscarinic-receptor \nantagonist\t(Chs\t14\tand\t29),\tis\ta\tquaternary\tammonium\tion \t\nanalogue of atropine. It is used as an inhaled bronchodilator \nbecause\t its\tpoor\tabsorption\t reduces\t the\tlikelihood\t of\t\nsystemic adverse effects.\nADMINISTRATION\u2003 BY\u2003INJECTION\nIntravenous injection is the fastest and most certain route \nof drug administration. Bolus injection rapidly produces \na high concentration of drug, first in the right heart and \npulmonary vessels and then in the systemic circulation. \nThe\tpeak\tconcentration\treaching\tthe\ttissues\tdepends\tcriti -\ncally on the rate of injection. Administration by intravenous \ninfusion using a mechanical pump avoids the uncertainties \nof\tabsorption\t from\tother\tsites,\twhile\tavoiding\t high\tpeak\t\nplasma concentrations caused by bolus injection.\nSubcutaneous or intramuscular injection of drugs usually \nproduces a faster effect than oral administration, but the \nrate of absorption depends greatly on the site of injection \nand\ton\tlocal\tblood\tflow.\tThe\trate-limiting\tfactors\tin\tabsorp -\ntion from the injection site are:\n\u2022\tdiffusion\t through\t the\ttissue\n\u2022\tremoval\t by\tlocal\tblood\tflow\nAbsorption from a site of injection (sometimes but not always \ndesirable,\t", "start_char_idx": 0, "end_char_idx": 3146, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cc212c81-d538-4ec7-b810-ff69a2069cd2": {"__data__": {"id_": "cc212c81-d538-4ec7-b810-ff69a2069cd2", "embedding": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6dd44b4b-033c-446a-b98b-08686acb43d1", "node_type": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d3f7c3793eddc1c4c98121593ecbbd52fd409aeeaa0997dfe5553bca425ee9b6"}, "2": {"node_id": "02833468-9df0-4072-ac67-0d314a99792f", "node_type": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51587d35d6fe4152c5e87930d245326db7487c6c2fdafdb61fd10f7d5155d268"}, "3": {"node_id": "bb454d1a-ce1e-4c6e-a83b-de079f7efebc", "node_type": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2b22dd0f03343ad128b0459af9a64a55e5567ddb7e2d6fa47cf944db68b3a08"}}, "hash": "49d2745e752792632130ff99674f49819da6547143a346d1dbd6e2e75b7bd376", "text": "from a site of injection (sometimes but not always \ndesirable,\t see\tlater)\tis\tincreased\t by\tincreased\t blood\tflow.\t\nHyaluronidase \t(an\tenzyme\tthat\tbreaks\tdown\tthe\tintercellular \t\nmatrix, thereby increasing diffusion) also increases drug \nabsorption from the site of injection. Conversely, absorption entering the portal system, and so escape first-pass metabo -\nlism by enzymes in the gut wall and liver.\nRECTAL ADMINISTRATION\nRectal\tadministration\t is\tused\tfor\tdrugs\tthat\tare\trequired\t\neither\tto\tproduce\t a\tlocal\teffect\t(e.g.\tanti-inflammatory\t\ndrugs such as mesalazine suppositories or enemas for use \nin ulcerative colitis, see Ch. 31) or to produce systemic \neffects. Absorption following rectal administration may \nbe unreliable, but can be rapid and more complete than \nfollowing oral administration, since only a fraction of the \ncapillary drainage returns to the systemic circulation via \nthe portal vein. This route can be useful in patients who \nare\tvomiting\t or\tare\tunable\tto\ttake\tmedication\t by\tmouth\t\n(e.g. postoperatively or during palliative care), but rectal \nadministration has not been widely adopted even when \nthere is a seemingly good rationale and suppositories \ncommercially available, for example, ergotamine-containing \nsuppositories\t for\ttreating\t migraine\t attacks\t\u2013\ta\tcondition\t\nwhere gastric stasis and vomiting can limit the effectiveness \nof oral tablets (Ch. 16).\nAPPLICATION TO EPITHELIAL SURFACES\nCUTANEOUS\u2003 ADMINISTRATION\nCutaneous administration is used when a local effect on \nthe\tskin\tis\trequired\t(e.g.\ttopically\tapplied\t steroids,\tCh.\t28). \t\nAppreciable absorption may nonetheless occur and lead \nto systemic effects; absorption is sometimes exploited \ntherapeutically, for example, in local application of rub-on \ngels\tof\tnon-steroidal\t anti-inflammatory\t agents\tsuch\tas\t\nibuprofen (Ch. 27).\nMost\tdrugs\tare\tabsorbed\tvery\tpoorly\tthrough\tunbroken \t\nskin.\tHowever,\ta\tnumber\t of\torganophosphate\tinsecticides \t\n(see Ch. 14), which need to penetrate an insect\u2019s cuticle to \nwork,\tare\tabsorbed\tthrough\tskin,\tand\taccidental\tpoisoning \t\noccurs\tin\tfarm\tworkers.\n\u25bc\tA\tcase\tis\trecounted\tof\ta\t35-year-old\tflorist\tin\t1932.\t\u2018While\tengaged \t\nin\tdoing\ta\tlight\telectrical\t repair\tjob\tat\ta\twork\tbench\the\tsat\tdown\tin\t\na\tchair\ton\tthe\tseat\tof\twhich\tsome\t\u201cNico-Fume\tliquid\u201d\t(a\t40%\tsolution \t\nof free nicotine) had been spilled. He felt the solution wet through \nhis\tclothes\tto\tthe\tskin\tover\tthe\tleft\tbuttock,\t an\tarea\tabout\tthe\tsize\tof\t\nthe palm of his hand. He thought nothing further of it and continued \nat\this\twork\tfor\tabout\t15\tminutes,\twhen\the\twas\tsuddenly\tseized\twith \t\nnausea and faintness \u2026 and found himself in a drenching sweat. On \nthe way to hospital he lost consciousness.\u2019 He survived, just, and \nthen 4 days later: \u2018On discharge from the hospital he was given the \nsame clothes that he had worn when he was brought in. The clothes", "start_char_idx": 3093, "end_char_idx": 5956, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bb454d1a-ce1e-4c6e-a83b-de079f7efebc": {"__data__": {"id_": "bb454d1a-ce1e-4c6e-a83b-de079f7efebc", "embedding": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6dd44b4b-033c-446a-b98b-08686acb43d1", "node_type": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d3f7c3793eddc1c4c98121593ecbbd52fd409aeeaa0997dfe5553bca425ee9b6"}, "2": {"node_id": "cc212c81-d538-4ec7-b810-ff69a2069cd2", "node_type": null, "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "49d2745e752792632130ff99674f49819da6547143a346d1dbd6e2e75b7bd376"}}, "hash": "b2b22dd0f03343ad128b0459af9a64a55e5567ddb7e2d6fa47cf944db68b3a08", "text": "given the \nsame clothes that he had worn when he was brought in. The clothes \nhad\tbeen\tkept\tin\ta\tpaper\tbag\tand\twere\tstill\tdamp\twhere\tthey\thad\t\nbeen\twet\twith\tthe\tnicotine\tsolution.\u2019\tThe\tsequel\twas\tpredictable.\tHe\t\nsurvived again but felt thereafter \u2018unable to enter a greenhouse where \nnicotine was being sprayed\u2019. Transdermal dosage forms of nicotine \nare now used to reduce the withdrawal symptoms that accompany \nstopping\t smoking\t (Ch.\t50).\nTransdermal dosage forms, in which the drug is incorporated in a \nstick-on\tpatch\tapplied\tto\tthe\tskin,\tare\tused\tincreasingly,\tand\tseveral\t\ndrugs \u2013 for example oestrogen and testosterone for hormone replace -\nment (Ch. 36) are available in this form. Such patches produce a \nsteady rate of drug delivery and avoid presystemic metabolism. \nFentanyl \tis\tavailable\t in\ta\tpatch\tto\ttreat\tintermittent\t breakthrough\t\npain (Ch. 43). However, the method is suitable only for lipid-soluble \ndrugs and is relatively expensive.\nNASAL\u2003 SPRAYS\nSome peptide hormone analogues, for example, antidiuretic \nhormone (Ch. 34) and gonadotrophin-releasing hormone \n(see Ch. 36), are given as nasal sprays, as is calcitonin (Ch. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5934, "end_char_idx": 7567, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "08671d22-f881-4baf-afd8-6a588ce20637": {"__data__": {"id_": "08671d22-f881-4baf-afd8-6a588ce20637", "embedding": null, "metadata": {"page_label": "134", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3625a028-cf49-4d4f-bcc9-b1049d6d806b", "node_type": null, "metadata": {"page_label": "134", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "04a57d2f0b7dbfd54c6034910b7dbf788b3fee3a62e661f6c8d69b963bd99050"}, "3": {"node_id": "1926a2b9-922b-4335-af45-de73d49b09c3", "node_type": null, "metadata": {"page_label": "134", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e802a3156055331c0a0ca92262976d023ddd04d50acdb76ff3b2df35d9c04b4"}}, "hash": "97c3c4ab09c3b207492e2d6f092573aae37fc2549b14bd1084135755f1065330", "text": "9 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n128is\treduced \tin \tpatients \twith \tcirculatory \tfailure \t(shock) \tin \t\nwhom tissue perfusion is reduced (Ch. 23).\nMETHODS \u2003FOR \u2003DELAYING \u2003ABSORPTION\nIt may be desirable to delay absorption, either to produce \na local effect or to prolong systemic action. For example, \naddition of adrenaline (epinephrine) to a local anaesthetic \nreduces absorption of the anaesthetic into the general circulation, usefully prolonging the anaesthetic effect \n(Ch. 44). Formulation of insulin with protamine and \nzinc\tproduces \ta \tlong-acting \tform \t(see \tCh. \t32). \tProcaine \t\npenicillin (Ch. 52) is a poorly soluble salt of penicillin; \nwhen\tinjected \tas \tan \taqueous \tsuspension, \tit \tis \tslowly \t\nabsorbed and exerts a prolonged action. Esterification \nof steroid hormones (e.g. medroxyprogesterone acetate, \ntestosterone propionate; Ch. 36) and antipsychotic drugs (e.g. \nfluphenazine \tdecanoate; \tCh. \t47) \tincreases \ttheir \tsolubility \t\nin oil and slows their absorption when they are injected in \nan oily solution.\nAnother method used to achieve slow and continuous \nabsorption of certain steroid hormones (e.g. oestradiol ; Ch. \n36) is the subcutaneous implantation of drug substance, for example, formulated as a solid pellet. The rate of absorp -\ntion is proportional to the surface area of the implant.\nINTRATHECAL \u2003INJECTION\nInjection of a drug into the subarachnoid space via a lumbar \npuncture needle is used for some specialised purposes. \nMethotrexate (Ch. 57) is administered in this way in the \ntreatment \tof \tcertain \tchildhood \tleukaemias \tto \tprevent \t\nrelapse in the CNS. Regional anaesthesia can be produced \nby intrathecal administration of a local anaesthetic such \nas bupivacaine (see Ch. 44); opioid analgesics can also be \nused in this way (Ch. 43). Baclofen (a GABA analogue; Ch. \n39) is used to treat disabling muscle spasms. It has been administered intrathecally to minimise its adverse effects. \nSome antibiotics (e.g. aminoglycosides) cross the blood\u2013brain barrier very slowly, and in rare clinical situations where they \nare essential (e.g. nervous system infections with bacteria \nresistant to other antibiotics) can be given intrathecally or directly into the cerebral ventricles via a reservoir. Nusin-\nersen, an antisense oligonucleotide used to treat spinal \nmuscular atrophy (Ch. 41) is administered intrathecally and \nthis route may become increasingly important in view of the therapeutic potential of biopharmaceuticals in neurological \ndisorders and the access problem posed to these agents by \nthe blood\u2013brain barrier (see p. 129).\nINTRAVITREAL \u2003INJECTION\nRanibizumab (monoclonal antibody fragment that binds to vascular endothelial growth factor; Ch. 23) or a fusion \nprotein, aflibercept, are given by intravitreal injection by \nophthalmologists treating patients with wet age-related \nmacular degeneration, macular oedema and choroidal \nneovascularisation. Intravitreal implants that slowly release \ncorticosteroids (such as fluocinolone or dexamethasone) over a period of months are used in macular oedema.\nDISTRIBUTION OF DRUGS IN THE BODY\nBODY FLUID COMPARTMENTS\nBody water is distributed into four main compartments (Fig. 9.11). Water constitutes", "start_char_idx": 0, "end_char_idx": 3218, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1926a2b9-922b-4335-af45-de73d49b09c3": {"__data__": {"id_": "1926a2b9-922b-4335-af45-de73d49b09c3", "embedding": null, "metadata": {"page_label": "134", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3625a028-cf49-4d4f-bcc9-b1049d6d806b", "node_type": null, "metadata": {"page_label": "134", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "04a57d2f0b7dbfd54c6034910b7dbf788b3fee3a62e661f6c8d69b963bd99050"}, "2": {"node_id": "08671d22-f881-4baf-afd8-6a588ce20637", "node_type": null, "metadata": {"page_label": "134", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97c3c4ab09c3b207492e2d6f092573aae37fc2549b14bd1084135755f1065330"}}, "hash": "3e802a3156055331c0a0ca92262976d023ddd04d50acdb76ff3b2df35d9c04b4", "text": "water is distributed into four main compartments (Fig. 9.11). Water constitutes 50% to 70% of body weight, \nbeing rather less in women than in men.Drug absorption and bioavailability \n\u2022\tDrugs\tof \tvery \tlow \tlipid \tsolubility, \tincluding \tthose \tthat \t\nare strong acids or bases, are generally poorly \nabsorbed from the gut.\n\u2022\tSome\tdrugs \t(e.g. \tlevodopa) are absorbed by carrier-\nmediated transfer.\n\u2022\tAbsorption \tfrom \tthe \tgut \tdepends \ton \tmany \tfactors, \t\nincluding:\n\u2013 gastrointestinal motility\n\u2013 gastrointestinal pH\n\u2013 particle size\n\u2013 physicochemical interaction with gut contents (e.g. \nchemical interaction between calcium and tetracycline antibiotics)\n\u2013 genetic polymorphisms in drug transporters and \ncompetition for transporters.\n\u2022\tBioavailability \tis \tthe \tfraction \tof \tan \tingested \tdose \tof \ta \t\ndrug that gains access to the systemic circulation. It may be low because absorption is incomplete, or because the drug is metabolised in the gut wall or liver \nbefore reaching the systemic circulation.\n\u2022\tBioequivalence \timplies \tthat \tif \tone \tformulation \tof \ta \tdrug \t\nis substituted for another, no clinically untoward \nconsequences will ensue.B B BBB\nBBBBBBB B\nBBBTrans-\ncellular \nwater \n~2%Plasma \nwater \n~5%\nFree drug moleculesBound drug molecules\nFat ~20%Interstitial\nwater\n~16%Intracellular\nwater\n~35%\nFig. 9.11 The main body fluid compartments, expressed \nas a percentage of body weight. Drug molecules exist in \nbound or free form in each compartment, but only the free drug \nis able to move between the compartments. \nExtracellular \tfluid \tcomprises \tthe \tblood \tplasma \t(about \t\n4.5%\tof\tbody \tweight), \tinterstitial \tfluid \t(16%) \tand \tlymph \t\n(1.2%).\tIntracellular \tfluid \t(30%\u201340%) \tis \tthe \tsum \tof \tthe \t\nfluid\tcontents \tof \tall \tcells \tin \tthe \tbody. \tTranscellular \tfluid \t\n(2.5%) includes the cerebrospinal, intraocular, peritoneal, \npleural\tand \tsynovial \tfluids, \tand \tdigestive \tsecretions. \tThe \t\nfetus may also be regarded as a special type of transcellular \ncompartment. \tWithin\teach\tof\tthese\taqueous\tcompartments, \t\ndrug molecules usually exist both in free solution and in mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3139, "end_char_idx": 5729, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3d3b8780-6c9e-4c02-982a-f604b54faae3": {"__data__": {"id_": "3d3b8780-6c9e-4c02-982a-f604b54faae3", "embedding": null, "metadata": {"page_label": "135", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73100427-57d7-47c8-adc1-a9f74ccbcaa6", "node_type": null, "metadata": {"page_label": "135", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc079f7b683d56187dfec95d527f222aae221ec8759892f67485aaefb190449a"}, "3": {"node_id": "8c7e0ce7-d0d0-4bc5-a277-ef1d74174e4c", "node_type": null, "metadata": {"page_label": "135", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a427140bc69e4235946db52b1609df000ffaaa842f3af318b885750c8397d9d5"}}, "hash": "87ba220c8040008d454c4affda4cfd26b528ac10eb07d133dde40ed7e3530bee", "text": "9 AbSoRPtIoN AN d d IS t RI but I o N of d R u GS \n129can\talso\tdisrupt \tdrug \tefflux \tmechanisms; \tconsequently, \t\npenicillin (Ch. 52) can be given intravenously (rather than \nintrathecally) to treat bacterial meningitis, which is accom -\npanied\tby \tintense \tinflammation.\nFurthermore, in some parts of the CNS, including the \nchemoreceptor trigger zone ,\tthe\tbarrier\tis\tleaky.\tThis\tenables\t\ndomperidone, an antiemetic dopamine\u2013receptor antagonist (Chs 31 and 41) that does not penetrate the blood\u2013brain \nbarrier but does access the chemoreceptor trigger zone, to \nbe used to prevent the nausea caused by dopamine agonists such as apomorphine when these are used to treat advanced \nParkinson\u2019s \tdisease.\tThis\tis\tachieved \twithout\tloss\tof\tefficacy,\t\nbecause dopamine receptors in the basal ganglia are acces -\nsible only to drugs that have traversed the blood\u2013brain \nbarrier.\nMethylnaltrexone bromide is a peripherally acting \n\u00b5-opioid\u2013receptor antagonist used in treating opioid-induced \nconstipation \tin\tpatients\trequiring \topioids\tas\tpart\tof\tpalliative \t\ncare (Ch. 43). It has limited gastrointestinal absorption and \ndoes\tnot \tcross \tthe \tblood\u2013brain \tbarrier, \tso \tdoes \tnot \tblock \t\nthe desired CNS opioid effects. Several peptides, including \nbradykinin, \tincrease\tblood\u2013brain \tbarrier\tpermeability. \tThere\t\nis interest in exploiting this to improve penetration of \nanticancer drugs during treatment of brain tumours.\nVOLUME OF DISTRIBUTION\nThe apparent volume of distribution, Vd, (see Ch. 11) is \ndefined as the volume that would contain the total body \ncontent of the drug (Q )\tat\ta\tconcentration \tequal \tto \tthat \t\npresent in the plasma (C p):\nVQ\nCd\np=\nIt is important to avoid identifying a given range of Vd too \nclosely with a particular anatomical compartment. Drugs \nmay\tact\tat\tvery\tlow\tconcentrations \tin\tthe\tkey\tcompartment \t\nthat provides access to their receptors. For example, insulin \nhas a measured Vd similar to the volume of plasma water but \nexerts its effects on muscle, fat and liver via receptors that \nare\texposed \tto \tinterstitial \tfluid \tbut \tnot \tto \tplasma \t(Ch. \t32).\nDRUGS \u2003LARGELY \u2003CONFINED \u2003TO \u2003THE\u2003\u2003\nPLASMA \u2003COMPARTMENT\nThe\tplasma \tvolume \tis \tabout \t0.05 \tL/kg \tbody \tweight. \tA \t\nfew drugs, such as heparin (Ch. 25), are confined to plasma \nbecause the molecule is too large to cross the capillary wall \neasily. More often, retention of a drug in the plasma fol -\nlowing\ta \tsingle \tdose \treflects \tstrong \tbinding \tto \tplasma \t\nprotein. It is, nevertheless, the free drug in the interstitial \nfluid\tthat \texerts \ta \tpharmacological \teffect. \tFollowing \trepeated\t\ndosing,\tequilibration \toccurs \tand \tmeasured \tVd increases. \nSome dyes bind exceptionally strongly to plasma albumin, as with Evans blue, such that its V\nd is used experimentally \nto measure plasma volume.\nDRUGS \u2003DISTRIBUTED \u2003IN \u2003THE \u2003EXTRACELLULAR \u2003\nCOMPARTMENT\nThe\ttotal \textracellular \tvolume \tis \tabout \t0.2 \tL/kg, \tand \tthis \t\nis the approximate Vd for many polar compounds, such as \nvecuronium", "start_char_idx": 0, "end_char_idx": 3005, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8c7e0ce7-d0d0-4bc5-a277-ef1d74174e4c": {"__data__": {"id_": "8c7e0ce7-d0d0-4bc5-a277-ef1d74174e4c", "embedding": null, "metadata": {"page_label": "135", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73100427-57d7-47c8-adc1-a9f74ccbcaa6", "node_type": null, "metadata": {"page_label": "135", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc079f7b683d56187dfec95d527f222aae221ec8759892f67485aaefb190449a"}, "2": {"node_id": "3d3b8780-6c9e-4c02-982a-f604b54faae3", "node_type": null, "metadata": {"page_label": "135", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87ba220c8040008d454c4affda4cfd26b528ac10eb07d133dde40ed7e3530bee"}}, "hash": "a427140bc69e4235946db52b1609df000ffaaa842f3af318b885750c8397d9d5", "text": "the approximate Vd for many polar compounds, such as \nvecuronium (Ch. 14), gentamicin and carbenicillin (Ch. \n52). These drugs cannot easily enter cells because of their \nlow lipid solubility, and they do not traverse the blood\u2013brain or placental barriers freely. Many macromolecular \nbiopharmaceuticals, notably monoclonal antibodies (Ch. 5), Concentration (mg/mL)\n012345 650\n10100\n5\n1.0\n0.5\n0.1CSF\n(meningitis)Plasma\nCSF (normal)\nTime (hours)\nFig. 9.12 Plasma and cerebrospinal fluid concentrations of \nan antibiotic (thienamycin) following an intravenous dose \n(25 mg/kg). In normal rabbits, no drug reaches the cerebrospinal \nfluid (CSF), but in animals with experimental Escherichia coli \nmeningitis the concentration of drug in CSF approaches that in \nthe plasma. (From Patamasucon, P., McCracken Jr, G.H., 1973. Antimicrob. Agents Chemother. 3, 270.)bound\tform; \tfurthermore, \tdrugs \tthat \tare \tweak \tacids \tor \t\nbases\twill \texist \tas \tan \tequilibrium \tmixture \tof \tthe \tcharged \t\nand\tuncharged \tforms, \tthe \tposition \tof \tthe \tequilibrium \t\ndepending on the pH.\nThe\tequilibrium \tpattern \tof \tdistribution \tbetween \tthe \t\nvarious compartments will therefore depend on:\n\u2022\tpermeability \tacross \ttissue \tbarriers\n\u2022\tbinding \twithin \tcompartments\n\u2022\tpH\tpartition\n\u2022\tfat:water \tpartition\nTo enter the transcellular compartments from the extracel -\nlular compartment, a drug must cross a cellular barrier, a \nparticularly important example being the blood\u2013brain \nbarrier.\nTHE\u2003BLOOD\u2013BRAIN \u2003BARRIER\nThe concept of the blood\u2013brain barrier was introduced by \nPaul\tEhrlich \tto \texplain \this \tobservation \tthat \tintravenously \t\ninjected dye stained most tissues but not the brain. The barrier consists of a continuous layer of endothelial cells \njoined by tight junctions and surrounded by pericytes. The \nbrain\tis\tconsequently \tinaccessible \tto \tmany \tdrugs \tof \tlow \t\nlipid\tsolubility. \tHowever, \tinflammation \tcan \tdisrupt \tthe \t\nintegrity of the blood\u2013brain barrier, allowing normally \nimpermeant substances to enter the brain (Fig. 9.12) and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2941, "end_char_idx": 5462, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a9d4a86-8db7-41fc-8021-b7152c2240ca": {"__data__": {"id_": "7a9d4a86-8db7-41fc-8021-b7152c2240ca", "embedding": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1906ef21-c6c9-40f1-9d63-e8cc7de658d3", "node_type": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46385e9c47800ef1bb2fba6d1e784d9f3c4fe9d360aea7a3c2eedc0c190f9857"}, "3": {"node_id": "d54063b6-dbec-4924-a9e6-f1718d8697ec", "node_type": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef5e945ac86f563fdbcb46c7e2272ab9a3f58f67bf3982ba68511f91b372ad28"}}, "hash": "4fa950a27f9b3bc8f8ca432a608a959f78e35df85f7fafcef5ad6728333a42c9", "text": "9 SECTION 1\u2003\u2003 GENERAL PRINCIPLES\n130polymorphisms of drug transporters in intestine and \nhepatocytes and of drug\u2013drug interactions due to competi -\ntion for these transporters (Yoshida et al., 2013).\nDRUG \u2003INTERACTIONS \u2003CAUSED \u2003BY \u2003ALTERED \u2003\nDISTRIBUTION \u2003(SEE \u2003CH. \u200312 \u2003FOR \u2003A \u2003GENERAL \u2003APPROACH \u2003\nTO\u2003DRUG \u2003INTERACTIONS)\nOne drug may alter the distribution of another, by competing for a common binding site on plasma albumin or tissue \nprotein, but such interactions are seldom clinically important \nunless accompanied by a separate effect on drug elimination (see Chs 10, 12). Displacement of a drug from binding sites \nin plasma or tissues transiently increases the concentration \nof free (unbound) drug, but this is followed by increased elimination, so a new steady state results in which total \ndrug concentration in plasma is reduced but the free drug \nconcentration is similar to that before introduction of the \nsecond\t\u2018displacing\u2019 \tdrug.\tConsequences \tof\tpotential \tclinical\t\nimportance include:\n\u2022\tHarm\tfrom \tthe \ttransient \tincrease \tin \tconcentration \tof \t\nfree drug before the new steady state is reached.\n\u2022\tIf\tdose \tis \tbeing \tadjusted \taccording \tto \tmeasurements \t\nof total plasma concentration, it must be appreciated that the target therapeutic concentration range will be \naltered by co-administration of a displacing drug.\n\u2022\tWhen\tthe \tdisplacing \tdrug \tadditionally \treduces \t\nelimination of the first, so that the free concentration is \nincreased not only acutely but also chronically at the \nnew steady state, severe toxicity may ensue.\nAlthough many drugs have appreciable affinity for plasma \nalbumin, and therefore might potentially be expected to \ninteract in these ways, there are rather few instances of \nclinically \timportant \tinteractions \tof\tthis\ttype.\tProtein-bound \t\ndrugs that are given in large enough dosage to act as displac -\ning agents include various sulfonamides and chloral hydrate ; \ntrichloroacetic acid, a metabolite of chloral hydrate, binds \nvery strongly to plasma albumin. Displacement of bilirubin from albumin by such drugs in jaundiced premature \nneonates \tcan\thave\tclinically \tdisastrous \tconsequences: \tbili-\nrubin metabolism is undeveloped in the premature liver, \nand unbound bilirubin can cross the immature blood\u2013brain \nbarrier\tand\tcause\tkernicterus \t(staining \tof\tthe\tbasal\tganglia\t\nby bilirubin). This causes a distressing and permanent \ndisturbance \tof \tmovement \tknown \tas \tchoreoathetosis, \t\ncharacterised by involuntary writhing and twisting move -\nments in the child.\nPhenytoin \tdose \tis \tadjusted \taccording \tto \tmeasurement \t\nof its concentration in plasma, and such measurements do \nnot routinely distinguish bound from free phenytoin (i.e. \nthey\treflect \tthe \ttotal \tconcentration \tof \tdrug). \tIntroduction \t\nof a displacing drug in an epileptic patient whose condition is stabilised on phenytoin (Ch. 46) reduces the total plasma \nphenytoin concentration owing to increased elimination \nof free drug, but there is no loss of efficacy because the concentration of unbound (active) phenytoin at the new \nsteady state is unaltered. If it is not appreciated that the \ntherapeutic range of plasma concentrations has been reduced in this way, an increased dose may be prescribed, causing \nharm.\nDrugs that alter protein binding sometimes additionally \nreduce elimination of the displaced drug,", "start_char_idx": 0, "end_char_idx": 3361, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d54063b6-dbec-4924-a9e6-f1718d8697ec": {"__data__": {"id_": "d54063b6-dbec-4924-a9e6-f1718d8697ec", "embedding": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1906ef21-c6c9-40f1-9d63-e8cc7de658d3", "node_type": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46385e9c47800ef1bb2fba6d1e784d9f3c4fe9d360aea7a3c2eedc0c190f9857"}, "2": {"node_id": "7a9d4a86-8db7-41fc-8021-b7152c2240ca", "node_type": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4fa950a27f9b3bc8f8ca432a608a959f78e35df85f7fafcef5ad6728333a42c9"}, "3": {"node_id": "edd1f9e9-eeb4-43c2-8f1b-22d0be04f42d", "node_type": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "637af201fea66b501d84e637e7718722c27c199b2f61995c24576a32c58db73f"}}, "hash": "ef5e945ac86f563fdbcb46c7e2272ab9a3f58f67bf3982ba68511f91b372ad28", "text": "that alter protein binding sometimes additionally \nreduce elimination of the displaced drug, causing clinically \nimportant interactions. Salicylates displace methotrexate \nfrom binding sites on albumin and reduce its secretion \ninto the nephron by competition with the OAT (Ch. 10). distribute in the extracellular space and access receptors on cell surfaces but do not readily enter cells. Nucleic acid-based \nbiopharmaceuticals \twhich \twork \ton \tintracellular \tDNA \tor \t\nRNA\tare \toften \tpackaged \tin \tspecial \tdelivery \tsystems \t(see \t\np. 131) that facilitate access to the cell interior.\nDISTRIBUTION \u2003THROUGHOUT \u2003THE \u2003BODY \u2003WATER\nTotal\tbody\twater\trepresents \tabout\t0.55\tL/kg. \t This \t approxi -\nmates the distribution of many drugs that readily cross \ncell membranes, such as phenytoin (Ch. 46) and ethanol \n(Ch. 50). The binding of drugs outside the plasma compart -\nment, or partitioning into body fat, increases Vd beyond \ntotal\tbody\twater.\tConsequently, \tthere\tare\talso\tmany\tdrugs\t\nwith Vd greater than the total body volume, such as mor-\nphine (Ch. 43), tricyclic antidepressants (Ch. 48) and haloperidol (Ch. 47). Such drugs are not efficiently removed \nfrom the body by haemodialysis, which is therefore unhelp -\nful in managing overdose with such agents.\nDrug distribution \n\u2022\tThe\tmajor \tcompartments \tare:\n\u2013 plasma (5% of body weight)\n\u2013 interstitial fluid (16%)\n\u2013 intracellular fluid (35%)\n\u2013 transcellular fluid (2%)\n\u2013 fat (20%).\n\u2022\tVolume \tof \tdistribution \t(Vd) is defined as the volume of \nsolvent that would contain the total body content of \nthe drug (Q) at a concentration equal to the measured \nplasma concentration ( Cp), Vd = Q/C p.\n\u2022\tLipid-insoluble \tdrugs \tare \tmainly \tconfined \tto \tplasma \t\nand\tinterstitial \tfluids; \tmost \tdo \tnot \tenter \tthe \tbrain \t\nfollowing acute dosing.\n\u2022\tLipid-soluble \tdrugs \treach \tall \tcompartments \tand \tmay \t\naccumulate in fat.\n\u2022\tFor\tdrugs \tthat \taccumulate \toutside \tthe \tplasma \t\ncompartment (e.g. in fat or by being bound to tissues), \nVd may exceed total body volume.\nDRUG \u2003INTERACTIONS \u2003CAUSED \u2003BY \u2003ALTERED \u2003\nABSORPTION \u2003(SEE \u2003CH. \u200312 \u2003FOR \u2003A \u2003GENERAL \u2003APPROACH \u2003\nTO\u2003DRUG \u2003INTERACTIONS)\nGastrointestinal absorption is slowed by drugs that inhibit \ngastric emptying, such as atropine or opiates, or accelerated \nby drugs that hasten gastric emptying (e.g. metoclopramide; \nsee Ch. 31). Alternatively, drug A may interact physically or chemically with drug B in the gut in such a way as to \ninhibit absorption of B. For example, Ca\n2+ and Fe2+ each \nform insoluble complexes with tetracycline that retard their \nabsorption; colestyramine , a bile acid-binding resin, binds \nseveral drugs (e.g. warfarin, digoxin), preventing their \nabsorption if administered simultaneously. Another example \nis the addition of adrenaline (epinephrine ) to local anaes -\nthetic injections; the resulting vasoconstriction slows the \nabsorption of the anaesthetic, thus prolonging its local effect \n(Ch.\t44).\tPhysiologically \tbased\tmodelling \tis\tnow\tbeginning \t\nto\tbe\tused \tto \tpredict", "start_char_idx": 3281, "end_char_idx": 6306, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "edd1f9e9-eeb4-43c2-8f1b-22d0be04f42d": {"__data__": {"id_": "edd1f9e9-eeb4-43c2-8f1b-22d0be04f42d", "embedding": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1906ef21-c6c9-40f1-9d63-e8cc7de658d3", "node_type": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46385e9c47800ef1bb2fba6d1e784d9f3c4fe9d360aea7a3c2eedc0c190f9857"}, "2": {"node_id": "d54063b6-dbec-4924-a9e6-f1718d8697ec", "node_type": null, "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef5e945ac86f563fdbcb46c7e2272ab9a3f58f67bf3982ba68511f91b372ad28"}}, "hash": "637af201fea66b501d84e637e7718722c27c199b2f61995c24576a32c58db73f", "text": "\tis\tnow\tbeginning \t\nto\tbe\tused \tto \tpredict \tquantitatively \tthe \teffects \tof \tgenetic \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6344, "end_char_idx": 6911, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1c46215d-a5bf-43e6-98fd-5cf6ca4f297f": {"__data__": {"id_": "1c46215d-a5bf-43e6-98fd-5cf6ca4f297f", "embedding": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "25ce6b27-ee2e-465a-a9de-a8450c8e453b", "node_type": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e2765dfee8621c563477cfbefc3460e13a00a26eda9ad7b4894c420abcaf93a"}, "3": {"node_id": "bf63903c-8af3-4842-9ff1-367fb8dcc98e", "node_type": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97c1532dc501c9d52a95d6eab37df75d6e01bc08d7b8802b994715d31b9a5576"}}, "hash": "5e16fa3d64c22628f8cc2a53d4fa9dfaf7b10c0a45739e5ecb27c480eab8a957", "text": "9 AbSoRPtIoN AN d d IS t RI but I o N of d R u GS \n131galactose and N-acetyl galactosamine (GalNAc) residues, \nleading\tto\tselective\thepatocyte \tuptake\t(Prakash \tet\tal., \t 2016).\nOther problems could theoretically be overcome by using \nsuitable prodrugs; for example, instability of drugs at gastric \npH, direct gastric irritation (aspirin was synthesised in the \n19th century in a deliberate attempt to produce a prodrug \nof\tsalicylic \tacid \tthat \twould \tbe \ttolerable \twhen \ttaken \tby \t\nmouth), failure of drug to cross the blood\u2013brain barrier and so on. While the optimistic prodrug designer \u2018will \nhave to bear in mind that an organism\u2019s normal reaction \nto a foreign substance is to burn it up for food\u2019, the successes mentioned above in delivering nucleic acid drugs to \nhepatocytes is a notable encouragement, with early human \nstudies that have provided proof of concept in patients with dyslipidaemia, haemophilia and one form of amyloi -\ndosis, for example.\nANTIBODY\u2013DRUG \u2003CONJUGATES\n\u25bc One of the aims of cancer chemotherapy is to improve the selectivity \nof cytotoxic drugs (see Ch. 57). One approach is to attach the drug \nor toxin to an antibody directed against a tumour-specific antigen, \nwhich will bind selectively to tumour cells (Thomas et al., 2016). \nAdo-trastuzumab emtansine and brentuximab vedotin have been \napproved by the FDA for treatment of selected cases of, respectively, \nmetastatic \tbreast \tcancer \tand \tHodgkin\u2019s \tlymphoma.\nPACKAGING \u2003IN \u2003LIPOSOMES\n\u25bc Liposomes are vesicles 0.1\u20131 \u00b5m in diameter produced by sonication \nof\tan\taqueous \tsuspension \tof \tphospholipids. \tThey \tcan \tbe \tfilled \twith \t\nnon lipid-soluble drugs, which are retained until the liposome is \ndisrupted. \tLiposomes \tare \ttaken \tup \tby \treticuloendothelial \tcells, \t\nespecially in the liver. They are also concentrated in malignant tumours, and several liposomal chemotherapeutic formulations are commercially \navailable (see Yingchoncharoeu et al., 2016). Amphotericin, an \nantifungal drug used to treat systemic mycoses (Ch. 54), is available \nin a liposomal formulation that is less nephrotoxic and better tolerated \nthan the conventional form, albeit considerably more expensive. A long-acting form of doxorubicin encapsulated in liposomes is available \nfor the treatment of malignancies (including ovarian cancer and myeloma), and paclitaxel is available in an albumin nanoparticle used to treat breast cancer (Ch. 57). A liposomal preparation of cyta-\nrabine is available for intrathecal treatment of lymphomatous meningitis, and a liposomal formulation of vincristine is available \nfor\tselected \tpatients \twith \tacute \tlymphoblastic \tleukaemia.\nCOATED \u2003IMPLANTABLE \u2003DEVICES\n\u25bc Impregnated coatings have been developed that permit localised \ndrug delivery from implants. Examples include hormonal delivery to the endometrium from intrauterine devices, and delivery of \nantithrombotic and antiproliferative agents (drugs or radiopharma -\nceuticals) to the coronary arteries from stents (tubular devices inserted \nvia a catheter after a diseased coronary artery has been dilated with a balloon). Stents reduce the occurrence of re-stenosis, but this can \nstill occur at the margin of the device. Coating stents with drugs such as", "start_char_idx": 0, "end_char_idx": 3243, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bf63903c-8af3-4842-9ff1-367fb8dcc98e": {"__data__": {"id_": "bf63903c-8af3-4842-9ff1-367fb8dcc98e", "embedding": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "25ce6b27-ee2e-465a-a9de-a8450c8e453b", "node_type": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e2765dfee8621c563477cfbefc3460e13a00a26eda9ad7b4894c420abcaf93a"}, "2": {"node_id": "1c46215d-a5bf-43e6-98fd-5cf6ca4f297f", "node_type": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e16fa3d64c22628f8cc2a53d4fa9dfaf7b10c0a45739e5ecb27c480eab8a957"}, "3": {"node_id": "f851b475-eec3-469c-ba10-e3af8413411a", "node_type": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed3a9892e53f26e99a5f9e6343ba2ae420f08ccea5bb3f07c95989e7f3ce99f7"}}, "hash": "97c1532dc501c9d52a95d6eab37df75d6e01bc08d7b8802b994715d31b9a5576", "text": "\nstill occur at the margin of the device. Coating stents with drugs such as sirolimus (a potent immunosuppressant; see Ch. 27) embedded \nin a surface polymer prevents this important clinical problem.Quinidine and several other antidysrhythmic drugs includ -\ning verapamil and amiodarone (Ch. 22) displace digoxin \nfrom tissue-binding sites while simultaneously reducing \nits\trenal \texcretion; \tthey \tconsequently \tcan \tcause \tsevere \t\ndysrhythmias through digoxin toxicity.\nSPECIAL DRUG DELIVERY SYSTEMS\nSeveral approaches are used or in development to improve \ndrug delivery and localise the drug to the target tissue. \nThey include:\n\u2022\tprodrugs\n\u2022\tantibody\u2013drug \tconjugates\n\u2022\tpackaging \tin \tliposomes\n\u2022\tcoated \timplantable \tdevices\nPRODRUGS\nProdrugs \tare \tinactive \tprecursors \tthat \tare \tmetabolised \tto \t\nactive metabolites; they are described in Chapter 10. Some \nof the examples in clinical use confer no obvious benefits \nand have been found to be prodrugs only retrospectively, \nnot having been designed with this in mind. However, some do have advantages. For example, the cytotoxic drug \ncyclophosphamide (see Ch. 57) becomes active only after \nit has been metabolised in the liver; it can therefore be \ntaken\torally \twithout \tcausing \tserious \tdamage \tto \tthe \t\ngastrointestinal epithelium. Levodopa is absorbed from the gastrointestinal tract and crosses the blood\u2013brain barrier \nvia an amino acid transport mechanism before conversion \nto active dopamine in nerve terminals in the basal ganglia (Ch. 41). Zidovudine is phosphorylated to its active \ntriphosphate metabolite only in cells containing the appro -\npriate reverse transcriptase, hence conferring selective \ntoxicity towards cells infected with HIV (Ch. 53). Valaci-\nclovir and famciclovir are each ester prodrugs, respectively \nof aciclovir and of penciclovir. Their bioavailability is \ngreater than that of aciclovir and penciclovir, which are themselves prodrugs that are converted into active metabo -\nlites in virally infected cells (Ch. 53). Diacetyl morphine \n(heroin) is a prodrug that penetrates the blood\u2013brain barrier even faster than its active metabolites morphine and \n6-monoacetyl morphine (Ch. 43), accounting for increased \n\u2018buzz\u2019 and hence abuse potential.\nDelivering nucleic acid-based drugs (antisense oligonu -\ncleotides and small interfering RNA drugs) to their intracellular sites of action is a major issue with this class of biopharmaceutical (Ch. 5). Modifying these agents with \nchemical groups that bind specific surface transporters \npermits drug delivery to specific cells. The asialoglycoprotein receptor (ASGR) is a lectin that is abundantly expressed \non the cell surface of hepatocytes and binds terminal \nREFERENCES AND FURTHER READING\nDrug absorption and bioequivalence\nEMEA,\t2010. \tGuideline \ton \tthe \tinvestigation \tof \tbioequivalence. \thttp://\nwww.ema.europa.eu/docs/en_GB/document_library/Scientific_\nguideline/2010/01/WC500070039.pdf. (Accessed 19 March 2017).\nYoshida, K., Maeda, K., Sugiyama, Y., 2013. Hepatic and intestinal drug \ntransporters: \tprediction \tof \tpharmacokinetic \teffects \tcaused \tby \t\ndrug-drug interactions and genetic polymorphisms. Ann. Rev. \nPharmacol. \tToxicol. \t53, \t581\u2013612. \t(Reviews the status of predicting pharmacokinetic behaviour on the basis of transporter-mediated", "start_char_idx": 3182, "end_char_idx": 6495, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f851b475-eec3-469c-ba10-e3af8413411a": {"__data__": {"id_": "f851b475-eec3-469c-ba10-e3af8413411a", "embedding": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "25ce6b27-ee2e-465a-a9de-a8450c8e453b", "node_type": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e2765dfee8621c563477cfbefc3460e13a00a26eda9ad7b4894c420abcaf93a"}, "2": {"node_id": "bf63903c-8af3-4842-9ff1-367fb8dcc98e", "node_type": null, "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97c1532dc501c9d52a95d6eab37df75d6e01bc08d7b8802b994715d31b9a5576"}}, "hash": "ed3a9892e53f26e99a5f9e6343ba2ae420f08ccea5bb3f07c95989e7f3ce99f7", "text": "status of predicting pharmacokinetic behaviour on the basis of transporter-mediated drug \ninteractions and pharmacogenetics)\nDrug distribution (including blood\u2013brain barrier)\nCiarimboli, G., 2008. Organic cation transporters. Xenobiotica 38, \n936\u2013971. (Discusses species- and tissue-specific distribution of different OCT isoforms and polymorphisms in OCTs as a source of variation in drug \nresponse)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6474, "end_char_idx": 7353, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d5244149-0cef-402c-801e-e99c38af57d8": {"__data__": {"id_": "d5244149-0cef-402c-801e-e99c38af57d8", "embedding": null, "metadata": {"page_label": "138", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d1f79cd1-e2c2-433e-90a2-a20d61debba2", "node_type": null, "metadata": {"page_label": "138", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f89f2748f75ceda691fc37a3915bbde3883a2f8e809e20c50dd5ed6613f3529"}, "3": {"node_id": "ead9324a-5314-47f1-b9ab-348352ed84bc", "node_type": null, "metadata": {"page_label": "138", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f19f14bc22cc037be2662edb83ca15906172b7edc06777eb5ae697bb9747dfa"}}, "hash": "b38016cc488239ccc70376573296155c9cafcf346444588582743eb1ef26532e", "text": "9 SECTION 1 \u2003\u2003GENERAL PRINCIPLES\n132chemical\t motifs.\tJ.\tPharmacol.\t Exp.\tTher.\t339,\t132\u2013142.\t (Ingenious \nmethod of targeting drugs to this cell lineage which selectively expresses an \nesterase that releases the charged form of drug intracellularly where it is \ntrapped and where its target resides )\nPrakash,\t T.P.,\tYu,\tJ.,\tMigawa,\t M.T.,\tet\tal.,\t2016.\tComprehensive\t\nstructure activity relationship of triantennary N-acetylgalactosamine \nconjugated antisense oligonucleotides for targeted delivery to \nhepatocytes. J. Med. Chem. 59, 2718\u20132733. ( Enabling technology: \npotential gateway to a flood of nucleic acid based therapeutics )\nRenukuntla,\t J.,\tVadlapudi,\t A.D.,\tPatel,\tA.,\tBoddu,\tS.H.S.,\tMitra,\tA.K.,\t\n2013. Approaches for enhancing oral bioavailability of peptides and \nproteins.\t Int.\tJ.\tPharm.\t447,\t75\u201393.\t(Limited success only )\nThomas, A., Teichner, B.A., Hassan, R., 2016. Antibody-drug conjugates \nfor cancer therapy. Lancet Oncol. 17 (6), e254\u2013e262. ( Attractive \napproach, two FDA-licensed products )\nYingchoncharoeu,\t P.,\tKanilowski,\t D.S.,\tRichardson,\t D.R.,\t2016.\t\nLipid-based drug delivery systems in cancer therapy: what is \navailable\t and\twhat\tis\tyet\tto\tcome.\tPharmacol.\t Rev.\t63,\t701\u2013787.\t\n(Potential of lipid nanoparticles \u2013 several have already been licensed )Miller, D.S., Bauer, B., Hartz, A.M.S., 2008. Modulation of \nP-glycoprotein\t at\tthe\tblood\u2013brain\t barrier:\topportunities\t to\timprove\t\ncentral\tnervous\t system\tpharmacotherapy.\t Pharmacol.\t Rev.\t60,\t\n196\u2013209.\nDrug delivery and routes of administration\nBrigo,\tF.,\tNardone,\t R.,\tTezzon,\t F.,\tTrinka,\tE.,\t2015.\tNonintravenous\t\nmidazolam versus intravenous or rectal diazepam for the treatment of \nearly status epilepticus: a systematic review with meta-analysis. \nEpilepsy Behav. 49, 325\u2013336. (\u201c Non-intravenous midazolam is as effective \nand safe as intravenous or rectal diazepam in terminating early status \nepilepticus in children and probably also in adults.\u201d Buccal midazolam was \nsocially more acceptable and easier to administer, and might also have a \nhigher efficacy than rectal diazepam in seizure control )\nHuttunen,\t K.M.,\tRaunio,\tH.,\tRautio,\tJ.,\t2011.\tProdrugs\t \u2013\tfrom\t\nserendipity\t to\trational\tdesign.\tPharmacol.\t Rev.\t63,\t750\u2013771.\t (Reviews \nprodrug strategy )\nNeedham, L.A., Davidson, A.H., Bawden, L.J., Belfield, A., 2011. Drug \ntargeting to monocytes and macrophages using esterase-sensitive mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 0, "end_char_idx": 2729, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ead9324a-5314-47f1-b9ab-348352ed84bc": {"__data__": {"id_": "ead9324a-5314-47f1-b9ab-348352ed84bc", "embedding": null, "metadata": {"page_label": "138", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d1f79cd1-e2c2-433e-90a2-a20d61debba2", "node_type": null, "metadata": {"page_label": "138", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f89f2748f75ceda691fc37a3915bbde3883a2f8e809e20c50dd5ed6613f3529"}, "2": {"node_id": "d5244149-0cef-402c-801e-e99c38af57d8", "node_type": null, "metadata": {"page_label": "138", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b38016cc488239ccc70376573296155c9cafcf346444588582743eb1ef26532e"}}, "hash": "6f19f14bc22cc037be2662edb83ca15906172b7edc06777eb5ae697bb9747dfa", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2682, "end_char_idx": 2873, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a327baaa-73e6-40b0-bfed-c363bec408b2": {"__data__": {"id_": "a327baaa-73e6-40b0-bfed-c363bec408b2", "embedding": null, "metadata": {"page_label": "139", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3a549ae4-3030-47d2-853a-e833c30cc76a", "node_type": null, "metadata": {"page_label": "139", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82f688d9a28c95fd2588316fdf4d292d677f940bd4088038e81b0c48500d2823"}, "3": {"node_id": "8a358024-096b-4cba-bc21-a672895f26dc", "node_type": null, "metadata": {"page_label": "139", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bf4130e12b953b98785000ee6c30c6f126e225c89b2934c9112d237bc72b7ac3"}}, "hash": "e35a4fbe1f4e8d4682cce48de4335d67cf3a4093358aa6b9760b535ca7281a60", "text": "133\nDrug metabolism and elimination 10 GENERAL PRINCIPLES SECTION 1 \nOVERVIEW\nWe describe phases 1 and 2 of drug metabolism, \nemphasising the importance of the cytochrome P450 \nmonooxygenase system. We then cover the processes \nof biliary excretion and enterohepatic recirculation of drugs, and of drug interactions caused by induction \nor inhibition of metabolism. Drug and drug metabolite \nelimination by the kidney are described and drug inter -\nactions due to effects on renal elimination considered.\nINTRODUCTION\nDrug elimination is the irreversible loss of drug from the \nbody. It occurs by two processes: metabolism and excretion. \nMetabolism consists of anabolism and catabolism, that is, respectively, the build-up and breakdown of substances by enzymic conversion of one chemical entity to another \nwithin the body, whereas excretion consists of elimination \nfrom the body of drug or drug metabolites. The main excretory routes are:\n\u2022\tthe\tkidneys\n\u2022\tthe\thepatobiliary \tsystem\n\u2022\tthe\tlungs \t(important \tfor \tvolatile/gaseous \tanaesthetics)\nMost drugs leave the body in the urine, either unchanged or as polar metabolites. Some drugs are secreted into bile \nvia the liver, but most of these are then reabsorbed from \nthe\tintestine. \tThere\tare,\thowever, \tinstances \t(e.g.\trifampicin ; \nCh.\t52)\twhere \tfaecal \tloss \taccounts \tfor \tthe \telimination \tof \ta \t\nsubstantial fraction of unchanged drug in healthy individu -\nals, and faecal elimination of drugs such as digoxin that \nare\tnormally \texcreted \tin \turine \t(Ch. \t22) \tbecomes \tprogres -\nsively more important in patients with advancing renal impairment. Excretion via the lungs occurs only with highly \nvolatile\tor \tgaseous \tagents \t(e.g. \tgeneral \tanaesthetics; \tCh. \t\n42).\tSmall \tamounts \tof \tsome \tdrugs \tare \talso \texcreted \tin \t\nsecretions such as milk or sweat. Elimination by these routes \nis quantitatively negligible compared with renal excretion, \nalthough excretion into milk can sometimes be important \nbecause\tof \teffects \ton \tthe \tbaby \t().\nLipophilic \tsubstances \tare \tnot \teliminated \tefficiently \t\nby\tthe\tkidney \t(see \tlater, \tp. \t140). \tConsequently, \tmost \t\nlipophilic drugs are metabolised to more polar products, \nwhich are then excreted in urine. Drugs are metabolised \npredominantly in the liver, especially by the cytochrome \nP450\t(CYP) \tsystem. \tSome \tP450 \tenzymes \tare \textrahepatic \t\nand play an important part in the biosynthesis of steroid \nhormones \t(Ch. \t34) \tand \teicosanoids \t(Ch. \t18), \tbut \there \twe \t\nare concerned with catabolism of drugs by the hepatic \nP450 system.DRUG METABOLISM\nAnimals have evolved complex systems that detoxify foreign \nchemicals \t(\u2018xenobiotics\u2019), \tincluding \tcarcinogens \tand\ttoxins\t\npresent in poisonous plants. Drugs are a special case of \nsuch xenobiotics and, like plant alkaloids, they often exhibit \nchirality\t(i.e.\tthere \tis \tmore \tthan \tone \tstereoisomer), \twhich \t\naffects their overall metabolism. Drug metabolism involves \ntwo kinds of reaction, known as phase 1 and phase 2, which \noften occur sequentially. Both phases decrease lipid", "start_char_idx": 0, "end_char_idx": 3116, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8a358024-096b-4cba-bc21-a672895f26dc": {"__data__": {"id_": "8a358024-096b-4cba-bc21-a672895f26dc", "embedding": null, "metadata": {"page_label": "139", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3a549ae4-3030-47d2-853a-e833c30cc76a", "node_type": null, "metadata": {"page_label": "139", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82f688d9a28c95fd2588316fdf4d292d677f940bd4088038e81b0c48500d2823"}, "2": {"node_id": "a327baaa-73e6-40b0-bfed-c363bec408b2", "node_type": null, "metadata": {"page_label": "139", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e35a4fbe1f4e8d4682cce48de4335d67cf3a4093358aa6b9760b535ca7281a60"}}, "hash": "bf4130e12b953b98785000ee6c30c6f126e225c89b2934c9112d237bc72b7ac3", "text": "and phase 2, which \noften occur sequentially. Both phases decrease lipid solubil -\nity, thus increasing renal elimination.\nPHASE 1 REACTIONS\nPhase\t1\treactions \t(e.g. \toxidation, \treduction \tor \thydrolysis) \t\nare catabolic, and the products are often more chemically \nreactive and hence, paradoxically, sometimes more toxic \nor carcinogenic than the parent drug. Phase 1 reactions \noften introduce a reactive group, such as hydroxyl, into \nthe\tmolecule, \ta \tprocess \tknown \tas \t\u2018functionalisation\u2019. \tThis \t\ngroup then serves as the point of attack for the conjugating \nsystem\tto \tattach \ta \tsubstituent \tsuch \tas \tglucuronide \t(Fig. \t\n10.1),\texplaining \twhy \tphase \t1 \treactions \tso \toften \tprecede \t\nphase 2 reactions. The liver is especially important in phase 1 reactions. Many hepatic drug-metabolising enzymes, \nincluding \tCYP \tenzymes, \tare \tembedded \tin \tthe \tsmooth \t\nendoplasmic \treticulum. \tThey\tare\toften\tcalled\t\u2018microsomal\u2019 \t\nenzymes because, on homogenisation and differential centrifugation, the endoplasmic reticulum is broken into \nvery small fragments that sediment only after prolonged \nhigh-speed centrifugation in the microsomal fraction. To reach these metabolising enzymes in life, a drug must cross \nthe plasma membrane. Polar molecules do this less readily \nthan\tnon-polar \tmolecules \texcept \twhere \tthere \tare \tspecific \t\ntransport \tmechanisms \t(Ch.\t9),\tso\tintracellular \tmetabolism \t\nis important for lipid-soluble drugs, while polar drugs are, \nat least partly, excreted unchanged in the urine.\nTHE P450 MONOOXYGENASE SYSTEM\nNature, classification and mechanism of \nP450 enzymes\nCytochrome P450 enzymes are haem proteins, compris -\ning\ta\tlarge \tfamily \t(\u2018superfamily\u2019) \tof \trelated \tbut \tdistinct \t\nenzymes, \teach \treferred \tto \tas \tCYP \tfollowed \tby \ta \tdefining \t\nset\tof\tnumbers \tand \ta \tletter. \tP450 \tenzymes \t(reviewed \tby \t\nGuengerich \tet \tal., \t2016 \tand \tNair \tet \tal., \t2016) \tdiffer \tfrom \t\none another in amino acid sequence, in sensitivity to inhibi -\ntors\tand\tinducing \tagents \t(see \tlater), \tand \tin \tthe \tspecificity \t\nof the reactions that they catalyse. Different members of the family have distinct, but often overlapping, substrate \nspecificities. \tPurification \tand\tcloning\tof\tP450\tenzymes \tform\t\nthe\tbasis \tof \tthe \tcurrent \tclassification, \twhich \tis \tbased \ton \t\namino\tacid \tsequence \tsimilarities. \tNot \tall \t57 \thuman \tCYPs \t\nare involved in drug metabolism, but it has been estimated \nthat\tCYP \tenzymes \tin \tfamilies \t1\u20133 \tmediate \t70%\u201380% \tof \tall \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3044, "end_char_idx": 6026, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "90b83da5-94f7-4657-bf4f-41e6b08c5932": {"__data__": {"id_": "90b83da5-94f7-4657-bf4f-41e6b08c5932", "embedding": null, "metadata": {"page_label": "140", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "76cf222d-11a7-4b46-b259-ea0a75b40846", "node_type": null, "metadata": {"page_label": "140", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "609f3e813ebbe38adfa9f03a298c8968d2fe3ff783b614e88d8141c36bc3267b"}, "3": {"node_id": "afc12c8a-6647-433d-9925-2add8421bbf1", "node_type": null, "metadata": {"page_label": "140", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9a57ebbe61ee4d52e816b1d3d7381e360a8711ddff1f97b70e3ca98f95699bc9"}}, "hash": "409b044559fa21e558416b843aabf7b1f522fff22f5d987f6036e3f5fe14358d", "text": "10 SECTION 1 GENERAL PRINCIPLES\n134Drug oxidation by the monooxygenase P450 system \nrequires\tdrug\t(substrate, \t\u2018DH\u2019),\tP450\tenzyme,\tmolecular \t\noxygen,\tNADPH \tand\tNADPH\u2013P450 \treductase \t(a\tflavo -\nprotein). \tThe\tmechanism \tinvolves\ta\tcomplex \tcycle\t(Fig.\t\n10.2),\tbut\tthe\toutcome\tof\tthe\treaction\tis\tquite\tsimple,\tnamely\t\nthe\taddition\tof\tone\tatom\tof\toxygen\t(from\tmolecular \toxygen)\t\nto\tthe\tdrug\tto\tform\ta\thydroxylated \tproduct\t(DOH),\tthe\t\nother atom of oxygen being converted to water.\n\u25bc P450 enzymes have unique spectral properties, and the reduced \nforms combine with carbon monoxide to form a pink compound \n(hence\t\u2018P\u2019)\twith\tabsorption \tpeaks\tnear\t450\tnm\t(range\t447\u2013452\tnm).\t\nThe\tfirst\tclue\tthat\tthere\tis\tmore\tthan\tone\tform\tof\tCYP\tcame\tfrom\tthe\t\nobservation \tthat\ttreatment \tof\trats\twith\t3-methylcholanthrene \t(3-MC),\t\nan\tinducing \tagent\t(see\tlater),\tcauses\ta\tshift\tin\tthe\tabsorption \tmaximum \t\nfrom\t450\tto\t448\tnm\t\u2013\tthe\t3-MC-induced \tisoform\tof\tthe\tenzyme\tabsorbs\t\nlight maximally at a slightly shorter wavelength than the un-induced \nenzyme.\nP450 and biological variation\nThere are important variations in the expression and regula -\ntion\tof\tP450\tenzymes \tbetween\tspecies.\tFor\tinstance, \tthe\t\npathways by which certain dietary heterocyclic amines \n(formed\twhen\tmeat\tis\tcooked)\tgenerate\tgenotoxic \tproducts \t\ninvolves\tone\tmember\tof\tthe\tP450\tsuperfamily \t(CYP1A2) \t\nthat\tis\tconstitutively \tpresent\tin\thumans\tand\trats\t(which\t\ndevelop\tcolon\ttumours \tafter\ttreatment \twith\tsuch\tamines)\t\nbut\tnot\tin\tcynomolgus \tmonkeys \t(which\tdo\tnot).\tSuch\tspecies\t\ndifferences have crucial implications for the choice of species \nto be used for toxicity and carcinogenicity testing during the development of new drugs for use in humans.\nWithin human populations, there are major sources of \ninter-individual variation in P450 enzymes that are of great importance in therapeutics. These include genetic poly -\nmorphisms \t(alternative \tsequences \tat\ta\tlocus\twithin\tthe\t\nDNA\tstrand\t\u2013\talleles\t\u2013\tthat\tpersist\tin\ta\tpopulation \tthrough\t\nseveral\tgenerations; \tCh.\t12).\tEnvironmental \tfactors\tare\talso\t\nimportant, since enzyme inhibitors and inducers are present \nin\tthe\tdiet\tand\tenvironment. \tFor\texample, \ta\tcomponent \t\nof\tgrapefruit \tjuice\tinhibits\tdrug\tmetabolism \t(leading\tto\t\npotentially disastrous consequences, including cardiac phase 1-dependent metabolism of clinically used small-\nmolecule \tdrugs\t(Ingelman-Sundberg, \t2004).\tTwelve\tCYPs\t\naccounted \tfor\t93.0%\tof\tdrug\tmetabolism \tof\t1839\tknown\t\ndrug-metabolising reactions in a large international database \n(Preissner \tet\tal.,\t2013 ).\tCYPs\t1A2,\t3A4,\t2D6,\t2C9\tand\t2C19\t\nwere\tresponsible \tfor\tapproximately \t60%\tof\tdrug\tmetabolism. \t\nExamples of therapeutic drugs that are substrates for some important P450 isoenzymes are shown in Table", "start_char_idx": 0, "end_char_idx": 2770, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "afc12c8a-6647-433d-9925-2add8421bbf1": {"__data__": {"id_": "afc12c8a-6647-433d-9925-2add8421bbf1", "embedding": null, "metadata": {"page_label": "140", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "76cf222d-11a7-4b46-b259-ea0a75b40846", "node_type": null, "metadata": {"page_label": "140", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "609f3e813ebbe38adfa9f03a298c8968d2fe3ff783b614e88d8141c36bc3267b"}, "2": {"node_id": "90b83da5-94f7-4657-bf4f-41e6b08c5932", "node_type": null, "metadata": {"page_label": "140", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "409b044559fa21e558416b843aabf7b1f522fff22f5d987f6036e3f5fe14358d"}}, "hash": "9a57ebbe61ee4d52e816b1d3d7381e360a8711ddff1f97b70e3ca98f95699bc9", "text": "drugs that are substrates for some important P450 isoenzymes are shown in Table 10.1, and a useful table of drug substrates, inhibitors and inducers \nof\tCYP\tsubtypes \tis\tprovided \tby\tthe\tIndiana\tUniversity \t\nDepartment \tof\tMedicine/Clinical \tPharmacology \t().OHOHOH\nHO\nOCOOH COOH\nCOOHCOOH\nOCOCH3\nGlucuronideConjugation\nSalicylic acid AspirinExampleOxidation \nHydroxylation \nDealkylation \nDeamination\nHydrolysisPhase 2 Phase 1\nDrug Derivative Conjugate\nO\nFig. 10.1 The two phases of drug metabolism. \nTable 10.1 Examples of drugs that are substrates of \nP450 isoenzymes\nIsoenzyme P450 Drug(s)\nCYP1A2 Caffeine, paracetamol (\u2192NAPQI), \ntacrine, theophylline\nCYP2B6 Cyclophosphamide, methadone\nCYP2C8 Paclitaxel, repaglinide\nCYP2C19 Omeprazole, phenytoin\nCYP2C9 Ibuprofen, tolbutamide, warfarin\nCYP2D6 Codeine, debrisoquine, S-metoprolol\nCYP2E1 Alcohol, paracetamol\nCYP3A4, 5, 7 Ciclosporin, nifedipine, indinavir, simvastatin\nNAPQI, N-acetyl-p-benzoquinone imine \u2013 the metabolite responsible for paracetamol toxicity in overdose.(Adapted from http://medicine.iupui.edu/flockhart/table.htm)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2691, "end_char_idx": 4339, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "446cfb8f-5e51-4a91-ae90-cf40e9380b99": {"__data__": {"id_": "446cfb8f-5e51-4a91-ae90-cf40e9380b99", "embedding": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9172e4dd-4452-42ed-b90c-f98743565b96", "node_type": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b6b4050333b376908455d592f91a52f17f4eeb100f5d46d983a2b854e82a3e65"}, "3": {"node_id": "b7dbfbf1-60ef-4403-8702-d87696596a90", "node_type": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6496b5299493be7a81ad2ece5919bb0feba6982c375372b033b9f4ca61f26c52"}}, "hash": "8b762ab28bda85c7ac080a4bdee92123bdc6f2d7b3ff88149199c376093db913", "text": "10 DRuG mEtAboLISm AND ELI m INA t I o N\n135warfarin \t(Ch.\t25) \tis \tinactivated \tby \treduction \tof \ta \tketone \t\nto\ta\thydroxyl \tgroup \tby \tCYP2A6.\nPHASE 2 REACTIONS\nPhase\t2\treactions \tare \tsynthetic \t(\u2018anabolic\u2019) \tand \tinvolve \t\nconjugation \t(i.e. \tattachment \tof \ta \tsubstituent \tgroup), \t\nwhich usually results in inactive products, although \nthere\tare \texceptions \t(e.g. \tthe \tactive \tsulphate \tmetabolite \t\nof minoxidil, a potassium channel activator used to treat \nsevere\thypertension \t(Ch. \t23) \tand \t(as \ta \tcream) \tto \tpromote \t\nhair growth. Phase 2 reactions take place mainly in the \nliver. If a drug molecule or phase 1 product has a suitable \n\u2018handle\u2019\t(e.g. \ta \thydroxyl, \tthiol \tor \tamino \tgroup), \tit \tis \tsus-\nceptible to conjugation. The chemical group inserted may \nbe\tglucuronyl \t(Fig. \t10.3), \tsulphate, \tmethyl \tor \tacetyl. \tThe \t\ntripeptide glutathione conjugates drugs or their phase 1 \nmetabolites \tvia \tits \tsulfhydryl \tgroup, \tas \tin \tthe \tdetoxification \t\nof paracetamol \t(see\tFig. \t58.1). \tGlucuronidation \tinvolves \t\nthe\tformation \tof \ta \thigh-energy \tphosphate \t(\u2018donor\u2019) \tcom -\npound,\turidine \tdiphosphate \tglucuronic \tacid \t(UDPGA), \t\nfrom which glucuronic acid is transferred to an electron-\nrich\tatom \t(N, \tO \tor \tS) \ton \tthe \tsubstrate, \tforming \tan \tamide, \t\nester\tor\tthiol \tbond. \tUDP-glucuronyl \ttransferase, \twhich \t\ncatalyses these reactions, has very broad substrate speci -\nficity\tembracing \tmany \tdrugs \tand \tother \tforeign \tmolecules. \t\nSeveral important endogenous substances, including bili -\nrubin and adrenal corticosteroids, are conjugated by the \nsame pathway.\nAcetylation and methylation reactions occur with acetyl-\nCoA and S-adenosyl methionine, respectively, acting as \nthe donor groups. Many conjugation reactions occur in the \nliver, but other tissues, such as lung and kidney, are also involved.\nSTEREOSELECTIVITY\nMany clinically important drugs, such as sotalol\t(Ch.\t\n22),\twarfarin \t(Ch.\t25) \tand \tcyclophosphamide \t(Ch.\t57), \t\nare mixtures of stereoisomers, the components of which differ not only in their pharmacological effects but also in \ntheir metabolism, which may follow completely distinct \npathways \t(Campo \tet \tal., \t2009). \tSeveral \tclinically \timpor -\ntant\tdrug \tinteractions \tinvolve \tstereospecific \tinhibition \tof \t\nmetabolism \tof \tone \tdrug \tby \tanother \t(see \tTable \t10.6). \tIn \t\nsome cases, drug toxicity is mainly linked to one of the \nstereoisomers, not necessarily the pharmacologically active \none. Where practicable, regulatory authorities urge that dysrhythmias), \twhereas \tBrussels \tsprouts", "start_char_idx": 0, "end_char_idx": 2575, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b7dbfbf1-60ef-4403-8702-d87696596a90": {"__data__": {"id_": "b7dbfbf1-60ef-4403-8702-d87696596a90", "embedding": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9172e4dd-4452-42ed-b90c-f98743565b96", "node_type": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b6b4050333b376908455d592f91a52f17f4eeb100f5d46d983a2b854e82a3e65"}, "2": {"node_id": "446cfb8f-5e51-4a91-ae90-cf40e9380b99", "node_type": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b762ab28bda85c7ac080a4bdee92123bdc6f2d7b3ff88149199c376093db913"}, "3": {"node_id": "d74e4bb9-9e67-4404-92df-840b39c390f1", "node_type": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "395958598b0de388ea0a76ffcd829d770c937ac1b22368d6d95c1a9918f51927"}}, "hash": "6496b5299493be7a81ad2ece5919bb0feba6982c375372b033b9f4ca61f26c52", "text": "\tand \tcigarette \t\nsmoke induce P450 enzymes. Components of the herbal \nmedicine \tS t \tJ ohn\u2019s\tw ort\t( Ch.\t4 8)\ti nduce\tC YP450\ti soenzymes \t\nas\twell\tas \tP-glycoprotein \t(P-gp) \t(see \tCh. \t9). \tDrug \tinteractions \t\nbased on one drug altering the metabolism of another are \ncommon \tand \tclinically \timportant \t(see \tCh. \t12).\nNot all drug oxidation reactions involve the P450 system. \nSome\tdrugs \tare \tmetabolised \tin \tplasma \t(e.g. \thydrolysis \tof \t\nsuxamethonium \tby\tplasma \tcholinesterase; \tCh. \t14), \tlung \t\n(e.g.\tvarious \tprostanoids; \tCh. \t18) \tor \tgut \t(e.g. \ttyramine, \nsalbutamol ;\tChs\t15\tand\t29).\tEthanol\t(Ch.\t50)\tis\tmetabolised \t\nby a soluble cytoplasmic enzyme, alcohol dehydrogenase, \nin\taddition \tto \tCYP2E1. \tOther \tP450-independent \tenzymes \t\ninvolved in drug oxidation include xanthine oxidase, \nwhich inactivates 6-mercaptopurine \t(Ch.\t57), \tand \tmono -\namine oxidase, which inactivates many biologically active \namines\t(e.g. \tnoradrenaline [norepinephrine], tyramine, \n5-hydroxytryptamine; \tChs \t15 \tand \t16).\nHYDROLYTIC REACTIONS\nHydrolysis \t(e.g. \tof \taspirin;\tsee\tFig. \t10.1) \toccurs \tin \tplasma \t\nand\tin\tmany \ttissues. \tBoth \tester \tand \t(less \treadily) \tamide \t\nbonds are susceptible to hydrolytic cleavage. Reduction is less common in phase 1 metabolism than oxidation, but H2O\nH+O2\nH+,e\u2013e\u2013Product (DOH) Drug (DH)\nFe3+\nP450Fe3+\nDH\nFe2+\nDH\nDHFe2+O2 Fe2+OOH\nDH(FeO)3+\nDHFe3+\nDOH\nNADPH\u2013P450 reductase\nCytochrome b5\nFig. 10.2 The monooxygenase P450 cycle. Each of the pink \nor blue rectangles represents one single molecule of cytochrome \nP450 (P450) undergoing a catalytic cycle. Iron in P450 is in \neither the ferric (pink rectangles) or ferrous (blue rectangles) \nstate. P450 containing ferric iron (Fe3+) combines with a \nmolecule of drug (\u2018DH\u2019), and receives an electron from NADPH\u2013P450 reductase, which reduces the iron to Fe\n2+. This combines \nwith molecular oxygen, a proton and a second electron (either from NADPH\u2013P450 reductase or from cytochrome b\n5) to form \nan Fe2+OOH\u2013DH complex. This combines with another proton to \nyield water and a ferric oxene (FeO)3+\u2013DH complex. (FeO)3+ \nextracts a hydrogen atom from DH, with the formation of a pair of short-lived free radicals (see text), liberation from the complex of oxidised drug (\u2018DOH\u2019), and regeneration of P450 enzyme. Glucuronide\nDrug-\u03b2-glucuronide conjugateUDP-glucuronyl transferase Glucuronyl transferUDP-\u03b1-glucuronide\nDrug\nFig. 10.3 The glucuronide conjugation reaction. A \nglucuronyl group is transferred from uridine diphosphate glucuronic acid (UDPGA) to a drug molecule. mebooksfree.net mebooksfree.net", "start_char_idx": 2576, "end_char_idx": 5176, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d74e4bb9-9e67-4404-92df-840b39c390f1": {"__data__": {"id_": "d74e4bb9-9e67-4404-92df-840b39c390f1", "embedding": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9172e4dd-4452-42ed-b90c-f98743565b96", "node_type": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b6b4050333b376908455d592f91a52f17f4eeb100f5d46d983a2b854e82a3e65"}, "2": {"node_id": "b7dbfbf1-60ef-4403-8702-d87696596a90", "node_type": null, "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6496b5299493be7a81ad2ece5919bb0feba6982c375372b033b9f4ca61f26c52"}}, "hash": "395958598b0de388ea0a76ffcd829d770c937ac1b22368d6d95c1a9918f51927", "text": "drug molecule. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5130, "end_char_idx": 5624, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b2fa92ac-48e0-4b49-a331-413bc0897440": {"__data__": {"id_": "b2fa92ac-48e0-4b49-a331-413bc0897440", "embedding": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "05c7d225-9d45-4c17-b29c-5ac8c09d4c0d", "node_type": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f57af12a7647b4bfc4560f0ba83c956e40a1c8ee766e3e07208622b101753774"}, "3": {"node_id": "601c4ce1-c194-4936-a449-f85cefb4b761", "node_type": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e2492ab4f946b0b7e2c1ca518704448f4a639f1be0dedc5591325192e1244be"}}, "hash": "025ec46c97df7ff1153f26ee8db562729a1c3ecb1459e703909b74a342eb315b", "text": "10 SECTION 1 GENERAL PRINCIPLES\n136rate of benzpyrene metabolism 2 days after a single dose. \nThe effect is referred to as induction, and is the result of \nincreased \tsynthesis \tand/or \treduced \tbreakdown \tof \tmicro -\nsomal\tenzymes \t(Pelkonen \tet \tal., \t2008).\nEnzyme induction can increase drug toxicity and carci -\nnogenicity, because several phase 1 metabolites are toxic \nor carcinogenic: paracetamol is an important example of \na\tdrug\twith\ta\thighly\ttoxic\tmetabolite \t(see\tCh.\t58).\tEnzyme\t\ninduction is exploited therapeutically by administering \nphenobarbital to premature babies to induce glucuronyl -\ntransferase, thereby increasing bilirubin conjugation and \nreducing \tthe\trisk\tof\tkernicterus \t(staining \tand\tneurological \t\ndamage\tof \tthe \tbasal \tganglia \tby \tbilirubin, \tCh. \t9).\n\u25bc The mechanism of induction is incompletely understood but is \nsimilar to that involved in the action of steroid and other hormones \nthat\tbind\tto\tnuclear\treceptors \t(see\tCh.\t3).\tThe\tmost\tthoroughly \tstudied\t\ninducing \tagents \tare \tpolycyclic \taromatic \thydrocarbons \t(e.g. \t3-MC). \t\nThese bind to the ligand-binding domain of a soluble protein, termed \nthe\ta romatic \th ydrocarbon \t( Ah)\tr eceptor.\tT his\tc omplex\ti s\tt ransported \t\nto the nucleus by an Ah receptor nuclear translocator and binds Ah \nreceptor response elements in the DNA, thereby promoting transcrip -\ntion of the gene CYP1A1 . In addition to enhanced transcription, some \ninducing \tagents \t(e.g. \tethanol, \twhich \tinduces \tCYP2E1 \tin \thumans) \t\nalso stabilise mRNA or P450 protein.\nPRESYSTEMIC (\u2018FIRST-PASS\u2019) METABOLISM\nSome\tdrugs \tare \textracted \tso \tefficiently \tby \tthe \tliver \tor \tgut \t\nwall that the amount reaching the systemic circulation is \nconsiderably less than the amount absorbed. This is known \nas\tpresystemic \t(or \tfirst-pass) \tmetabolism \tand \treduces \t\nbioavailability \t(Ch.\t9),\teven\t when\t a\t drug\t is \t well\t absorbed. \t\nPresystemic metabolism is important for many therapeutic \ndrugs\t(Table\t10.2\tshows\tsome\texamples), \tand\tis\ta\tproblem\t\nbecause:\n\u2022\tA\tmuch \tlarger \tdose \tof \tthe \tdrug \tis \tneeded \twhen \tit \tis \t\ntaken by mouth than when it is given parenterally.\n\u2022\tMarked \tindividual \tvariations \toccur \tin \tthe \textent \t \nof\tfirst-pass \tmetabolism, \tboth \tin \tthe \tactivities \tof \t\ndrug-metabolising enzymes and also as a result of \nvariations \tin \thepatic \tor \tintestinal \tblood \tflow. \tHepatic \t\nblood\tflow \tcan \tbe \treduced \tin \tdisease \t(e.g. \theart \t\nfailure)\tor \tby \tdrugs, \tsuch \tas \t\u03b2-adrenoceptor \nantagonists, which impair the clearance of unrelated \ndrugs, such as lidocaine, that are subject to \npresystemic metabolism due to a high hepatic \nextraction \tratio. \tIntestinal \tblood \tflow \tis \tstrongly \t\ninfluenced \tby \teating \tand \tstudies \ton \tthe \t\npharmacokinetic", "start_char_idx": 0, "end_char_idx": 2760, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "601c4ce1-c194-4936-a449-f85cefb4b761": {"__data__": {"id_": "601c4ce1-c194-4936-a449-f85cefb4b761", "embedding": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "05c7d225-9d45-4c17-b29c-5ac8c09d4c0d", "node_type": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f57af12a7647b4bfc4560f0ba83c956e40a1c8ee766e3e07208622b101753774"}, "2": {"node_id": "b2fa92ac-48e0-4b49-a331-413bc0897440", "node_type": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "025ec46c97df7ff1153f26ee8db562729a1c3ecb1459e703909b74a342eb315b"}, "3": {"node_id": "3c4eac3e-29dd-4e59-85b9-598437522fac", "node_type": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5b8b20fe4ef89e5bcf653d2bd46041737cd5fb7c968dac93c16fe60ec81c6202"}}, "hash": "4e2492ab4f946b0b7e2c1ca518704448f4a639f1be0dedc5591325192e1244be", "text": "effects of food are routine in the development of orally administered drugs.new drugs should consist of single isomers to lessen these complications.\n1\nINHIBITION OF P450\nInhibitors of P450 differ in their selectivity towards different \nisoforms \tof\tthe\tenzyme,\tand\tare\tclassified \tby\ttheir\tmecha -\nnism of action. Some drugs compete for the active site but \nare\tnot\tthemselves \tsubstrates \t(e.g. \tquinidine is a potent \ncompetitive \tinhibitor \tof \tCYP2D6 \tbut \tis \tnot \ta \tsubstrate \tfor \t\nit).\tNon-competitive \tinhibitors \tinclude \tdrugs \tsuch \tas \t\nketoconazole ,\twhich\tforms \ta \ttight \tcomplex \twith \tthe \tFe3+ \nform\tof\tthe\thaem\tiron\tof\tCYP3A4, \tcausing\treversible \tnon-\ncompetitive inhibition. So-called mechanism-based inhibitors require oxidation by a P450 enzyme. Examples include the \noral contraceptive gestodene\n\t(CYP3A4) \tand\tthe\tanthelmintic \t\ndrug diethylcarbamazine \t(CYP2E1). \tAn\toxidation \tproduct\t\n(e.g.\ta\tpostulated \tepoxide\tintermediate \tof\tgestodene) \tbinds\t\ncovalently \tto\tthe\tenzyme,\twhich\tthen\tdestroys\titself\t(\u2018suicide\t\ninhibition\u2019; \tsee \tPelkonen \tet \tal., \t2008).\nINDUCTION OF MICROSOMAL ENZYMES\nA number of drugs, such as rifampicin \t(Ch.\t52), \tethanol \n(Ch.\t50)\tand \tcarbamazepine \t(Ch.\t46), \tincrease \tthe \tactivity \t\nof microsomal oxidase and conjugating systems when \nadministered \trepeatedly. \tMany\tcarcinogenic \tchemicals \t(e.g.\t\nbenzpyrene, \t3-MC) \talso \thave \tthis \teffect, \twhich \tcan \tbe \t\nsubstantial; \tFig.\t10.4\tshows\ta\tnearly\t10-fold\tincrease\tin\tthe\t\nBenzpyrene administered4 \u00b5mol dose\n0.4 \u00b5mol dose\nControl (zero dose)10\n8\n642\n00Rate of benzpyrene metabolism relative \nto control\nDays123 46 5\nFig. 10.4 Stimulation of hepatic metabolism of \nbenzpyrene. Young rats were given benzpyrene \n(intraperitoneally) in the doses shown, and the benzpyrene-metabolising activity of liver homogenates was measured at \ntimes up to 6 days. (From Conney, A.H. et al., 1957. J. Biol. \nChem. 228, 753.)\n1Well-intentioned \t\u2013 \tthough \tthe \tusefulness \tof \texpensive \t\u2018novel\u2019 \tentities \t\nthat are actually just the pure active isomer of well-established and safe \nracemates has been questioned, and enzymic interconversion of \nstereoisomers may subvert such chemical sophistication.Table 10.2 Examples of drugs that undergo substantial \npre-systemic (\u201cfirst-pass\u201d) elimination\nAspirin\nGlyceryl trinitrate\nIsosorbide dinitrate\nLevodopa\nLidocaineMetoprololMorphinePropranololSalbutamolVerapamilmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2761, "end_char_idx": 5561, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3c4eac3e-29dd-4e59-85b9-598437522fac": {"__data__": {"id_": "3c4eac3e-29dd-4e59-85b9-598437522fac", "embedding": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "05c7d225-9d45-4c17-b29c-5ac8c09d4c0d", "node_type": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f57af12a7647b4bfc4560f0ba83c956e40a1c8ee766e3e07208622b101753774"}, "2": {"node_id": "601c4ce1-c194-4936-a449-f85cefb4b761", "node_type": null, "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e2492ab4f946b0b7e2c1ca518704448f4a639f1be0dedc5591325192e1244be"}}, "hash": "5b8b20fe4ef89e5bcf653d2bd46041737cd5fb7c968dac93c16fe60ec81c6202", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5514, "end_char_idx": 5657, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ca0fa20d-90fd-45a4-929f-ca1d5a52bc6d": {"__data__": {"id_": "ca0fa20d-90fd-45a4-929f-ca1d5a52bc6d", "embedding": null, "metadata": {"page_label": "143", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4e478a52-8834-4568-baad-42bbcecb007b", "node_type": null, "metadata": {"page_label": "143", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "235e3e6413739ea0ff9ecbcfd9a2cff7d2edfa41b6e46c41b0378636e25cc7f2"}, "3": {"node_id": "a9c49ad1-2db4-451f-9c81-fd8b1242a47c", "node_type": null, "metadata": {"page_label": "143", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "944e9250f95100aa49115cac18b58353a0a4cd363c6e038753ebd08ab162267e"}}, "hash": "80541984296d6b019c1fc48cad956b211d587afff675c4715a18ae6d61982cc9", "text": "10 DRuG mEtAboLISm AND ELI m INA t I o N\n137contribute to the insidious nature of the clinical problems \nthat induction presents. Adverse clinical outcomes from \nsuch interactions are very diverse, including graft rejection \nas a result of loss of effectiveness of immunosuppressive treatment, seizures due to loss of anticonvulsant effective -\nness, unwanted pregnancy from loss of oral contraceptive \naction\tand\tthrombosis \t(from\tloss\tof\teffectiveness \tof\twarfarin) \t\nor\tbleeding \t(from \tfailure \tto \trecognise \tthe \tneed \tto \treduce \t\nwarfarin dose when induction wanes after an inducing \nagent\tis\tdiscontinued). \tOver \t200 \tdrugs \tcause \tenzyme \t\ninduction and thereby decrease the pharmacological activity PHARMACOLOGICALLY ACTIVE \nDRUG METABOLITES\nIn\tsome\tcases \t(Table \t10.3) \ta \tdrug \tbecomes \tpharmaco -\nlogically \tactive \tonly \tafter \tit \thas \tbeen \tmetabolised. \tFor \t\nexample, azathioprine ,\tan\timmunosuppressant \tdrug \t(Ch. \t\n27),\tis\tmetabolised \tto \tmercaptopurine; and enalapril, an \nangiotensin-converting \tenzyme \tinhibitor \t(Ch. \t23), \tis \t\nhydrolysed to its active form enalaprilat. Such drugs, \nin which the parent compound lacks activity of its own, \nare known as prodrugs. These are sometimes designed \ndeliberately \tto \tovercome \tproblems \tof \tdrug \tdelivery \t(Ch. \t\n9).\tMetabolism \tcan \talter \tthe \tpharmacological \tactions \tof \ta \t\ndrug qualitatively. Aspirin inhibits platelet function and has \nanti-inflammatory \tactivity\t(Chs\t25\tand\t27).\tIt\tis\thydrolysed \t\nto\tsalicylic\tacid\t(see\tFig.\t10.1),\twhich\thas\tanti-inflammatory \t\nbut not antiplatelet activity. In other instances, metabolites \nhave pharmacological actions similar to those of the parent \ncompound \t(e.g. \tbenzodiazepines, \tmany \tof \twhich \tform \t\nlong-lived active metabolites that cause sedation to persist \nafter\tthe\tparent \tdrug \thas \tdisappeared; \tCh. \t45). \tThere \tare \t\nalso cases in which metabolites are responsible for toxicity. Bladder toxicity of cyclophosphamide, which is caused \nby\tits\ttoxic \tmetabolite \tacrolein \t(Ch. \t57), \tis \tan \texample. \t\nMethanol and ethylene glycol both exert their toxic effects via metabolites formed by alcohol dehydrogenase. Poisoning \nwith\tthese \tagents \tis \ttreated \twith \tethanol \t(or \twith \ta \tmore \t\npotent\tinhibitor), \twhich \tcompetes \tfor \tthe \tactive \tsite \tof \t \nthe enzyme.\nDRUG INTERACTIONS DUE TO ENZYME \nINDUCTION OR INHIBITION\nINTERACTIONS CAUSED BY ENZYME INDUCTION\nEnzyme induction is an important cause of drug interaction. \nThe slow onset of induction and slow recovery after \nwithdrawal of the inducing agent, together with the potential \nfor\tselective \tinduction \tof \tone \tor \tmore \tCYP \tisoenzymes, \t\nTable 10.3 Some drugs that produce active or toxic metabolites\nInactive (prodrugs) Active drug Active metabolite Toxic metaboliteSee \nChapter\nAzathioprine Mercaptopurine 27\nCortisone Hydrocortison e3 4\nPrednisone", "start_char_idx": 0, "end_char_idx": 2869, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a9c49ad1-2db4-451f-9c81-fd8b1242a47c": {"__data__": {"id_": "a9c49ad1-2db4-451f-9c81-fd8b1242a47c", "embedding": null, "metadata": {"page_label": "143", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4e478a52-8834-4568-baad-42bbcecb007b", "node_type": null, "metadata": {"page_label": "143", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "235e3e6413739ea0ff9ecbcfd9a2cff7d2edfa41b6e46c41b0378636e25cc7f2"}, "2": {"node_id": "ca0fa20d-90fd-45a4-929f-ca1d5a52bc6d", "node_type": null, "metadata": {"page_label": "143", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80541984296d6b019c1fc48cad956b211d587afff675c4715a18ae6d61982cc9"}}, "hash": "944e9250f95100aa49115cac18b58353a0a4cd363c6e038753ebd08ab162267e", "text": "Prednisolone 34\nEnalapril Enalaprilat 23\nZidovudine Zidovudine trisphosphat e5 3\nCyclophosphamide Phosphoramide mustard Acrolein 57\nDiazepam Oxazepam 45\nMorphine Morphine 6-glucuronide 43\nHalothane Tri\ufb02uoroacetic aci d4 2\nMethoxy\ufb02urane Fluoride 42\nParacetamol N-Acetyl-p- benzoquinone\nimine27, 58Drug metabolism \n\u2022\tPhase\t1 \treactions \tinvolve \toxidation, \treduction \tand \t\nhydrolysis. They:\n\u2013 usually form more chemically reactive products, \nwhich can be pharmacologically active, toxic or \ncarcinogenic.\n\u2013 often involve a monooxygenase system in which \ncytochrome P450 plays a key role.\n\u2022\tPhase\t2 \treactions \tinvolve \tconjugation \t(e.g. \t\nglucuronidation) of a reactive group (often inserted \nduring phase 1 reaction) and usually lead to inactive and polar products that are readily excreted in urine.\n\u2022\tSome\tconjugated \tproducts \tare \texcreted \tvia \tbile, \tare \t\nreactivated in the intestine and then reabsorbed (\u2018enterohepatic circulation\u2019).\n\u2022\tInduction \tof \tP450 \tenzymes \tcan \tgreatly \taccelerate \t\nhepatic drug metabolism. It can increase the toxicity of drugs with toxic metabolites, and is an important cause of drug\u2013drug interaction, as is enzyme inhibition.\n\u2022\tPresystemic \tmetabolism \tin \tliver \tor \tgut \twall \treduces \tthe \t\nbioavailability of several drugs when they are administered by mouth.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2870, "end_char_idx": 4654, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a174fdab-7b6b-4a26-b9f1-eeab34a4968b": {"__data__": {"id_": "a174fdab-7b6b-4a26-b9f1-eeab34a4968b", "embedding": null, "metadata": {"page_label": "144", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "23124eee-36a5-464f-af92-2b8219e75626", "node_type": null, "metadata": {"page_label": "144", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3eed1566a0711f4f30bc5fbce9703a26f209dcda6f857a4e1c8fff9229ff8f1b"}, "3": {"node_id": "da34b2a8-381b-4247-bb9e-3192f0761d2d", "node_type": null, "metadata": {"page_label": "144", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ebb78e11dbf9bc95263d0ccbe38c91cc85361c07439bb09e134a444fad2f9c7"}}, "hash": "6d8e6302f3877040c9a371604ed0ede45d43e542008b9b83d1f0076eecc26018", "text": "10 SECTION 1 GENERAL PRINCIPLES\n138of a range of other drugs. Some examples are given in \nTable 10.4, and further examples are given at the Indiana \nUniversity \tDepartment \tof\tMedicine \twebsite\tcited\tpreviously \t\n(p.\t134).\tBecause\tthe\tinducing \tagent\tis\toften\titself\ta\tsubstrate \t\nfor the induced enzymes, the process can result in slowly developing tolerance. This pharmacokinetic kind of tolerance \nis generally less marked than pharmacodynamic tolerance, \nfor\texample, \tto\topioids\t(Ch.\t43),\tbut\tit\tis\tclinically \timportant \t\nwhen starting treatment with the antiepileptic drug carba -\nmazepine \t(Ch.\t46).\tTreatment \tstarts\tat\ta\tlow\tdose\tto\tavoid\t\ntoxicity\t(because \tliver \tenzymes \tare \tnot \tinduced \tinitially) \t\nand is gradually increased over a period of a few weeks, \nduring which it induces its own metabolism.\nFig.\t10.5\tshows \thow \tthe \tantibiotic \trifampicin, given for \n3\tdays,\treduces \tthe \teffectiveness \tof \twarfarin as an antico -\nagulant. Conversely, enzyme induction can increase toxicity \nof a second drug if the toxic effects are mediated via an \nactive metabolite. Paracetamol \t(acetaminophen )\ttoxicity \t\nis\ta\tcase\tin \tpoint \t(see \tFig. \t58.1): \tthis \tis \tcaused \tby \tits \tCYP \t\nmetabolite N-acetyl-p- benzoquinone \timine \t(NAPQI). \t\nConsequently, the risk of serious hepatic injury following paracetamol overdose is increased in patients in whom \nCYP\thas \tbeen \tinduced, \tfor \texample, \tby \tchronic \talcohol \t\nconsumption.\nINTERACTIONS CAUSED BY ENZYME INHIBITION\nAs with induction, interactions caused by enzyme inhi -\nbition\tare \thard \tto \tanticipate \tfrom \tfirst \tprinciples. \tIf \tin \t\ndoubt about the possibility of an interaction, it is best to \nlook\tit\tup \t(e.g. \tin \tthe \tBritish National Formulary, which \nhas an invaluable appendix on drug interactions indicat -\ning\twhich \tare \tof \tknown \tclinical \timportance) \tor \tat \tthe \t\nIndiana\tUniversity \tDepartment \tof \tMedicine \twebsite \tcited \t \npreviously \t(p. \t134).\nEnzyme\tinhibition, \tparticularly \tof \tCYP \tenzymes, \tslows \t\nthe metabolism and hence increases the action of other drugs inactivated by the enzyme. Such effects can be \nclinically important and are major considerations in the \ntreatment \to f \tp atients \tw ith\tH IV\ti nfection \twi th\tc ombination \t\ntherapy,\t because\t several \t protease\t inhibitors \t are \tpot ent \tCYP\t\ninhibitors \t(Ch . \t 53). \tOth er \t examples \t of\t drugs \t that \t are \t enzyme\t\ninhibitors are shown in Table 10.5. To make life even more \ndifficult, \tseveral \tinhibitors \tof \tdrug \tmetabolism \tinfluence \t\nthe metabolism of different stereoisomers selectively. \nExamples of drugs that inhibit the metabolism of the active \n(S)\tand\tless \tactive \t(R)\tisomers \tof \twarfarin \tin \tthis \tway \tare \t\nshown in Table 10.6.\nTable 10.4 Examples of drugs that induce drug-\nmetabolising enzymes\nExamples of drugs with\nmetabolism affectedDrugs", "start_char_idx": 0, "end_char_idx": 2848, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "da34b2a8-381b-4247-bb9e-3192f0761d2d": {"__data__": {"id_": "da34b2a8-381b-4247-bb9e-3192f0761d2d", "embedding": null, "metadata": {"page_label": "144", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "23124eee-36a5-464f-af92-2b8219e75626", "node_type": null, "metadata": {"page_label": "144", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3eed1566a0711f4f30bc5fbce9703a26f209dcda6f857a4e1c8fff9229ff8f1b"}, "2": {"node_id": "a174fdab-7b6b-4a26-b9f1-eeab34a4968b", "node_type": null, "metadata": {"page_label": "144", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6d8e6302f3877040c9a371604ed0ede45d43e542008b9b83d1f0076eecc26018"}}, "hash": "1ebb78e11dbf9bc95263d0ccbe38c91cc85361c07439bb09e134a444fad2f9c7", "text": "inducing\nenzyme action\nPhenobarbital Warfarin\nRifampici nO ral contraceptives\nGriseofulvin Corticosteroids\nPhenytoin Ciclosporin\nDrugs listed in left-hand column\nwill also be affectedEthanol\nCarbamazepine20\n1436103060\n123040\n10 8 6 4 2 0Plasma warfarin concentration ( \u00b5mol/L) Prothrombin time (s)\nDaysNormal\nranget0.5 < 1 day\nt0.5 = approx 2 daysA\nB\nFig. 10.5 Effect of rifampicin on the metabolism and \nanticoagulant action of warfarin. (A) Plasma concentration of \nwarfarin (log scale) as a function of time following a single oral \ndose of 5 \u00b5moL/kg\tbody \tweight. \tAfter \tthe \tsubject \twas \tgiven \t\nrifampicin (600 mg daily for a few days), the plasma half-life of \nwarfarin decreased from approximately 2 days to <1 day. \n(B) The effect of a single dose of warfarin on prothrombin time \nunder normal conditions (red curve) and after rifampicin \nadministration (green curve) . (Redrawn from O\u2019 Reilly, R.A. 1974. \nAnn. Intern. Med. 81, 337.)\nTable 10.5 Examples of drugs that inhibit drug-\nmetabolising enzymes\nDrugs inhibiting enzyme \nactionDrugs with metabolism affected\nAllopurinol Mercaptopurine, azathioprine\nChloramphenicol Phenytoin\nCimetidine Amiodarone, phenytoin, \npethidine\nCiprofloxacin Theophylline\nCorticosteroids Tricyclic antidepressants, cyclophosphamide\nDisulfiram Warfarin\nErythromycin Ciclosporin, theophylline\nMonoamine oxidase inhibitors Pethidine\nRitonavir Saquinavirmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2849, "end_char_idx": 4729, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f9eb6eee-bc3e-44e5-a61b-718ae430eae1": {"__data__": {"id_": "f9eb6eee-bc3e-44e5-a61b-718ae430eae1", "embedding": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd8a1d5f-b7e7-4da6-af6d-889c7a6d0f8a", "node_type": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "56258b4d39075c8fb2bb2d1da48f23c2f513200d5dbc442f379f7b51423ce637"}, "3": {"node_id": "92653808-ff9e-4ee3-821c-7363e5e24792", "node_type": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "adcd0ba3b05ee33e6c147e2312a44c1883d8c0d7ec6a1b036e84b05dd25b1aa2"}}, "hash": "7ba33c836987ea246bb9e8d9d7529bbb9045374b6f203020c8230471ad59db11", "text": "10 DRuG mEtAboLISm AND ELI m INA t I o N\n139then be reabsorbed and the cycle repeated, a process referred \nto as enterohepatic circulation .\tThe\tresult \tis \ta \t\u2018reservoir\u2019 \tof \t\nrecirculating \tdrug \tthat \tcan \tamount \tto \tabout \t20% \tof \ttotal \t\ndrug in the body, prolonging drug action. Examples where this is important include morphine\n\t(Ch.\t43) \tand \t\nethinylestradiol \t(Ch.\t36).\tSeveral\tdrugs\tare\texcreted\tto\tan\t\nappreciable extent in bile. Vecuronium \t(a\tnon-depolarising \t\nmuscle\trelaxant; \tCh. \t14) \tis \tan \texample \tof \ta \tdrug \tthat \tis \t\nexcreted mainly unchanged in bile. Rifampicin \t(Ch.\t52)\tis\t\nabsorbed from the gut and slowly deacetylated, retaining its biological activity. Both forms are secreted in the bile, \nbut the deacetylated form is not reabsorbed, so eventually \nmost of the drug leaves the body in this form in the faeces.\nRENAL EXCRETION OF DRUGS AND \nMETABOLITES\nRENAL CLEARANCE\nElimination \tof \tdrugs \tby \tthe \tkidneys \tis \tbest \tquantified \tby \t\nthe\trenal \tclearance \t(CL ren,\tsee\tChs \t11, \t30). \tThis \tis \tdefined \t\nas the volume of plasma containing the amount of substance \nthat is removed from the body by the kidneys in unit time. \nIt is calculated from the plasma concentration, Cp, the urinary \nconcentration, Cu,\tand\tthe \trate \tof \tflow \tof \turine, \tVu, by the \nequation:\nCL CV C renu up =\u00d7() .\nCL ren\tvaries\tgreatly\tfor\tdifferent\tdrugs,\tfrom\tless\tthan\t1\tmL/\nmin to the theoretical maximum set by the renal plasma \nflow,\twhich \tis \tapproximately \t700 \tmL/min, \tmeasured \tby \t\np-aminohippuric \tacid\t(PAH)\tclearance \t(renal\textraction \tof\t\nPAH\tapproaches \t100%).\nDrugs differ greatly in the rate at which they are excreted \nby the kidney, ranging from penicillin \t(Ch.\t52), \twhich \tis \t\n(like\tPAH) \tcleared \tfrom \tthe \tblood \talmost \tcompletely \ton \t\na single transit through the kidney, to amiodarone \t(Ch.\t\n22)\tand\trisedronate \t(Ch.\t37), \twhich \tare \tcleared \textremely \t\nslowly. Most drugs fall between these extremes. Three \nfundamental processes account for renal drug excretion:\n1.\tglomerular \tfiltration\n2. active tubular secretion\n3.\tpassive \treabsorption \t(diffusion \tfrom \tthe \tconcentrated \t\ntubular\tfluid \tback \tacross \ttubular \tepithelium)\nGLOMERULAR FILTRATION\nGlomerular capillaries allow drug molecules of molecular \nweight below about 20 kDa to pass into the glomerular \nfiltrate.\tPlasma\talbumin\t(molecular \tweight\tapproximately \t\n68\tk Da)\ti s \ta lmost\tc ompletely \ti mpermeant, \tb ut\tm ost \td rugs\t\n\u2013\twith\tthe \texception \tof \tmacromolecules \tsuch \tas \theparin \n(Ch.\t25)\tor \tbiopharmaceuticals \t(Ch. \t5) \t\u2013 \tcross", "start_char_idx": 0, "end_char_idx": 2568, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "92653808-ff9e-4ee3-821c-7363e5e24792": {"__data__": {"id_": "92653808-ff9e-4ee3-821c-7363e5e24792", "embedding": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd8a1d5f-b7e7-4da6-af6d-889c7a6d0f8a", "node_type": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "56258b4d39075c8fb2bb2d1da48f23c2f513200d5dbc442f379f7b51423ce637"}, "2": {"node_id": "f9eb6eee-bc3e-44e5-a61b-718ae430eae1", "node_type": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ba33c836987ea246bb9e8d9d7529bbb9045374b6f203020c8230471ad59db11"}, "3": {"node_id": "bde34af4-4420-4352-9f39-da6f4c16b4aa", "node_type": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dc58670ab2d0fefa761268fb2030d8786c10b57857cd6de7736ac4702928df6b"}}, "hash": "adcd0ba3b05ee33e6c147e2312a44c1883d8c0d7ec6a1b036e84b05dd25b1aa2", "text": "\tthe \tbarrier \t\nfreely. If a drug binds to plasma albumin, only free drug \nis\tfiltered.\tIf,\tlike\twarfarin \t(Ch.\t25),\ta\tdrug\tis\tapproximately \t\n98%\tbound \tto \talbumin, \tthe \tconcentration \tin \tthe \tfiltrate \tis \t\nonly\t2%\tof \tthat \tin \tplasma, \tand \tclearance \tby \tfiltration \tis \t\ncorrespondingly reduced.\nTUBULAR SECRETION\nUp\tto\t20% \tof \trenal \tplasma \tflow \tis \tfiltered \tthrough \tthe \t\nglomerulus, \tleaving\tat\tleast\t80%\tof\tdelivered \tdrug\tto\tpass\t\non to the peritubular capillaries of the proximal tubule. \nHere,\tdrug\tmolecules \tare\ttransferred \tto\tthe\ttubular\tlumen\t\nby two independent and relatively non-selective carrier The therapeutic effects of some drugs are a direct con -\nsequence \tof \tenzyme \tinhibition \t(e.g. \tthe \txanthine \toxidase \t\ninhibitor allopurinol ,\tused\tto\tprevent\tgout;\tCh.\t27).\tXanthine \t\noxidase metabolises several cytotoxic and immunosuppres -\nsant drugs, including mercaptopurine \t(the\tactive\tmetabolite \t\nof azathioprine ),\tthe\taction \tof \twhich \tis \tthus \tpotentiated \t\nand prolonged by allopurinol. Disulfiram, an inhibitor of \naldehyde dehydrogenase that is used to produce an aversive \nreaction\tto \tethanol \t(see \tCh. \t50), \talso \tinhibits \tmetabolism \t\nof other drugs, including warfarin, which it potentiates. \nMetronidazole, an antimicrobial used to treat anaerobic \nbacterial \tinfections \tand\tseveral\tprotozoal \tdiseases\t(Chs\t52\t\nand\t55),\talso\tinhibits\tthis\tenzyme,\tand\tpatients\tprescribed \t\nit are advised to avoid alcohol for this reason.\nThere are also examples of drugs that inhibit the metabo -\nlism of other drugs, even though enzyme inhibition is not the main mechanism of action of the offending agents. Thus, glucocorticosteroids and cimetidine potentiate a range of \ndrugs, including some antidepressant and cytotoxic drugs.\nInhibition of the conversion of a prodrug to its active \nmetabolite can result in loss of activity. Proton pump inhibi -\ntors\t(such \tas \tomeprazole ,\tCh.\t31)\tand \tthe \tantiplatelet \tdrug\t\nclopidogrel \t(Ch.\t25)\thave\tbeen\twidely\tco-prescribed, \tbecause\t\nclopidogrel is often used with other antithrombotic drugs pre -\ndisposing \tto\tbleeding\tfrom\tthe\tstomach\t\u2013\tomeprazole \treduces\t\ngastric\tacid\tsecretion\tand\tthe\trisk\tof\tgastric\thaemorrhage \t(Ch.\t\n31).\tClopidogrel \tworks\tthrough\tan\tactive\tmetabolite \tformed\t\nby\tCYP2C19 \twhich \tis \tinhibited \tby \tomeprazole, \tpossibly\t\nthereby reducing the antiplatelet effect. It is unclear how \nclinically \timportant \tthis \tmay \tbe, \tbut \tthe \tFDA \tcontinues \tto\t\nwarn against concomitant use of these drugs for this reason.\nDRUG AND METABOLITE EXCRETION\nBILIARY EXCRETION AND ENTEROHEPATIC \nCIRCULATION\nLiver\tcells \ttransfer \tvarious \tsubstances, \tincluding \tdrugs, \t\nfrom plasma to bile by transport systems similar to those \nof", "start_char_idx": 2569, "end_char_idx": 5307, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bde34af4-4420-4352-9f39-da6f4c16b4aa": {"__data__": {"id_": "bde34af4-4420-4352-9f39-da6f4c16b4aa", "embedding": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd8a1d5f-b7e7-4da6-af6d-889c7a6d0f8a", "node_type": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "56258b4d39075c8fb2bb2d1da48f23c2f513200d5dbc442f379f7b51423ce637"}, "2": {"node_id": "92653808-ff9e-4ee3-821c-7363e5e24792", "node_type": null, "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "adcd0ba3b05ee33e6c147e2312a44c1883d8c0d7ec6a1b036e84b05dd25b1aa2"}}, "hash": "dc58670ab2d0fefa761268fb2030d8786c10b57857cd6de7736ac4702928df6b", "text": "the renal tubule; these include organic cation trans -\nporters\t(OCTs), \torganic \tanion \ttransporters \t(OATs) \tand \t\nP-glycoproteins \t(P-gps) \t(see \tCh. \t9). \tVarious \thydrophilic \t\ndrug\tconjugates \t(particularly \tglucuronides) \tare\tconcentrated \t\nin bile and delivered to the intestine, where the glucuronide can be hydrolysed, regenerating active drug; free drug can Table 10.6 Stereoselective and non-stereoselective \ninhibition of warfarin metabolism\nInhibition of metabolism Drug(s)\nStereoselective for (S) isomer Phenylbutazone\nMetronidazoleSulfinpyrazoneTrimethoprim\u2013\nsulfamethoxazole\nDisulfiram\nStereoselective for (R) isomer Cimetidine\na\nOmeprazolea\nNon-stereoselective effect on both isomersAmiodarone\naMinor effect only on prothrombin time.\n(From Hirsh, J., 1991. N. Engl. J. Med. 324, 1865\u20131875.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5308, "end_char_idx": 6595, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "914b724b-a57c-437c-b031-29ea9e7c103e": {"__data__": {"id_": "914b724b-a57c-437c-b031-29ea9e7c103e", "embedding": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "48be290e-5b34-4eac-b488-ba8f4d5264ef", "node_type": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9868414a5421ecc8532df3b51adc1a0f3734ac7104b3df3de55b6317761b408b"}, "3": {"node_id": "b2c16b7c-14fb-4ecf-9d73-b4e50857569b", "node_type": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "665d1cf002aaf1fab440cd8ab06978b1ec3af0d09ff43839202ece3cf36f99f9"}}, "hash": "789d53b54ee911df72a403aad4dd74c3b6e153b6079f89e62badf7f1aeb99634", "text": "10 SECTION 1 GENERAL PRINCIPLES\n140permeability remain in the lumen and become progressively \nconcentrated as water is reabsorbed. Polar drugs handled \nin this way include digoxin and aminoglycoside antibiotics. \nThese exemplify a relatively small but important group of \ndrugs\t(Table \t10.8) \tthat \tare \tnot \tinactivated \tby \tmetabolism, \t\nthe rate of renal elimination being the main factor that \ndetermines their duration of action. These drugs have to \nbe used with special care in individuals whose renal function \nmay be impaired, including the elderly and patients with renal disease or any severe acute illness.\nThe\tdegree \tof \tionisation \tof \tmany \tdrugs \t\u2013 \tweak \tacids \tor \t\nweak\tbases\t\u2013\tis\tpH-dependent, \tand\tthis\tmarkedly \tinfluences \t\ntheir\trenal \texcretion. \tThe \tion-trapping \teffect \t(see \tCh. \t9) \t\nmeans that a basic drug is more rapidly excreted in an acid urine that favours the charged form and thus inhibits \nreabsorption. Conversely, acidic drugs are most rapidly \nexcreted\tif \tthe \turine \tis \talkaline \t(Fig. \t10.6).\nDRUG INTERACTIONS DUE TO ALTERED \nDRUG EXCRETION\nThe main mechanisms by which one drug can affect the \nrate of renal excretion of another are by:\n\u2022\taltering \tprotein \tbinding, \tand \thence \tfiltration\n\u2022\tinhibiting \ttubular \tsecretion\n\u2022\taltering \turine \tflow \tand/or \turine \tpH\nINHIBITION OF TUBULAR SECRETION\nProbenecid \t(Ch.\t27)\twas \tdeveloped \tto \tinhibit \tsecretion \tof \t\npenicillin and thus prolong its action. It also inhibits the excretion of other drugs, including zidovudine\n\t(see\tCh. \t\n53).\tOther \tdrugs \thave \tan \tincidental \tprobenecid-like \teffect \t\nand can enhance the actions of substances that rely on \ntubular\tsecretion \tfor\ttheir\telimination. \tTable\t10.9\tgives\tsome\t\nexamples. Because diuretics, such as furosemide, act from within the tubular lumen, drugs that inhibit their secretion \ninto\tthe\ttubular \tfluid, \tsuch \tas \tnon-steroidal \tanti-inflammatory \t\ndrugs, reduce their effect.\nALTERATION OF URINE FLOW AND PH\nDiuretics tend to increase the urinary excretion of other drugs and their metabolites, but this is seldom immediately \nclinically important. Conversely, loop and thiazide diuretics \nindirectly decrease the excretion of lithium ; they cause Na\n+ \ndepletion, to which the kidney responds by increased \nproximal tubular reabsorption of Na+,\tand\tLi+, which is \nhandled in a similar way to Na+, and this can cause lithium \ntoxicity in patients treated with lithium carbonate for mood \ndisorders \t(Ch.\t48).\tThe\teffect\tof\turinary\tpH\ton\tthe\texcretion \t\nof weak acids and bases is put to use in the treatment of \npoisoning with salicylate \t(see\tCh. \t27), \tbut \tis \tnot \ta \tcause \tof \t\naccidental interactions.systems\t(see\tCh.\t9).\tOne\tof\tthese,\tthe\tOAT,\ttransports \tacidic\t\ndrugs\tin\ttheir \tnegatively \tcharged \tanionic \tform \t(as \twell \tas \t\nvarious\tendogenous \tacids,\tsuch\tas\turic\tacid),\twhile\tan\tOCT\t\nhandles organic bases in their protonated cationic form. Some important drugs that are transported by these two \ncarrier\tsystems \tare \tshown", "start_char_idx": 0, "end_char_idx": 3014, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b2c16b7c-14fb-4ecf-9d73-b4e50857569b": {"__data__": {"id_": "b2c16b7c-14fb-4ecf-9d73-b4e50857569b", "embedding": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "48be290e-5b34-4eac-b488-ba8f4d5264ef", "node_type": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9868414a5421ecc8532df3b51adc1a0f3734ac7104b3df3de55b6317761b408b"}, "2": {"node_id": "914b724b-a57c-437c-b031-29ea9e7c103e", "node_type": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "789d53b54ee911df72a403aad4dd74c3b6e153b6079f89e62badf7f1aeb99634"}, "3": {"node_id": "148e8707-bd69-417a-b26c-07175052f97a", "node_type": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bb9bc6377e27b7242933f7e2f0277ef907978c8d4321d10664885d75b6bb98ad"}}, "hash": "665d1cf002aaf1fab440cd8ab06978b1ec3af0d09ff43839202ece3cf36f99f9", "text": "two \ncarrier\tsystems \tare \tshown \tin \tTable \t10.7. \tThe \tOAT \tcarrier \t\ncan transport drug molecules against an electrochemical gradient, and can therefore reduce the plasma concentration \nnearly\tto\tzero,\twhereas\tOCT\tfacilitates \ttransport \tdown\tan\t\nelectrochemical \tgradient. \tBecause \tat \tleast \t80% \tof \tthe \tdrug \t\ndelivered to the kidney is presented to the carrier, tubular secretion is potentially the most effective mechanism of \nrenal\tdrug\telimination. \tUnlike\tglomerular \tfiltration, \tcarrier-\nmediated transport can achieve maximal drug clearance even when most of the drug is bound to plasma protein.\n2 \nPenicillin \t(Ch.\t52), \tfor \texample, \talthough \tabout \t80% \t\nprotein-bound \tand\ttherefore \tcleared\tonly\tslowly\tby\tfiltra -\ntion, is almost completely removed by proximal tubular \nsecretion, and is therefore rapidly eliminated.\nMany drugs compete for the same transport systems \n(Table\t10.7), \tleading \tto \tdrug \tinteractions. \tFor \texample, \t\nprobenecid was developed originally to potentiate penicillin \nby\tretarding \tits \ttubular \tsecretion \t(see \tlater).\nDIFFUSION ACROSS THE RENAL TUBULE\nWater\tis\treabsorbed \tas\tfluid\ttraverses \tthe\ttubule,\tthe\tvolume\t\nof\turine\temerging \tbeing \tonly \tabout \t1% \tof \tthat \tof \tthe \t\nglomerular \tfiltrate. \tConsequently, \tif \tthe \ttubule \tis \tfreely \t\npermeable \tto \tdrug \tmolecules, \tsome \t99% \tof \tthe \tfiltered \t\ndrug will be reabsorbed passively down the resulting \nconcentration \tgradient. \tLipid-soluble \tdrugs \tare \ttherefore \t\nexcreted poorly, whereas polar drugs of low tubular Table 10.7 Important drugs and related substances \nsecreted into the proximal renal tubule by OAT or OCT \ntransporters\nOAT OCT\np-Aminohippuric acidFurosemideGlucuronic acid conjugatesGlycine conjugatesIndometacinMethotrexatePenicillinProbenecidSulfate conjugatesThiazide diureticsUric acidAmilorideDopamineHistamineMepacrineMorphinePethidineQuaternary ammonium \ncompounds\nQuinine5-Hydroxytryptamine \n(serotonin)\nTriamtereneTable 10.8 Examples of drugs that are excreted largely \nunchanged in the urine\nPercentage Drugs excreted\n100\u201375 Furosemide, gentamicin, methotrexate, atenolol, digoxin\n75\u201350 Benzylpenicillin, cimetidine, oxytetracycline, neostigmine\n~50 Propantheline, tubocurarine\n2Because\tfiltration \tinvolves \tisosmotic \tmovement \tof \tboth \twater \tand \t\nsolutes, it does not affect the free concentration of drug in the plasma. \nThus the equilibrium between free and bound drug is not disturbed, \nand there is no tendency for bound drug to dissociate as blood \ntraverses the glomerular capillary. The rate of clearance of a drug by \nfiltration \tis \ttherefore \treduced \tdirectly \tin \tproportion \tto \tthe \tfraction \tthat \t\nis bound. In the case of active tubular secretion, this is not so because the carrier transports drug molecules unaccompanied by water. As free \ndrug molecules are taken from the plasma, therefore, the free plasma \nconcentration falls, causing dissociation of bound drug from plasma albumin. Secretion is only retarded slightly, even though the drug is \nmostly\tbound, \tbecause \teffectively \t100%", "start_char_idx": 2986, "end_char_idx": 6053, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "148e8707-bd69-417a-b26c-07175052f97a": {"__data__": {"id_": "148e8707-bd69-417a-b26c-07175052f97a", "embedding": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "48be290e-5b34-4eac-b488-ba8f4d5264ef", "node_type": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9868414a5421ecc8532df3b51adc1a0f3734ac7104b3df3de55b6317761b408b"}, "2": {"node_id": "b2c16b7c-14fb-4ecf-9d73-b4e50857569b", "node_type": null, "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "665d1cf002aaf1fab440cd8ab06978b1ec3af0d09ff43839202ece3cf36f99f9"}}, "hash": "bb9bc6377e27b7242933f7e2f0277ef907978c8d4321d10664885d75b6bb98ad", "text": "\tbecause \teffectively \t100% \tof \tthe \tdrug, \tboth \tbound \tand \t\nfree, is available to the carrier.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6055, "end_char_idx": 6632, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8dd11c35-410a-4ff6-9227-e3631d2f9b7c": {"__data__": {"id_": "8dd11c35-410a-4ff6-9227-e3631d2f9b7c", "embedding": null, "metadata": {"page_label": "147", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eaf97933-456d-456d-9892-432956ba6b4b", "node_type": null, "metadata": {"page_label": "147", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d8d0f678eea2125e4a8a5d24ad4c94785f70832ab76452f833f64f29f6dada27"}}, "hash": "d8d0f678eea2125e4a8a5d24ad4c94785f70832ab76452f833f64f29f6dada27", "text": "10 DRuG mEtAboLISm AND ELImINAtIoN\n141Acidic urine (pH~5)Score \u00b5mol/L \u00b5mol/hClearance (mL/min)\nUrine flow (mL/min)Urinary\nexcretionPlasma\nconcentrationPsychological\nresponse \nAlkaline urine\npH 7.8\u20138.0\nAlkaline urine (pH~7)50\n40\n30\n20\n10\n0\n00 22 44 66 81 35 7\nDaysAcidic urine\npH<7Phenobarbital (dog)\n[a weak acid]Amphetamine (human)\n[a weak base]\n40\n20\n0\n2\n1\n0\n30\n15\n0A B\nFig. 10.6 The effect of urinary pH on drug excretion. (A) Phenobarbital clearance in the dog as a function of urine flow. Because \nphenobarbital is acidic, alkalinising the urine increases clearance about five-fold. (B) Amphetamine excretion in humans. Acidifying the urine \nincreases\t the\trate\tof\trenal\telimination\t of\tamphetamine,\t reducing\tits\tplasma\tconcentration\t and\tits\teffect\ton\tthe\tsubject\u2019s\t mental\tstate.\t(Data\t\nfrom Gunne & Anggard, 1974. In: Torrell, T. et al. (eds) Pharmacology and Pharmacokinetics. Plenum, New York.)\nTable 10.9 Examples of drugs that inhibit renal \ntubular secretion\nDrug(s) causing inhibition Drug(s) affected\nProbenecid\nPenicillin\nAzidothymidine\nIndometacinSul\ufb01npyrazone\nPhenylbutazoneSulfonamides\nAspirin\nThiazide diuretics\nIndometacin\nVerapamil\nDigoxin Amiodarone\nQuinidine\nIndometacin Furosemide \n(frusemide)\nAspirin\nMethotrexate Non-steroidal anti-in\ufb02ammatory \ndrugsElimination of drugs by the kidney \n\u2022\tMost\tdrugs,\tunless\thighly\tbound\tto\tplasma\tprotein,\t\ncross the glomerular filter freely.\n\u2022\tMany\tdrugs,\tespecially\t weak\tacids\tand\tweak\tbases,\t\nare actively secreted into the renal tubule and rapidly \nexcreted.\n\u2022\tLipid-soluble\t drugs\tare\tpassively\t reabsorbed\t along\t\nwith water by diffusion across the tubular barrier, so \nare not efficiently excreted in the urine.\n\u2022\tBecause\t of\tpH\tpartition,\tweak\tacids\tare\tmore\trapidly\t\nexcreted in alkaline urine, and vice versa.\n\u2022\tSeveral\t important\t drugs\tare\tremoved\tpredominantly\t by\t\nrenal excretion, and are liable to cause toxicity in \nelderly persons and patients with renal disease.\n\u2022\tThere\tare\tinstances\t of\tclinically\timportant\t drug\u2013drug\t\ninteractions due to one drug reducing the renal \nclearance of another (examples include diuretics/lithium \nand indometacin/methotrexate), but these are less \ncommon than interactions due to altered drug \nmetabolism.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2701, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3d6c3d4d-315c-4b7d-9f11-357ba3861f07": {"__data__": {"id_": "3d6c3d4d-315c-4b7d-9f11-357ba3861f07", "embedding": null, "metadata": {"page_label": "148", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "33f0e91a-5c4b-4790-b7d2-f19f24b1a55d", "node_type": null, "metadata": {"page_label": "148", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3149a4d19b83a6c7557086c27e0f42533fc516b1211c0e8d212bf1a80b1f4957"}, "3": {"node_id": "79726254-c1af-485f-8ac4-b1ad9a2cb23f", "node_type": null, "metadata": {"page_label": "148", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc97180c33b6ed6a4aa1792ddbb206fc9a772b0490aa093f751e9fa16c8bc2be"}}, "hash": "86e96d5ba8e805b475ea6935eae6ea2ab4efd6da8f5f516fdd0f686aa0a68eed", "text": "10 SECTION 1 GENERAL PRINCIPLES\n142REFERENCES AND FURTHER READING\nGeneral further reading\nCoon,\tM.J.,\t2005.\tCytochrome\t P450:\tnature\u2019s\t most\tversatile\t biological\t\ncatalyst.\t Annu.\tRev.\tPharmacol.\t Toxicol.\t 45,\t1\u201325.\t(Summarises the \nindividual steps in the P450 and reductase reaction cycles )\nNassar,\tA.F.,\t2009.\tDrug\tMetabolism\t Handbook:\t Concepts\t and\t\nApplications.\t Wiley-Blackwell,\t Hoboken,\t NJ.\t(Multi-authored handbook \naimed at bench scientists; will be invaluable for pharmaceutical industry \nscientists)\nTesta,\tB.,\tKr\u00e4mer,\t S.D.,\t2009.\tThe\tBiochemistry\t of\tDrug\tMetabolism.\t\nWiley-VCH,\t Weinheim.\t (Two-volume reference work )\nDrug metabolism\nCampo,\t V.L.,\tBernardes,\t L.S.C.,\tCarvalho,\t I.,\t2009.\tStereoselectivity\t in\t\ndrug metabolism: molecular mechanisms and analytical methods. \nCurr.\tDrug\tMetab.\t10,\t188\u2013205.\nGuengerich,\t F.P.,\tWaterman,\t M.R.,\tEgli,\tM.,\t2016.\tRecent\tstructural\t\ninsights\t into\tcytochrome\t P450\tfunction.\t Trends\tPharmacol.\t Sci.\t37,\t\n625\u2013640.\t (Review)\nIngelman-Sundberg, M., 2004. Pharmacogenetics of cytochrome P450 \nand its applications in drug therapy: the past, present and future. \nTrends\tPharmacol.\t Sci.\t25,\t193\u2013200.\t (Estimates that personalized P450 \ngene-based treatment would be relevant for 10%\u201320% of all small molecule \ndrug therapy )\nNair,\tP.C.,\tMcKinnon,\t R.A.,\tMiners,\tJ.O.,\t2016.\tCytochrome\t P450\t\nstructure-function: insights from molecular dynamics simulations. \nDrug\tMetab.\tRev.\t48,\t434\u2013452.\t (Structure-function relations in P450 )Preissner,\t S.C.,\tHoffmann,\t M.F.,\tPreissner,\t R.,\tDunkel,\t M.,\tGewiess,\t A.,\t\nPreissner,\t S.,\t2013.\tPolymorphic\t Cytochrome\t P450\tEnzymes\t (CYPs)\t\nand\ttheir\trole\tin\tpersonalized\t therapy.\t PLoS\tONE\t8\t(12),\te82562.\t(Use \nof a text mining approach to identify the most relevant polymorphisms in \nhuman CYPs. The most important polymorphic CYPs were 1A2, 2D6, 2C9 \nand 2C19. Thirty-four common allele variants in caucasians led to altered \nenzyme activity )\nP450 enzyme induction and inhibition\nHenderson,\t L.,\tYue,\tQ.Y.,\tBergquist,\t C.,\tet\tal.,\t2002.\tSt\tJohn\u2019s\twort\t\n(Hypericum perforatum ):\tdrug\tinteractions\t and\tclinical\toutcomes.\t Br.\tJ.\t\nClin.\tPharmacol.\t 54,\t349\u2013356.\t (Reviews the induction of CYP450 \nisoenzymes and of P-glycoprotein by constituents in this herbal remedy )\nPelkonen,\t O.,\tTurpeinen,\t M.,\tHakkola,\t J.,\tet\tal.,\t2008.\tInhibition\t and\t\ninduction of human cytochrome P450 enzymes: current status. Arch. \nToxicol.\t 82,\t667\u2013715.\t (Review)\nDrug elimination\nKusuhara,\t", "start_char_idx": 0, "end_char_idx": 2479, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "79726254-c1af-485f-8ac4-b1ad9a2cb23f": {"__data__": {"id_": "79726254-c1af-485f-8ac4-b1ad9a2cb23f", "embedding": null, "metadata": {"page_label": "148", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "33f0e91a-5c4b-4790-b7d2-f19f24b1a55d", "node_type": null, "metadata": {"page_label": "148", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3149a4d19b83a6c7557086c27e0f42533fc516b1211c0e8d212bf1a80b1f4957"}, "2": {"node_id": "3d6c3d4d-315c-4b7d-9f11-357ba3861f07", "node_type": null, "metadata": {"page_label": "148", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86e96d5ba8e805b475ea6935eae6ea2ab4efd6da8f5f516fdd0f686aa0a68eed"}}, "hash": "bc97180c33b6ed6a4aa1792ddbb206fc9a772b0490aa093f751e9fa16c8bc2be", "text": "(Review)\nDrug elimination\nKusuhara,\t H.,\tSugiyama,\t Y.,\t2009.\tIn\tvitro\u2013in\t vivo\textrapolation\t of\t\ntransporter-mediated clearance in the liver and kidney. Drug Metab. \nPharmacokinet.\t 24,\t37\u201352.\t(Review)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2443, "end_char_idx": 3125, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f0f8399a-f0e2-452e-aa85-231699cdeeaf": {"__data__": {"id_": "f0f8399a-f0e2-452e-aa85-231699cdeeaf", "embedding": null, "metadata": {"page_label": "149", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "638feaa1-a6b0-421a-b9a5-bb5990325961", "node_type": null, "metadata": {"page_label": "149", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "608e9c572cd6870e2aea4d19266c15ff79bab6e340347df5f1423d8feddfa75e"}, "3": {"node_id": "bd389323-3c72-4147-9eac-02ae56878502", "node_type": null, "metadata": {"page_label": "149", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ce1a570fac5abee9821dc816883b9ca961c07e1df3c8995a935d05b81adff4e"}}, "hash": "e3ff37153c6d2fd37bf7f9db02b144b8aa62b407dcfd3f137df7d5aaf5c96e4a", "text": "143\nPharmacokinetics 11\u2003GENERAL PRINCIPLES SECTION \u20031\u2003\nOVERVIEW\nWe\u2003explain \u2003the \u2003importance \u2003of \u2003pharmacokinetic \u2003\nanalysis \u2003and\u2003present \u2003a\u2003simple \u2003approach \u2003to\u2003this\u2003topic. \u2003\nWe\u2003explain \u2003how \u2003drug \u2003clearance \u2003determines \u2003the\u2003\nsteady-state \u2003plasma \u2003concentration \u2003during \u2003constant-rate \u2003\ndrug \u2003administration \u2003and \u2003how \u2003the \u2003characteristics \u2003of\u2003\nabsorption \u2003a nd\u2003d istribution \u2003( considered \u2003i n Ch.\u20039)\u2003p lus \u2003\nmetabolism \u2003and \u2003excretion \u2003(considered \u2003in Ch.\u200310)\u2003\ndetermine \u2003the \u2003time \u2003course \u2003of \u2003drug \u2003concentration \u2003in\u2003\nblood \u2003plasma \u2003during \u2003and\u2003following \u2003drug \u2003administra -\ntion.\u2003The \u2003effect \u2003of \u2003different \u2003dosing \u2003regimens \u2003on \u2003the\u2003\ntime\u2003course \u2003of \u2003drug \u2003concentration \u2003in \u2003plasma \u2003is\u2003\nexplained. \u2003Population \u2003pharmacokinetics \u2003is\u2003mentioned \u2003\nbriefly, \u2003and \u2003a \u2003final \u2003section \u2003considers \u2003limitations \u2003to\u2003\nthe\u2003pharmacokinetic \u2003approach.\nINTRODUCTION: \u2003DEFINITION \u2003AND \u2003USES \u2003\nOF\u2003PHARMACOKINETICS\nPharmacokinetics is the branch of pharmacology dedicated \nto determining the fate of chemical substances administered \nto a living organism \u2013 \u2018what the body does to the drug\u2019. \nIn practice this involves the measurement and formal interpretation of changes with time of drug and drug \nmetabolite concentrations in plasma, urine and sometimes \nother accessible regions of the body, in relation to dosing. It provides a framework for understanding what happens \nto a drug when given to an animal or human, where it \ngoes in the body, and how quickly, that enables one to understand the effects that it produces. In contrast, phar -\nmacodynamics (\u2018what the drug does to the body\u2019), describes \nevents consequent on interaction of the drug with its receptor \nor other primary site of action. The distinction is useful, although the words cause dismay to etymological purists.\n\u2018Pharmacodynamic\u2019 received an entry in a dictionary of \n1890 (\u2018relating to the powers or effects of drugs\u2019) whereas pharmacokinetic studies only became possible in the latter \npart of the 20th century with the development of sensitive, \nspecific and accurate physicochemical analytical techniques, especially high-performance chromatography and mass \nspectrometry, for measuring drug concentrations in biologi -\ncal fluids. The time course of drug concentration following \ndosing depends on the processes of absorption, distribution, \nmetabolism and excretion (ADME) that we have considered \nqualitatively in Chapters 9 and 10.\nIn practice, pharmacokinetics usually focuses on con-\ncentrations of drug in blood plasma, which is easily sampled \nvia venepuncture, since plasma concentrations are assumed usually to bear a clear relation to the concentration of drug in extracellular fluid surrounding cells that express the \nreceptors or other targets with which drug molecules combine. This underpins what is termed the target concentra -\ntion strategy . Individual variation in response to a given dose \nof a drug is often greater than variability in the plasma \nconcentration at that dose. Plasma concentrations (C\np) are \ntherefore useful in the early stages of drug development (see later), and in the case of a few drugs plasma drug \nconcentrations are also used in", "start_char_idx": 0, "end_char_idx": 3143, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bd389323-3c72-4147-9eac-02ae56878502": {"__data__": {"id_": "bd389323-3c72-4147-9eac-02ae56878502", "embedding": null, "metadata": {"page_label": "149", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "638feaa1-a6b0-421a-b9a5-bb5990325961", "node_type": null, "metadata": {"page_label": "149", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "608e9c572cd6870e2aea4d19266c15ff79bab6e340347df5f1423d8feddfa75e"}, "2": {"node_id": "f0f8399a-f0e2-452e-aa85-231699cdeeaf", "node_type": null, "metadata": {"page_label": "149", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e3ff37153c6d2fd37bf7f9db02b144b8aa62b407dcfd3f137df7d5aaf5c96e4a"}}, "hash": "1ce1a570fac5abee9821dc816883b9ca961c07e1df3c8995a935d05b81adff4e", "text": "and in the case of a few drugs plasma drug \nconcentrations are also used in routine clinical practice to individualise dosage, to achieve the desired therapeutic \neffect while minimising adverse effects in each individual \npatient \u2013 an approach known as therapeutic drug monitoring, \noften abbreviated TDM. Table 11.1 shows examples of some \ndrugs where a therapeutic range of plasma concentrations \nhas been established, enabling TDM. Concentrations of drug in other body fluids (e.g. urine,\n1 saliva, cerebrospinal \nfluid, milk) may add useful information.\nFormal interpretation of pharmacokinetic data consists \nof fitting concentration-versus-time data to a model (whether abstract or, more usefully, physiologically based) and \ndetermining parameters that describe the observed behav -\niour. The parameters can then be used to adjust the dose \nregimen to achieve a desired target plasma concentration, \nThe pharmacologically active concentration range is esti -\nmated from experiments on cells, tissues or laboratory \nanimals, and modified as data emerge from early human pharmacology trials, which often test single doses of the \nnew drug administered to successive groups of volunteers \nin progressively increasing doses - single ascending dose (SAD) studies (Ch. 8). Some descriptive pharmacokinetic \ncharacteristics can be estimated directly by inspecting the \ntime course of drug concentration in plasma following dosing \u2013 important examples,\n2 illustrated more fully later, \nare the maximum plasma concentration following a given \ndose of a drug administered in a defined dosing form ( Cmax) \nand the time ( Tmax) between drug administration and achiev -\ning Cmax. Other pharmacokinetic parameters are estimated \nmathematically from experimental data; examples include volume of distribution (V\nd) and clearance (CL), concepts that \nhave been introduced in Chapters 9 and 10, respectively, and to which we return below. This approach applies both \nto classical low molecular-weight drugs and to macromo -\nlecular biopharmaceuticals (Ch. 5), although qualitative \naspects of absorption, distribution and elimination are, of \ncourse, very different and pharmacokinetic parameters differ markedly \u2013 for example, antibodies have evolved to \npersist for long periods after exposure to antigen, and \ntherapeutic antibodies commonly have low rates of clearance and long elimination half-lives in consequence.\n1Clinical pharmacology became at one time so associated with the \nmeasurement of drugs in urine that the canard had it that clinical \npharmacologists were the new alchemists \u2013 they turned urine into \nairline tickets.\n2Important because dose-related adverse effects often occur around Cmax.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3068, "end_char_idx": 6251, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7b4175af-eae3-4992-908d-154124bd7f43": {"__data__": {"id_": "7b4175af-eae3-4992-908d-154124bd7f43", "embedding": null, "metadata": {"page_label": "150", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ff47b8c3-5623-4947-8d32-1b3e911f1fc4", "node_type": null, "metadata": {"page_label": "150", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d43ba90984487d01c4606c22e9b67934230771a0770807aac2301d65c9fa9657"}, "3": {"node_id": "aa49d000-bc96-423a-be8c-c216f43a9e08", "node_type": null, "metadata": {"page_label": "150", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "40b2e15022c4bfbe72fb6c7b199100d1ba19307d03895c3db81cef15e47c24cf"}}, "hash": "f4e682e65bdc174ba13897181dc76853f0971bfe4af54b8653b662b487ee425b", "text": "11 SECTION \u20031\u2003\u2003GENERAL PRINCIPLES\n144\u2022\tsituations \twhere \tthis \tmodel \tis \tinadequate, \tand \t\nintroduce a two-compartment model;\n\u2022\tsituations \twhere \tclearance \tvaries \twith \tdrug \t\nconcentration (\u2018non-linear kinetics\u2019);\n\u2022\tsituations \t(such \tas \tpaediatric \tpharmacokinetics) \twhere \t\nonly a few samples are available and population \nkinetics may be used.\nFinally, we consider some of the limitations inherent in \nthe pharmacokinetic approach. More detailed accounts are \nprovided by Atkinson et al. (2012), Birkett (2010) and \nRowland and Tozer (2010).\nDRUG \u2003ELIMINATION \u2003EXPRESSED \u2003AS \u2003\nCLEARANCE\nThe overall clearance of a drug by all routes ( CL tot) is the \nfundamental pharmacokinetic parameter describing drug elimination. It is defined as the volume of plasma which \ncontains the total amount of drug that is removed from the body in unit time. It is thus expressed as volume per \nunit time, e.g. mL/min or L/h. Renal clearance ( CL\nren), an \nimportant component of CL tot, was described in Chapter \n10.\nThe overall clearance of a drug ( CL tot) is the sum of \nclearance rates for each mechanism involved in eliminating the drug, usually renal clearance ( CL\nren) and metabolic \nclearance ( CL met) plus any additional appreciable routes of \nelimination (faeces, breath, etc.). It relates the rate of elimina -\ntion of a drug (in units of mass/unit time) to the plasma \nconcentration, Cp:\n Rate of drug elimin ation pt ot =\u00d7CC L (11.1)\nDrug clearance can be determined in an individual subject by measuring the plasma concentration of the drug (in \nunits of, say, mg/L) at intervals during a constant-rate \nintravenous infusion (delivering, say, X mg of drug per \nh), until a steady state is approximated (Fig. 11.1A). At \nsteady state, the rate of input to the body is equal to the \nrate of elimination, so:\n XC CL =\u00d7 ss tot (11.2)\nRearranging this,\n CLX\nCtot\nss= (11.3)\nwhere CSS is the plasma concentration at steady state, and \nCL tot is in units of volume/time (L/h in the example given).\nFor many drugs, clearance in an individual subject is \nindependent of dose (at least within the range of doses used therapeutically \u2013 but see the section on saturation kinetics later for exceptions), so knowing the clearance \nenables one to calculate the dose rate needed to achieve a \ndesired steady-state (\u2018target\u2019) plasma concentration from Eq. 11.2.\nCL\ntot can also be estimated by measuring plasma con -\ncentrations at intervals following a single intravenous bolus \ndose of, say, Q mg (Fig. 11.1B):\n CLQ\nAUCtot=\n\u2212\u221e0 (11.4)USES \u2003OF \u2003PHARMACOKINETICS\nKnowledge of the pharmacokinetic behaviour of drugs in \nanimals and man is crucial in drug development, both to \nmake sense of preclinical toxicological and pharmacological \ndata3 and to decide on an appropriate dose and dosing \nregimen for clinical trials (see Ch. 60). Drug regulators \nhave developed concepts such as bioavailability and bio-\nequivalence (Ch. 9) to support the licensing of generic versions \nof drugs produced when originator products lose patent protection. Understanding the general principles of phar -\nmacokinetics is also important in clinical practice, to \nunderstand the rationale of recommended dosing regimens, \nto interpret drug concentrations for TDM and to adjust \ndose regimens rationally, and to identify and evaluate possible", "start_char_idx": 0, "end_char_idx": 3320, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aa49d000-bc96-423a-be8c-c216f43a9e08": {"__data__": {"id_": "aa49d000-bc96-423a-be8c-c216f43a9e08", "embedding": null, "metadata": {"page_label": "150", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ff47b8c3-5623-4947-8d32-1b3e911f1fc4", "node_type": null, "metadata": {"page_label": "150", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d43ba90984487d01c4606c22e9b67934230771a0770807aac2301d65c9fa9657"}, "2": {"node_id": "7b4175af-eae3-4992-908d-154124bd7f43", "node_type": null, "metadata": {"page_label": "150", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4e682e65bdc174ba13897181dc76853f0971bfe4af54b8653b662b487ee425b"}}, "hash": "40b2e15022c4bfbe72fb6c7b199100d1ba19307d03895c3db81cef15e47c24cf", "text": "TDM and to adjust \ndose regimens rationally, and to identify and evaluate possible drug interactions (see Chs 9 and 10). In particular, intensive-care specialists and anaesthetists dealing with a \nseverely ill patient often need to individualise the dose \nregimen depending on the urgency of achieving a thera -\npeutic plasma concentration, and whether the pharmacoki -\nnetic behaviour of the drug is likely to be affected by illness such as renal impairment or liver disease.\nSCOPE \u2003OF \u2003THIS \u2003CHAPTER\nWe describe:\n\u2022\thow\ttotal \tdrug \tclearance \tdetermines \tsteady-state \t\nplasma concentration during continuous administration;\n\u2022\thow\tdrug \tconcentration \tversus \ttime \tcan \tbe \tdescribed \t\nby a simple model in which the body is represented as a single well-stirred compartment, of volume V\nd. This \ndescribes the situation before steady state (or after \ndrug is discontinued) in terms of elimination \nhalf-life (t 1/2);Table 11.1 Examples of drugs where therapeutic \ndrug monitoring (TDM) of plasma concentrations is \nused clinically\nCategory Example(s) See chapter\nImmunosuppressants Ciclosporin, \ntacrolimus27\nCardiovascular Digoxin 22\nRespiratory Theophylline 17, 29\nCNS Lithium, phenytoin 48, 46\nAntibacterials Aminoglycosides 52\nAnticancer drugs Methotrexate 57\n3For example, doses used in experimental animals often need to be \nmuch greater than those in humans (on a \u2018per unit body weight\u2019 basis), \nbecause drug metabolism is commonly much more rapid in rodents \n\u2013 methadone (Ch. 43) is one of many such examples. When using \nanimal data to estimate a \u2018human equivalent dose\u2019 in planning the \nfirst-in-human study, doses of low molecular-weight drugs are \nnormalised (so-called \u2018allometric scaling\u2019) to estimated body surface area rather than to body weight. Paediatricians commonly use the same \napproach, estimating appropriate doses for babies and young children \nfrom adult human doses in terms of dose/unit of estimated body surface area rather than dose/kg body weight.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3238, "end_char_idx": 5703, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b3ce1b5f-02d2-485c-8914-3d8a07292b30": {"__data__": {"id_": "b3ce1b5f-02d2-485c-8914-3d8a07292b30", "embedding": null, "metadata": {"page_label": "151", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d97df45d-02e0-4469-8511-c788726d6024", "node_type": null, "metadata": {"page_label": "151", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e755c5ecad9ac80ff34826769f7dc827925f545c536d21633fe8a5a090ba015"}, "3": {"node_id": "1afd66a4-7eaa-4005-b32f-08f8922e41b4", "node_type": null, "metadata": {"page_label": "151", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "466f1c4ccdaf541b22f5e6d62957f2eef6241c5e98c9be0c50463cac26505e8e"}}, "hash": "98f0e66d3f9c02d1d363acc8aad79131a22f01af71dd48b29c1d5af31172d1aa", "text": "11 PhARmACokINEtICS\n145effects in patients with disordered kidney or liver function \nmay differ from those observed in healthy volunteer subjects. \nIn early phase clinical trials these measures of drug exposure \nare determined at each dose level and the protocol includes \u2018stopping rules\u2019 to avoid dose increments that caused toxicity \nduring animal experiments. See Chapter 9, and Birkett, \n2010 for a fuller account.\nNote that these estimates of CL\ntot, unlike estimates based \non the rate constant or half-life (see later), do not depend \non any particular compartmental model.\nSINGLE-COMPARTMENT \u2003MODEL\nConsider a highly-simplified model of a human being, which \nconsists of a single well-stirred compartment, of volume \nVd (distribution volume), into which a quantity of drug Q \nis introduced rapidly by intravenous injection, and from which it is removed either by being metabolised or by \nbeing excreted (Fig. 11.2). For most drugs, V\nd is an apparent \nvolume rather than the volume of an anatomical compart -\nment. It links the total amount of drug in the body to its concentration in plasma (see Ch. 9). The quantity of drug in the body immediately after it is administered as a single \nbolus is equal to the administered dose Q. The initial \nconcentration, C\n0, will therefore be given by:\n CQ\nV0=\nd (11.5)\nIn practice, C0 is estimated by extrapolating the linear portion \nof a semilogarithmic plot of Cp against time back to its \nintercept at time 0 (Fig. 11.1C). C p at any time depends on \nthe rate of elimination of the drug (i.e. on its total clearance, CL\ntot) as well as on the dose and Vd. Many drugs exhibit \nfirst-order kinetics, where the rate of elimination is directly proportional to drug concentration. (An analogy is letting \nyour bath drain down the plug hole where the water, analogous to drug, initially rushes out whereas the last bit \nalways takes an age to drain away. Contrast this with \nso-called zero-order kinetics where the water is pumped out \nof the bath at a constant rate.) With first-order kinetics where AUC\n0\u2013\u221e is the area under the full curve4 relating C p \nto time following a bolus dose given at time t = 0. AUC 0\u2013\u221e \nprovides an integrated measure of tissue exposure to the \ndrug in units of time multiplied by drug concentration. \nTogether with Cmax it informs as to drug effects, both desired \nand toxic, and so is important in anticipating possible effects \nin humans from those observed during animal pharmacol -\nogy and toxicology experiments, and in anticipating how (Infusion) X mg/h)Plasma\nconcentrationPlasma concentration\n(log scale)Plasma\nconcentration0\n0100\n50\n1CSS CSS=X/CL\nBolus (Q mg) Time\nBolus (Q mg)10C0100\nTimeVd=Q/C0TimeA\nB\nC\nFig. 11.1 Plasma drug concentration\u2013time curves. \n(A) During a constant intravenous infusion at rate X mg/h, \nindicated by the horizontal bar, the plasma concentration ( C) \nincreases from zero to a steady-state value ( CSS); when the \ninfusion is stopped, C declines to zero. (B) Following an \nintravenous bolus dose (Q mg), the plasma concentration rises \nabruptly and then declines towards zero. (C) Data from panel (B) plotted with plasma concentrations on a logarithmic scale. The straight line shows that concentration declines exponentially. Extrapolation back to the ordinate at zero time gives an estimate of C\n0, the concentration at zero time, and hence of Vd, the \nvolume of distribution.", "start_char_idx": 0, "end_char_idx": 3397, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1afd66a4-7eaa-4005-b32f-08f8922e41b4": {"__data__": {"id_": "1afd66a4-7eaa-4005-b32f-08f8922e41b4", "embedding": null, "metadata": {"page_label": "151", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d97df45d-02e0-4469-8511-c788726d6024", "node_type": null, "metadata": {"page_label": "151", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e755c5ecad9ac80ff34826769f7dc827925f545c536d21633fe8a5a090ba015"}, "2": {"node_id": "b3ce1b5f-02d2-485c-8914-3d8a07292b30", "node_type": null, "metadata": {"page_label": "151", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "98f0e66d3f9c02d1d363acc8aad79131a22f01af71dd48b29c1d5af31172d1aa"}}, "hash": "466f1c4ccdaf541b22f5e6d62957f2eef6241c5e98c9be0c50463cac26505e8e", "text": "at zero time, and hence of Vd, the \nvolume of distribution. Excretion MetabolismAbsorption\nDose, Q\n(intravenous)Dose, Q\n(oral)\nVolume Vd\nSingle well-stirred\ncompartmentkabs\nkexc kmet\nFig. 11.2 Single-compartment pharmacokinetic model. \nThis model is applicable if the plasma concentration falls exponentially after drug administration (as in Fig. 11.1). \n4The area is obtained by integrating from time = 0 to time = \u221e, and is \ndesignated AUC 0\u2013\u221e. The area under the curve has units of time \u2013 on the \nabscissa \u2013 multiplied by concentration (mass/volume) \u2013 on the \nordinate; so CL = Q/AUC 0\u2013\u221e has units of volume/time as it should.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3338, "end_char_idx": 4448, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dc8c7d11-0049-418e-9ed3-bb59802cc972": {"__data__": {"id_": "dc8c7d11-0049-418e-9ed3-bb59802cc972", "embedding": null, "metadata": {"page_label": "152", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eb05d631-5357-4c34-a19b-ce6e809dd7c0", "node_type": null, "metadata": {"page_label": "152", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb87026e18aa6dc97753c4ffb3a9b5267157baef696b0032aeb396a72272f338"}, "3": {"node_id": "f3ef9508-1eb3-4e0b-b582-aa0a955fdcf7", "node_type": null, "metadata": {"page_label": "152", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4f81ac78cde006a21346f63e70c2f4d70658fca5b448a363eebf3c855c599d8"}}, "hash": "a58c8cd3e1d75b6cc8049b8f52d4459277f26825d73f2958297b88f89574f6f1", "text": "11 SECTION \u20031\u2003\u2003GENERAL PRINCIPLES\n146of 1/time. It represents the fraction of drug in the body \neliminated per unit of time. For example, if the rate constant \nis 0.1/h this implies that one-tenth of the drug remaining \nin the body is eliminated each hour.\nThe elimination half-life, t1/2, is the time taken for Cp to \ndecrease by half, and is equal to ln2/k el (=0.693/k el). The \nplasma half-life is therefore determined by V d as well as \nby CL tot. It enables one to predict the time course of Cp after \na bolus of drug is given or after the start or end of an \ninfusion, when Cp is rising to its steady-state level or declin -\ning to zero.\nWhen a single-compartment model is applicable, the \ndrug concentration in plasma approaches the steady-state \nvalue approximately exponentially during a constant infu -\nsion (see Fig. 11.1A). When the infusion is discontinued, \nthe concentration falls exponentially towards zero with the same half-life: after one half-life, the concentration will have \nfallen to half the initial concentration; after two half-lives, \nit will have fallen to one-quarter the initial concentration; after three half-lives, to one-eighth; and so on. It is intuitively obvious that the longer the half-life, the longer the drug \nwill persist in the body after dosing is discontinued. It is \nless obvious, but nonetheless true, that during chronic drug administration, the longer the half-life, the longer it will \ntake for the drug to accumulate to its steady-state level: \none half-life to reach 50% of the steady-state value, two to reach 75%, three to reach 87.5% and so on. This is extremely \nhelpful to a clinician deciding how to start treatment. If the \ndrug in question has a half-life of approximately 24 h, for \nexample, it will take 3\u20135 days to approximate the steady-\nstate concentration during a constant-rate infusion. If this \nis too slow in the face of the prevailing clinical situation, a \nloading dose may be used in order to achieve a therapeutic concentration of drug in the plasma more rapidly (see later). \nThe size of such a dose is determined by the volume of \ndistribution (Eq. 11.5).\nEFFECT \u2003OF \u2003REPEATED \u2003DOSING\nDrugs are usually given therapeutically as repeated doses \nrather than single injections or a constant infusion. Repeated \ninjections (each of dose Q) give a more complicated pattern \nthan the smooth exponential rise during intravenous infusion, \nbut the principle is the same (Fig. 11.4). The concentration \nwill rise to a mean steady-state concentration with an \napproximately exponential time course, but will oscillate (through a range Q/V\nd). The smaller and more frequent \nthe doses, the more closely the situation approaches that \nof a continuous infusion, and the smaller the swings in \nconcentration. The exact dosage schedule, however, does not affect the mean steady-state concentration, or the rate \nat which it is approached. In practice, a steady state is \neffectively achieved after three to five half-lives. Speedier attainment of the steady state can be achieved by starting \nwith a larger dose, as mentioned earlier. Such a loading \ndose is sometimes used when starting treatment with a drug with a half-life that is long in the context of the urgency of the clinical situation, as may be the case when treating \ncardiac dysrhythmias with drugs such as amiodarone \nor digoxin (Ch. 22) or initiating anticoagulation with \nheparin (Ch. 25).\nEFFECT \u2003OF \u2003VARIATION \u2003IN \u2003RATE", "start_char_idx": 0, "end_char_idx": 3458, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f3ef9508-1eb3-4e0b-b582-aa0a955fdcf7": {"__data__": {"id_": "f3ef9508-1eb3-4e0b-b582-aa0a955fdcf7", "embedding": null, "metadata": {"page_label": "152", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eb05d631-5357-4c34-a19b-ce6e809dd7c0", "node_type": null, "metadata": {"page_label": "152", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb87026e18aa6dc97753c4ffb3a9b5267157baef696b0032aeb396a72272f338"}, "2": {"node_id": "dc8c7d11-0049-418e-9ed3-bb59802cc972", "node_type": null, "metadata": {"page_label": "152", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a58c8cd3e1d75b6cc8049b8f52d4459277f26825d73f2958297b88f89574f6f1"}}, "hash": "d4f81ac78cde006a21346f63e70c2f4d70658fca5b448a363eebf3c855c599d8", "text": "25).\nEFFECT \u2003OF \u2003VARIATION \u2003IN \u2003RATE \u2003\u2003\nOF\u2003ABSORPTION\nIf a drug is absorbed slowly from the gut or from an injec -\ntion site into the plasma, it is (in terms of a compartmental drug concentration decays exponentially (Fig. 11.3), being \ndescribed by the equation:\n CCCL\nVt ttot\nd=\u2212\n0exp (11.6)\n(Note that exp is another way of writing \u2018e to the power of\u2019, so this has the same form as C\nt= C0.e\u2212kt.)\nTaking logarithms to the base e (written as ln):\n ln lnCCCL\nVt ttot\nd=\u2212\u22120 (11.7)\nPlotting Ct on a logarithmic scale against t (on a linear \nscale) yields a straight line with slope \u2212CL tot/Vd. The constant \nCL tot/V d is the elimination rate constant k el, which has units A\nB(kel = 0.05/h)(kel = 0.2/h)\n(kel = 0.05/h)\nt value\nfor at valueab\u00b4b\nab\u00b4bHours\nHours0 3.5 13.9 25 5010\n8\n6420Plasma concentration (\u00b5mol/L) Plasma concentration (\u00b5mol/L, log scale)10\n5\n2\n1\n0.5\n0.2\n0 25 50for b & b \u00b4\nFig. 11.3 Predicted behaviour of single-compartment \nmodel following intravenous drug administration at time 0. \nDrugs a and b differ only in their elimination rate constant, kel. \nCurve b\u2032 shows the plasma concentration time course for a \nsmaller dose of b. Note that the half-life ( t1/2) (indicated by \nbroken lines ) does not depend on the dose. (A) Linear \nconcentration scale. (B) Logarithmic concentration scale. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3422, "end_char_idx": 5215, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "38be8a6b-1b56-4f70-90aa-a03bc1ea12b0": {"__data__": {"id_": "38be8a6b-1b56-4f70-90aa-a03bc1ea12b0", "embedding": null, "metadata": {"page_label": "153", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ca35b61b-e782-4dd2-bd02-e039c5a86e8b", "node_type": null, "metadata": {"page_label": "153", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "911ede231cf05f4a4ff7d35e0a01c1a1e94b866482125186de25f88ed1ef3e3d"}, "3": {"node_id": "1204d647-08a9-4c6c-81c3-da81d681cb54", "node_type": null, "metadata": {"page_label": "153", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "46873a757c9d5b7a29b1d28c44ecdce10b4cb95aa49ed51170a68c2fcf843489"}}, "hash": "44b90b12fc7342de3aa45725aa8a81612022558ce4d9dc585b40a7e3cbff4c64", "text": "11 PhARmACokINEtICS\n147model) as though it were being slowly infused at a variable \nrate into the bloodstream. For the purpose of kinetic model -\nling, the transfer of drug from the site of administration to the central compartment can be represented approximately by a rate constant, k\nabs (see Fig. 11.2). This assumes that \nthe rate of absorption is directly proportional, at any \nmoment, to the amount of drug still unabsorbed, which \nis at best a rough approximation to reality. The effect of slow absorption on the time course of the rise and fall \nof the plasma concentration is shown in Fig. 11.5. The \ncurves show the effect of spreading out the absorption of the same total amount of drug over different times. \nIn each case, the drug is absorbed completely, but the \npeak concentration appears later and is lower and less sharp if absorption is slow. In the limiting case, a dosage form that releases drug at a constant rate as it traverses \nthe ileum (Ch. 9) approximates a constant-rate infusion. \nOnce absorption is complete, the plasma concentration declines with the same half-time, irrespective of the rate of \nabsorption.\n\u25bc For the kind of pharmacokinetic model discussed here, the area \nunder the plasma concentration\u2013time curve ( AUC) is directly pro-\nportional to the total amount of drug introduced into the plasma \ncompartment, irrespective of the rate at which it enters. Incomplete \nabsorption, or destruction by first-pass metabolism before the drug reaches the plasma compartment, reduces AUC after oral administration \n(see Ch. 9). Changes in the rate of absorption, however, do not affect AUC . Again, it is worth noting that provided absorption is complete, \nthe relation between the rate of administration and the steady-state \nplasma concentration (Eq. 11.3) is unaffected by k\nabs, although the \nsize of the oscillation of plasma concentration with each dose is reduced if absorption is slowed.\nMORE \u2003COMPLICATED \u2003KINETIC \u2003MODELS\nSo far, we have considered a single-compartment pharma -\ncokinetic model in which the rates of absorption, metabolism Plasma concentration (\u00b5mol/L)\nA Infusion at 200 \u00b5mol/day\nB Injection 100 \u00b5 mol twice daily\nC Injection 200 \u00b5 mol once daily\nDays0 12 315\n10\n50ABC\nPlasmaFig. 11.4 Predicted behaviour of single-\ncompartment model with continuous or \nintermittent drug administration. Smooth \ncurve A shows the effect of continuous infusion \nfor 4 days; curve B the same total amount of \ndrug given in eight equal doses; and curve C \nthe same total amount of drug given in four \nequal doses. The drug has a half-life of 17 h \nand a volume of distribution of 20 L. Note that \nin each case a steady state is effectively reached after about 2 days (about three half-lives), and that the mean concentration reached in the steady state is the same for all three schedules. \nPharmacokinetics \n\u2022\tTotal\tclearance \t(CLtot) of a drug is the fundamental \nparameter describing its elimination: the rate of \nelimination equals CL tot multiplied by plasma \nconcentration.\n\u2022\tCLtot determines steady-state plasma concentration \n(CSS): CSS = rate of drug administration/ CLtot.\n\u2022\tFor\tmany \tdrugs, \tdisappearance \tfrom \tthe \tplasma \t\nfollows an approximately exponential time course. Such drugs can be described by a model where the body is treated as a single well-stirred compartment of \nvolume V\nd. Vd is an apparent volume linking the \namount of drug in the body at any time to the plasma \nconcentration.\n\u2022\tElimination \thalf-life \t(t1/2) is directly proportional to Vd \nand inversely proportional to", "start_char_idx": 0, "end_char_idx": 3554, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1204d647-08a9-4c6c-81c3-da81d681cb54": {"__data__": {"id_": "1204d647-08a9-4c6c-81c3-da81d681cb54", "embedding": null, "metadata": {"page_label": "153", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ca35b61b-e782-4dd2-bd02-e039c5a86e8b", "node_type": null, "metadata": {"page_label": "153", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "911ede231cf05f4a4ff7d35e0a01c1a1e94b866482125186de25f88ed1ef3e3d"}, "2": {"node_id": "38be8a6b-1b56-4f70-90aa-a03bc1ea12b0", "node_type": null, "metadata": {"page_label": "153", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44b90b12fc7342de3aa45725aa8a81612022558ce4d9dc585b40a7e3cbff4c64"}}, "hash": "46873a757c9d5b7a29b1d28c44ecdce10b4cb95aa49ed51170a68c2fcf843489", "text": "is directly proportional to Vd \nand inversely proportional to CLtot.\n\u2022\tWith\trepeated \tdosage \tor \tsustained \tdelivery \tof \ta \tdrug, \t\nthe plasma concentration approaches a steady value within three to five plasma half-lives.\n\u2022\tIn\turgent \tsituations, \ta \tloading \tdose \tmay \tbe \tneeded \tto \t\nachieve therapeutic concentration rapidly.\n\u2022\tThe\tloading \tdose \t(L) needed to achieve a desired initial \nplasma concentration Ctarget is determined by Vd: L = \nCtarget \u00d7 Vd.\n\u2022\tA\ttwo-compartment \tmodel \tis \toften \tneeded. \tIn \tthis \t\ncase, the kinetics are biexponential. The two components roughly represent the processes of transfer between plasma and tissues ( \u03b1 phase) and \nelimination from the body ( \u03b2 phase).\n\u2022\tSome\tdrugs \tshow \tnon-exponential \t\u2018saturation\u2019 \t\nkinetics, with important clinical consequences, especially a disproportionate increase in steady-state plasma concentration when daily dose is increased.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3493, "end_char_idx": 4883, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0d0601af-ee22-483d-b97b-e0ca454583c4": {"__data__": {"id_": "0d0601af-ee22-483d-b97b-e0ca454583c4", "embedding": null, "metadata": {"page_label": "154", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ebcd2d0-4dd0-42b0-b8a7-c0d474a7a5d8", "node_type": null, "metadata": {"page_label": "154", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bcb12c76fb67d69f1f41ecf6e8a1a15510239fc19808e270c73d15d21d12bc59"}, "3": {"node_id": "918661fb-1789-4889-8e43-62a36dfe01b1", "node_type": null, "metadata": {"page_label": "154", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5f425225cd9af5efd3b244b71b5633b62d4f99764260be29b4b6ce6f3378c17"}}, "hash": "3c9c37206d7127aaa1d03655986db28642f29cc1d4207b79a4b2df1890b1cdfd", "text": "11 SECTION \u20031\u2003\u2003GENERAL PRINCIPLES\n148and excretion are all assumed to be directly proportional \nto the concentration of drug in the compartment from which \ntransfer is occurring. This is a useful way to illustrate some \nbasic principles but is clearly a physiological oversimplifica -\ntion. The characteristics of different parts of the body, such \nas brain, body fat and muscle, are quite different in terms \nof their blood supply, partition coefficient for drugs and the permeability of their capillaries to drugs. These differ -\nences, which the single-compartment model ignores, can markedly affect the time courses of drug distribution and action, and much theoretical work has gone into the mathematical analysis of more complex models (see \nAtkinson et al., 2012; Rowland & Tozer, 2010). They are \nbeyond the scope of this book, and perhaps also beyond the limit of what is actually useful, for the experimental \ndata on pharmacokinetic properties of drugs are seldom \naccurate or reproducible enough to enable complex models to be tested critically.\nThe two-compartment model, which introduces a separate \n\u2018peripheral\u2019 compartment to represent the tissues, in com -\nmunication with the \u2018central\u2019 plasma compartment, more \nclosely resembles the real situation without involving \nexcessive complications.\nTWO-COMPARTMENT \u2003MODEL\nThe two-compartment model is a widely used approxima -\ntion in which the tissues are lumped together as a peripheral \ncompartment. Drug molecules can enter and leave the \nperipheral compartment only via the central compartment (Fig. 11.6), which usually represents the plasma (or plasma \nplus some extravascular space in the case of a few drugs \nthat distribute especially rapidly). The effect of adding a second compartment to the model is to introduce a second \nexponential component into the predicted time course of \nthe plasma concentration, so that it comprises a fast and a slow phase. This pattern is often found experimentally, and is most clearly revealed when the concentration data \nPlasma aminophylline concentration (\u00b5mol/L) Plasma concentration (arbitrary units) \nHours Hourst abs\nIntravenousOral \nEffective conc. 10\n5\n0\n08 16 2420\n10\n0\n0246 80 h\n1 h3 h6 hA B\nFig. 11.5 The effect of slow drug absorption on plasma drug concentration. (A) Predicted behaviour of single-compartment model \nwith drug absorbed at different rates from the gut or an injection site. The elimination half-time is 6 h. The absorption half-times ( t1/2 abs) \nare marked on the diagram. (Zero indicates instantaneous absorption, corresponding to intravenous administration.) Note that the peak \nplasma concentration is reduced and delayed by slow absorption, and the duration of action is somewhat increased. (B) Measurements of plasma aminophylline concentration in humans following equal oral and intravenous doses. (Data from Swintowsky, J.V., 1956. J. Am. Pharm. Assoc. 49, 395.)\nExcretion MetabolismAbsorption\nCentral\ncompartment\n(1)Peripheral\ncompartment\n(2)kabs\nkexc kmetk12\nk21Intravenous\ndoseOral dose\nFig. 11.6 Two-compartment pharmacokinetic model. \nare plotted semilogarithmically (Fig. 11.7). If, as is often \nthe case, the transfer of drug between the central and \nperipheral compartments is relatively fast compared with \nthe rate of elimination, then the fast phase (often called the \u03b1 phase) can be taken to represent the redistribution \nof the drug (i.e. drug molecules passing from plasma to tissues, thereby rapidly lowering the plasma concentra -\ntion). The plasma concentration reached when the fast \nphase is complete, but before", "start_char_idx": 0, "end_char_idx": 3582, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "918661fb-1789-4889-8e43-62a36dfe01b1": {"__data__": {"id_": "918661fb-1789-4889-8e43-62a36dfe01b1", "embedding": null, "metadata": {"page_label": "154", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ebcd2d0-4dd0-42b0-b8a7-c0d474a7a5d8", "node_type": null, "metadata": {"page_label": "154", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bcb12c76fb67d69f1f41ecf6e8a1a15510239fc19808e270c73d15d21d12bc59"}, "2": {"node_id": "0d0601af-ee22-483d-b97b-e0ca454583c4", "node_type": null, "metadata": {"page_label": "154", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3c9c37206d7127aaa1d03655986db28642f29cc1d4207b79a4b2df1890b1cdfd"}}, "hash": "f5f425225cd9af5efd3b244b71b5633b62d4f99764260be29b4b6ce6f3378c17", "text": "The plasma concentration reached when the fast \nphase is complete, but before appreciable elimination has \noccurred, allows a measure of the combined distribution volumes of the two compartments; the half-time for the slow phase (the \u03b2 phase) provides an estimate of k\nel. If a \ndrug is rapidly metabolised or excreted, the \u03b1 and \u03b2 phases \nare not well separated, and the calculation of separate V\nd and kel values for each phase is not straightforward. \nProblems also arise with drugs (e.g. very fat-soluble drugs) mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3505, "end_char_idx": 4500, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b68b54a1-d1e2-4e41-ac04-52ffa3aece54": {"__data__": {"id_": "b68b54a1-d1e2-4e41-ac04-52ffa3aece54", "embedding": null, "metadata": {"page_label": "155", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8313d47c-8e42-4ae9-adc0-c72f881ea45d", "node_type": null, "metadata": {"page_label": "155", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9ac27d018e8f5e350d78926a4dece313e13f878adf09038fe698a85b39cf3e42"}, "3": {"node_id": "12e975ce-2ae1-4170-8334-7f26497bda69", "node_type": null, "metadata": {"page_label": "155", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3e0f7bb03c41e2755af9ab457e20fc8004acfd549732ebb5c1c1ad957905c21"}}, "hash": "ce8704ea694238590fbeb690f80f28ad8a631ffdceb7fc2969797f34ea01249c", "text": "11 PhARmACokINEtICS\n149Plasma diazepam concentration (\u00b5mol/L)\nHoursFast phase\nt? = 1.2 hSlow phase\nt? = 30 hDiazepam 105 \u00b5mol orally5\n2\n1.0\n0.5\n0.2\n0.1\n01 2 24\nFig. 11.7 Kinetics of diazepam elimination in humans \nfollowing a single oral dose. The graph shows a \nsemilogarithmic plot of plasma concentration versus time. The \nexperimental data (black symbols) follow a curve that becomes \nlinear after about 8 h (slow phase). Plotting the deviation of the \nearly points (pink shaded area) from this line on the same \ncoordinates (red symbols) reveals the fast phase. This type of \ntwo-component decay is consistent with the two-compartment model (see Fig. 11.6) and is obtained with many drugs. (Data from Curry, S.H., 1980. Drug Disposition and Pharmacokinetics. Blackwell, Oxford.)Dose\n(mmol/kg)\nAbsorptionDose\nadministeredBlood alcohol concentration (mmol/L)\nTime after ingestion (minutes)20\n10\n0\n06 09 0 12014.1\n10.9\n7.6\n4.3\nFig. 11.8 Saturating kinetics of alcohol elimination in \nhumans. The blood alcohol concentration falls linearly rather \nthan exponentially, and the rate of fall does not vary with dose. \n(From Drew, G.C. et al., 1958. Br. Med. J. 2, 5103.)\nfor which it is unrealistic to lump all the peripheral tissues \ntogether.\nSATURATION \u2003KINETICS\nIn the case of some drugs, including ethanol, phenytoin \nand salicylate, the time course of disappearance of drug \nfrom the plasma does not follow the exponential or biex -\nponential patterns shown in Figs 11.3 and 11.7 but is initially \nlinear (i.e. drug is removed at a constant rate that is \nindependent of plasma concentration). This is often called \nzero-order kinetics to distinguish it from the usual first-order \nkinetics that we have considered so far (these terms have \ntheir origin in chemical kinetic theory). Saturation kinetics \nis a better term, because it conveys the underlying mecha -\nnism, namely that a carrier or enzyme saturates and so as \nthe concentration of drug substrate increases, the rate of \nelimination approaches a constant value. Fig. 11.8 shows \nthe example of ethanol. It can be seen that the rate of disap -\npearance of ethanol from the plasma is constant at approxi -\nmately 4 mmol/L per h, irrespective of dose or of the plasma \nconcentration of ethanol. The explanation for this is that the rate of oxidation by the enzyme alcohol dehydrogenase \nreaches a maximum at low ethanol concentrations, because \nof limited availability of the cofactor NAD\n+ (see Ch. 49, \nFig. 49.6).\nSaturation kinetics has several important consequences \n(Fig. 11.9). One is that the duration of action is more strongly \ndependent on dose than is the case with drugs that do not show metabolic saturation. Another consequence is that the relationship between dose and steady-state \nplasma concentration is steep and unpredictable, and it \ndoes not obey the proportionality rule implicit in Eq. 11.3 for non-saturating drugs (see Fig. 49.6 for another example \nrelated to ethanol). The maximum rate of metabolism sets \na limit to the rate at which the drug can be administered; if this rate is exceeded, the amount of drug in the body \nwill, in principle, increase indefinitely and never reach a \nsteady state (see Fig. 11.9). This does not actually happen, because there is always some dependence of the rate of elimination on the", "start_char_idx": 0, "end_char_idx": 3321, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "12e975ce-2ae1-4170-8334-7f26497bda69": {"__data__": {"id_": "12e975ce-2ae1-4170-8334-7f26497bda69", "embedding": null, "metadata": {"page_label": "155", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8313d47c-8e42-4ae9-adc0-c72f881ea45d", "node_type": null, "metadata": {"page_label": "155", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9ac27d018e8f5e350d78926a4dece313e13f878adf09038fe698a85b39cf3e42"}, "2": {"node_id": "b68b54a1-d1e2-4e41-ac04-52ffa3aece54", "node_type": null, "metadata": {"page_label": "155", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce8704ea694238590fbeb690f80f28ad8a631ffdceb7fc2969797f34ea01249c"}}, "hash": "b3e0f7bb03c41e2755af9ab457e20fc8004acfd549732ebb5c1c1ad957905c21", "text": "happen, because there is always some dependence of the rate of elimination on the plasma concentration (usually because \nother, non-saturating metabolic pathways or renal excretion \ncontribute significantly at high concentrations). Nevertheless, steady-state plasma concentrations of drugs of this kind \nvary widely and unpredictably with dose. Similarly, \nvariations in the rate of metabolism (e.g. through enzyme induction) cause disproportionately large changes in the \nplasma concentration. These problems are well recognised \nfor drugs such as phenytoin, an anticonvulsant for which plasma concentration needs to be closely controlled to \nachieve an optimal clinical effect (see Ch. 46, Fig. 46.4). \nDrugs showing saturation kinetics are less predictable in clinical use than ones with first-order kinetics, so may be \nrejected during drug development if a pharmacologically \nsimilar candidate with first-order kinetics is available \n(Ch. 60).\nClinical applications of pharmacokinetics are summarised \nin the clinical box.\nPOPULATION \u2003PHARMACOKINETICS\n\u25bc In some situations, for example when a drug is intended for use \nin chronically ill children, it is desirable to obtain pharmacokinetic \ndata in a patient population rather than in healthy adult volunteers. \nSuch studies in children are inevitably limited and samples for \ndrug analysis are often obtained opportunistically during clinical care, with limitations as to quality of the data and on the number mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3240, "end_char_idx": 5186, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4c3b32ab-d1b7-4db6-ad92-dff87c342cbc": {"__data__": {"id_": "4c3b32ab-d1b7-4db6-ad92-dff87c342cbc", "embedding": null, "metadata": {"page_label": "156", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce4c54d1-fbf8-4fa5-a264-ad97b022f123", "node_type": null, "metadata": {"page_label": "156", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e891a7a8acb7297425c3dee9172c62ce312ca302d08b8de3f4ed89b333fccb40"}, "3": {"node_id": "6d835313-a35a-4337-846b-27bccb3f181f", "node_type": null, "metadata": {"page_label": "156", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01efd956728807902811cb0c412d2de038019ec49a1dc962ff0e4d459cf54692"}}, "hash": "bd5d18cde941e12cb4429b769283d3c1714686f35b18f2d334ee51b76feaed55", "text": "11 SECTION \u20031\u2003\u2003GENERAL PRINCIPLES\n150Dose (\u00b5mol/kg) Therapeutic rangePlasma concentration (\u00b5mol/L)10\n102030\n1015202540\nDays02468 10\nDays0246810150\n100\n50\n0\nPlasma concentration (\u00b5mol/L)150100\n50\n0Saturating kinetics Normal kinetics\nA B\nFig. 11.9 Comparison of non-saturating and saturating kinetics for drugs given orally every 12 h. (A) The curves showing an \nimaginary drug, similar to the antiepileptic drug phenytoin at the lowest dose, but with linear kinetics. The steady-state plasma \nconcentration is reached within a few days, and is directly proportional to dose. (B) Curves for saturating kinetics calculated from the known pharmacokinetic parameters of phenytoin (see Ch. 45). Note that no steady state is reached with higher doses of phenytoin, and that a small increment in dose results after a time in a disproportionately large effect on plasma concentration. (Curves were calculated with the Sympak pharmacokinetic modelling program written by Dr J.G. Blackman, University of Otago.)\nUses of pharmacokinetics \n\u2022\tPharmacokinetic \tstudies \tperformed \tduring \tdrug \t\ndevelopment underpin the standard dose regimens \napproved by regulatory agencies.\n\u2022\tClinicians \tsometimes \tneed \tto \tindividualise \tdose \tregimens \t\nto account for individual variation in a particular patient (e.g. a neonate, a patient with impaired and changing renal function, or a patient taking drugs that interfere \nwith drug metabolism; see Ch. 10).\n\u2022\tDrug\teffect \t(pharmacodynamics) \tis \toften \tused \tfor \tsuch \t\nindividualisation, but there are drugs (including some \nanticonvulsants, immunosuppressants and antineoplastics) where a therapeutic range of plasma \nconcentrations has been defined, and for which it is \nuseful to adjust the dose to achieve a concentration in this range.\n\u2022\tKnowledge \tof \tkinetics \tenables \trational \tdose \tadjustment. \t\nFor example:\n\u2013 the frequency of dosing of a drug such as gentamicin \neliminated by renal excretion may need to be markedly reduced in a patient with renal impairment (Ch. 52);\n\u2013 the dose increment needed to achieve a target plasma \nconcentration range of a drug such as phenytoin with \nsaturation kinetics (Ch. 46, Fig. 46.4) is much less than for a drug with linear kinetics.\n\u2022\tKnowing \tthe \tapproximate \tt1/2 of a drug can be very \nuseful, even if a therapeutic concentration is not known:\n\u2013 in correctly interpreting adverse events that occur \nsome considerable time after starting regular treatment (e.g. benzodiazepines; see Ch. 45);\n\u2013 in deciding on the need or otherwise for an initial \nloading dose when starting treatment with drugs such as digoxin and amiodarone (Ch. 22).\n\u2022\tThe\tvolume \tof \tdistribution \t(Vd) of a drug determines the \nsize\tof\tloading \tdose \tneeded. \tIf \tVd is large (as for many \ntricyclic antidepressants), haemodialysis will not be an effective way of increasing the rate of elimination in \ntreating overdose.\nof samples collected from each patient. Population pharmacokinet -\nics addresses how best to analyse such data. Fitting data from all \nsubjects as if there were no kinetic differences between individuals, \nand fitting each individual\u2019s data separately and then combining the individual parameter estimates, each have obvious shortcom -\nings. A better method is to use non-linear mixed effects modelling (NONMEM). The statistical technicalities are considerable and beyond the scope of this chapter: the interested reader is referred to Sheiner \net al. (1997).LIMITATIONS", "start_char_idx": 0, "end_char_idx": 3453, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d835313-a35a-4337-846b-27bccb3f181f": {"__data__": {"id_": "6d835313-a35a-4337-846b-27bccb3f181f", "embedding": null, "metadata": {"page_label": "156", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce4c54d1-fbf8-4fa5-a264-ad97b022f123", "node_type": null, "metadata": {"page_label": "156", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e891a7a8acb7297425c3dee9172c62ce312ca302d08b8de3f4ed89b333fccb40"}, "2": {"node_id": "4c3b32ab-d1b7-4db6-ad92-dff87c342cbc", "node_type": null, "metadata": {"page_label": "156", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bd5d18cde941e12cb4429b769283d3c1714686f35b18f2d334ee51b76feaed55"}}, "hash": "01efd956728807902811cb0c412d2de038019ec49a1dc962ff0e4d459cf54692", "text": "interested reader is referred to Sheiner \net al. (1997).LIMITATIONS \u2003OF \u2003PHARMACOKINETICS\nSome limitations of the pharmacokinetic approach will be \nobvious from the above account, such as the proliferation \nof parameters in even quite conceptually simple models. \nThere are also limitations in the usefulness of monitoring drug concentrations in plasma as an approach to reducing \nindividual variability in drug response (see Ch. 12). Two mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3385, "end_char_idx": 4304, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ca8f7f67-d41b-484f-8046-dbf9f5ea57b7": {"__data__": {"id_": "ca8f7f67-d41b-484f-8046-dbf9f5ea57b7", "embedding": null, "metadata": {"page_label": "157", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "81af5941-b959-4b1d-824f-30de3496ca4d", "node_type": null, "metadata": {"page_label": "157", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ebacfe4e149ad1a8eb4b5ea17ea8a519089ca3b49bd395e81249821363b3e69"}}, "hash": "4ebacfe4e149ad1a8eb4b5ea17ea8a519089ca3b49bd395e81249821363b3e69", "text": "11 PhARmACokINEtICS\n151main assumptions underpin the expectation that by relating \nresponse to a drug to its plasma concentration we can reduce \nvariability of response by accounting for pharmacokinetic \nvariation \u2013 that is, variation in ADME. They are:\n1. That plasma concentration of a drug bears a precise \nrelation to the concentration of drug in the immediate \nenvironment of its target (receptor, enzyme, etc.).\n2. That drug response depends only on the \nconcentration of the drug in the immediate \nenvironment of its target.\nWhile the first of these assumptions is very plausible for \nthose few drugs that work through a target in the circulating \nblood (e.g. a fibrinolytic drug working on fibrinogen) and \nreasonably plausible for a drug working on an enzyme, \nion channel or G protein\u2013coupled or kinase-linked receptor \nlocated in the cell membrane, it is less likely in the case of a nuclear receptor or when an active metabolite is involved. \nBecause of the blood\u2013brain barrier, plasma concentrations \nrarely reflect local drug concentrations in the brain, so, \nwith exception of lithium (Ch. 48) and some antiepileptic \ndrugs (Ch. 46), monitoring of plasma concentrations is not \nclinically useful.,\nThe second assumption is untrue in the case of drugs \nthat form a stable covalent attachment with their target, \nand so produce an effect that outlives their presence in \nsolution. Examples include the antiplatelet effects of aspirin \nand clopidogrel (Ch. 25) and the effect of some monoamine \noxidase inhibitors (Ch. 48). In other cases, drugs in thera -\npeutic use act only after delay (e.g. antidepressants, Ch. \n48), or gradually induce tolerance (e.g. opioids, Ch. 43) or \nphysiological adaptations (e.g. corticosteroids, Ch. 34) that \nalter the relation between concentration and drug effect in \na time-dependent manner.\nREFERENCES\u2003 AND\u2003 FURTHER\u2003 READING\nAtkinson, A., Huang, S.M., Lertora, J., Markey, S. (Eds.), 2012. Principles \nof Clinical Pharmacology, third ed. Academic Press, London. ( Includes \ndetailed section on pharmacokinetics )\nBirkett, D.J., 2010. Pocket Guide: Pharmacokinetics Made Easy. \nMcGraw\u2013Hill Australia, Sydney. ( Excellent slim volume that lives up to \nthe promise of its title )\nRowland, M., Tozer, T.N., 2010. Clinical Pharmacokinetics and \nPharmacodynamics. Concepts and Applications. Wolters Kluwer/Lippincott Williams & Wilkins, Baltimore. Online simulations by H. \nDerendorf and G. Hochhaus. ( Excellent text; emphasises clinical \napplications )\nPopulation pharmacokinetics\nSheiner, L.B., Rosenberg, B., Marethe, V.V., 1997. Estimation of \npopulation characteristics of pharmacokinetic parameters from routine \nclinical data. J. Pharmacokinet. Biopharm. 5, 445\u2013479.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3198, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2278994b-8766-4065-9b64-8652e3259b1c": {"__data__": {"id_": "2278994b-8766-4065-9b64-8652e3259b1c", "embedding": null, "metadata": {"page_label": "158", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4d7bcb60-5d9e-4105-b17c-af8a1988ee80", "node_type": null, "metadata": {"page_label": "158", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95e1af48141c1522a1c6bfcb3a3d2fa526cc756826cb5fade0ced0a762029584"}, "3": {"node_id": "68c0b906-16e6-41d8-ae1a-ae95eb1e04bd", "node_type": null, "metadata": {"page_label": "158", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8c2a05fdce49c1edafab8516c321eb297d93be22e10a33582b5e7d46aef8e804"}}, "hash": "f6f115eea1478feb9a3f57a33a4d5cd6d9b25ea2a35d7d2fbb316934bdcb5e48", "text": "152\nIndividual variation, \npharmacogenomics and \npersonalised medicine12 GENERAL PRINCIPLES SECTION 1\nOVERVIEW\nThis chapter addresses sources of variation between \nindividuals (inter-individual variation) in their responses \nto drugs. Important factors, including ethnicity, age, \npregnancy, disease and drug interaction (i.e. modifica -\ntion of the action of one drug by another), are \ndescribed. The concept of individualising drug therapy \nin light of genomic information (\u2018personalised medi -\ncine\u2019) \u2013 a rapidly developing area of clinical pharmacol -\nogy \u2013 is introduced. We explain relevant elementary genetic concepts and describe briefly several single-gene pharmacogenetic disorders that affect drug \nresponses. We then cover pharmacogenomic tests, \nincluding tests for variations in human leukocyte antigen (HLA) genes, in genes influencing drug \nmetabolism, and encoding drug targets.\nINTRODUCTION\nTherapeutics would be a great deal easier if the same dose \nof drug always produced the same response. In reality, \ninter- and even intra-individual variation is often substantial \nand this can lead to important differences in the balance between benefit and harm of treatment. Physicians need \nto be aware of the sources of such variation to prescribe \ndrugs safely and effectively. Variation can be caused by different concentrations at sites of drug action or by different \nresponses to the same drug concentration. The first kind \nis called pharmacokinetic variation and can occur because of \ndifferences in absorption, distribution, metabolism or excretion (ADME; Chs 9 and 10). The second kind is called \npharmacodynamic variation. Responses to some therapeutic \nagents, for example, most vaccines and oral contraceptives (Ch. 36), are sufficiently predictable to permit a standard \ndose regimen, whereas treatment with lithium (Ch. 48), \nantihypertensive drugs (Ch. 23), anticoagulants (Ch. 25) \nand many other drugs is individualised, doses being \nadjusted on the basis of monitoring the drug concentration \nin the plasma or a response such as change in blood pressure, together with any adverse effects.\nInter-individual variation in response to some drugs is \na serious problem; if not taken into account, it can result in lack of efficacy or unexpected adverse effects. Whilst \nlarge-scale clinical trials may be able to predict the \u2018average\u2019 \neffect of a drug, clinicians also recognise that there are subgroups of individuals who have a greater potential for \nbeneficial response than others. Variation is partly caused \nby environmental factors, but studies comparing identical with non-identical twins suggest that much of the variation in response to some drugs is genetically determined; for \nexample, elimination half-lives of antipyrine, a probe of hepatic drug oxidation, and of warfarin, an oral antico -\nagulant (Ch. 25), differ much less between identical than between fraternal twins. However, even for drugs with a \nknown genetic component such as warfarin (see p. 161 \nand Ch. 25), addition of pharmacogenetic information to \na dosing algorithm incorporating other clinical sources of \nvariation (age, sex and so on) does not improve outcome significantly, although when compared with a standardised \n(i.e. trial and error) loading dose strategy, a genetically \nguided dose-initiation strategy does result in a greater fraction of time in the therapeutic range during the first \nweeks of treatment (see Zineh et al., 2013 and Stergiopoulos \net al., 2014 for a discussion of randomised controlled trials \nof pharmacogenetics and warfarin dosing).\nGenes influence pharmacokinetics by altering the expres -\nsion of proteins involved in drug ADME; pharmacodynamic variation reflects differences in drug targets, G proteins or other downstream pathways; and individual susceptibility \nto", "start_char_idx": 0, "end_char_idx": 3821, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "68c0b906-16e6-41d8-ae1a-ae95eb1e04bd": {"__data__": {"id_": "68c0b906-16e6-41d8-ae1a-ae95eb1e04bd", "embedding": null, "metadata": {"page_label": "158", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4d7bcb60-5d9e-4105-b17c-af8a1988ee80", "node_type": null, "metadata": {"page_label": "158", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95e1af48141c1522a1c6bfcb3a3d2fa526cc756826cb5fade0ced0a762029584"}, "2": {"node_id": "2278994b-8766-4065-9b64-8652e3259b1c", "node_type": null, "metadata": {"page_label": "158", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f6f115eea1478feb9a3f57a33a4d5cd6d9b25ea2a35d7d2fbb316934bdcb5e48"}}, "hash": "8c2a05fdce49c1edafab8516c321eb297d93be22e10a33582b5e7d46aef8e804", "text": "G proteins or other downstream pathways; and individual susceptibility \nto uncommon qualitatively distinct adverse reactions (Ch. \n58) can result from genetically determined differences in enzymes or immune mechanisms. It is hoped that as our \nunderstanding of the human genome improves, together \nwith the introduction of simpler methods to identify genetic differences between individuals, it will become possible to use genetic information specific to an individual patient \nto preselect a drug that will be effective and not cause \ntoxicity, rather than relying on trial and error supported by physiological clues as at present \u2013 an aspiration referred \nto as personalised medicine. Thus far, this approach, which \nwas initially over-hyped, has yielded relatively little in the \nway of clinical benefit. Research continues at a breakneck \npace however, and the US FDA has approved over 200 \npharmacogenomic biomarkers for inclusion in drug labelling information \u2013 a doubling since the last edition of this book. \nThe Genetic Testing Registry in the United States accepts \nsubmissions from laboratories worldwide regarding the genetic tests that are made available for the purposes of \nscreening, diagnosis, drug/disease monitoring and treatment \nresponse. As of April 2017, the registry has recorded information on 49,500 tests covering 16,233 genes that are \nassociated with 10,733 diseases (Khoury, 2017). However, \nthe use of pharmacogenomic tests is not consistently sup -\nported by evidence of improved outcomes from clinical \ntrials (Zineh et al., 2013; Phillips, 2017) and indeed the FDA \napproach to pharmacogenetic labelling has been criticised (Shah & Shah, 2012). Nevertheless, pharmacogenetic testing \nseems likely ultimately to make an important contribution \nto therapeutics, though at a cost.\nIn this chapter we first describe the most important \nepidemiological sources of variation in drug responsiveness, before revisiting some elementary genetics as a basis for understanding genetic disorders characterised by abnormal \nresponses to drugs. We conclude with a brief account of \ncurrently available pharmacogenomic tests and how these \nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3747, "end_char_idx": 6387, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d9b7ba0c-0153-4a6f-8584-96ba653c35b3": {"__data__": {"id_": "d9b7ba0c-0153-4a6f-8584-96ba653c35b3", "embedding": null, "metadata": {"page_label": "159", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "078e2284-0b57-4fd2-b67a-a9630c585bbc", "node_type": null, "metadata": {"page_label": "159", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f999b298def0648379cde142fe37075cdbbea986be6358afa5abf79c9e654d45"}, "3": {"node_id": "2daf7b62-9a93-4ece-8f36-00de033fcc49", "node_type": null, "metadata": {"page_label": "159", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ccb35a3c246f070b44cc1fc3673fcb55ddc4f93010fb96e16a1f05b01073fe9e"}}, "hash": "7771ac439bb4e0e0ea70c42048fb8b90e866da9655d1e9a9cd599edff089e81b", "text": "12 INdIvIduAL vARIA tIoN, P h AR m AC o GEN om ICS AN d PERS o NALISE d m E d ICINE\n153antagonists, Chinese subjects metabolise propranolol faster \nthan white people, implying that the difference relates to \npharmacodynamic differences at or beyond the \u03b2 \nadrenoceptors.\nOverall effectiveness of gefitinib (Ch. 57) in treating \npatients with advanced lung tumours has been disappoint -\ning, but in about 10% of patients, lung tumours shrink \nrapidly in response to this drug. Japanese patients are three \ntimes as likely as whites to respond in this way. The \nunderlying difference is that patients who respond well have specific mutations in the receptor for epidermal growth factor (see Wadman, 2005). It is probable that many such \nethnic differences are genetic in origin, but environmental \nfactors, for example, relating to distinctive dietary habits, may also contribute. It is important not to abandon the \nmuch more sophisticated search for ways to individualise \nmedicine on the basis of pharmacogenomics just because the much simpler and cheaper process of asking patients \nto define their ethnic group has had some success: this \nshould rather act as a spur. If such a crude and imperfect approach has had some success, we ought surely to be able \nto do better with genomic testing!\nAGE\nThe main reason that age affects drug action is that drug \nelimination is less efficient in newborn babies and in older \npeople, so that drugs commonly produce greater and more \nprolonged effects at the extremes of life. Other age-related factors, such as variations in pharmacodynamic sensitivity, \nare also important with some drugs. Body composition \nchanges with age, fat contributing a greater proportion to body mass in the elderly, with consequent changes in \ndistribution volume of drugs. Elderly people typically \nconsume more drugs than do younger adults, so the potential for drug interactions is also increased. For fuller accounts of drug therapy in paediatrics and in the elderly, \nsee the chapters on renal and hepatic disease in Atkinson \net al. (2012).\nEFFECT OF AGE ON RENAL EXCRETION OF DRUGS\nGlomerular filtration rate (GFR) in the newborn, normalised \nto body surface area, is only about 20% of the adult value. \nAccordingly, plasma elimination half-lives of renally \neliminated drugs are longer in neonates than in adults (Table 12.1). In babies born at term, renal function increases \nto values similar to those in young adults in less than a week, and continues to increase to a maximum of approxi -\nmately twice the adult value at 6 months of age. Improve -\nment in renal function occurs more slowly in premature infants. Renal immaturity in premature infants can have a substantial effect on drug elimination. For example, in premature newborn babies, the antibiotic gentamicin (see \nCh. 52) has a plasma half-life of \u2265\n18 h, compared with \n1\u20134 h for adults and approximately 10 h for babies born \nat term. It is therefore necessary to reduce and/or space out doses to avoid toxicity in premature babies.\nGFR declines slowly from about 20 years of age, falling \nby about 25% at 50 years and by 50% at 75 years. Fig. 12.1 shows that the renal clearance of digoxin in young and \nelderly subjects is closely correlated with creatinine clear -\nance, a measure of GFR. Consequently, chronic administra -\ntion over the years of the same daily dose of digoxin to an \nindividual as he or she ages leads to a progressive increase \nin plasma concentration, and this is a common cause of glycoside toxicity in elderly people (see Ch. 22).are beginning to be applied to individualise drug therapy", "start_char_idx": 0, "end_char_idx": 3611, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2daf7b62-9a93-4ece-8f36-00de033fcc49": {"__data__": {"id_": "2daf7b62-9a93-4ece-8f36-00de033fcc49", "embedding": null, "metadata": {"page_label": "159", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "078e2284-0b57-4fd2-b67a-a9630c585bbc", "node_type": null, "metadata": {"page_label": "159", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f999b298def0648379cde142fe37075cdbbea986be6358afa5abf79c9e654d45"}, "2": {"node_id": "d9b7ba0c-0153-4a6f-8584-96ba653c35b3", "node_type": null, "metadata": {"page_label": "159", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7771ac439bb4e0e0ea70c42048fb8b90e866da9655d1e9a9cd599edff089e81b"}}, "hash": "ccb35a3c246f070b44cc1fc3673fcb55ddc4f93010fb96e16a1f05b01073fe9e", "text": "people (see Ch. 22).are beginning to be applied to individualise drug therapy (pharmacogenomics).\nVariation is usually quantitative in the sense that the \ndrug produces a larger or smaller effect, or acts for a longer or shorter time, while still exerting qualitatively the same \neffect. But, importantly, the effect may be qualitatively \ndifferent in susceptible individuals, often because of genetic or immunological differences. Examples include primaquine -\ninduced haemolysis in individuals with glucose 6-phosphate \ndehydrogenase deficiency whose red blood cells are thereby \nmore susceptible to the effect of oxidative stress (Ch. 55), and immune-mediated haemolytic anaemia caused by \nmethyldopa \u2013 a drug that commonly causes antidrug \nantibodies \u2013 whereas only a few individuals expressing such antibodies develop haemolysis (Ch. 15).\nIndividual variation \n\u2022\tVariability \tis \ta \tserious \tproblem; \tif \tnot \ttaken \tinto \t\naccount,\tit \tcan \tresult \tin:\n\u2013\tlack\tof\tefficacy\n\u2013\tunexpected \tharmful \teffects\n\u2022\tTypes\tof \tvariability \tmay \tbe \tclassified \tas:\n\u2013\tpharmacokinetic\n\u2013\tpharmacodynamic\n\u2022\tThe\tmain \tcauses \tof \tvariability \tare:\n\u2013\tage\n\u2013\tgenetic\tfactors\n\u2013\timmunological \tfactors \t(Ch. \t58)\n\u2013\tdisease \t(especially \twhen \tthis \tinfluences \tdrug \t\nelimination \tor \tmetabolism, \te.g. \tkidney \tor \tliver \t\ndisease)\n\u2013\tdrug\tinteractions\nEPIDEMIOLOGICAL FACTORS AND \nINTER-INDIVIDUAL VARIATION OF \nDRUG RESPONSE\nETHNICITY\nEthnic means \u2018pertaining to race\u2019, and many anthropologists \nare sceptical as to the value of this concept (see, for example, \nCooper et al., 2003). Members of racial groups share some \ncharacteristics on the basis of common genetic and cultural heritage, but there is enormous diversity within each group.\nDespite the crudeness of such categorisation, it can \ngive some pointers to drug responsiveness (Wood, 2001). One example is the evidence discussed in Chapter 23 \nthat the life expectancy of African-Americans with heart \nfailure is increased by treatment with a combination of hydralazine plus a nitrate, whereas that of white Americans \nmay not be.\nSome adverse effects may also be predicted on the basis \nof race; for example, many Chinese subjects differ from Europeans in the way that they metabolise ethanol (Ch. \n49), producing a higher plasma concentration of acetalde -\nhyde, which can cause flushing and palpitations. Chinese \nsubjects are considerably more sensitive to the cardiovascular \neffects of propranolol (Ch. 15) than white Europeans, \nwhereas Afro-Caribbean individuals are less sensitive. Despite their increased sensitivity to \u03b2-adrenoceptor mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3534, "end_char_idx": 6610, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "60b5ac3a-6dd9-425b-8d58-4b61eb19c577": {"__data__": {"id_": "60b5ac3a-6dd9-425b-8d58-4b61eb19c577", "embedding": null, "metadata": {"page_label": "160", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "224344af-e9f6-4e94-88ec-e1dfa76512f1", "node_type": null, "metadata": {"page_label": "160", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c68ee3cf32bfb42f22ac18f35f94fe14dc7de40caa006d2bb82ab7e0d84c065"}, "3": {"node_id": "35af1083-b48f-4243-bb1a-2e74c7fc0b74", "node_type": null, "metadata": {"page_label": "160", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f228b8a741192ae1db5f00fb4d43125382d9d97b9cbe9b7884bc416ae4c3fcd8"}}, "hash": "f83e4eacfcc432aa9442d6793abf443ddc0611693ee62e20a6d75d09a7acccbf", "text": "12 SECTION 1 GENERAL PRINCIPLES\n154EFFECT OF AGE ON DRUG METABOLISM\nSeveral important enzymes, including hepatic microsomal \noxidase, glucuronyltransferase, acetyltransferase and plasma \nesterases, have low activity in neonates, especially if pre -\nmature. These enzymes take 8 weeks or longer to reach \nthe adult level of activity. The relative lack of conjugating \nactivity in the newborn can have serious consequences, as \nin kernicterus caused by drug displacement of bilirubin from \nits binding sites on albumin (Ch. 9) and in the \u2018grey baby\u2019 \nsyndrome caused by the antibiotic chloramphenicol (see \nCh. 52). This sometimes-fatal condition, at first thought to \nbe a specific biochemical sensitivity to the drug in young babies, actually results simply from accumulation of very \nhigh tissue concentrations of chloramphenicol because of \nslow hepatic conjugation. Chloramphenicol is no more toxic to babies than to adults, provided the dose is reduced to \nmake allowance for this. Slow conjugation is also one reason \nwhy morphine (which is excreted mainly as the glucuronide, \nsee Ch. 43) is not used as an analgesic in labour, because \ndrug transferred via the placenta has a long half-life in \nthe newborn baby and can cause prolonged respiratory \ndepression.\nThe activity of hepatic microsomal enzymes declines \nslowly (and very variably) with age, and the distribution volume of lipid-soluble drugs increases, because the propor -\ntion of the body that is fat increases with advancing age. The increasing half-life of the anxiolytic drug diazepam \nwith advancing age (Fig. 12.2) is one consequence of this. \nSome other benzodiazepines and their active metabolites \nshow even greater age-related increases in half-life. Because half-life determines the time course of drug accumulation during repeated dosing (Ch. 11), insidious effects, develop -\ning over days or weeks, can occur in elderly people and may be misattributed to age-related memory impairment rather than to drug accumulation. Even if the mean half-life \nof a drug is little affected, there is often a striking increase \nin the variability of half-life between individuals with increasing age (as in Fig. 12.2). This is important, because \na population of older people will contain some individuals \nwith grossly reduced rates of drug metabolism, whereas such extremes do not occur so commonly in young adult \npopulations. Drug regulatory authorities therefore usually \n\u25bc The age-related decline in GFR is not reflected by an increase \nin plasma creatinine concentration, as distinct from creatinine clear-\nance. Plasma creatinine typically remains within the normal adult \nrange in elderly persons despite substantially diminished GFR. \nThis is because creatinine synthesis is reduced in elderly persons because of their reduced muscle mass. Consequently, a \u2018normal\u2019 \nplasma creatinine in an elderly person does not indicate that they \nhave a normal GFR. Failure to recognise this and reduce the dose of drugs that are eliminated by renal excretion can lead to drug \ntoxicity.Table 12.1 Effect of age on plasma elimination half-lives \nof various drugs\nDrugMean or range of half-life (h)\nTerm \nneonateaAdultElderly person\nDrugs that are mainly excreted unchanged in the urine\nGentamicin 10 2 4\nLithium 120 24 48\nDigoxin 200 40 80\nDrugs that are mainly metabolisedDiazepam 25\u2013100 15\u201325 50\u2013150\nPhenytoin 10\u201330 10\u201330 10\u201330\nSulfamethoxypyridazine 140 60 100\naEven\tgreater \tdifferences \tfrom \tmean \tadult \tvalues \toccur \tin \t\npremature", "start_char_idx": 0, "end_char_idx": 3511, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "35af1083-b48f-4243-bb1a-2e74c7fc0b74": {"__data__": {"id_": "35af1083-b48f-4243-bb1a-2e74c7fc0b74", "embedding": null, "metadata": {"page_label": "160", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "224344af-e9f6-4e94-88ec-e1dfa76512f1", "node_type": null, "metadata": {"page_label": "160", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c68ee3cf32bfb42f22ac18f35f94fe14dc7de40caa006d2bb82ab7e0d84c065"}, "2": {"node_id": "60b5ac3a-6dd9-425b-8d58-4b61eb19c577", "node_type": null, "metadata": {"page_label": "160", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f83e4eacfcc432aa9442d6793abf443ddc0611693ee62e20a6d75d09a7acccbf"}}, "hash": "f228b8a741192ae1db5f00fb4d43125382d9d97b9cbe9b7884bc416ae4c3fcd8", "text": "\tdifferences \tfrom \tmean \tadult \tvalues \toccur \tin \t\npremature \tbabies.\n(Data\tfrom \tReidenberg, \tM.M., \t1971. \tRenal \tFunction \tand \tDrug \t\nAction.\tSaunders, \tPhiladelphia; \tand \tDollery, \tC.T., \t1991. \t\nTherapeutic \tDrugs. \tChurchill \tLivingstone, \tEdinburgh.)\n04080120160\n120 80 40 0\nDigoxin clearance (mL/min per 1.73 m2)Old\n77\u00b14 yrYoung27\u00b14 yrCreatinine clearance (mL/min per 1.73 m2)\nFig. 12.1 \tRelationship between renal function (measured \nas creatinine clearance) and digoxin clearance in young and \nolder subjects. \t(From\tEwy, \tG.A. \tet \tal., \t1969. \tCirculation \t34, \t\n452.)04080120\n80 40 0Plasma half-life (h)\nAge (yr)20 60\nFig. 12.2 \tIncreasing plasma half-life for diazepam with \nage in 33 normal subjects. \tNote\tthe\tincreased \tvariability \tas \t\nwell\tas\tincreased \thalf-life \twith \tageing. \t(From \tKlotz, \tU. \tet \tal., \t\n1975.\tJ.\tClin. \tlnvest. \t55, \t347.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3449, "end_char_idx": 4797, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7d744ee3-b96f-4fa9-9872-564059eb5fd9": {"__data__": {"id_": "7d744ee3-b96f-4fa9-9872-564059eb5fd9", "embedding": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d6c94082-27b9-4bd9-83e7-cd39cd0b8ad2", "node_type": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "253806d81cc9937363c491fbfaf31e9ec2d55c56b8d150fcb3858e7498d5a897"}, "3": {"node_id": "9a650489-83d1-43d3-92fe-9bc4f158c38b", "node_type": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42ef6e064c0776a3d995f9afeb1b8b802b1752b25b59f241fe66ce41a65989ba"}}, "hash": "b1e315946f8390a78e63fb1e3b37c673133baf0200eb69f24fd9ee21c4c0f666", "text": "12 INdIvIduAL vARIA tIoN, P h AR m AC o GEN om ICS AN d PERS o NALISE d m E d ICINE\n155\u2022\tDiseases \tthat \tinfluence \treceptors:\n\u2022\tmyasthenia gravis, an autoimmune disease \ncharacterised by antibodies to nicotinic acetylcholine \nreceptors (Ch. 14) and increased sensitivity to \nneuromuscular-blocking agents (e.g. vecuronium) and other drugs that may influence neuromuscular \ntransmission (e.g. aminoglycoside antibiotics, Ch. 52);\n\u2022\tX-linked nephrogenic diabetes insipidus, characterised \nby abnormal antidiuretic hormone (ADH, \nvasopressin) receptors (Ch. 30) and insensitivity \nto ADH;\n\u2022\tfamilial hypercholesterolaemia, an inherited disease of low-density lipoprotein receptors (Ch. 24); the \nhomozygous form is relatively resistant to treatment \nwith statins (which act partly by causing increased hepatic expression of these receptors), whereas the \nmuch commoner heterozygous form responds well \nto statins.\n\u2022\tDiseases \tthat \tinfluence \tsignal-transduction \t\nmechanisms:\u2022\tpseudohypoparathyroidism, which stems from \nimpaired coupling of G protein\u2013coupled receptors \nwith adenylyl cyclase;\n\u2022\tfamilial precocious puberty and hyperthyroidism caused \nby functioning thyroid adenomas, which are each \ncaused by mutations in G protein\u2013coupled receptors that result in the receptors remaining \u2018turned on\u2019 \neven in the absence of the hormones that are their \nnatural agonists.\nDRUG INTERACTIONS\nMany patients, especially elderly ones, are treated continu -\nously with one or more drugs for chronic diseases such as \nhypertension, heart failure, osteoarthritis and so on. Acute \nevents (e.g. infections, myocardial infarction) are treated with additional drugs. The potential for drug interactions \nis therefore substantial, and drug interactions account for \n5%\u201320% of adverse drug reactions. These may be serious (approximately 30% of fatal adverse drug reactions are \nestimated to be the consequence of drug interaction). Drugs \ncan also interact with chemical entities in other dietary constituents (e.g. grapefruit juice, which down-regulates expression of CYP3A4 in the gut) and herbal remedies \n(such as St John\u2019s wort; Ch. 48). The administration of one \nchemical entity (A) can alter the action of another (B) by one of two general mechanisms\n1:\n1. Modifying the pharmacological effect of B without \naltering its concentration in the tissue fluid (pharmacodynamic interaction).\n2. Altering the concentration of B at its site of action \n(pharmacokinetic interaction), as described in Chapters 9 and 10.require studies in elderly persons as part of the evaluation of drugs likely to be used in older people.\nAGE-RELATED VARIATION IN SENSITIVITY TO DRUGS\nThe same plasma concentration of a drug can cause different effects in young and old subjects. Benzodiazepines (Ch. \n45) exemplify this, producing more confusion and less \nsedation in elderly than in young subjects; similarly, hypotensive drugs (Ch. 23) cause postural hypotension \nmore commonly in elderly than in younger adult patients.\nPREGNANCY\nPregnancy causes physiological changes that influence drug \ndisposition in mother and fetus. Maternal plasma albumin \nconcentration is reduced, influencing drug protein binding. \nCardiac output is increased, leading to increased renal blood flow and GFR, and increased renal elimination of drugs. \nLipophilic molecules rapidly traverse the placental barrier,", "start_char_idx": 0, "end_char_idx": 3365, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9a650489-83d1-43d3-92fe-9bc4f158c38b": {"__data__": {"id_": "9a650489-83d1-43d3-92fe-9bc4f158c38b", "embedding": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d6c94082-27b9-4bd9-83e7-cd39cd0b8ad2", "node_type": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "253806d81cc9937363c491fbfaf31e9ec2d55c56b8d150fcb3858e7498d5a897"}, "2": {"node_id": "7d744ee3-b96f-4fa9-9872-564059eb5fd9", "node_type": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b1e315946f8390a78e63fb1e3b37c673133baf0200eb69f24fd9ee21c4c0f666"}, "3": {"node_id": "1471e469-6350-49c6-aa04-dbc1814a712a", "node_type": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "371e9768fc2c4cb66a1fedb9f4e9dd18c9943ffad82294635d78989c0dc98c3b"}}, "hash": "42ef6e064c0776a3d995f9afeb1b8b802b1752b25b59f241fe66ce41a65989ba", "text": "\nLipophilic molecules rapidly traverse the placental barrier, \nwhereas transfer of hydrophobic drugs is slow, limiting fetal drug exposure following a single maternal dose. The \nplacental barrier excludes some drugs (e.g. low molecular-\nweight heparins; Ch. 25) so effectively that they can be administered chronically to the mother without causing effects in the fetus. However, drugs that are transferred to \nthe fetus are eliminated more slowly than from the mother. \nThe activity of most drug-metabolising enzymes in fetal liver is much less than in the adult. Furthermore, the fetal \nkidney is not an efficient route of elimination because \nexcreted drug enters the amniotic fluid, which is swal -\nlowed by the fetus. For a fuller account, see Atkinson et al. \n(2012).\nDISEASE\nTherapeutic drugs are prescribed to patients, so effects of disease on drug response are very important, especially \ndisease of the major organs responsible for drug metabolism \nand drug (and drug metabolite) excretion. Detailed con -\nsideration is beyond the scope of this book, and interested \nreaders should refer to a clinical text such as the chapters \non renal and hepatic disease in Atkinson et al. (2012). Disease \ncan cause pharmacokinetic or pharmacodynamic variation. \nCommon disorders such as impaired renal or hepatic \nfunction predispose to toxicity by causing unexpectedly \nintense or prolonged drug effects as a result of increased drug concentration following a \u2018standard\u2019 dose. Drug \nabsorption is slowed in conditions causing gastric stasis \n(e.g. migraine, diabetic neuropathy) and may be incomplete in patients with malabsorption owing to ileal or pancreatic \ndisease or to oedema of the ileal mucosa caused by heart \nfailure or nephrotic syndrome. Nephrotic syndrome (char-\nacterised by heavy proteinuria, oedema and a reduced concentration of albumin in plasma) alters drug absorption \nbecause of oedema of intestinal mucosa; alters drug disposi -\ntion through changes in binding to plasma albumin; and \ncauses insensitivity to diuretics such as furosemide that \nact on ion transport mechanisms in the lumenal surface of tubular epithelium (Ch. 30), through drug binding to albumin in tubular fluid. Hypothyroidism is associated with \nincreased sensitivity to several drugs (e.g. pethidine), for \nreasons that are poorly understood. Hypothermia (to which \nelderly persons, in particular, are predisposed) markedly reduces the clearance of many drugs.\nOther disorders affect drug sensitivity by altering receptor \nor signal-transduction mechanisms (see Ch. 3). Examples include the following:1A third category of pharmaceutical interactions should be mentioned, \nin which drugs interact in vitro so that one or both are inactivated. No \npharmacological principles are involved, just chemistry. An example is \nthe formation of a complex between thiopental and suxamethonium, which must not be mixed in the same syringe. Heparin is highly \ncharged and interacts in this way with many basic drugs; it is \nsometimes used to keep intravenous lines or cannulae open and can inactivate basic drugs if they are injected without first clearing the line \nwith saline.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3311, "end_char_idx": 6861, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1471e469-6350-49c6-aa04-dbc1814a712a": {"__data__": {"id_": "1471e469-6350-49c6-aa04-dbc1814a712a", "embedding": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d6c94082-27b9-4bd9-83e7-cd39cd0b8ad2", "node_type": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "253806d81cc9937363c491fbfaf31e9ec2d55c56b8d150fcb3858e7498d5a897"}, "2": {"node_id": "9a650489-83d1-43d3-92fe-9bc4f158c38b", "node_type": null, "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42ef6e064c0776a3d995f9afeb1b8b802b1752b25b59f241fe66ce41a65989ba"}}, "hash": "371e9768fc2c4cb66a1fedb9f4e9dd18c9943ffad82294635d78989c0dc98c3b", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6869, "end_char_idx": 7012, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "959274cb-af91-4990-a46d-2df7df9a1153": {"__data__": {"id_": "959274cb-af91-4990-a46d-2df7df9a1153", "embedding": null, "metadata": {"page_label": "162", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f333b79-639c-4bc8-9cb5-55ccdd770842", "node_type": null, "metadata": {"page_label": "162", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "60f98dc89f92c12396490bc2cdceb60b7a52c2da56e7eb849baf8f84d714726c"}, "3": {"node_id": "404650b7-5139-469d-b38f-b9c5488e693d", "node_type": null, "metadata": {"page_label": "162", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a967c0eb109cbccfae1fa770df981187ece0b3b30f7613f8f02461c3a2822d0"}}, "hash": "1d3f54c3b870ba96a4212c33e1aee304ffc571606b4d8b58ca1b10a426bb00e4", "text": "12 SECTION 1 GENERAL PRINCIPLES\n156Pharmacokinetic interaction\nAll the four major processes that determine pharmacokinet -\nics \u2013 absorption, distribution, metabolism and excretion \n(ADME) \u2013 can be affected by drugs. Such interactions are \ncovered in Chapters 9 and 10.PHARMACODYNAMIC INTERACTION\nPharmacodynamic interaction can occur in many different ways (including those discussed under Drug antagonism in \nCh. 2). There are many mechanisms, and some examples of practical importance are probably more useful than attempts at classification.\n\u2022\t\u03b2-Adrenoceptor antagonists diminish the \neffectiveness of \u03b2-adrenoceptor agonists such as salbutamol (Ch. 15).\n\u2022\tMany\tdiuretics \tlower \tplasma \tK+ concentration (see \nCh. 30), and thereby predispose to digoxin toxicity \nand to toxicity with class III antidysrhythmic drugs \n(Ch. 22).\n\u2022\tSildenafil inhibits the isoform of phosphodiesterase (type V) that inactivates cGMP (Chs 21 and 36); \nconsequently, it potentiates organic nitrates, which activate guanylyl cyclase, and can cause severe \nhypotension in patients taking these drugs.\n\u2022\tMonoamine oxidase inhibitors increase the amount of \nnoradrenaline stored in noradrenergic nerve terminals and interact dangerously with drugs, such as \nephedrine or tyramine, that release stored \nnoradrenaline. This can also occur with tyramine-rich foods \u2013 particularly fermented cheeses such as \nCamembert (see Ch. 48).\n\u2022\tWarfarin competes with vitamin K, preventing \nhepatic synthesis of various coagulation factors (see \nCh. 25). If vitamin K production in the intestine is \ninhibited (e.g. by antibiotics), the anticoagulant action of warfarin is increased.\n\u2022\tThe\trisk \tof \tbleeding, \tespecially \tfrom \tthe \t \nstomach, caused by warfarin is increased by \ndrugs that cause bleeding by different mechanisms \n(e.g. aspirin, which inhibits platelet thromboxane \nA2 biosynthesis and which can damage the stomach; \nCh. 27).\n\u2022\tSulfonamides prevent the synthesis of folic acid by bacteria and other microorganisms; trimethoprim inhibits its reduction to its active tetrahydrofolate \nform. Given together, the drugs have a synergistic \naction of value in treating Pneumocystis infection (Chs 54 and 55).\n\u2022\tNon-steroidal anti-inflammatory drugs (NSAIDs; Ch. 27), such as ibuprofen or indometacin, inhibit biosynthesis of prostaglandins, including renal vasodilator/natriuretic prostaglandins (prostaglandin \nE\n2, prostaglandin I 2). If administered to patients \nreceiving treatment for hypertension, they increase \nthe blood pressure. If given to patients being treated \nwith diuretics for chronic heart failure, they cause salt and water retention and hence cardiac \ndecompensation.\n2\n\u2022\tHistamine \tH1-receptor antagonists, such as \npromethazine, commonly cause drowsiness as an unwanted effect. This is more troublesome if such \ndrugs are taken with alcohol, leading to accidents at work or on the road.Drug interactions \n\u2022\tThese\tare \tmany \tand \tvaried: \tif \tin \tdoubt, \tlook \tit \tup.\n\u2022\tInteractions \tmay \tbe \tpharmacodynamic \tor \t\npharmacokinetic.\n\u2022\tPharmacodynamic \tinteractions \tare \toften \tpredictable \t\nfrom\tthe\tactions \tof \tthe \tinteracting \tdrugs.\n\u2022\tPharmacokinetic \tinteractions \tcan \tinvolve \teffects \ton:\n\u2013\tabsorption \t(Ch. \t9)\n\u2013\tdistribution", "start_char_idx": 0, "end_char_idx": 3241, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "404650b7-5139-469d-b38f-b9c5488e693d": {"__data__": {"id_": "404650b7-5139-469d-b38f-b9c5488e693d", "embedding": null, "metadata": {"page_label": "162", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f333b79-639c-4bc8-9cb5-55ccdd770842", "node_type": null, "metadata": {"page_label": "162", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "60f98dc89f92c12396490bc2cdceb60b7a52c2da56e7eb849baf8f84d714726c"}, "2": {"node_id": "959274cb-af91-4990-a46d-2df7df9a1153", "node_type": null, "metadata": {"page_label": "162", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1d3f54c3b870ba96a4212c33e1aee304ffc571606b4d8b58ca1b10a426bb00e4"}}, "hash": "6a967c0eb109cbccfae1fa770df981187ece0b3b30f7613f8f02461c3a2822d0", "text": "\ton:\n\u2013\tabsorption \t(Ch. \t9)\n\u2013\tdistribution \t(e.g. \tcompetition \tfor \tprotein \tbinding, \tCh. \t\n9)\n\u2013\thepatic\tmetabolism \t(induction \tor \tinhibition, \tCh. \t10)\n\u2013\trenal\texcretion \t(Ch. \t10)\n2The interaction with diuretics may involve a pharmacokinetic \ninteraction in addition to the pharmacodynamic effect described here, \nbecause NSAIDs compete with weak acids, including diuretics, for renal \ntubular secretion; see Ch. 9.3The genetic code is said to be \u2019degenerate\u2019 because of presence of \nredundancy, where more than one set of nucleotide base triplets code \nfor each amino acid. A \u2018silent\u2019 mutation with no change in the protein \nand consequently no change in function can stem from a base change involving a triplet that codes for the same amino acid as the original. \nSuch mutations are neither advantageous nor disadvantageous, so they \nwill neither be eliminated by natural selection nor accumulate in the population at the expense of the wild-type gene.GENETIC VARIATION IN DRUG \nRESPONSIVENESS\nA patient\u2019s response to a particular drug may be influenced \nby a rare genetic trait, or a complex multifactorial trait \ninvolving effects of several genetic and environmental \nfactors. Complex traits may not adhere to typical Mendelian or familial inheritance because they involve the additive \nor synergistic influence of multiple gene variants that can \ninteract with environmental factors to result in a wide spectrum of inter-individual drug response. Potential \npharmacogenetic markers of variation may include measur -\nable differences in gene expression or functional deficiencies \nrelated to genetic factors, i.e. somatic or germline mutations and chromosomal abnormalities.\nMutations are heritable changes in the base sequence of \nDNA. These may, or may not,\n3 result in a change in the \namino acid sequence of the protein for which the gene \ncodes. Germline or hereditary mutations are those that affect \nthe body\u2019s reproductive cells (egg or sperm) and can be \npassed to the next generation where they are present in all \ncells. In practice, tests for such germline mutations in \nindividuals are usually made on venous blood samples that contain chromosomal and mitochondrial DNA in white \nblood cells. Germline genetic variations that contribute to \ndifferences in drug response and adverse effects in specific populations can be assessed in large cohort or case\u2013control studies that use microarrays or whole genome/exome \nsequencing strategies to analyse several million genetic \nvariants. The recent emergence of high-throughput genotyp -\ning technology has enabled genome wide association studies \nto identify loci that are potentially linked to drug effect.\nSomatic or acquired mutations are not present at birth, \nbut can occur in any of the body cells (except the ova and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3199, "end_char_idx": 6473, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f8279be1-f2de-4735-9e36-ab397a3d3f89": {"__data__": {"id_": "f8279be1-f2de-4735-9e36-ab397a3d3f89", "embedding": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "754bc852-8f56-4e70-9b15-21bf00a90135", "node_type": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06e060820f2fe86089e6c6a15e41a80180d79a829f29514ec013ae4dc5ad0739"}, "3": {"node_id": "a2140e28-4d8c-4ab9-9b9e-d75e5cb5cebf", "node_type": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a9b5f86ea8893ab1131d84f4360e8b0d6de2480d33781877148cebdda4b1fddd"}}, "hash": "269eeb0aa33a0db85fc2248c68405a8b72701edeefbe7d8c48296632cacf445c", "text": "12 INdIvIduAL vARIA tIoN, P h AR m AC o GEN om ICS AN d PERS o NALISE d m E d ICINE\n157health conditions, some SNPs have a demonstrable relation -\nship with susceptibility to harmful chemicals, magnitude \nof drug response, and likelihood of developing a disease. \nFor example, SNPs affecting the F5 gene can cause factor \nV Leiden blood-clotting disorder, which is the commonest \nform of inherited thrombophilia (Ch. 25). The abnormality \nin the factor V clotting factor confers an increased risk of venous thrombosis in response to environmental factors \nsuch as prolonged immobility, but might perhaps have \nbeen an advantage to ancestors more at risk of haemorrhage than of thrombosis.\nSINGLE-GENE PHARMACOKINETIC DISORDERS\nThe classical Mendelian model contrasts with the complex disease paradigm because it applies to single-gene or \nmonogenic disorders where a mutation in a gene is the \nprimary or sole cause of profound disruption. These are typically rare disorders where the underlying genetic \nvariants have very high penetrance with inheritance patterns \nthat are readily predicted in a Mendelian fashion. This was recognised for albinism (albinos lack an enzyme that is \nneeded to synthesise the brown pigment melanin) and other \n\u2018inborn errors of metabolism\u2019 in the early part of the 20th century by Archibald Garrod, a British physician who initiated the study of biochemical genetics. Investigation \nof this large group of individually rare diseases has con -\ntributed to our understanding of this particular aspect of \nmolecular pathology \u2013 familial hypercholesterolaemia and \nthe mechanism of action of statins (Ch. 24) is one example; \nfurther examples of single-gene disorders are given below.\nPLASMA CHOLINESTERASE DEFICIENCY\nIn the 1950s Walter Kalow discovered that suxamethonium \nsensitivity is due to genetic variation in the rate of drug \nmetabolism as a result of a Mendelian autosomal recessive \ntrait. This short-acting neuromuscular-blocking drug is widely used in anaesthesia and is normally rapidly hydro-\nlysed by plasma cholinesterase (Ch. 14). About 1 in 3000 \nindividuals fail to inactivate suxamethonium rapidly and experience prolonged neuromuscular block if treated with \nit; this is because a recessive gene gives rise to an abnormal \ntype of plasma cholinesterase. The abnormal enzyme has a modified pattern of substrate and inhibitor specificity. It is detected by a blood test that measures the effect of \ndibucaine, which inhibits the abnormal enzyme less than \nthe normal enzyme. Heterozygotes can hydrolyse suxam -\nethonium at a more or less normal rate, but their plasma \ncholinesterase has reduced sensitivity to dibucaine, inter -\nmediate between normal subjects and homozygotes. Only \nhomozygotes express the disease: they appear completely \nhealthy unless exposed to suxamethonium or mivacurium \n(which is also inactivated by plasma cholinesterase) but \nexperience prolonged paralysis if exposed to a dose that \nwould cause neuromuscular block for only a few minutes \nin a healthy person.\n4 There are other reasons why responses sperm) during a lifetime, and are not passed on to the offspring. Whilst the vast majority of somatic mutations \nare thought to have no clinical consequence, those that \naffect key signalling pathways involved in cell growth, division and differentiation can predispose to carcinogenesis, \nas well as late-onset mitochondrial and neurogenerative \ndisorders. Somatic cell mutations underlie the pathogenesis of some tumours (Ch. 6),", "start_char_idx": 0, "end_char_idx": 3514, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a2140e28-4d8c-4ab9-9b9e-d75e5cb5cebf": {"__data__": {"id_": "a2140e28-4d8c-4ab9-9b9e-d75e5cb5cebf", "embedding": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "754bc852-8f56-4e70-9b15-21bf00a90135", "node_type": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06e060820f2fe86089e6c6a15e41a80180d79a829f29514ec013ae4dc5ad0739"}, "2": {"node_id": "f8279be1-f2de-4735-9e36-ab397a3d3f89", "node_type": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "269eeb0aa33a0db85fc2248c68405a8b72701edeefbe7d8c48296632cacf445c"}, "3": {"node_id": "e8251df0-ad92-4a9e-8116-db91407f09a5", "node_type": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b7bfc0829c0d7c4d322225f94b15aaceddb539b91e7183c2ccfeb370e02630dc"}}, "hash": "a9b5f86ea8893ab1131d84f4360e8b0d6de2480d33781877148cebdda4b1fddd", "text": "Somatic cell mutations underlie the pathogenesis of some tumours (Ch. 6), and the presence or absence of such somatic cell mutations guides drug selection. The \ngenomic tests are performed on DNA from samples of the \ntumour obtained surgically. The tests themselves involve amplification of the relevant sequence(s) and molecular \nbiological methods, often utilising chip technology, to \nidentify the various polymorphisms.\nGenetic variation or mutations are not always deleterious \nand they may confer an advantage under some environ -\nmental circumstances. A pharmacogenetically relevant example is the X-linked gene for glucose 6-phosphate dehy -\ndrogenase (G6PD); deficiency of this enzyme confers partial \nresistance to malaria (a considerable selective advantage in parts of the world where this disease is common) at the \nexpense of susceptibility to haemolysis in response to \noxidative stress in the form of exposure to various dietary constituents, including several drugs (e.g. the antimalarial \ndrug primaquine; see Ch. 55). This ambiguity gives rise \nto the abnormal gene being preserved in future generations, \nat a frequency that depends on the balance of selective pressures in the environment. Thus the distribution of G6PD \ndeficiency is similar to the geographical distribution of \nmalaria. The situation where functionally distinct forms of a gene are common in a population is called a \u2018balanced\u2019 \npolymorphism (balanced because a disadvantage, for \nexample in a homozygote, is balanced by an advantage, for example in a heterozygote).\nPolymorphisms are relatively common variants (alternative \nsequences at a locus within the DNA strand) that are found in >1% of individuals within a given population. They arise \ninitially because of a mutation, and are stable if they are non-functional, or die out during subsequent generations if (as is usually the case) they are disadvantageous. However, \nif the prevailing selective pressures in the environment are \nfavourable, leading to a selective advantage, a polymorphism may increase in frequency over successive generations. \nNow that genes can be sequenced readily, it has become \napparent that single nucleotide polymorphisms ([SNPs] \u2013 DNA \nsequence variations that occur when a single nucleotide in the genome sequence is altered) are very common. They \nmay entail substitution of one nucleotide for another \n(substitution of C for T in two-thirds of SNPs), or deletion or insertion of a nucleotide. Insertions and deletions of one \nor more nucleotides (other than when the change in number \nof nucleotides is a multiple of three) result in a \u2018frame shift\u2019 in translation. For example, after an insertion of one \nnucleotide, the first element of the next triplet in the code \nbecomes the second and all subsequent bases are shifted \none \u2018to the right\u2019. Changes to the coding region of a gene may result in loss of protein synthesis, abnormal protein \nsynthesis or an abnormal rate of protein synthesis.\nOn average, SNPs occur once in every 300 bases along \nthe 3-billion base human genome, thus resulting in the presence of about 10 million SNPs. They can occur in coding \n(gene) and non-coding regions of the genome, and they may have a greater role in physiological function if located \nwithin a gene or in a regulatory sequence close to the gene. \nWhilst many SNPs do not have a clear association with 4An apparently healthy middle-aged man saw one of the authors over \nseveral months because of hypertension; he also saw a psychiatrist \nbecause of depression. This failed to improve with other treatment and \nhe underwent electroconvulsive therapy (ECT). Suxamethonium was used to prevent injury caused by convulsions; this usually results in \nshort-lived paralysis but this poor man recovered consciousness some 2 \ndays later to find", "start_char_idx": 3452, "end_char_idx": 7266, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e8251df0-ad92-4a9e-8116-db91407f09a5": {"__data__": {"id_": "e8251df0-ad92-4a9e-8116-db91407f09a5", "embedding": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "754bc852-8f56-4e70-9b15-21bf00a90135", "node_type": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06e060820f2fe86089e6c6a15e41a80180d79a829f29514ec013ae4dc5ad0739"}, "2": {"node_id": "a2140e28-4d8c-4ab9-9b9e-d75e5cb5cebf", "node_type": null, "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a9b5f86ea8893ab1131d84f4360e8b0d6de2480d33781877148cebdda4b1fddd"}}, "hash": "b7bfc0829c0d7c4d322225f94b15aaceddb539b91e7183c2ccfeb370e02630dc", "text": "paralysis but this poor man recovered consciousness some 2 \ndays later to find himself being weaned from artificial ventilation in an intensive care unit. Subsequent analysis showed him to be homozygous \nfor an ineffective form of plasma cholinesterase.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7251, "end_char_idx": 7983, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "049fdac9-5d2c-46b5-8c84-c14552286b28": {"__data__": {"id_": "049fdac9-5d2c-46b5-8c84-c14552286b28", "embedding": null, "metadata": {"page_label": "164", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f06a5d4e-0d97-4095-9ae4-a5d7adc918d6", "node_type": null, "metadata": {"page_label": "164", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "780d63861344be7e55229d350ee3a80a9e4c94965279c43418485752a773e005"}, "3": {"node_id": "10102bad-9a1a-4cc7-b0d2-62823e0dcba3", "node_type": null, "metadata": {"page_label": "164", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "496e74852a7f548de21da54e340a987fe8c630e34f823014c88ff26450c68636"}}, "hash": "d54bb042265e47ddc3d12d06e1afe18d4fb74121d952e91169bffac74afbd793", "text": "12 SECTION 1 GENERAL PRINCIPLES\n158enzymes (e.g. barbiturates, griseofulvin, carbamazepine, \noestrogens \u2013 see Ch. 10), can precipitate acute attacks in \nsusceptible individuals. Porphyrins are synthesised from \n\u03b4-amino laevulinic acid (ALA) which is formed by ALA synthase in the liver. This enzyme is induced by drugs \nsuch as barbiturates, resulting in increased ALA production \nand, hence, increased porphyrin accumulation. As men -\ntioned previously, the genetic trait is inherited as an \nautosomal dominant trait, but frank disease is approximately \nfive times more common in women than in men, because hormonal fluctuations precipitate acute attacks.\nDRUG ACETYLATION DEFICIENCY\nBoth examples considered so far are uncommon diseases. However, in the 1960s Price-Evans demonstrated that the \nrate of drug acetylation varied in different populations \nas a result of balanced polymorphism. Fig. 12.3 contrasts the approximately Gaussian distribution of plasma con -\ncentrations achieved 3 h after administration of a dose \nof salicylate with the bimodal distribution of plasma \nconcentrations after a dose of isoniazid. The isoniazid \nconcentration was <20 \u00b5mol/L in about half the population, \nand in this group the mode was approximately 9 \u00b5mol/L. \nIn the other half of the population (plasma concentration \n>20 \u00b5mol/L), the mode was approximately 30 \u00b5mol/L. \nElimination of isoniazid depends mainly on acetylation, catalysed by an acetyltransferase enzyme, and some studies \nhave reported that slow acetylators are at higher risk of isoniazid-associated hepatotoxicity. However, ongoing \nresearch has suggested that adverse effects can arise through \nseveral different mechanisms, and that no single pathway or genetic variant is fully responsible for liver toxicity with \nisoniazid.\nAcetyltransferase is also important in the metabolism of \nother drugs, including hydralazine (Ch. 22), procainamide \n(Ch. 22), dapsone and various other sulfonamides (Ch. 52) \nand acetylator status influences drug-induced lupus (an \nautoimmune disorder affecting many organs including skin, to suxamethonium may be abnormal in an individual \npatient, notably malignant hyperpyrexia (Ch. 14), a genetically \ndetermined idiosyncratic adverse drug reaction involving \nthe ryanodine receptor (Ch. 4). It is important to check the \nfamily history and test family members who may be affected, \nbut the disorder is so rare that it is currently impractical to screen for it routinely before therapeutic use of \nsuxamethonium.\nACUTE INTERMITTENT PORPHYRIA\nThe hepatic porphyrias are prototypic pharmacogenetic \ndisorders in which patients may be symptomatic even if \nthey are not exposed to a drug, but where many drugs can \nprovoke very severe worsening of the course of the disease. They are inherited disorders involving the biochemical \npathway of porphyrin haem biosynthesis. Acute intermittent \nporphyria is the most common acute and severe form. It is \ninherited as an autosomal dominant trait and is due to one \nof many different mutations in the gene coding porpho-\nbilinogen deaminase (PBGD), a key enzyme in haem biosyn -\nthesis in red cell precursors, hepatocytes and other cells. \nAll of these mutations reduce the activity of this enzyme, \nand clinical features are caused by the resulting build-up \nof haem precursors, including porphyrins. There is a strong interplay with the environment through exposure to drugs, \nhormones and other chemicals. The use of sedative, anti", "start_char_idx": 0, "end_char_idx": 3481, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "10102bad-9a1a-4cc7-b0d2-62823e0dcba3": {"__data__": {"id_": "10102bad-9a1a-4cc7-b0d2-62823e0dcba3", "embedding": null, "metadata": {"page_label": "164", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f06a5d4e-0d97-4095-9ae4-a5d7adc918d6", "node_type": null, "metadata": {"page_label": "164", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "780d63861344be7e55229d350ee3a80a9e4c94965279c43418485752a773e005"}, "2": {"node_id": "049fdac9-5d2c-46b5-8c84-c14552286b28", "node_type": null, "metadata": {"page_label": "164", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d54bb042265e47ddc3d12d06e1afe18d4fb74121d952e91169bffac74afbd793"}}, "hash": "496e74852a7f548de21da54e340a987fe8c630e34f823014c88ff26450c68636", "text": "to drugs, \nhormones and other chemicals. The use of sedative, anti -\nconvulsant or other drugs in patients with undiagnosed \nporphyria can be lethal, though with appropriate supportive \nmanagement most patients recover completely.\n5 Many drugs, \nespecially but not exclusively those that induce CYP 0510152025Number of subjects\n400 200 0 90 80 70 60 50 40 30 20 10 0\nConcentration (\u00b5mol/L) Plasma concentration (\u00b5mol/L)A B\nFig. 12.3 \tDistribution of individual plasma concentrations for two drugs in humans. \t(A)\tPlasma \tsalicylate \tconcentration \t3 \th \tafter \t\noral\tdosage \twith \tsodium \tsalicylate. \t(B) \tPlasma \tisoniazid \tconcentration \t6 \th \tafter \toral \tdosage. \tNote \tthe \tnormally \tdistributed \tvalues \tfor \t\nsalicylate,\tcompared \twith \tthe \tbimodal \tdistribution \tof \tisoniazid. \t(Panel \t[A] \tfrom \tEvans, \tD.A., \tClarke, \tC.A., \t1961. \tBr. \tMed. \tBull. \t17, \t234\u2013280; \t\npanel\t[B]\tfrom \tPrice-Evans, \tD.A., \t1963. \tAm. \tJ. \tMed. \t3, \t639.)\n5Life expectancy, obtained from parish records, of patients with \nporphyria diagnosed retrospectively within large kindreds in \nScandinavia was normal until the advent and widespread use of \nbarbiturates and other sedative and anticonvulsant drugs in the 20th century, when it plummeted. There is a long and useful list of drugs to \navoid in the British National Formulary, together with the warning that \ndrugs not on the list may not necessarily be safe in such patients!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3415, "end_char_idx": 5316, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d83304ff-cb95-48dd-83da-f9412d51bf33": {"__data__": {"id_": "d83304ff-cb95-48dd-83da-f9412d51bf33", "embedding": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "83df579a-999b-4903-af19-bd51898da017", "node_type": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9a5d4e2ea58a14c531933c92bfaab43017f3a62c431ce40f16392ad99e86571d"}, "3": {"node_id": "a5fd2d7a-0165-48a4-934b-ad64d34e1647", "node_type": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9a2179e9364fe2aa9eb78075bee820ec22d162acc46f0949208df94eac53c4b3"}}, "hash": "53a440a52185264f5075752fe6b0c90e8aa4f5bb5380afbb849dea4981009282", "text": "12 INdIvIduAL vARIA tIoN, P h AR m AC o GEN om ICS AN d PERS o NALISE d m E d ICINE\n159effect. In reality, however, the probability of drug benefit \nand harm is often a continuum with a wide range of vari -\nation across individuals in a population (Manrai et al., 2016), \nand reliance on a single predictive biomarker may not be sufficiently precise or reliable to guide treatment of serious \ndisease.\nThe key steps in evaluating pharmacogenetic markers \nin clinical care should be confirmation of analytic validity (accuracy and reliability of the test) and determination of \na robust, replicable relationship between the marker and drug response in the population (clinical validity). Clinical \nutility must then be demonstrated through improved efficacy \nor safety in patients receiving the biomarker-guided thera -\npeutic regimens. There are also health economic considera -\ntions as to whether the genetic markers are of sufficiently \nhigh frequency in their patient population to justify the \ncosts of screening. Policy makers and funding agencies will then have to look at feasibility of using the biomarker \ntesting strategy in a way that does not delay patient treat -\nment. Here, the historical approach of single-gene as needed, \nor \u2018one at a time\u2019 testing can seem slow, inefficient and \ncostly when compared with the recent availability of pre-\nemptive testing for multiple genetic markers. The growing availability of rapid testing using multi-gene panels means \nthat the individual\u2019s genetic data from a single sample can \nbe used to inform many different treatment decisions that subsequently arise in their lifetime.\nAt present, pharmacogenetic evaluation can include tests \nfor (a) variants of different HLAs that have been strongly linked to susceptibilities to several severe harmful drug \nreactions that are likely to have arisen from an immunologi -\ncal interaction between the drug molecule and the major \nhistocompatibility molecules in the patient (Chan et al., \n2015); (b) genes controlling aspects of drug metabolism; \nand (c) genes encoding drug targets, where the concept of \n\u2018companion diagnostics\u2019 (defined by the FDA as: \u2018a diag -\nnostic test used as a companion to a therapeutic drug to \ndetermine its applicability to a specific person\u2019) involves \ndetection of a pharmacogenetic marker so that rational drug \nselection can be made based on the pathway related to the underlying mutation. For one drug ( warfarin), a test \ncombines genetic information about metabolism with information about its target.\nHLA GENE TESTS\nABACAVIR AND HLAB*5701\n\u25bc Abacavir (Ch. 53) is a reverse transcriptase inhibitor that is highly \neffective in treating HIV infection. Its use has been limited by severe \nrashes. Susceptibility to this adverse effect is closely linked to the \nHLA variant HLAB*5701 , and testing for this variant is now considered \na standard of care supported by prospective randomised trials (Fig. \n12.4; Martin, 2013).\nANTICONVULSANTS AND HLAB*1502\n\u25bc Carbamazepine (Ch. 46) can also cause severe (life-threatening) \nrashes including Stevens\u2013Johnson syndrome and toxic epidermal necrolysis \n(multiform rashes with painful blistering lesions and skin detachment \nsometimes extending into the gastrointestinal tract) and now considered to be a disease continuum distinguished chiefly by severity, based \nupon the percentage of body surface involved with skin detachment. \nThese are associated with a particular HLA allele, HLAB*1502 , which \noccurs more commonly in ethnic groups in Thailand, Malaysia and \nTaiwan (Barbarino, 2015), but with far lower frequencies in Korean, \nJapanese and Caucasian populations. Screening for this allele before \nstarting treatment is potentially worthwhile in ethnic", "start_char_idx": 0, "end_char_idx": 3740, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a5fd2d7a-0165-48a4-934b-ad64d34e1647": {"__data__": {"id_": "a5fd2d7a-0165-48a4-934b-ad64d34e1647", "embedding": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "83df579a-999b-4903-af19-bd51898da017", "node_type": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9a5d4e2ea58a14c531933c92bfaab43017f3a62c431ce40f16392ad99e86571d"}, "2": {"node_id": "d83304ff-cb95-48dd-83da-f9412d51bf33", "node_type": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53a440a52185264f5075752fe6b0c90e8aa4f5bb5380afbb849dea4981009282"}, "3": {"node_id": "624305f7-cb70-4b6b-8f7e-290e8fd798c1", "node_type": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "21287b4ac68ef2ca765875cdd1572ba19f570b12a511ea59210ee900efaaa363"}}, "hash": "9a2179e9364fe2aa9eb78075bee820ec22d162acc46f0949208df94eac53c4b3", "text": "populations. Screening for this allele before \nstarting treatment is potentially worthwhile in ethnic populations \nwhere the allele frequency is high. People who develop such a reaction joints and kidneys) caused by several of these agents. \nHowever, neither phenotyping (by measuring kinetics of \ndrug transformation) nor genotyping for acetyltransferase \nhas found a way into routine clinical practice, probably \nbecause these drugs are relatively little used and there are several alternative treatments available that are usually \npreferred.\nAMINOGLYCOSIDE OTOTOXICITY\nIn the examples above, variations in chromosomal genes \ncause variations in drug response. Increased susceptibility \nto hearing loss caused by aminoglycoside antibiotics (see \nCh. 52) is, in some families, inherited quite differently, namely exclusively through the mother to all her children. \nThis is the pattern expected of a mitochondrial gene, and \nindeed the most common predisposing mutation is a single nucleotide (A to G) substitution at position 1555 of the \nmitochondrial genome which is referred to as m.1555A >G. \nThis mutation accounts for 30%\u201360% of aminoglycoside \nototoxicity in China, where aminoglycoside use is common. Aminoglycosides work by binding to bacterial ribosomes \n(Ch. 52), which share properties with human mitochondrial \nribosomes (mitochondria are believed to have evolved from symbiotic bacteria); aminoglycosides cause ototoxity in all \nindividuals exposed to too high a dose. The m.1555A>G \nmutation makes mitochondrial ribosomes even more similar \nto their bacterial counterpart, increasing the affinity of the \ndrug which remains bound to ribosomes in the hair cells \nin the ear for several months following a single dose in susceptible individuals. Although the clinical utility has \nyet to be proven, some experts have suggested that screening \nfor this variant may be appropriate in children who are likely to require treatment with aminoglycosides (Linden \nPhillips, 2013).\nTHERAPEUTIC DRUGS AND CLINICALLY \nAVAILABLE PHARMACOGENOMIC TESTS\nClinical tests to predict drug responsiveness were anticipated \nto be one of the first applications of sequencing the human \ngenome. Although a profusion of new pharmacogenetic \ntests are now marketed to healthcare professionals as well as direct to consumer, the adoption and implementation \nin routine clinical practice has been slowed by various \nscientific, commercial, political and educational barriers. Reimbursement for expensive tests and drugs, whether \nprovided by the state or by insurance schemes, depends \nincreasingly on evidence of cost-effectiveness. Here, new pharmacogenetic tests are required to have a positive or meaningful influence on prescribing practice, such as the \nuse of an alternative drug or a different dosing regimen \nthat leads to measurable improvements in patient outcomes \n(Khoury & Galea, 2016; Manrai et al., 2016). So far the \nevidence in support of any pharmacogenetic test is less convincing and falls short of the ideal of a randomised \ncontrolled trial of a pharmacogenomics-informed prescribing \nstrategy versus current best practice.\nMoreover, evaluation of drug response in complex \nmultifactorial traits is a major challenge because multiple genes and genetic variants interact with environmental factors, and the genetic component may only have a modest \ninfluence on treatment effect. Much of the earlier research \nhas been focused on striking single pathogenic variants that have readily apparent or clear-cut \u2018all or none\u2019 treatment mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3652, "end_char_idx": 7530, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "624305f7-cb70-4b6b-8f7e-290e8fd798c1": {"__data__": {"id_": "624305f7-cb70-4b6b-8f7e-290e8fd798c1", "embedding": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "83df579a-999b-4903-af19-bd51898da017", "node_type": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9a5d4e2ea58a14c531933c92bfaab43017f3a62c431ce40f16392ad99e86571d"}, "2": {"node_id": "a5fd2d7a-0165-48a4-934b-ad64d34e1647", "node_type": null, "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9a2179e9364fe2aa9eb78075bee820ec22d162acc46f0949208df94eac53c4b3"}}, "hash": "21287b4ac68ef2ca765875cdd1572ba19f570b12a511ea59210ee900efaaa363", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7572, "end_char_idx": 7763, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "34bf32f1-44a2-4601-9ece-1aedd89feec7": {"__data__": {"id_": "34bf32f1-44a2-4601-9ece-1aedd89feec7", "embedding": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce3d5358-8574-47e9-bf56-ca93795acfe2", "node_type": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20c7ff2e8a7b639e207a3072128cba61c4e1c55135dd9ce92cef89dcce7c1aae"}, "3": {"node_id": "c52ef99a-8f59-49a2-a5dd-ca532295be03", "node_type": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a0ee050d327a7879596b5a58825382a5a904e0702327ebcd8e984402645e2d6"}}, "hash": "650d03d2cbec460e4def2dfae36bb936184d7de5c25860258e800f2dee50c431", "text": "12 SECTION 1 GENERAL PRINCIPLES\n160Sladek, 1980); low TPMT activity in blood is associated with high \nconcentrations of active 6-thioguanine nucleotides (TGN) in blood \nand with bone marrow toxicity, whereas high TPMT activity is \nassociated with lower concentrations of TGN and reduced efficacy. Before starting treatment, phenotyping (by a blood test for TPMT \nactivity) or genotyping of TMPT alleles TPMT*3A, TPMT*3C, TPMT*2 \nis recommended. Even with such testing, careful monitoring of the \nwhite blood cell count is needed because of environmental susceptibility \nfactors (e.g. drug interaction with allopurinol via inhibition of xanthine \noxidase).\n5-FLUOROURACIL (5-FU) AND DPYD\n\u25bc 5-FU (see Ch. 57, Fig. 57.6) and related compounds such as \ncapecitabine and tegafur are used extensively to treat solid tumours, but have variable efficacy and unpredictable mucocutaneous toxicity. \nIt is detoxified by dihydropyrimidine dehydrogenase (DPYD), which has multiple clinically identifiable functional genetic variants. Defi -\nciency of DPYD occurs in 4%\u20135% of the population and is associated with serious toxicity from 5-FU. Currently available genetic information is not completely sensitive nor specific, and recent proposals have \nfocused on dosage adjustments that are guided by gene activity scores \nthat take several polymorphisms into account.\nTAMOXIFEN, OPIOID ANALGESICS AND CYP2D6\n\u25bc Tamoxifen (Chs 36 and 57) is metabolised to an oestrogen antagonist \nendoxifen by CYP2D6, an enzyme that is subject to marked poly -\nmorphic variation; several small association studies have suggested a link between CYP2D6 genotype and efficacy. Genotyping tests for \nCYP2D6 are available, but results from larger comparative trials of \ntamoxifen have yielded less consistent findings.\nOpioid analgesics such as codeine and tramadol are metabolised by \nCYP2D6 into active opioid compounds that have analgesic properties, \nbut also carry serious adverse effects such as sedation and respiratory depression. Slow metabolisers may only obtain limited pain relief \nfrom codeine or tramadol, whereas rapid metabolisers may suffer \nexcess toxicity.to carbamazepine may develop a similar problem if treated with \nphenytoin , and the same allele has been associated with hypersensitiv -\nity reactions to this drug too.\nDRUG METABOLISM-RELATED GENE TESTS\nTHIOPURINES AND TPMT\n\u25bc Thiopurine drugs ( tioguanine, mercaptopurine and its prodrug \nazathioprine; Ch. 57) have been used for the past 50 years to treat \nleukaemias, including acute lymphoblastic leukaemia (ALL, which \naccounts for approximately one-fifth of all childhood malignancies), and more recently to cause immunosuppression, for example, in \ntreating inflammatory bowel disease. All of these drugs cause bone \nmarrow and liver toxicity, and are detoxified by thiopurine-S-methyltransferase (TPMT), which is present in blood cells, as well \nas by xanthine oxidase. There are large inherited variations in TPMT \nactivity with a trimodal frequency distribution (Weinshilboum & Pharmacogenetics and \npharmacogenomics \n\u2022\tSeveral\tinherited \tdisorders \tinfluence \tresponses \tto \t\ndrugs,\tincluding:\n\u2013\tglucose 6-phosphatase deficiency, \ta\tsex-linked \t\ndisorder\tin \twhich \taffected \tmen \t(or \trare \thomozygous \t\nwomen)\texperience \thaemolysis \tif", "start_char_idx": 0, "end_char_idx": 3293, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c52ef99a-8f59-49a2-a5dd-ca532295be03": {"__data__": {"id_": "c52ef99a-8f59-49a2-a5dd-ca532295be03", "embedding": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce3d5358-8574-47e9-bf56-ca93795acfe2", "node_type": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20c7ff2e8a7b639e207a3072128cba61c4e1c55135dd9ce92cef89dcce7c1aae"}, "2": {"node_id": "34bf32f1-44a2-4601-9ece-1aedd89feec7", "node_type": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "650d03d2cbec460e4def2dfae36bb936184d7de5c25860258e800f2dee50c431"}, "3": {"node_id": "be4e6aad-c56c-436d-b3c1-0f3d0bbc0500", "node_type": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d03291af8d7e757e6fd6b3ad801b2aaf57efbd8efa5055f1c95acc57e83836eb"}}, "hash": "7a0ee050d327a7879596b5a58825382a5a904e0702327ebcd8e984402645e2d6", "text": "\thomozygous \t\nwomen)\texperience \thaemolysis \tif \texposed \tto \tvarious \t\nchemicals \tincluding \tthe \tantimalarial \tdrug \t\nprimaquine;\n\u2013\tplasma cholinesterase deficiency, \tan\tautosomal \t\nrecessive\tdisorder \tthat \tconfers \tsensitivity \tto \tthe \t\nneuromuscular \tblocker \tsuxamethonium;\n\u2013\tacute intermittent porphyria, \tan\tautosomal \tdominant \t\ndisease\tmore \tsevere \tin \twomen \tand \tin \twhich \tsevere \t\nattacks\tare \tprecipitated \tby \tdrugs \tor \tendogenous \t\nsex\thormones \tthat \tinduce \tCYP \tenzymes;\n\u2013\tdrug acetylator deficiency, \ta\tbalanced \t\npolymorphism;\n\u2013\tincreased susceptibility to ototoxicity from \naminoglycosides, \twhich\tis\tconferred \tby \ta \tmutation \t\nin\tmitochondrial \tDNA.\n\u2022\tThese\tpharmacogenetic \tdisorders \tprove \tthat \tdrug \t\nresponses \tcan \tbe \tgenetically \tdetermined \tin \tindividuals.\n\u2022\tSingle\tnucleotide \tpolymorphisms \t(SNPs) \tand \t\ncombinations \tof \tSNPs \t(haplotypes) \tin \tgenes \tcoding \tfor \t\nproteins\tinvolved \tin \tdrug \tdisposition \tor \tdrug \taction \tare \t\ncommon\tand \tmay \tpredict \tdrug \tresponse. \t\nPharmacogenomic \ttests \tin \tblood \tor \ttissue \tremoved \t\nsurgically\thave \testablished \tassociations \tbetween \t\nseveral\tsuch \tvariants \tand \tindividual \tdrug \tresponse, \t\nand\tseveral \tsuch \ttests \tare \tavailable \tfor \tclinical \tuse \t\nalthough\ttheir \tstatus \tin \tindividualising \tdrug \ttreatment \tis \t\nstill\tbeing\testablished.\n\u2022\tSuch\ttests \tare \tavailable \tfor:\n\u2013\tseveral\thuman \tleukocyte \tantigen \t(HLA) \tvariants \tthat \t\npredict\ttoxicity \tof \tabacavir,\tcarbamazepine \tand\t\nclozapine;\n\u2013\tgenes\tfor \tseveral \tenzymes \tin \tdrug \tmetabolism \t\nincluding\tCYP2D6 \tand \tCYP2C9, \tand \tthiopurine- S-\nmethyltransferase \t(TPMT);\n\u2013\tgermline \tand \tsomatic \tmutations \tin \tgrowth \tfactor \t\nreceptors\tthat \tpredict \tresponsiveness \tto \tcancer \t\ntreatments \tincluding \timatinib\tand\ttrastuzumab.02468\nC E C E***\n***% with reactionA B\nFig. 12.4 \tIncidence of abacavir hypersensitivity is reduced \nby pharmacogenetic screening. \tIn\tthe\tPREDICT-1 \tstudy \t\n(Mallal\tet\tal., \t2008), \tpatients \twere \trandomised \tto \tstandard \tcare \t\n(C,\tcontrol\tgroup) \tor \tprospective \tpharmacogenetic \tscreening \t(E,\t\nexperimental \tgroup). \tAll \tthe \tcontrol \tsubjects \twere \ttreated \twith \t\nabacavir,\tbut \tonly \tthose \texperimental \tsubjects \twho \twere \t\nHLA-B*5701 \tnegative\twere \ttreated \twith \tabacavir.", "start_char_idx": 3250, "end_char_idx": 5538, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "be4e6aad-c56c-436d-b3c1-0f3d0bbc0500": {"__data__": {"id_": "be4e6aad-c56c-436d-b3c1-0f3d0bbc0500", "embedding": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce3d5358-8574-47e9-bf56-ca93795acfe2", "node_type": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20c7ff2e8a7b639e207a3072128cba61c4e1c55135dd9ce92cef89dcce7c1aae"}, "2": {"node_id": "c52ef99a-8f59-49a2-a5dd-ca532295be03", "node_type": null, "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a0ee050d327a7879596b5a58825382a5a904e0702327ebcd8e984402645e2d6"}}, "hash": "d03291af8d7e757e6fd6b3ad801b2aaf57efbd8efa5055f1c95acc57e83836eb", "text": "\tThere \twere \t\ntwo\tprespecified \tend \tpoints: \tclinically \tsuspected \thypersensitivity \t\nreactions\t(A) \tand \tclinically \tsuspected \treactions \tthat \twere \t\nimmunologically \tconfirmed \tby \ta \tpositive \tpatch \ttest \t(B). \tBoth \tend \t\npoints\tfavoured \tthe \texperimental \tgroup \t(p\t<\t0.0001).\t(Figure \t\nredrawn\tfrom \tHughes, \tA.R. \tet \tal., \t2008. \tPharmacogenet. \tJ. \t8, \t\n365\u2013374.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5583, "end_char_idx": 6441, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "382a9231-f00a-4a70-9ce8-c81431fb935e": {"__data__": {"id_": "382a9231-f00a-4a70-9ce8-c81431fb935e", "embedding": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc7a119a-6a91-44e0-9732-a2bd363297fb", "node_type": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b67986be769739fd694bf3e53c563a72ea44c7b58f179a4a6de2610fb0ba420"}, "3": {"node_id": "6c458d90-c688-42cd-a285-a558de298e11", "node_type": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "301689f2b0c0658fc1fe9bbdaef34c4ce5db78537f4336fc608f6078ffaca93f"}}, "hash": "dd10f2feee4e3a6ceeb8e1a1a8b22ead9cd658d6a58b90ac91743fade4bc0bf8", "text": "12 INdIvIduAL vARIA tIoN, P h AR m AC o GEN om ICS AN d PERS o NALISE d m E d ICINE\n161maternally inherited mitochondrial disorders) prove the \nconcept that susceptibility to adverse drug effects can be \ngenetically determined. Pharmacogenomic testing offers \nthe possibility of more precise \u2018personalised\u2019 therapeutics for several drugs and disorders, but high-quality trial \nevidence of clinical utility in a large population is lacking, \nparticularly in instances where drug response is influenced by complex multifactorial traits. This is a field of intense \nresearch activity, rapid progress and high expectations, but \nproving that these tests add to present best practice and improve outcomes remains a challenge.DRUG TARGET-RELATED GENE TESTS \n(\u2018COMPANION DIAGNOSTICS\u2019)\nTRASTUZUMAB AND HER2\n\u25bc Trastuzumab (\u2018Herceptin\u2019; Ch. 57) is a monoclonal antibody that \nantagonises epidermal growth factor (EGF) by binding to one of its \nreceptors (human EGF receptor 2 \u2013 HER2) which can occur in tumour \ntissue as a result of somatic mutation. It is used in patients with breast cancer whose tumour tissue overexpresses this receptor. Other patients \ndo not benefit from it.\nDASATINIB, IMATINIB AND BCR-ABL1\n\u25bc Dasatinib and imatinib are first-line tyrosine kinase inhibitors \nused in haematological malignancies characterised by the presence of a Philadelphia chromosome, namely chronic myeloid leukaemia \n(CML) and in some adults with ALL. The Philadelphia chromosome results from a translocation defect when parts of two chromosomes \n(9 and 22) swap places; part of a \u2018breakpoint cluster region\u2019 (BCR) \nin chromosome 22 links to the \u2018Abelson-1\u2019 (ABL) region of chromosome 9. A mutation (T315I) in BCR/ABL confers resistance to the inhibitory \neffect of dasatinib and patients with this variant do not benefit from \nthis drug. Ponatinib is licensed in the United States for treatment of \npatients who have this BCR-ABL T315I mutation.\nCOMBINED (METABOLISM AND TARGET) \nGENE TESTS\nWARFARIN AND CYP2C9 + VKORC1 GENOTYPING\n\u25bc Warfarin is a par excellence example of a drug with a narrow \nbenefit:harm balance where dosing must be individualised. This is \ndone by measuring the international normalised ratio (INR), a measure \nof its effect on blood coagulability (Ch. 25), but thrombotic events \ndespite treatment (lack of efficacy) and serious adverse effects (usually \nbleeding) remain all too common. Warfarin is the most widely used \ndrug for which pharmacogenetic testing has been proposed, based on a study showing that polymorphisms in its key target, vitamin K \nepoxide reductase (VKOR; see Fig. 25.5) and in CYP2C9, involved in \nits metabolism, are associated with outcomes. Fig. 12.5 shows the \neffects of VKOR haplotype and of CYP2C9 genotype on the mean \ndose of warfarin needed to achieve therapeutic INR. Dosing algorithms have been proposed based on the results of testing for polymorphisms \nof these genes. A randomised trial favoured this strategy for initiating \ntreatment versus a standard loading dose approach, but genetic testing did not improve on an individualised algorithm for dose initiation \nbased on other clinical variables (Zineh et al., 2013).\nCONCLUSIONS\nTwin studies as well as several well-documented single-gene \ndisorders (including Mendelian chromosomal \u2013 autoso-\nmal recessive, autosomal dominant and X-linked \u2013 and 0\n*2 or", "start_char_idx": 0, "end_char_idx": 3360, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6c458d90-c688-42cd-a285-a558de298e11": {"__data__": {"id_": "6c458d90-c688-42cd-a285-a558de298e11", "embedding": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc7a119a-6a91-44e0-9732-a2bd363297fb", "node_type": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b67986be769739fd694bf3e53c563a72ea44c7b58f179a4a6de2610fb0ba420"}, "2": {"node_id": "382a9231-f00a-4a70-9ce8-c81431fb935e", "node_type": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd10f2feee4e3a6ceeb8e1a1a8b22ead9cd658d6a58b90ac91743fade4bc0bf8"}, "3": {"node_id": "bca3d97e-0a8d-4d60-a7fd-38e928c95090", "node_type": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "13fa54b867f47b36baf6c34b1e12d233a22811c53fc510be030db938054c5543"}}, "hash": "301689f2b0c0658fc1fe9bbdaef34c4ce5db78537f4336fc608f6078ffaca93f", "text": "recessive, autosomal dominant and X-linked \u2013 and 0\n*2 or *3\ncarriersA/AA/B\nVKORC1\nhaplotypeMean\nwarfarin\ndose\n(mg/day)\nB/B\n*1 / *1All\nCYP2C9\ngenotype1234567\nFig. 12.5 \tEffect of VKOR haplotype and CYP2C9 \ngenotype on warfarin dose. \tA\tseries\tof \t186 \tpatients \ton \t\nlong-term\twarfarin \ttreatment \twho \thad \talready \tbeen \tstudied \tfor \t\nCYP2C9\twere\tstudied \tretrospectively \tfor \tgenetic \tvariants \tof \t\nVKOR\t(Rieder\tet \tal., \t2005). \tVKOR\thaplotype \tas \twell \tas \tCYP2C9\t\ngenotype\tinfluenced \tthe \tmean \twarfarin \tdose \t(which \thad \tbeen \t\nadjusted\tto \tachieve \ttherapeutic \tINR). \tA,\tHaplotypes \t1 \tand \t2; \tB,\t\nhaplotypes \t7, \t8 \tand \t9. \tA/A, A/B\tand\tB/B\trepresent \thaplotype \t\ncombinations. \t*1/*1\trepresents \tCYP2C9 \twild-type \thomozygotes; \t\n*2\tand\t*3\trepresent \tCYP2C9 \tvariants. \t(Figure \tredrawn \tfrom \t\nBeitelshees, \tA.L., \tMcLeod, \tH.L., \t2006. \tApplying \t\npharmacogenomics \tto \tenhance \tthe \tuse \tof \tbiomarkers \tfor \tdrug \t\neffect\tand \tdrug \tsafety. \tTIPS \t27, \t498\u2013502.)\nREFERENCES AND FURTHER READING\nFurther reading\nDoogue, M.P., Polasek, T.M., 2011. Drug dosing in renal disease. Clin. \nBiochem. Rev. 32, 69\u201373. (Principles and practice of dose adjustment in \npatients with renal failure)\nChan, S.L., Jin, S., Loh, M., Brunham, L.R., 2015. Progress in \nunderstanding the genomic basis for adverse drug reactions: a comprehensive review and focus on the role of ethnicity. \nPharmacogenomics 16, 1161\u20131178. (Describes how genetic testing has progressed in assessing susceptibility for adverse drug \nreactions)\nKhoury, M.J., 2017. No shortcuts on the long road to evidence-based \ngenomic medicine. JAMA 318 (1), 27\u201328.\nPavlos, R., Mallal, S., Phillips, E., 2012. HLA and pharmacogenetics of \ndrug hypersensitivity. Pharmacogenomics 13, 1285\u20131306.Phillips, E.J., Mallal, S.A., 2011. HLA-B*1502 screening and toxic effects \nof carbamazepine. N. Engl. J. Med. 365, 672.\nPhillips, K.A., Deverka, P.A., Sox, H.C., et al., 2017. Making genomic \nmedicine evidence-based and patient-centered: a structured review \nand landscape analysis of comparative effectiveness research. Genet. \nMed. 19 (10), 1081\u20131091. (Comprehensive review that reports lack of \nevidence of clinical utility and patient benefit)\nRelling, M.V., Evans, W.E., 2015. Pharmacogenomics in the clinic. \nNature 526, 343\u2013350. (Excellent review article about pharmacogenetic tests that are clinically important, and the barriers to widespread adoption)\nWeng, L.M., Zhang, L., Peng, Y., Huang, R.S., 2013. Pharmacogenetics \nand pharmacogenomics: a bridge to individualized cancer therapy. Pharmacogenomics 14, 315\u2013324.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3313, "end_char_idx": 6001, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bca3d97e-0a8d-4d60-a7fd-38e928c95090": {"__data__": {"id_": "bca3d97e-0a8d-4d60-a7fd-38e928c95090", "embedding": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc7a119a-6a91-44e0-9732-a2bd363297fb", "node_type": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b67986be769739fd694bf3e53c563a72ea44c7b58f179a4a6de2610fb0ba420"}, "2": {"node_id": "6c458d90-c688-42cd-a285-a558de298e11", "node_type": null, "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "301689f2b0c0658fc1fe9bbdaef34c4ce5db78537f4336fc608f6078ffaca93f"}}, "hash": "13fa54b867f47b36baf6c34b1e12d233a22811c53fc510be030db938054c5543", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6002, "end_char_idx": 6433, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "19a3aff6-07dc-4ea7-bb1c-bce8bd448c7b": {"__data__": {"id_": "19a3aff6-07dc-4ea7-bb1c-bce8bd448c7b", "embedding": null, "metadata": {"page_label": "168", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "65ac99fb-4fb5-41ca-bce6-79346b6cfaa7", "node_type": null, "metadata": {"page_label": "168", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "612200bfb7974f2f42036cdbc070379bfffa4ed96d31feedba89ddeebd8735e0"}, "3": {"node_id": "8f88aa5a-30d6-4131-bac6-06f764f8ab2f", "node_type": null, "metadata": {"page_label": "168", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9082d0f8a68ffd3069489b3f3a261ef65044ec4af412b4013c5539414d0f96bf"}}, "hash": "20a77310d9eda0630c4d1309ec74b8ee1369ca8aad53ba25313e528c1933b046", "text": "12 SECTION 1 GENERAL PRINCIPLES\n162Rieder, M.J., Reiner, A.P., Gage, B.F., et al., 2005. Effect of VKORC1 \nhaplotype on transcriptional regulation and warfarin dose. N. Engl. J. \nMed. 352, 2285\u20132293.\nShah, R.R., Shah, D.R., 2012. Personalized medicine: is it a \npharmacogenetic mirage? Br. J. Clin. Pharmacol. 74, SI 698\u2013SI 721.\nStergiopoulos, K., Brown, D.L., 2014. Genotype-guided vs clinical \ndosing of warfarin and its analogues: meta-analysis of randomized \nclinical trials. JAMA Intern. Med. 174, 1330\u20131338. ( Meta-analysis of \nrandomised controlled trials of genotype guided warfarin regimens )\nTeml, A., Schaeffeler, E., Schwab, M., 2009. Pretreatment determination \nof TPMT \u2013 state of the art in clinical practice. Eur. J. Clin. Pharmacol. \n65, 219\u2013221, and related articles. ( Introduces an issue devoted to the \nimpact of TPMT polymorphisms on thiopurine use in clinical practice )\nWadman, M., 2005. Drug targeting: is race enough? Nature 435, \n1008\u20131009. ( No!)\nWeinshilboum, R.M., Sladek, S.L., 1980. Mercaptopurine \npharmacogenetics: monogenic inheritance of erythrocyte thiopurine \nmethyltransferase activity. Am. J. Hum. Genet. 32, 651\u2013662.\nWood, A.J.J., 2001. Racial differences in response to drugs \u2013 pointers to \ngenetic differences. N. Engl. J. Med. 344, 1393\u20131396.\nZineh, I., Pacanowski, M., Woodcock, J., 2013. Pharmacogenetics and \ncoumarins dosing \u2013 recalibrating expectations. N. Engl. J. Med. 369, \n2273\u20132275.References\nAtkinson, A.J., Jr., Huang, S.M., Lertora, J., et al., 2012. Principles of \nClinical Pharmacology, second ed. Academic Press, San Diego. \n(Includes detailed accounts of clinical aspects including effects of renal and \nliver disease on pharmacokinetics, of effects of age and on drug therapy in \npregnant and nursing women )\nBarbarino, J.M., Kroetz, D.L., Klein, T.E., Altman, R.B., 2015. PharmGKB \nsummary: very important pharmacogene information for Human \nLeukocyte Antigen B (HLA-B). Pharmacogenet. Genomics 25, 205\u2013221.\nCooper, R.S., Kaufman, J.S., Ward, R., 2003. Race and genomics. N. \nEngl. J. Med. 348, 1166\u20131170. ( Scholarly and appropriately sceptical \nanalysis )\nKhoury, M.J., Galea, S., 2016. Will precision medicine improve \npopulation health? JAMA 316, 1357\u20131358.\nLinden Phillips, L., Bitner-Glindzicz, M., Lench, N., et al., 2013. The \nfuture role of genetic screening to detect newborns at risk of \nchildhood-onset hearing loss. Int. J. Audiol. 52, 124\u2013133.\nManrai, A.K., Ioannidis, J.A., Kohane, I.S., 2016. Clinical genomics: from \npathogenicity claims to quantitative risk estimates. JAMA 315, \n1233\u20131234. ( Argues that clinically useful impact on patient care has yet to \nbe consistently demonstrated with pharmacogenetic testing )\nMallal, S., Phillips, E., Carosi, G., et al., 2008. HLA-B*5701 screening for \nhypersensitivity to abacavir. N. Engl. J. Med. 358,", "start_char_idx": 0, "end_char_idx": 2829, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8f88aa5a-30d6-4131-bac6-06f764f8ab2f": {"__data__": {"id_": "8f88aa5a-30d6-4131-bac6-06f764f8ab2f", "embedding": null, "metadata": {"page_label": "168", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "65ac99fb-4fb5-41ca-bce6-79346b6cfaa7", "node_type": null, "metadata": {"page_label": "168", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "612200bfb7974f2f42036cdbc070379bfffa4ed96d31feedba89ddeebd8735e0"}, "2": {"node_id": "19a3aff6-07dc-4ea7-bb1c-bce8bd448c7b", "node_type": null, "metadata": {"page_label": "168", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20a77310d9eda0630c4d1309ec74b8ee1369ca8aad53ba25313e528c1933b046"}}, "hash": "9082d0f8a68ffd3069489b3f3a261ef65044ec4af412b4013c5539414d0f96bf", "text": "to abacavir. N. Engl. J. Med. 358, 568\u2013579.\nMartin, M.A., Kroetz, D.L., 2013. Abacavir pharmacogenetics \u2013 from \ninitial reports to standard of care. Pharmacotherapy 33, 765\u2013775.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2795, "end_char_idx": 3451, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4868c63e-d47f-4b73-8f63-1b305829701d": {"__data__": {"id_": "4868c63e-d47f-4b73-8f63-1b305829701d", "embedding": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b887db02-1ee8-463b-8fe2-4b74bc8da920", "node_type": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44a2143fbbf022d5e4c74c0b4f9d3f8839f10a6a2337bbe43c85b6188494f116"}, "3": {"node_id": "5ba20086-79b0-4cb7-a96b-b71a4256675f", "node_type": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dddde7247b8c5ccf5e9fb39a3a9591e37e11ff717618d9321fdbf4aaefd4da9e"}}, "hash": "aa991ccdb8fc12228648801d2f8cc19315bb29096503156dbee6eebb7aa5e845", "text": "163\nChemical mediators and the \nautonomic nervous system 13 CHEMICAL MEDIATORS SECTION 2 \nOVERVIEW\nThe network of chemical signals and associated recep -\ntors by which cells in the body communicate with \none another provides many targets for drug action, \nand has always been a focus of attention for phar -\nmacologists. Chemical transmission in the peripheral \nautonomic nervous system, and the various ways in \nwhich the process can be pharmacologically subverted, is the main focus of this chapter, but the mechanisms \ndescribed operate also in the central nervous system \n(CNS). In addition to neurotransmission, we also consider briefly the less clearly defined processes, \ncollectively termed neuromodulation, by which many \nmediators and drugs exert control over the function of the nervous system. The relative anatomical and \nphysiological simplicity of the peripheral nervous \nsystem has made it the proving ground for many important discoveries about chemical transmission, \nand the same general principles apply to the CNS \n(see Ch. 38). For more detail than is given here, see \nRobertson et al. (2012) and Iversen et al. (2009) .\nHISTORICAL ASPECTS\n\u25bc Studies initiated on the peripheral nervous system have been central \nto the understanding and classification of many major types of drug \naction, so it is worth recounting a little history. Excellent accounts \nare given by Bacq (1975), Valenstein (2005) and Burnstock (2009).\nExperimental physiology became established as an approach to the \nunderstanding of the function of living organisms in the middle of \nthe 19th century. The peripheral nervous system, and particularly the autonomic nervous system, received a great deal of attention. The \nfact that electrical stimulation of nerves could elicit a whole variety \nof physiological effects \u2013 from blanching of the skin to arrest of the heart \u2013 presented a real challenge to comprehension, particularly \nof the way in which the signal was passed from the nerve to the \neffector tissue. In 1877, Du Bois-Reymond was the first to put the alternatives clearly: \u2018Of known natural processes that might pass on \nexcitation, only two are, in my opinion, worth talking about \u2013 either \nthere exists at the boundary of the contractile substance a stimulatory secretion \u2026 or the phenomenon is electrical in nature.\u2019 The latter \nview was generally favoured. In 1869, it had been shown that an \nexogenous substance, muscarine , could mimic the effects of stimulating \nthe vagus nerve, and that atropine could inhibit the actions both of \nmuscarine and of nerve stimulation. In 1905, Langley showed the same for nicotine and curare acting at the neuromuscular junction. \nMost physiologists interpreted these phenomena as stimulation and inhibition of the nerve endings, respectively, rather than as evidence for chemical transmission. Hence the suggestion of T.R. Elliott, in 1904, \nthat adrenaline (epinephrine) might act as a chemical transmitter \nmediating the actions of the sympathetic nervous system was coolly \nreceived, until Langley, the Professor of Physiology at Cambridge and \na powerful figure at that time, suggested, a year later, that transmission to skeletal muscle involved the secretion by the nerve terminals of a \nsubstance related to nicotine.\nOne of the key observations for Elliott was that degeneration of \nsympathetic nerve terminals did not abolish the sensitivity of smooth \nmuscle preparations to adrenaline (which the electrical theory pre -\ndicted) but actually enhanced it. The hypothesis of chemical transmis -\nsion was put to direct test in 1907 by Dixon, who tried to show that vagus nerve stimulation released from a dog\u2019s heart into the blood \na substance capable of inhibiting another heart. The experiment failed, and the atmosphere of", "start_char_idx": 0, "end_char_idx": 3786, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5ba20086-79b0-4cb7-a96b-b71a4256675f": {"__data__": {"id_": "5ba20086-79b0-4cb7-a96b-b71a4256675f", "embedding": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b887db02-1ee8-463b-8fe2-4b74bc8da920", "node_type": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44a2143fbbf022d5e4c74c0b4f9d3f8839f10a6a2337bbe43c85b6188494f116"}, "2": {"node_id": "4868c63e-d47f-4b73-8f63-1b305829701d", "node_type": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa991ccdb8fc12228648801d2f8cc19315bb29096503156dbee6eebb7aa5e845"}, "3": {"node_id": "2ee3e7c4-a584-4e0f-8230-0d0d29881fcb", "node_type": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a2b06de7012678e2a0b6a602fb11878f0e94dc3b36fe2550f87d2fbd0728d62"}}, "hash": "dddde7247b8c5ccf5e9fb39a3a9591e37e11ff717618d9321fdbf4aaefd4da9e", "text": "capable of inhibiting another heart. The experiment failed, and the atmosphere of scepticism prevailed.\nIt was not until 1921, in Germany, that Loewi showed that stimulation \nof the vagosympathetic trunk connected to an isolated and cannulated \nfrog\u2019s heart could cause the release into the cannula of a substance \n(\u2018Vagusstoff\u2019) that, if the cannula fluid was transferred from the first \nheart to a second, would inhibit the second heart. This is a classic \nand much-quoted experiment that proved extremely difficult for even Loewi to perform reproducibly. In an autobiographical sketch, Loewi \ntells us that the idea of chemical transmission arose in a discussion \nthat he had in 1903, but no way of testing it experimentally occurred to him until he dreamt of the appropriate experiment one night in \n1920. He wrote some notes of this very important dream in the middle \nof the night, but in the morning could not read them. The dream obligingly returned the next night and, taking no chances, he went \nto the laboratory at 3 a.m. and carried out the experiment successfully. \nLoewi\u2019s experiment may be, and was, criticised on numerous grounds (it could, for example, have been potassium rather than a neurotrans -\nmitter that was acting on the recipient heart), but a series of further experiments proved him to be right. His findings can be summarised as follows:\n\u2022\tStimulation \tof \tthe \tvagus \tcaused \tthe \tappearance \tin \tthe \t \nperfusate of the frog heart of a substance capable of producing, \nin a second heart, an inhibitory effect resembling vagus \nstimulation.\n\u2022\tStimulation \tof \tthe \tsympathetic \tnervous \tsystem \tcaused \tthe \t\nappearance of a substance capable of accelerating a second heart. By fluorescence measurements, Loewi concluded later that \nthis substance was adrenaline.\n\u2022\tAtropine \tprevented \tthe \tinhibitory \taction \tof \tthe \tvagus \ton \tthe \t\nheart\tbut \tdid \tnot \tprevent \trelease \tof \tVagusstoff. \tAtropine \t \nthus prevented the effects, rather than the release, of the transmitter.\n\u2022\tWhen\tVagusstoff \twas \tincubated \twith \tground-up \theart \t \nmuscle, it became inactivated. This effect is now known to \nbe due to enzymatic destruction of acetylcholine by \ncholinesterase.\n\u2022\tPhysostigmine, which potentiated the effect of vagus \nstimulation on the heart, prevented destruction of Vagusstoff by \nheart muscle, providing evidence that the potentiation is due to inhibition of cholinesterase, which normally destroys the \ntransmitter substance acetylcholine.\nA\tfew\tyears \tlater, \tin \tthe \tearly \t1930s, \tDale \tshowed \tconvincingly \tthat \t\nacetylcholine was also the transmitter substance at the neuromuscular \njunction of striated muscle and at autonomic ganglia. One of the \nkeys to Dale\u2019s success lay in the use of highly sensitive bioassays, \nespecially the leech dorsal muscle, for measuring acetylcholine \nrelease. Chemical transmission at sympathetic nerve terminals was demonstrated at about the same time as cholinergic transmission and \nby very similar methods. Cannon and his colleagues at Harvard first \nshowed unequivocally the phenomenon of chemical transmission at mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3717, "end_char_idx": 7125, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2ee3e7c4-a584-4e0f-8230-0d0d29881fcb": {"__data__": {"id_": "2ee3e7c4-a584-4e0f-8230-0d0d29881fcb", "embedding": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b887db02-1ee8-463b-8fe2-4b74bc8da920", "node_type": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44a2143fbbf022d5e4c74c0b4f9d3f8839f10a6a2337bbe43c85b6188494f116"}, "2": {"node_id": "5ba20086-79b0-4cb7-a96b-b71a4256675f", "node_type": null, "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dddde7247b8c5ccf5e9fb39a3a9591e37e11ff717618d9321fdbf4aaefd4da9e"}}, "hash": "5a2b06de7012678e2a0b6a602fb11878f0e94dc3b36fe2550f87d2fbd0728d62", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7148, "end_char_idx": 7371, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "47d5f94e-5121-43db-85b4-359c99d5bbb1": {"__data__": {"id_": "47d5f94e-5121-43db-85b4-359c99d5bbb1", "embedding": null, "metadata": {"page_label": "170", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6c1c8907-4eff-4222-92e9-036d8df972fd", "node_type": null, "metadata": {"page_label": "170", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e840db0b243e097699413c3edea6f1950190a8ac2edcfcd733567d010bf40ab8"}, "3": {"node_id": "c60c83ba-8987-40f9-bc2e-142685b73e85", "node_type": null, "metadata": {"page_label": "170", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "96820bc13e30ab3c84a6ff09bf7810c3c36d40f8d1afa6da05016268064dacd5"}}, "hash": "12c9170cdf9edc893b07385a25ea12971c6e5ae1697e5d4de48ead5b688583be", "text": "13 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n164system has sufficient integrative capabilities to allow it to \nfunction independently of the CNS, but the sympathetic \nand parasympathetic systems are agents of the CNS and \ncannot function without it. The autonomic nervous system is largely outside the influence of voluntary control. The \nmain processes that it regulates, to a greater or lesser \nextent, are:\n\u2022\tcontraction \tand \trelaxation \tof \tvascular \tand \tvisceral \t\nsmooth muscle\n\u2022\tall\texocrine \tand \tcertain \tendocrine \tsecretions\n\u2022\tthe\theartbeat\n\u2022\tenergy \tmetabolism, \tparticularly \tin \tliver \tand \tskeletal \t\nmuscle\nA\tdegree \tof \tautonomic \tcontrol \talso \taffects \tmany \tother \t\nsystems, including the kidney, immune system and soma -\ntosensory system. The autonomic efferent pathway consists of two neurons arranged in series, whereas in the somatic \nmotor system a single motor neuron connects the CNS to the skeletal muscle fibre ( Fig. 13.2). The two neurons in the \nautonomic pathway are known, respectively, as preganglionic \nand postganglionic . In the sympathetic nervous system, the \nintervening synapses lie in autonomic ganglia, which are \noutside the CNS, and contain the nerve endings of pregan -\nglionic fibres and the cell bodies of postganglionic neurons. In parasympathetic pathways, the postganglionic cells are mainly found in the target organs, discrete parasympathetic sympathetic nerve endings, by experiments in vivo in which tissues \nmade supersensitive to adrenaline by prior sympathetic denervation \nwere shown to respond, after a delay, to the transmitter released by \nstimulation of the sympathetic nerves to other parts of the body. The chemical identity of the transmitter, tantalisingly like adrenaline but \nnot identical to it, caused confusion for many years, until, in 1946, von \nEuler showed it to be the non-methylated derivative noradrenaline (norepinephrine).\nTHE AUTONOMIC NERVOUS SYSTEM\nThe autonomic nervous system for a long time occupied \ncentre stage in the pharmacology of chemical transmission.\nBASIC ANATOMY AND PHYSIOLOGY\nThe autonomic nervous system (see Robertson et al., \n2012) consists of three main anatomical divisions: sym-\npathetic, parasympathetic and enteric nervous systems. The \nsympathetic and parasympathetic systems (Fig. 13.1) provide a link between the CNS and peripheral organs. The enteric nervous system comprises the intrinsic nerve \nplexuses of the gastrointestinal tract, which are closely \ninterconnected with the sympathetic and parasympathetic \nsystems.\nThe autonomic nervous system conveys all the outputs \nfrom the CNS to the rest of the body, except for the motor innervation of skeletal muscle. The enteric nervous \nSLTCMSympathetic\nXIXVIIIII\nPreganglionic\nPostganglionicGenitaliaBladderPelvic gangliaLungHeartSalivary glandsLacrimal glandEyeParasympathetic\nGenitaliaLungsHeart\nBladderLiverStructures in \nhead and neck:\n \nEye \nBlood vessels \nSalivary glands \netc.\nAdrenal medulla\nPrevertebral \nganglia\n(midline)\nGI tract\nBlood vessels\nSweat glands\netc. Segmental\noutflowParavertebraI \nsympathetic \nchain\n(bilateral)Nervi erigentes\nLower GI tractUpper GI tract\nFig. 13.1 Basic plan of the mammalian autonomic nervous system. C, cervical; GI, gastrointestinal; L, lumbar; M, medullary; S,", "start_char_idx": 0, "end_char_idx": 3269, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c60c83ba-8987-40f9-bc2e-142685b73e85": {"__data__": {"id_": "c60c83ba-8987-40f9-bc2e-142685b73e85", "embedding": null, "metadata": {"page_label": "170", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6c1c8907-4eff-4222-92e9-036d8df972fd", "node_type": null, "metadata": {"page_label": "170", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e840db0b243e097699413c3edea6f1950190a8ac2edcfcd733567d010bf40ab8"}, "2": {"node_id": "47d5f94e-5121-43db-85b4-359c99d5bbb1", "node_type": null, "metadata": {"page_label": "170", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "12c9170cdf9edc893b07385a25ea12971c6e5ae1697e5d4de48ead5b688583be"}}, "hash": "96820bc13e30ab3c84a6ff09bf7810c3c36d40f8d1afa6da05016268064dacd5", "text": "gastrointestinal; L, lumbar; M, medullary; S, \nsacral; T, thoracic. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3224, "end_char_idx": 3771, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "81ce6e04-5a88-4b1f-bc89-965670eb2c4c": {"__data__": {"id_": "81ce6e04-5a88-4b1f-bc89-965670eb2c4c", "embedding": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87d7e1c1-59b5-44e3-af81-232286fe0460", "node_type": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b4ee5fd90683d70fece47c414ba64d120a1d85a265e3a2835dab336c6142e74"}, "3": {"node_id": "e45466c9-3438-4239-b49e-0b779934dbe4", "node_type": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e09b8b42dee857bca0d2c75de7fba4b3af17865a3419857645c28f21288a8a3"}}, "hash": "9db5fc0c60d2ff1cd032910b7734eb767adba4248421d8d0f2f8cca8d0b22db6", "text": "13 CHEMICAL MEDIATORS A n D THE A u TO n OMIC n ER v O u S S y STEM\n165such as the bladder, rectum and genitalia. The pelvic ganglia \ncarry both sympathetic and parasympathetic fibres, and \nthe two divisions are not anatomically distinct in this region.\nThe enteric nervous system (reviewed by Furness et al., \n2014) consists of the neurons whose cell bodies lie in the \nintramural plexuses in the wall of the intestine. It is esti -\nmated that there are more cells in this system than in the spinal cord, and functionally they do not fit simply into the sympathetic/parasympathetic classification. Incoming \nnerves from both the sympathetic and the parasympathetic \nsystems terminate on enteric neurons, as well as running directly to smooth muscle, glands and blood vessels. \nSome enteric neurons function as mechanoreceptors or \nchemoreceptors, providing local reflex pathways that can control gastrointestinal function without external inputs. The enteric nervous system is pharmacologically \nmore complex than the sympathetic or parasympathetic \nsystems, involving many neuropeptide and other transmit -\nters\t(such \tas \t5-hydroxytryptamine, \tnitric \toxide \tand \tATP; \t \nsee Ch. 31).\nIn some places (e.g. in the visceral smooth muscle of the \ngut and bladder, and in the heart), the sympathetic and the parasympathetic systems produce opposite effects, but \nthere are others where only one division of the autonomic \nsystem operates. The sweat glands and most blood vessels, for example, have only a sympathetic innervation, whereas \nthe ciliary muscle of the eye has only a parasympathetic \ninnervation. Bronchial smooth muscle has only a parasympa -\nthetic (constrictor) innervation (although its tone is highly \nsensitive to circulating adrenaline). Resistance arteries (see \nCh. 23) have a sympathetic vasoconstrictor innervation but \nno\tp arasympathetic \ti nnervation; \ti nstead, \tt he\tc onstrictor \tt one\t\nis opposed by a background release of nitric oxide from the endothelial cells (see Ch. 21). There are other examples, \nsuch as the salivary glands , where the two systems produce \nsimilar, rather than opposing, effects.\nIt is therefore a mistake to think of the sympathetic and \nparasympathetic systems simply as physiological opponents. \nEach serves its own physiological function and can be more or less active in a particular organ or tissue according to \nthe need of the moment. Cannon rightly emphasised the \ngeneral role of the sympathetic system in evoking \u2018fight or flight\u2019 reactions in an emergency, but emergencies are rare for most animals. In everyday life, the autonomic \nnervous system functions continuously to control specific \nlocal functions, such as adjustments to postural changes, exercise or ambient temperature. The popular concept \nof a continuum from the extreme \u2018rest and digest\u2019 state \n(parasympathetic active, sympathetic quiescent) to the extreme emergency fight or flight state (sympathetic active, \nparasympathetic quiescent) is an oversimplification, albeit \none that provides the student with a generally reliable aide \nmemoire.\nTable 13.1 lists some of the more important autonomic \nresponses in humans.\nTRANSMITTERS IN THE AUTONOMIC \nNERVOUS SYSTEM\nThe two main neurotransmitters that operate in the auto -\nnomic system are acetylcholine and noradrenaline , whose \nsites of action are shown diagrammatically in Fig. 13.2. This diagram also shows the type of postsynaptic receptor with which the transmitters interact at the different sites \n(discussed more fully in Chs 14 and 15). Some general rules \napply:ganglia (e.g. the ciliary", "start_char_idx": 0, "end_char_idx": 3595, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e45466c9-3438-4239-b49e-0b779934dbe4": {"__data__": {"id_": "e45466c9-3438-4239-b49e-0b779934dbe4", "embedding": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87d7e1c1-59b5-44e3-af81-232286fe0460", "node_type": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b4ee5fd90683d70fece47c414ba64d120a1d85a265e3a2835dab336c6142e74"}, "2": {"node_id": "81ce6e04-5a88-4b1f-bc89-965670eb2c4c", "node_type": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9db5fc0c60d2ff1cd032910b7734eb767adba4248421d8d0f2f8cca8d0b22db6"}, "3": {"node_id": "60cb0188-3b5e-499f-a8aa-aa579e72d9ea", "node_type": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27c4252466e299c518b44b9885ba944e62c43c8c56cc81a2af8a6b11d7bc4bed"}}, "hash": "2e09b8b42dee857bca0d2c75de7fba4b3af17865a3419857645c28f21288a8a3", "text": "14 and 15). Some general rules \napply:ganglia (e.g. the ciliary ganglion) being found only in the head and neck.\nThe cell bodies of the sympathetic preganglionic neurons \nlie in the lateral horn of the grey matter of the thoracic and \nlumbar segments of the spinal cord, and the fibres leave the spinal cord in the spinal nerves as the thoracolumbar \nsympathetic outflow . The preganglionic fibres synapse in the \nparavertebral chains of sympathetic ganglia, lying on either side of the spinal column. These ganglia contain the cell bodies of the postganglionic sympathetic neurons, the axons \nof which rejoin the spinal nerve. Many of the postganglionic \nsympathetic fibres reach their peripheral destinations via the branches of the spinal nerves. Others, destined for \nabdominal and pelvic viscera, have their cell bodies in a \ngroup of unpaired prevertebral ganglia in the abdominal \ncavity. The only exception to the two-neuron arrangement \nis the innervation of the adrenal medulla. The catecholamine-\nsecreting cells of the adrenal medulla are, in effect, modified postganglionic sympathetic neurons, and the nerves sup -\nplying the gland are equivalent to preganglionic fibres.\nThe parasympathetic nerves emerge from two separate \nregions of the CNS. The cranial outflow consists of pregan-\nglionic fibres in certain cranial nerves, namely the oculomotor \nnerve (carrying parasympathetic fibres destined for the eye), \nthe facial and glossopharyngeal nerves (carrying fibres to the \nsalivary glands and the nasopharynx), and the vagus nerve \n(carrying fibres to the thoracic and abdominal viscera). The \nganglia\tlie \tscattered \tin \tclose \trelation \tto \tthe \ttarget \torgans; \t\nthe postganglionic axons are very short compared with those of the sympathetic system. Parasympathetic fibres \ndestined for the pelvic and abdominal viscera emerge as \nthe sacral outflow from the spinal cord in a bundle of nerves \nknown as the nervi erigentes (because stimulation of these \nnerves evokes genital erection \u2013 a fact of some importance to those responsible for artificial insemination of livestock). These fibres synapse in a group of scattered pelvic ganglia, \nwhence the short postganglionic fibres run to target tissues Parasympathetic\nsystem Salivary\nglands\netc.Sympathetic\nsystem \nAdrenal\nmedullaSweat\nglands Blood\nvessels\netc. Somatic efferent\nsystemSkeletal\nmuscle\nNA\n(\u03b1, \u03b2)ACh\n(nic)\nACh\n(nic)\nACh\n(nic)\nACh\n(nic)ACh\n(nic)ACh\n(mus)\nACh\n(mus)CENTRAL NERVOUS SYSTEM\nFig. 13.2 Acetylcholine and noradrenaline as transmitters \nin the peripheral nervous system. The two main types of \nacetylcholine (ACh) receptor, nicotinic (nic) and muscarinic (mus) \n(see Ch. 14) and two types of adrenoceptor, \u03b1 and \u03b2 (Ch. 15), \nare indicated. NA, noradrenaline (norepinephrine). mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3542, "end_char_idx": 6666, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "60cb0188-3b5e-499f-a8aa-aa579e72d9ea": {"__data__": {"id_": "60cb0188-3b5e-499f-a8aa-aa579e72d9ea", "embedding": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87d7e1c1-59b5-44e3-af81-232286fe0460", "node_type": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b4ee5fd90683d70fece47c414ba64d120a1d85a265e3a2835dab336c6142e74"}, "2": {"node_id": "e45466c9-3438-4239-b49e-0b779934dbe4", "node_type": null, "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e09b8b42dee857bca0d2c75de7fba4b3af17865a3419857645c28f21288a8a3"}}, "hash": "27c4252466e299c518b44b9885ba944e62c43c8c56cc81a2af8a6b11d7bc4bed", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6673, "end_char_idx": 6848, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a75373c6-5a45-4f86-8344-3e3d3e6b4cda": {"__data__": {"id_": "a75373c6-5a45-4f86-8344-3e3d3e6b4cda", "embedding": null, "metadata": {"page_label": "172", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "71728c91-bcc9-42cc-8857-36a8f4e48c31", "node_type": null, "metadata": {"page_label": "172", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5ad5dd446699e28620831e8f71dc851fd64c87a737270df0ad8ea2faa21fdb2f"}}, "hash": "5ad5dd446699e28620831e8f71dc851fd64c87a737270df0ad8ea2faa21fdb2f", "text": "13 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n166Table 13.1 The main effects of the autonomic nervous system\nOrgan Sympathetic effectAdrenoceptor \ntypeaParasympathetic effectCholinoceptor type\na\nHeart\nSinoatrial node Rate \u2191 \u03b21 Rate \u2193 M2\nAtrial muscle Force \u2191 \u03b21 Force \u2193 M2\nAtrioventricular nodeAutomaticity \u2191 \u03b2\n1 Conduction velocity \u2193 M2\nAtrioventricular block M2\nVentricular muscle Automaticity \u2191 \u03b21 No effect M2\nForce \u2191\nBlood vessels\nARTERIOLES\nLarge coronary Constriction \u03b11, \u03b12 No effect \u2014\nSmall coronary Dilatation \u03b22 No effect \u2014\nMuscle Dilatation \u03b22 No effect \u2014\nViscera, skin, brain Constriction \u03b11 No effect \u2014\nErectile tissue Constriction \u03b11 Dilatation M3b\nVEINS Constriction \u03b11, \u03b12 No effect \u2014\nDilatation \u03b22 No effect \u2014\nViscera\nBRONCHI\nSmooth muscle No sympathetic innervation, but dilated by circulating adrenaline (epinephrine)\u03b2\n2 Constriction M3\nGlands No effect \u2014 Secretion M3\nGASTROINTESTINAL TRACT\nSmooth muscle Motility \u2193 \u03b11, \u03b12, \u03b22 Motility \u2191 M3\nSphincters Constriction \u03b11, \u03b12, \u03b22 Dilatation M3\nGlands No effect \u2014 Secretion M3\n\u2014 Gastric acid secretion M1\nBLADDER Relaxation \u03b22 Contraction M3\nSphincter contraction \u03b11 Sphincter relaxation M3\nUTERUS\nPregnant Contraction \u03b11 Variable \u2014\nNon-pregnant Relaxation \u03b22\nMALE SEX ORGANS Ejaculation \u03b11 Erection M3b\nEyePupil Dilatation \u03b1\n1 Constriction M3\nCiliary muscle Relaxation (slight) \u03b22 Contraction M3\nSkinSweat glands Secretion (mainly cholinergic via M\n3 receptors) \u2014 No effect \u2014\nPilomotor Piloerection \u03b11 No effect \u2014\nSalivary glands Secretion \u03b11, \u03b21, \u03b22 Secretion M3\nLacrimal glands No effect \u2014 Secretion M3\nKidney Renin secretion \u03b21 No effect \u2014\nLiver Glycogenolysis \u03b11, \u03b22 No effect \u2014\nGluconeogenesis\nAdipose tissuecLipolysis \u03b23 No effect \u2014\nThermogenesis\nPancreatic isletscInsulin secretion \u2193 \u03b12 No effect \u2014\naThe adrenoceptor and cholinoceptor types shown are described more fully in Chapters 14 and 15. Transmitters other than acetylcholine \nand noradrenaline contribute to many of these responses (see Table 13.2).\nbVasodilator effects of M 3 receptors are due to nitric oxide release from endothelial cells (see Ch. 21).\ncNo direct innervation. Effect mediated by circulating adrenaline released from the adrenal medulla.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2658, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "37f67ac2-da52-4ac8-a08d-595c8b5ae4cf": {"__data__": {"id_": "37f67ac2-da52-4ac8-a08d-595c8b5ae4cf", "embedding": null, "metadata": {"page_label": "173", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2adadb5b-fc95-4760-9ae0-93d6fa79a344", "node_type": null, "metadata": {"page_label": "173", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b9aad972ef674b0104aa6165a0240b8d8ad7c839ae4a1010bc0fbd99bc60899"}, "3": {"node_id": "2d6bc0ca-4ac5-4862-a3b9-b92d6bbba0b9", "node_type": null, "metadata": {"page_label": "173", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2947fbe1b5a2eef7fb7a65ca82b3cac4efb36f22c956edf605be55906da6ffb1"}}, "hash": "e875a69f7c9e49a02efee8ae9e9b54dcae8eb147a66f868b8376b7fce415133b", "text": "13 CHEMICAL MEDIATORS A n D THE A u TO n OMIC n ER v O u S S y STEM\n167Basic anatomy and physiology of the autonomic nervous system \nAnatomy\n\u2022\tThe\tautonomic \tnervous \tsystem \tcomprises \tthree \t\ndivisions: sympathetic, parasympathetic and enteric.\n\u2022\tThe\tbasic \t(two-neuron) \tpattern \tof \tthe \tsympathetic \tand \t\nparasympathetic systems consists of a preganglionic \nneuron with a cell body in the central nervous system \n(CNS) and a postganglionic neuron with a cell body in an \nautonomic ganglion.\n\u2022\tThe\tparasympathetic \tsystem \tis \tconnected \tto \tthe \t \nCNS via:\n\u2013 cranial nerve outflow (III, VII, IX, X)\n\u2013 sacral outflow.\n\u2022\tParasympathetic \tganglia \tusually \tlie \tclose \tto \tor \twithin \tthe \t\ntarget organ.\n\u2022\tSympathetic \toutflow \tleaves \tthe \tCNS \tin \tthoracic \tand \t\nlumbar spinal roots. Sympathetic ganglia form two paravertebral chains, plus some midline ganglia.\n\u2022\tThe\tenteric \tnervous \tsystem \tconsists \tof \tneurons \tlying \tin \t\nthe intramural plexuses of the gastrointestinal tract. It receives inputs from sympathetic and parasympathetic systems, but can act on its own to control the motor and secretory functions of the intestine.\nPhysiology\n\u2022\tThe\tautonomic \tsystem \tcontrols \tsmooth \tmuscle \t(visceral \t\nand vascular), exocrine (and some endocrine) secretions, rate and force of contraction of the heart, and certain metabolic processes (e.g. glucose utilisation).\n\u2022\tSympathetic \tand \tparasympathetic \tsystems \thave \t\nopposing actions in some situations (e.g. control of heart rate, gastrointestinal smooth muscle), but not in others (e.g. salivary glands, ciliary muscle).\n\u2022\tSympathetic \tactivity \tincreases \tin \tstress \t(\u2018fight \tor \tflight\u2019 \t\nresponse), whereas parasympathetic activity predominates during satiation and repose. Both systems \nexert\ta\tcontinuous \tphysiological \tcontrol \tof \tspecific \t\norgans under normal conditions, when the body is at neither extreme.\nTransmitters of the autonomic \nnervous system \n\u2022\tThe\tprincipal \ttransmitters \tare \tacetylcholine (ACh) and \nnoradrenaline.\n\u2022\tPreganglionic \tneurons \tare \tcholinergic, \tand \tganglionic \t\ntransmission occurs via nicotinic ACh receptors (although excitatory muscarinic ACh receptors are also present on postganglionic cells).\n\u2022\tPostganglionic \tparasympathetic \tneurons \tare \tcholinergic, \t\nacting on muscarinic receptors in target organs.\n\u2022\tPostganglionic \tsympathetic \tneurons \tare \tmainly \t\nnoradrenergic, although a few are cholinergic (e.g. sweat glands).\n\u2022\tTransmitters \tother \tthan \tnoradrenaline \tand \t\nacetylcholine (NANC transmitters) are also abundant in the autonomic nervous system. The main ones are nitric oxide and vasoactive intestinal peptide \n(parasympathetic), \tATP \tand \tneuropeptide \tY \t\n(sympathetic). \tOthers, \tsuch \tas \t5-hydroxytryptamine, \t\nGABA and dopamine, also play a role.\n\u2022\tCo-transmission \tis \ta \tgeneral \tphenomenon.\u2022\tAll\tautonomic \tnerve \tfibres \tleaving \tthe \tCNS \trelease \t\nacetylcholine, which acts on nicotinic", "start_char_idx": 0, "end_char_idx": 2937, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2d6bc0ca-4ac5-4862-a3b9-b92d6bbba0b9": {"__data__": {"id_": "2d6bc0ca-4ac5-4862-a3b9-b92d6bbba0b9", "embedding": null, "metadata": {"page_label": "173", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2adadb5b-fc95-4760-9ae0-93d6fa79a344", "node_type": null, "metadata": {"page_label": "173", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b9aad972ef674b0104aa6165a0240b8d8ad7c839ae4a1010bc0fbd99bc60899"}, "2": {"node_id": "37f67ac2-da52-4ac8-a08d-595c8b5ae4cf", "node_type": null, "metadata": {"page_label": "173", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e875a69f7c9e49a02efee8ae9e9b54dcae8eb147a66f868b8376b7fce415133b"}}, "hash": "2947fbe1b5a2eef7fb7a65ca82b3cac4efb36f22c956edf605be55906da6ffb1", "text": "receptors \n(although in autonomic ganglia a minor component of \nexcitation is due to activation of muscarinic receptors ;\t\nsee Ch. 14).\n\u2022\tAll\tpostganglionic \tparasympathetic \tfibres \trelease \t\nacetylcholine, which acts on muscarinic receptors.\n\u2022\tAll\tpostganglionic \tsympathetic \tfibres \t(with \tone \t\nimportant exception) release noradrenaline, which \nmay act on either \u03b1 or \u03b2 adrenoceptors (see Ch. 15). The \nexception is the sympathetic innervation of sweat \nglands, where transmission is due to acetylcholine acting on muscarinic receptors. In some species, but \nnot humans, vasodilatation in skeletal muscle is \nproduced by cholinergic sympathetic nerve fibres.\nAcetylcholine \tand \tnoradrenaline \tare \tthe \tgrandees \tamong \t\nautonomic transmitters, and are central to understanding autonomic pharmacology. However, many other chemical \nmediators are also released by autonomic neurons (see pp. \n170\u2013173), and their functional significance is gradually becoming clearer.\nSOME GENERAL PRINCIPLES OF \nCHEMICAL TRANSMISSION\nThe essential processes in chemical transmission \u2013 the release \nof mediators, and their interaction with receptors on target \ncells \u2013 are described in Chapters 4 and 3, respectively. Here \nwe consider some general characteristics of chemical transmission of particular relevance to pharmacology. Many \nof these principles apply also to the CNS and are taken up \nagain in Chapter 38.\nPRESYNAPTIC MODULATION\nThe presynaptic terminals that synthesise and release transmitter in response to electrical activity in the nerve fibre are often themselves sensitive to transmitter substances and \nto other substances that may be produced locally in tissues \n(for review see Boehm & Kubista, 2002). Such presynaptic effects most commonly act to inhibit transmitter release, but \nmay\tenhance \tit. \tFig. \t13.3A \tshows \tthe \tinhibitory \teffect \tof \t\nadrenaline on the release of acetylcholine (evoked by electri -\ncal stimulation) from the postganglionic parasympathetic \nnerve terminals of the intestine. The release of noradrenaline \nfrom nearby sympathetic nerve terminals can also inhibit release of acetylcholine. Noradrenergic and cholinergic nerve mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2938, "end_char_idx": 5582, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "77a8fcd8-5b61-49bd-91d5-7c5340e2d123": {"__data__": {"id_": "77a8fcd8-5b61-49bd-91d5-7c5340e2d123", "embedding": null, "metadata": {"page_label": "174", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8ee06383-fab5-404c-ae63-cf6ed68fcad6", "node_type": null, "metadata": {"page_label": "174", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c962682501a8fc27eb25cb9ee557663fda79f571c4710403e5ce9a6c404311c"}, "3": {"node_id": "3dfabd00-d757-42e9-9a07-5665637045e7", "node_type": null, "metadata": {"page_label": "174", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a7dd6e1a6d3a88fb988f4103ebb343aec4d28948a1ae110ac894e94d2f7d9eb"}}, "hash": "9d2037cb1307d77170ae7b2a88f154d252c825816df6be8e9dd4a1c1a6453ceb", "text": "13 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n168Cholinergic and noradrenergic nerve terminals respond \nnot only to acetylcholine and noradrenaline, as described \nabove, but also to other substances that are released as \nco-transmitters, \tsuch \tas \tATP \tand \tneuropeptide \tY \t(NPY), \t\nor derived from other sources, including nitric oxide, \nprostaglandins, adenosine, dopamine, 5-hydroxytryptamine, \n\u03b3-aminobutyric \tacid \t(GABA), \topioid \tpeptides, \tendocan -\nnabinoids and many other substances. The description of the autonomic nervous system represented in Fig. 13.2 is \nundoubtedly oversimplified. Fig. 13.4 shows some of the main presynaptic interactions between autonomic neurons, \nand summarises the many chemical influences that regulate \ntransmitter release from noradrenergic neurons.\nPresynaptic receptors regulate transmitter release mainly \nby affecting Ca\n2+ entry into the nerve terminal (see Ch. 4), \nbut also by other mechanisms (see Kubista & Boehm, 2006). \nMost presynaptic receptors are of the G protein\u2013coupled \ntype (see Ch. 3), which control the function of calcium channels and potassium channels either through a direct \ninteraction of G proteins with the channels or by second \nmessengers that regulate the state of phosphorylation of the channel proteins. Transmitter release is inhibited when \ncalcium channel opening is inhibited, or when potassium \nchannel\topening \tis \tincreased \t(see \tCh. \t4); \tin \tmany \tcases, \t\nboth mechanisms operate simultaneously. Presynaptic \nregulation by receptors linked directly to ion channels \n(ionotropic \treceptors; \tsee \tCh. \t3) \trather \tthan \tto \tG \tproteins \t\nalso occurs (see Dorostkar & Boehm, 2008). Nicotinic \nacetylcholine \treceptors \t(nAChRs) \tare\tparticularly \timportant \t\nin this respect. They can either facilitate or inhibit the release of other transmitters, such as glutamate (see Ch. 39), and \nmost\tof\tthe \tnAChRs \texpressed \tin \tthe \tCNS \tare \tlocated \t\npresynaptically. \tAnother \texample \tis \tthe \tGABA A receptor, terminals often lie close together in the myenteric plexus, so the opposing effects of the sympathetic and parasympathetic \nsystems result not only from the opposite effects of the \ntwo transmitters on the smooth muscle cells, but also from the inhibition of acetylcholine release by noradrenaline \nacting\ton \tthe \tparasympathetic \tnerve \tterminals. \tA \tsimilar \t\nsituation of mutual presynaptic inhibition exists in the heart, where noradrenaline inhibits acetylcholine release \nand acetylcholine also inhibits noradrenaline release. \nThese are examples of heterotropic interactions, where one neurotransmitter affects the release of another. Homotropic \ninteractions also occur, where the transmitter, by binding to presynaptic autoreceptors, affects the nerve terminals from which it is being released. This type of autoinhibitory \nfeedback acts powerfully at noradrenergic nerve terminals \n(see Starke et al., 1989). Fig. 13.3B shows that in normal \nmice, noradrenaline release increases only slightly as the number of stimuli increases from 1 to 64. In transgenic \nmice lacking a specific type of presynaptic \u03b1\n2 adrenoceptor \n(see Ch. 15), the amount released by the longer stimulus train is greatly increased, though the amount released by \na single stimulus is unaffected. This is because with one or a few stimuli, there is no opportunity for autoinhibitory \nfeedback to develop, whereas with longer trains the inhibi -\ntion\toperates\tpowerfully.", "start_char_idx": 0, "end_char_idx": 3441, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3dfabd00-d757-42e9-9a07-5665637045e7": {"__data__": {"id_": "3dfabd00-d757-42e9-9a07-5665637045e7", "embedding": null, "metadata": {"page_label": "174", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8ee06383-fab5-404c-ae63-cf6ed68fcad6", "node_type": null, "metadata": {"page_label": "174", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c962682501a8fc27eb25cb9ee557663fda79f571c4710403e5ce9a6c404311c"}, "2": {"node_id": "77a8fcd8-5b61-49bd-91d5-7c5340e2d123", "node_type": null, "metadata": {"page_label": "174", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d2037cb1307d77170ae7b2a88f154d252c825816df6be8e9dd4a1c1a6453ceb"}}, "hash": "7a7dd6e1a6d3a88fb988f4103ebb343aec4d28948a1ae110ac894e94d2f7d9eb", "text": "with longer trains the inhibi -\ntion\toperates\tpowerfully. \tA\tsimilar\tautoinhibitory \tfeedback \t\noccurs with many transmitters, including acetylcholine and \n5-hydroxytryptamine.\nIn both the noradrenergic and cholinergic systems, \nthe presynaptic autoreceptors are pharmacologically distinct from the postsynaptic receptors (see Fig. 13.4 and \nChs 14 and 15), and there are drugs that act selectively, \nas agonists or antagonists, on the pre- or postsynaptic \nreceptors.500\nAdrenaline\n(\u00b5mol/L)Stim. 0.4 Hz15 min\n0.5 1.0 1.0 0.5ACh release\n(pmol/g per min)\nNumber of stimuli8\n01234567Percentage release\n1241 66 4\nAdrenoceptor knockoutWild typeA B\nFig. 13.3 Examples of presynaptic inhibition. (A) Inhibitory effect of adrenaline on acetylcholine (ACh) release from postganglionic \nparasympathetic nerves in the guinea pig ileum. The intramural nerves were stimulated electrically where indicated, and the ACh released \ninto the bathing fluid determined by bioassay. Adrenaline strongly inhibits ACh release. (B) Noradrenaline release from mouse hippocampal slices in response to trains of electrical stimuli. Blue bars\n\tshow\tnormal \t(wild-type) \tmice. \tRed bars show \u03b12-adrenoceptor \tknockout \tmice. \t\nThe\tlack\tof \tpresynaptic \tautoinhibition \tin \tthe \tknockout \tmice \tresults \tin \ta \tlarge \tincrease \tin \trelease \twith \ta \tlong \tstimulus \ttrain, \tbut \tdoes \tnot \t\naffect\trelease \tby \tfewer \tthan \tfour \tstimuli, \tbecause \tthe \tautoinhibition \ttakes \ta \tfew \tseconds \tto \tdevelop. \tThis \texample \tis \ttaken \tfrom \ta \tstudy \tof \t\nbrain\tnoradrenergic \tnerves, \tbut \tsimilar \tfindings \thave \tbeen \tmade \ton \tsympathetic \tnerves. \t(Panel \t[A] \tfrom \tVizi, \tE.S., \t1979. \tProg. \tNeurobiol. \t\n12,\t181;\tpanel \t[B] \tredrawn \tfrom \tTrendelenburg, \tet \tal., \t2001. \tNaunyn \tSchmiedeberg\u2019s \tArch \tPharmacol \t364, \t117\u2013130.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3384, "end_char_idx": 5676, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "40bebad0-1edc-4978-a9dc-514e8c3977d5": {"__data__": {"id_": "40bebad0-1edc-4978-a9dc-514e8c3977d5", "embedding": null, "metadata": {"page_label": "175", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fbf03dd6-a28c-422c-bbee-08d5e343c2cd", "node_type": null, "metadata": {"page_label": "175", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "523fe6a44316092eb7a25ae0aefd8608d55463b31d3c5f69bad84852c9607a99"}}, "hash": "523fe6a44316092eb7a25ae0aefd8608d55463b31d3c5f69bad84852c9607a99", "text": "13 CHEMICAL MEDIATORS AnD THE AuTOnOMIC nERvOuS SySTEM\n169NA releaseSmooth muscle Exocr ine glandEndothelial\ncellsPG releaseParasympathetic Sympathetic\nNANA\nAChAC\nh\nNO\nDopamine\nEndocannabinoidsEndorphinsHistaminePGE\nATPAdenosine5-HTNA/AAChMediator\nH2\nD2\nCB1Musc.\nEP5-HT1\nA1\nP2X / P2YReceptor type\nAdrenalin e\nAT1 Angiotensin IIReceptor type MediatorA\nB\n\u00b5,\u03b4\nFig. 13.4 Presynaptic regulation of transmitter release from noradrenergic and cholinergic nerve terminals. \t(A)\tPostulated\t\nhomotropic\t and\theterotropic\t interactions\t between\tsympathetic\t and\tparasympathetic\t nerves.\t(B)\tSome\tof\tthe\tknown\tinhibitory\tand\t\nfacilitatory influences on noradrenaline release from sympathetic nerve endings. 5-HT,\t5-hydroxytryptamine;\t ACh, acetylcholine; NA, \nnoradrenaline; NO, nitric oxide; PG, prostaglandin; PGE, prostaglandin E. \nwhose action is to inhibit transmitter release (see Chs 4 \nand 38). Other ionotropic receptors, such as those activated \nby\tATP\tand\t5-hydroxytryptamine\t(Chs\t16,\t17\tand\t40),\thave \t\nsimilar effects on transmitter release.\nPOSTSYNAPTIC MODULATION\nChemical mediators often act on postsynaptic structures, \nincluding neurons, smooth muscle cells, cardiac muscle cells, and so on, in such a way that their excitability or \nspontaneous firing pattern is altered. In many cases, as \nwith presynaptic modulation, this is caused by changes in \ncalcium\tand/or\tpotassium\tchannel\tfunction.\tWe\tgive\tonly \t\na few examples here.\n\u2022\tThe\tslow\texcitatory\t effect\tproduced\t by\tvarious\t\nmediators, including acetylcholine and peptides such mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2022, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "01665665-7125-4a69-818f-78a8c3732746": {"__data__": {"id_": "01665665-7125-4a69-818f-78a8c3732746", "embedding": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "319e6c49-ccec-47c6-9b76-caa61ea5e016", "node_type": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e0b44c86a2682828d00866a60e7528daf8ad9f2d17784dcc8606279f03d19bc"}, "3": {"node_id": "3fac88bf-75bb-491d-a935-65dcdf8584e1", "node_type": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f1a3cd0babbc07e3342bf8a0478a7d41db403d735dbdd4cd98e95f55dca81ccf"}}, "hash": "484d1d4b51e0b084da3dbe8f7a58b84f65b86daf5c32d735bcae2449ec2d673a", "text": "13 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n170well\tas\tsubstance \tP, \t5-hydroxytryptamine, \tGABA \tand \t\ndopamine, which play a role in ganglionic transmission \n(see Lundberg, 1996, for a comprehensive review).\nCO-TRANSMISSION\nIt is the rule rather than the exception that neurons release more than one transmitter or modulator (see Lundberg, \n1996), each of which interacts with specific receptors and \nproduces effects, often both pre- and postsynaptically. The \nexample\tof\tnoradrenaline/ATP \tco-transmission \tat\tsympa -\nthetic nerve endings is shown in Fig. 13.5, and the best-\nstudied examples and mechanisms are summarised in Table \n13.2 and Figs 13.6 and 13.7.\nWhat,\tone \tmight \twell \task, \tcould \tbe \tthe \tfunctional \t\nadvantage of co-transmission, compared with a single \ntransmitter acting on various different receptors? The \npossible advantages include the following:\n\u2022\tOne\tconstituent \tof \tthe \tcocktail \t(e.g. \ta \tpeptide) \tmay \tbe \t\nremoved or inactivated more slowly than the other \n(e.g. a monoamine), and therefore reach targets further \nfrom the site of release and produce longer-lasting \neffects. This appears to be the case, for example, with acetylcholine and gonadotrophin-releasing hormone in \nsympathetic ganglia.\n\u2022\tThe\tbalance \tof \tthe \ttransmitters \treleased \tmay \tvary \t\nunder\tdifferent \tconditions. \tAt \tsympathetic \tnerve \t\nterminals, \tfor \texample, \twhere \tnoradrenaline \tand \tNPY \t\nare\tstored \tin \tseparate \tvesicles, \tNPY \tis \tpreferentially \t\nreleased at high stimulation frequencies, so that \ndifferential release of one or other mediator may result \nfrom varying impulse patterns. Differential effects of \npresynaptic \tmodulators \tare \talso \tpossible; \tfor \texample, \t\nactivation of \u03b2 \tadrenoceptors \tinhibits \tATP \trelease \t\nwhile enhancing noradrenaline release from \nsympathetic nerve terminals.\nTERMINATION OF TRANSMITTER ACTION\nChemically transmitting synapses other than the peptidergic variety (Ch. 19) invariably incorporate a mechanism for \ndisposing rapidly of the released transmitter, so that its \naction\tremains\tbrief\tand\tlocalised. \tAt\tcholinergic \tsynapses \t\n(Ch. 14), the released acetylcholine is inactivated very rapidly \nin the synaptic cleft by acetylcholinesterase. In most other \ncases (see Fig. 13.8), transmitter action is terminated by active reuptake into the presynaptic nerve, or into sup -\nporting cells such as glia. Such reuptake depends on \ntransporter proteins (see Ch. 4), each being specific for a \nparticular transmitter. The major class (Na\n+/Cl\u2212 co-\ntransporters) whose molecular structure and function are \nwell\tunderstood \t(see\tTorres\tet\tal., \t 2003; \t Gether \t et \tal., \t 2006),\t\nconsists of a family of membrane proteins, each possessing 12 transmembrane helices. Different members of the family \nshow selectivity for each of the main monoamine transmit -\nters\t(e.g. \tthe \tnoradrenaline \t[norepinephrine] \ttransporter; \t\nNET,\tthe \tserotonin \ttransporter; \tSERT, \twhich \ttransports \t\n5-hydroxytryptamine; \tand\tthe\tdopamine \ttransporter, \tDAT)\t\n(see Manepalli et al., 2012). These transporters are important \ntargets for psychoactive drugs, particularly antidepressants \n(Ch. 48), anxiolytic", "start_char_idx": 0, "end_char_idx": 3160, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3fac88bf-75bb-491d-a935-65dcdf8584e1": {"__data__": {"id_": "3fac88bf-75bb-491d-a935-65dcdf8584e1", "embedding": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "319e6c49-ccec-47c6-9b76-caa61ea5e016", "node_type": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e0b44c86a2682828d00866a60e7528daf8ad9f2d17784dcc8606279f03d19bc"}, "2": {"node_id": "01665665-7125-4a69-818f-78a8c3732746", "node_type": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "484d1d4b51e0b084da3dbe8f7a58b84f65b86daf5c32d735bcae2449ec2d673a"}, "3": {"node_id": "4723c30e-aeae-4f63-91b0-66e2315f3431", "node_type": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "affec2a93829400669b006eccf65c660334f69e1406404209f0f0560a1211db9"}}, "hash": "f1a3cd0babbc07e3342bf8a0478a7d41db403d735dbdd4cd98e95f55dca81ccf", "text": "drugs, particularly antidepressants \n(Ch. 48), anxiolytic drugs (Ch. 45) and stimulants (Ch. 49). \nTransporters \tfor \tglycine \tand \tGABA \tbelong \tto \tthe \tsame \t\nfamily.\nVesicular transporters (Ch. 4), which load synaptic \nvesicles with transmitter molecules, are closely related to plasma membrane transporters. Membrane transporters as substance P (see Ch. 19), results mainly from a \ndecrease in K\n+ permeability. Conversely, the inhibitory \neffect of various opioid peptides in the gut is mainly \ndue to increased K+ permeability.\n\u2022\tNeuropeptide Y (NPY), which is released as a co-transmitter with noradrenaline at many \nsympathetic nerve endings and acts on smooth muscle cells to enhance the vasoconstrictor effect of \nnoradrenaline, thus greatly facilitating transmission.\nThe pre- and postsynaptic effects described above are often \ndescribed as neuromodulation , because the mediator acts to \nincrease or decrease the efficacy of synaptic transmission \nwithout participating directly as a transmitter. Many \nneuropeptides, for example, affect membrane ion channels in such a way as to increase or decrease excitability and \nthus control the firing pattern of the cell. Neuromodulation \nis loosely defined but, in general, involves slower processes (taking seconds to days) than neurotransmission (which occurs in milliseconds), and operates through cascades of \nintracellular messengers (see Ch. 3) rather than directly on \nligand-gated ion channels.\nTRANSMITTERS OTHER THAN ACETYLCHOLINE \nAND NORADRENALINE\nAs\tmentioned \tabove, \tacetylcholine \tor \tnoradrenaline \tare \t\nnot the only autonomic transmitters. The rather grudging \nrealisation that this was so dawned many years ago when \nit was noticed that autonomic transmission in many organs \ncould not be completely blocked by drugs that abolish responses to these transmitters. The dismal but tenacious \nterm non-adrenergic non-cholinergic\n\t(NANC) \ttransmission \t\nwas coined. Later, fluorescence and immunocytochemical \nmethods showed that neurons, including autonomic \nneurons, contain many potential transmitters, often several \nin the same cell. Compounds now known to function as \nNANC\ttransmitters \tinclude \tATP, \tvasoactive \tintestinal \t\npeptide\t(VIP), \tNPY \tand \tnitric \toxide \t(Fig. \t13.5 \tand \tTable \t\n13.2), which function at postganglionic nerve terminals, as Neuromodulation and presynaptic \ninteractions \n\u2022\tAs\twell\tas \tfunctioning \tdirectly \tas \tneurotransmitters, \t\nchemical mediators may regulate:\n\u2013 presynaptic transmitter release\n\u2013 neuronal excitability.\n\u2022\tBoth\tare \texamples \tof \tneuromodulation and generally \ninvolve second messenger regulation of membrane ion \nchannels.\n\u2022\tPresynaptic \treceptors \tmay \tinhibit \tor \tincrease \t\ntransmitter release, the former being more important.\n\u2022\tInhibitory \tpresynaptic autoreceptors occur on \nnoradrenergic and cholinergic neurons, causing each transmitter to inhibit its own release ( autoinhibitory \nfeedback).\n\u2022\tMany\tendogenous \tmediators \t(e.g. \tGABA, \t\nprostaglandins, opioid and other peptides), as well as the transmitters themselves, exert presynaptic control (mainly inhibitory) over autonomic transmitter release.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3109, "end_char_idx": 6443, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4723c30e-aeae-4f63-91b0-66e2315f3431": {"__data__": {"id_": "4723c30e-aeae-4f63-91b0-66e2315f3431", "embedding": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "319e6c49-ccec-47c6-9b76-caa61ea5e016", "node_type": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e0b44c86a2682828d00866a60e7528daf8ad9f2d17784dcc8606279f03d19bc"}, "2": {"node_id": "3fac88bf-75bb-491d-a935-65dcdf8584e1", "node_type": null, "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f1a3cd0babbc07e3342bf8a0478a7d41db403d735dbdd4cd98e95f55dca81ccf"}}, "hash": "affec2a93829400669b006eccf65c660334f69e1406404209f0f0560a1211db9", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6448, "end_char_idx": 6783, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fd4c89ea-d0bd-4630-a2c7-9ec85cb73a63": {"__data__": {"id_": "fd4c89ea-d0bd-4630-a2c7-9ec85cb73a63", "embedding": null, "metadata": {"page_label": "177", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8f893d7b-6f44-473b-95b3-1dee90e9cb64", "node_type": null, "metadata": {"page_label": "177", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "96ffc5a10b7660509d5fe67741bc8c9582ff0d10246f42f4b84de63708841659"}, "3": {"node_id": "29c0dde8-6896-4ce8-8ce4-b044792ff7a6", "node_type": null, "metadata": {"page_label": "177", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b8ce5cdf046dd1792778cb6be220a4edcb4136976891abc09006effb2a42163"}}, "hash": "c5dc786af954d50508dc1e676dc3a06959a293d33372a0905967ab1da65626b9", "text": "13 CHEMICAL MEDIATORS A n D THE A u TO n OMIC n ER v O u S S y STEM\n171S\nS + P\nL-NameRelaxationContraction\nGuanethidineP + SPCCA\nB\nFig. 13.5 ATP and nitric oxide as neurotransmitters. \t(A)\tNoradrenaline \tand \tATP \tare \tco-transmitters \treleased \tfrom \tthe \tsame \tnerves \tin \t\nthe guinea pig vas deferens. Contractions of the tissue are shown in response to a single electrical stimulus causing excitation of \nsympathetic \tnerve \tendings. \tWith \tno \tblocking \tdrugs \tpresent, \ta \ttwin-peaked \tresponse \tis \tproduced \t(C).\tThe\tearly \tpeak \tis \tselectively \t\nabolished\tby \tthe \tATP \tantagonist \tsuramin \t(S),\twhile\tthe \tlate \tpeak \tis \tblocked \tby \tthe \t\u03b11-adrenoceptor \tantagonist \tprazosin \t(P). The response \nis completely eliminated when both drugs are present. (B) Noradrenaline and nitric oxide are neurotransmitters in the rat anococcygeus \nmuscle but are probably released from different nerves. The nerves innervating the muscle were stimulated with brief trains of pulses. \nInitially,\tnerve \tstimulation \tevoked \trapid \tcontractions \tby \treleasing \tnoradrenaline. \tApplication \tof \tguanethidine \tblocked \tstimulus-evoked \t\nnoradrenaline \trelease \tand \traised \tthe \ttone \tof \tthe \tpreparation \trevealing \tnerve-evoked \trelaxations \tthat \twere \tblocked \tby \tL-NAME, \tan \tinhibitor \t\nof\tnitric\toxide \tsynthesis. \t(Panel \t[A] \treproduced \twith \tpermission \tfrom \tvon \tKugelglen, \tI., \tStarke, \tK., \t1991. \tTrends \tPharmacol. \tSci. \t12, \t\n319\u2013324;\tdata \tin \tpanel \t[B] \tare \tfrom \ta \tstudent \tpractical \tclass \tat \tGlasgow \tCaledonian \tUniversity, \tcourtesy \tA. \tCorbett.)\nusually act as co-transporters of Na+, Cl\u2212 and transmit-\nter molecules, and it is the inwardly directed \u2018downhill\u2019 \ngradient for Na+ that provides the energy for the inward \n\u2018uphill\u2019 movement of the transmitter. The simultaneous transport of ions along with the transmitter means that \nthe process generates a net current across the membrane, which can be measured directly and used to monitor the \ntransport process. Very similar mechanisms are responsible \nfor other physiological transport processes, such as glucose uptake (Ch. 32) and renal tubular transport of amino acids. \nBecause it is the electrochemical gradient for sodium that \ndrives the inward transport of transmitter molecules, a reduction of this gradient can reduce or even reverse the flow of transmitter. This is probably not important under \nphysiological conditions, but when the nerve terminals are \ndepolarised or abnormally loaded with sodium (e.g. in ischaemic conditions), the resulting non-vesicular release of \ntransmitter (and inhibition of the normal synaptic reuptake \nmechanism) may play a significant role in the effects of ischaemia on tissues such as heart and brain (see Chs 22 and 41). Studies with transgenic \u2018knockout\u2019 mice (see Torres \net al., 2003) show that the store of releasable transmitter \nis substantially depleted in animals lacking the membrane transporter, showing that synthesis is unable to maintain \nthe\tstore \tif \tthe \trecapture \tmechanism \tis \tdisabled. \tAs \twith \t\nreceptors (see Ch. 3), many genetic polymorphisms of transporter genes occur in humans, finding associations", "start_char_idx": 0, "end_char_idx": 3165, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "29c0dde8-6896-4ce8-8ce4-b044792ff7a6": {"__data__": {"id_": "29c0dde8-6896-4ce8-8ce4-b044792ff7a6", "embedding": null, "metadata": {"page_label": "177", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8f893d7b-6f44-473b-95b3-1dee90e9cb64", "node_type": null, "metadata": {"page_label": "177", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "96ffc5a10b7660509d5fe67741bc8c9582ff0d10246f42f4b84de63708841659"}, "2": {"node_id": "fd4c89ea-d0bd-4630-a2c7-9ec85cb73a63", "node_type": null, "metadata": {"page_label": "177", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c5dc786af954d50508dc1e676dc3a06959a293d33372a0905967ab1da65626b9"}}, "hash": "0b8ce5cdf046dd1792778cb6be220a4edcb4136976891abc09006effb2a42163", "text": "genes occur in humans, finding associations \nwith various neurological, cardiovascular and psychiatric \ndisorders has provided insight into their aetiology and may explain altered responsiveness to drugs (see Reynolds \net al., 2014).\nAs\twe\tshall \tsee \tin \tsubsequent \tchapters, \tboth \tplasma \t\nmembrane and vesicular transporters are targets for various drugs, and defining the physiological role and pharm -\nacological properties of these molecules has been the focus of much research.\nDENERVATION SUPERSENSITIVITY\nIt is known, mainly from the work of Cannon on the sympathetic system, that if a nerve is cut and its terminals mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3122, "end_char_idx": 4230, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bb14f7c6-e571-4076-94ff-c64ca84a2680": {"__data__": {"id_": "bb14f7c6-e571-4076-94ff-c64ca84a2680", "embedding": null, "metadata": {"page_label": "178", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9038d23d-b6e8-405b-a623-002d24169ed5", "node_type": null, "metadata": {"page_label": "178", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "66c9e2e2e6a2964ff0bd8fd75f02db5ea358ecbb7e1f4b467fcf866d63b633d8"}, "3": {"node_id": "689fa769-2761-4b5c-a2df-d49230301f91", "node_type": null, "metadata": {"page_label": "178", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5fbf29f4c7c4be01442f9905eb948ffcb0e14847a91c55437e3673d76d0ba1ba"}}, "hash": "fa43bb9b6a77e88875270771f4e88d8a00456895b7e6bf919e9db1d205340985", "text": "13 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n172is evidence that pathways in the CNS show the same \nphenomenon.\n\u25bc Several mechanisms contribute to denervation supersensitivity, \nand the extent and mechanism of the phenomenon varies from organ \nto organ. Reported mechanisms include the following (see Luis & \nNoel, 2009).\n\u2022\tProliferation of receptors. This is particularly marked in skeletal \nmuscle, in which the number of acetylcholine receptors increases \n20-fold\tor \tmore \tafter \tdenervation; \tthe \treceptors, \tnormally \t\nlocalised to the endplate region of the fibres (Ch. 14), spread \nover the whole surface. Elsewhere, increases in receptor number \nare much smaller, or absent altogether.\n\u2022\tLoss of mechanisms for transmitter removal. \tAt\tnoradrenergic \t\nsynapses, the loss of neuronal uptake of noradrenaline (see \nCh. 15) contributes substantially to denervation supersensitivity. \nAt\tcholinergic \tsynapses, \ta \tpartial \tloss \tof \tcholinesterase \toccurs \t\n(see Ch. 14).\n\u2022\tIncreased postjunctional responsiveness. Smooth muscle cells \nbecome partly depolarised and hyperexcitable after denervation (due in part to reduced Na\n+-K+-ATPase\tactivity; \tsee \tCh. \t4) \tand \t\nthis phenomenon contributes appreciably to their supersensitivity. Increased Ca\n2+ signalling, resulting in enhanced \nexcitation\u2013contraction coupling, may also occur.\nSupersensitivity can occur, but is less marked, when \ntransmission is interrupted by processes other than nerve \nsection. Pharmacological block of ganglionic transmis -\nsion, for example, if sustained for a few days, causes \nsome degree of supersensitivity of the target organs, and \nlong-term blockade of postsynaptic receptors also causes \nreceptors to proliferate, leaving the cell supersensitive when the blocking agent is removed. Phenomena such as this Table 13.2 Examples of non-adrenergic non-cholinergic transmitters and co-transmitters in the peripheral nervous system\nTransmitter Location Function\nNon-peptides\nATP Postganglionic sympathetic neurons Fast depolarisation/contraction of smooth \nmuscle cells (e.g. blood vessels, vas deferens)\nGABA, 5-HT Enteric neurons Peristaltic reflex\nDopamine Some sympathetic neurons (e.g. kidney) Vasodilatation\nNitric oxide Pelvic nerves Erection\nGastric nerves Gastric emptying\nPeptides\nNeuropeptide Y Postganglionic sympathetic neurons Facilitates constrictor action of noradrenaline; \ninhibits noradrenaline release (e.g. blood vessels)\nVIP Parasympathetic nerves to salivary glands Vasodilatation; co-transmitter with acetylcholine\nNANC innervation of airways smooth muscle Bronchodilatation\nGonadotrophin-releasing hormoneSympathetic ganglia Slow depolarisation; co-transmitter with acetylcholine\nSubstance P Sympathetic ganglia, enteric neurons Slow depolarisation; co-transmitter with acetylcholine\nCalcitonin gene-related peptideNon-myelinated sensory neurons Vasodilatation; vascular leakage; neurogenic inflammation\n5-HT,\n\t5-hydroxytryptamine; \tATP, adenosine triphosphate; GABA,\tgamma-aminobutyric \tacid; \tNANC,\tnon-adrenergic \tnon-cholinergic; \tVIP, \nvasoactive intestinal peptide.\nTissue responseNPYNAATP\nSlow\nresponseIntermediate\nresponseRapid\nresponse\nVIPNOAChSympathetic Parasympathetic\nFig. 13.6 ", "start_char_idx": 0, "end_char_idx": 3198, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "689fa769-2761-4b5c-a2df-d49230301f91": {"__data__": {"id_": "689fa769-2761-4b5c-a2df-d49230301f91", "embedding": null, "metadata": {"page_label": "178", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9038d23d-b6e8-405b-a623-002d24169ed5", "node_type": null, "metadata": {"page_label": "178", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "66c9e2e2e6a2964ff0bd8fd75f02db5ea358ecbb7e1f4b467fcf866d63b633d8"}, "2": {"node_id": "bb14f7c6-e571-4076-94ff-c64ca84a2680", "node_type": null, "metadata": {"page_label": "178", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fa43bb9b6a77e88875270771f4e88d8a00456895b7e6bf919e9db1d205340985"}}, "hash": "5fbf29f4c7c4be01442f9905eb948ffcb0e14847a91c55437e3673d76d0ba1ba", "text": "Parasympathetic\nFig. 13.6 The main co-transmitters at postganglionic \nparasympathetic and sympathetic neurons. The different \nmediators generally give rise to fast, intermediate and slow responses of the target organ. ACh, acetylcholine; ATP, \nadenosine triphosphate; NA, noradrenaline; NO, nitric oxide; \nNPY,\n\tneuropeptide \tY; \tVIP, vasoactive intestinal peptide. \nallowed to degenerate, the structure supplied by it becomes \nsupersensitive to the transmitter substance released by the \nterminals. Thus skeletal muscle, which normally responds \nto injected acetylcholine only if a large dose is given directly \ninto the arterial blood supply, will, after denervation, respond by contracture to much smaller amounts. Other \norgans, such as salivary glands and blood vessels, show \nsimilar supersensitivity to acetylcholine and noradrenaline when the postganglionic nerves degenerate, and there mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3172, "end_char_idx": 4548, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "664d9ffd-7067-4174-b75b-48802386d358": {"__data__": {"id_": "664d9ffd-7067-4174-b75b-48802386d358", "embedding": null, "metadata": {"page_label": "179", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f8dc7d31-c021-4a2f-80d4-39c5d89fe64c", "node_type": null, "metadata": {"page_label": "179", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "871733ea9880986b7a4e789df889c543f2cab2f11664c9c8119b99e0e00d891f"}, "3": {"node_id": "f91b9717-94b9-4bd8-8a66-a865658dc511", "node_type": null, "metadata": {"page_label": "179", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c8faa3d306d5c37741b03609827ef33576edda0a109905e938016cb1db475f12"}}, "hash": "b52b3c9fc66a845aca6415f224c2842dd712f613a67704af61be28b3def0aa7a", "text": "13 CHEMICAL MEDIATORS A n D THE A u TO n OMIC n ER v O u S S y STEM\n173many different classes of drug, discussed in later chap -\nters, that act by facilitating or blocking neurochemical \ntransmission.\nAll\tthe\tsteps \tshown \tin \tFig. \t13.8 \t(except \tfor \ttransmitter \t\ndiffusion, step 8) can be influenced by drugs. For example, \nthe enzymes involved in synthesis or inactivation of the \ntransmitter can be inhibited, as can the transport systems \nresponsible for the neuronal and vesicular uptake of the transmitter or its precursor. The actions of the great \nmajority of drugs that act on the peripheral nervous \nsystem (Chs 14 and 15) and the CNS fit into this general \nscheme.are of importance in the CNS, where such supersensitiv -\nity can cause \u2018rebound\u2019 effects when drugs that impair \nsynaptic transmission are given for some time and then \ndiscontinued.\nBASIC STEPS IN NEUROCHEMICAL \nTRANSMISSION: SITES OF DRUG ACTION\nFig. 13.8 summarises the main processes that occur in a \nclassical chemically transmitting synapse, and provides \na useful basis for understanding the actions of the Presynaptic inhibition\nHeterotropic presynaptic inhibition\nPostsynaptic synergismX\nXY\nXYX YXYMany noradrenergic and \ncholinergic terminals\nNoradrenergic/cholinergic\nnerve terminals\nin the heart\nNoradrenaline/NPY in blood vessels\nNoradrenaline/ATP in blood \nvessels, vas deferensACh/GnRH in sympathetic gangliaACh/SP in enteric ganglia\nACh/VIP in salivary glandSlow\nGland Blood vesselFastA\nB\nC\nFig. 13.7 Co-transmission and neuromodulation \u2013 some \nexamples. \t(A)\tPresynaptic \tinhibition. \t(B) \tHeterotropic \t\npresynaptic \tinhibition. \t(C) \tPostsynaptic \tsynergism. \tACh, \nacetylcholine; ATP, adenosine triphosphate; GnRH, \ngonadotrophin-releasing \thormone \t(luteinising \thormone-releasing \t\nhormone); NPY,\tneuropeptide \tY; \tSP,\tsubstance \tP; \tVIP, \nvasoactive intestinal peptide. 121311\n10\n98765\n4321\nCa2+\nCa2+ TNERVE TERMINAL\nDepolarisation\nDegradation\nproducts\nTT\nT\nTT\nTTPrecursorTransmitter\nprecursor\nInactivated\ntransmitter\nNON-NEURONAL\nCELL\nFig. 13.8 The main processes involved in synthesis, \nstorage and release of amine and amino acid transmitters. \n1,\tUptake\tof \tprecursors; \t2, synthesis of transmitter; 3,\tuptake/\ntransport of transmitter into vesicles; 4, degradation of surplus \ntransmitter; 5, depolarisation by propagated action potential; 6, \ninflux of Ca2+ in response to depolarisation; 7, release of \ntransmitter by exocytosis; 8, diffusion to postsynaptic \nmembrane; 9, interaction with postsynaptic receptors; 10, \ninactivation of transmitter; 11,\treuptake\tof \ttransmitter \tor \t\ndegradation products by nerve terminals; 12,\tuptake\tand \trelease \t\nof\ttransmitter \tby \tnon-neuronal \tcells; \tand \t13, interaction with \npresynaptic receptors. The transporters (11 and 12) can release \ntransmitter \tunder \tcertain \tconditions \tby \tworking \tin \treverse. \tThese \t\nprocesses are well characterised for many transmitters (e.g. \nacetylcholine, \tmonoamines, \tamino \tacids, \tATP).", "start_char_idx": 0, "end_char_idx": 2992, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f91b9717-94b9-4bd8-8a66-a865658dc511": {"__data__": {"id_": "f91b9717-94b9-4bd8-8a66-a865658dc511", "embedding": null, "metadata": {"page_label": "179", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f8dc7d31-c021-4a2f-80d4-39c5d89fe64c", "node_type": null, "metadata": {"page_label": "179", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "871733ea9880986b7a4e789df889c543f2cab2f11664c9c8119b99e0e00d891f"}, "2": {"node_id": "664d9ffd-7067-4174-b75b-48802386d358", "node_type": null, "metadata": {"page_label": "179", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b52b3c9fc66a845aca6415f224c2842dd712f613a67704af61be28b3def0aa7a"}}, "hash": "c8faa3d306d5c37741b03609827ef33576edda0a109905e938016cb1db475f12", "text": "\tmonoamines, \tamino \tacids, \tATP). \tPeptide \t\nmediators (see Ch. 18) differ in that they may be synthesised \nand\tpackaged \tin \tthe \tcell \tbody \trather \tthan \tthe \tterminals. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2958, "end_char_idx": 3612, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "53e8e424-bd02-411b-a478-7804b1ef747d": {"__data__": {"id_": "53e8e424-bd02-411b-a478-7804b1ef747d", "embedding": null, "metadata": {"page_label": "180", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ed5c95ab-7707-4325-ad71-3c0376fb493e", "node_type": null, "metadata": {"page_label": "180", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8108bd2269e0a546f5970ee558dcd730f21b3cafe90b8a4ab167660af54f6fe6"}, "3": {"node_id": "0d9e8d95-f399-42b0-8883-0ca268295c8c", "node_type": null, "metadata": {"page_label": "180", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bbce94ddc209c71d0a1b2960399679fdb5f11fbf7ad45aa2f6de1578c6909a64"}}, "hash": "82cb21fd03ba287713d252c5ee2df657687ac9b6ca84ad1ac89994e903cd4503", "text": "13 SECTION 2 \u2003\u2003CHEMICAL MEDIATORS\n174REFERENCES AND FURTHER READING\nGeneral references\nBacq,\tZ.M.,\t1975.\tChemical\t Transmission\t of\tNerve\tImpulses:\t A\t\nHistorical Sketch. Pergamon Press, Oxford. ( Lively account of the history \nof the discovery of chemical transmission )\nBurnstock,\t G.,\t2009.\tAutonomic\t neurotransmission:\t 60\tyears\tsince\tSir\t\nHenry\tDale.\tAnn.\tRev.\tPharmacol.\t 49,\t1\u201330.\t(Elegant and well- \nillustrated account of many of the topics discussed in this chapter. \nRecommended )\nFurness, J.B., Callaghan, B.P., Rivera, L.R., Cho, H.J., 2014. The enteric \nnervous system and gastrointestinal innervation: integrated local and \ncentral\tcontrol.\tAdv.\tExp.\tMed.\tBiol.\t817,\t39\u201371.\t(Excellent review of the \nanatomy and physiology of the enteric nervous system )\nIversen, L.L., Iversen, S.D., Bloom, F.E., Roth, R.H., 2009. \nIntroduction to Neuropsychopharmacology. Oxford University \nPress,\tNew\tYork.\t(Excellent general account covering many aspects of \nneuropharmacology )\nLuis, E.M.Q., Noel, F., 2009. Mechanisms of adaptive supersensitivity in \nvas\tdeferens.\t Auton.\tNeurosci.\t 146,\t38\u201346.\t(Summarises mechanisms \ncontributing to denervation supersensitivity in a typical organ supplied by \nthe sympathetic nervous system )\nRobertson,\t D.W.,\tBiaggioni,\t I.,\tBurnstock,\t G.,\tLow,\tP.A.,\tPaton,\tJ.F.R.\t\n(Eds.),\t2012.\tPrimer\ton\tthe\tAutonomic\t Nervous\t System,\tthird\ted.\t\nAcademic\t Press,\tLondon.\t (An excellent comprehensive textbook on all \naspects, including pharmacology, of the autonomic nervous system. By no \nmeans elementary despite its title )\nValenstein,\t E.S.,\t2005.\tThe\tWar\tof\tthe\tSoups\tand\tthe\tSparks.\tColumbia\t\nUniversity\t Press,\tNew\tYork.\t(Readable and informative account of origins \nof the theory of chemical transmission )\nPresynaptic modulation\nBoehm, S., Kubista, H., 2002. Fine tuning of sympathetic transmitter \nrelease via ionotropic and metabotropic receptors. Pharm. Rev. 54, \n43\u201399. ( Comprehensive review of presynaptic modulation, focusing on \nsympathetic neurons though mechanisms are widespread )Dorostkar, M.M., Boehm, S., 2008. Presynaptic ionotropic receptors. \nHandb. Exp. Pharmacol. 184, 479\u2013527. ( Review of how presynaptic \nionotropic receptors modify transmitter release )\nKubista, H., Boehm, S., 2006. Molecular mechanisms underlying the \nmodulation of exocytotic noradrenaline release via presynaptic \nreceptors. Pharm. Ther. 112, 213\u2013242. ( Describes the wide variety of \nmechanisms by which presynaptic receptors affect transmitter release )\nStarke, K., Gothert, M., Kilbinger, H., 1989. Modulation of \nneurotransmitter release by presynaptic autoreceptors. Physiol. Rev. \n69, 864\u2013989. ( Comprehensive review article )\nCo-transmission\nLundberg, J.M., 1996. Pharmacology of co-transmission in the \nautonomic nervous system: integrative aspects on amines, \nneuropeptides, adenosine triphosphate, amino acids and nitric oxide. \nPharmacol. Rev.", "start_char_idx": 0, "end_char_idx": 2892, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0d9e8d95-f399-42b0-8883-0ca268295c8c": {"__data__": {"id_": "0d9e8d95-f399-42b0-8883-0ca268295c8c", "embedding": null, "metadata": {"page_label": "180", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ed5c95ab-7707-4325-ad71-3c0376fb493e", "node_type": null, "metadata": {"page_label": "180", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8108bd2269e0a546f5970ee558dcd730f21b3cafe90b8a4ab167660af54f6fe6"}, "2": {"node_id": "53e8e424-bd02-411b-a478-7804b1ef747d", "node_type": null, "metadata": {"page_label": "180", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82cb21fd03ba287713d252c5ee2df657687ac9b6ca84ad1ac89994e903cd4503"}}, "hash": "bbce94ddc209c71d0a1b2960399679fdb5f11fbf7ad45aa2f6de1578c6909a64", "text": "amino acids and nitric oxide. \nPharmacol. Rev. 48, 114\u2013192. ( Detailed and informative review article )\nTransporters\nGether,\tU.,\tAndersen,\t P.H.,\tLarsson,\t O.M.,\tet\tal.,\t2006.\tNeurotransmitter\t\ntransporters: molecular function of important drug targets. Trends \nPharmacol. Sci. 27, 375\u2013383. ( Useful short review article )\nManepalli, S., Surratt, C.K., Madura, J.D., Nolan, T.L., 2012. Monoamine \ntransporter structure, function, dynamics, and drug discovery: a \ncomputational\t perspective.\t AAPS\tJ.\t\t14,\t820\u2013831.\t (Complex review \nconcentrating on molecular modelling of substrate and drug interactions \nwith monoamine transporters )\nReynolds, G.P., McGowan, O.O., Dalton, C.F., 2014. Pharmacogenomics \nin psychiatry: the relevance of receptor and transporter \npolymorphisms. Br. J. Clin. Pharmacol. 77, 654\u2013672. ( Reviews the role of \npolymorphisms in membrane transporters in altered responses to drugs )\nTorres, G.E., Gainetdinov, R.R., Caron, M.G., 2003. Plasma membrane \nmonoamine transporters: structure, regulation and function. Nat. Rev. \nNeurosci. 4, 13\u201325. ( Describes molecular, physiological and pharmacological \naspects of transporters )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2846, "end_char_idx": 4476, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3af372fc-e003-4005-8e46-f7eb25d83a34": {"__data__": {"id_": "3af372fc-e003-4005-8e46-f7eb25d83a34", "embedding": null, "metadata": {"page_label": "181", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bf6a332a-0836-49e5-ad43-4ea1a2f97f6d", "node_type": null, "metadata": {"page_label": "181", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a6878f6a542cbd62536203a21e163bef297fa7d747f6533dde3f6c402a5d423"}, "3": {"node_id": "217119c4-3098-456b-b166-9611c6c9ed8f", "node_type": null, "metadata": {"page_label": "181", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2addaa12f0ab15a490bcd33329fadf7782951fa1e644cf5ea0c596a2a6e5da5"}}, "hash": "6eddc33c70b89b1d2d3d08d7ef1afce357928b8b5be875c0d29dfb86bef9bb8c", "text": "175\nCholinergic transmission 14 CHEMICAL MEDIATORS SECTION 2 \nOVERVIEW\nThis chapter is concerned mainly with cholinergic \ntransmission in the periphery, and the ways in which \ndrugs affect it. Here we describe the different types of \nacetylcholine (ACh) receptors and their functions, as well as the synthesis and release of ACh. Drugs that \nact on ACh receptors, many of which have clinical uses, \nare described in this chapter. Cholinergic mechanisms in the central nervous system (CNS) and their relevance \nto dementia are discussed in Chapters 40 and 41.\nMUSCARINIC AND NICOTINIC ACTIONS \nOF ACETYLCHOLINE\n\u25bc The discovery of the pharmacological action of ACh came, \nparadoxically, from work on adrenal glands, extracts of which were \nknown to produce a rise in blood pressure owing to their content \nof adrenaline (epinephrine). In 1900, Reid Hunt found that after \nadrenaline had been removed from such extracts, they produced a fall in blood pressure instead of a rise. He attributed the fall to the \npresence of choline, but later concluded that a more potent derivative \nof choline must be responsible. With Taveau, he tested a number of choline derivatives and discovered that ACh was some 100,000 times \nmore active than choline in lowering the rabbit\u2019s blood pressure. \nThe physiological role of ACh was not apparent at that time, and \nit remained a pharmacological curiosity until Loewi, Dale and their \ncolleagues discovered its transmitter role in the 1930s.\nAnalysing the pharmacological actions of ACh in 1914, Dale \ndistinguished two types of activity, which he designated as \nmuscarinic and nicotinic because they mimicked, respectively, \nthe effects of muscarine , the active principle of the poisonous \nmushroom Amanita muscaria, and of nicotine. Muscarinic \nactions closely resemble the effects of parasympathetic \nstimulation (Table 13.1). After the muscarinic effects have been blocked by atropine, larger doses of ACh produce \nnicotine-like effects, which include:\n\u2022\tstimulation \tof \tall \tautonomic \tganglia\n\u2022\tstimulation \tof \tvoluntary \tmuscle\n\u2022\tsecretion \tof \tadrenaline \tfrom \tthe \tadrenal \tmedulla\nThe muscarinic and nicotinic actions of ACh are dem -\nonstrated in Fig. 14.1. Small and medium doses of ACh produce a transient fall in blood pressure due to arteriolar \nvasodilatation and slowing of the heart \u2013 muscarinic effects that are abolished by atropine. A large dose of ACh given \nafter atropine produces nicotinic effects: an initial rise in \nblood pressure due to a stimulation of sympathetic ganglia and consequent vasoconstriction, and a secondary rise \nresulting from secretion of adrenaline.\nDale\u2019s pharmacological classification corresponds closely \nto the main physiological functions of ACh in the body. The \nmuscarinic actions correspond to those of ACh released at postganglionic parasympathetic nerve endings, with two significant exceptions:\n1. ACh causes generalised vasodilatation, even though \nmost blood vessels have no parasympathetic innervation. This is an indirect effect: ACh (like many \nother mediators) acts on vascular endothelial cells to \nrelease nitric oxide (see Ch. 21), which relaxes smooth \nmuscle. The physiological function of this is uncertain, \nbecause ACh is not normally present in circulating \nblood.\n2. ACh evokes secretion from sweat glands, which are \ninnervated by cholinergic fibres of the sympathetic nervous system (see Table 13.1).\nThe nicotinic actions correspond to those of ACh acting on autonomic ganglia of the sympathetic and parasympathetic systems, the motor endplate of voluntary muscle and the", "start_char_idx": 0, "end_char_idx": 3588, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "217119c4-3098-456b-b166-9611c6c9ed8f": {"__data__": {"id_": "217119c4-3098-456b-b166-9611c6c9ed8f", "embedding": null, "metadata": {"page_label": "181", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bf6a332a-0836-49e5-ad43-4ea1a2f97f6d", "node_type": null, "metadata": {"page_label": "181", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a6878f6a542cbd62536203a21e163bef297fa7d747f6533dde3f6c402a5d423"}, "2": {"node_id": "3af372fc-e003-4005-8e46-f7eb25d83a34", "node_type": null, "metadata": {"page_label": "181", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6eddc33c70b89b1d2d3d08d7ef1afce357928b8b5be875c0d29dfb86bef9bb8c"}}, "hash": "b2addaa12f0ab15a490bcd33329fadf7782951fa1e644cf5ea0c596a2a6e5da5", "text": "and parasympathetic systems, the motor endplate of voluntary muscle and the \nsecretory cells of the adrenal medulla.\nACETYLCHOLINE RECEPTORS\nAlthough Dale himself dismissed the concept of receptors \nas sophistry rather than science, his functional classifica -\ntion provided the basis for distinguishing muscarinic and nicotinic receptors, the two major classes of ACh receptor \n(see Ch. 3 and Southan et al., 2016). Many important \ntherapeutic drugs target these receptors, and despite their long and distinguished history, recent advances continue \nto open new opportunities for drug development in both \nmuscarinic (Kruse et al., 2014; Carruthers et al., 2015) and \nnicotinic (Dinely et al., 2015) fields.\nNICOTINIC RECEPTORS\nNicotinic ACh receptors (nAChRs) fall into three main \nclasses \u2013 the muscle, ganglionic and CNS types \u2013 whose \nsubunit compositions are summarised in Table 14.1. Muscle \nreceptors are confined to the skeletal neuromuscular junction; ganglionic receptors are responsible for fast transmission at \nsympathetic and parasympathetic ganglia; and CNS-type \nreceptors are widespread in the brain, and are heterogeneous with respect to their molecular composition and location \n(see Ch. 40). Most of the CNS-type nAChRs are located \npresynaptically and serve to facilitate or inhibit the release of other mediators, such as glutamate and dopamine.\n\u25bc All nAChRs are pentameric structures that function as ligand-\ngated ion channels (see Fig. 3.4). The five subunits that form the \nreceptor\u2013channel complex are similar in structure, and so far 17 \ndifferent members of the family have been identified and cloned, \ndesignated \u03b1 (ten types), \u03b2 (four types), \u03b3, \u03b4 and \u03b5 (one of each). The \nfive subunits each possess four membrane-spanning helical domains, \nand one of these helices (M 2) from each subunit defines the central pore mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3513, "end_char_idx": 5844, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "02c09b02-55b2-4748-bb0b-8325dd772dee": {"__data__": {"id_": "02c09b02-55b2-4748-bb0b-8325dd772dee", "embedding": null, "metadata": {"page_label": "182", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "16b77040-2cfe-4a37-a1f3-5b48343b1019", "node_type": null, "metadata": {"page_label": "182", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d54488612d2ca23b764f0b01d1b419fc627b6a6fcb37ed1409988c92fd56b8ba"}}, "hash": "d54488612d2ca23b764f0b01d1b419fc627b6a6fcb37ed1409988c92fd56b8ba", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n176200\n150100\n50Blood pressure (mmHg)1 min\nACh\n2 \u00b5gACh\n5 mgACh\n50 \u00b5gACh\n50 \u00b5gAtropine\n2 mgA B C D\nFig. 14.1 Dale\u2019s experiment showing that acetylcholine (ACh) produces two kinds of effect on the cat\u2019s blood pressure. Arterial \npressure was recorded with a mercury manometer from a spinal cat. (A) ACh causes a fall in blood pressure due to vasodilatation. (B) A \nlarger dose also produces bradycardia. Both (A) and (B) are muscarinic effects. (C) After atropine (muscarinic antagonist), the same dose of ACh has no effect. (D) Still under the influence of atropine, a much larger dose of ACh causes a rise in blood pressure due to stimulation of sympathetic ganglia, accompanied by tachycardia, followed by a secondary rise (due to release of adrenaline from the adrenal gland). These effects result from its action on nicotinic receptors. (From Burn, J.H., 1963. Autonomic Pharmacology. Blackwell, Oxford.)\nTable 14.1 Nicotinic receptor subtypesa\nMuscle type Ganglion type CNS type Notes\nMain molecular form (\u03b11) 2\u03b21\u03b4\u03b5 (adult form) (\u03b13) 2(\u03b22) 3 (\u03b14) 2(\u03b22) 3 (\u03b17) 5 \u2014\nMain synaptic locationSkeletal neuromuscular junction: mainly postsynapticAutonomic ganglia: mainly postsynapticMany brain regions: pre- and postsynapticMany brain regions: pre- and postsynaptic\u2014\nMembrane response ExcitatoryIncreased cation permeability (mainly Na\n+, K+)ExcitatoryIncreased cation permeability (mainly Na\n+, K+)Pre- and postsynaptic excitationIncreased cation permeability (mainly Na\n+, K+)Pre- and postsynaptic excitationIncreased cation permeability(\u03b17)\n5 receptor \nproduces large \nCa2+ entry, evoking \ntransmitter release\nAgonists AcetylcholineCarbacholSuccinylcholineAcetylcholineCarbacholNicotineEpibatidineDimethylphenyl-piperaziniumNicotineEpibatidineAcetylcholineCytosineVarenicline\nbEpibatidineDimethylphenyl-piperaziniumVarenicline\nb\u2014\nAntagonists TubocurarinePancuroniumAtracuriumVecuronium\u03b1-Bungarotoxin\u03b1-ConotoxinMecamylamineTrimetaphanHexamethonium\u03b1-ConotoxinMecamylamine\nMethylaconitine\u03b1-Bungarotoxin\u03b1-ConotoxinMethylaconitine\u2014\naThis table shows only the main subtypes expressed in mammalian tissues. Several other subtypes are expressed in selected brain \nregions, and also in the peripheral nervous system and in non-neuronal tissues. For further details, see Ch. 40 and review by Kalamida \net al. (2007).\nbVarenicline is used as an aid to smoking cessation. It acts as a partial agonist on ( \u03b14) 2(\u03b22) 3 receptors and a full agonist on ( \u03b17) 5 receptors \n(see Ch. 50).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2987, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f2264ba6-8609-4e6d-988b-716d5031ed50": {"__data__": {"id_": "f2264ba6-8609-4e6d-988b-716d5031ed50", "embedding": null, "metadata": {"page_label": "183", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e16cfc28-71bf-45e6-bdd9-94e670a8f14a", "node_type": null, "metadata": {"page_label": "183", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dfee9f0b3cffbf62015db9930d7345f137c01d731735627c44ac1f27e87f021a"}, "3": {"node_id": "94468084-e547-470a-b086-f702a8ba2457", "node_type": null, "metadata": {"page_label": "183", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f34224d709e2181a5831aba5526b84a41e54ce9aa48ca85c89eeda0e35274f91"}}, "hash": "da6aceb1963d67140ecbd409dc72871a76b054c0bd1cbf1d80d2c3e90f5d7418", "text": "14 CHOLI nERgIC TRA n SMISSIO n\n177(M 1\u2013M 5) are known. The odd-numbered members of the \ngroup (M 1, M 3, M 5) couple with G q to activate the inositol \nphosphate pathway (Ch. 3), while the even-numbered \nreceptors (M 2, M 4) act through G i to open potassium (K ir) \nchannels causing membrane hyperpolarisation; they also inhibit adenylyl cyclase but intracellular cAMP is usually \nlow. Muscarinic agonists with either transduction mecha -\nnism also activate the mitogen-activated protein kinase \npathway. The location and pharmacology of the various \nreceptor subtypes are summarised in Table 14.2.\nM\n1 receptors (\u2018neural\u2019) are found mainly on CNS and \nperipheral neurons and on gastric parietal cells. They \nmediate excitatory effects, for example, the slow muscarinic \nexcitation mediated by ACh in sympathetic ganglia (Ch. 13) and central neurons. This excitation is produced by a \ndecrease in K\n+ conductance, which causes membrane \ndepolarisation. Deficiency of this kind of ACh-mediated effect in the brain is possibly associated with dementia (see \nCh. 41), although transgenic M\n1-receptor knockout mice \nshow only slight cognitive impairment. M 1 receptors are \nalso involved in the increase of gastric acid secretion fol -\nlowing vagal stimulation (see Ch. 31).(see Ch. 3). nAChR subtypes generally contain both \u03b1 and \u03b2 subunits, \nthe exception being the homomeric ( \u03b17) 5 subtype found mainly in \nthe brain (Ch. 40). The adult muscle receptor has the composition \n\u03b12\u03b21\u03b51\u03b41, while the main ganglionic subtype is \u03b12\u03b23 (for more detail \non which subunits are present in the different subtypes see Southan \net al., 2016). The two binding sites for ACh (both of which need to \nbe occupied to cause the channel to open) reside at the interface \nbetween the extracellular domain of each of the \u03b1 subunits and its \nneighbour. The diversity of the nAChR family (for details see Kalamida \net al., 2007), which emerged from cloning studies in the 1980s, took \npharmacologists somewhat by surprise. Although they knew that the neuromuscular and ganglionic synapses differed pharmacologically, \nand suspected that cholinergic synapses in the CNS might be different \nagain, the molecular diversity goes far beyond this, and its functional significance is only slowly emerging.\nThe different action of agonists and antagonists on \nneuromuscular, ganglionic and brain synapses is of practical \nimportance and mainly reflects the differences between \nthe muscle and neuronal nAChRs (Table 14.1).\nMUSCARINIC RECEPTORS\nMuscarinic receptors (mAChRs) are typical G protein\u2013coupled receptors (see Ch. 3), and five molecular subtypes \nTable 14.2 Muscarinic receptor subtypesa\nM1 (\u2018neural\u2019) M2 (\u2018cardiac\u2019)M3 (\u2018glandular/smooth \nmuscle\u2019) M4 M5\nMain locations Autonomic ganglia \n(including intramural ganglia in stomach)gastric oxyntic glands (acid secretion)Glands: salivary, lacrimal, etc.Cerebral cortexHeart: atriaCNS: widely distributedExocrine glands: salivary, etc.Smooth muscle: gastrointestinal tract, eye, airways, bladderBlood vessels: endotheliumCNS CNS: very localised expression in substantia nigraSalivary glandsIris/ciliary muscle\nCellular response \u2191 IP\n3, DAG \nDepolarisation Excitation (slow epsp) \u2193 K\n+ \nconductance\u2193 cAMPInhibition\u2193 Ca\n2+", "start_char_idx": 0, "end_char_idx": 3246, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "94468084-e547-470a-b086-f702a8ba2457": {"__data__": {"id_": "94468084-e547-470a-b086-f702a8ba2457", "embedding": null, "metadata": {"page_label": "183", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e16cfc28-71bf-45e6-bdd9-94e670a8f14a", "node_type": null, "metadata": {"page_label": "183", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dfee9f0b3cffbf62015db9930d7345f137c01d731735627c44ac1f27e87f021a"}, "2": {"node_id": "f2264ba6-8609-4e6d-988b-716d5031ed50", "node_type": null, "metadata": {"page_label": "183", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "da6aceb1963d67140ecbd409dc72871a76b054c0bd1cbf1d80d2c3e90f5d7418"}}, "hash": "f34224d709e2181a5831aba5526b84a41e54ce9aa48ca85c89eeda0e35274f91", "text": "\u2193 K\n+ \nconductance\u2193 cAMPInhibition\u2193 Ca\n2+ conductance\n\u2191 K+ conductance\u2191 IP 3\nStimulation\u2191 [Ca\n2+]i\u2193 cAMPInhibition\u2191 IP\n3\nExcitation\nFunctional responseCNS excitation(? improved cognition)Gastric secretionCardiac inhibitionNeural inhibition Central muscarinic effects (e.g. tremor, hypothermia)Gastric, salivary secretion Gastrointestinal smooth muscle contractionOcular accommodation VasodilatationEnhanced locomotionNot known\nNon-selective agonists (see also Table 14.3)AcetylcholineCarbacholOxotremorinePilocarpineBethanechol\nSelective agonists McNA343 Cevimeline\nNon-selective antagonists (see also Table 14.5)AtropineDicycloverineTolterodineOxybutyninIpratropium\nSelective antagonistsPirenzepineMamba toxin MT7Gallamine (see p. 178) Darifenacin Mamba toxin MT3\naThis table shows only the predominant subtypes expressed in mammalian tissues. For further details, see Ch. 40 and review by Kalamida \net al. (2007).\nDrugs in clinical use are shown in bold.\nDAG, diacylglycerol; epsp, excitatory postsynaptic potential; IP3, inositol trisphosphate.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3205, "end_char_idx": 4731, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "db5888f4-7ed8-40ec-a703-dc07b2105bdb": {"__data__": {"id_": "db5888f4-7ed8-40ec-a703-dc07b2105bdb", "embedding": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b0e630f4-ec5a-47e0-9c31-b3fd2f0a6c68", "node_type": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f1961c4ed19925c1a18023c5cefcbda00002cd1794cc22e446fe1feb3d961d4c"}, "3": {"node_id": "7dd67af5-e81f-41c5-b444-0c6162e99f9d", "node_type": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e5aeb6c2bfdcdd7bc9f80aac69c978141c0332a048c303186fff5dffef9b74ff"}}, "hash": "1eac94f8bb06ea2e1aceb90e054f3e8a9aa0d42ef20df99cac73e2e1bb0b11e1", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n178ACETYLCHOLINE SYNTHESIS AND RELEASE\nACh is synthesised within the nerve terminal from choline, \nwhich is taken up into the nerve terminal by a specific \ntransporter (Ch. 13), similar to those that operate for many \ntransmitters but which transports the precursor, choline, not ACh, so it is not important in terminating the action of \nthe transmitter. The concentration of choline in the blood \nand body fluids is normally about 10 \u00b5mol/L, but in the \nimmediate vicinity of cholinergic nerve terminals it increases, \nprobably to about 1 mmol/L, when the released ACh is \nhydrolysed, and more than 50% of this choline is normally \nrecaptured by the nerve terminals. Free choline within the \nnerve terminal is acetylated by a cytosolic enzyme, choline \nacetyltransferase (CAT), which transfers the acetyl group \nfrom acetyl coenzyme A. The rate-limiting process in ACh \nsynthesis appears to be choline transport, which is deter-\nmined by the extracellular choline concentration and hence is linked to the rate at which ACh is being released (see \nFig. 14.2). Cholinesterase is present in the presynaptic nerve M2 receptors (\u2018cardiac\u2019 ) occur in the heart, and also on the \npresynaptic terminals of peripheral and central neurons. They exert inhibitory effects, mainly by increasing K\n+ \nconductance and by inhibiting calcium channels (see Ch. 4). M\n2-receptor activation is responsible for cholinergic \ninhibition of the heart, as well as presynaptic inhibition in the CNS and periphery (Ch. 13). They are also co-expressed \nwith M\n3 receptors in visceral smooth muscle, and contribute \nto the smooth-muscle-stimulating effect of muscarinic \nagonists in several organs.\nM3 receptors (glandular/smooth muscle) produce mainly \nexcitatory effects, i.e. stimulation of glandular secretions (salivary, bronchial, sweat, etc.) and contraction of visceral \nsmooth muscle. M\n3 receptor activation also causes relaxation \nof some smooth muscles (mainly vascular) via the release \nof nitric oxide from neighbouring endothelial cells (Ch. \n21). M 3 receptors occur also in specific locations in the CNS \n(see Ch. 40).\nM4 and M5 receptors are largely confined to the CNS, and \ntheir functional role is not well understood, although mice \nlacking these receptors do show behavioural changes.\nCytokine secretion from lymphocytes and other cells is \nregulated by M 1 and M 3 receptors, while M 2 and M 4 receptors \naffect cell proliferation in various situations, opening up the possibility of new therapeutic roles for mAChR ligands \n(see Wessler & Kirkpatrick, 2008).\nThe agonist binding region is highly conserved between \nthe different subtypes, so attempts to develop selective ago -\nnists and antagonists have had limited success. Most known agonists are non-selective, though an experimental com -\npound, McNA343 , is selective for M\n1 receptors. Cevimeline , \na relatively selective M 3-receptor agonist, is used to improve \nsalivary and lacrimal secretion in Sj\u00f6gren\u2019s syndrome, an \nautoimmune disorder characterised by dryness of mouth \nand eyes. It is possible that new allosteric mAChR ligands, such as positive allosteric modulators (PAMs, see Ch. 3, \nFig. 3.7), which are the focus of much current interest (see \nNickols & Conn, 2014), will allow better subtype selectivity for drugs acting on this important class of receptors, for \nexample, by targeting CNS muscarinic", "start_char_idx": 0, "end_char_idx": 3410, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7dd67af5-e81f-41c5-b444-0c6162e99f9d": {"__data__": {"id_": "7dd67af5-e81f-41c5-b444-0c6162e99f9d", "embedding": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b0e630f4-ec5a-47e0-9c31-b3fd2f0a6c68", "node_type": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f1961c4ed19925c1a18023c5cefcbda00002cd1794cc22e446fe1feb3d961d4c"}, "2": {"node_id": "db5888f4-7ed8-40ec-a703-dc07b2105bdb", "node_type": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1eac94f8bb06ea2e1aceb90e054f3e8a9aa0d42ef20df99cac73e2e1bb0b11e1"}, "3": {"node_id": "1a9abb1e-24f5-491f-a622-ebd64b270d89", "node_type": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a145fed0253dce9d7a7b67bdbcdb218b0a65ff0f0fb0078cd0946746fe2a963"}}, "hash": "e5aeb6c2bfdcdd7bc9f80aac69c978141c0332a048c303186fff5dffef9b74ff", "text": "this important class of receptors, for \nexample, by targeting CNS muscarinic receptors without \nproducing unwanted cardiovascular effects (see Ch. 41).\nThere is more subtype selectivity among antagonists. \nAlthough most of the classic muscarinic antagonists (e.g. \natropine , hyoscine ) are non-selective, pirenzepine (previ -\nously used for peptic ulcer disease) is selective for M\n1 \nreceptors, and darifenacin (used for urinary incontinence \nin adults with detrusor muscle instability, known as \u2018overac -\ntive bladder\u2019) is selective for M 3 receptors. Gallamine , once \nused as a neuromuscular-blocking drug, is also a selective, although weak, allosteric M\n2 receptor antagonist.1 Toxins \nfrom the venom of the green mamba have been discovered to be highly selective mAChR antagonists (see Table 14.2).\nPHYSIOLOGY OF CHOLINERGIC \nTRANSMISSION\nThe physiology of cholinergic neurotransmission is described \nin detail by Nicholls et al. (2012). The main ways in which \ndrugs can affect cholinergic transmission are shown in \nFig. 14.2.Acetylcholine receptors \n\u2022\tMain\tsubdivision \tis \tinto \tnicotinic \t(nAChR) \tand \t\nmuscarinic \t(mAChR) \tsubtypes.\n\u2022\tnAChRs \tare \tdirectly \tcoupled \tto \tcation \tchannels, \tand \t\nmediate fast excitatory synaptic transmission at the \nneuromuscular junction, autonomic ganglia and various \nsites\tin\tthe \tCNS. \tMuscle \tand \tneuronal \tnAChRs \tdiffer \t\nin their molecular structure and pharmacology.\n\u2022\tmAChRs \tand \tnAChRs \toccur \tpresynaptically \tas \twell \tas \t\npostsynaptically, and function to regulate transmitter release.\n\u2022\tmAChRs \tare \tG \tprotein\u2013coupled \treceptors \tcausing:\n\u2013\tactivation \tof \tphospholipase \tC \t(hence \tformation \tof \t\ninositol trisphosphate and diacylglycerol as second messengers)\n\u2013\tinhibition \tof \tadenylyl \tcyclase\n\u2013\tactivation \tof \tpotassium \tchannels \tand/or \tinhibition \tof \t\ncalcium channels.\n\u2022\tmAChRs \tmediate \tacetylcholine \teffects \tat \t\npostganglionic parasympathetic synapses (mainly heart, smooth muscle and glands), and contribute to ganglionic excitation. They occur in many parts of the \nCNS.\n\u2022\tThree\tmain \ttypes \tof \tmAChR \toccur:\n\u2013\tM 1 receptors (\u2018neural\u2019) producing slow excitation of \nganglia. They are selectively blocked by \npirenzepine.\n\u2013\tM 2 receptors (\u2018cardiac\u2019) causing decrease in cardiac \nrate and force of contraction (mainly of atria). They are selectively blocked by gallamine\n.\tM2 receptors \nalso mediate presynaptic inhibition.\n\u2013\tM 3 receptors (\u2018glandular\u2019) causing secretion, \ncontraction of visceral smooth muscle, vascular relaxation. Cevimeline\n\tis\ta\tselective \tM3 agonist.\n\u2022\tTwo\tfurther \tmolecular \tmAChR \tsubtypes, \tM4\tand\tM5, \noccur mainly in the CNS.\n\u2022\tAll\tmAChRs \tare \tactivated \tby \tacetylcholine \tand \t\nblocked by atropine. There are also subtype-selective \nagonists and antagonists.\n1Unlike most other antagonists, gallamine acts allosterically (i.e. at a site \ndistinct from the ACh binding site).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3345, "end_char_idx": 6336, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1a9abb1e-24f5-491f-a622-ebd64b270d89": {"__data__": {"id_": "1a9abb1e-24f5-491f-a622-ebd64b270d89", "embedding": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b0e630f4-ec5a-47e0-9c31-b3fd2f0a6c68", "node_type": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f1961c4ed19925c1a18023c5cefcbda00002cd1794cc22e446fe1feb3d961d4c"}, "2": {"node_id": "7dd67af5-e81f-41c5-b444-0c6162e99f9d", "node_type": null, "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e5aeb6c2bfdcdd7bc9f80aac69c978141c0332a048c303186fff5dffef9b74ff"}}, "hash": "5a145fed0253dce9d7a7b67bdbcdb218b0a65ff0f0fb0078cd0946746fe2a963", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6355, "end_char_idx": 6786, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b074302d-f077-47e4-a057-c7ec61ba6dea": {"__data__": {"id_": "b074302d-f077-47e4-a057-c7ec61ba6dea", "embedding": null, "metadata": {"page_label": "185", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0fb1f8a2-bdf8-4bf0-88bc-8c31c5ae0e36", "node_type": null, "metadata": {"page_label": "185", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "da346ce642506b0580ce4bdf0086541f875be38933d81c52578ff6e8071356be"}, "3": {"node_id": "823cbd72-0ba4-40b7-a028-8a7d0216e512", "node_type": null, "metadata": {"page_label": "185", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "479558fd3fec0622eb5b31c3614b3417ffe96fb2ab3b0801e994133d9392d073"}}, "hash": "d45e1a5648606d1bbd4c37fb2a4d9b0dae8ba33acad2e659381631e36b14d2b9", "text": "14 CHOLInERgIC TRAnSMISSIOn\n179the basement membrane that lies between the pre- and \npostsynaptic membranes. At fast cholinergic synapses (e.g. \nthe neuromuscular and ganglionic synapses), but not at slow \nones (smooth muscle, gland cells, heart, etc.), the released \nACh is hydrolysed very rapidly (within 1 ms), so that it \nacts only very briefly.\n\u25bc At the neuromuscular junction, which is a highly specialised \nsynapse, a single nerve impulse releases about 300 synaptic vesicles \n(altogether about 3 million ACh molecules) from the nerve terminals \nsupplying a single muscle fibre, which contain altogether about 3 \nmillion synaptic vesicles. The synaptic vesicles are the structural basis \nfor the release of ACh from the nerve terminal in packets (\u2018quanta\u2019). \nApproximately 2 million ACh molecules combine with receptors, of \nwhich there are about 30 million on each muscle fibre, the rest being \nhydrolysed without reaching a receptor. The ACh molecules remain \nbound to receptors for, on average, about 2 ms, and are quickly \nhydrolysed after dissociating. The result is that transmitter action is \nvery rapid and very brief, which is important for a synapse that initiates \nspeedy muscular responses and transmits signals faithfully at high terminals, and ACh is continually being hydrolysed and \nresynthesised. Inhibition of the nerve terminal cholinesterase \ncauses the accumulation of surplus ACh in the cytosol, which \nis not available for release by nerve impulses (although it \nis able to leak out via the choline carrier). Most of the ACh \nsynthesised, however, is packaged into synaptic vesicles, \nin which its concentration is extraordinarily high (about \n100 mmol/L), and from which release occurs by exocytosis \ntriggered by Ca2+ entry into the nerve terminal (see Ch. 4).\nCholinergic vesicles accumulate ACh actively, by means \nof a specific transporter belonging to the family of amine \ntransporters described in Chapter 13. Accumulation of ACh \nis coupled to the large electrochemical gradient for protons \nthat exists between acidic intracellular organelles and the \ncytosol; it is blocked selectively by the experimental drug \nvesamicol . Following its release, ACh diffuses across the \nsynaptic cleft to combine with receptors on the postsynaptic \ncell. Some of it succumbs on the way to hydrolysis by \nacetylcholinesterase (AChE), an enzyme that is bound to Presynaptic\ntoxins,\ne.g. botulinum\nDepolarising\nblocking agents,\ne.g. suxamethoniumAcCoA\nCoA\nACh\ncarrierPresynaptic\nnicotinic\nACh receptor\nACh leakExocytosisCholine carrier\nCholine\n+\nAcetateAChCholine\nACh\nPostsynaptic nicotinic\nACh receptorCAT\nEmpty\nvesicle\nAChE\nNa+\nK+AChVesamicol\nNon-depolarising\nblocking agents,\ne.g. tubocurarine\nAnticholinesterases,\ne.g. neostigmineHemicholinium\nFig. 14.2 Events and sites of drug action at a nicotinic cholinergic synapse. Acetylcholine (ACh) is shown acting postsynaptically on \na nicotinic receptor controlling a cation channel (e.g. at the neuromuscular or ganglionic synapse), and also on a presynaptic nicotinic \nreceptor that acts to facilitate ACh release during sustained synaptic activity. The nerve terminal also contains acetylcholinesterase (not \nshown); when this is inhibited, the amount of free ACh, and the rate of leakage of ACh via the", "start_char_idx": 0, "end_char_idx": 3281, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "823cbd72-0ba4-40b7-a028-8a7d0216e512": {"__data__": {"id_": "823cbd72-0ba4-40b7-a028-8a7d0216e512", "embedding": null, "metadata": {"page_label": "185", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0fb1f8a2-bdf8-4bf0-88bc-8c31c5ae0e36", "node_type": null, "metadata": {"page_label": "185", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "da346ce642506b0580ce4bdf0086541f875be38933d81c52578ff6e8071356be"}, "2": {"node_id": "b074302d-f077-47e4-a057-c7ec61ba6dea", "node_type": null, "metadata": {"page_label": "185", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d45e1a5648606d1bbd4c37fb2a4d9b0dae8ba33acad2e659381631e36b14d2b9"}}, "hash": "479558fd3fec0622eb5b31c3614b3417ffe96fb2ab3b0801e994133d9392d073", "text": "the amount of free ACh, and the rate of leakage of ACh via the choline carrier, is increased. Under normal \nconditions, this leakage of ACh is insignificant. At muscarinic cholinergic junctions (e.g. heart, smooth muscle and exocrine glands), both \npostsynaptic and presynaptic (inhibitory) receptors are of the muscarinic type. AcCoA, acetyl coenzyme A; AChE, acetylcholinesterase; \nCAT, choline acetyltransferase; CoA, coenzyme A. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3219, "end_char_idx": 4135, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e1d16cb-6ca1-4845-8dc3-943d41efe29c": {"__data__": {"id_": "8e1d16cb-6ca1-4845-8dc3-943d41efe29c", "embedding": null, "metadata": {"page_label": "186", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a0bf1ddf-b5c1-4b6a-899e-a8e7ad45902b", "node_type": null, "metadata": {"page_label": "186", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2786728c836aaf2e3e28330bdfa50b9876fd5d433610af8dc5295fd8c11956d"}, "3": {"node_id": "6ae9df9b-7bb3-4600-aeb4-1f54aef245e2", "node_type": null, "metadata": {"page_label": "186", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ef9a517172afb7aa12629d0d05c6742d6753425e66d01bbd5eaa62d5ce7eef9"}}, "hash": "b70a31f4b01bd3bb3d5f274bdd2ea184086a7910776d411fb9a71bf2ea76df5a", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n180TC 72 \u00b5 mol/L\n60 min40 min30 minControl 50 mV\n20 msA\nB\nC\nD\nFig. 14.3 Cholinergic transmission in an autonomic \nganglion cell. \tRecords\twere \tobtained \twith \tan \tintracellular \t\nmicroelectrode from a guinea pig parasympathetic ganglion cell. \nThe artefact at the beginning of each trace shows the moment of stimulation of the preganglionic nerve. Tubocurarine (TC), an acetylcholine antagonist, causes the excitatory postsynaptic potential (epsp) to become smaller. In record (C), it only just succeeds in triggering the action potential, and in (D) it has fallen below the threshold. Following complete block, antidromic stimulation (not shown) will still produce an action potential (cf. \ndepolarisation \tblock, \tFig. \t14.4). \t(From \tBlackman, \tJ.G. \tet \tal., \t\n1969. J Physiol 201, 723.)\n(M 2)-receptor-mediated increase in K+ conductance, but other \ntransmitters, such as dopamine and adenosine, also contribute.\n\u2022\tA\tslow epsp , which lasts for about 10 s. This is produced by ACh \nacting on M 1 receptors, which close K+ channels.\n\u2022\tA\tlate slow epsp , lasting for 1\u20132 min. This is thought to be \nmediated by a peptide co-transmitter, substance P in some \nganglia, and a gonadotrophin-releasing hormone-like peptide in \nothers (see Ch. 13). Like the slow epsp, it is produced by a \ndecrease in K+ conductance.\nDEPOLARISATION \u2003BLOCK\n\u25bc Depolarisation block occurs at cholinergic synapses when the \nexcitatory nAChRs are persistently activated, and it results from a decrease in the electrical excitability of the postsynaptic cell. This is \nshown in Fig. 14.4. Application of nicotine to a sympathetic ganglion \nactivates nAChRs, causing a depolarisation of the cell, which at first initiates action potential discharge. After a few seconds, this discharge \nceases and transmission is blocked. The loss of electrical excitability \nis shown by the fact that electrical stimuli also fail to produce an action potential. The main reason for the loss of electrical excitability \nduring a period of maintained depolarisation is that the voltage-\nsensitive sodium channels (see Ch. 4) become inactivated (i.e. refrac -\ntory) and no longer able to open in response to a brief depolarising stimulus.\nA second type of effect is also seen in the experiment shown in Fig. \n14.4. After nicotine has acted for several minutes, the cell partially \nrepolarises and its electrical excitability returns but, despite this, frequency. Muscle cells are much larger than neurons and require \nmuch more synaptic current to generate an action potential. Thus all \nthe chemical events happen on a larger scale than at a neuronal synapse; the number of transmitter molecules in a quantum, the number of \nquanta released, and the number of receptors activated by each \nquantum are all 10\u2013100 times greater. Our brains would be huge, but not very clever, if their synapses were built on the industrial scale \nof the neuromuscular junction.\nPRESYNAPTIC \u2003MODULATION\nACh release is regulated by mediators, including ACh itself, \nacting on presynaptic receptors, as discussed in Chapter 13. \nAt postganglionic parasympathetic nerve endings, inhibitory \nM2 receptors participate in autoinhibition of ACh release; \nother mediators, such as noradrenaline, also inhibit the \nrelease of ACh (see Ch. 13). At the neuromuscular junction, \nhowever, presynaptic nAChRs", "start_char_idx": 0, "end_char_idx": 3370, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6ae9df9b-7bb3-4600-aeb4-1f54aef245e2": {"__data__": {"id_": "6ae9df9b-7bb3-4600-aeb4-1f54aef245e2", "embedding": null, "metadata": {"page_label": "186", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a0bf1ddf-b5c1-4b6a-899e-a8e7ad45902b", "node_type": null, "metadata": {"page_label": "186", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2786728c836aaf2e3e28330bdfa50b9876fd5d433610af8dc5295fd8c11956d"}, "2": {"node_id": "8e1d16cb-6ca1-4845-8dc3-943d41efe29c", "node_type": null, "metadata": {"page_label": "186", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b70a31f4b01bd3bb3d5f274bdd2ea184086a7910776d411fb9a71bf2ea76df5a"}}, "hash": "7ef9a517172afb7aa12629d0d05c6742d6753425e66d01bbd5eaa62d5ce7eef9", "text": "the neuromuscular junction, \nhowever, presynaptic nAChRs facilitate ACh release, a mechanism that may allow the synapse to function reliably \nduring prolonged high-frequency activity. In the brain, as \nmentioned above, presynaptic nAChRs either facilitate or inhibit the release of other mediators.\nELECTRICAL EVENTS IN TRANSMISSION AT FAST \nCHOLINERGIC SYNAPSES\nACh, acting on the postsynaptic membrane of a nicotinic \n(neuromuscular or ganglionic) synapse, causes a large \nincrease in its permeability to cations, particularly to Na+ \nand K+, and to a lesser extent Ca2+. The resulting inflow of \nNa+ depolarises the postsynaptic membrane. This \ntransmitter-mediated depolarisation is called an endplate \npotential (epp) in a skeletal muscle fibre, or a fast excitatory \npostsynaptic potential (fast epsp) at the ganglionic synapse. \nIn a muscle fibre, the localised epp spreads to adjacent, \nelectrically excitable parts of the muscle fibre; if its amplitude \nreaches the threshold for excitation, an action potential is initiated, which propagates to the rest of the fibre and evokes \na contraction (Ch. 4).\nIn a nerve cell, depolarisation of the soma or a dendrite by \nthe fast epsp causes a local current to flow. This depolarises \nthe axon hillock region of the cell, where, if the epsp is large \nenough, an action potential is initiated. Fig. 14.3 shows \nthat tubocurarine, a drug that blocks postsynaptic nACh \nreceptors, reduces the amplitude of the fast epsp until it \nno longer initiates an action potential, although the cell is \nstill capable of responding when it is stimulated electrically. Most ganglion cells are supplied by several presynaptic \naxons, and it requires simultaneous activity in more \nthan one to make the postganglionic cell fire (integrative action). At the neuromuscular junction, only one nerve \nfibre supplies each muscle fibre \u2013 like a relay station in a \ntelegraph line the synapse ensures faithful 1 : 1 transmission \ndespite the impedance mismatch between the fine nerve \nfibre and the much larger muscle fibre. The amplitude of \nthe epp is normally more than enough to initiate an action \npotential \u2013 indeed, transmission still occurs when the epp is reduced by 70%\u201380%, showing a large margin of safety so \nthat fluctuations in transmitter release (e.g. during repetitive \nstimulation) do not affect transmission.\n\u25bc Transmission at the ganglionic synapse is more complex than at \nthe neuromuscular junction. Although the primary event at both is \nthe depolarisation (fast epsp or epp, respectively) produced by ACh \nacting on nAChRs, this is followed in the ganglion by a succession \nof much slower postsynaptic responses:\n\u2022\tA\tslow inhibitory (hyperpolarising) postsynaptic potential (slow ipsp), \nlasting 2\u20135 s. This mainly reflects a muscarinic mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3314, "end_char_idx": 6588, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "25fd0c30-0db6-4e79-994c-a49efda63ffc": {"__data__": {"id_": "25fd0c30-0db6-4e79-994c-a49efda63ffc", "embedding": null, "metadata": {"page_label": "187", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8db36e24-62d7-40bf-9f81-83711e111b50", "node_type": null, "metadata": {"page_label": "187", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c7072c5ca8191fccacbf40c847e06d6bcd908229a6983c49b4b50c87eb2a04fd"}, "3": {"node_id": "c78f4413-8239-42dd-b013-b6008d1920e9", "node_type": null, "metadata": {"page_label": "187", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a05703474ea263846c6ccd61ac93f953b39952cbf3d9ba2db7bcb6b7af6d7ce"}}, "hash": "dbb6baa607883108d0cb184104474011f25ccbd31f963bcb34a3243fe9969e15", "text": "14 CHOLI nERgIC TRA n SMISSIO n\n181\u2022\tneuromuscular-blocking \tdrugs\n\u2022\tanticholinesterases \tand \tother \tdrugs \tthat \tenhance \t\ncholinergic transmission\nDRUGS AFFECTING MUSCARINIC RECEPTORS\nMUSCARINIC \u2003AGONISTS\nStructure\u2013activity relationships\nMuscarinic agonists, as a group, are often referred to as \nparasympathomimetic, because the main effects that they \nproduce in the whole animal resemble those of parasym -\npathetic stimulation. The structures of ACh and related \ncholine esters are given in Table 14.3. They are agonists at transmission remains blocked. This type of secondary, non-depolarising \nblock occurs also at the neuromuscular junction if repeated doses of \nthe depolarising drug suxamethonium2 (see below) are used. The \nmain factor responsible for the secondary block (known clinically as phase II block ) appears to be receptor desensitisation (see Ch. 2). This \ncauses the depolarising action of the blocking drug to subside, but \ntransmission remains blocked because the receptors are desensitised \nto ACh.\nEFFECTS OF DRUGS ON CHOLINERGIC \nTRANSMISSION\nAs shown in Fig. 14.2, drugs can influence cholinergic \ntransmission either by acting on postsynaptic ACh receptors \nas agonists or antagonists (see Tables 14.1 and 14.2), or by \naffecting the release or destruction of endogenous ACh.\nIn the rest of this chapter, we describe the following \ngroups of drugs, subdivided according to their site of action:\n\u2022\tmuscarinic \tagonists\n\u2022\tmuscarinic \tantagonists\n\u2022\tganglion-stimulating \tdrugs\n\u2022\tganglion-blocking \tdrugsCholinergic transmission \n\u2022\tAcetylcholine \t(ACh) \tsynthesis:\n\u2013\trequires \tcholine, \twhich \tenters \tthe \tneuron \tvia \t\ncarrier-mediated transport\n\u2013\tcholine\tis \tacetylated \tto \tform \tACh \tby \tcholine \tacetyl \t\ntransferase, a cytosolic enzyme found only in \ncholinergic neurons. Acetyl coenzyme A is the source of acetyl groups.\n\u2022\tACh\tis\tpackaged \tinto \tsynaptic \tvesicles \tat \thigh \t\nconcentration by carrier-mediated transport.\n\u2022\tACh\trelease \toccurs \tby \tCa2+-mediated exocytosis. At \nthe neuromuscular junction, one presynaptic nerve \nimpulse\treleases \t100\u2013500 \tvesicles.\n\u2022\tAt\tthe\tneuromuscular \tjunction, \tACh \tacts \ton \tnicotinic \t\nreceptors to open cation channels, producing a rapid depolarisation (endplate potential), which normally initiates an action potential in the muscle fibre. \nTransmission at other \u2018fast\u2019 cholinergic synapses (e.g. \nganglionic) is similar.\n\u2022\tAt\t\u2018fast\u2019 \tcholinergic \tsynapses, \tACh \tis \thydrolysed \twithin \t\nabout 1 ms by acetylcholinesterase, so a presynaptic \naction potential produces only one postsynaptic action potential.\n\u2022\tTransmission \tmediated \tby \tmuscarinic \treceptors \tis \t\nmuch slower in its time course, and synaptic structures are less clearly defined. In many such situations, ACh functions as a modulator (i.e. where \nthe mediator acts indirectly to alter the efficiency of \ntransmission \trather \tthan \tas \ta \tdirect \ttransmitter \t\u2013 \tsee \t\nCh. 13).\n\u2022\tMain\tmechanisms \tof \tpharmacological \tblock: \tinhibition \t\nof choline uptake, inhibition of ACh release, block of postsynaptic receptors or ion channels, persistent postsynaptic depolarisation.Stim Stim\nCell bodyRecord", "start_char_idx": 0, "end_char_idx": 3149, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c78f4413-8239-42dd-b013-b6008d1920e9": {"__data__": {"id_": "c78f4413-8239-42dd-b013-b6008d1920e9", "embedding": null, "metadata": {"page_label": "187", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8db36e24-62d7-40bf-9f81-83711e111b50", "node_type": null, "metadata": {"page_label": "187", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c7072c5ca8191fccacbf40c847e06d6bcd908229a6983c49b4b50c87eb2a04fd"}, "2": {"node_id": "25fd0c30-0db6-4e79-994c-a49efda63ffc", "node_type": null, "metadata": {"page_label": "187", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dbb6baa607883108d0cb184104474011f25ccbd31f963bcb34a3243fe9969e15"}}, "hash": "0a05703474ea263846c6ccd61ac93f953b39952cbf3d9ba2db7bcb6b7af6d7ce", "text": "channels, persistent postsynaptic depolarisation.Stim Stim\nCell bodyRecord Microelectrode\nPreganglionic\ntrunk\nGanglionPostganglionic\ntrunk\nAA\nAA\nAA\nO O \nO O \nO O \n(d) 1 min(a) Control\n(e) 2 min(b) 14 s\n(f) 6.5 min(c) 18 s\n40 ms50 mVNicotine (50 \u00b5mol/L)A OA\nB\nFig. 14.4 Depolarisation block of ganglionic transmission \nby nicotine. (A) System used for intracellular recording from \nsympathetic ganglion cells of the frog, showing the location of \northodromic (O) and antidromic (A) stimulating (stim) electrodes. \nStimulation at O excites the cell via the cholinergic synapse, whereas stimulation at A excites it by electrical propagation of \nthe action potential. (B) The effect of nicotine. (a) Control \nrecords. The membrane potential is \u2212\n55 mV (dotted line = \n0 mV), and the cell responds to both O and A. (b) Shortly after \nadding nicotine, the cell is slightly depolarised and spontaneously active, but still responsive to O and A. (c and d) \nThe cell is further depolarised, to \u2212\n25 mV, and produces only a \nvestigial action potential. The fact that it does not respond to A shows that it is electrically inexcitable. (e and f) In the continued \npresence of nicotine, the cell repolarises and regains its responsiveness to A, but it is still unresponsive to O because \nthe\tACh\treceptors \tare \tdesensitised \tby \tnicotine. \t(From \tGinsborg, \t\nB.L.,\tGuerrero, \tS., \t1964. \tJ. \tPhysiol. \t172, \t189.)\n2Also known as succinylcholine.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3075, "end_char_idx": 4991, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "85327d0c-1b6c-46e3-95a9-d04f357ecbf8": {"__data__": {"id_": "85327d0c-1b6c-46e3-95a9-d04f357ecbf8", "embedding": null, "metadata": {"page_label": "188", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "333a3c20-05a3-468f-8d5f-66fe014292c4", "node_type": null, "metadata": {"page_label": "188", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f81cb69b4fcdccd85f4fca9c285af9bfbe3ff98e304ac946af0fd24f20db4ea"}, "3": {"node_id": "baa66798-96a6-4468-aa17-a0a9391213a8", "node_type": null, "metadata": {"page_label": "188", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "13bb8347588f3f0ac9f62a568a65235f6b1e29e1fca39d725ed05ec5bb8b6160"}}, "hash": "e2059ea6daf977d7ed28056a385ce8e5825b7ebfbd9dd63d45361e33efe690ad", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n182oxide, NO; see Ch. 21) and, combined with the reduced \ncardiac output, produces a sharp fall in arterial pressure \n(see Fig. 14.1). Parasympathetic regulation of the heart is \ndiscussed in Chapter 22 (see Fig. 22.7).\nSmooth muscle. Smooth muscle generally contracts in \ndirect response to muscarinic agonists, in contrast to their \nindirect effect via NO on vascular smooth muscle. Peristaltic \nactivity of the gastrointestinal tract is increased, which can cause colicky pain, and the bladder and bronchial smooth \nmuscle also contract.\nSweating, lacrimation, salivation and bronchial secre-\ntion. Muscarinic agonists stimulate exocrine glands. The \ncombined effect of bronchial secretion and constriction can interfere with breathing. Methacholine is used as an \ninhaled challenge agent in the investigation of airways responsiveness.\nEffects on the eye. Ocular effects of muscarinic agents \nare clinically important. The parasympathetic nerves to \nthe eye supply the constrictor pupillae muscle, which runs \ncircumferentially in the iris, and the ciliary muscle, which adjusts the curvature of the lens (Fig. 14.5). Contraction \nof the ciliary muscle in response to activation of mAChRs \npulls the ciliary body forward and inward, thus relaxing the tension on the suspensory ligament of the lens, allowing \nthe lens to bulge more and reducing its focal length. This \nparasympathetic reflex is thus necessary to accommodate the eye for near vision. The constrictor pupillae is important not only for adjusting the pupil in response to changes in light \nintensity, but also in regulating the intraocular pressure. \nAqueous humour is secreted slowly and continuously \nby the cells of the epithelium covering the ciliary body, \nand drains into the canal of Schlemm (see Fig. 14.5), which both mAChRs and nAChRs, but act more potently on \nmAChRs (see Fig. 14.1). Bethanechol, pilocarpine and \ncevimeline are the main ones used clinically.\nThe key features of the ACh molecule that are important \nfor its activity are the quaternary ammonium group, which \nbears a positive charge, and the ester group, which bears \na partial negative charge and is susceptible to rapid hydrolysis by cholinesterase. Variants of the choline ester structure (see Table 14.3) have the effect of reducing the \nsusceptibility of the compound to hydrolysis by cholinest -\nerase, and altering the relative activity on mAChRs and \nnAChRs.\nCarbachol and methacholine are less rapidly hydrolysed \nby cholinesterase enzymes than is ACh. They are used as experimental tools. Bethanechol, which is a hybrid of these \ntwo molecules, is stable to hydrolysis and selective for \nmAChRs, and is occasionally used clinically (see clinical box, p. 184). Pilocarpine is a partial agonist and shows \nsome selectivity in stimulating secretion from sweat, sali-\nvary, lacrimal and bronchial glands, and contracting iris smooth muscle (see later), with weak effects on gastro -\nintestinal smooth muscle and the heart.\nEffects of muscarinic agonists\nThe main actions of muscarinic agonists are readily under -\nstood in terms of the parasympathetic nervous system.\nCardiovascular effects. These include cardiac slowing \nand a decrease in cardiac output due both to the reduced \nheart rate and to a decreased force of contraction of the \natria (the ventricles have only a sparse parasympathetic innervation and a low sensitivity to muscarinic agonists). \nGeneralised vasodilatation also occurs (mediated by nitric Table", "start_char_idx": 0, "end_char_idx": 3516, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "baa66798-96a6-4468-aa17-a0a9391213a8": {"__data__": {"id_": "baa66798-96a6-4468-aa17-a0a9391213a8", "embedding": null, "metadata": {"page_label": "188", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "333a3c20-05a3-468f-8d5f-66fe014292c4", "node_type": null, "metadata": {"page_label": "188", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f81cb69b4fcdccd85f4fca9c285af9bfbe3ff98e304ac946af0fd24f20db4ea"}, "2": {"node_id": "85327d0c-1b6c-46e3-95a9-d04f357ecbf8", "node_type": null, "metadata": {"page_label": "188", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2059ea6daf977d7ed28056a385ce8e5825b7ebfbd9dd63d45361e33efe690ad"}}, "hash": "13bb8347588f3f0ac9f62a568a65235f6b1e29e1fca39d725ed05ec5bb8b6160", "text": "agonists). \nGeneralised vasodilatation also occurs (mediated by nitric Table 14.3 Muscarinic agonists\nCompound StructureReceptor specificity\nHydrolysis by \ncholinesterase Clinical uses Muscarinic Nicotinic\nAcetylcholine+CH3 O\nCH3CH3 N\nO H3C+++ +++ +++ None\nCarbachol+CH3 O\nCH3CH3 N\nO H2N++ +++ \u2014 None\nMethacholine+CH3 CH3 O\nCH3CH3 N\nO H3C+++ + ++ None\nBethanechol+CH3 CH3 O\nCH3CH3 N\nO H2N+++ \u2014 \u2014 Treatment of bladder and gastrointestinal \nhypotoniaa\nMuscarine +++ \u2014 \u2014 Noneb\nPilocarpine ++ \u2014 \u2014 Glaucoma\nOxotremorine ++ \u2014 \u2014 None\nCevimeline ++c\u2014 \u2014 Sj\u00f6gren\u2019s syndrome (to increase salivary and lacrimal secretion)\naEssential to check that bladder neck is not obstructed.\nbCause of one type of mushroom poisoning.\ncSelective\tfor \tM3 receptors.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3440, "end_char_idx": 4658, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3e9b88fa-73b0-4531-9239-b34424c60680": {"__data__": {"id_": "3e9b88fa-73b0-4531-9239-b34424c60680", "embedding": null, "metadata": {"page_label": "189", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "859e9e4d-a244-49b8-a712-7a4a74570068", "node_type": null, "metadata": {"page_label": "189", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a9a6a5f684e1fa45dfe443677e6df1f8bde7219c10a4b553e2455179ff65e3e"}, "3": {"node_id": "04b72a2c-8ab0-4a4b-9d4f-6f069be974d0", "node_type": null, "metadata": {"page_label": "189", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea5533c10b878ee60c628a9fbfb6e2e61069e48e6d2c59933d66b18d22fd363b"}}, "hash": "ffa201be291d25e92844fa60100b908a6507babcba949c06f7c60b1b0870e2d7", "text": "14 CHOLI nERgIC TRA n SMISSIO n\n183receptors in the brain. These include tremor, hypothermia \nand increased locomotor activity (see also Ch. 41 for effects \nof cholinesterase inhibitors in improving cognition in \nAlzheimer\u2019s disease).\nClinical use\nCurrently there are few important uses for muscarinic ago -\nnists (though there are still hopes that new, more selective \nagents may prove useful in various CNS disorders). Current \nclinical uses are summarised in the clinical box (p. 184).\nMUSCARINIC \u2003ANTAGONISTS\nmAChR antagonists (parasympatholytic drugs; Table 14.5) are competitive antagonists whose chemical structures usually \ncontain ester and basic groups in the same relationship as \nACh, but they have a bulky aromatic group in place of the acetyl group. The two naturally occurring compounds, \natropine and hyoscine (also known as scopolamine), runs around the eye close to the outer margin of the iris. \nThe intraocular pressure is normally 10\u201315 mmHg above \natmospheric, which keeps the eye slightly distended. \nAbnormally raised intraocular pressure (which leads to \nthe pathological condition of glaucoma) damages the eye \nand is one of the commonest preventable causes of blind -\nness. In acute glaucoma, drainage of aqueous humour becomes impeded when the pupil is dilated, because \nfolding of the iris tissue occludes the drainage angle, causing the intraocular pressure to rise. Activation of the \nconstrictor pupillae muscle by muscarinic agonists in these \ncircumstances lowers the intraocular pressure, whereas in a healthy individual it has little effect on intraocular pressure. Drugs used in the treatment of glaucoma are summarised in \nTable 14.4.\nIn addition to these peripheral effects, muscarinic agonists \nthat penetrate the blood\u2013brain barrier produce marked \ncentral effects due to activation of muscarinic (mainly M\n1) Cornea\nIris Constrictor\nmuscleDilator\nmuscle Pathway for\naqueous humour\nCanal of\nSchlemm\nSuspensory\nligamentsLens\nCiliary\nmuscleCiliary\nbody\nFig. 14.5 The anterior chamber of the eye, showing the pathway for secretion and drainage of the aqueous humour. \nTable 14.4 Drugs that lower intraocular pressure\nDrugaMechanism Notes See Chapter\nTimolol, carteolol \u03b2-adrenoceptor \nantagonistGiven as eye drops but may still cause systemic side effects: bradycardia, bronchoconstriction15\nAcetazolamide, dorzolamideCarbonic anhydrase inhibitorAcetazolamide is given systemicallySide effects include diuresis, loss of appetite, tingling, neutropeniaDorzolamide is used as eye dropsSide effects include bitter taste and burning sensation30\nClonidine, apraclonidine \u03b1\n2-adrenoceptor \nagonistUsed as eye drops 15\nLatanoprost Prostaglandin analogueCan alter iris pigmentation 18\nPilocarpine Muscarinic agonist Used as eye drops This chapter\nEcothiophate Anticholinesterase Used as eye drops\nCan cause muscle spasm and systemic effectsThis chapter\naThe most important drugs are shown in bold.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3395, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "04b72a2c-8ab0-4a4b-9d4f-6f069be974d0": {"__data__": {"id_": "04b72a2c-8ab0-4a4b-9d4f-6f069be974d0", "embedding": null, "metadata": {"page_label": "189", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "859e9e4d-a244-49b8-a712-7a4a74570068", "node_type": null, "metadata": {"page_label": "189", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a9a6a5f684e1fa45dfe443677e6df1f8bde7219c10a4b553e2455179ff65e3e"}, "2": {"node_id": "3e9b88fa-73b0-4531-9239-b34424c60680", "node_type": null, "metadata": {"page_label": "189", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ffa201be291d25e92844fa60100b908a6507babcba949c06f7c60b1b0870e2d7"}}, "hash": "ea5533c10b878ee60c628a9fbfb6e2e61069e48e6d2c59933d66b18d22fd363b", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3348, "end_char_idx": 3411, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f6f62ee1-375f-41a9-9fc5-f196b817a4d0": {"__data__": {"id_": "f6f62ee1-375f-41a9-9fc5-f196b817a4d0", "embedding": null, "metadata": {"page_label": "190", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "884c0ae6-1eea-4eb3-893b-4a2f878b6f94", "node_type": null, "metadata": {"page_label": "190", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d38afc2a6e0ef2b8c221e92ea61e79cb3b5bad8215eac9bfcb1b2265665729fe"}, "3": {"node_id": "f6d4ef3e-27a2-490a-956c-2e56bce0b21d", "node_type": null, "metadata": {"page_label": "190", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c6204a9f43c07f8571ed47b3d12dbfe60a6c593440b383caf1e0d97a67557afb"}}, "hash": "4f70c8ebe38271938b403199362a662459fdbb3b771937dc052b642405be8c19", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n184Effects of muscarinic antagonists\nAll the muscarinic antagonists produce similar peripheral \neffects, although some show a degree of selectivity, for \nexample, for the heart or bladder, reflecting heterogeneity \namong mAChRs.\nThe main effects of atropine are:\nInhibition of secretions. Salivary, lacrimal, bronchial and \nsweat glands are inhibited by very low doses of atropine, \nproducing uncomfortably dry eyes, mouth and skin. Gastric \nsecretion is only slightly reduced. Mucociliary clearance in the bronchi is inhibited, so that residual secretions tend \nto accumulate in the lungs. Ipratropium lacks this effect.\nEffects on heart rate. Atropine causes tachycardia through \nblock of cardiac mAChRs. The tachycardia is modest, up to 80\u201390 beats/min in humans, since it has no effect on the \nsympathetic system, but only inhibition of tonic parasym -\npathetic tone. Tachycardia is most pronounced in young \npeople, in whom vagal tone at rest is highest; it is often \nabsent in the elderly. At very low doses, atropine causes a paradoxical bradycardia, possibly due to a central action. \nArterial blood pressure and the response of the heart to \nexercise are unaffected.\nEffects on the eye. The pupil is dilated (mydriasis) by \natropine administration, and becomes unresponsive to \nlight. Relaxation of the ciliary muscle causes paralysis of \naccommodation ( cycloplegia ), so that near vision is impaired. \nIntraocular pressure may rise; although this is unimpor -\ntant in normal individuals, it is dangerous in patients suffering from narrow-angle glaucoma due to impaired drainage of aqueous humour into the canal of Schlemm \n(see earlier). Cyclopentolate and tropicamide are tertiary \namine muscarinic antagonists developed for ophthalmic \nuse and administered as eye drops to facilitate fundoscopy are alkaloids found in solanaceous plants. The deadly \nnightshade (Atropa belladonna ) contains mainly atropine, \nwhereas the thorn apple ( Datura stramonium ) contains mainly \nhyoscine. These are tertiary ammonium compounds that are sufficiently lipid-soluble to be readily absorbed from \nthe gut or conjunctival sac and, importantly, to penetrate the blood\u2013brain barrier. Analogues containing quaternary \nrather than tertiary ammonium groups have peripheral \nactions very similar to those of atropine but, because of their exclusion from the brain, lack central actions. Clinically \nimportant examples include hyoscine butylbromide and \npropantheline . Other muscarinic antagonists in clinical use \nare described below.Clinical uses of muscarinic \nagonists and related drugs \n\u2022\tPilocarpine eye drops cause constriction of the pupils \n(miosis) and have been used to treat glaucoma (raised pressure within the eye).\n\u2022\tPilocarpine or cevimeline\n,\ta\tselective \tM3 agonist, \ncan be used to increase salivation and lacrimal secretion in patients with dry mouth or dry eyes (e.g. \nfollowing irradiation, or in patients with autoimmune \ndamage to the salivary or lacrimal glands as in Sj\u00f6gren\u2019s syndrome).\n\u2022\tBethanechol or distigmine (a cholinesterase \ninhibitor) are now seldom used as stimulant laxatives or to stimulate bladder emptying.Table 14.5 Muscarinic antagonistsa\nCompound Pharmacological properties Notes\nAtropine Non-selective antagonist\nWell absorbed orallyCNS stimulantBelladonna alkaloidMain side effects: urinary retention, dry mouth, blurred visionDicycloverine", "start_char_idx": 0, "end_char_idx": 3420, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f6d4ef3e-27a2-490a-956c-2e56bce0b21d": {"__data__": {"id_": "f6d4ef3e-27a2-490a-956c-2e56bce0b21d", "embedding": null, "metadata": {"page_label": "190", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "884c0ae6-1eea-4eb3-893b-4a2f878b6f94", "node_type": null, "metadata": {"page_label": "190", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d38afc2a6e0ef2b8c221e92ea61e79cb3b5bad8215eac9bfcb1b2265665729fe"}, "2": {"node_id": "f6f62ee1-375f-41a9-9fc5-f196b817a4d0", "node_type": null, "metadata": {"page_label": "190", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f70c8ebe38271938b403199362a662459fdbb3b771937dc052b642405be8c19"}}, "hash": "c6204a9f43c07f8571ed47b3d12dbfe60a6c593440b383caf1e0d97a67557afb", "text": "side effects: urinary retention, dry mouth, blurred visionDicycloverine (dicyclomine) is similar and used mainly as an antispasmodic agent\nHyoscine Similar to atropineCNS depressantBelladonna alkaloid (also known as scopolamine)Causes sedation; other side effects as atropine\nHyoscine butylbromideSimilar to atropine but poorly absorbed and lacks CNS effectsSignificant ganglion-blocking activityQuaternary ammonium derivativeSimilar drugs include atropine methonitrate, propantheline\nTiotropium Similar to atropine methonitrateDoes not inhibit mucociliary clearance from bronchiQuaternary ammonium compoundIpratropium similar\nTropicamide Similar to atropineMay raise intraocular pressure\u2014\nCyclopentolate Similar to tropicamide \u2014\nDarifenacin Selective for M\n3 receptors Used to treat unstable bladder and associated urge incontinence. Causes fewer adverse effects than unselective muscarinic antagonists\nOther non-selective muscarinic antagonists in clinical use, with very similar actions and side effects, include oxybutynin, tolterodine, \nfesoterodine, \tsolifenacin \tand \ttrospium \t\u2013 \tan \texample \tof \tme-too \tdevelopment \tby \tpharmaceutical \tcompanies.\naFor chemical structures, see Southan et al. (2016).\nCNS, central nervous system.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3349, "end_char_idx": 5067, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "791fb779-c035-45e6-a342-55f2ddfc51f9": {"__data__": {"id_": "791fb779-c035-45e6-a342-55f2ddfc51f9", "embedding": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2146d6b2-2d26-4f2d-a88a-aa5b95d2a783", "node_type": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e62e86df9fb2431a1b5ee58257056e86692293b1d7af09a76208a0a1dec59f6"}, "3": {"node_id": "dfd6aeac-9eed-433a-b4dc-f0e2e9657cd5", "node_type": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0909f82f4d7141fdf84448fa4a7461a7bf7e65235e5ef87c1e33d25ed56ea8a1"}}, "hash": "cef8d8d32430c563186842d5c2001d50b832dc5ca4a713bdeb633a8a02115610", "text": "14 CHOLI nERgIC TRA n SMISSIO n\n185Drugs acting on muscarinic \nreceptors\nMuscarinic agonists\n\u2022\tImportant \tcompounds \tinclude \tacetylcholine, \ncarbachol, methacholine, muscarine and \npilocarpine .\tThey\tvary \tin \tmuscarinic/nicotinic \t\nselectivity, and in susceptibility to cholinesterase.\n\u2022\tMain\teffects \tare \tbradycardia \tand \tvasodilatation \t\n(endothelium-dependent), leading to fall in blood \npressure; contraction of visceral smooth muscle (gut, bladder, bronchi, etc.); exocrine secretions (e.g. \nsalivation); pupillary constriction and ciliary muscle \ncontraction, leading to decrease of intraocular pressure.\n\u2022\tMain\tuse \tis \tin \ttreatment \tof \tglaucoma \t(especially \t\npilocarpine).\n\u2022\tMost\tagonists \tcurrently \tin \ttherapeutic \tuse \tshow \tlittle \t\nreceptor subtype selectivity; cevimeline, a selective \nM3 agonist, is an exception.\n\u2022\tPositive \tallosteric \tmodulators \toffer \tprospects \tfor \tmore \t\nselective clinical agents.\nMuscarinic antagonists\n\u2022\tThe\tmain \tdrugs \tare \tatropine, hyoscine \nbutylbromide, ipratropium, tiotropium and \npirenzepine.\n\u2022\tMain\teffects \tare \tinhibition \tof \tsecretions; \ttachycardia, \t\npupillary dilatation and paralysis of accommodation; relaxation of smooth muscle (gut, bronchi, biliary tract, bladder); inhibition of gastric acid secretion (especially \npirenzepine); central nervous system effects (mainly \nexcitatory with atropine; depressant, including amnesia, with hyoscine), including antiemetic effect \nand antiparkinsonian effect.\nreceptors but not, apart from nicotine and ACh, on both \n(Table 14.6).\nNicotine and lobeline are tertiary amines found in \nthe leaves of tobacco and lobelia plants, respectively. \nNicotine belongs in pharmacological folklore, as it was the substance on the tip of Langley\u2019s paintbrush causing \nstimulation of muscle fibres when applied to the endplate \nregion, leading him to postulate in 1905 the existence of a \u2018receptive substance\u2019 on the surface of the fibres (Ch. \n13). Epibatidine, found in the skin of poisonous frogs, is \na highly potent nicotinic agonist selective for ganglionic \nand CNS receptors. It was found, unexpectedly, to be a powerful analgesic (see Ch. 43), though its autonomic side \neffects ruled out its clinical use. Varenicline, a synthetic \nagonist relatively selective for CNS receptors, is used \n(as is nicotine itself) to treat nicotine addiction (Ch. 50). \nOtherwise these drugs are used only as experimental \ntools.\nThey cause complex peripheral responses associated with \ngeneralised stimulation of autonomic ganglia. The effects \nof nicotine on the gastrointestinal tract and sweat glands are familiar to neophyte smokers (see Ch. 50), although \nusually insufficient to act as an effective deterrent.(looking at the back of the eye with an ophthalmoscope, a key part of the examination of the eye).\nEffects on the gastrointestinal tract. Gastrointestinal \nmotility is inhibited by atropine, although this requires larger doses than the other effects listed, and is not complete \nsince excitatory transmitters other than ACh are important in normal function of the myenteric plexus (see Ch. 13). \nAtropine-like drugs such as hyoscine butylbromide \n(a quaternary ammonium antimuscarinic agent) relax \nintestinal spasm and are used for symptomatic relief in \npathological conditions in which there is", "start_char_idx": 0, "end_char_idx": 3306, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dfd6aeac-9eed-433a-b4dc-f0e2e9657cd5": {"__data__": {"id_": "dfd6aeac-9eed-433a-b4dc-f0e2e9657cd5", "embedding": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2146d6b2-2d26-4f2d-a88a-aa5b95d2a783", "node_type": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e62e86df9fb2431a1b5ee58257056e86692293b1d7af09a76208a0a1dec59f6"}, "2": {"node_id": "791fb779-c035-45e6-a342-55f2ddfc51f9", "node_type": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cef8d8d32430c563186842d5c2001d50b832dc5ca4a713bdeb633a8a02115610"}, "3": {"node_id": "1b54f372-937a-492a-b4f1-93451e8f8789", "node_type": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "de2381714b31f823c181f11e5e8eefa791240c08f7b164f70c0a41dd3ca29d53"}}, "hash": "0909f82f4d7141fdf84448fa4a7461a7bf7e65235e5ef87c1e33d25ed56ea8a1", "text": "and are used for symptomatic relief in \npathological conditions in which there is gastrointestinal \nspasm, as well as in gastrointestinal imaging to improve resolution. Pirenzepine, owing to its selectivity for M\n1 \nreceptors, inhibits gastric acid secretion in doses that do \nnot affect other systems.\nEffects on other smooth muscle. Bronchial, biliary and \nurinary tract smooth muscle are all relaxed by atropine. Reflex bronchoconstriction (e.g. during anaesthesia) is \nprevented by atropine, whereas bronchoconstriction caused by local mediators, such as histamine and leukotrienes \n(e.g. in asthma; Ch. 29) is unaffected. Ipratropium and \ntiotropium , quaternary ammonium antimuscarinic drugs, \nare administered by inhalation as bronchodilators (Ch. 29). Biliary and urinary tract smooth muscle are only slightly \naffected in normal individuals, probably because transmit -\nters other than ACh (see Ch. 13) are important in these organs; nevertheless, atropine and similar drugs commonly \nprecipitate urinary retention in elderly men with prostatic \nenlargement. Oxybutynin, tolterodine and darifenacin \n(M\n3-selective) act on the bladder to inhibit micturition, \nand are used for treating overactive bladder. They produce \nunwanted effects typical of muscarinic antagonists, such \nas dry mouth, constipation and blurred vision, but these are less severe than with less selective drugs.\nEffects on the CNS. Atropine produces mainly excitatory \neffects on the CNS. At low doses, this causes mild restless -\nness; higher doses cause agitation and disorientation. In atropine poisoning, which occurs in young children who eat deadly nightshade berries, marked excitement and irritabil -\nity result in hyperactivity and a considerable rise in body temperature, which is accentuated by the loss of sweating. These central effects are the result of blocking mAChRs in \nthe brain, and are less marked or absent with quaternary \nammonium drugs such as hyoscine butylbromide, pro -\npantheline, ipratropium and tiotropium that have limited access beyond the blood\u2013brain barrier. The central effects \nof muscarinic antagonists are opposed by anticholinesterase \ndrugs such as physostigmine , which have been used to treat \natropine poisoning. Hyoscine in low doses causes marked \nsedation, but has similar effects to atropine in high dosage. \nHyoscine additionally has a central anti-emetic effect and is used to prevent motion sickness. Muscarinic antagonists also \naffect the extrapyramidal system, reducing the involuntary \nmovement and rigidity of patients with Parkinson\u2019s disease (Ch. 41) and counteracting the extrapyramidal side effects \nof many antipsychotic drugs (Ch. 47).\nClinical use\nThe main uses of muscarinic antagonists are summarised \nin the clinical box (p. 186).\nDRUGS AFFECTING AUTONOMIC GANGLIA\nGANGLION \u2003STIMULANTS\nMost nAChR agonists act on either neuronal (ganglionic and CNS) nAChRs or on striated muscle (motor endplate) mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3238, "end_char_idx": 6597, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1b54f372-937a-492a-b4f1-93451e8f8789": {"__data__": {"id_": "1b54f372-937a-492a-b4f1-93451e8f8789", "embedding": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2146d6b2-2d26-4f2d-a88a-aa5b95d2a783", "node_type": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e62e86df9fb2431a1b5ee58257056e86692293b1d7af09a76208a0a1dec59f6"}, "2": {"node_id": "dfd6aeac-9eed-433a-b4dc-f0e2e9657cd5", "node_type": null, "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0909f82f4d7141fdf84448fa4a7461a7bf7e65235e5ef87c1e33d25ed56ea8a1"}}, "hash": "de2381714b31f823c181f11e5e8eefa791240c08f7b164f70c0a41dd3ca29d53", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6619, "end_char_idx": 6730, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e7ea6979-37fa-42bc-99ea-31a8913923da": {"__data__": {"id_": "e7ea6979-37fa-42bc-99ea-31a8913923da", "embedding": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2973ce2-bf8b-4fe8-8e40-bc659bab8aa7", "node_type": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cf9943c89adee2703b584c7e462add689994eb91c1037cec97a10f62449bde29"}, "3": {"node_id": "3edbbf1d-ce85-480b-b65c-0ec35171fcd3", "node_type": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e93ec3deba63994f234b1770e760d16b4710e07539d9c222708675d3212eee20"}}, "hash": "8cba9079d3bd7a330cc90aeb01af439846f394157305aa62471c6a1d75324c70", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n186Effects of ganglion-blocking drugs\nThe effects of ganglion-blocking drugs are diverse, because \nboth divisions of the autonomic nervous system are blocked \nindiscriminately. The description by Paton of \u2018hexametho -\nnium man\u2019 cannot be bettered:\n\u25bc He is a pink-complexioned person, except when he has stood in \na queue for a long time, when he may get pale and faint. His handshake \nis warm and dry. He is a placid and relaxed companion; for instance \nhe may laugh but he can\u2019t cry because the tears cannot come. Your \nrudest story will not make him blush, and the most unpleasant cir -\ncumstances will fail to make him turn pale. His collars and socks \nstay very clean and sweet. He wears corsets and may, if you meet \nhim out, be rather fidgety (corsets to compress his splanchnic vascular pool, fidgety to keep the venous return going from his legs). He \ndislikes speaking much unless helped with something to moisten his \ndry mouth and throat. He is long-sighted and easily blinded by bright \nlight. The redness of his eyeballs may suggest irregular habits and \nin fact his head is rather weak. But he always behaves like a gentleman and never belches or hiccups. He tends to get cold and keeps well \nwrapped up. But his health is good; he does not have chilblains and \nthose diseases of modern civilisation, hypertension and peptic ulcer, pass him by. He gets thin because his appetite is modest; he never \nfeels hunger pains and his stomach never rumbles. He gets rather \nconstipated so that his intake of liquid paraffin is high. As old age comes on, he will suffer from retention of urine and impotence, but \nfrequency, precipitancy and strangury (i.e. an intensely painful sensa -\ntion of needing to pass urine coupled with an inability to do so) will \nnot worry him. One is uncertain how he will end, but perhaps if he \nis not careful, by eating less and less and getting colder and colder, \nhe will sink into a symptomless, hypoglycaemic coma and die, as \nwas proposed for the universe, a sort of entropy death.\n(From Paton, W.D.M., 1954. The principles of ganglion block. Lectures \non the Scientific Basis of Medicine, Vol. 2.)\nIn practice, the main effect is a marked fall in arterial \nblood pressure resulting mainly from block of sympathetic \nganglia, which causes arteriolar vasodilatation, and the \nblock of cardiovascular reflexes. Venoconstriction, which occurs normally when a subject stands up and prevents \na fall in central venous pressure and cardiac output, is \nreduced. Standing thus causes a sudden fall in arterial pressure (postural hypotension ) that can cause fainting. The \nvasodilatation of skeletal muscle that occurs during exercise is normally accompanied by vasoconstriction elsewhere (e.g. splanchnic area) produced by sympathetic activity. Ganglion blockers prevent this adjustment, so the overall \nperipheral resistance falls leading to postexercise hypotension .\nNEUROMUSCULAR-BLOCKING \u2003DRUGS\nDrugs can block neuromuscular transmission either by \nacting presynaptically to inhibit ACh synthesis or release, \nor by acting postsynaptically.\nNeuromuscular block is an important adjunct to general \nanaesthesia (Ch. 42). The drugs used for this purpose all work postsynaptically, either (a) by blocking ACh recep -\ntors (or in some cases the ion channel) or (b) by activating \nACh receptors and thus causing persistent depolarisation \nof the motor endplate. Suxamethonium (see", "start_char_idx": 0, "end_char_idx": 3450, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3edbbf1d-ce85-480b-b65c-0ec35171fcd3": {"__data__": {"id_": "3edbbf1d-ce85-480b-b65c-0ec35171fcd3", "embedding": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2973ce2-bf8b-4fe8-8e40-bc659bab8aa7", "node_type": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cf9943c89adee2703b584c7e462add689994eb91c1037cec97a10f62449bde29"}, "2": {"node_id": "e7ea6979-37fa-42bc-99ea-31a8913923da", "node_type": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8cba9079d3bd7a330cc90aeb01af439846f394157305aa62471c6a1d75324c70"}, "3": {"node_id": "3bc0c0ce-d09f-4052-85f6-e191e5e927af", "node_type": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e623126523d5d31ffd97956b52207921566467e974df6f87e8fe88bbabae375"}}, "hash": "e93ec3deba63994f234b1770e760d16b4710e07539d9c222708675d3212eee20", "text": "depolarisation \nof the motor endplate. Suxamethonium (see pp. 189\u2013190) \nis the only depolarising blocker in clinical use, while all \nof the other drugs used clinically are non-depolarising \nagents.\nNON-DEPOLARISING \u2003BLOCKING \u2003AGENTS\nIn 1856, Claude Bernard, in a famous experiment, showed that \u2018curare\u2019 causes paralysis by blocking neuromuscular \ntransmission, rather than by abolishing nerve conduction \nor muscle contractility. Curare is a mixture of naturally GANGLION-BLOCKING \u2003DRUGS\nGanglion-blocking drugs are used experimentally to study autonomic function, but their clinical use is obsolete. \nGanglion block can occur by several mechanisms:\n\u2022\tBy\tinterference \twith \tACh \trelease, \tas \tat \tthe \t\nneuromuscular junction (Ch. 13).\n\u2022\tBy\tprolonged \tdepolarisation. \tNicotine \t(see \tFig. \t14.4) \t\ncan block ganglia, after initial stimulation, in this way, \nas can ACh itself if cholinesterase is inhibited, thereby \nprolonging its action on the postsynaptic membrane.\n\u2022\tInterfering \twith \tthe \tpostsynaptic \taction \tof \tACh, \tby \t\nblocking neuronal nAChRs or the associated ion \nchannels.\n\u25bc In the middle of the last century, Paton and Zaimis investigated \na series of linear bisquaternary compounds. Compounds with five \nor six carbon atoms ( hexamethonium is obsolete clinically but famous \nas the first effective antihypertensive agent) in the methylene chain linking the two quaternary groups produced ganglionic block.\n3Clinical uses of muscarinic \nantagonists \nCardiovascular\n\u2022\tTreatment \tof \tsinus \tbradycardia \t(e.g. \tafter \tmyocardial \t\ninfarction; \tsee \tCh. \t22): \tfor \texample, \tatropine.\nOphthalmic\n\u2022\tTo\tdilate \tthe \tpupil: \tfor \texample \ttropicamide or \ncyclopentolate eye drops.\nNeurological\n\u2022\tPrevention \tof \tmotion \tsickness: \tfor \texample, \thyoscine.\n\u2022\tParkinsonism \t(see \tCh. \t41), \tespecially \tto \tcounteract \t\nmovement disorders caused by antipsychotic drugs \n(see\tCh.\t47): \tfor \texample, \tbenzhexol, benztropine.\nRespiratory\n\u2022\tAsthma \tand \tchronic \tobstructive \tpulmonary \tdisease \t\n(see\tCh.\t29): \tipratropium or tiotropium by inhalation.\nPalliative care\n\u2022\tBowel\tcolic \tand \texcessive \tsalivation/respiratory \t\nsecretion: \thyoscine \tor \tglycopyrronium.\nAnaesthetic premedication\n\u2022\tTo\tdry\tsecretions: \tfor \texample, \tatropine, hyoscine. \n(Current anaesthetics are relatively non-irritant, see Ch. \n42, so this is less important than in the past.)\nGastrointestinal\n\u2022\tTo\tfacilitate \tendoscopy \tand \tgastrointestinal \tradiology \t\nby relaxing gastrointestinal smooth muscle \n(antispasmodic \taction; \tsee \tCh. \t31): \tfor \texample, \t\nhyoscine butylbromide.\n\u2022\tAs\tan\tantispasmodic \tin \tirritable \tbowel \tsyndrome \tor \t\ncolonic\tdiverticular \tdisease: \tfor \texample, \t\ndicycloverine (dicyclomine).\nUrinary tract\n\u2022\tTo\trelieve \tsymptoms \tof \toveractive", "start_char_idx": 3400, "end_char_idx": 6165, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3bc0c0ce-d09f-4052-85f6-e191e5e927af": {"__data__": {"id_": "3bc0c0ce-d09f-4052-85f6-e191e5e927af", "embedding": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2973ce2-bf8b-4fe8-8e40-bc659bab8aa7", "node_type": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cf9943c89adee2703b584c7e462add689994eb91c1037cec97a10f62449bde29"}, "2": {"node_id": "3edbbf1d-ce85-480b-b65c-0ec35171fcd3", "node_type": null, "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e93ec3deba63994f234b1770e760d16b4710e07539d9c222708675d3212eee20"}}, "hash": "4e623126523d5d31ffd97956b52207921566467e974df6f87e8fe88bbabae375", "text": "\tbladder: \tfor \t\nexample, oxybutynin, tolterodine, darifenacin.\n3Based on their structural similarity to ACh, these compounds were \noriginally assumed to compete with ACh for its binding site. However, \nthey are now known to act mainly by blocking the ion channel rather \nthan the receptor itself.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6217, "end_char_idx": 6993, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "024af8d9-dbd0-4b93-84c9-474b50f78319": {"__data__": {"id_": "024af8d9-dbd0-4b93-84c9-474b50f78319", "embedding": null, "metadata": {"page_label": "193", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d96c5c0a-ca95-4de3-b3d2-bdf73fd89ac6", "node_type": null, "metadata": {"page_label": "193", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9fc5a0c1f11261260cec33cc41d54fcea2a4ba80be2b48d7f62543370d01a0d6"}, "3": {"node_id": "b766b9e3-41e0-47f0-91ce-41b24b8be76f", "node_type": null, "metadata": {"page_label": "193", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eb71f2dffdb62c9e698d6c96a9231f57cc91822871cf0ae6ab83f80da23330c8"}}, "hash": "dde15767b61d305cbb4acfbf3c125762cfbb69528601bd1555cab92546e8f5a6", "text": "14 CHOLI nERgIC TRA n SMISSIO n\n187occurring alkaloids found in various South American plants \nand used as arrow poisons by South American Indians. The \nmost important component is tubocurarine , itself now rarely \nused in clinical medicine, being superseded by synthetic \ndrugs with improved properties. The most important are \npancuronium, vecuronium, cisatracurium and mivacu-\nrium (Table 14.7), which differ mainly in their duration \nof action. These substances are all quaternary ammonium \ncompounds, so are poorly absorbed4 (they are administered \nintravenously) and generally are efficiently excreted by the kidneys. They do not cross the placenta, which is important \nin relation to their use in obstetric anaesthesia.\nMechanism of action\nNon-depolarising blocking agents act as competitive antagonists (see Ch. 2) at the ACh receptors of the endplate.\n\u25bc The amount of ACh released by a nerve impulse normally exceeds \nby several-fold what is needed to elicit an action potential in the \nmuscle fibre. It is therefore necessary to block 70%\u201380% of the receptor \nsites before transmission actually fails. In any individual muscle fibre, \ntransmission is all-or-nothing, so graded degrees of block represent a varying proportion of muscle fibres failing to respond. In this situ -\nation, where the amplitude of the epp in all the fibres is close to threshold (just above in some, just below in others), small variations in the amount of transmitter released, or in the rate at which it is \ndestroyed, will have a large effect on the proportion of fibres contract -\ning, so the degree of block is liable to vary according to various physiological circumstances (e.g. stimulation frequency, temperature \nand cholinesterase activity), which otherwise have little effect on the efficiency of transmission.Table 14.6 Nicotinic receptor agonists and antagonists\nDrug Main site Type of action Notes\nAgonists\nNicotine Autonomic ganglia\nCNSStimulation then blockStimulationSee Ch. 50\nLobeline Autonomic gangliaSensory nerve terminalsStimulationStimulation\u2014\nEpibatidine Autonomic ganglia CNS Stimulation Isolated from frog skinHighly potentNo clinical use\nVarenicline CNSAutonomic gangliaStimulation Used for nicotine addiction (see Ch. 50)\nSuxamethonium Neuromuscular junction Depolarisation block Used clinically as muscle relaxant\nDecamethonium Neuromuscular junction Depolarisation block No clinical use\nAntagonists\nHexamethonium Autonomic ganglia Transmission block No clinical use\nTrimetaphan Autonomic ganglia Transmission block Blood pressure-lowering in surgery (rarely used)\nTubocurarine Neuromuscular junction Transmission block Now rarely used\nPancuronium\nAtracuriumVecuroniumNeuromuscular junction Transmission block Widely used as muscle relaxants in anaesthesia\nCNS, central nervous system.\n4Animals killed by curare-tipped arrows are safe to eat because of this.Drugs acting on autonomic ganglia \nGanglion-stimulating drugs\n\u2022\tCompounds \tinclude \tnicotine, dimethylphenyl-\npiperazinium (DMPP).\n\u2022\tBoth\tsympathetic \tand \tparasympathetic \tganglia \tare \t\nstimulated, so effects are complex, including \ntachycardia and increase of blood pressure; variable effects on gastrointestinal motility and secretions; \nincreased bronchial, salivary and sweat secretions. \nAdditional effects result from stimulation of other neuronal structures, including sensory and noradrenergic nerve terminals.\n\u2022\tGanglion \tstimulation \tmay \tbe \tfollowed \tby \tdepolarisation \t\nblock.\n\u2022\tNicotine also has important central nervous system effects.\n\u2022\tTherapeutic \tuses \tare \tlimited", "start_char_idx": 0, "end_char_idx": 3564, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b766b9e3-41e0-47f0-91ce-41b24b8be76f": {"__data__": {"id_": "b766b9e3-41e0-47f0-91ce-41b24b8be76f", "embedding": null, "metadata": {"page_label": "193", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d96c5c0a-ca95-4de3-b3d2-bdf73fd89ac6", "node_type": null, "metadata": {"page_label": "193", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9fc5a0c1f11261260cec33cc41d54fcea2a4ba80be2b48d7f62543370d01a0d6"}, "2": {"node_id": "024af8d9-dbd0-4b93-84c9-474b50f78319", "node_type": null, "metadata": {"page_label": "193", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dde15767b61d305cbb4acfbf3c125762cfbb69528601bd1555cab92546e8f5a6"}}, "hash": "eb71f2dffdb62c9e698d6c96a9231f57cc91822871cf0ae6ab83f80da23330c8", "text": "important central nervous system effects.\n\u2022\tTherapeutic \tuses \tare \tlimited \tto \tassisting \tsmoking \t\ncessation (nicotine, varenicline).\nGanglion-blocking drugs\n\u2022\tCompounds \tinclude \thexamethonium, tubocurarine \n(also nicotine;\tsee\tp.\t185).\n\u2022\tBlock\tall \tautonomic \tganglia \tand \tenteric \tganglia. \tMain \t\neffects:\thypotension \tand \tloss \tof \tcardiovascular \t\nreflexes, inhibition of secretions, gastrointestinal paralysis, impaired micturition.\n\u2022\tClinically \tobsolete \t(historically: \tthe \tfirst \ttherapeutic \t\ndrugs for treating hypertension).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3489, "end_char_idx": 4512, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ce9a216-2d4a-4a4a-b318-10a03c406a4f": {"__data__": {"id_": "8ce9a216-2d4a-4a4a-b318-10a03c406a4f", "embedding": null, "metadata": {"page_label": "194", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d485b745-5e24-4f10-98bf-783d60fffab2", "node_type": null, "metadata": {"page_label": "194", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42e69ae0d739c208db3f1cad1fa91e5b8a89d286437de5fe3f37ac3d5d276969"}, "3": {"node_id": "295f7078-2f49-446e-b059-d91c55eaaf27", "node_type": null, "metadata": {"page_label": "194", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "070954324209681173bc4f49a588e593c2c13e23a89d25466e7446dc81713e0d"}}, "hash": "4b6a93332b4a8ad1f3de1d0495d6a5ad25cb8d08771ac57b23d36d3decfa56fc", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n188was fully curarised while conscious under artificial ventilation \nestablished this orderly paralytic march, and showed that consciousness \nand awareness of pain were quite normal even when paralysis was \ncomplete.5\nUnwanted effects\nAn important unwanted effect of tubocurarine is a fall in \narterial pressure, due to (a) sympathetic ganglion block and (b) histamine release from mast cells (see Ch. 18), which \ncan also give rise to bronchospasm in sensitive individuals. \nThis is unrelated to nAChRs but also occurs with atracurium \nand mivacurium (as well as with some pharmacologically \nunrelated drugs such as morphine; see Ch. 43). Other non-depolarising blocking drugs lack these adverse effects. Non-depolarising blocking agents also block facilitatory presynaptic autoreceptors, and thus inhibit the release of ACh during repetitive stimulation of the motor nerve, \nresulting in the phenomenon of \u2018tetanic fade\u2019, used by \nanaesthetists to monitor postoperative recovery of neuromuscular transmission.\nEffects of non-depolarising blocking drugs\nThe effects of non-depolarising neuromuscular-blocking agents are mainly due to motor paralysis, although some \nof the drugs also produce clinically significant autonomic \neffects.\n\u25bc The first muscles to be affected are the extrinsic eye muscles (causing \ndouble vision), reminiscent of the disease myasthenia gravis, which \nis caused by autoantibodies directed against nAChR (see pp. 195\u2013196), \nand the small muscles of the face, limbs and pharynx (causing difficulty \nin swallowing). Respiratory muscles are the last to be affected and the first to recover. An experiment in 1947 in which a heroic volunteer Table 14.7 Characteristics of neuromuscular-blocking drugsa\nDrugSpeed of \nonsetDuration of action Main side effects Notes\nTubocurarine Slow \n(>5 min)Long (1\u20132 h) Hypotension (ganglion block plus histamine release)Bronchoconstriction (histamine release)Plant alkaloid, now rarely usedAlcuronium is a semisynthetic derivative with similar properties but fewer side effects\nPancuronium Intermediate \n(2\u20133 min)Long (1\u20132 h) Slight tachycardiaHypertensionThe first steroid-based compoundBetter side effect profile than tubocurarineWidely usedPipecuronium is similar\nVecuronium Intermediate Intermediate \n(30\u201340 min)Few side effects Widely usedOccasionally causes prolonged paralysis, probably owing to active metaboliteRocuronium is similar, with faster onset\nAtracurium Intermediate Intermediate (<\n30 min)Transient hypotension (histamine release)Unusual mechanism of elimination (spontaneous non-enzymic chemical degradation in plasma); degradation slowed by acidosisWidely usedDoxacurium is chemically similar but stable in plasma, giving it long duration of actionCisatracurium is the pure active isomeric constituent of atracurium, more potent but with less histamine release\nMivacurium Fast \n(~2 min)Short \n(~15 min)Transient hypotension (histamine release)Chemically similar to atracurium but rapidly inactivated by plasma cholinesterase (therefore longer acting in patients with liver disease or with genetic cholinesterase deficiency [see p. 189 and Ch. 12])\nSuxamethonium Fast Short \n(~10 min)Bradycardia (muscarinic agonist effect)Cardiac dysrhythmias (increased plasma K\n+ \nconcentration \u2013 avoid in patients with burns or severe trauma)Raised intraocular pressure (nicotinic agonist effect on extraocular muscles)Postoperative muscle painActs by depolarisation of endplate (nicotinic agonist effect) \u2013 the only drug of this", "start_char_idx": 0, "end_char_idx": 3536, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "295f7078-2f49-446e-b059-d91c55eaaf27": {"__data__": {"id_": "295f7078-2f49-446e-b059-d91c55eaaf27", "embedding": null, "metadata": {"page_label": "194", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d485b745-5e24-4f10-98bf-783d60fffab2", "node_type": null, "metadata": {"page_label": "194", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42e69ae0d739c208db3f1cad1fa91e5b8a89d286437de5fe3f37ac3d5d276969"}, "2": {"node_id": "8ce9a216-2d4a-4a4a-b318-10a03c406a4f", "node_type": null, "metadata": {"page_label": "194", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b6a93332b4a8ad1f3de1d0495d6a5ad25cb8d08771ac57b23d36d3decfa56fc"}}, "hash": "070954324209681173bc4f49a588e593c2c13e23a89d25466e7446dc81713e0d", "text": "by depolarisation of endplate (nicotinic agonist effect) \u2013 the only drug of this type still in useParalysis is preceded by transient muscle fasciculationsShort duration of action owing to hydrolysis by plasma cholinesterase (prolonged action in patients with liver disease or genetic deficiency of plasma cholinesterase)Used for brief procedures (e.g. tracheal intubation, electroconvulsive shock therapy)Rocuronium has similar speed of onset and recovery, with fewer unwanted effects\naFor\tchemical \tstructures, \tsee \tHardman, \tJ.G., \tLimbird, \tL.E., \tGilman, \tA.G., \tGoodman-Gilman \tA. \tet \tal., \t2001. \tGoodman \tand \tGilman\u2019s \t\nPharmacological \tBasis \tof \tTherapeutics, \t10th \ted. \tMcGraw\u2013Hill, \tNew \tYork.\n5The risk of patients waking up paralysed during surgery, and \nsubsequently recalling this (awareness during anaesthesia) is a serious \nconcern.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3456, "end_char_idx": 4788, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f160a1a9-cbc3-4a8f-abaa-a042655fc386": {"__data__": {"id_": "f160a1a9-cbc3-4a8f-abaa-a042655fc386", "embedding": null, "metadata": {"page_label": "195", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8ec4e6a4-cb49-4cca-903d-2bbdefa4c112", "node_type": null, "metadata": {"page_label": "195", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e2295c2a8ad4d2f1e20ea15a3a1ce5e11b402e3f45a89388eff902122cb846f"}, "3": {"node_id": "6e47cef6-3566-460e-b3a6-7292cd8caa15", "node_type": null, "metadata": {"page_label": "195", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b7731097d70b0a22768dc17d3eed7211a82c28163e3db45de0e41b37fa75490a"}}, "hash": "d81ada6939c8a572cba28ea152261ac18449da920146a5e0ef0c096c98f782f7", "text": "14 CHOLI nERgIC TRAnSMISSIO n\n189Rapid postoperative recovery of muscle strength after \nsurgery is important to minimise respiratory complications. \nThe cholinesterase inhibitor, neostigmine (Table 14.8) is often used to reverse the action of non-depolarising drugs postoperatively. Co-administration of atropine is necessary to prevent unwanted parasympathomimetic effects.\n\u25bc Anticholinesterase drugs overcome the blocking action of non-\ndepolarising agents because released ACh, protected from hydrolysis, \ncan diffuse further within the synaptic cleft and so access a wider area of postsynaptic membrane. The chances of an ACh molecule finding an unoccupied receptor before being hydrolysed are thus increased. This diffusional effect seems to be more important than a truly competitive interaction, for it is unlikely that appreciable dissociation of the antagonist can occur in the short time for which the ACh is present. In contrast, depolarisation block is unaffected by anticholinesterase drugs, or even increased via potentiation of the depolarising action of endogenous ACh.\nAn alternative approach for reversal of neuromuscular \nblockade induced by rocuronium or vecuronium is the use \nof a synthetic cyclodextrin, sugammadex, a macromolecule \nthat selectively binds steroidal neuromuscular-blocking drugs \nas an inactive complex in the plasma (Nicholson et al., 2007). \nThe complex is excreted unchanged in the urine. Sugammadex rapidly reverses block with few unwanted effects.\nDEPOLARISING \u2003BLOCKING \u2003AGENTS\nSuxamethonium is the only depolarising agent used clinically. There are several differences in the pattern of neuromuscular block produced by depolarising and non-depolarising mechanisms:\n\u2022\tFasciculation, \tseen\twith\tsuxamethonium \t(see\tTable\t\n14.7) as a prelude to paralysis, does not occur with non-depolarising drugs. Its severity is linked to postoperative muscle pain experienced after suxamethonium.\n\u2022\tTetanic fade (see earlier) occurs with non-depolarising blocking drugs, but not with suxamethonium, which does not block presynaptic nAChRs.\nUnwanted effects and dangers of suxamethonium\nSuxamethonium has several adverse effects (see Table 14.7), but remains in use for short-lasting procedures because of the rapid recovery that follows its intravenous administration.\nBradycardia. This is preventable by atropine and is due \nto a direct muscarinic action.\nPotassium release. The increase in cation permeability \nof the motor endplates causes a net loss of K+ from muscle, \nand thus a small rise in plasma K+ concentration. This is not \nusually important, but may be an issue following trauma, burns or injuries causing muscle denervation (Fig. 14.7). Denervation increases the rise in plasma K\n+ caused by \nsuxamethonium because it causes ACh receptors to spread to regions of the muscle fibre away from the endplates (see Ch. 13), so that a much larger area of membrane is sensitive to suxamethonium. The resulting hyperkalaemia can be enough to cause ventricular dysrhythmia or cardiac arrest.\nIncreased intraocular pressure. Extraocular muscles are \nunusual in containing a population of fibres with nAChRs distributed along their length, rather than localised at motor endplates; these respond to suxamethonium with a sustained contracture, applying pressure to the eyeball. It is particularly important to avoid this if the eyeball has been injured.Pancuronium also blocks mAChRs, particularly in the heart, \ncausing tachycardia.\nPharmacokinetic", "start_char_idx": 0, "end_char_idx": 3489, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6e47cef6-3566-460e-b3a6-7292cd8caa15": {"__data__": {"id_": "6e47cef6-3566-460e-b3a6-7292cd8caa15", "embedding": null, "metadata": {"page_label": "195", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8ec4e6a4-cb49-4cca-903d-2bbdefa4c112", "node_type": null, "metadata": {"page_label": "195", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e2295c2a8ad4d2f1e20ea15a3a1ce5e11b402e3f45a89388eff902122cb846f"}, "2": {"node_id": "f160a1a9-cbc3-4a8f-abaa-a042655fc386", "node_type": null, "metadata": {"page_label": "195", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d81ada6939c8a572cba28ea152261ac18449da920146a5e0ef0c096c98f782f7"}}, "hash": "b7731097d70b0a22768dc17d3eed7211a82c28163e3db45de0e41b37fa75490a", "text": "particularly in the heart, \ncausing tachycardia.\nPharmacokinetic aspects\nNeuromuscular-blocking drugs are given intravenously. They differ in their rates of onset and recovery (Fig. 14.6 and Table 14.7).\nMost non-depolarising blocking agents are metabolised \nby the liver or excreted unchanged in the urine, exceptions being atracurium, which hydrolyses spontaneously in \nplasma, and mivacurium , which, like suxamethonium (see \nlater), is hydrolysed by plasma cholinesterase. Their duration \nof action varies between about 15 min and 1\u20132 h (see Table \n14.7), by which time the patient regains enough strength to cough and breathe properly. The route of elimination is important, because many patients undergoing anaesthesia have impaired renal or hepatic function, which can enhance or prolong paralysis to an important degree.\nAtracurium was designed to be chemically unstable at \nphysiological pH (splitting into two inactive fragments by cleavage at one of the quaternary nitrogen atoms), although stable when stored at an acid pH. It has a short duration of action, which is unaffected by renal or hepatic function. Because of the marked pH dependence of its degradation, however, its action becomes considerably briefer during respiratory alkalosis caused by hyperventilation.80 60 40 20 \nTime (min) \nAtracuriumGallamineFazadinium\nPancuroniumTubocurarineDimethyltubocurarine020406080100Block (%)\n0\nFig. 14.6 Rate of recovery from various non-depolarising \nneuromuscular-blocking drugs in humans. Drugs were given \nintravenously to patients undergoing surgery, in doses just sufficient to cause 100% block of the tetanic tension of the \nindirectly\tstimulated \tadductor\tpollicis\tmuscle.\tRecovery\tof\t\ntension was then followed as a function of time. (From Payne, \nJ.P.,\tHughes,\tR.,\t1981.\tBr.\tJ.\tAnaesth.\t53,\t45.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3425, "end_char_idx": 5724, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "480c185a-de7a-4b68-8ae8-f95bb131ce63": {"__data__": {"id_": "480c185a-de7a-4b68-8ae8-f95bb131ce63", "embedding": null, "metadata": {"page_label": "196", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5aeaae6d-4448-49b4-a851-777b28f031ec", "node_type": null, "metadata": {"page_label": "196", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b7d8398217383c22776af072e32e326ef64e4529a6afe2120e513f25370bd93"}, "3": {"node_id": "b23d7495-dc38-4b47-8b55-7d5e6b099202", "node_type": null, "metadata": {"page_label": "196", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "440887f26bb59942a63c5c04f368cae2869d212e60175fb8cd1d9ef6a0915271"}}, "hash": "e3989049f1b0c46963105df9ac7c358e0cd52cc41f014e6143d475a5367564c4", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n190\u2022\tNeonates \tmay \thave \tlow \tplasma \tcholinesterase \tactivity \t\nand experience prolonged paralysis if treated with \nsuxamethonium.\nMalignant hyperpyrexia. This is a rare inherited condi -\ntion, due to a mutation of the Ca2+ release channel of the \nsarcoplasmic reticulum (the ryanodine receptor, see Ch. \n4), which results in intense muscle spasm and a dramatic \nrise in body temperature when certain drugs are given (see Ch. 12). Suxamethonium is now the commonest culprit, \nalthough an episode of malignant hyperpyrexia can also be \nprecipitated by a variety of other drugs. The condition carries a high mortality (about 65%) and is treated by administration \nof dantrolene, a drug that inhibits muscle contraction by \npreventing Ca\n2+ release from the sarcoplasmic reticulum.\nDRUGS THAT ACT PRESYNAPTICALLY\nDRUGS \u2003THAT \u2003INHIBIT \u2003ACETYLCHOLINE \u2003SYNTHESIS\nThe steps in the synthesis of ACh in the presynaptic nerve \nterminals are shown in Fig. 14.2. The rate-limiting process \nappears to be the transport of choline into the nerve terminal. \nHemicholinium blocks this transport and thereby inhibits \nACh synthesis. It is useful as an experimental tool but has Prolonged paralysis. The action of suxamethonium, given \nas an intravenous bolus to achieve relaxation during tracheal \nintubation, normally lasts for only 2\u20136 min, because the \ndrug is hydrolysed by plasma cholinesterase. Its action is prolonged by various factors that reduce the activity of \nthis enzyme:\n\u2022\tGenetic \tvariants \tof \tplasma \tcholinesterase \twith \t\nreduced activity (see Ch. 12). Severe deficiency, \nenough to increase the duration of action to 2 h or \nmore, occurs in approximately 1 in 3500 individuals. \nRarely, the enzyme is completely absent and paralysis \nlasts for many hours. Biochemical testing of enzyme \nactivity in the plasma and its sensitivity to inhibitors is used clinically to diagnose this problem; genotyping \nis possible but as yet not practicable for routine \nscreening to prevent the problem.\n\u2022\tAnticholinesterase \tdrugs. \tThe \tuse \tof \t\norganophosphates to treat glaucoma (see Table 14.4) can inhibit plasma cholinesterase and prolong the \naction of suxamethonium. Competing substrates for \nplasma cholinesterase (e.g. procaine, propanidid) can \nalso have this effect.Table 14.8 Anticholinesterase drugs\nDrug Structure Duration of action Main site of action Notes\nEdrophonium\n+CH3\nCH3CH3\nHO NShort NMJ Used mainly in diagnosis of \nmyasthenia gravisToo short-acting for therapeutic use\nNeostigmine\nCH3\nCH3CH3H3C\nH3CO N\nON+Medium NMJ Used intravenously to reverse competitive neuromuscular blockUsed orally in treatment of myasthenia gravisVisceral side effects\nPhysostigmine\nN NCH3\nCH3H\nH3CO N\nO\nCH3Medium P Used as eye drops in treatment of glaucoma\nPyridostigmine\n+ H3CCH3\nH3CO N N\nOMedium NMJ Used orally in treatment of myasthenia gravisBetter absorbed than neostigmine and has longer duration of action\nDyflos\nH3COO\nOFPH3C\nH3C\nH3CLong P Highly toxic organophosphate, with very prolonged actionHas been used as eye drops for", "start_char_idx": 0, "end_char_idx": 3069, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b23d7495-dc38-4b47-8b55-7d5e6b099202": {"__data__": {"id_": "b23d7495-dc38-4b47-8b55-7d5e6b099202", "embedding": null, "metadata": {"page_label": "196", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5aeaae6d-4448-49b4-a851-777b28f031ec", "node_type": null, "metadata": {"page_label": "196", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b7d8398217383c22776af072e32e326ef64e4529a6afe2120e513f25370bd93"}, "2": {"node_id": "480c185a-de7a-4b68-8ae8-f95bb131ce63", "node_type": null, "metadata": {"page_label": "196", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e3989049f1b0c46963105df9ac7c358e0cd52cc41f014e6143d475a5367564c4"}}, "hash": "440887f26bb59942a63c5c04f368cae2869d212e60175fb8cd1d9ef6a0915271", "text": "toxic organophosphate, with very prolonged actionHas been used as eye drops for glaucoma\nEcothiophate\n+CH3\nCH3CH3 NH3C OO\nOSP\nH3CLong P Used as eye drops in treatment of glaucomaProlonged action; may cause systemic effects\nParathion\nNO2H3C OS\nOOP\nH3CLong \u2013 Converted to active metabolite by replacement of sulfur by oxygenUsed as insecticide but also causes poisoning in humans\nOther anticholinesterase drugs developed for the treatment of dementia are described in Chapter 41.NMJ, neuromuscular junction; P, postganglionic parasympathetic junction.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2990, "end_char_idx": 4018, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "87a18f21-26e6-42b7-9e36-9967c0962176": {"__data__": {"id_": "87a18f21-26e6-42b7-9e36-9967c0962176", "embedding": null, "metadata": {"page_label": "197", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f506ce48-764f-42c3-a927-d3048c952f07", "node_type": null, "metadata": {"page_label": "197", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be3874c40351d3aa1de0dfc7e2b73d1df97081cd0b25f29551ec04ecc7e11fd6"}, "3": {"node_id": "f719bcf1-051b-45dd-b38a-d3f374b7f509", "node_type": null, "metadata": {"page_label": "197", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19aa628d76fb57fe696873fa0126d22c6f88b3e2507f6e504fcfeb87c427ca93"}}, "hash": "f46b391bf522256dd25571278c749ac13ab5c10e968bcc2d6d2d982b348d602e", "text": "14 CHOLI nERgIC TRA n SMISSIO n\n191the other subunit produces the toxic effect. Botulinum toxin contains \nseveral components (A\u2013G, see Zhongxing Peng Chen et al., 2012). \nThey are peptidases that cleave specific proteins involved in exo -\ncytosis (synaptobrevins, syntaxins, etc.; see Ch. 4), thereby producing \na long-lasting block of synaptic function. Each toxin component \ninactivates a different functional protein \u2013 a remarkably coordinated attack by a humble bacterium on a vital component of mammalian \nphysiology.\nBotulinum poisoning causes progressive parasympathetic \nand motor paralysis, with dry mouth, blurred vision and \ndifficulty in swallowing, followed by progressive respiratory \nparalysis. Treatment with antitoxin is effective only if given before symptoms appear, for once the toxin is bound its \naction cannot be reversed. Mortality is high, and recovery \ntakes several weeks. Anticholinesterases and drugs that increase transmitter release are ineffective in restoring \ntransmission. Botulinum toxin, given by local injection, \nhas a number of clinical and cosmetic uses (a testament to no clinical applications. Its blocking effect on transmission develops slowly, as the existing stores of ACh become \ndepleted. Vesamicol , which acts by blocking ACh transport \ninto synaptic vesicles, has a similar effect.\nDRUGS \u2003THAT \u2003INHIBIT \u2003ACETYLCHOLINE \u2003RELEASE\nACh release by a nerve impulse involves the entry of Ca2+ \ninto the nerve terminal; the increase in [Ca2+]i stimulates \nexocytosis and increases the rate of quantal release (see \nFig. 14.2). Agents that inhibit Ca2+ entry include Mg2+ and \nvarious aminoglycoside antibiotics (e.g. streptomycin and \nneomycin; see Ch. 52), which can unpredictably prolong \nmuscle paralysis when used clinically in patients treated with neuromuscular-blocking agents as an adjunct to general \nanaesthesia.\nTwo potent neurotoxins, namely botulinum toxin and \n\u03b2-bungarotoxin, act specifically to inhibit ACh release. Botulinum toxin is a protein produced by the anaerobic \nbacillus Clostridium botulinum , an organism that can multiply \nin preserved food and can cause botulism, an extremely serious type of food poisoning.\n6\n\u25bc The potency of botulinum toxin is extraordinary, the minimum \nlethal dose in a mouse being less than 10\u221212 g \u2013 only a few million \nmolecules. It belongs to the group of potent bacterial exotoxins that \nincludes tetanus and diphtheria toxins. They possess two subunits, \none of which binds to a membrane receptor and is responsible for \ncellular specificity. By this means, the toxin enters the cell, where 23456789\n20 16 12 8 4 0SuxNormalParalysed\nMinutesPlasma [K+] (mmol/L)\nFig. 14.7 Effect of suxamethonium (Sux) on plasma \npotassium concentration in humans. Blood was collected \nfrom veins draining paralysed and non-paralysed limbs of seven \ninjured patients undergoing surgery. The injuries had resulted in motor nerve degeneration, and hence denervation \nsupersensitivity \tof \tthe \taffected \tmuscles. \t(From \tTobey, \tR.E. \t\net al., 1972. Anaesthesiology 37, 322.)Neuromuscular-blocking drugs \n\u2022\tSubstances \tthat \tblock \tcholine \tuptake: \tfor \texample, \t\nhemicholinium (not used clinically).\n\u2022\tSubstances \tthat \tblock \tacetylcholine \trelease: \t\naminoglycoside antibiotics, botulinum toxin.\n\u2022\tDrugs\tused", "start_char_idx": 0, "end_char_idx": 3299, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f719bcf1-051b-45dd-b38a-d3f374b7f509": {"__data__": {"id_": "f719bcf1-051b-45dd-b38a-d3f374b7f509", "embedding": null, "metadata": {"page_label": "197", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f506ce48-764f-42c3-a927-d3048c952f07", "node_type": null, "metadata": {"page_label": "197", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be3874c40351d3aa1de0dfc7e2b73d1df97081cd0b25f29551ec04ecc7e11fd6"}, "2": {"node_id": "87a18f21-26e6-42b7-9e36-9967c0962176", "node_type": null, "metadata": {"page_label": "197", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f46b391bf522256dd25571278c749ac13ab5c10e968bcc2d6d2d982b348d602e"}}, "hash": "19aa628d76fb57fe696873fa0126d22c6f88b3e2507f6e504fcfeb87c427ca93", "text": "antibiotics, botulinum toxin.\n\u2022\tDrugs\tused \tto \tcause \tparalysis \tduring \tanaesthesia \t\ncomprise:\n\u2013\tDepolarising \tneuromuscular-blocking \tagents: \t\nsuxamethonium, short-acting and used during \ninduction of anaesthesia and intubation of the airway.\n\u2013\tNon-depolarising \tneuromuscular-blocking \tagents:\t\ntubocurarine, pancuronium, atracurium, \nvecuronium, mivacuronium. These block nicotinic \nacetylcholine receptors and differ mainly in duration of \naction; they are used to maintain neuromuscular \nrelaxation throughout a surgical operation, or in patients in an intensive care unit who may otherwise experience muscular spasm or involuntary movement.\n\u2022\tImportant \tcharacteristics \tof \tnon-depolarising \tand \t\ndepolarising \tblocking \tdrugs:\n\u2013\tNon-depolarising \tblock \tis \treversible \tby \t\nanticholinesterase drugs, depolarising block is not.\n\u2013\tSteroidal \t(\u2018curonium\u2019) \tdrugs \t(rocuronium, \nvecuronium) are reversed by sugammadex.\n\u2013\tDepolarising \tblock \tproduces \tinitial \tfasciculations \tand \t\noften postoperative muscle pain.\n\u2013\tSuxamethonium is hydrolysed by plasma cholinesterase and is normally very short-acting, but \nmay cause long-lasting paralysis in congenitally \ncholinesterase-deficient individuals.\n\u2022\tMain\tside \teffects: \tearly \tcurare \tderivatives \tcaused \t\nganglion block, histamine release and hence hypotension and bronchoconstriction; newer non-depolarising blocking drugs have fewer side effects; \nsuxamethonium may cause bradycardia, cardiac \ndysrhythmias due to K\n+ release (especially in burned or \ninjured patients), increased intraocular pressure, or (in rare genetically susceptible individuals) malignant \nhyperthermia.\n6Among the more spectacular outbreaks of botulinum poisoning was an \nincident on Loch Maree in Scotland in 1922, when all eight members of \na fishing party died after eating duck p\u00e2t\u00e9 for their lunch. Their ghillies, \nconsuming humbler fare no doubt, survived. The innkeeper committed suicide.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3257, "end_char_idx": 5672, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c4f485bf-b5e0-4eba-8f97-cbf674deb6e4": {"__data__": {"id_": "c4f485bf-b5e0-4eba-8f97-cbf674deb6e4", "embedding": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "24564321-94c2-48e2-9faa-250076614265", "node_type": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b1151afa043d3e42ddf04ebbb6880a5d0f6d6a014eea407150e82e7f9feb742"}, "3": {"node_id": "510fbcb9-51bd-4135-baa9-64c5544b9764", "node_type": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c98fb6a32afed7a0e3ded566bb1d8ad9eac03bcbf7c2e8c680beda7a370e97b6"}}, "hash": "2da32fab658a131a87f378cf1e1cd4a731ade6ef76bba4ff22411e5b1a72a157", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n192The bound AChE at cholinergic synapses serves to \nhydrolyse the released transmitter and terminate its action \nrapidly. Soluble AChE is also present in cholinergic nerve \nterminals, where it has a role in regulating the free ACh concentration, and from which it may be secreted; the \nfunction of the secreted enzyme is so far unclear. AChE \nis quite specific for ACh and closely related esters such as methacholine. Certain neuropeptides, such as substance \nP (Ch. 19) are inactivated by AChE, but it is not known \nwhether this is of physiological significance. Overall, there is poor correspondence between the distribution of cholinergic synapses and that of AChE, both in the brain and in the \nperiphery, and AChE most probably has synaptic func -\ntions additional to disposal of ACh, although the details \nremain unclear (see review by Zimmerman & Soreq, \n2006).\nBuChE has a widespread distribution, being found in \ntissues such as liver, skin, brain and gastrointestinal smooth \nmuscle, as well as in soluble form in the plasma. It is not \nparticularly associated with cholinergic synapses, and its physiological function is unclear. It has a broader substrate \nspecificity than AChE. It hydrolyses the synthetic substrate \nbutyrylcholine more rapidly than ACh, as well as other esters, such as procaine , suxamethonium and propanidid \n(a short-acting anaesthetic agent; see Ch. 42). The plasma enzyme is important in relation to the inactivation of the drugs listed previously. Genetic variants of BuChE causing \nsignificantly reduced enzymic activity occur rarely (see Ch. \n12), and these partly account for the variability in the dura -\ntion of action of these drugs. The short duration of action of ACh given intravenously (see Fig. 14.1) results from its \nrapid hydrolysis in the plasma. Normally, AChE and BuChE \nbetween them keep the plasma ACh at an undetectably low level, so ACh is strictly a neurotransmitter and not \na hormone.\n\u25bc Both AChE and BuChE belong to the class of serine hydrolases, \nwhich includes many proteases such as trypsin. The active site of AChE \ncomprises two distinct regions (Fig. 14.8): an anionic site (glutamate \nresidue), which binds the basic (choline) moiety of ACh; and an esteratic \n(catalytic) site (histidine + serine). As with other serine hydrolases, \nthe acidic (acetyl) group of the substrate is transferred to the serine \nhydroxyl group, leaving (transiently) an acetylated enzyme molecule \nand a molecule of free choline. Spontaneous hydrolysis of the serine acetyl group occurs rapidly, and the overall turnover number of AChE \nis extremely high (over 10,000 molecules of ACh hydrolysed per \nsecond by a single active site).\nDRUGS \u2003THAT \u2003INHIBIT \u2003CHOLINESTERASE\nPeripherally acting anticholinesterase drugs, summarised in \nTable 14.8 , fall into three main groups according to the nature \nof their interaction with the active site, which determines their duration of action. Most of them inhibit AChE and BuChE about equally. Centrally acting anticholinesterases, \ndeveloped for the treatment of dementia, are discussed in \nChapter 41.\nShort-acting anticholinesterases\nThe only important drug of this type is edrophonium, a \nquaternary ammonium compound that binds to the anionic \nsite of the enzyme only. The ionic bond formed is readily \nreversible, and the action of the drug is very brief. It is used mainly for diagnostic purposes, because", "start_char_idx": 0, "end_char_idx": 3439, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "510fbcb9-51bd-4135-baa9-64c5544b9764": {"__data__": {"id_": "510fbcb9-51bd-4135-baa9-64c5544b9764", "embedding": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "24564321-94c2-48e2-9faa-250076614265", "node_type": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b1151afa043d3e42ddf04ebbb6880a5d0f6d6a014eea407150e82e7f9feb742"}, "2": {"node_id": "c4f485bf-b5e0-4eba-8f97-cbf674deb6e4", "node_type": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2da32fab658a131a87f378cf1e1cd4a731ade6ef76bba4ff22411e5b1a72a157"}, "3": {"node_id": "d3790280-3ab7-4876-93a5-0df2a2b54448", "node_type": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "165437e7c1ee2155de11d9d203031d5941fe5611036bcfca71379e591d11d33c"}}, "hash": "c98fb6a32afed7a0e3ded566bb1d8ad9eac03bcbf7c2e8c680beda7a370e97b6", "text": "of the drug is very brief. It is used mainly for diagnostic purposes, because improvement of \nmuscle strength by an anticholinesterase is characteristic \nof myasthenia gravis (see pp. 195\u2013196) but does not occur when muscle weakness is due to other causes.Paracelsus\u2019 dictum that all drugs are poisons, the distinction lying in the dose), including:\n\u2022\tblepharospasm (persistent and disabling eyelid spasm) \nand other forms of unwanted movement disorder including torsion dystonia and spasmodic torticollis \n(twisting movements of, respectively, limbs or neck);\n\u2022\tspasticity (excessive extensor muscle tone, associated with developmental brain abnormalities or birth \ninjury);\n\u2022\turinary incontinence associated with bladder \noveractivity (given by intravesical injection);\n\u2022\tsquint (given by injection into extraocular muscles);\n\u2022\thyperhidrosis (injected intradermally into axillary skin), for excessive sweating resistant to other treatment;\n\u2022\tsialorrhoea (excessive salivary secretion);\n\u2022\theadache prophylaxis (in adults with chronic migraine and frequent headaches);\n\u2022\tforehead wrinkles (injected intradermally it removes frown lines by paralysing the superficial muscles that pucker the skin).\nInjections need to be repeated every few months. Botuli -\nnum toxin is antigenic, and may lose its effectiveness due to its immunogenicity. There is a risk of more general \nmuscle paralysis if the toxin spreads beyond the injected \nregion.\n\u25bc \u03b2-Bungarotoxin is a protein contained in the venom of various \nsnakes of the cobra family, and has a similar action to botulinum \ntoxin, although its active component is a phospholipase rather than \na peptidase. The same venoms also contain \u03b1-bungarotoxin (Ch. 3), \nwhich blocks postsynaptic ACh receptors. These snakes evidently \ncover all eventualities as far as causing paralysis of their victims is \nconcerned.\nDRUGS THAT ENHANCE CHOLINERGIC \nTRANSMISSION\nDrugs that enhance cholinergic transmission act either by \ninhibiting cholinesterase (the main group) or by increasing \nACh release. In this chapter, we focus on the peripheral \nactions of such drugs; drugs affecting cholinergic trans -\nmission in the CNS, used to treat senile dementia, are \ndiscussed in Chapter 41, which also mentions spinal muscular \natrophy \u2013 a rare disorder characterised by degeneration \nof the anterior horn cells in the spinal cord and motor \nnuclei in the lower brainstem resulting in clinical features \nreminiscent of infant botulism and caused by loss of a survival protein in the motoneurones. Such patients may be treated with nusinersen, an antisense oligonucleotide \ndesigned to increase expression of the survival protein and administered intrathecally (see Chs 9, 40, 41).\nDISTRIBUTION \u2003AND \u2003FUNCTION \u2003OF \u2003CHOLINESTERASE\nThere are two distinct types of cholinesterase, namely acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE, \nsometimes called pseudocholinesterase), closely related in molecular structure but differing in their distribu -\ntion, substrate specificity and functions. Both consist of \nglobular catalytic subunits, which constitute the soluble \nforms found in plasma (BuChE) and cerebrospinal fluid (AChE). Elsewhere, the catalytic units are linked to accessory \nproteins, which tether them like a bunch of balloons to the \nbasement membrane (at the neuromuscular junction) or to the neuronal membrane at neuronal synapses (and also, oddly, the", "start_char_idx": 3376, "end_char_idx": 6784, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d3790280-3ab7-4876-93a5-0df2a2b54448": {"__data__": {"id_": "d3790280-3ab7-4876-93a5-0df2a2b54448", "embedding": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "24564321-94c2-48e2-9faa-250076614265", "node_type": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b1151afa043d3e42ddf04ebbb6880a5d0f6d6a014eea407150e82e7f9feb742"}, "2": {"node_id": "510fbcb9-51bd-4135-baa9-64c5544b9764", "node_type": null, "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c98fb6a32afed7a0e3ded566bb1d8ad9eac03bcbf7c2e8c680beda7a370e97b6"}}, "hash": "165437e7c1ee2155de11d9d203031d5941fe5611036bcfca71379e591d11d33c", "text": "neuronal membrane at neuronal synapses (and also, oddly, the erythrocyte membrane, where the function of \nthe enzyme is unknown).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6788, "end_char_idx": 7396, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2d80e7f8-9280-4ba2-82ab-1b68f1308272": {"__data__": {"id_": "2d80e7f8-9280-4ba2-82ab-1b68f1308272", "embedding": null, "metadata": {"page_label": "199", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "575d8d5b-c815-4fc4-8dab-2af6ec4728a9", "node_type": null, "metadata": {"page_label": "199", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "757e2e6dbb5ce545d6000e9d64058a296fb1bcde7e4ecca101967ecbee3647bc"}, "3": {"node_id": "ee75f496-cf2d-4264-a817-9b87bee303ad", "node_type": null, "metadata": {"page_label": "199", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0a87cfdc6cdb0f95a91c753d61332df273bb4bc84927b309237928e049a561d"}}, "hash": "ea5e2a8d8dd089033134782ccadd3d8027853fd5cb66a54714472f1cd289480e", "text": "14 CHOLI nERgIC TRA n SMISSIO n\n193FPOPr\nHO OPr\nDyflos\nP PrO\nOHOPr\nN+NON+N HO\nPralidoximeN NOO\n+\nNeostigmineReversible anticholinesterase\nReactivationIrreversible anticholinesterase\nCOO \u2212N\nN\nHOActive enzyme\nN NO\n+\nO\nCOO \u2212NN\nHO\nN\nO\nCOO \u2212NN\nOPOPr\nHO OPr\nCOO \u2212NN\nO\nPOPr\nHO OPr\nN+N HO\nCOO \u2212NN\nOCarbamyl \ntransferred\nto serine \u2013OHNo spontaneous \nhydrolysisHistidine\nSerine GlutamateCatalytic\nsiteAnionic\nsitePhosphorylated\nenzyme\nCarbamyl-serine \nhydrolysed\n(slow)Enzyme\nreactivated\nFig. 14.8 Action of anticholinesterase drugs. \tReversible \tanticholinesterase \t(neostigmine): \trecovery \tof \tactivity \tby \thydrolysis \tof \tthe \t\ncarbamylated \tenzyme \ttakes \tmany \tminutes. \tIrreversible \tanticholinesterase \t(dyflos): \treactivation \tof \tphosphorylated \tenzyme \tby \tpralidoxime. \t\nThe representation of the active site is purely diagrammatic and by no means representative of the actual molecular structure. \n7Otherwise known as the ordeal bean. In the Middle Ages, extracts of \nthese beans were used to determine the guilt or innocence of those \naccused of crime or heresy. Death implied guilt.Irreversible anticholinesterases\nIrreversible anticholinesterases (see Table 14.8) are penta -\nvalent phosphorus compounds containing a labile group \nsuch as fluoride (in dyflos ) or an organic group (in parathion \nand ecothiophate ). This group is released, leaving the serine \nhydroxyl group of the enzyme phosphorylated (see Fig. 14.8). Most of these organophosphate compounds, of which \nthere are many, were developed as weapons, such as sarin, \nand the more potent VX\n (10 mg of which through skin \ncontact is said to be fatal) which acquired notoriety as an agent of state-sponsored assassination.\n8 Some are used as Medium-duration anticholinesterases\nThese include neostigmine and pyridostigmine , which are \nquaternary ammonium compounds of clinical importance, \nand physostigmine (eserine), a tertiary amine, which occurs \nnaturally in the Calabar bean.7\nThese drugs are all carbamyl, as opposed to acetyl, esters \nand all possess basic groups that bind to the anionic site. Transfer of the carbamyl group to the serine hydroxyl group \nof the esteratic site occurs as with ACh, but the carbamylated enzyme is very much slower to hydrolyse (see Fig. 14.8), \ntaking minutes rather than microseconds. The anticholinest -\nerase drug is therefore hydrolysed, but at a negligible rate \ncompared with ACh, and the slow recovery of the carbamyl -\nated enzyme means that the action of these drugs is quite long-lasting.\nDonepezil is a CNS-active drug developed for the treat -\nment of Alzheimer\u2019s disease (Ch. 41).8On February 13, 2017, Kin Jong-nam, half-brother of North Korean \nleader Kim Jong-un, died after an assault in Kuala Lumpur International \nAirport. According to the authorities he was murdered by poisoning with \nVX, which was found on his face. The authorities further reported that one of the women suspected of applying the nerve agent experienced \nsome physical symptoms of VX poisoning. The director of a research \nprogram of the Middlebury Institute of International Studies at Monterey stated that VX fumes would have", "start_char_idx": 0, "end_char_idx": 3133, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ee75f496-cf2d-4264-a817-9b87bee303ad": {"__data__": {"id_": "ee75f496-cf2d-4264-a817-9b87bee303ad", "embedding": null, "metadata": {"page_label": "199", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "575d8d5b-c815-4fc4-8dab-2af6ec4728a9", "node_type": null, "metadata": {"page_label": "199", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "757e2e6dbb5ce545d6000e9d64058a296fb1bcde7e4ecca101967ecbee3647bc"}, "2": {"node_id": "2d80e7f8-9280-4ba2-82ab-1b68f1308272", "node_type": null, "metadata": {"page_label": "199", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea5e2a8d8dd089033134782ccadd3d8027853fd5cb66a54714472f1cd289480e"}}, "hash": "b0a87cfdc6cdb0f95a91c753d61332df273bb4bc84927b309237928e049a561d", "text": "of the Middlebury Institute of International Studies at Monterey stated that VX fumes would have killed the suspected attackers even if \nthey had been wearing gloves, suggesting that the VX was applied as \ntwo non-lethal components that would mix to form VX only on the victim\u2019s face. (Wikipedia, accessed July 30, 2017).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3037, "end_char_idx": 3837, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "84bd0ac4-b9ef-48bb-86be-56ef8829ffa3": {"__data__": {"id_": "84bd0ac4-b9ef-48bb-86be-56ef8829ffa3", "embedding": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "119b31fa-17bb-415d-99bf-ce595eefb120", "node_type": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0d813789aa2107cfd4f99723cd03d9c0507e722afc905a5d19a9c9022327fdc1"}, "3": {"node_id": "3dd5252b-ab8c-453f-9478-3fc321c7edce", "node_type": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "edd27c73831d6976f71bddf14d287c289dcb1f0c435e5114f29f009c805689df"}}, "hash": "5b6ef77261ce60e831f12930a68cc4facebc027f26da9c897da0a34a215d71aa", "text": "14 SECTION 2 \u2003\u2003CHEMICAL MEDIATORS\n194are too few ACh receptors, and cholinesterase inhibition \nimproves transmission just as it does in curarised muscle.\nIn large doses, such as can occur in poisoning, anticho -\nlinesterases initially cause twitching of muscles. This is \nbecause spontaneous ACh release can give rise to endplate \npotentials that reach the firing threshold. Later, paralysis \nmay occur due to depolarisation block, which is associated \nwith the build-up of ACh.\nEffects on the CNS. Tertiary compounds, such as phys -\nostigmine, and the non-polar organophosphates penetrate \nthe blood\u2013brain barrier freely and affect the brain. The \nresult is an initial excitation, which can result in convulsions, \nfollowed by depression, which can cause unconsciousness \nand respiratory failure. These central effects result mainly \nfrom the activation of mAChRs, and are antagonised by \natropine. The use of anticholinesterases to treat senile \ndementia is discussed in Chapter 41.pesticides as well as for clinical use; they interact only with \nthe esteratic site of the enzyme and have no cationic group. \nEcothiophate is an exception in having a quaternary nitrogen \ngroup designed to bind also to the anionic site.\nThe inactive phosphorylated enzyme is usually very \nstable. With drugs such as dyflos, no appreciable hydrolysis \noccurs, and recovery of enzymic activity depends on the \nsynthesis of new enzyme molecules, a process that may take \nweeks. With other drugs, such as ecothiophate, hydrolysis \noccurs over the course of a few days, so that their action is \nnot strictly irreversible. Dyflos and parathion are volatile \nnon-polar substances of very high lipid solubility, and are \nrapidly absorbed through mucous membranes and even \nthrough unbroken skin and insect cuticles; the use of these \nagents as war gases or insecticides relies on this property. \nThe lack of a specificity-conferring quaternary group means \nthat most of these drugs block other serine hydrolases (e.g. \ntrypsin, thrombin), although their pharmacological effects \nresult mainly from cholinesterase inhibition.\nEffects of anticholinesterase drugs\nCholinesterase inhibitors affect peripheral as well as central \ncholinergic synapses.\nSome organophosphate compounds can produce, in \naddition, a severe form of neurotoxicity.\nEffects on autonomic cholinergic synapses. These mainly \nreflect enhancement of ACh activity at parasympathetic \npostganglionic synapses (i.e. increased secretions from \nsalivary, lacrimal, bronchial and gastrointestinal glands; \nincreased peristaltic activity; bronchoconstriction; brady -\ncardia and hypotension; pupillary constriction; fixation of \naccommodation for near vision; fall in intraocular pressure). \nLarge doses can stimulate, and later block, autonomic \nganglia, producing complex autonomic effects. The block, \nif it occurs, is a depolarisation block and is associated with \na build-up of ACh in the plasma and body fluids. Neostig -\nmine and pyridostigmine tend to affect neuromuscular \ntransmission more than the autonomic system, whereas \nphysostigmine and organophosphates show the reverse \npattern. The reason is not clear, but therapeutic usage takes \nadvantage of this partial selectivity.\nAcute anticholinesterase poisoning (e.g. from contact \nwith insecticides or war gases) causes severe bradycardia, \nhypotension and difficulty in breathing. Combined with a \ndepolarising neuromuscular block and central effects (see \nbelow), the result may be fatal.\nEffects on the", "start_char_idx": 0, "end_char_idx": 3508, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3dd5252b-ab8c-453f-9478-3fc321c7edce": {"__data__": {"id_": "3dd5252b-ab8c-453f-9478-3fc321c7edce", "embedding": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "119b31fa-17bb-415d-99bf-ce595eefb120", "node_type": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0d813789aa2107cfd4f99723cd03d9c0507e722afc905a5d19a9c9022327fdc1"}, "2": {"node_id": "84bd0ac4-b9ef-48bb-86be-56ef8829ffa3", "node_type": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5b6ef77261ce60e831f12930a68cc4facebc027f26da9c897da0a34a215d71aa"}, "3": {"node_id": "cd3afcd4-68c7-4e8d-af11-00a80c77cd88", "node_type": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ccade97588039badb951772c9c2a5f2054482b84ee99fd86f1a89dc1b2fd20d"}}, "hash": "edd27c73831d6976f71bddf14d287c289dcb1f0c435e5114f29f009c805689df", "text": "block and central effects (see \nbelow), the result may be fatal.\nEffects on the neuromuscular junction. The twitch tension \nof a muscle stimulated via its motor nerve is increased by \nanticholinesterases, owing to repetitive firing in the muscle \nfibre associated with prolongation of the epp. Normally, the \nACh is hydrolysed so quickly that each stimulus initiates \nonly one action potential in the muscle fibre, but when \nAChE is inhibited this is converted to a short train of action \npotentials in the muscle fibre, and hence greater tension. \nMuch more important is the effect produced when trans -\nmission has been blocked by a non-depolarising blocking \nagent such as pancuronium. In this case, addition of an \nanticholinesterase can dramatically restore transmission. If a \nlarge proportion of the receptors is blocked, the majority of \nACh molecules will normally encounter, and be destroyed \nby, an AChE molecule before reaching a vacant receptor; \ninhibiting AChE gives the ACh molecules a greater chance \nof finding a vacant receptor before being destroyed, and thus \nincrease the epp so that it reaches threshold. In myasthenia \ngravis (see pp. 195\u2013196), transmission fails because there Cholinesterase and \nanticholinesterase drugs \n\u2022\tThere\tare\ttwo\tmain\tforms\tof\tcholinesterase:\t\nacetylcholinesterase (AChE), which is mainly \nmembrane-bound, relatively specific for acetylcholine, \nand responsible for rapid acetylcholine hydrolysis at \ncholinergic synapses; and butyrylcholinesterase \n(BuChE) or pseudocholinesterase, which is relatively \nnon-selective and occurs in plasma and many tissues. \nBoth enzymes belong to the family of serine \nhydrolases.\n\u2022\tAnticholinesterase\t drugs\tare\tof\tthree\tmain\ttypes:\t\nshort-acting ( edrophonium ); medium-acting \n(neostigmine , physostigmine ); irreversible \n(organophosphates, dyflos , ecothiophate ). They \ndiffer in the nature of their chemical interaction with the \nactive site of cholinesterase.\n\u2022\tEffects\t of\tanticholinesterase\t drugs\tare\tdue\tmainly\tto\t\nenhancement of cholinergic transmission at cholinergic \nautonomic synapses and at the neuromuscular \njunction.\tAnticholinesterases\t that\tcross\tthe\tblood\u2013brain\t\nbarrier (e.g. physostigmine , organophosphates) also \nhave marked central nervous system effects. \nAutonomic effects include bradycardia, hypotension, \nexcessive secretions, bronchoconstriction, \ngastrointestinal hypermotility and decrease of \nintraocular pressure. Neuromuscular action causes \nmuscle fasciculation and increased twitch tension, and \ncan produce depolarisation block.\n\u2022\tAnticholinesterase\t poisoning\t may\toccur\tfrom\texposure\t\nto insecticides or nerve gases.\nToxicity of organophosphates. Many organophosphates \ncan cause a severe type of delayed peripheral nerve degen -\neration, leading to progressive weakness and sensory loss. \nThis is not a problem with clinically used anticholinesterases \nbut occasionally results from poisoning with insecticides \nor nerve gases. In 1931, an estimated 20,000 Americans \nwere affected, some fatally, by contamination of fruit juice \nwith an organophosphate insecticide, and other similar \noutbreaks have been recorded. The mechanism of this mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3442, "end_char_idx": 6757, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cd3afcd4-68c7-4e8d-af11-00a80c77cd88": {"__data__": {"id_": "cd3afcd4-68c7-4e8d-af11-00a80c77cd88", "embedding": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "119b31fa-17bb-415d-99bf-ce595eefb120", "node_type": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0d813789aa2107cfd4f99723cd03d9c0507e722afc905a5d19a9c9022327fdc1"}, "2": {"node_id": "3dd5252b-ab8c-453f-9478-3fc321c7edce", "node_type": null, "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "edd27c73831d6976f71bddf14d287c289dcb1f0c435e5114f29f009c805689df"}}, "hash": "7ccade97588039badb951772c9c2a5f2054482b84ee99fd86f1a89dc1b2fd20d", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6777, "end_char_idx": 7160, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "05565224-f223-408c-ba4e-7a706407c763": {"__data__": {"id_": "05565224-f223-408c-ba4e-7a706407c763", "embedding": null, "metadata": {"page_label": "201", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1147ffe-7582-48e2-9797-5710e3f1676a", "node_type": null, "metadata": {"page_label": "201", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f57e3f92e58c0bd7556cdcac4b90b5260d83d305c8317f2fea1b162094b8ab0b"}, "3": {"node_id": "81a5347a-519a-4286-9bff-9e0bd9a0bde1", "node_type": null, "metadata": {"page_label": "201", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "029573a40e768219f656a99a483c83134443d3581f09fd3bc12b7b8e65b45416"}}, "hash": "7dde7700ae5155c7f4dd3b496f005e9a252faf108c12eab0dea511c1a7e85a34", "text": "14 CHOLI nERgIC TRA n SMISSIO n\n195Clinical uses of anticholinesterase \ndrugs \n\u2022\tTo\treverse \tthe \taction \tof \tnon-depolarising \t\nneuromuscular-blocking drugs after surgery \n(neostigmine). Atropine must be given to limit \nparasympathomimetic effects.\n\u2022\tTo\ttreat \tmyasthenia \tgravis \t(neostigmine or \npyridostigmine).\n\u2022\tAs\ta\ttest \tfor \tmyasthenia \tgravis \tand \tto \tdistinguish \t\nweakness caused by anticholinesterase overdosage (\u2018cholinergic crisis\u2019) from the weakness of myasthenia \nitself\t(\u2018myasthenic \tcrisis\u2019): \tedrophonium, a short-\nacting drug given intravenously.\n\u2022\tAlzheimer\u2019s \tdisease \t(e.g. \tdonepezil; see Ch. 41).\n\u2022\tGlaucoma \t(ecothiophate eye drops).\n100\n80\n604020\n0\n02 04\n06 0\nTime (min)Plasma ChE activity (%-control)PralidoximeOrganophosphate\n(dyflos)\nFig. 14.9 Reactivation of plasma cholinesterase (ChE) in a \nvolunteer subject by intravenous injection of pralidoxime. to organophosphate poisoning is that, within a few hours, \nthe phosphorylated enzyme undergoes a chemical change \n(\u2018ageing\u2019) that renders it no longer susceptible to reactivation, \nso that pralidoxime must be given early in order to work. Pralidoxime does not enter the brain, but related compounds \nhave been developed to treat the central effects of organo -\nphosphate poisoning.\nMyasthenia gravis\n\u25bc The neuromuscular junction is a robust structure that very rarely \nfails, myasthenia gravis and the Lambert\u2013Eaton myasthenic syndrome \n(see p. 196) being two of the few disorders that specifically affect it. \nMyasthenia gravis affects about 1 in 2000 individuals, often, but by \nno means always, young women who are particularly susceptible to autoimmune disorders. It is characterised by weakness and increased \nfatigability of skeletal muscles resulting from impaired neuromuscular \ntransmission. The tendency for transmission to fail during repetitive activity can be seen in Fig. 14.10. Muscles cannot produce prolonged \ncontractions, resulting in the characteristic drooping eyelids and double \nvision on attempting to sustain lateral gaze. The effectiveness of \nanticholinesterase drugs in improving muscle strength in myasthenia \nwas discovered in 1931, long before the pathophysiology of the disease was understood.\nThe cause of the transmission failure is an autoimmune response to \nnAChRs of the neuromuscular junction, first revealed in studies showing that the number of bungarotoxin-binding sites at the endplates \nof myasthenic patients was reduced by about 70% compared with \nnormal. It had been suspected that myasthenia had an immunological \nbasis, because the disease is sometimes accompanied by a tumour of \nthe thymus gland and removal of the thymus improves the motor symptoms. Immunisation of rabbits with purified ACh receptor causes, \nafter a delay, a disorder very similar to human myasthenia gravis. \nThe presence of antibody directed against the ACh receptor protein can be detected in the serum of myasthenic patients, but the reason reaction is only partly understood, but it seems to result \nfrom inhibition of a neuropathy target esterase distinct from \ncholinesterase. Chronic low-level exposure of agricultural and other workers to organophosphorous pesticides has been associated with neurobehavioural disorders", "start_char_idx": 0, "end_char_idx": 3234, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "81a5347a-519a-4286-9bff-9e0bd9a0bde1": {"__data__": {"id_": "81a5347a-519a-4286-9bff-9e0bd9a0bde1", "embedding": null, "metadata": {"page_label": "201", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1147ffe-7582-48e2-9797-5710e3f1676a", "node_type": null, "metadata": {"page_label": "201", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f57e3f92e58c0bd7556cdcac4b90b5260d83d305c8317f2fea1b162094b8ab0b"}, "2": {"node_id": "05565224-f223-408c-ba4e-7a706407c763", "node_type": null, "metadata": {"page_label": "201", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7dde7700ae5155c7f4dd3b496f005e9a252faf108c12eab0dea511c1a7e85a34"}}, "hash": "029573a40e768219f656a99a483c83134443d3581f09fd3bc12b7b8e65b45416", "text": "workers to organophosphorous pesticides has been associated with neurobehavioural disorders (Blanc-\nLapierre et al., 2013). Other serine hydrolases apart from \nacetylcholinesterase can be secondary organophosphate targets including neuropathy target esterase, lipases, and \nendocannabinoid hydrolases (Casida, 2017).\nThe main uses of anticholinesterases are summarised in \nthe clinical box (see below).\nA\nBNormal \n10 mV Action \npotential \n10 kg Tension \nMyasthenia \n10 mV \nControl \n10 kg \n10 mV After\nneostigmine\n10 kg \nFig. 14.10 Neuromuscular transmission in a normal and a \nmyasthenic human subject. Electrical activity was recorded \nwith a needle electrode in the adductor pollicis muscle, in \nresponse to ulnar nerve stimulation (3 Hz) at the wrist. In a \nnormal subject, electrical and mechanical response is well sustained. In a myasthenic patient, transmission fails rapidly when the nerve is stimulated. Treatment with neostigmine improves transmission. (From Desmedt, J.E., 1962. Bull. Acad. \nR.\tMed.\tBelg. \tVII \t2, \t213.)CHOLINESTERASE \u2003REACTIVATION\nSpontaneous hydrolysis of phosphorylated cholinesterase \nis extremely slow, so poisoning with organophosphates \nnecessitates prolonged supportive care. Pralidoxime (see \nFig. 14.8) reactivates the enzyme by bringing an oxime group into close proximity with the phosphorylated esteratic \nsite. This group is a strong nucleophile and lures the \nphosphate group away from the serine hydroxyl group of the enzyme. The effectiveness of pralidoxime in reactivating \nplasma cholinesterase activity in a poisoned subject is shown \nin Fig. 14.9. The main limitation to its use as an antidote mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3143, "end_char_idx": 5269, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c86f2ca3-0782-4030-8a29-db674a981453": {"__data__": {"id_": "c86f2ca3-0782-4030-8a29-db674a981453", "embedding": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5b91e2ad-4505-4fe4-b467-5d72c77ae1c1", "node_type": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "833c4fa76e99113b9f15acd8e4af08c98415536066967f2a044eca0e06b31cd6"}, "3": {"node_id": "6d9b002e-a54a-4d7c-8db2-647cc5057802", "node_type": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "03087a4beb66f109ed2fb76ff8b6e6dcb36048892360240d8ce55cb6b414993b"}}, "hash": "899c42e781ecbc70f7550b468455767742685d907fbbfa1d25d6630343a4f564", "text": "14 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n196could reverse the neuromuscular-blocking action of tubo -\ncurarine by prolonging the action potential in the nerve \nterminal and hence increasing the release of transmitter \nevoked by nerve stimulation. Subsequently, more potent and selective potassium-channel blocking drugs, such as \namifampridine, were developed. These drugs are not \nselective for cholinergic nerves but increase the evoked release of many different transmitters. Amifampridine is \nused to treat the muscle weakness associated with Lambert\u2013\nEaton myasthenic syndrome, a complication of certain neoplastic diseases in which ACh release is inhibited because antitumour antibodies cross react with Ca\n2+ channels on \nthe prejunctional membrane.for the development of the autoimmune response in humans is \nunknown (Gilhus, 2016).\nThe improvement of neuromuscular function by anticholinesterase \ntreatment (shown in Fig. 14.10) can be dramatic, but if the disease \nprogresses too far, the number of receptors remaining may be insuf -\nficient to produce an adequate epp, and anticholinesterase drugs will \nthen cease to be effective.\nAlternative approaches to the treatment of myasthenia are to remove \ncirculating antibody by plasma exchange, which is transiently effective, \nor, for a more prolonged effect, to inhibit antibody production with \nimmunosuppressant drugs (e.g. prednisolone , azathioprine, mycophe -\nnolate, cyclosporine and tacrolimus; see Ch. 27) or thymectomy.\nOTHER DRUGS THAT ENHANCE \nCHOLINERGIC TRANSMISSION\nIt was observed many years ago that tetraethylammonium , \na potassium-channel blocker and ganglion-blocking drug, \nREFERENCES AND FURTHER READING\nFurther reading\nChangeux, J.P., 2012. The nicotinic acetylcholine receptor: the founding \nfather of the pentameric ligand-gated ion channel superfamily. J. Biol. \nChem. 287, 40207\u201340215. (Min-review describing how electrophysiology, \npharmacology, and biochemistry joined forces to identify the mechanisms that transduce a chemical signal into an electrical one. The nicotinic receptor is \nthe founding father of the family of pentameric membrane receptors \u2013 see \nFig. 3.4)\nFagerlund, M.J., Eriksson, L.I., 2009. Current concepts in neuromuscular \ntransmission. Br. J. Anaesth. 103, 108\u2013114. (Concentrates on findings of potential clinical importance)\nNicholls, J.G., Martin, A.R., Fuchs, P.A., Brown, D.A., Diamond, M.E., \nWeisblat, D., 2012. From neuron to brain, fifth ed. Sinauer, Sunderland. (Excellent general textbook)\nAcetylcholine receptors\nCarruthers, S.P., Gurrich, C.T., Rossell, S.L., 2015. The muscarinic \nsystem, cognition and schizophrenia. Neurosci. Biobehav. Rev. 55, \n393\u2013402. (M1 and M4 receptor manipulation has promise in treatment of \ncognitive impairment in schizophrenia)\nDinely, K.T., Pandya, A.A., Yakel, J.L., 2015. Nicotinic ACh receptors as \ntherapeutic targets in CNS disorders. Trends Pharmacol. Sci. 36, 96\u2013108. (nACh receptors are widely distributed in CNS neurons and non-neuronal cells, and participate in anxiety, the central processing of pain, \nfood intake, nicotine-seeking behavior, and cognitive function. Nine different \nsubunits occur in mammalian brain, assembled into diverse pentameric", "start_char_idx": 0, "end_char_idx": 3214, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d9b002e-a54a-4d7c-8db2-647cc5057802": {"__data__": {"id_": "6d9b002e-a54a-4d7c-8db2-647cc5057802", "embedding": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5b91e2ad-4505-4fe4-b467-5d72c77ae1c1", "node_type": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "833c4fa76e99113b9f15acd8e4af08c98415536066967f2a044eca0e06b31cd6"}, "2": {"node_id": "c86f2ca3-0782-4030-8a29-db674a981453", "node_type": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "899c42e781ecbc70f7550b468455767742685d907fbbfa1d25d6630343a4f564"}, "3": {"node_id": "7aa05708-5b99-4839-bae3-cb47ebe6c7a4", "node_type": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f57094697fd1271c863ca581eca348ec5dc612454ab2f0fe4c6488464d21d693"}}, "hash": "03087a4beb66f109ed2fb76ff8b6e6dcb36048892360240d8ce55cb6b414993b", "text": "Nine different \nsubunits occur in mammalian brain, assembled into diverse pentameric complexes)\nKalamida, D., Poulas, K., Avramopoulou, V., et al., 2007. Muscle and \nneuronal nicotinic acetylcholine receptors: structure, function and pathogenicity. FEBS J. 274, 3799\u20133845. (Excellent comprehensive review)\nKruse, A.C., Kobilka, B.K., Gautam, D., et al., 2014. Muscarinic \nacetylcholine receptors: novel opportunities for drug development. Nat. Rev. Drug Discov. 13, 549\u2013560. (Solution of resting and active \nreceptor structures and insight into allosteric control should lead to new \nmuscarinic receptor subtype-selective drugs)\nNickols, H.H., Conn, P.J., 2014. Development of allosteric modulators of \nGPCRs for the treatment of CNS disorders. Neurobiol. Dis. 61 (Special Issue), SI 55\u2013SI 71. (Describes development of novel allosteric modulators [including modulators of muscarinic receptors] as potential therapeutic \nagents)Southan, C., Sharman, J.L., Benson, H.E., et al., 2016. The IUPHAR/BPS \nGuide to Pharmacology in 2016: towards curated quantitative \ninteractions between 1300 protein targets and 6000 ligands. Nucl. \nAcids Res. 44 (Database Issue), D1054\u2013D1068. (See Acetylcholine \nreceptors (muscarinic), Nicotinic acetylcholine receptors)\nWessler, I., Kirkpatrick, C.J., 2008. Acetylcholine beyond neurons: the \nnon-neuronal cholinergic system in humans. Br. J. Pharmacol. 154, 1558\u20131571. (Summarises findings that reveal surprisingly diverse roles for acetylcholine)\nCholinergic transmission\nGilhus, N.E., 2016. Myasthenia gravis. N. Engl. Med. 375, 2570\u20132581. \n(Recent review)\nDrugs affecting the neuromuscular junction\nPeng Chen, Z., Morris, J.G., Rodriguez, R.L., Shukla, A.W., \nTapia-Nunez, J., Okun, M.S., 2012. Emerging opportunities for \nserotypes of botulinum neurotoxins. Toxins (Basel) 4, 1196\u20131222. \n(Reviews current research on botulinum serotypes A-G)\nNicholson, W.T., Sprung, J., Jankowski, C.J., 2007. Sugammadex: a novel \nagent for the reversal of neuromuscular blockade. Pharmacotherapy 27, 1181\u20131188. (An alternative to neostigmine)\nCholinesterase\nBlanc-Lapierre, A., Bouvier, G., Gruber, A., 2013. Cognitive disorders \nand occupational exposure to organophosphates: results from the \nPHYTONER Study. Am. J. Epidemiol. 177, 1086\u20131096. (Cognitive \ndisorders in vine workers may be associated with specific organophosphate exposure over long periods.)\nCasida, J., 2017. Organophosphate xenobiotic toxicology. Ann. Rev. \nPharmacol. Toxocol. 57, 309\u2013327. (Topical review: other serine hydrolases than acetylcholinesterase can be secondary targets. \u201cThe organophosphate \nherbicides glyphosate and glufosinate act in plants but not animals to block \naromatic amino acid and glutamine biosynthesis, respectively, with safety for crops conferred by their expression of herbicide-tolerant targets and \ndetoxifying enzymes from bacteria.\u201d)\nZimmerman, G., Soreq, H., 2006. Termination and beyond: \nacetylcholinesterase as a modulator of synaptic transmission. Cell Tissue Res. 326,", "start_char_idx": 3141, "end_char_idx": 6146, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7aa05708-5b99-4839-bae3-cb47ebe6c7a4": {"__data__": {"id_": "7aa05708-5b99-4839-bae3-cb47ebe6c7a4", "embedding": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5b91e2ad-4505-4fe4-b467-5d72c77ae1c1", "node_type": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "833c4fa76e99113b9f15acd8e4af08c98415536066967f2a044eca0e06b31cd6"}, "2": {"node_id": "6d9b002e-a54a-4d7c-8db2-647cc5057802", "node_type": null, "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "03087a4beb66f109ed2fb76ff8b6e6dcb36048892360240d8ce55cb6b414993b"}}, "hash": "f57094697fd1271c863ca581eca348ec5dc612454ab2f0fe4c6488464d21d693", "text": "as a modulator of synaptic transmission. Cell Tissue Res. 326, 655\u2013669. (Review of evidence suggesting functions for \nAChE other than ACh hydrolysis)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6158, "end_char_idx": 6786, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "897eed84-ad1c-478f-9d4c-f3daae453bfd": {"__data__": {"id_": "897eed84-ad1c-478f-9d4c-f3daae453bfd", "embedding": null, "metadata": {"page_label": "203", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "53f48a50-6bcd-4ed6-b5b6-1356f7c5890f", "node_type": null, "metadata": {"page_label": "203", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "60fc6dcae11edc0077fc768c1ea6e57252291f7ccbfb18e275edcf0732bc6925"}, "3": {"node_id": "5b058686-57da-4a0f-bf58-9468f175872b", "node_type": null, "metadata": {"page_label": "203", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "52ba650422902cdcb5fac53004144678c202440c70a3973e377d58e3e95d100a"}}, "hash": "1a175431be64c35acafdc93bc488ba21a54e37639633ee998fa43d57775b724c", "text": "197\nNoradrenergic transmission 15 CHEMICAL MEDIATORS SECTION 2 \nOVERVIEW\nPeripheral noradrenergic neurons and the structures \nthat they innervate are fundamental components of \nautonomic function, and are the targets of many thera -\npeutic drugs. In this chapter we describe the physiol -\nogy of noradrenergic neurons and the properties of adrenoceptors (the receptors on which noradrenaline \nand adrenaline act), and discuss the various classes of drugs that affect them. For convenience, much of \nthe pharmacological information is summarised in \ntables later in the chapter.\nCATECHOLAMINES\nCatecholamines contain a catechol moiety (a benzene ring \nwith two adjacent hydroxyl groups) and an amine side \nchain (Fig. 15.1). The most important are:\n\u2022\tnoradrenaline (norepinephrine), a transmitter released by \nsympathetic nerve terminals;\n\u2022\tadrenaline (epinephrine), a hormone secreted by chromaffin cells in the adrenal medulla;\n\u2022\tdopamine, the metabolic precursor of noradrenaline \nand adrenaline, also a transmitter/neuromodulator in \nthe central nervous system (CNS);\n\u2022\tisoprenaline (isoproterenol), a synthetic derivative of \nnoradrenaline and pharmacological tool.\nCLASSIFICATION OF ADRENOCEPTORS\nIn 1896, Oliver and Schafer discovered that intravenous \ninjection of extracts of adrenal gland in anaesthetised cats \ncaused a rise in arterial pressure. Adrenaline was identi -\nfied as the active principle, and was shown by Dale in \n1913 to cause two distinct kinds of vascular effect, namely \nvasoconstriction in certain vascular beds and vasodilatation \nin others. Dale showed that the vasoconstrictor component disappeared if the animal was first injected with an ergot \nderivative\n1 (see Ch. 16), and noticed that adrenaline then \ncaused a fall, instead of a rise, in arterial pressure, reminis -\ncent of his demonstration of the separate muscarinic and nicotinic components of the action of acetylcholine (see Ch. \n14). He avoided interpreting it in terms of different types of receptor, but later pharmacological work, beginning with \nthat of Ahlquist, showed clearly the existence of several \nsubclasses of adrenoceptor with distinct tissue distributions and actions (Table 15.1).\nIn 1948 Ahlquist found that the rank order of the \npotencies of various catecholamines, including adrenaline, noradrenaline and isoprenaline, fell into two distinct pat -\nterns, depending on what response was being measured. He postulated the existence of two kinds of receptor, \u03b1 \nand \u03b2, defined in terms of agonist potencies as follows:\n\u03b1: noradrenaline > adrenaline > isoprenaline\u03b2: isoprenaline > adrenaline > noradrenaline\nIt was then recognised that certain ergot alkaloids, which \nDale had studied, act as selective \u03b1-receptor antagonists \nand that Dale\u2019s adrenaline reversal experiment reflected \nthe unmasking of the \u03b2 effects of adrenaline by \u03b1-receptor \nblockade. Selective \u03b2-receptor antagonists were not devel -\noped until 1955, when their effects fully confirmed Ahlquist\u2019s original classification and also suggested the existence of \nfurther subdivisions of both \u03b1 and \u03b2 receptors. Subsequently \nit has emerged that there are two \u03b1-receptor subtypes ( \u03b1\n1 \nand \u03b12), each comprising three further subclasses ( \u03b11A, \u03b11B, \n\u03b11D and \u03b1 2A, \u03b12B, \u03b12C) and three \u03b2-receptor subtypes ( \u03b21, \u03b22 \nand \u03b23) \u2013 altogether nine distinct subtypes \u2013 all of which are \ntypical G protein\u2013coupled receptors (Table", "start_char_idx": 0, "end_char_idx": 3398, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5b058686-57da-4a0f-bf58-9468f175872b": {"__data__": {"id_": "5b058686-57da-4a0f-bf58-9468f175872b", "embedding": null, "metadata": {"page_label": "203", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "53f48a50-6bcd-4ed6-b5b6-1356f7c5890f", "node_type": null, "metadata": {"page_label": "203", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "60fc6dcae11edc0077fc768c1ea6e57252291f7ccbfb18e275edcf0732bc6925"}, "2": {"node_id": "897eed84-ad1c-478f-9d4c-f3daae453bfd", "node_type": null, "metadata": {"page_label": "203", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1a175431be64c35acafdc93bc488ba21a54e37639633ee998fa43d57775b724c"}}, "hash": "52ba650422902cdcb5fac53004144678c202440c70a3973e377d58e3e95d100a", "text": "\u2013 all of which are \ntypical G protein\u2013coupled receptors (Table 15.2). Genetic variants of both \u03b2\n1 and \u03b2 2 receptors occur in humans, and \ninfluence the effects of agonists and antagonists (see Ahles \n& Engelhardt, 2014). Evidence from specific agonists and \nantagonists, as well as studies on receptor knockout mice (Philipp & Hein, 2004), has shown that \u03b1\n1 receptors are \nparticularly important in the cardiovascular system and \nlower urinary tract, while \u03b12 receptors are predominantly \nneuronal, acting to inhibit transmitter release both in the brain and at autonomic nerve terminals in the periphery. \nThe \u03b1\n2B subtype appears to be involved in neurotransmis -\nsion in the spinal cord and \u03b12C in regulating catecholamine \nrelease from adrenal medulla (Alexander et al., 2015), but \nthe distinct functions of the different subclasses of \u03b11 and \n\u03b12 adrenoceptors remain for the most part unclear; they are \nfrequently co-expressed in the same tissues, and may form \nheterodimers, making pharmacological analysis difficult.\nEach of the three main receptor subtypes is associated with \na specific second messenger system (see Table 15.2). Thus \u03b11 \nreceptors are coupled through Gq to phospholipase C and produce their effects mainly by the release of intracellular \nCa\n2+; \u03b12 receptors couple through Gi/Go to inhibit adenylyl \ncyclase, and thus reduce cAMP formation as well as inhibit -\ning Ca2+ channels and activating K+ channels; and all three \ntypes of \u03b2 receptor couple through Gs to stimulate adenylyl \ncyclase. \u03b2-Adrenoceptor agonists may act not only through \ncAMP formation, but also through other signal transduction pathways (e.g. the mitogen-activated protein [MAP] kinase 1Dale was a new recruit in the laboratories of the Wellcome \npharmaceutical company, given the job of checking the potency of \nbatches of adrenaline coming from the factory. He tested one batch at \nthe end of a day\u2019s experimentation on a cat that he had earlier injected with an ergot preparation. Because it produced a fall in blood pressure \nrather than the expected rise, he advised that the whole expensive \nconsignment should be rejected. Unknown to him, he was given the same sample to test a few days later, and reported it to be normal. How \nhe explained this to Wellcome\u2019s management is not recorded.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3336, "end_char_idx": 6117, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2cdddb58-3993-4867-bad2-a2970342fbd9": {"__data__": {"id_": "2cdddb58-3993-4867-bad2-a2970342fbd9", "embedding": null, "metadata": {"page_label": "204", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "65a7075e-254d-4f76-b909-96c749acd8e8", "node_type": null, "metadata": {"page_label": "204", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a0bb5c1fb84a317cdcfe84b5233071633ab4f7cc5eeaffe672e216c864d1082"}, "3": {"node_id": "3b606e49-1883-4fa6-85b9-ddc930414465", "node_type": null, "metadata": {"page_label": "204", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c042437037eb33c09af2bff656ea4065b2a93508d93b898b901168389fd4a7f"}}, "hash": "4dc88c2b87b31deabe88b38e56077d5922bf305d6c2307349256cf584f035ad3", "text": "15 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n198pathway which may be important in trophic actions; see \nCh. 3 and p. 212, later).The major effects that are produced \nby adrenoceptors, and the main drugs that act on them, \nare shown in Tables 15.1 and 15.2.\nThe distinction between \u03b21 and \u03b22 receptors is an important \none, because \u03b2 1 receptors are found mainly in the heart, \nwhere they are responsible for the positive inotropic and \nchronotropic effects of catecholamines (see Ch. 22), whereas \n\u03b22 receptors are responsible for causing smooth muscle \nrelaxation in many organs, most importantly in the lungs, \nwhere they relax the bronchioles and relieve bronchocon -\nstriction in asthmatics, a useful therapeutic effect (see Ch. \n29). The cardiac effects can be harmful, predisposing to \ncardiac dysrhythmia and increasing myocardial oxygen \ndemand (see Ch. 22); consequently, considerable efforts have been made to discover selective \u03b2\n2 agonists to relax \nsmooth muscle without affecting the heart, and selective \n\u03b21 antagonists to exert a useful blocking effect on the heart \nwithout blocking \u03b22 receptors at the same time (see Table \n15.1). The available drugs are not completely specific, and marketed selective \u03b2\n1 antagonists have some action on \u03b22 \nreceptors as well, which can cause unwanted effects such as bronchoconstriction.\nIn relation to vascular control, it is important to note that \nboth \u03b1- and \u03b2-receptor subtypes are expressed in smooth \nmuscle cells, nerve terminals and endothelial cells, and HO\nHONH2 CH2 CHOH\nNoradrenaline\nHOHONH CH\n3 CH2 CHOH\nAdrenalineHOHONH\n2 CH2 CH2 DopamineHOHONH\n2 CH2CHCOOH\ndopaHONH2 CH2CHCOOH\nTyrosine\nRate-limiting step Tyrosine hydroxylase\nDOPA decarboxylase\nPhenylethanolamine\nN-methyltransferaseDopamine \u03b2-hydroxylase\nFig. 15.1 Structures of the major catecholamines. \n2Just how long may be appreciated by scaling up the 20 \u00b5m diameter of \na neuronal cell body to that of a golf ball (~40,000 \u00b5m diameter, a \nscaling factor of about 2000); proportionately the axon (length from \nsympathetic chain ganglion to, say, a blood vessel in the calf, \n(approximately 1 metre in humans, never mind giraffes) will now reach \nabout 2 km \u2013 some challenge in terms of command and control!Classification of adrenoceptors \n\u2022\tMain\tpharmacological \tclassification \tinto \t\u03b1\tand\t\u03b2 \nsubtypes, \tbased \toriginally \ton \torder \tof \tpotency \tamong \t\nagonists,\tlater \ton \tselective \tantagonists.\n\u2022\tAdrenoceptor \tsubtypes:\n\u2013\ttwo\tmain \t\u03b1-adrenoceptor \tsubtypes, \t\u03b11\tand\t\u03b12,\teach\t\ndivided\tinto \tthree \tfurther \tsubtypes \t(\u03b11A,\t\u03b11B,\t\u03b11D\tand\t\n\u03b12A,\t\u03b12B,\t\u03b12C)\n\u2013\tthree\t\u03b2-adrenoceptor \tsubtypes \t(\u03b21,\t\u03b22,\t\u03b23)\n\u2013\tall\tbelong \tto \tthe \tsuperfamily \tof \tG \tprotein\u2013coupled \t\nreceptors\t(see \tCh. \t3).\n\u2022\tSecond \tmessengers:\n\u2013 \u03b11\treceptors \tactivate \tphospholipase \tC, \tproducing \t\ninositol\ttrisphosphate \tand \tdiacylglycerol \tas \tsecond \t\nmessengers\n\u2013 \u03b12\treceptors \tinhibit \tadenylyl \tcyclase \t(but \tcAMP \tis \t\nusually\tlow), \tand \talso \tmodulate", "start_char_idx": 0, "end_char_idx": 2955, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3b606e49-1883-4fa6-85b9-ddc930414465": {"__data__": {"id_": "3b606e49-1883-4fa6-85b9-ddc930414465", "embedding": null, "metadata": {"page_label": "204", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "65a7075e-254d-4f76-b909-96c749acd8e8", "node_type": null, "metadata": {"page_label": "204", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a0bb5c1fb84a317cdcfe84b5233071633ab4f7cc5eeaffe672e216c864d1082"}, "2": {"node_id": "2cdddb58-3993-4867-bad2-a2970342fbd9", "node_type": null, "metadata": {"page_label": "204", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4dc88c2b87b31deabe88b38e56077d5922bf305d6c2307349256cf584f035ad3"}}, "hash": "4c042437037eb33c09af2bff656ea4065b2a93508d93b898b901168389fd4a7f", "text": "\tcAMP \tis \t\nusually\tlow), \tand \talso \tmodulate \tCa2+\tand\tK+ \nchannels.\n\u2013\tall\ttypes \tof \t\u03b2\treceptor\tstimulate \tadenylyl \tcyclase.\n\u2022\tThe\tmain \teffects \tof \treceptor \tactivation \tare \tas \tfollows:\n\u2013 \u03b11\treceptors: \tvasoconstriction, \trelaxation \tof \t\ngastrointestinal \tsmooth \tmuscle, \tsalivary \tsecretion \t\nand\thepatic \tglycogenolysis\n\u2013 \u03b12\treceptors: \tinhibition \tof: \ttransmitter \trelease \t\n(including\tnoradrenaline \tand \tacetylcholine \trelease \t\nfrom\tautonomic \tnerves) \tcaused \tby \topening \tof \tK+ \nchannels\tand \tinhibition \tof \tCa2+\tchannels; \tplatelet \t\naggregation; \tvascular \tsmooth \tmuscle \tcontraction; \t\ninhibition\tof \tinsulin \trelease\n\u2013 \u03b21\treceptors: \tincreased \tcardiac \trate \tand \tforce\n\u2013 \u03b22\treceptors: \tbronchodilatation; \tvasodilatation; \t\nrelaxation\tof \tvisceral \tsmooth \tmuscle; \thepatic \t\nglycogenolysis; \tmuscle \ttremor\n\u2013 \u03b23\treceptors: \tlipolysis \tand \tthermogenesis; \tbladder \t\ndetrusor\tmuscle \trelaxation.\ntheir role in physiological regulation and pharmacological \nresponses of the cardiovascular system is only partly \nunderstood (see Guimaraes & Moura, 2001).\nPHYSIOLOGY OF NORADRENERGIC \nTRANSMISSION\nTHE NORADRENERGIC NEURON\nNoradrenergic neurons in the periphery are postganglionic \nsympathetic neurons whose cell bodies are situated in \nsympathetic ganglia (see Ch. 13). They generally have long2 \naxons that end in a series of varicosities strung along the branching terminal network. These varicosities contain \nnumerous synaptic vesicles, which are the sites of synthesis and release of noradrenaline and of co-released mediators \nsuch as ATP and neuropeptide Y (see Ch. 13), which are mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2909, "end_char_idx": 5002, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b7fd384d-bcbd-4d13-a229-c0c6091729b4": {"__data__": {"id_": "b7fd384d-bcbd-4d13-a229-c0c6091729b4", "embedding": null, "metadata": {"page_label": "205", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eb14bd1a-b712-491d-8a82-6b8c8d7b1061", "node_type": null, "metadata": {"page_label": "205", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5bbf101855af6812887c30b6524780efc0d6bcd3f4052c1d45a9f97454b7b8df"}}, "hash": "5bbf101855af6812887c30b6524780efc0d6bcd3f4052c1d45a9f97454b7b8df", "text": "15 NORADRENER gIC TRANSMISSION\n199Table 15.1 Distribution and actions of adrenoceptors\nTissues and effects \u03b11 \u03b12 \u03b21 \u03b22 \u03b23\nSmooth muscle\nBlood vessels Constrict Constrict/dilate \u2014 Dilate \u2014\nBronchi Constrict \u2014 \u2014 Dilate \u2014\nGastrointestinal tract Relax Relax (presynaptic effect) \u2014 Relax \u2014\nGastrointestinal sphincters Contract \u2014 \u2014 \u2014 \u2014\nUterus Contract \u2014 \u2014 Relax \u2014\nBladder detrusor \u2014 \u2014 \u2014 Relax Relax\nBladder sphincter Contract \u2014 \u2014 \u2014 \u2014\nSeminal tract Contract \u2014 \u2014 Relax \u2014\nIris (radial muscle) Contract \u2014 \u2014 \u2014 \u2014\nCiliary muscle \u2014 \u2014 \u2014 Relax \u2014\nHeartRate \u2014 \u2014 Increase Increase\na\u2014\nForce of contraction \u2014 \u2014 Increase Increasea\u2014\nOther tissues/cellsSkeletal muscle \u2014 \u2014 \u2014 Tremor\nIncreased muscle mass and speed of contractionGlycogenolysisThermogenesis\nLiver (hepatocytes) Glycogenolysis \u2014 \u2014 Glycogenolysis \u2014\nFat (adipocytes) \u2014 \u2014 \u2014 \u2014 LipolysisThermogenesis\nPancreatic islets (B cells) \u2014 Decrease insulin secretion \u2014 \u2014 \u2014\nSalivary gland K\n+ release \u2014 Amylase secretion\u2014 \u2014\nPlatelets \u2014 Aggregation \u2014 \u2014 \u2014\nMast cells \u2014 \u2014\n\u2014 Inhibition of histamine release\u2014\nBrain stem \u2014 Inhibits sympathetic outflow \u2014 \u2014 \u2014\nNerve terminals\nAdrenergic \u2014 Decrease release \u2014 Increase release \u2014\nCholinergic \u2014 Decrease release \u2014 \u2014 \u2014\naMinor\tcomponent \tnormally \tbut \tmay \tbecome \tsignificant \tin \theart \tfailure.\nTable 15.2 Characteristics of adrenoceptors\n\u03b11(A,B,D) \u03b12(A,B,C) \u03b21 \u03b22 \u03b23\nG protein coupling Gq Gi/Go GS GS GS\nSecond messengers \nand effectorsPhospholipase C activation\u2191 Inositol trisphosphate\u2191 Diacylglycerol\u2191 Ca\n2+\u2193 cAMP\u2193 Calcium channels\u2191 Potassium channels\u2191 cAMP \u2191 cAMP \u2191 cAMP\nAgonist potency order NA > A \u226b ISO A > NA \u226b ISO ISO > NA > A ISO > A > NA ISO > NA = A\nSelective agonists PhenylephrineMethoxamineClonidine DobutamineXamoterolSalbutamolTerbutalineSalmeterolFormoterolClenbuterolMirabegron\nSelective antagonists PrazosinDoxazocinYohimbineIdazoxanAtenololMetoprololButoxamine \u2014\nA,\n\tadrenaline; \tISO,\tisoprenaline; \tNA,\tnoradrenaline.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2385, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1520b403-943d-4b13-88cf-f0a6ae8f6b8d": {"__data__": {"id_": "1520b403-943d-4b13-88cf-f0a6ae8f6b8d", "embedding": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4183ba17-28e1-4b9b-88b6-9c964ce6a9c9", "node_type": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e79da06ee631220309510383224b49e1eb46933a0ce219e437170db9c9d9cd0d"}, "3": {"node_id": "fcfc858c-f0d5-4059-b4c6-3c5c8e75a493", "node_type": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "90373b305ec2e59c33a4fe68df55f3fa45be735084392158537dee6e25ba045a"}}, "hash": "a421de0ef51a1c0967170b77419b31214cc5279ad9fbd3e242831538b4cee976", "text": "15 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n200which contains a population of adrenaline-releasing (A) \ncells separate from the smaller proportion of noradrenaline-\nreleasing (N) cells. The A cells, which appear only after \nbirth, lie adjacent to the adrenal cortex, and the production of PNMT is induced by an action of the steroid hormones \nsecreted by the adrenal cortex (see Ch. 34). PNMT is also \nfound in certain parts of the brain, where adrenaline may function as a transmitter, but little is known about its role \nin the CNS.\nIn peripheral tissues, the turnover time of noradrenaline \nis generally about 5\u201315 h, but it becomes much shorter if \nsympathetic nerve activity is increased. Under normal \ncircumstances, the rate of synthesis closely matches the \nrate of release, so that the noradrenaline content of tissues \nis constant regardless of how fast it is being released.\nNORADRENALINE \u2003STORAGE\nMost of the noradrenaline in nerve terminals and adrenal medulla is contained in vesicles; only a little is free in the \ncytoplasm under normal circumstances. The concentration \nin the vesicles is very high (0.3\u20131.0 mol/L) and is maintained \nby the vesicular monoamine transporter (VMAT), which shares \nsome features of the amine transporter responsible for noradrenaline uptake into the nerve terminal (see Ch. 13), \nbut uses the transvesicular proton gradient as its driving force. Certain drugs, such as reserpine (see p. 213; Table \n15.3) block this transport and cause nerve terminals to become depleted of their vesicular noradrenaline stores. The vesicles contain two major constituents besides \nnoradrenaline, namely ATP (about four molecules per \nmolecule of noradrenaline) and a protein called chromogranin \nA. These substances are released along with noradrenaline, \nand it is generally assumed that a reversible complex, \ndepending partly on the opposite charges on the molecules \nof noradrenaline and ATP, is formed within the vesicle. This would serve both to reduce the osmolarity of the vesicle \ncontents and to reduce the tendency of noradrenaline to \nleak out of the vesicles within the nerve terminal.\nATP itself has a transmitter function at sympathetic nerve \nsynapses (see Fig. 13.5; Ch. 17), being responsible for the fast-excitatory synaptic potential and the rapid phase of contraction produced by sympathetic nerve activity in many \nsmooth muscle tissues.\nNORADRENALINE \u2003RELEASE\nThe processes linking the arrival of a nerve impulse at a \nnerve terminal, Ca2+ entry, and the release of transmitter \nare described in Chapter 4. Drugs that affect noradrenaline \nrelease are summarised in Table 15.6 (p. 206).\nAn unusual feature of the release mechanism at the \nvaricosities of noradrenergic nerves is that the probability of release, even of a single vesicle, when a nerve impulse \narrives at a varicosity is very low (less than 1 in 50). A single neuron possesses many thousand varicosities, so \none impulse leads to the discharge of a few hundred vesicles, \nscattered over a wide area. This contrasts sharply with the neuromuscular junction (Ch. 14), where the release prob-ability at a single terminal is high, and release of acetyl -\ncholine is sharply localised.\nRegulation of noradrenaline release\nNoradrenaline release is affected by a variety of substances that act on presynaptic receptors (see Ch. 13). Many different \ntypes of nerve terminal (cholinergic, noradrenergic, dopa -\nminergic, 5-HT-ergic, etc.) are subject to this type of control, stored in vesicles", "start_char_idx": 0, "end_char_idx": 3499, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fcfc858c-f0d5-4059-b4c6-3c5c8e75a493": {"__data__": {"id_": "fcfc858c-f0d5-4059-b4c6-3c5c8e75a493", "embedding": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4183ba17-28e1-4b9b-88b6-9c964ce6a9c9", "node_type": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e79da06ee631220309510383224b49e1eb46933a0ce219e437170db9c9d9cd0d"}, "2": {"node_id": "1520b403-943d-4b13-88cf-f0a6ae8f6b8d", "node_type": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a421de0ef51a1c0967170b77419b31214cc5279ad9fbd3e242831538b4cee976"}, "3": {"node_id": "6f06a860-1237-4180-bd0b-f3addfd0e354", "node_type": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a68f3d6cab8d2f03742c7b42acbf50558b7be463c2f929bd3f312a8147761c9"}}, "hash": "90373b305ec2e59c33a4fe68df55f3fa45be735084392158537dee6e25ba045a", "text": "etc.) are subject to this type of control, stored in vesicles and released by exocytosis (Ch. 4). In \nmost peripheral tissues, the tissue content of noradrenaline closely parallels the density of the sympathetic innervation. \nWith the exception of the adrenal medulla, sympathetic \nnerve terminals account for all the noradrenaline content of peripheral tissues. Organs such as the heart, spleen, vas \ndeferens and some blood vessels are particularly rich in \nnoradrenaline (5\u201350 nmol/g of tissue) and have been widely \nused for studies of noradrenergic transmission. For detailed \ninformation on noradrenergic neurons, see Robertson (2004) \nand Cooper et al. (2002).\nNORADRENALINE \u2003SYNTHESIS\nThe biosynthetic pathway for noradrenaline synthesis is shown in Fig. 15.1 and drugs that affect noradrenaline \nsynthesis are summarised in Table 15.6 (p. 206). The \nmetabolic precursor for noradrenaline is L-tyrosine, an \naromatic amino acid that is present in body fluids and \nis taken up by adrenergic neurons . Tyrosine hydroxylase, \na cytosolic enzyme that catalyses the conversion of \ntyrosine to dihydroxyphenylalanine (dopa), is found only \nin catecholamine-containing cells. It is a rather selective \nenzyme; unlike other enzymes involved in catecholamine metabolism, it does not accept indole derivatives as sub -\nstrates, and is not involved in 5-hydroxytryptamine (5-HT) \nsynthesis This first hydroxylation step is the main control \npoint for noradrenaline synthesis. Tyrosine hydroxylase is inhibited by the end product of the biosynthetic pathway, \nnoradrenaline, and this provides the mechanism for the \nmoment-to-moment regulation of the rate of synthesis; much slower regulation, taking hours or days, occurs by \nchanges in the rate of production of the enzyme.\nThe tyrosine analogue \u03b1-methyltyrosine strongly inhibits \ntyrosine hydroxylase and has been used experimentally to block noradrenaline synthesis.\nThe next step, conversion of dopa to dopamine, is \ncatalysed by dopa decarboxylase , a cytosolic enzyme that \nis not confined to catecholamine-synthesising cells. It is \nrelatively non-specific, and catalyses the decarboxylation of various other L-aromatic amino acids, such as L-histidine \nand L-tryptophan, which are precursors in the synthesis of \nhistamine (Ch. 18) and 5-HT (Ch. 16), respectively. Dopa decarboxylase activity is not rate-limiting for noradrenaline synthesis and its activity does not regulate noradrenaline \nsynthesis.\nDopamine-\u03b2-hydroxylase (DBH) is also a relatively \nnon-specific enzyme, but is restricted to catecholamine-synthesising cells. It is located in synaptic vesicles, mainly \nin membrane-bound form. A small amount of the enzyme is released from adrenergic nerve terminals in company \nwith noradrenaline, representing the small proportion in \na soluble form within the vesicle. Unlike noradrenaline, the released DBH is not subject to rapid degradation or \nuptake, so its concentration in plasma and body fluids can \nbe used as an index of overall sympathetic nerve activity.\nMany drugs inhibit DBH, including copper-chelating \nagents and disulfiram (a drug used mainly for its effect \non ethanol metabolism; see Ch. 49). Such drugs can cause a partial depletion of noradrenaline stores and interference \nwith sympathetic transmission. A rare genetic disorder, \nDBH deficiency, causes failure of noradrenaline synthesis", "start_char_idx": 3449, "end_char_idx": 6827, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6f06a860-1237-4180-bd0b-f3addfd0e354": {"__data__": {"id_": "6f06a860-1237-4180-bd0b-f3addfd0e354", "embedding": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4183ba17-28e1-4b9b-88b6-9c964ce6a9c9", "node_type": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e79da06ee631220309510383224b49e1eb46933a0ce219e437170db9c9d9cd0d"}, "2": {"node_id": "fcfc858c-f0d5-4059-b4c6-3c5c8e75a493", "node_type": null, "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "90373b305ec2e59c33a4fe68df55f3fa45be735084392158537dee6e25ba045a"}}, "hash": "7a68f3d6cab8d2f03742c7b42acbf50558b7be463c2f929bd3f312a8147761c9", "text": "\nDBH deficiency, causes failure of noradrenaline synthesis resulting in severe orthostatic hypotension (see Ch. 23).\nPhenylethanolamine N-methyl transferase (PNMT) catalyses \nthe N-methylation of noradrenaline to form adrenaline. \nThe main location of this enzyme is in the adrenal medulla, mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6820, "end_char_idx": 7592, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6f71c9e5-7a76-495e-a16b-8b4aa39ff2d9": {"__data__": {"id_": "6f71c9e5-7a76-495e-a16b-8b4aa39ff2d9", "embedding": null, "metadata": {"page_label": "207", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fc62c00e-813e-4b94-9f59-4784f709b2da", "node_type": null, "metadata": {"page_label": "207", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a2091f73a1f7e8404300090350f23d096d60984f51ec668976d6c669f81f20a7"}, "3": {"node_id": "90945b90-5c50-4ee8-a55a-93c4dd016407", "node_type": null, "metadata": {"page_label": "207", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "75277fdb66d35cdbdfd18c8a9fb39e7186b16bb99734e3baf124e367c6e65a98"}}, "hash": "f6c66645afbaa4aca40ba47432a551aa2cb1b0ee3197e17facdcb10e7f3db695", "text": "15 NORADRENER gIC TRANSMISSION\n201and many different mediators (acetylcholine acting through \nmuscarinic receptors, catecholamines acting through \u03b1 and \n\u03b2 receptors, angiotensin II, prostaglandins, purine nucleo-tides, neuropeptides, etc.) can act on presynaptic terminals. Presynaptic modulation represents an important physio -\nlogical control mechanism throughout the nervous system.\n\u25bc Noradrenaline, by acting on presynaptic \u03b12 receptors, can regulate \nits own release, and also that of co-released ATP (see Ch. 13). This \nis believed to occur physiologically, so that released noradrenaline \nexerts a local inhibitory effect on the terminals from which it came \u2013 the so-called autoinhibitory feedback mechanism (Fig. 15.2; see Gilsbach \n& Hein, 2012 ). Agonists or antagonists affecting presynaptic receptors \ncan have large effects on sympathetic transmission. However, the physiological significance of presynaptic autoinhibition in the sym -\npathetic nervous system is still somewhat contentious, and there is evidence that, in most tissues, it is less influential than biochemical \nmeasurements of transmitter overflow would seem to imply. Thus, \nalthough blocking autoreceptors causes large changes in noradrenaline overflow \u2013 the amount of noradrenaline released into the bathing \nsolution or the bloodstream when sympathetic nerves are stimulated \n\u2013 the associated changes in the tissue response are often rather small. This suggests that what is measured in overflow experiments may \nnot be the physiologically important component of transmitter release.\nThe inhibitory feedback mechanism operates through \u03b12 \nreceptors, which inhibit adenylyl cyclase and prevent the \nopening of calcium channels (see Fig. 15.2). Sympathetic \nnerve terminals also possess \u03b22 receptors, coupled to activa -\ntion of adenylyl cyclase, which increase noradrenaline release. \nWhether they have any physiological function is not clear.\nUPTAKE AND DEGRADATION OF \nCATECHOLAMINES\nThe action of released noradrenaline is terminated mainly by \nreuptake of the transmitter into noradrenergic nerve termi -\nnals. Some is also sequestered by other cells in the vicinity. Circulating adrenaline and noradrenaline are degraded Table 15.3 Characteristics of noradrenaline (norepinephrine) transport systems\nNeuronal (NET) Extraneuronal (EMT) Vesicular (VMAT)\nTransport of NA (rat heart)\nVmax (nmol g\u22121 min\u22121)1.2 100 \u2014\nKm (\u00b5mol/L) 0.3 250 ~0.2\nSpecificity NA > A > ISO A > NA > ISO NA = A = ISO\nLocation Neuronal membrane Non-neuronal cell membrane (smooth muscle, cardiac muscle, endothelium)Synaptic vesicle membrane\nOther substrates TyramineMethylnoradrenalineAdrenergic neuron-blocking drugs (e.g. guanethidine)Amphetamine\na(+)-NoradrenalineDopamine5-HydroxytryptamineHistamineDopamine5-HydroxytryptamineGuanethidineMPP\n+ (see Ch. 41)\nInhibitors Cocaine\nTricyclic antidepressants \n(e.g. desipramine)\nPhenoxybenzamine\nAmphetamineaNormetanephrineSteroid hormones (e.g. corticosterone)PhenoxybenzamineReserpineTetrabenazine\naAmphetamine \tis \ttransported \tslowly, \tso \tacts \tboth \tas \ta \tsubstrate \tand \tas \tan \tinhibitor \tof \tnoradrenaline \tuptake. \tFor \tdetails, \tsee \tGainetdinov \t\n&\tCaron,\t2003.\nA,\tadrenaline;", "start_char_idx": 0, "end_char_idx": 3197, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "90945b90-5c50-4ee8-a55a-93c4dd016407": {"__data__": {"id_": "90945b90-5c50-4ee8-a55a-93c4dd016407", "embedding": null, "metadata": {"page_label": "207", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fc62c00e-813e-4b94-9f59-4784f709b2da", "node_type": null, "metadata": {"page_label": "207", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a2091f73a1f7e8404300090350f23d096d60984f51ec668976d6c669f81f20a7"}, "2": {"node_id": "6f71c9e5-7a76-495e-a16b-8b4aa39ff2d9", "node_type": null, "metadata": {"page_label": "207", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f6c66645afbaa4aca40ba47432a551aa2cb1b0ee3197e17facdcb10e7f3db695"}}, "hash": "75277fdb66d35cdbdfd18c8a9fb39e7186b16bb99734e3baf124e367c6e65a98", "text": "\t\n&\tCaron,\t2003.\nA,\tadrenaline; \tEMT,\textraneuronal \tmonoamine \ttransporter; \tISO,\tisoprenaline; \tMPP+,\ttoxic\tmetabolite \tof \tMPTP \t(see \tp. \t213 \tand \tCh \t41); \t \nNA,\tnoradrenaline; \tNET,\tnorepinephrine \ttransporter; \tVMAT,\tvesicular\tmonoamine \ttransporter.\nNA\nATP\nATPAdenylyl\ncyclase\n\u03b12 Adrenoceptor\nGi/Go\nproteinsPotassium\nchannelsExocytosis\nNAATP\nK+K+cAMPCa2+\nCalcium channels\nCa2+\nPOSTSYNAPTIC RECEPTORS\nFig. 15.2 Feedback control of noradrenaline (NA) release. \nThe\tpresynaptic \t\u03b12\treceptor\tinhibits \tCa2+\tinflux\tin\tresponse \tto \t\nmembrane \tdepolarisation \tvia \tan \taction \tof \tthe \t\u03b2\u03b3\tsubunits\tof \tthe \t\nassociated \tG \tprotein \ton \tthe \tvoltage-dependent \tCa2+\tchannels\t\n(Ch.\t3).\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3166, "end_char_idx": 4334, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3a04d944-b78c-4ea6-b94f-508856887a4a": {"__data__": {"id_": "3a04d944-b78c-4ea6-b94f-508856887a4a", "embedding": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3e416ff4-f607-41fd-b9ed-83dba994ea8a", "node_type": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd414f6733dc60db0bfad5427efecfe294f2d0d2a8e6ae702378fc050713c133"}, "3": {"node_id": "bfb3ecde-f6e6-40f2-a65e-c51b11ff24b8", "node_type": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3a3c6ba3199ade39e7ce7288270740915410b8b6fd108cd56844c900ad7c665"}}, "hash": "6aafe8662a4335711d1601a9aaa6e2f75f4992519735d2a7a21088f727bb1840", "text": "15 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n202noradrenaline increases if the enzyme is inhibited. MAO \nand its inhibitors are discussed in more detail in Chapter 48.\nThe second major pathway for catecholamine metabolism \ninvolves methylation of one of the catechol hydroxyl groups \nby COMT to give a methoxy derivative. COMT is absent from noradrenergic neurons but present in the adrenal \nmedulla and many other tissues. The final product formed \nby the sequential action of MAO and COMT is 3-methoxy-\n4-hydroxyphenylglycol (MHPG; see Fig. 15.3). This is partly \nconjugated to sulfate- or glucuronide- derivatives, which are excreted in the urine and reflect noradrenaline release in brain, but most of it is converted to vanillylmandelic acid \n(VMA; see Fig. 15.3) and excreted in the urine in this form. \nIn patients with tumours of chromaffin tissue that secrete \nthese amines (a rare cause of high blood pressure), the urinary excretion of VMA is markedly increased, this being \nused as a diagnostic test for such tumours.\nIn the periphery, neither MAO nor COMT is primarily \nresponsible for the termination of transmitter action, most of the released noradrenaline being quickly recaptured \nby NET. Circulating catecholamines are sequestered and inactivated by a combination of NET, EMT and COMT, the \nrelative importance of these processes varying according \nto the agent concerned. Thus circulating noradrenaline is removed mainly by NET, whereas adrenaline is more \ndependent on EMT. Isoprenaline, however, is not a sub -\nstrate for NET, and is removed by a combination of EMT \nand COMT.\nIn the CNS (see Ch. 40), MAO is more important as a \nmeans of terminating transmitter action than it is in the \nperiphery, and MAO knockout mice show a greater enhance -\nment of noradrenergic transmission in the brain than do \nNET knockouts, in which neuronal stores of noradrenaline \nare much depleted (see Gainetdinov & Caron, 2003). The \nmain excretory product of noradrenaline released in the \nbrain is MHPG.\nDRUGS ACTING ON NORADRENERGIC \nTRANSMISSION\nMany clinically important drugs, particularly those used to \ntreat cardiovascular, respiratory and psychiatric disorders \n(see Chs 22, 23, 29, 48 and 49), act by affecting noradrenergic \nneuron function, acting on adrenoceptors, transporters or catecholamine-metabolising enzymes. The properties of the \nmost important drugs in this category are summarised in \nTables 15.4\u201315.6.\nDRUGS ACTING ON ADRENOCEPTORS\nThe overall activity of these drugs is governed by their affinity, efficacy and selectivity with respect to different \ntypes of adrenoceptor, and intensive research has been \ndevoted to developing drugs with the right properties for specific clinical indications. As a result, the pharmacopoeia \nis awash with adrenoceptor ligands. Many clinical needs \nare met, it turns out, by drugs that relax smooth muscle in different organs of the body\n4 and those that block the cardiac enzymically, but much more slowly than acetylcholine (see Ch. 14), where synaptically located acetylcholinesterase inactivates the transmitter in milliseconds. The two main \ncatecholamine-metabolising enzymes are located intracel -\nlularly, so uptake into cells necessarily precedes metabolic \ndegradation.\nUPTAKE \u2003OF \u2003CATECHOLAMINES\nAbout 75% of the noradrenaline released by sympathetic neurons is recaptured and repackaged into vesicles. This \nserves to cut short the action of the released noradrenaline, as \nwell as", "start_char_idx": 0, "end_char_idx": 3453, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bfb3ecde-f6e6-40f2-a65e-c51b11ff24b8": {"__data__": {"id_": "bfb3ecde-f6e6-40f2-a65e-c51b11ff24b8", "embedding": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3e416ff4-f607-41fd-b9ed-83dba994ea8a", "node_type": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd414f6733dc60db0bfad5427efecfe294f2d0d2a8e6ae702378fc050713c133"}, "2": {"node_id": "3a04d944-b78c-4ea6-b94f-508856887a4a", "node_type": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6aafe8662a4335711d1601a9aaa6e2f75f4992519735d2a7a21088f727bb1840"}, "3": {"node_id": "2724ce16-9214-4d87-bc19-49e080540b79", "node_type": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bd4f45c09c858f430539d0a8fb20d43f2ca5b689bd2a32fe78ce48ae72d0079f"}}, "hash": "c3a3c6ba3199ade39e7ce7288270740915410b8b6fd108cd56844c900ad7c665", "text": "\nserves to cut short the action of the released noradrenaline, as \nwell as recycling it. The remaining 25% is captured by non-neuronal cells in the vicinity, limiting its local spread. These \ntwo uptake mechanisms depend on distinct transporter \nmolecules. Neuronal uptake is performed by the plasma membrane noradrenaline transporter (generally known \nas NET, the norepinephrine transporter), which belongs to \nthe family of neurotransmitter transporter proteins (NET, \nDAT, SERT, etc.) specific for different amine transmitters, described in Chapter 13; these act as co-transporters of Na\n+, \nCl\u2212 and the amine in question, using the electrochemical \ngradient for Na+ as a driving force. Packaging into vesicles \noccurs through the VMAT, driven by the proton gradient \nbetween the cytosol and the vesicle contents. Extraneuronal \nuptake is performed by the extraneuronal monoamine trans -\nporter (EMT), which belongs to a large and widely distributed \nfamily of organic cation transporters (OCTs, see Ch. 9). NET is relatively selective for noradrenaline, with high affinity and a low maximum rate of uptake, and it is important \nin maintaining releasable stores of noradrenaline. NET \nis blocked by tricyclic antidepressant drugs and cocaine. \nEMT has lower affinity and higher transport capacity than NET, and transports adrenaline and isoprenaline as well \nas noradrenaline. The effects of several important drugs \nthat act on noradrenergic neurons depend on their ability either to inhibit NET or to enter the nerve terminal with \nits help. Table 15.3 summarises the properties of neuronal \nand extraneuronal uptake.\nMETABOLIC \u2003DEGRADATION \u2003OF \u2003CATECHOLAMINES\nEndogenous and exogenous catecholamines are metabolised mainly by two intracellular enzymes: monoamine oxidase \n(MAO) and catechol- O-methyl transferase (COMT). MAO (of \nwhich there are two distinct isoforms, MAO-A and MAO-B; see Chs 40 and 48) is bound to the surface membrane \nof mitochondria. It is abundant in noradrenergic nerve \nterminals but is also present in liver, intestinal epithelium and other tissues. MAO converts catecholamines to their \ncorresponding aldehydes,\n3 which, in the periphery, are \nrapidly metabolised by aldehyde dehydrogenase to the cor -\nresponding carboxylic acid (3,4-dihydroxyphenylglycol \nbeing formed from noradrenaline; Fig. 15.3). MAO can also oxidise other monoamines, including dopamine and 5-HT. \nIt is inhibited by various drugs which are used mainly for \ntheir antidepressant effects in the CNS (see Ch. 48), where these three amines all have transmitter functions (see Ch. 40). \nThese drugs have important harmful effects that are related \nto disturbances of peripheral noradrenergic transmission. Within sympathetic neurons, MAO controls the content of dopamine and noradrenaline, and the releasable store of \n3Aldehyde metabolites are potentially neurotoxic, and are thought to \nplay a role in certain degenerative CNS disorders (see Ch. 41).4And conversely, contracting smooth muscle is often bad news. This \nbald statement must not be pressed too far, but the exceptions (such as \nnasal decongestants and drugs acting on the eye) are surprisingly few. \nEven adrenaline (potentially life-saving in cardiac arrest) dilates some vessels while constricting others to less immediately essential tissues \nsuch as skin).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3392, "end_char_idx": 6897, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2724ce16-9214-4d87-bc19-49e080540b79": {"__data__": {"id_": "2724ce16-9214-4d87-bc19-49e080540b79", "embedding": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3e416ff4-f607-41fd-b9ed-83dba994ea8a", "node_type": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd414f6733dc60db0bfad5427efecfe294f2d0d2a8e6ae702378fc050713c133"}, "2": {"node_id": "bfb3ecde-f6e6-40f2-a65e-c51b11ff24b8", "node_type": null, "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3a3c6ba3199ade39e7ce7288270740915410b8b6fd108cd56844c900ad7c665"}}, "hash": "bd4f45c09c858f430539d0a8fb20d43f2ca5b689bd2a32fe78ce48ae72d0079f", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6912, "end_char_idx": 7263, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "28223e36-c6c9-48d3-bd07-488b0c6d76c9": {"__data__": {"id_": "28223e36-c6c9-48d3-bd07-488b0c6d76c9", "embedding": null, "metadata": {"page_label": "209", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "25195db6-534b-49b6-bdef-24880a902456", "node_type": null, "metadata": {"page_label": "209", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2cd60fb54bb04066d717ce2e8f83e7c8ba8238dc38de6971816c2f399bbb654"}, "3": {"node_id": "e5a7c814-8f21-411d-a56c-6cd30c5d98c5", "node_type": null, "metadata": {"page_label": "209", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43b7a045d47b5d3c482e6c4b98f6fe865e7acb2cacb97f5347e483b3a4c2fa94"}}, "hash": "f452ee3350ab3e24b67ea5fd48127905e4ecd7b6a68d4b9d69db689c2d580a38", "text": "15 NORADRENERgIC TRANSMISSION\n203URINE\nURINEMajor metabolite\nMinor metaboliteMHPG\nsulfateCOMT COMT\nCOMTCOMT\nMAO\nMAOADH\nADH\nARARNH2\nNH2OH OHOH\nOH\nOHOH\nOH OHHO HOHO\nHO\nHOHOHO\nHO\nHO HO\nHO HOCH3OC H3OCH3O\nCH3O CH2OH\nCH2OHCHO\nCHOCOOH\nCOOH\nDHPGMHPGDHMAVMA\nNA\naldehydeNM\naldehyde\nNANM\nFig. 15.3 The main pathways of noradrenaline metabolism. \tThe\toxidative\tbranch\t(catalysed\t by\taldehyde\t dehydrogenase\t [ADH])\t\npredominates,\t giving\tvanillylmandelic\t acid\t(VMA)\tas\tthe\tmain\turinary\tmetabolite.\t The\treductive\t branch\t(catalysed\t by\taldehyde\t reductase\t\n[AR])\tproduces\t the\tless\tabundant\t metabolite,\t 3-methoxy-4-hydroxyphenylglycol\t (MHPG),\twhich\tis\tconjugated\t to\tMHPG\tsulfate\tbefore\tbeing\t\nexcreted;\t MHPG\tsulfate\texcretion\t reflects\tnoradrenaline\t (NA)\trelease\tin\tbrain.\t COMT,\tcatechol- O-methyl\ttransferase;\t DHMA, \n3,4-dihydroxymandelic\t acid;\t DHPG,\t3,4-dihydroxyphenylglycol;\t MAO,\tmonoamine\t oxidase;\t NM,\tnormetanephrine.\t\nNoradrenergic transmission \n\u2022\tTransmitter\t synthesis\t involves\tthe\tfollowing:\n\u2013\tL-tyrosine\t is\tconverted\t to\tdihydroxyphenylalanine\t (dopa)\t\nby\ttyrosine\thydroxylase\t (rate-limiting\t step).\tTyrosine\t\nhydroxylase\t occurs\tonly\tin\tcatecholaminergic\t neurons.\n\u2013\tDopa\tis\tconverted\t to\tdopamine\t by\tdopa\t\ndecarboxylase.\n\u2013\tDopamine\t is\tconverted\t to\tnoradrenaline\t by\tdopamine-\n\u03b2-hydroxylase\t (DBH),\tlocated\tin\tsynaptic\tvesicles.\n\u2013\tIn\tthe\tadrenal\tmedulla,\tnoradrenaline\t is\tconverted\t to\t\nadrenaline\t by\tphenylethanolamine\t N-methyltransferase.\n\u2022\tTransmitter\t storage:\tnoradrenaline\t is\tstored\tat\thigh\t\nconcentration\t in\tsynaptic\tvesicles,\ttogether\twith\tATP,\t\nchromogranin\t and\tDBH,\twhich\tare\tco-released\t by\t\nexocytosis.\t Transport\t of\tnoradrenaline\t into\tvesicles\t\noccurs\tby\ta\treserpine-sensitive\t transporter,\t vesicular\t\nmonoamine\t transporter\t (VMAT).\tNoradrenaline\t content\tof\t\ncytosol\tis\tnormally\tlow\tdue\tto\tmonoamine\t oxidase\tin\t\nnerve\tterminals.\u2022\tTransmitter\t release\toccurs\tnormally\tby\tCa2+-mediated\t\nexocytosis\t from\tvaricosities\t on\tthe\tterminal\tnetwork.\t\nNon-exocytotic\t release\toccurs\tin\tresponse\t to\tindirectly\t\nacting\tsympathomimetic\t drugs\t(e.g.\t tyramine\tand\t\namphetamine ),\twhich\tdisplace\tnoradrenaline\t from\t\nvesicles.\tNoradrenaline\t escapes\tvia\tthe\tnorepinephrine\t\ntransporter\t (NET;\treverse\ttransport).\n\u2022\tTransmitter\t action\tis\tterminated\t mainly\tby\treuptake\tof\t\nnoradrenaline\t", "start_char_idx": 0, "end_char_idx": 2321, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e5a7c814-8f21-411d-a56c-6cd30c5d98c5": {"__data__": {"id_": "e5a7c814-8f21-411d-a56c-6cd30c5d98c5", "embedding": null, "metadata": {"page_label": "209", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "25195db6-534b-49b6-bdef-24880a902456", "node_type": null, "metadata": {"page_label": "209", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2cd60fb54bb04066d717ce2e8f83e7c8ba8238dc38de6971816c2f399bbb654"}, "2": {"node_id": "28223e36-c6c9-48d3-bd07-488b0c6d76c9", "node_type": null, "metadata": {"page_label": "209", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f452ee3350ab3e24b67ea5fd48127905e4ecd7b6a68d4b9d69db689c2d580a38"}}, "hash": "43b7a045d47b5d3c482e6c4b98f6fe865e7acb2cacb97f5347e483b3a4c2fa94", "text": "mainly\tby\treuptake\tof\t\nnoradrenaline\t into\tnerve\tterminals\t via\tthe\tNET\t\ntransporter.\t NET\tis\tblocked\tby\ttricyclic\tantidepressant\t\ndrugs\tand\tcocaine.\n\u2022\tNoradrenaline\t release\tis\tcontrolled\t by\tautoinhibitory\t\nfeedback\t mediated\t by\t\u03b12\treceptors.\n\u2022\tCo-transmission\t occurs\tat\tmany\tnoradrenergic\t nerve\t\nterminals,\t ATP\tand\tneuropeptide\t Y\tbeing\tfrequently\t\nco-released\t with\tNA.\tATP\tmediates\t the\tearly\tphase\tof\t\nsmooth\tmuscle\tcontraction\t in\tresponse\t to\tsympathetic\t\nnerve\tactivity.\nstimulant effects of the sympathetic nervous system; on the \nother hand, cardiac stimulation is generally undesirable in \nchronic disease.\nBroadly speaking, \u03b22-adrenoceptor agonists are useful as \nsmooth muscle relaxants (especially in the airways), while \u03b21-adrenoceptor antagonists (often called \u03b2 blockers) are used \nmainly for their cardiodepressant effects. \u03b11-Adrenoceptor \nantagonists are used mainly for their vasodilator effects in \ncardiovascular indications and also for the treatment of \nprostatic hyperplasia. Adrenaline, with its mixture of cardiac mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2284, "end_char_idx": 3810, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2bb9159d-1969-4015-b01b-e33ab5b091e2": {"__data__": {"id_": "2bb9159d-1969-4015-b01b-e33ab5b091e2", "embedding": null, "metadata": {"page_label": "210", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "960cfba2-9407-4a16-97e1-019ca4251dd9", "node_type": null, "metadata": {"page_label": "210", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2b15b503955e1465181ce0230d68b202f0c4ecaeaf0cc71e180ed4e27bead621"}, "3": {"node_id": "f36e78b0-f7df-4288-8481-684150c8dbd7", "node_type": null, "metadata": {"page_label": "210", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0035f9fe54e2c902c071bc299f7456c6d025b29862a40c2f72feb6bccbf4c830"}}, "hash": "de93a2bf2ee236fe76c3a19e453eb51f02f81a8666705402337fecbd36775c6e", "text": "15 SECTION 2 \u2003\u2003CHEMICAL MEDIATORS\n204Table 15.4 Adrenoceptor agonists\nDrug Main action Uses/function Unwanted effectsPharmacokinetic \naspects Notes\nNoradrenaline \n(Norepinephrine)\u03b1/\u03b2 agonist Sometimes used for \nhypotension in intensive \ncare\nTransmitter at \npostganglionic \nsympathetic neurons, \nand in CNSHypertension, \nvasoconstriction, \ntachycardia (or reflex \nbradycardia), \nventricular \ndysrhythmiasPoorly absorbed by \nmouth\nRapid removal by \ntissues\nMetabolised by \nMAO and COMT\nPlasma t1/2 ~2 min\u2014\nAdrenaline \n(Epinephrine)\u03b1/\u03b2 agonist Anaphylactic shock, \ncardiac arrest\nAdded to local \nanaesthetic solutions\nMain hormone of adrenal \nmedullaAs norepinephrine As norepinephrine\nGiven i.m. or s.c. \n(i.v. infusion in \nintensive care \nsettings)\nIsoprenaline \u03b2 agonist \n(non-selective)Asthma (obsolete) Tachycardia, \ndysrhythmiasSome tissue \nuptake, followed by \ninactivation (COMT)\nPlasma t1/2 ~2 hNow replaced by \nsalbutamol in \ntreatment of asthma \n(see Ch. 29)\nDobutamine \u03b21 agonist (also \nhas weak \u03b22 and \n\u03b11 activity)Cardiogenic shock Dysrhythmias Plasma t1/2 ~2 min\nGiven i.v.See Ch. 22\nSalbutamol \u03b22 agonist Asthma, premature \nlabourTachycardia, \ndysrhythmias, \ntremor, peripheral \nvasodilatationGiven orally or by \naerosol\nMainly excreted \nunchanged\nPlasma t1/2 ~4 hSee Ch. 29\nSalmeterol \u03b22 agonist Asthma As salbutamol Given by aerosol\nLong actingFormoterol is similar\nTerbutaline \u03b22 agonist Asthma\nDelay of parturitionAs salbutamol Poorly absorbed \norally\nGiven by aerosol\nMainly excreted \nunchanged\nPlasma t1/2 ~4 hSee Ch. 29\nClenbuterol \u03b22 agonist \u2018Anabolic\u2019 action to \nincrease muscle strengthAs salbutamol Active orally\nLong actingIllicit use in sport, \nsee Ch. 59\nMirabegron \u03b23 agonist Symptoms of overactive \nbladderTachycardia Active orally, given \nonce dailySee Ch. 30\nPhenylephrine \u03b11 agonist Nasal decongestion Hypertension, reflex \nbradycardiaGiven intranasally\nMetabolised by \nMAO\nShort plasma t1/2\u2014\nMethoxamine \u03b1 agonist \n(non-selective)Nasal decongestion As phenylephrine Given intranasally\nPlasma t1/2 ~1 h\u2014\nClonidine, \nlofexidine\u03b12 partial agonist Hypertension, migraine \nprophylaxis, vasomotor \ninstability (\u2018hot flushes\u2019); \nlofexidine is used to \nreduce symptoms during \nopioid withdrawalDrowsiness, \nhypotension, \noedema and weight \ngain, rebound \nhypertensionWell absorbed \norally\nExcreted \nunchanged and as \nconjugate\nPlasma t1/2 ~12 h\u2014\nCNS,\tcentral\tnervous\tsystem;\t COMT,\tcatechol- O-methyl\ttransferase;\t MAO,\tmonoamine\t oxidase.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2849, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f36e78b0-f7df-4288-8481-684150c8dbd7": {"__data__": {"id_": "f36e78b0-f7df-4288-8481-684150c8dbd7", "embedding": null, "metadata": {"page_label": "210", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "960cfba2-9407-4a16-97e1-019ca4251dd9", "node_type": null, "metadata": {"page_label": "210", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2b15b503955e1465181ce0230d68b202f0c4ecaeaf0cc71e180ed4e27bead621"}, "2": {"node_id": "2bb9159d-1969-4015-b01b-e33ab5b091e2", "node_type": null, "metadata": {"page_label": "210", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "de93a2bf2ee236fe76c3a19e453eb51f02f81a8666705402337fecbd36775c6e"}}, "hash": "0035f9fe54e2c902c071bc299f7456c6d025b29862a40c2f72feb6bccbf4c830", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2802, "end_char_idx": 2945, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0e54cae2-d7c3-47e5-8270-f6842180c699": {"__data__": {"id_": "0e54cae2-d7c3-47e5-8270-f6842180c699", "embedding": null, "metadata": {"page_label": "211", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "548c15b1-cd2c-4ad7-a4ce-aaee167fc75c", "node_type": null, "metadata": {"page_label": "211", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5ca2872705de43b7d2c13c4e54412af821efb025a545c9dbc91329b373e1415a"}, "3": {"node_id": "8dc956bc-7c23-44ab-a1fb-9afe5d6ea402", "node_type": null, "metadata": {"page_label": "211", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e57679f6458c9fac43dd1acf35637b0a5162a2dbd7f27a96e73ae1f136e6f77"}}, "hash": "4bd84ee4ecd7ca5913b7cb66b2427ca6f1d91f99ffab4ed47f1f36926a1c5547", "text": "15 NORADRENERgIC TRANSMISSION\n205Table 15.5 Adrenoceptor antagonists\nDrug Main action Uses/function Unwanted effectsPharmacokinetic \naspects Notes\n\u03b1-Adrenoceptor antagonists\nPhenoxybenzamine \u03b1 antagonist \n(non-selective, \nirreversible)\nUptake 1 \ninhibitorPhaeochromocytoma Postural \nhypotension, \ntachycardia, nasal \ncongestion, \nimpotenceAbsorbed orally\nPlasma t1/2 ~12 hAction outlasts \npresence of drug in \nplasma, because of \ncovalent binding to \nreceptor\nPhentolamine \u03b1 antagonist \n(non-selective), \nvasodilatorRarely used As \nphenoxybenzamineUsually given i.v.\nMetabolised by liver\nPlasma t1/2 ~2 h\nPrazosin \u03b11 antagonist Hypertension As \nphenoxybenzamineAbsorbed orally\nMetabolised by liver\nPlasma t1/2 ~4 hDoxazosin, terazosin \nare similar but longer \nacting See Ch. 23\nTamsulosin \u03b11A antagonist \n(\u2018uroselective\u2019)Prostatic hyperplasia Failure of ejaculation Absorbed orally\nPlasma t1/2 ~5 hSelective for \n\u03b11A-adrenoceptor\nYohimbine \u03b12 antagonist Not used clinically\nClaimed to be \naphrodisiacExcitement, \nhypertensionAbsorbed orally\nMetabolised by liver\nPlasma t1/2 ~4 h\n\u03b2-Adrenoceptor antagonists\nPropranolol \u03b2 antagonist \n(non-selective)Angina, hypertension, \ncardiac dysrhythmias, \nanxiety, tremor, \nglaucomaBronchoconstriction, \ncardiac failure, cold \nextremities, fatigue \nand depression, \nhypoglycaemiaAbsorbed orally\nExtensive first-pass \nmetabolism\nAbout 90% bound \nto plasma protein\nPlasma t1/2 ~4 hTimolol is similar and \nused mainly to treat \nglaucoma\nSee Ch. 22\nAlprenolol \u03b2 antagonist \n(non-selective)\n(partial agonist)As propranolol As propranolol Absorbed orally\nMetabolised by liver\nPlasma t1/2 ~4 hOxprenolol and \npindolol are similar\nSee Ch. 22\nMetoprolol \u03b21 antagonist Angina, hypertension, \ndysrhythmiasAs propranolol, less \nrisk of \nbronchoconstrictionAbsorbed orally\nMainly metabolised \nin liver\nPlasma t1/2 ~3 hAtenolol is similar, \nwith a longer half-life\nSee Ch. 22\nNebivolol \u03b21 antagonist\nEnhances nitric \noxide synthesisHypertension Fatigue, headache Absorbed orally\nt1/2 ~10 h\u2014\nButoxamine \u03b22-selective \nantagonist\nWeak \u03b1 agonistNo clinical uses \u2014 \u2014 \u2014\nMixed ( \u03b1-/\u03b2-) antagonists\nLabetalol \u03b1/\u03b2 antagonist Hypertension in \npregnancyPostural \nhypotension, \nbronchoconstrictionAbsorbed orally\nConjugated in liver\nPlasma t1/2 ~4 hSee Chs 22 and 23\nCarvedilol \u03b2/\u03b11 antagonist Heart failure As for other \u03b2 \nblockers\nInitial exacerbation \nof heart failure\nRenal failureAbsorbed orally t1/2 \n~10 hAdditional actions \nmay contribute to \nclinical benefit. See \nCh. 22mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2843, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8dc956bc-7c23-44ab-a1fb-9afe5d6ea402": {"__data__": {"id_": "8dc956bc-7c23-44ab-a1fb-9afe5d6ea402", "embedding": null, "metadata": {"page_label": "211", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "548c15b1-cd2c-4ad7-a4ce-aaee167fc75c", "node_type": null, "metadata": {"page_label": "211", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5ca2872705de43b7d2c13c4e54412af821efb025a545c9dbc91329b373e1415a"}, "2": {"node_id": "0e54cae2-d7c3-47e5-8270-f6842180c699", "node_type": null, "metadata": {"page_label": "211", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4bd84ee4ecd7ca5913b7cb66b2427ca6f1d91f99ffab4ed47f1f36926a1c5547"}}, "hash": "5e57679f6458c9fac43dd1acf35637b0a5162a2dbd7f27a96e73ae1f136e6f77", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2796, "end_char_idx": 2971, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6305dfcd-1cb1-4ac4-be14-c59f36b7040c": {"__data__": {"id_": "6305dfcd-1cb1-4ac4-be14-c59f36b7040c", "embedding": null, "metadata": {"page_label": "212", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ca895a7a-4dcf-42e9-a381-3f0ee01cee17", "node_type": null, "metadata": {"page_label": "212", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7dbc341cf106642072a5651016befcffa7ade3d62bf26e825bd4029e8b86168e"}, "3": {"node_id": "1983d50f-56ab-4a9e-bea5-e078e0e22762", "node_type": null, "metadata": {"page_label": "212", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b15020545508ec3a7f2883cbf607cb6b6ddf4f92362c222903773d3d339e8fac"}}, "hash": "3e248cdf8f4a4708adc1b77bec909f286b9ed88d724938f11f50f084299a6ce7", "text": "15 SECTION 2 \u2003\u2003CHEMICAL MEDIATORS\n206Table 15.6 Drugs that affect noradrenaline synthesis, release or uptake\nDrug Main action Uses/functionUnwanted \neffectsPharmacokinetic \naspects Notes\nDrugs affecting NA synthesis\n\u03b1-Methyl-p-tyrosine Inhibits tyrosine \nhydroxylaseOccasionally used in \nphaeochromocytomaHypotension, \nsedation\u2014 \u2014\nCarbidopa Inhibits dopa \ndecarboxylaseUsed as adjunct to \nlevodopa to prevent \nperipheral effects\u2014 Absorbed orally\nDoes not enter brainSee Ch. 41\nMethyldopa False transmitter \nprecursorHypertension in \npregnancyHypotension, \ndrowsiness, \ndiarrhoea, \nimpotence, \nhypersensitivity \nreactionsAbsorbed slowly by \nmouth\nExcreted unchanged \nor as conjugate\nPlasma t1/2 ~6 hSee Ch. 23\nDroxidopa \n(L-dihydroxyphenylserine, \nL-DOPS)Converted to NA by \ndopa decarboxylase, \nthus increasing NA \nsynthesis and \nreleaseNeurogenic \northostatic \nhypotensionNot known Absorbed orally\nDuration of action \n~6 hFDA approved\nDrugs that release NA (indirectly acting sympathomimetic amines)\nTyramine NA release No clinical uses\nPresent in various \nfoodsAs \nnorepinephrineNormally destroyed \nby MAO in gut\nDoes not enter brainSee Ch. 48 for \ninteraction with \nMAO inhibitors\nAmphetamine NA release,\nMAO inhibitor, NET \ninhibitor, CNS \nstimulantUsed as CNS \nstimulant in \nnarcolepsy, also \n(paradoxically) in \nhyperactive children\nAppetite \nsuppressant\nDrug of abuseHypertension, \ntachycardia, \ninsomnia\nAcute psychosis \nwith overdose\nDependenceWell absorbed orally\nPenetrates freely \ninto brain\nExcreted unchanged \nin urine\nPlasma t1/2 ~12 h, \ndepending on urine \nflow and pHSee Ch. 49\nMethylphenidate \nand atomoxetine \nare similar (used \nfor CNS effects; \nsee Ch. 49)\nEphedrine NA release, \u03b2 \nagonist, weak CNS \nstimulant actionNasal decongestion As amphetamine \nbut less \npronouncedSimilar to \namphetamine \naspectsInteracts with \nMAO inhibitors, \nCh. 48\nDrugs that inhibit NA release\nReserpine Depletes NA stores \nby inhibiting VMATHypertension \n(obsolete)As methyldopa\nAlso depression, \nparkinsonism, \ngynaecomastiaPoorly absorbed \norally\nSlowly metabolised\nPlasma t1/2 ~100 h\nExcreted in milkAntihypertensive \neffect develops \nslowly and \npersists when \ndrug is stopped\nGuanethidine Inhibits NA release\nAlso causes NA \ndepletion and can \ndamage NA neurons \nirreversiblyHypertension \n(obsolete)As methyldopa\nHypertension on \nfirst \nadministrationPoorly absorbed \norally\nMainly excreted \nunchanged in urine\nPlasma t1/2 ~100 hAction \nprevented by \nNET inhibitors\nDrugs affecting NA uptake\nImipramine Blocks neuronal \ntransporter (NET)\nAlso has atropine-\nlike\nactionDepression Atropine-like \nside effects\nCardiac \ndysrhythmias in \noverdoseWell absorbed orally\n95% bound to \nplasma protein\nConverted to active \nmetabolite \n(desmethylimipramine)\nPlasma t1/2 ~4 hDesipramine \nand amitriptyline \nare similar\nSee Ch. 48\nCocaine Local anaesthetic; \nblocks NET\nCNS stimulantRarely used local \nanaesthetic\nMajor drug of abuseHypertension, \nexcitement, \nconvulsions, \ndependenceWell absorbed orally \nor intranasallySee Chs", "start_char_idx": 0, "end_char_idx": 3023, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1983d50f-56ab-4a9e-bea5-e078e0e22762": {"__data__": {"id_": "1983d50f-56ab-4a9e-bea5-e078e0e22762", "embedding": null, "metadata": {"page_label": "212", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ca895a7a-4dcf-42e9-a381-3f0ee01cee17", "node_type": null, "metadata": {"page_label": "212", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7dbc341cf106642072a5651016befcffa7ade3d62bf26e825bd4029e8b86168e"}, "2": {"node_id": "6305dfcd-1cb1-4ac4-be14-c59f36b7040c", "node_type": null, "metadata": {"page_label": "212", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e248cdf8f4a4708adc1b77bec909f286b9ed88d724938f11f50f084299a6ce7"}}, "hash": "b15020545508ec3a7f2883cbf607cb6b6ddf4f92362c222903773d3d339e8fac", "text": "\ndependenceWell absorbed orally \nor intranasallySee Chs 44 and \n50\nCNS,\tcentral\tnervous\tsystem;\t MAO,\tmonoamine\t oxidase;\t NA,\tnoradrenaline;\t NET,\tnorepinephrine\t transporter;\t VMAT,\tvesicular\tmonoamine\t\ntransporter.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2968, "end_char_idx": 3664, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "250c6006-8434-49ee-bba6-2212a554ea09": {"__data__": {"id_": "250c6006-8434-49ee-bba6-2212a554ea09", "embedding": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6e37c40c-4d85-4332-9a0b-e684fa078caf", "node_type": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "550efbb24eb2709f8766e67bd806a32e051efcbcdb396490fe1bd042f8f4dc34"}, "3": {"node_id": "d9799c5c-251d-42af-8359-368046e17561", "node_type": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b3beb20949da2ba7945f5212c2a186c14f4128e29ea4814f492a7dcbd746653"}}, "hash": "66be23ec63bba8b8463b4a90bd84e27478f9d38533e99d5be8dea1668c6342b0", "text": "15 NORADRENER gIC TRANSMISSION\n207in the treatment of asthma (see Ch. 29). Uterine smooth \nmuscle responds similarly, and these drugs are also used to \ndelay premature labour (Ch. 36). Bladder detrusor muscle \nis relaxed by activation of \u03b23 adrenoceptors, and selective \u03b23 \nagonists are used to treat symptoms of overactive bladder \n(see Sacco & Bientinesi, 2012).\n\u03b11 adrenoceptors have long-lasting trophic effects stimu -\nlating smooth muscle proliferation in various tissues, for example, in blood vessels and in the prostate gland, which \nis of pathological importance. Benign prostatic hyperplasia (see Ch. 36) is commonly treated with \u03b1\n1-adrenoceptor \nantagonists. \u2018Cross-talk\u2019 between the \u03b11 adrenoceptor and \nthe growth factor signalling pathways (see Ch. 3) probably \ncontributes to the clinical effect, in addition to immediate \nsymptomatic improvement which is probably mediated by smooth muscle relaxation.\nNerve terminals\nPresynaptic adrenoceptors are present on both cholinergic and noradrenergic nerve terminals (see Chs 4 and 13). As \nmentioned previously, the main effect ( \u03b1\n2-mediated) is \ninhibitory, but a weaker facilitatory action of \u03b2 receptors \non noradrenergic nerve terminals has also been described.\nHeart\nCatecholamines, acting on \u03b21 receptors, exert a powerful \nstimulant effect on the heart (see Ch. 22). Both the heart rate ( chronotropic effect ) and the force of contraction ( inotropic \neffect) are increased, resulting in a markedly increased \ncardiac output and cardiac oxygen consumption. Cardiac \nefficiency (see Ch. 22) is reduced. Catecholamines can \nalso disturb cardiac rhythm, culminating in ventricular fibrillation. (Paradoxically, but importantly, adrenaline is \nalso used to treat ventricular fibrillation arrest as well as \nother forms of cardiac arrest; Ch. 22). Fig. 15.4 shows the overall pattern of cardiovascular responses to catecholamine infusions in humans, reflecting their actions on both the \nheart and vascular system.\nCardiac hypertrophy occurs in response to activation \nof both \u03b2\n1 and \u03b11 receptors, probably by a mechanism \nsimilar to the hypertrophy of vascular and prostatic smooth muscle. This may be important in the pathophysiology of \nhypertension and of cardiac failure (which is associated with sympathetic overactivity); see Chapters 22 and 23.\nMetabolism\nCatecholamines encourage the conversion of energy stores (glycogen and fat) to freely available fuels (glucose and free \nfatty acids), and cause an increase in the plasma concentra -\ntion of the latter substances. The detailed biochemical mecha -\nnisms (see review by Nonogaki, 2000) vary from species to species, but in most cases the effects on carbohydrate \nmetabolism of liver and muscle (Fig. 15.5) are mediated through \u03b2\n1 receptors and the stimulation of lipolysis and \nthermogenesis is produced by \u03b2 3 receptors (see Table 15.1). \nActivation of \u03b1 2 receptors inhibits insulin secretion, an effect \nthat further contributes to the hyperglycaemia. The produc -\ntion of leptin by adipose tissue (see Ch. 33) is also inhibited. \nAdrenaline-induced hyperglycaemia in humans is blocked completely by a combination of \u03b1 and \u03b2 antagonists but \nnot by either on its own.\nOther effects\nSkeletal muscle is affected by adrenaline, acting on \u03b22 \nreceptors, although the effect is far less dramatic than that stimulant, vasodilator and vasoconstrictor actions is uniquely important in cardiac arrest (Ch. 22). \u03b1\n1-adrenoceptor agonists \nare widely used intranasally as decongestants.\nADRENOCEPTOR", "start_char_idx": 0, "end_char_idx": 3522, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d9799c5c-251d-42af-8359-368046e17561": {"__data__": {"id_": "d9799c5c-251d-42af-8359-368046e17561", "embedding": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6e37c40c-4d85-4332-9a0b-e684fa078caf", "node_type": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "550efbb24eb2709f8766e67bd806a32e051efcbcdb396490fe1bd042f8f4dc34"}, "2": {"node_id": "250c6006-8434-49ee-bba6-2212a554ea09", "node_type": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "66be23ec63bba8b8463b4a90bd84e27478f9d38533e99d5be8dea1668c6342b0"}, "3": {"node_id": "3fdcb52a-fa85-4a01-ae89-54773ed49eb6", "node_type": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "162c5b03d71c2832cd2fb577abe84970ba625cff7fe8b8192de431e381d058f3"}}, "hash": "4b3beb20949da2ba7945f5212c2a186c14f4128e29ea4814f492a7dcbd746653", "text": "widely used intranasally as decongestants.\nADRENOCEPTOR \u2003AGONISTS\nExamples of adrenoceptor agonists (also known as directly-\nacting sympathomimetic drugs) are given in Table 15.2, and \nthe characteristics of individual drugs are summarised in \nTable 15.4.\nActions\nThe major physiological effects mediated by different types of adrenoceptor are summarised in Table 15.1.\nSmooth muscle\nAll types of smooth muscle, except that of the gastrointestinal tract, contract in response to stimulation of \u03b1\n1 adrenoceptors, \nthrough activation of the signal transduction mechanism, \nleading to intracellular Ca2+ release described in Chapter 4. \nAlthough vascular smooth muscle possesses both \u03b11 and \u03b12 \nreceptors, it appears that \u03b1 1 receptors lie close to the sites \nof noradrenaline release (and are mainly responsible for neurally mediated vasoconstriction), while \u03b1\n2 receptors lie \nelsewhere on the muscle fibre surface.\nWhen \u03b11 agonists are given systemically to experimental \nanimals or humans, the most important action is on vascular smooth muscle, particularly in the small arteries and arteri -\noles in skin and splanchnic vascular beds, which are strongly \nconstricted increasing total peripheral vascular resistance. \nSmooth muscle cells in the walls of large arteries and veins, \nalso contract, resulting in decreased arterial compliance and increased central venous pressure, which contribute to \nan increase in arterial and venous pressure and increased \ncardiac work. Some vascular beds (e.g. cerebral, coronary and pulmonary) are relatively little affected.\nIn the whole animal, baroreceptor reflexes are activated \nby the rise in arterial pressure produced by \u03b1\n1 agonists, \ncausing reflex bradycardia and inhibition of respiration.\nSmooth muscle in the vas deferens, spleen capsule and \neyelid retractor muscles (or nictitating membrane, in some species) is also stimulated by \u03b1\n1 agonists, and these organs \nwere once widely used for pharmacological studies.\nStimulation of \u03b2 receptors causes relaxation of most kinds \nof smooth muscle by increasing cAMP formation (see Ch. 4). Additionally, \u03b2-receptor activation enhances Ca\n2+ extrusion \nand intracellular Ca2+ binding, both effects acting to reduce \nintracellular Ca2+ concentration. In the vascular system, \n\u03b22-mediated vasodilatation is (particularly in humans) \nmainly endothelium dependent and mediated by nitric \noxide release (see Ch. 21). It occurs in many vascular beds \nand is especially marked in skeletal muscle.\nThe powerful inhibitory effect of the sympathetic system \non gastrointestinal smooth muscle is produced by both \u03b1 \nand \u03b2 receptors, this tissue being unusual in that \u03b1 recep-\ntors cause relaxation in most regions. Part of the effect is \ndue to stimulation of presynaptic \u03b12 receptors (see later), \nwhich inhibit the release of excitatory transmitters (e.g. acetylcholine) from intramural nerves, but there are also \n\u03b1\n1 and \u03b1 2 receptors on the muscle cells, stimulation of \nwhich hyperpolarises the cell (by increasing the membrane \npermeability to K+) and inhibits action potential discharge. \nThe sphincters of the gastrointestinal tract are contracted by \u03b1-receptor activation.\nBronchial smooth muscle is relaxed by activation of \u03b2\n2 \nadrenoceptors, and selective \u03b22 agonists are important mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3472, "end_char_idx": 7041, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3fdcb52a-fa85-4a01-ae89-54773ed49eb6": {"__data__": {"id_": "3fdcb52a-fa85-4a01-ae89-54773ed49eb6", "embedding": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6e37c40c-4d85-4332-9a0b-e684fa078caf", "node_type": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "550efbb24eb2709f8766e67bd806a32e051efcbcdb396490fe1bd042f8f4dc34"}, "2": {"node_id": "d9799c5c-251d-42af-8359-368046e17561", "node_type": null, "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b3beb20949da2ba7945f5212c2a186c14f4128e29ea4814f492a7dcbd746653"}}, "hash": "162c5b03d71c2832cd2fb577abe84970ba625cff7fe8b8192de431e381d058f3", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7061, "end_char_idx": 7284, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dec79278-f773-4924-a0cd-56df0e4aee4e": {"__data__": {"id_": "dec79278-f773-4924-a0cd-56df0e4aee4e", "embedding": null, "metadata": {"page_label": "214", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0e8e8fb8-6f97-4fd2-b926-dd2b2289f7f7", "node_type": null, "metadata": {"page_label": "214", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7474d351474e8e8ed75ae87a9b01a14a24160e457df0c4395a7931c4860e8c4b"}}, "hash": "7474d351474e8e8ed75ae87a9b01a14a24160e457df0c4395a7931c4860e8c4b", "text": "15 SECTION 2 \u2003\u2003CHEMICAL MEDIATORS\n208Arterial\npressure\n(mmHg)\nPeripheral\nresistance\n(arbitrary units)\n010203050100150200\n50100150\nHeart rate\n(beats/min)\nIsoprenaline Noradrenaline Adrenaline Systolic\nMean\nDiastolic\nFig. 15.4 Schematic representation of the cardiovascular effects of intravenous infusions of adrenaline, noradrenaline and \nisoprenaline in humans. \tNoradrenaline\t (predominantly\t \u03b1\tagonist)\tcauses\tvasoconstriction\t and\tincreased\t systolic\tand\tdiastolic\tpressure,\t\nwith\ta\treflex\tbradycardia.\t Isoprenaline\t (\u03b2\tagonist)\tis\ta\tvasodilator,\t but\tstrongly\tincreases\t cardiac\tforce\tand\trate.\tMean\tarterial\tpressure\tfalls.\t\nAdrenaline\t combines\t both\tactions.\t\nGlucoseGlucose Glucose-6-P Glucose-6-PGlucose-1-P\nFatty acidsGlucose-1-PGlycogen\nTriglycerideGlycogen\nGlycogen\nsynthaseGlycogen\nsynthase\nPhosphatasePhosphorylase\nLipasePhosphorylaseLIVER MUSCLE\nENERGYFATBloodstream\nTCA\ncycle\nFig. 15.5 Regulation of energy metabolism by catecholamines. \tThe\tmain\tenzymic\tsteps\tthat\tare\taffected\tby\t\u03b2-adrenoceptor\t\nactivation\t are\tindicated\t by\t+\tand\t\u2212\tsigns,\tdenoting\tstimulation\t and\tinhibition,\t respectively.\t The\toverall\teffect\tis\tto\tmobilise\tglycogen\t and\tfat\t\nstores\tto\tmeet\tenergy\tdemands.\t TCA,\ttricarboxylic\t acid.\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1707, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4fde5575-def6-41ab-bd0a-19cf8ec7f22e": {"__data__": {"id_": "4fde5575-def6-41ab-bd0a-19cf8ec7f22e", "embedding": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1e253b0-415c-4eec-9e86-01415cbfc2bd", "node_type": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "448c9ea5be34f2bccea3be349817c356e285f50bc907ff78fc4f233c96e6bf62"}, "3": {"node_id": "6fd631d9-6c17-456a-a1e9-c91205945518", "node_type": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "11be4c339f5b503a0bfb00600d705f42203e1eb702d519efbb8a111ad54c6590"}}, "hash": "180023b484a33f262895bb10b1884394dccb672612d5c98b3e35a4f9f8862571", "text": "15 NORADRENER gIC TRANSMISSION\n209important being the use of \u03b2-adrenoceptor agonists for the \ntreatment of asthma (Ch. 29).\nAdrenoceptor agonists \n\u2022\tNoradrenaline \tand\tadrenaline \tshow\trelatively \tlittle \t\nreceptor\tselectivity.\n\u2022\tSelective \t\u03b11\tagonists\tinclude \tphenylephrine \tand\t\noxymetazoline.\n\u2022\tSelective \t\u03b12\tagonists\tinclude \tclonidine \tand \t\n\u03b1-methylnoradrenaline .\tThey\tcause \ta \tfall \tin \tblood \t\npressure,\tpartly \tby \tinhibition \tof \tnoradrenaline \trelease \t\nand\tpartly \tby \ta \tcentral \taction. \tMethylnoradrenaline \tis \t\nformed\tas \ta \tfalse \ttransmitter \tfrom \tmethyldopa ,\t\ndeveloped \tas \ta \thypotensive \tdrug \t(now \tlargely \t\nobsolete,\texcept \tduring \tpregnancy).\n\u2022\tSelective \t\u03b21\tagonists\tinclude \tdobutamine .\tIncreased \t\ncardiac\tcontractility \tmay \tbe \tuseful \tclinically, \tbut \tall \t\u03b21 \nagonists\tcan \tcause \tcardiac \tdysrhythmias.\n\u2022\tSelective \t\u03b22\tagonists\tinclude \tsalbutamol ,\tterbutaline \nand\tsalmeterol ;\tused\tmainly \tfor \ttheir \tbronchodilator \t\naction\tin\tasthma.\n\u2022\tA\tselective \t\u03b23\tagonist,\tmirabegron ,\tis\tused\tto \ttreat \t\noveractive \tbladder; \t\u03b23\tagonists\tpromote \tlipolysis \tand \t\nhave\tpotential \tin \tthe \ttreatment \tof \tobesity.on the heart. The twitch tension of fast-contracting fibres \n(white muscle) is increased by adrenaline, particularly if \nthe muscle is fatigued, whereas the twitch of slow (red) \nmuscle is reduced. These effects depend on an action on the \ncontractile proteins, rather than on the membrane, and the mechanism is poorly understood. In humans, adrenaline \nand other \u03b2\n2 agonists cause a marked tremor, the shakiness \nthat accompanies fear, excitement, withdrawal from alcohol (Ch. 49) or the excessive use of \u03b2\n2 agonists (e.g. salbutamol ) \nin the treatment of asthma being examples of this. It prob -\nably results from an increase in muscle spindle discharge, \ncoupled with an effect on the contraction kinetics of the fibres, these effects combining to produce an instability in \nthe reflex control of muscle length. \u03b2-receptor antagonists \nare sometimes used to control pathological tremor. Increased \nsusceptibility to cardiac dysrhythmias associated with \u03b2\n2 \nagonists is thought to be partly due to hypokalaemia, \ncaused by an increase in K+ uptake by skeletal muscle. \u03b22 \nagonists also cause long-term changes in the expression of sarcoplasmic reticulum proteins that control contrac -\ntion kinetics, and thereby increase the rate and force of \ncontraction of skeletal muscle. Clenbuterol, an \u2018anabolic\u2019 \ndrug used illicitly by athletes to improve performance (see Ch. 59), is a \u03b2\n2 agonist that acts in this way.\nHistamine release by human and guinea pig lung tissue \nin response to anaphylactic challenge (see Ch. 18) is inhibited by catecholamines, acting on \u03b2\n2 receptors.\nLymphocytes and other cells of the immune system also \nexpress adrenoceptors (mainly \u03b2 adrenoceptors). Lympho -\ncyte proliferation, lymphocyte-mediated cell killing, and production of many cytokines are inhibited by \u03b2-adrenoceptor \nagonists. The physiological and clinical importance of these effects has not yet been established. For a review of the effects of the sympathetic nervous system on immune \nfunction, see Elenkov et al., 2000.\nClinical use\nThe main clinical uses of", "start_char_idx": 0, "end_char_idx": 3213, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6fd631d9-6c17-456a-a1e9-c91205945518": {"__data__": {"id_": "6fd631d9-6c17-456a-a1e9-c91205945518", "embedding": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1e253b0-415c-4eec-9e86-01415cbfc2bd", "node_type": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "448c9ea5be34f2bccea3be349817c356e285f50bc907ff78fc4f233c96e6bf62"}, "2": {"node_id": "4fde5575-def6-41ab-bd0a-19cf8ec7f22e", "node_type": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "180023b484a33f262895bb10b1884394dccb672612d5c98b3e35a4f9f8862571"}, "3": {"node_id": "46d92ebe-8fc6-4810-a3f3-89c83ebb5b4e", "node_type": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c45b78c3c61242ae32d48b7dcd302f4267fe1492d29c0b44bc2ba8410dc34241"}}, "hash": "11be4c339f5b503a0bfb00600d705f42203e1eb702d519efbb8a111ad54c6590", "text": "see Elenkov et al., 2000.\nClinical use\nThe main clinical uses of adrenoceptor agonists are sum-marised in the clinical box (below) and Table 15.4, the most Clinical uses of adrenoceptor \nagonists \n\u2022\tCardiovascular \tsystem:\n\u2013\tcardiac\tarrest: \tadrenaline\n\u2013\tcardiogenic \tshock \t(see \tChs \t22 \tand \t23): \t\ndobutamine \t(\u03b21\tagonist).\n\u2022\tAnaphylaxis \t(acute \thypersensitivity, \tsee \tChs \t18 \tand \t\n29):\tadrenaline.\n\u2022\tRespiratory \tsystem:\n\u2013\tasthma \t(Ch. \t29): \tselective \t\u03b22-receptor\tagonists \t\n(salbutamol ,\tterbutaline ,\tsalmeterol ,\tformoterol)\n\u2013\tnasal\tdecongestion: \tdrops \tcontaining \t\nxylometazoline \tor\tephedrine \tfor\tshort-term \tuse.\n\u2022\tMiscellaneous \tindications:\n\u2013 adrenaline :\twith\tlocal \tanaesthetics \tto \tprolong \ttheir \t\naction\t(see \tCh. \t44).\n\u2013\tpremature \tlabour \t(salbutamol; \tsee \tCh. \t36).\n\u2013 \u03b12\tagonists\t(e.g. \tclonidine ,\tlofexidine ):\tto\tlower \t\nblood\tpressure, \tbut \tare \tnow \tseldom \tprescribed \tfor \t\nthis\tother\tthan \tin \tspecialist \tsituations \t(Ch. \t23) \tand \t\nintraocular \tpressure; \tlofexidine \tis \tused \tas \tan \tadjunct \t\nduring\topioid \twithdrawal, \tto \treduce \tmenopausal \t\nflushing,\tespecially \twhen \toestrogen \tis\t\ncontraindicated \tas \tin \tpatients \twith \tbreast \tcancer; \t\nand\tto\treduce \tfrequency \tof \tmigraine \tattacks \t(Ch. \t\n16).\tTourette \tsyndrome, \tcharacterised \tby \tmultiple \t\ntics\tand\toutbursts \tof \tfoul \tlanguage, \tis \tan \tunlicensed \t\nindication.\n\u2013\tA\t\u03b23\tagonist,\tmirabegron :\tto\ttreat\turgency, \t\nincreased\tmicturition \tfrequency \tand \tincontinence \t\n(overactive \tbladder \tsymptoms).\nADRENOCEPTOR \u2003ANTAGONISTS\nThe main drugs are listed in Table 15.2, and further informa -\ntion is given in Table 15.5. Most are selective for \u03b1 or \u03b2 \nreceptors, and many are also subtype-selective.\n\u03b1-Adrenoceptor antagonists\nThe main groups of \u03b1-adrenoceptor antagonists are:\n\u2022\tnon-selective \tbetween \tsubtypes \t(e.g. \t\nphenoxybenzamine, phentolamine)\n\u2022\t\u03b11-selective (e.g. prazosin, doxazosin, terazosin)\n\u2022\t\u03b12-selective (e.g. yohimbine, idazoxan)\nIn addition, ergot derivatives (e.g. ergotamine, dihydroer-\ngotamine ) block \u03b1 receptors as well as having many other \nactions, notably on 5-HT receptors. They are described in Chapter 16. Their action on \u03b1 adrenoceptors is of pharm-\nacological interest but not used therapeutically.\nNon-selective \u03b1-adrenoceptor antagonists\nPhenoxybenzamine is not specific for \u03b1 receptors, and also \nantagonises the actions of acetylcholine, histamine and \n5-HT. It is long lasting because it binds covalently to the \nreceptor. Phentolamine is more selective, but it binds \nreversibly and its action is short lasting. In", "start_char_idx": 3159, "end_char_idx": 5729, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "46d92ebe-8fc6-4810-a3f3-89c83ebb5b4e": {"__data__": {"id_": "46d92ebe-8fc6-4810-a3f3-89c83ebb5b4e", "embedding": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1e253b0-415c-4eec-9e86-01415cbfc2bd", "node_type": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "448c9ea5be34f2bccea3be349817c356e285f50bc907ff78fc4f233c96e6bf62"}, "2": {"node_id": "6fd631d9-6c17-456a-a1e9-c91205945518", "node_type": null, "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "11be4c339f5b503a0bfb00600d705f42203e1eb702d519efbb8a111ad54c6590"}}, "hash": "c45b78c3c61242ae32d48b7dcd302f4267fe1492d29c0b44bc2ba8410dc34241", "text": "humans, these \ndrugs cause a fall in arterial pressure (because of block of mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5785, "end_char_idx": 6340, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ef455ee-9141-4a92-8fae-d44b906db305": {"__data__": {"id_": "8ef455ee-9141-4a92-8fae-d44b906db305", "embedding": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "50858789-c188-4766-b41c-4ab82da440bf", "node_type": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce98784f70782bc19e6ccbe0aa37fd4b5585114031f35d39b3104796e8879411"}, "3": {"node_id": "7b48b15d-f765-4f78-aebd-792a46f67b54", "node_type": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3120a1ef6fa8581aac05a086786c410a3b4fb0f0047a225833332600ebfa3d7f"}}, "hash": "b636e956d4007769b740e1b6f6a368715e61b0aa6777e036819ca3427f1711f0", "text": "15 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n210terazosin ) are, however, useful. They do not directly affect \ncardiac function appreciably, and postural hypotension is \nless troublesome than with prazosin or non-selective \n\u03b1-receptor antagonists. They have a place in treating severe \nhypertension, where they are added to treatment with \nfirst- and second-line drugs, but are not used as first-line \nagents (see Ch. 23). Unlike other antihypertensive drugs, they cause a modest decrease in low-density lipoprotein, \nand an increase in high-density lipoprotein cholesterol (see \nCh. 24), although the clinical importance of these potentially beneficial effects is uncertain. They are also used to control obstructive symptoms in patients with benign prostatic \nhypertrophy.\nPhaeochromocytoma is a catecholamine-secreting tumour \nof chromaffin tissue, which causes severe and initially episodic hypertension. A combination of \u03b1- and \u03b2-receptor \nantagonists is the most effective way of controlling the \nblood pressure. The tumour may be surgically removable, \nand it is essential to block \u03b1 and \u03b2 receptors before surgery \nis begun, to avoid the effects of a sudden release of cat -\necholamines when the tumour is disturbed. Phenoxyben-zamine, an irreversible \u03b1 antagonist which reduces the \nmaximum of the agonist dose\u2013response curve (see Ch. 2, \nFig. 2.4B) is combined with a \u03b2-adrenoceptor antagonist \nfor this purpose.\u03b1-receptor-mediated vasoconstriction) and postural hypoten -\nsion. The cardiac output and heart rate are increased. This is a reflex response to the fall in arterial pressure, mediated through \u03b2 receptors. The concomitant block of \u03b1\n2 receptors \ntends to increase noradrenaline release, which has the effect \nof enhancing the reflex tachycardia that occurs with any \nblood pressure-lowering agent. Phenoxybenzamine retains a niche use in preparing patients with phaeochromocytoma \n(Ch. 23, and below) for surgery.\nLabetalol and carvedilol\n5 are mixed \u03b1 1- and \u03b2-receptor- \nblocking drugs, although at doses used clinically they act \npredominantly on \u03b2 receptors. Carvedilol is used mainly \nto treat hypertension and heart failure (see Chs 21 and \n22); labetalol is used to treat hypertension in pregnancy.\nSelective \u03b11 antagonists\nPrazosin was the first selective \u03b11 antagonist/inverse \nagonist; it acts on all three subtypes of \u03b11 receptor (Alexander \net al., 2016). Similar drugs with longer half-lives (e.g. \ndoxazosin , terazosin ), which have the advantage of allowing \nonce-daily dosing, are now preferred. They are highly \nselective for \u03b11 adrenoceptors and cause vasodilatation and \nfall in arterial pressure, but less tachycardia than occurs with non-selective \u03b1-receptor antagonists, presumably \nbecause they do not increase noradrenaline release from sympathetic nerve terminals. Mild postural hypotension \nis common, but is less problematic than with shorter-acting \nprazosin.\nThe \u03b1\n1-receptor antagonists cause relaxation of the smooth \nmuscle of the bladder neck and prostate capsule, and inhibit \nhypertrophy of these tissues, and are therefore useful in \ntreating urinary retention associated with benign prostatic \nhypertrophy. Tamsulosin, an \u03b1 1A-receptor antagonist, shows \nsome selectivity for the bladder, and causes less hypotension \nthan the less selective \u03b1 1-receptor antagonists.\nIt is believed that \u03b11A receptors play a part in the patho -\nlogical hypertrophy not only of prostatic and vascular smooth muscle, but", "start_char_idx": 0, "end_char_idx": 3452, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7b48b15d-f765-4f78-aebd-792a46f67b54": {"__data__": {"id_": "7b48b15d-f765-4f78-aebd-792a46f67b54", "embedding": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "50858789-c188-4766-b41c-4ab82da440bf", "node_type": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce98784f70782bc19e6ccbe0aa37fd4b5585114031f35d39b3104796e8879411"}, "2": {"node_id": "8ef455ee-9141-4a92-8fae-d44b906db305", "node_type": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b636e956d4007769b740e1b6f6a368715e61b0aa6777e036819ca3427f1711f0"}, "3": {"node_id": "e553f738-8abd-4e02-90e3-85edb84a3b61", "node_type": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "307fe64f4e5d1b3abbc4bcd0b959312636386f460680d14dd0cae117350ba3da"}}, "hash": "3120a1ef6fa8581aac05a086786c410a3b4fb0f0047a225833332600ebfa3d7f", "text": "hypertrophy not only of prostatic and vascular smooth muscle, but also in the cardiac hypertrophy that \noccurs in hypertension and heart failure (Papay et al., 2013), \nand the use of selective \u03b11A-receptor antagonists to treat \nthese chronic conditions is under investigation.\nSelective \u03b12 antagonists\nYohimbine is a naturally occurring alkaloid; various \nsynthetic analogues have been made, such as idazoxan. \nThese drugs are used experimentally to analyse \u03b1-receptor \nsubtypes, and yohimbine, possibly by virtue of its vasodila -\ntor effect, historically enjoyed notoriety as an aphrodisiac, \nbut they are not used therapeutically.\nClinical uses and unwanted effects of \n\u03b1-adrenoceptor antagonists\nThe main uses of \u03b1-adrenoceptor antagonists are related \nto their cardiovascular actions, and are summarised in the \nclinical box (below) These drugs have only limited thera -\npeutic applications. Non-selective \u03b1-blocking drugs are \nunsatisfactory in treating hypertension, because of their tendency to produce tachycardia, postural hypotension and \ngastrointestinal symptoms. Selective \u03b1\n1-receptor antagonists \n(especially the longer-acting compounds doxazosin and \u03b1-Adrenoceptor antagonists \n\u2022\tSelective \t\u03b11\tantagonists \t(e.g. \tprazosin,\tdoxazosin ,\t\nterazosin )\tare\tused \tin \ttreating \thypertension \tand \tfor \t\nbenign\tprostatic \thypertrophy. \tPostural \thypotension, \t\nstress\tincontinence \tand \timpotence \tare \tunwanted \t\neffects.\n\u2022\tTamsulosin \tis\t\u03b11A\tselective\tand \tacts \tmainly \ton \tthe \t\nurogenital \ttract. \tIt \tis \tused \tto \ttreat \tbenign \tprostatic \t\nhypertrophy \tand \tmay \tcause \tless \tpostural \thypotension \t\nthan\tother \t\u03b11\tagonists.\n\u2022\tYohimbine \tis\ta\tselective \t\u03b12\tantagonist. \tIt \tis \tnot \tused \t\nclinically.\nClinical uses of \u03b1-adrenoceptor \nantagonists \n\u2022\tSevere\thypertension \t(see \tCh. \t23): \t\u03b11-selective\t\nantagonists \t(e.g. \tdoxazosin )\tin\tcombination \twith \tother \t\ndrugs.\n\u2022\tBenign\tprostatic \thypertrophy \t(e.g. \ttamsulosin ,\ta\t\nselective\t\u03b11A-receptor\tantagonist).\n\u2022\tPhaeochromocytoma: \tphenoxybenzamine \n(irreversible \tantagonist) \tin \tpreparation \tfor \tsurgery.\n5Carvedilol is also a biased agonist, acting through the arrestin pathway \n(Ch. 3).\u03b2-Adrenoceptor antagonists\n\u03b2-Adrenoceptor antagonists are therapeutically important. \nThey were first discovered in 1958, 10 years after Ahlquist \nhad postulated the existence of \u03b2 adrenoceptors. The first \ncompound, dichloroisoprenaline, was a partial agonist. \nFurther development led to propranolol, which is much more potent and a pure antagonist that blocks \u03b2\n1 and \u03b22 mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3397, "end_char_idx": 6401, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e553f738-8abd-4e02-90e3-85edb84a3b61": {"__data__": {"id_": "e553f738-8abd-4e02-90e3-85edb84a3b61", "embedding": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "50858789-c188-4766-b41c-4ab82da440bf", "node_type": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce98784f70782bc19e6ccbe0aa37fd4b5585114031f35d39b3104796e8879411"}, "2": {"node_id": "7b48b15d-f765-4f78-aebd-792a46f67b54", "node_type": null, "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3120a1ef6fa8581aac05a086786c410a3b4fb0f0047a225833332600ebfa3d7f"}}, "hash": "307fe64f4e5d1b3abbc4bcd0b959312636386f460680d14dd0cae117350ba3da", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6410, "end_char_idx": 6473, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0db7928d-d0e8-4e78-9cc9-7c8b4bb3be5f": {"__data__": {"id_": "0db7928d-d0e8-4e78-9cc9-7c8b4bb3be5f", "embedding": null, "metadata": {"page_label": "217", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "394d6162-782a-4701-acd5-5352694594cb", "node_type": null, "metadata": {"page_label": "217", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c6022ec772e82a92769e13701d0c8c083f140ee0448906633c20503c13a5e53c"}, "3": {"node_id": "ad04fc59-deb5-4342-aaa1-51468e1b2360", "node_type": null, "metadata": {"page_label": "217", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a9979db40be90d5be691f4f914e42e22712205a50c1b1b6fe85612c7d48dca7e"}}, "hash": "dda4e4f13de77316e9ea0f5d407b0277d9ad749311a3e0956c4771031107aff5", "text": "15 NORADRENER gIC TRANSMISSION\n211than the myocardial oxygen consumption, so oxygenation \nof the myocardium is improved, an effect of importance \nin the treatment of angina pectoris (see Ch. 22). In healthy \nsubjects, the reduction of the force of contraction of the heart is not important, in contrast to patients with heart \ndisease (see further in chapter).\nAn important, and somewhat unexpected, effect of \n\u03b2-receptor antagonists is their antihypertensive action (see \nCh. 23). Patients with hypertension show a gradual fall in \narterial pressure that takes several days to develop fully. The mechanism is complex and involves the following:\n\u2022\treduction \tin \tcardiac \toutput;\n\u2022\treduction \tof \trenin \trelease \tfrom \tthe \tjuxtaglomerular \t\ncells of the kidney;\n\u2022\ta\tcentral \taction, \treducing \tsympathetic \tactivity.\nVasodilatation may contribute to the antihypertensive action of drugs (e.g. carvedilol and nebivolol, see earlier) with \nsuch properties.\nBlockade of the facilitatory effect of presynaptic \u03b2 recep -\ntors on noradrenaline release (see Table 15.1) may also contribute to the antihypertensive effect. The antihyper -\ntensive effect of \u03b2-receptor antagonists is clinically useful. \nBecause reflex vasoconstriction is preserved, postural and \nexercise-induced hypotension are less troublesome than \nwith many other antihypertensive drugs.\nMany \u03b2-receptor antagonists have an important antidys -\nrhythmic effect on the heart (see Ch. 22).\nAirways resistance in normal subjects is only slightly \nincreased by \u03b2-receptor antagonists, and this is of no \nconsequence. In asthmatic subjects, however, non-selective \n\u03b2-receptor antagonists (such as propranolol) can cause severe \nbronchoconstriction, which does not, of course, respond \nto the usual doses of drugs such as salbutamol or adrenaline. receptors equally. The potential clinical advantages of drugs with some partial agonist activity, and/or with selectivity \nfor \u03b2\n1 receptors, led to the development of practolol (selec -\ntive for \u03b21 receptors but withdrawn because of its off-target \ntoxicity), oxprenolol and alprenolol (non-selective with \nconsiderable partial agonist activity), and atenolol (\u03b2 1-\nselective with no agonist activity). Two newer drugs are carvedilol (a non-selective \u03b2-adrenoceptor antagonist with \nadditional \u03b1\n1-blocking activity) and nebivolol (a \u03b21-selective \nantagonist with vasodilator nitric oxide-mediated activity; see Ch. 21). Both these drugs have proven more effective \nthan conventional \u03b2-adrenoceptor antagonists in treating heart failure (see Chs 22 and 23). The characteristics of the \nmost important compounds are set out in Table 15.5. Most \nclinically available \u03b2-receptor antagonists are inactive on \n\u03b2\n3 receptors so do not affect lipolysis.\nActionsThe main pharmacological actions of \u03b2-receptor antagonists \ncan be deduced from Table 15.1. The acute effects produced \nin humans depend on the degree of sympathetic activity \nand are modest in subjects at rest. The most important effects are on the cardiovascular system and on bronchial \nsmooth muscle (see Chs 22, 23 and 29).\nIn a healthy subject at rest, propranolol causes modest \nchanges in heart rate, cardiac output or arterial pressure, \nbut \u03b2-blockade markedly reduces the effect of exercise or \nexcitement on these variables (Fig. 15.6). Drugs with partial agonist activity, such as oxprenolol, increase the heart rate at rest but reduce it during exercise. Maximum exercise \ntolerance is considerably reduced in normal subjects, partly \nbecause of the limitation", "start_char_idx": 0, "end_char_idx": 3537, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ad04fc59-deb5-4342-aaa1-51468e1b2360": {"__data__": {"id_": "ad04fc59-deb5-4342-aaa1-51468e1b2360", "embedding": null, "metadata": {"page_label": "217", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "394d6162-782a-4701-acd5-5352694594cb", "node_type": null, "metadata": {"page_label": "217", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c6022ec772e82a92769e13701d0c8c083f140ee0448906633c20503c13a5e53c"}, "2": {"node_id": "0db7928d-d0e8-4e78-9cc9-7c8b4bb3be5f", "node_type": null, "metadata": {"page_label": "217", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dda4e4f13de77316e9ea0f5d407b0277d9ad749311a3e0956c4771031107aff5"}}, "hash": "a9979db40be90d5be691f4f914e42e22712205a50c1b1b6fe85612c7d48dca7e", "text": "is considerably reduced in normal subjects, partly \nbecause of the limitation of the cardiac response, and partly because the \u03b2-mediated vasodilatation in skeletal muscle \nis reduced. Coronary flow is reduced, but relatively less \nSecond half Interval First half ControlHeart rate (beats/min)\n6080100120140160\n90 60 30 0Time (min)Oxprenolol 40 mg orally\nFig. 15.6 \tHeart\trate \trecorded \tcontinuously \tin \ta \tspectator \twatching \ta \tlive \tfootball \tmatch, \tshowing \tthe \teffect \tof \tthe \t\u03b2-adrenoceptor \t\nantagonist \toxprenolol. \t(From \tTaylor, \tS.H., \tMeeran, \tM.K., \t1973. \tIn: \tBurley \tet \tal. \t(Eds) \tNew \tPerspectives \tin \tBeta-Blockade. \tCIBA \t\nLaboratories, \tHorsham.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3460, "end_char_idx": 4613, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "97a2ce90-434e-483d-8937-a2c864d50519": {"__data__": {"id_": "97a2ce90-434e-483d-8937-a2c864d50519", "embedding": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d2e016b-3b75-4279-9b43-550b03801229", "node_type": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c1d9e7d9db10213308ec32805129a9b72ebbb2c5f6d341c24ea70c609c1ef9c"}, "3": {"node_id": "8e1057f3-5412-4e73-8f34-49051886d79a", "node_type": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a28d7a4a5452ad5f752a3dc8492ff5374203fbc0ec70b583f4b9f53b78926e5a"}}, "hash": "6093fc050644efae83d6705ce1af882d006184f767bb8b43d5ba58e3d37091e5", "text": "15 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n212Infantile haemangioma is the commonest soft-tissue \ntumour in children, occurring in 3%\u201310% of infants and \nusually regressing without treatment. Approximately 12% \nare complicated by, for example, impingement on vital organs such as the eye, and require intervention. In 2008 \na chance observation that treatment of heart failure with \npropranolol in two young children with severe haeman -\ngiomas was associated with their regression led to clinical \ntrials that confirmed the effectiveness of propranolol for \nthis indication. Such use has been approved by the FDA as well as in Europe, and propranolol is now standard therapy for severe infantile haemangioma. The evidence of such \nmarked efficacy (L\u00e9aut\u00e9-Labr\u00e8ze et al., 2015) highlights the \nprobable importance of \u03b2-adrenoceptor-mediated trophic \nactions, at the least in this paediatric endothelial tumour. \nMilder uncomplicated forms of infantile haemangioma are \nsometimes treated with topical timolol or propranolol.This danger is less with \u03b21-selective antagonists, but none \nis so selective that this danger can be ignored.\nDespite the involvement of \u03b2 receptors in the hypergly -\ncaemic actions of adrenaline, \u03b2-receptor antagonists cause \nonly minor metabolic changes in normal subjects. They do \nnot affect the onset of hypoglycaemia following an injection \nof insulin, but somewhat delay the recovery of blood glucose concentration. In diabetic patients, the use of \u03b2-receptor \nantagonists increases the likelihood of exercise-induced hypoglycaemia, because the normal adrenaline-induced release of glucose from the liver is diminished. Furthermore, \u03b2-receptor antagonists may alter the awareness of hypo-\nglycaemia by blunting its symptoms (see Ch. 32 and later, \np. 213).\n\u03b2-Adrenoceptor antagonists \n\u2022\tNon-selective \tbetween \t\u03b21\tand\t\u03b22\tadrenoceptors: \t\npropranolol ,\talprenolol ,\toxprenolol.\n\u2022\t\u03b21-selective: \tatenolol,\tnebivolol.\n\u2022\tAlprenolol \tand\toxprenolol \thave\tpartial \tagonist \t\nactivity.\n\u2022\tMany\tclinical \tuses \t(see \tclinical \tbox, \tsee \tlater).\n\u2022\tImportant \thazards \tare \tbronchoconstriction, \tand \t\nbradycardia \tand \tcardiac \tfailure \t(when \tadministered \tto \t\nunstable\tpatients \twith \tdeteriorating \tcardiac \tfunction).\n\u2022\tAdverse \teffects \tinclude \tcold \textremities, \tinsomnia, \t\ndepression, \tfatigue.\n\u2022\tSome\t(e.g. \tpropranolol) \tshow \trapid \tfirst-pass \t\nmetabolism, \thence \tpoor \tbioavailability.\n\u2022\tSome\tdrugs \t(e.g. \tlabetalol,\tcarvedilol )\tblock\tboth \t\u03b1 \nand\t\u03b2\tadrenoceptors.Clinical uses of \u03b2-adrenoceptor \nantagonists \n\u2022\tCardiovascular \t(see \tChs \t22 \tand \t23):\n\u2013\tangina\tpectoris\n\u2013\tmyocardial \tinfarction, \tand \tfollowing \tinfarction\n\u2013\tprevention \tof \trecurrent \tdysrhythmias \t(especially \tif \t\ntriggered\tby \tsympathetic \tactivation)\n\u2013\theart\tfailure \t(in \twell-compensated \tpatients)\n\u2013\thypertension \t(no \tlonger \tfirst \tchoice; \tCh. \t23).\n\u2022\tOther\tuses:\n\u2013\tsevere/complicated \tinfantile \thaemangioma\n\u2013\tglaucoma \t(e.g. \ttimolol\teye\tdrops)\n\u2013\tthyrotoxicosis \t(Ch. \t35), \tas", "start_char_idx": 0, "end_char_idx": 2993, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e1057f3-5412-4e73-8f34-49051886d79a": {"__data__": {"id_": "8e1057f3-5412-4e73-8f34-49051886d79a", "embedding": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d2e016b-3b75-4279-9b43-550b03801229", "node_type": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c1d9e7d9db10213308ec32805129a9b72ebbb2c5f6d341c24ea70c609c1ef9c"}, "2": {"node_id": "97a2ce90-434e-483d-8937-a2c864d50519", "node_type": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6093fc050644efae83d6705ce1af882d006184f767bb8b43d5ba58e3d37091e5"}, "3": {"node_id": "6d7c6f87-2d44-4678-8677-7d67822726ca", "node_type": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "348db578186e0143470b78743b8e06a5d5c6ae72f76fe2f4752a6981f556580d"}}, "hash": "a28d7a4a5452ad5f752a3dc8492ff5374203fbc0ec70b583f4b9f53b78926e5a", "text": "\t(Ch. \t35), \tas \tadjunct \tto \tdefinitive \t\ntreatment\t(e.g. \tpreoperatively \tand \tduring \tinitiation \tof \t\ncarbimazole \ttreatment)\n\u2013\tanxiety\t(Ch. \t45), \tto \tcontrol \tsomatic \tsymptoms \t(e.g. \t\npalpitations, \ttremor)\n\u2013\tmigraine \tprophylaxis \t(Ch. \t16)\n\u2013\tbenign\tessential \ttremor \t(a \tfamilial \tdisorder).Clinical use\nThe main uses of \u03b2-receptor antagonists are connected with \ntheir effects on the cardiovascular system, and are discussed \nin Chapters 22 and 23. They are as summarised in the \nclinical box below.\nThe use of \u03b2-receptor antagonists in cardiac failure \ndeserves special mention, as clinical opinion has undergone a U-turn. Patients with heart disease may rely on a degree of sympathetic drive to the heart to maintain an adequate \ncardiac output, and removal of this by blocking \u03b2 receptors \ncan exacerbate cardiac failure, so using these drugs in \npatients with cardiac failure was considered ill-advised. In theory, drugs with partial agonist activity (e.g. oxprenolol, \nalprenolol) offer an advantage because they can, by their \nown action, maintain a degree of \u03b2\n1-receptor activation, \nwhile at the same time blunting the cardiac response to \nincreased sympathetic nerve activity or to circulating \nadrenaline. Clinical trials, however, have not shown a clear advantage of these drugs measurable as a reduced incidence \nof cardiac failure, and one such drug (xamoterol, since \nwithdrawn) with particularly marked agonist activity clearly made matters worse.\nParadoxically, \u03b2-receptor antagonists are used in low \ndoses to treat well-compensated cardiac failure and there is strong evidence that this improves survival in carefully selected patients (Ch. 23), although at the outset there is a \ndanger of exacerbating the problem (Bristow, 2011). Carve -\ndilol is often used for this purpose.Unwanted effects\nThe principal unwanted effects of \u03b2-receptor antagonists \nin therapeutic use result from their main (receptor-blocking) \naction.\nBronchoconstriction. This is of little importance in the \nabsence of airways disease, but in asthmatic patients the \neffect can be life-threatening. It is also of clinical importance \nin patients with other forms of obstructive lung disease (e.g. chronic bronchitis, emphysema), although the risk\u2013\nbenefit balance may favour cautious treatment in individual \npatients and, as mentioned previously, it has been hypoth -\nesised that \u03b2-receptor antagonists might actually be of value \nin treating stable asthmatic patients.\nCardiac depression. Cardiac depression can occur, leading \nto signs of heart failure, particularly in elderly people. \nPatients suffering from heart failure who are treated with \n\u03b2-receptor antagonists (see earlier) often deteriorate symp -\ntomatically in the first few weeks before the beneficial effect \ndevelops.\nBradycardia. Sinus bradycardia can progress to life-\nthreatening heart block, particularly if \u03b2-adrenoceptor \nantagonists are co-administered with other antidysrhythmic \ndrugs that impair cardiac conduction (see Ch. 22).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 2981, "end_char_idx": 6411, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d7c6f87-2d44-4678-8677-7d67822726ca": {"__data__": {"id_": "6d7c6f87-2d44-4678-8677-7d67822726ca", "embedding": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d2e016b-3b75-4279-9b43-550b03801229", "node_type": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c1d9e7d9db10213308ec32805129a9b72ebbb2c5f6d341c24ea70c609c1ef9c"}, "2": {"node_id": "8e1057f3-5412-4e73-8f34-49051886d79a", "node_type": null, "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a28d7a4a5452ad5f752a3dc8492ff5374203fbc0ec70b583f4b9f53b78926e5a"}}, "hash": "348db578186e0143470b78743b8e06a5d5c6ae72f76fe2f4752a6981f556580d", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6393, "end_char_idx": 6488, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8dc0111f-bf65-4b3a-ac40-3d821a7acbee": {"__data__": {"id_": "8dc0111f-bf65-4b3a-ac40-3d821a7acbee", "embedding": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5cda025d-fd73-4f4c-ad13-dc33f12a4a74", "node_type": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc310759243aef03b18945ce6f0a49ad083ab9e576c909c78123cefd21b91561"}, "3": {"node_id": "e6c08247-2f55-4359-bd2f-8f988fabbbaa", "node_type": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "73703e87aa78e1de6d6127b7f519234aca97188aecaacc518e98978cc29d0c7d"}}, "hash": "52e3273bd6680397a187121988b2f6e276a0d52e112b9f3b4ffb71377bdd00cc", "text": "15 NORADRENER gIC TRANSMISSION\n213horse kind. It is taken up selectively by noradrenergic nerve \nterminals, where it is converted to a reactive quinone, \nwhich destroys the nerve terminal, producing a \u2018chemical \nsympathectomy\u2019. The cell bodies survive, and eventually the sympathetic innervation recovers. The drug is useful for \nexperimental purposes but has no clinical uses. If injected \ndirectly into the brain, it selectively destroys those nerve terminals (i.e. dopaminergic, noradrenergic and adrenergic) \nthat take it up, but it does not reach the brain if given \nsystemically.\nMPTP (1-methyl-4-phenyl-1,2,3,5-tetrahydropyridine; \nsee Ch. 41) is a similar selective neurotoxin acting on \ndopaminergic neurons.\nDroxidopa (dihydroxyphenylserine, L-DOPS) is under \ninvestigation for treating hypotension. It penetrates the blood\u2013brain barrier and is a prodrug being converted to \nnoradrenaline by dopa decarboxylase, bypassing the DBH-catalysed hydroxylation step. It raises blood pressure by \nincreasing noradrenaline release.\nDRUGS \u2003THAT \u2003AFFECT \u2003NORADRENALINE \u2003STORAGE\nReserpine is an alkaloid from the shrub Rauwolfia, which \nhas been used in India for centuries for the treatment of mental disorders. Reserpine potently blocks the transport \nof noradrenaline and other amines into storage vesicles, by blocking the VMAT. Noradrenaline accumulates instead \nin the cytoplasm, where it is degraded by MAO. The \nnoradrenaline content of tissues drops, and sympathetic transmission is blocked. Reserpine also depletes 5-HT \nand dopamine from neurons in the brain, where these \namines are transmitters (see Ch. 40). Reserpine is now used only experimentally, but was at one time used as an antihypertensive drug. Its central effects, especially \ndepression, which probably result from impairment of \nnoradrenergic and 5-HT-mediated transmission in the brain (see Ch. 48), were a serious problem when its dose was \nincreased.\nDRUGS \u2003THAT \u2003AFFECT \u2003NORADRENALINE \u2003RELEASE\nDrugs can affect noradrenaline release in four main ways:\n\u2022\tby\tdirectly \tblocking \trelease \t(noradrenergic \t\nneuron-blocking drugs)\n\u2022\tby\tevoking \tnoradrenaline \trelease \tin \tthe \tabsence \t\nof nerve terminal depolarisation (indirectly acting sympathomimetic drugs)\n\u2022\tby\tacting \ton \tpresynaptic \treceptors \tthat \tindirectly \t\ninhibit or enhance depolarisation-evoked release; examples include \u03b1\n2 agonists (see pp. 200\u2013201), \nangiotensin II, dopamine and prostaglandins\n\u2022\tby\tincreasing \tor \tdecreasing \tavailable \tstores \tof \t\nnoradrenaline (e.g. reserpine, see p. 213; MAO inhibitors, see Ch. 48).\nNORADRENERGIC \u2003NEURON-BLOCKING \u2003DRUGS\nNoradrenergic neuron-blocking drugs (e.g. guanethidine) \nwere discovered in the mid-1950s when alternatives to \nganglion-blocking drugs were being sought for use in the \ntreatment of hypertension. The main effect of guanethidine is to inhibit the release of noradrenaline from sympathetic \nnerve terminals. It has little effect on the adrenal medulla, \nand none on nerve terminals that release transmitters other than noradrenaline. Related drugs include bretylium, \nbethanidine and debrisoquin (now of interest mainly as a tool for studying drug metabolism; see Ch. 12).Hypoglycaemia. Glucose release in response", "start_char_idx": 0, "end_char_idx": 3223, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e6c08247-2f55-4359-bd2f-8f988fabbbaa": {"__data__": {"id_": "e6c08247-2f55-4359-bd2f-8f988fabbbaa", "embedding": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5cda025d-fd73-4f4c-ad13-dc33f12a4a74", "node_type": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc310759243aef03b18945ce6f0a49ad083ab9e576c909c78123cefd21b91561"}, "2": {"node_id": "8dc0111f-bf65-4b3a-ac40-3d821a7acbee", "node_type": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "52e3273bd6680397a187121988b2f6e276a0d52e112b9f3b4ffb71377bdd00cc"}, "3": {"node_id": "5c094d98-eb65-43db-bfe9-7138681de068", "node_type": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f055d6d048eadeece937bf21fbb062f8b8d493bcae203503f9fc6339fdee120"}}, "hash": "73703e87aa78e1de6d6127b7f519234aca97188aecaacc518e98978cc29d0c7d", "text": "see Ch. 12).Hypoglycaemia. Glucose release in response to adrenaline \nis a safety device that may be important to diabetic patients \nand to other individuals prone to hypoglycaemic attacks. The \nsympathetic response to hypoglycaemia produces symptoms (especially tachycardia) that warn patients of the urgent \nneed for carbohydrate (usually in the form of a sugary \ndrink). \u03b2-Receptor antagonists reduce these symptoms, so \nincipient hypoglycaemia is more likely to go unnoticed \nby the patient. There is a theoretical advantage in using \n\u03b2\n1-selective agents, because glucose release from the liver \nis controlled by \u03b2 2 receptors.\nFatigue. This is probably due to reduced cardiac \noutput and reduced muscle perfusion in exercise. It is a \nfrequent complaint of patients taking \u03b2-receptor-blocking \ndrugs.\nCold extremities. This is common, due to a loss of \n\u03b2-receptor-mediated vasodilatation in cutaneous vessels. Theoretically, \u03b2\n1-selective drugs are less likely to produce \nthis effect, which may also be less marked in patients treated with \u03b2-adrenoceptor antagonists with additional vasodilating \nproperties, but it is not clear that this is so in practice.\nOther adverse effects associated with \u03b2-receptor antago -\nnists are not obviously the result of \u03b2-receptor blockade. \nOne is the occurrence of bad dreams, which occur mainly with highly lipid-soluble drugs such as propranolol, which \nenter the brain easily.\nDRUGS THAT AFFECT \nNORADRENERGIC NEURONS\nEmphasis in this chapter is placed on peripheral sympathetic \ntransmission. The same principles, however, are applicable \nto the CNS (see Ch. 40, where many of the drugs mentioned \nhere also act). The major drugs and mechanisms are sum-marised in Table 15.6.\nDRUGS \u2003THAT \u2003AFFECT \u2003NORADRENALINE \u2003SYNTHESIS\n\u03b1-Methyltyrosine , which inhibits tyrosine hydroxylase, has \nbeen used experimentally but is no longer used clinically. \nIndeed, very few clinically important drugs affect noradrena -\nline synthesis directly. Carbidopa, a hydrazine derivative \nof dopa, which inhibits dopa decarboxylase is one example and is used in the treatment of parkinsonism (see Ch. 41).\nMethyldopa, still used in the treatment of hyperten -\nsion during pregnancy (see Ch. 23), is taken up by noradrenergic neurons, where it is converted to the false \ntransmitter \u03b1-methylnoradrenaline. This substance is not \ndeaminated within the neuron by MAO, so it accumulates and displaces noradrenaline from the synaptic vesicles. \n\u03b1-Methylnoradrenaline is released in the same way as \nnoradrenaline, but is less active than noradrenaline on \u03b1\n1 \nreceptors and thus is less effective in causing vasoconstric -\ntion. However, it is more active on presynaptic ( \u03b12) receptors, \nso the autoinhibitory feedback mechanism operates more \nstrongly than normal, thus reducing transmitter release. \nBoth of these effects (as well as a central effect, probably caused by the same cellular mechanism) contribute to \nthe hypotensive action. It produces side effects typical of \ncentrally acting antiadrenergic drugs (e.g. sedation), as well as carrying \u2018off-target\u2019 risks of immune haemolytic \nreactions and liver toxicity, so it is now little used, except \nfor hypertension in the second half of pregnancy where there is considerable experience of its use and no suggestion of harm to the unborn baby.\n6-Hydroxydopamine (identical with dopamine except \nfor an extra hydroxyl group) is a neurotoxin of the Trojan mebooksfree.net", "start_char_idx": 3176, "end_char_idx": 6629, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5c094d98-eb65-43db-bfe9-7138681de068": {"__data__": {"id_": "5c094d98-eb65-43db-bfe9-7138681de068", "embedding": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5cda025d-fd73-4f4c-ad13-dc33f12a4a74", "node_type": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc310759243aef03b18945ce6f0a49ad083ab9e576c909c78123cefd21b91561"}, "2": {"node_id": "e6c08247-2f55-4359-bd2f-8f988fabbbaa", "node_type": null, "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "73703e87aa78e1de6d6127b7f519234aca97188aecaacc518e98978cc29d0c7d"}}, "hash": "2f055d6d048eadeece937bf21fbb062f8b8d493bcae203503f9fc6339fdee120", "text": "hydroxyl group) is a neurotoxin of the Trojan mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6616, "end_char_idx": 7141, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "034f0d7a-1167-4ba4-bc56-34e5c4b952f3": {"__data__": {"id_": "034f0d7a-1167-4ba4-bc56-34e5c4b952f3", "embedding": null, "metadata": {"page_label": "220", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "18c912ae-0f98-4e58-a28c-d6cbcf9843ca", "node_type": null, "metadata": {"page_label": "220", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f56b3a7c8f9fa07b97b090b618223881524c097b855e3e0ffb4fa9ad7ab201c0"}, "3": {"node_id": "1a5f47ee-e12b-4dd8-a41f-1866192537cc", "node_type": null, "metadata": {"page_label": "220", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c8a64f2f93e10f67cb82ba75a443793ccf9fe9d7a61416e5facc9747913f65b9"}}, "hash": "1fcb67237d8411138842daeeff8ef6235d0b27667a607d644771be172c4f471b", "text": "15 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n214Brie) can then provoke a sudden and dangerous rise in \nblood pressure. Inhibitors of NET, such as imipramine (see \nTable 15.6), interfere with the effects of indirectly acting sympathomimetic amines by preventing their uptake into the nerve terminals.\nThese drugs, especially amphetamine, have important \neffects on the CNS (see Chs 49 and 50) that depend on their ability to release not only noradrenaline, but also 5-HT and \ndopamine from nerve terminals in the brain. An important \ncharacteristic of the effects of indirectly acting sympatho -\nmimetic amines is that marked tolerance develops. Repeated doses of amphetamine or tyramine, for example, produce \nprogressively smaller pressor responses. This is probably \ncaused by depletion of the releasable store of noradrenaline. Tolerance to the central effects also develops with repeated \nadministration.\nActions\nThe peripheral actions of the indirectly acting sympatho -\nmimetic amines include bronchodilatation, raised arterial pressure, peripheral vasoconstriction, increased heart rate \nand force of myocardial contraction, and inhibition of gut motility. Their central actions account for their significant \nabuse potential and for limited therapeutic applications \n(see Chs 49, 50 and 59). Apart from ephedrine, which is still used as a nasal decongestant because its central action Actions\nDrugs of this class reduce or abolish the response of tissues to sympathetic nerve stimulation.\n\u25bc The action of guanethidine on noradrenergic transmission is \ncomplex. It is selectively accumulated by noradrenergic nerve terminals, \nbeing a substrate for NET (see Table 15.6). Its initial activity is due \nto block of impulse conduction in the nerve terminals that selectively accumulate the drug \u2013 acting as a local anaesthetic selective for \nnoradrenergic nerves, the selectivity being down to its uptake by \nNET in the terminals of these axons. Consequently, its action is prevented by drugs such as tricyclic antidepressants (see Ch. 48) that \nblock NET.\nGuanethidine is also concentrated in synaptic vesicles by means of \nthe vesicular transporter VMAT, possibly interfering with their ability \nto undergo exocytosis, and displacing noradrenaline. In this way, it causes a gradual and long-lasting depletion of noradrenaline in \nsympathetic nerve endings, similar to the effect of reserpine.\nLarge doses of guanethidine cause structural damage to noradrenergic \nneurons, probably due to its accumulation in high concentration in \nthe nerve terminals. It can therefore be used experimentally as a neurotoxin selective for sympathetic neurons.\nGuanethidine, bethanidine and debrisoquin are no longer used \nclinically, now that better antihypertensive drugs are available. \nAlthough extremely effective in lowering standing blood pressure, \nthey produce severe side effects associated with the loss of sympathetic reflexes. The most troublesome include postural hypotension, diar -\nrhoea, nasal congestion and failure of ejaculation. They also fail to lower blood pressure effectively at night, when patients are lying flat.\nINDIRECTLY \u2003ACTING \u2003SYMPATHOMIMETIC \u2003AMINES\nMechanism of action and \nstructure\u2013activity relationships\nTyramine, amphetamine and ephedrine are structurally \nrelated to noradrenaline and, although much less potent, \nhave qualitatively similar effects. However, rather than \nacting directly on adrenoceptors they mainly act indirectly by releasing endogenous noradrenaline from the sympathetic \nnerve endings. Drugs that act similarly and are used for \ntheir central effects (see Ch. 49) include methylphenidate \nand atomoxetine.\nThese drugs have only weak actions on adrenoceptors, but \nsufficiently resemble", "start_char_idx": 0, "end_char_idx": 3726, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1a5f47ee-e12b-4dd8-a41f-1866192537cc": {"__data__": {"id_": "1a5f47ee-e12b-4dd8-a41f-1866192537cc", "embedding": null, "metadata": {"page_label": "220", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "18c912ae-0f98-4e58-a28c-d6cbcf9843ca", "node_type": null, "metadata": {"page_label": "220", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f56b3a7c8f9fa07b97b090b618223881524c097b855e3e0ffb4fa9ad7ab201c0"}, "2": {"node_id": "034f0d7a-1167-4ba4-bc56-34e5c4b952f3", "node_type": null, "metadata": {"page_label": "220", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1fcb67237d8411138842daeeff8ef6235d0b27667a607d644771be172c4f471b"}}, "hash": "c8a64f2f93e10f67cb82ba75a443793ccf9fe9d7a61416e5facc9747913f65b9", "text": "drugs have only weak actions on adrenoceptors, but \nsufficiently resemble noradrenaline to be transported into nerve terminals by NET. Once inside the nerve terminals, they are taken up into the vesicles by VMAT, in exchange \nfor noradrenaline, which escapes into the cytosol. Cytosolic \nnoradrenaline escapes via NET, in exchange for the foreign monoamine, to act on postsynaptic receptors (Fig. 15.7). \nExocytosis is not involved in the release process, so their \nactions do not require the presence of Ca\n2+. They are not \ncompletely specific in their actions, and act partly by a \ndirect effect on adrenoceptors, partly by inhibiting NET \n(thereby enhancing the effect of the released noradrenaline) and partly by inhibiting MAO.\nAs would be expected, the effects of these drugs are \nstrongly influenced by other drugs that modify noradren -\nergic transmission. Thus reserpine and 6-hydroxydopamine \nabolish their effects by depleting the terminals of noradrena -\nline. MAO inhibitors, on the other hand, strongly potentiate \ntheir effects by preventing inactivation, within the terminals, of the transmitter displaced from the vesicles. MAO inhibi -\ntion particularly enhances the action of tyramine, because this substance is itself a substrate for MAO. Normally, dietary tyramine is destroyed by MAO in the gut wall \nand liver before reaching the systemic circulation. When \nMAO is inhibited this is prevented, and ingestion of tyramine-rich foods such as fermented cheese (e.g. ripe POSTSYNAPTIC RECEPTORSSynaptic\nvesicleAmphetamine\nNETNA\nNA\nNAMAOMetabolitesVMAT\nAmphetamine\nFig. 15.7 The mode of action of amphetamine, an \nindirectly acting sympathomimetic amine. \tAmphetamine \t\nenters\tthe \tnerve \tterminal \tvia \tthe \tnoradrenaline \ttransporter \t(NET) \t\nand\tenters \tsynaptic \tvesicles \tvia \tthe \tvesicular \tmonoamine \t\ntransporter \t(VMAT), \tin \texchange \tfor \tnoradrenaline \t(NA), \twhich \t\naccumulates \tin \tthe \tcytosol. \tSome \tof \tthe \tNA \tis \tdegraded \tby \t\nmonoamine \toxidase \t(MAO) \twithin \tthe \tnerve \tterminal \tand \tsome \t\nescapes,\tin \texchange \tfor \tamphetamine \tvia \tthe \tnoradrenaline \t\ntransporter, \tto \tact \ton \tpostsynaptic \treceptors. \tAmphetamine \talso \t\nreduces\tNA \treuptake \tvia \tthe \ttransporter, \tso \tenhancing \tthe \t\naction\tof\tthe \treleased \tNA. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3653, "end_char_idx": 6408, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "25bc0db2-ddff-4850-a0a7-969e01a40d81": {"__data__": {"id_": "25bc0db2-ddff-4850-a0a7-969e01a40d81", "embedding": null, "metadata": {"page_label": "221", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "515451a5-541a-4908-86cc-9e283f5a90ab", "node_type": null, "metadata": {"page_label": "221", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4426b306ec1bd7319da6b6811920040b748035a7976586797e004fc466ee69d4"}}, "hash": "4426b306ec1bd7319da6b6811920040b748035a7976586797e004fc466ee69d4", "text": "15 NORADRENER gIC TRANSMISSION\n215Its central effects of euphoria and excitement (Ch. 49) are \nprobably a manifestation of the same mechanism acting \nvia dopamine and 5-HT in the brain. It strongly potentiates \nthe actions of noradrenaline in experimental animals or in isolated tissues provided the sympathetic nerve terminals \nare intact.\nMany drugs that act mainly on other steps in sympathetic \ntransmission also inhibit NET to some extent, presumably \nbecause the carrier molecule has structural features in \ncommon with other noradrenaline recognition sites, such as receptors and degradative enzymes.\nThe extraneuronal monoamine transporter EMT, which \nis important in clearing circulating adrenaline from the bloodstream, is not affected by most of the drugs that block NET. It is inhibited by phenoxybenzamine , however, \nand by various corticosteroids (see Ch. 27). This action of \ncorticosteroids may have some relevance to their therapeutic effect in conditions such as asthma, but is probably of minor \nimportance.\nThe main sites of action of drugs that affect adrenergic \ntransmission are summarised in Fig. 15.8.is minor, these drugs are no longer used for their peripheral \nsympathomimetic effects.\nINHIBITORS \u2003OF \u2003NORADRENALINE \u2003UPTAKE\nReuptake of released noradrenaline by NET is the most important mechanism by which its action is terminated. \nMany drugs inhibit NET, and thereby enhance the \neffects of both sympathetic nerve activity and circulating noradrenaline. NET is not responsible for clearing circulating \nadrenaline, so these drugs do not affect responses to this \namine.\nThe main class of drugs whose primary action is \ninhibition of NET are the tricyclic antidepressants (see Ch. \n48), for example imipramine. These drugs have their major effect on the CNS but also cause tachycardia and cardiac dysrhythmias, reflecting their peripheral effect on \nsympathetic transmission. Cocaine, known mainly for its \nabuse liability (Chs 49 and 50) and local anaesthetic activ -\nity (Ch. 44), enhances sympathetic transmission, causing tachycardia and increased arterial pressure (and, with \nchronic use, cardiomyopathy and cardiac hypertrophy). \nNANANANA synthesisTyrosine\nMetabolitesMethyldopa\nMeNA MeNA\nMeNAMAO\n\u03b2\u03b1 Noradrenergic varicosity\nNA\na-Adrenoceptor\nantagonists\nPOSTSYNAPTIC CELLNET\nNET inhibitors\nNET inhibitors\nEMTMAO inhibitors\nReserpine\na2-Adrenoceptor\nagonists\nb-Adrenoceptor\nantagonistsa2-Adrenoceptor\nantagonistsa-Methyltyrosine\nFig. 15.8 Generalised diagram of a noradrenergic nerve terminal, showing sites of drug action. EMT,\textraneuronal \tmonoamine \t\ntransporter; \tMAO,\tmonoamine \toxidase; \tMeNA,\tmethylnoradrenaline; \tNA,\tnoradrenaline; \tNET,\tneuronal\tnoradrenaline \ttransporter. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3208, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "46a2502e-3483-4a3c-a578-cd0957ea9425": {"__data__": {"id_": "46a2502e-3483-4a3c-a578-cd0957ea9425", "embedding": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43ebeb43-2d9e-434a-bb78-d9dc09bdbe67", "node_type": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c73e1ab677b119e8a94875f59c51c53777da3d3cd120a9deafcb50c52011a84"}, "3": {"node_id": "5c748ed3-3c06-4e8e-843e-31b10469da33", "node_type": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57d142115f9d2f548ae7f06a66017ada8395a4520232b4e3a791a4266e61085e"}}, "hash": "f373b15af63ee44b0d897696fe39f65363877b77e58f732b536862b1466f86ca", "text": "15 SECTION 2 \u2003\u2003CHEMICAL MEDIATORS\n216REFERENCES AND FURTHER READING\nGeneral\nRobertson, D., Biaggioni, I., Burnstock, G., Low, P.A., Paton, G.F.R. \n(Eds.), 2012. Primer on the autonomic nervous system, third ed. \nAcademic Press, Elsevier, Amsterdam. ( An excellent comprehensive \ntextbook on all aspects, including pharmacology, of the autonomic nervous \nsystem. By no means elementary despite the \u201cprimer\u201d in its title )\nAdrenoceptors\nAhles, A., Engelhardt, S., 2014. Polymorphic variants of adrenoceptors: \npharmacology, physiology, and role in disease. Pharmacol. Rev. 66, \n598\u2013637. ( Comprehensive overview of adrenoceptor variants with respect \nto the modulation of receptor function and expression and their role in \nphysiology and disease )\nAlexander, S.P.H., et al., 2015. The Concise Guide to Pharmacology \n2015/16: G protein-coupled receptors. Br. J. Pharmacol. 172, \n5744\u20135869. ( Summary articles on drug targets including adrenoceptors )\nBaker, J.G., Hall, I.P., Hill, S.J., 2003. Agonist and inverse agonist actions \nof \u03b2-blockers at the human \u03b22-adrenoceptor provide evidence for \nagonist-directed signalling. Mol. Pharmacol. 64, 1357\u20131369. ( \u03b2-blockers \ndiffer in their ability to activate and block cAMP and mitogen-activated \nprotein kinase pathways, pointing to possible differences in clinical efficacy \nbetween different members of the class )\nGilsbach, R., Hein, L., 2012. Are the pharmacology and physiology of \n\u03b12 adrenoceptors determined by \u03b12-heteroreceptors and autoreceptors \nrespectively? Br. J. Pharmacol. 165, 90\u2013102. ( Argues for the significance \nof auto- versus heteroreceptors in mediating the physiological functions \nof \u03b12-adrenoceptors and the pharmacological functions of \u03b12-adrenoceptor \nagonist drugs respectively )\nGuimaraes, S., Moura, D., 2001. Vascular adrenoceptors: an update. \nPharmacol. Rev. 53, 319\u2013356. ( Review describing the complex roles of \ndifferent adrenoceptors in blood vessels )\nKahsai, A.W., Xiao, K.H., Rajagopal, S., et al., 2011. Multiple \nligand-specific conformations of the beta(2)-adrenergic receptor. \nNature Chem. Biol. 7, 692\u2013700. ( Contrary to two-state models for receptor \nactivity, there is significant variability in receptor conformations induced by \ndifferent ligands, with implications for the design of new therapeutic \nagents )\nPapay, R.S., Ting, S., Piascik, M.T., Prasad, S.V.N., Perez, D.M., 2013. \n\u03b11A-Adrenergic receptors regulate cardiac hypertrophy in vivo \nthrough interleukin-6 secretion. Mol. Pharmacol. 83, 939\u2013948. ( Evidence \nthat, in the mouse, IL-6 is a major mediator of \u03b11A-AR cardiac hypertrophy )\nPhilipp, M., Hein, L., 2004. Adrenergic receptor knockout mice: distinct \nfunctions of 9 receptor subtypes. Pharm. Ther. 101, 65\u201374.Miscellaneous topics\nBermingham, D.P., Blakely, R.D., 2016. Kinase-dependent regulation \nof monoamine neurotransmitter transporters. Pharmacol. Rev. 68, \n888\u2013953. ( Reviews evidence for kinase-dependent control of DAT, NET and \nSERT )\nBiaggioni, I., 2017. The pharmacology of autonomic failure: from \nhypotension to hypertension.", "start_char_idx": 0, "end_char_idx": 3057, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5c748ed3-3c06-4e8e-843e-31b10469da33": {"__data__": {"id_": "5c748ed3-3c06-4e8e-843e-31b10469da33", "embedding": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43ebeb43-2d9e-434a-bb78-d9dc09bdbe67", "node_type": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c73e1ab677b119e8a94875f59c51c53777da3d3cd120a9deafcb50c52011a84"}, "2": {"node_id": "46a2502e-3483-4a3c-a578-cd0957ea9425", "node_type": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f373b15af63ee44b0d897696fe39f65363877b77e58f732b536862b1466f86ca"}, "3": {"node_id": "1d7047f5-4fe0-4581-a670-c96f870412ee", "node_type": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "117d069ce5af0ee4ec3c1a117b619b2a88cf8f02dd0e83bd7f6c19da2f5b909a"}}, "hash": "57d142115f9d2f548ae7f06a66017ada8395a4520232b4e3a791a4266e61085e", "text": "The pharmacology of autonomic failure: from \nhypotension to hypertension. Pharmacol. Rev. 69, 53\u201362. ( Fascinating \napplied pharmacology of a relatively uncommon but highly informative \ndisorder )\nBristow, M.R., 2011. Treatment of chronic heart failure with \nbeta-adrenergic receptor antagonists: a convergence of receptor \npharmacology and clinical cardiology. Circ. Res. 109, 1176\u20131194. \n(Argues that there is: \u2018ample room to improve antiadrenergic therapy, \nthrough novel approaches exploiting the nuances of receptor biology and/or \nintracellular signaling, as well as through pharmacogenetic targeting \u2019)\nEisenhofer, G., Kopin, I.J., Goldstein, D.S., 2004. Catecholamine \nmetabolism: a contemporary view with implications for physiology \nand medicine. Pharmacol. Rev. 56, 331\u2013349. ( Review that dismisses a \nnumber of fallacies concerning the routes by which catecholamines from \ndifferent sources are metabolised and excreted )\nElenkov, I.J., Wilder, R.L., Chrousos, G.P., et al., 2000. The sympathetic \nnerve \u2013 an integrative interface between two supersystems: the brain \nand the immune system. Pharmacol. Rev. 52, 595\u2013638. ( Detailed \ncatalogue of effects of catecholamines and the sympathetic nervous system on \nthe immune system )\nGainetdinov, R.R., Caron, M.G., 2003. Monoamine transporters: from \ngenes to behaviour. Annu. Rev. Pharmacol. Toxicol. 43, 261\u2013284. \n(Review article focusing on the characteristics of transgenic mice lacking \nspecific monoamine transporters )\nL\u00e9aut\u00e9-Labr\u00e8ze, C., Hoeger, P., Mazereeuw-Hautier, J., et al., 2015. \nA randomized, controlled trial of oral propranolol in infantile \nhemangioma. N. Engl. J. Med. 372, 735\u2013746. ( Randomised controlled trial \nwith adaptive design elegantly identifying a highly effective dose regimen. \nWill this stimulate more \u201cbasic\u201d research on b-adrenoceptor mechanisms in \nendothelial cell growth and development? )\nNonogaki, K., 2000. New insights into sympathetic regulation of glucose \nand fat metabolism. Diabetologia 43, 533\u2013549. ( Review of the complex \nadrenoceptor-mediated effects on the metabolism of liver, muscle and adipose \ntissue )\nSacco, E., Bientinesi, R., 2012. Mirabegron: a review of recent data and \nits prospects in the management of overactive bladder. Ther. Adv. \nUrol. 4, 315\u2013324. ( Pharmacology of a selective \u03b23-adrenoceptor agonist, \nlicensed to treat symptoms of overactive bladder )Drugs acting on noradrenergic nerve terminals \n\u2022\tDrugs\tthat\tinhibit\tnoradrenaline\t synthesis\t include:\n\u2013 \u03b1-methyltyrosine :\tblocks\ttyrosine\thydroxylase;\t not\t\nused\tclinically\n\u2013 carbidopa :\tblocks\tdopa\tdecarboxylase\t and\tis\tused\tin\t\ntreatment\t of\tparkinsonism\t (see\tCh.\t41);\tlittle\teffect\ton\t\nnoradrenaline\t synthesis.\n\u2022\t\u03b1-Methyldopa \tgives\trise\tto\tfalse\ttransmitter\t\n(\u03b1-methylnoradrenaline),\t which\tis\ta\tpotent\t \u03b12\tagonist,\t\nthus\tcausing\tpowerful\tpresynaptic\t inhibitory\tfeedback\t\n(also\tcentral\tactions).\tIts\tuse\tas\tan\tantihypertensive\t\nagent\tis\tnow\tlimited\tmainly\tto\tduring\tpregnancy.\n\u2022\tReserpine \tblocks\tnoradrenaline\t accumulation\t", "start_char_idx": 2993, "end_char_idx": 6012, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1d7047f5-4fe0-4581-a670-c96f870412ee": {"__data__": {"id_": "1d7047f5-4fe0-4581-a670-c96f870412ee", "embedding": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43ebeb43-2d9e-434a-bb78-d9dc09bdbe67", "node_type": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c73e1ab677b119e8a94875f59c51c53777da3d3cd120a9deafcb50c52011a84"}, "2": {"node_id": "5c748ed3-3c06-4e8e-843e-31b10469da33", "node_type": null, "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57d142115f9d2f548ae7f06a66017ada8395a4520232b4e3a791a4266e61085e"}}, "hash": "117d069ce5af0ee4ec3c1a117b619b2a88cf8f02dd0e83bd7f6c19da2f5b909a", "text": "\tblocks\tnoradrenaline\t accumulation\t in\tvesicles\t\nby\tvesicular\tmonoamine\t transporter\t (VMAT),\tthus\t\ndepleting\t noradrenaline\t stores\tand\tblocking\ttransmission.\t\nEffective\tin\thypertension\t but\tmay\tcause\tsevere\t\ndepression.\t Clinically\tobsolete.\n\u2022\tNoradrenergic\t neuron-blocking\t drugs\t(e.g.\t\nguanethidine ,\tbethanidine )\tare\tselectively\t concentrated\t\nin\tterminals\t and\tin\tvesicles\t(by\tnorepinephrine\t transporter\t\n[NET]\tand\tVMAT\trespectively),\t and\tblock\ttransmitter\t\nrelease,\tpartly\tby\tlocal\tanaesthetic\t action.\tEffective\tin\thypertension\t but\tcause\tsevere\tside\teffects\t(postural\t\nhypotension,\t diarrhoea,\t nasal\tcongestion,\t etc.),\tso\tnow\t\nlittle\tused.\n\u2022\t6-Hydroxydopamine \tis\tselectively\t neurotoxic\t for\t\nnoradrenergic\t neurons,\tbecause\tit\tis\ttaken\tup\tand\t\nconverted\t to\ta\ttoxic\tmetabolite.\t Used\texperimentally\t to\t\neliminate\tnoradrenergic\t neurons,\tnot\tused\tclinically.\n\u2022\tIndirectly\t acting\tsympathomimetic\t amines\t(e.g.\t\namphetamine ,\tephedrine ,\ttyramine)\tare\taccumulated\t\nby\tNET\tand\tdisplace\tnoradrenaline\t from\tvesicles,\t\nallowing\tit\tto\tescape.\tEffect\tis\tmuch\tenhanced\t by\t\nmonoamine\t oxidase\t(MAO)\tinhibition,\t which\tcan\tlead\tto\t\nsevere\thypertension\t following\tingestion\t of\ttyramine-rich\t\nfoods\tby\tpatients\ttreated\twith\tMAO\tinhibitors.\n\u2022\tIndirectly\t acting\tsympathomimetic\t agents\tare\tcentral\t\nnervous\tsystem\tstimulants.\t Methylphenidate \tand\t\natomoxetine \tare\tused\tto\ttreat\tattention\tdeficit\u2013\nhyperactivity\t disorder.\n\u2022\tDrugs\tthat\tinhibit\tNET\tinclude\tcocaine\tand\ttricyclic \nantidepressant \tdrugs.\tSympathetic\t effects\tare\t\nenhanced\t by\tsuch\tdrugs.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6041, "end_char_idx": 8081, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9a4312b7-1678-4723-b21d-9ef7b7bfe4c0": {"__data__": {"id_": "9a4312b7-1678-4723-b21d-9ef7b7bfe4c0", "embedding": null, "metadata": {"page_label": "223", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c848c3b0-a715-4eda-8af5-58b89114c916", "node_type": null, "metadata": {"page_label": "223", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48d9397164824894ddefef5ef2ee9580fb650ae1a0aecb007cc6f7c422da2ab7"}, "3": {"node_id": "738706ff-0ab9-45ac-bc77-9afce0241364", "node_type": null, "metadata": {"page_label": "223", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e5c9c65561b1c410d437d29996454f3e6ed2f5f04458d58f80bacf8f4e15fcf"}}, "hash": "51020694cd5a2aa75cd02db73c33fa2fd217aafb9bb0dcde6e6c3d32edb65940", "text": "217\n5-Hydroxytryptamine and the \npharmacology of migraine 16 CHEMICAL MEDIATORS SECTION 2 \nOVERVIEW\n5-Hydroxytryptamine (5-HT) is an important neuro -\ntransmitter in the brain and periphery. It is also a \nlocal hormone and is important in platelet function. \nWe describe its synthesis, storage and release as well as its role in the pathophysiology of three disorders \n(migraine, carcinoid syndrome and pulmonary hyper -\ntension). We also review the pharmacology of the \nnumerous drugs that act at 5-HT receptors.\n5-HYDROXYTRYPTAMINE\nA biologically active, low molecular-weight factor originally \ndetected in extracts of gut (\u2018enteramine\u2019) and in blood \nserum (\u2018serotonin\u2019) was eventually identified chemically as \n5-hydroxytryptamine (Fig. 16.1). Today, the terms \u20185-HT\u2019 and \n\u2018serotonin\u2019 are used interchangeably. 5-HT was subsequently \nfound in the central nervous system (CNS) and shown to \nfunction both as a neurotransmitter and as a local hormone in the peripheral vascular system. This chapter deals with the \nmetabolism, distribution and physiological roles of 5-HT in \nthe periphery, and with the different types of 5-HT receptor and the drugs that act on them. Further information on the role of 5-HT in the brain, its relationship to psychiatric \ndisorders and the actions of psychotropic drugs, is presented \nin Chapters 40, 47 and 48. The use of drugs that modulate 5-HT in the gut is dealt with in Chapter 31.\nDISTRIBUTION, BIOSYNTHESIS \nAND DEGRADATION\nThe highest concentrations of 5-HT are found in three organs:\n\u2022\tIn the wall of the intestine. Over 90% of the total amount \nin the body is present in the enterochromaffin cells \n(endocrine cells with distinctive staining properties) \nin the gut. These cells are derived from the neural \ncrest and resemble those of the adrenal medulla. They are found mainly in the stomach and small intestine \ninterspersed with mucosal cells. Some 5-HT also \noccurs in nerve cells of the myenteric plexus, where it functions as an excitatory neurotransmitter (see Chs 13 \nand 31).\n\u2022\tIn blood. Platelets contain high concentrations of 5-HT. \nThey accumulate it from the plasma by an active \ntransport system and release it from cytoplasmic \ngranules when they aggregate (hence the high concentration of 5-HT in serum from clotted blood, \nsee Ch. 25).\n\u2022\tIn the CNS. 5-HT is a transmitter in the CNS and is \npresent in high concentrations in localised regions of the midbrain. Its functional role is discussed in Chapter 40.\nAlthough 5-HT is present in the diet, most of this is \nmetabolised before entering the bloodstream. Endogenous \n5-HT arises from a biosynthetic pathway similar to that of noradrenaline (see Ch. 15), except that the precursor amino \nacid is tryptophan instead of tyrosine (see Fig. 16.1). Tryp -\ntophan is converted to 5-hydroxytryptophan in chromaffin \ncells and neurons by the action of tryptophan hydroxylase , an \nenzyme confined to 5-HT-producing cells (but not present in platelets). The 5-hydroxytryptophan is then decarboxylated to 5-HT by the ubiquitous L-aromatic acid decarboxylase, which \nalso participates in the synthesis of catecholamines (Ch. 15) and histamine (Ch. 18). Platelets (and neurons) possess a high-affinity 5-HT uptake mechanism. They become loaded with 5-HT as they pass through the intestinal circulation, \nwhere the local concentration is relatively", "start_char_idx": 0, "end_char_idx": 3358, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "738706ff-0ab9-45ac-bc77-9afce0241364": {"__data__": {"id_": "738706ff-0ab9-45ac-bc77-9afce0241364", "embedding": null, "metadata": {"page_label": "223", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c848c3b0-a715-4eda-8af5-58b89114c916", "node_type": null, "metadata": {"page_label": "223", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48d9397164824894ddefef5ef2ee9580fb650ae1a0aecb007cc6f7c422da2ab7"}, "2": {"node_id": "9a4312b7-1678-4723-b21d-9ef7b7bfe4c0", "node_type": null, "metadata": {"page_label": "223", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51020694cd5a2aa75cd02db73c33fa2fd217aafb9bb0dcde6e6c3d32edb65940"}}, "hash": "2e5c9c65561b1c410d437d29996454f3e6ed2f5f04458d58f80bacf8f4e15fcf", "text": "as they pass through the intestinal circulation, \nwhere the local concentration is relatively high. Because \nthe mechanisms of synthesis, storage, release and reuptake of 5-HT are very similar to those of noradrenaline, many \ndrugs affect both processes indiscriminately (see Ch. 15). \nHowever, selective serotonin reuptake inhibitors (SSRIs) \nhave been developed and are important therapeutically \nas anxiolytics and antidepressants (Chs 45 and 48). 5-HT \nis often stored in neurons and chromaffin cells as a co-transmitter, together with various peptide hormones, such \nas somatostatin , substance P or vasoactive intestinal polypeptide \n(Ch. 19).\nDegradation of 5-HT (see Fig. 16.1) occurs mainly through \noxidative deamination, catalysed by monoamine oxidase A , \nfollowed by oxidation to 5-hydroxyindoleacetic acid (5-HIAA), \nthe pathway again being the same as that of noradrenaline catabolism. 5-HIAA is excreted in the urine and serves as \nan indicator of 5-HT production in the body. This is used, for example, in the diagnosis of carcinoid syndrome.\nCLASSIFICATION OF 5-HT RECEPTORS\n\u25bc It was realised long ago that the actions of 5-HT are not all mediated \nby receptors of the same type, and various pharmacological classifica -\ntions have come and gone. The current system is summarised in Table \n16.1 and full details are available at . \nThis classification takes into account sequence data derived from \ncloning, signal transduction mechanisms and pharmacological specific -\nity as well as the phenotypes of 5-HT receptor \u2018knock-out\u2019 mice.\nTheir diversity is astonishing. Currently, there are some 14 known \nreceptor subtypes (together with an extra gene in mouse). These are \ndivided into seven classes (5-HT 1\u20137), one of which (5-HT 3) is a ligand-\ngated cation channel while the remainder are G protein\u2013coupled \nreceptors (GPCRs; see Ch. 3). The six GPCR families are further \nsubdivided into some 13 receptor subtypes based on their sequence and pharmacology. Most subtypes are found in all species so far \nexamined, but there are some exceptions (the 5-HT\n5B gene is found \nin mouse but has not been found in humans). The sequences of 5-HT 1 \nand 5-HT 2 receptors are highly conserved among species, but the \n5-HT 4\u20137 receptors are more diverse and are grouped together largely mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3265, "end_char_idx": 6074, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "df0db0d6-f595-40ef-a7ed-052d6b6da95f": {"__data__": {"id_": "df0db0d6-f595-40ef-a7ed-052d6b6da95f", "embedding": null, "metadata": {"page_label": "224", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ac14d19a-bd21-4bb4-a1fb-50123ed126af", "node_type": null, "metadata": {"page_label": "224", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e714867f6dcc3b8b406200ae1f23ac132aea4d98dea3daf3f55b16a04255c78e"}, "3": {"node_id": "7100c01a-2f22-4f66-ba94-ab27768e543b", "node_type": null, "metadata": {"page_label": "224", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5b7563f3f9e6ea824833570cbf0a4dcfb33c1bfc355b614f0dede64acf1559c"}}, "hash": "43652f2bac12541d6025d67b4e0b213dbd202b9de058feef3c28c79d13b28036", "text": "16 SECTION 2 CHEMICAL MEDIATORS\n218on pharmacological grounds. Most 5-HT GPCRs signal through \nadenylyl cyclase/cAMP, but some (the 5-HT 2 subtype) activate \nphospholipase C to generate phospholipid-derived second messengers \n(see Ch. 3).\nIn addition to these main subtypes, many genetic isoforms have been \nfound, giving rise to four or more variants of some of these receptors. \nThe pharmacological and pathophysiological relevance of these genetic isoforms is unclear.\nWith the exception of 5-HT\n3-selective agents, 5-HT receptor agonists \nand antagonists are relatively non-selective with respect to different \nreceptor subtypes. This makes their pharmacology difficult to interpret \nand summarise.\nMany transgenic mice lacking functional members of this receptor \nfamily have been produced (see for example Bonasera & Tecott, 2000). The functional deficits in such animals are generally quite subtle, \nsuggesting that these receptors may serve to modulate, rather than \nto enable, physiological responses. Table 16.1 gives an overview of the most important receptors. Some of the more significant drug \ntargets include the following:\n5-HT\n1 receptors. Those of pharmacological significance occur mainly \nin the brain, the subtypes being distinguished on the basis of their \nregional distribution and their pharmacological specificity. Their \nfunction is mainly inhibitory. The 5-HT 1A subtype is particularly \nimportant in relation to mood and behaviour (see Chs 45, 47) and \n5-HT 1 \u2018knock-out\u2019 mice exhibit defects in sleep regulation, learning \nability and other CNS functions. Receptor polymorphisms may be associated with increased susceptibility to substance abuse. The 5-HT\n1B \nand 5-HT 1D subtypes, which are expressed in neurones innervating \ncerebral blood vessels, are believed to be important in migraine and are the target for triptans (e.g. sumatriptan), an important group of \ndrugs used to treat acute attacks ( Fig. 16.2 ). Unfortunately, the 5-HT\n1B \nreceptor is also present in the vasculature of the heart and elsewhere, explaining some of the unwanted effects associated with triptan N\nHCH2CHCOOH\nNH2\nNHCH\n2CHCOOH\nNH2HO\nNHCH\n2CH2NH2HO\nNHCH\n2CHO HO\nNHCH\n2COOH HOTryptophan hydroxylase\nL-Aromatic acid decarboxylase\n(= dopa decarboxylase)\nMonoamine oxidase\nAldehyde dehydrogenase\n5-Hydroxyindoleacetic\nacid (5-HIAA)5-Hydroxytryptamine\n(serotonin)5-HydroxytryptophanTryptophan\nFig. 16.1 Biosynthesis and metabolism of \n5-hydroxytryptamine. \nDistribution, biosynthesis and degradation \nof 5-hydroxytryptamine (5-HT) \n\u2022\tTissues \trich \tin \t5-HT \tare:\n\u2013\tgastrointestinal \ttract \t(chromaffin \tcells \tand \tenteric \t\nneurons)\n\u2013\tplatelets\n\u2013\tcentral\tnervous \tsystem.\n\u2022\tMetabolism \tclosely \tparallels \tthat \tof \tnoradrenaline.\n\u2013\t5-HT\tis \tformed \tfrom \tdietary \ttryptophan, \twhich \tis \t\nconverted \tto \t5-hydroxytryptophan \tby \ttryptophan \t\nhydroxylase, \tthen \tto \t5-HT \tby \ta \tnon-specific \t\ndecarboxylase.\n\u2022\t5-HT\tis \ttransported \tinto \tcells \tby \ta \tspecific \tserotonin \t\nuptake\ttransporter \t(SERT).\n\u2013\tDegradation \toccurs \tmainly \tby \tmonoamine \toxidase,", "start_char_idx": 0, "end_char_idx": 3071, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7100c01a-2f22-4f66-ba94-ab27768e543b": {"__data__": {"id_": "7100c01a-2f22-4f66-ba94-ab27768e543b", "embedding": null, "metadata": {"page_label": "224", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ac14d19a-bd21-4bb4-a1fb-50123ed126af", "node_type": null, "metadata": {"page_label": "224", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e714867f6dcc3b8b406200ae1f23ac132aea4d98dea3daf3f55b16a04255c78e"}, "2": {"node_id": "df0db0d6-f595-40ef-a7ed-052d6b6da95f", "node_type": null, "metadata": {"page_label": "224", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43652f2bac12541d6025d67b4e0b213dbd202b9de058feef3c28c79d13b28036"}}, "hash": "f5b7563f3f9e6ea824833570cbf0a4dcfb33c1bfc355b614f0dede64acf1559c", "text": "\toccurs \tmainly \tby \tmonoamine \toxidase, \t\nforming\t5-hydroxyindoleacetic \tacid \t(5-HIAA), \twhich \t\nis\texcreted \tin \turine.Actions and functions of \n5-hydroxytryptamine (5-HT)\n\u2022\tImportant \tactions \tare:\n\u2013\tincreased \tgastrointestinal \tmotility \t(direct \texcitation \tof \t\nsmooth\tmuscle \tand \tindirect \taction \tvia \tenteric \t\nneurons)\n\u2013\tcontraction \tof \tother \tsmooth \tmuscle \t(bronchi, \tuterus)\n\u2013\tmixture\tof \tvascular \tconstriction \t(direct \tand \tvia \t\nsympathetic \tinnervation) \tand \tdilatation \t(endothelium \t\ndependent)\n\u2013\tplatelet\taggregation\n\u2013\tstimulation \tof \tperipheral \tnociceptive \tnerve \tendings\n\u2013\texcitation/inhibition \tof \tcentral \tnervous \tsystem \t\nneurons.\n\u2022\tPostulated \tphysiological \tand \tpathophysiological \troles \t\ninclude:\n\u2013\tin\tperiphery: \tperistalsis, \tvomiting, \tplatelet \t\naggregation \tand \thaemostasis, \tinflammation, \t\nsensitisation \tof \tnociceptors \tand \tmicrovascular \t\ncontrol\n\u2013\tin\tcentral \tnervous \tsystem: \tmany \tpostulated \t\nfunctions, \tincluding \tcontrol \tof \tappetite, \tsleep, \tmood, \t\nhallucinations, \tstereotyped \tbehaviour, \tpain \t\nperception \tand \tvomiting.\n\u2022\tClinical\tconditions \tassociated \twith \tdisturbed \t\n5-hydroxytryptamine \t(5-HT) \tinclude:\n\u2013\tmigraine, \tcarcinoid \tsyndrome, \tpulmonary \t\nhypertension, \tmood \tdisorders \tand \tanxiety.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3031, "end_char_idx": 4783, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c65f434f-8d12-49bb-ade9-77664172f712": {"__data__": {"id_": "c65f434f-8d12-49bb-ade9-77664172f712", "embedding": null, "metadata": {"page_label": "225", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fee661cc-64cd-425c-bc88-4bdcf05df2de", "node_type": null, "metadata": {"page_label": "225", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ee5b018ac6e0807e8055c613b4ca46fc700bbd4c5eef22f09f52fd7563c966e6"}, "3": {"node_id": "597fdb15-60bd-4243-ba82-96debb052c8a", "node_type": null, "metadata": {"page_label": "225", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a9b38cebe28db867c9c2031cb82e23872b7f80a8a6fff242693f7a381231514"}}, "hash": "80bf5d4eb080604d59a3d71f077ce018f45103cd47a355afe39af7a9e082d078", "text": "16 5-Hy DRO xyTRypTAMI nE A n D THE p HARMACOLO gy O f MI g RAI n ETable 16.1 Some significant drugs acting at the main 5-HT receptor subtypes\nReceptor Location Main functionPrimary signalling \nsystemSignificant drugs\nAgonists Antagonists\n5-HT 1A Chiefly CNSNeuronal inhibition\nBehavioural effects: sleep, feeding, thermoregulation, anxietyG protein (G\ni/Go)\n8-OH-DPAT, triptans, clozapine, buspirone (PA), cabergolineMethiothepin, yohimbine, ketanserin, pizotifen, spiperone\u2193 cAMP (may also modulate Ca\n2+ channels)\n5-HT 1BCNS, vascular smooth muscle, many other sitesPresynaptic inhibition G protein (G\ni/Go) 8-OH-DPAT, triptans (PA), clozapine, cabergoline, dihydroergotamineMethiothepin (IA), yohimbine, ketanserin, spiperoneBehavioural effects \u2193 cAMP (may also modulate Ca\n2+ channels) Pulmonary vasoconstriction\n5-HT 1DCNS, blood vesselsCerebral vasoconstriction G protein (G\ni/Go) 8-OH-DPAT, triptans, clozapine, cabergoline (PA), dihydroergotamine/ ergotamineMethiothepin (IA), yohimbine, ketanserin, methysergide, spiperoneBehavioural effects: locomotion\u2193 cAMP (may also modulate Ca\n2+ channels)\n5-HT 1E CNS \u2014G protein (G i/Go)\n\u2193 cAMP (may also modulate Ca\n2+ channels)8-OH-DPAT, triptans; clozapine, dihydroergotamineMethiothepin, yohimbine, methysergide\n5-HT\n1FCNS, uterus, heart, GI tract\u2014G protein (G\ni/Go)\n\u2193 cAMP (may also modulate Ca\n2+ channels)8-OH-DPAT, triptans; clozapine dihydroergotamine/ ergotamine, lamistidanYohimbine, methysergide\n5-HT\n2ACNS, PNS, smooth muscle, plateletsNeuronal excitationBehavioural effectsSmooth muscle contraction (gut, bronchi, etc.)Platelet aggregationVasoconstriction/vasodilatationG protein (G\nq/G11)\n\u2191 IP 3, Ca2+LSD, cabergoline, methysergide (PA), 8-OH-DPAT, ergotamine (PA)Ketanserin, clozapine, \nmethysergide\n5-HT 2B Gastric fundus ContractionG protein (G q/G11)\n\u2191 IP 3, Ca2+LSD, cabergoline, methysergide (PA), 8-OH-DPAT, ergotamine (PA)Ketanserin, clozapine, yohimbine\n5-HT\n2CCNS, lymphocytes\u2014G protein (G\nq/G11)\n\u2191 IP 3, Ca2+LSD, cabergoline, methysergide (PA), 8-OH-DPAT, ergotamine (PA)Ketanserin, clozapine (IA), methysergide\n5-HT\n3 \n(recently renamed 5-HT\n3A)PNS, CNSNeuronal excitation (autonomic, nociceptive neurons)EmesisBehavioural effects: anxietyLigand-gated cation channel2-Me-5-HT,chloromethyl biguanideGranisetron, ondansetron, palonosetron.\n5-HT\n4PNS (GI tract), CNSNeuronal excitationGI motilityG protein (G\ns)\n\u2191 cAMPMetoclopramide, tegaserod (PA),", "start_char_idx": 0, "end_char_idx": 2425, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "597fdb15-60bd-4243-ba82-96debb052c8a": {"__data__": {"id_": "597fdb15-60bd-4243-ba82-96debb052c8a", "embedding": null, "metadata": {"page_label": "225", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fee661cc-64cd-425c-bc88-4bdcf05df2de", "node_type": null, "metadata": {"page_label": "225", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ee5b018ac6e0807e8055c613b4ca46fc700bbd4c5eef22f09f52fd7563c966e6"}, "2": {"node_id": "c65f434f-8d12-49bb-ade9-77664172f712", "node_type": null, "metadata": {"page_label": "225", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80bf5d4eb080604d59a3d71f077ce018f45103cd47a355afe39af7a9e082d078"}}, "hash": "5a9b38cebe28db867c9c2031cb82e23872b7f80a8a6fff242693f7a381231514", "text": "cAMPMetoclopramide, tegaserod (PA), cisaprideTropisetron\n5-HT\n5A CNSModulation of exploratory behaviour (rodents)?G protein (G\ns)\n\u2191 cAMPTriptans, 8-OH-DPATClozapine, methysergide, yohimbine, ketanserin\n5-HT\n6 CNS, leukocytesLearning and memory, modulation of neurotransmission.G protein (G\ns)\n\u2191 cAMPLSD, ergotamineClozapine (IA), spiperone, methysergide, dihydroergotamine\n5-HT\n7CNS, GI tract, blood vesselsThermoregulation?Circadian rhythm?G protein (G\ns)\n\u2191 cAMPBuspirone (PA), bromocriptine, cisapride, 8-OH-DPAT, LSD,Clozapine (IA), methysergide, buspirone, dihydroergotamine, ketanserin, yohimbine\nThe\treceptor \tclassification \tsystem \tis \tbased \tupon \tthe \tIUPHAR \tdatabase \tat \t\nMany\tdrugs \there \tare \tnot \tused \tclinically \tor \tare \tnot \tcurrently \tavailable \tin \tthe \tUnited \tKingdom \t(e.g. \ttropisetron), \tbut \tare \tincluded \tas \tthey \tare \toften \tused \texperimentally \tor \treferred \tto \tin \tthe \tliterature.\nThe\tlist\tof \tagonists \tand \tantagonists \tis \tnot \texhaustive.\n2-Me-5-HT, \t2-methyl-5-hydroxytryptamine; \t8-OH-DPAT, \t8-hydroxy-2-(di-n-propylamino) \ttetraline; \tCNS, central nervous system ;\tGI,\tgastrointestinal; \tIA,\tinverse\tagonist; \tIP3,\tinositol\t\ntrisphosphate; \tLSD,\tlysergic\tacid \tdiethylamide; \tPA,\tpartial\tagonist; \tPNS,\tperipheral \tnervous \tsystem.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2390, "end_char_idx": 4173, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "82183981-1f50-4cca-addd-985e85f83e8b": {"__data__": {"id_": "82183981-1f50-4cca-addd-985e85f83e8b", "embedding": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a5b4439a-e942-4634-99b3-45a57ba89e28", "node_type": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "441cc69136937dc667b5dd20daa9336b80c4554c98a0e16f8d3dfb4cb3b41530"}, "3": {"node_id": "743358ca-5775-43a6-a553-51840100d806", "node_type": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fcf52cfed645d37a40b2a45e829b6a5e8d4fea2217cbea5679f72d3cf71034f8"}}, "hash": "ea7776dbece8797feb14daa67224ef04fd745bd2038c72f27c99e2a4ed23bf59", "text": "16 SECTION 2 CHEMICAL MEDIATORS\n220exhibit a complex phenotype including abnormal feeding behaviour \nin response to stress.\n5-HT 5, 5-HT 6 and 5-HT 7 receptors. Little is known about these receptors. \nAll are present in the CNS as well as other tissues. There are two \ngenes for 5-HT 5 isoforms but only one codes for a functional receptor \nin humans although both may be functional in rodents. In addition to its action on 5-HT\n1B/D receptors, sumatriptan is also an antagonist \nat the 5-HT 7 receptor suggesting this receptor may also be a significant \ntarget for migraine treatment (Agosti, 2007).\ntherapy. The hapless \u20185-HT 1C\u2019 receptor \u2013 actually the first to be cloned \n\u2013 has been officially declared non-existent, having been ignominiously reclassified as the 5-HT\n2C receptor when it was found to be linked to \ninositol trisphosphate production rather than adenylyl cyclase.\n5-HT 2 receptors. These are present in the CNS but are also particularly \nimportant in the periphery. The effects of 5-HT on smooth muscle \nand platelets, which have been known for many years, are mediated \nby the 5-HT 2A receptor, as are some of the behavioural effects of \nagents such as lysergic acid diethylamide (LSD; see Table 16.1 and \nCh. 49). 5-HT 2 receptors are linked to phospholipase C and thus \nstimulate inositol trisphosphate formation. The 5-HT 2A subtype is \nfunctionally the most important, the others having a much more \nlimited distribution and functional role. The role of 5-HT 2 receptors \nin normal physiology is probably a minor one, but it becomes more prominent in pathological conditions such as asthma and vascular \nthrombosis (see Chs 25 and 29). Mice lacking 5-HT\n2 receptors exhibit \ndefects in colonic motility (5-HT 2A), heart defects (5-HT 2B) and CNS \ndisorders (5-HT 2C).\n5-HT 3 receptors. 5-HT 3 receptors are exceptional in being membrane \nion channels (Ch. 3) and cause excitation directly, without involvement \nof any second messenger. The receptor itself consists of a homo- or \nhetero-pentameric assembly of distinct subunits which are designated by further subscript letters (e.g. 5-HT\n3A\u2013E in humans). 5-HT 3 receptors \noccur mainly in the peripheral nervous system, particularly on \nnociceptive sensory neurons (see Ch. 43) and on autonomic and enteric \nneurons, where 5-HT exerts a strong excitatory effect. 5-HT evokes pain when injected locally; when given intravenously, it elicits a fine \ndisplay of autonomic reflexes, which result from excitation of many \ntypes of vascular, pulmonary and cardiac sensory nerve fibres. 5-HT\n3 \nreceptors also occur in the brain, particularly in the area postrema, a \nregion of the medulla involved in the vomiting reflex, and selective 5-HT\n3 antagonists are used as antiemetic drugs (see Ch. 31). Poly-\nmorphisms in the subunits are associated with increased susceptibility \nto nausea and vomiting.\n5-HT 4 receptors. These occur in the brain, as well as in peripheral \norgans such as the gastrointestinal tract, bladder and heart. Their \nmain physiological role appears to be in the gastrointestinal tract, \nwhere they produce neuronal excitation and mediate the effect of 5-HT in stimulating peristalsis. Mice deficient in the 5-HT\n4 receptor 100\n90\n8070605040302010\n0\n0 0.5 1.0 1.5\n2.0\nHours after dosingEstimated", "start_char_idx": 0, "end_char_idx": 3293, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "743358ca-5775-43a6-a553-51840100d806": {"__data__": {"id_": "743358ca-5775-43a6-a553-51840100d806", "embedding": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a5b4439a-e942-4634-99b3-45a57ba89e28", "node_type": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "441cc69136937dc667b5dd20daa9336b80c4554c98a0e16f8d3dfb4cb3b41530"}, "2": {"node_id": "82183981-1f50-4cca-addd-985e85f83e8b", "node_type": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea7776dbece8797feb14daa67224ef04fd745bd2038c72f27c99e2a4ed23bf59"}, "3": {"node_id": "aecf4001-6a3e-48e1-91a4-13d84799ba31", "node_type": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef9e05f71054114e82c69691a81ed2e60a5256488fd028a3bcdf4bd37390edff"}}, "hash": "fcf52cfed645d37a40b2a45e829b6a5e8d4fea2217cbea5679f72d3cf71034f8", "text": "0.5 1.0 1.5\n2.0\nHours after dosingEstimated probability of response (%)\nPlacebo (n = 623)Rizatriptan 10 mg (n = 1160)\nFig. 16.2 The triptan, rizatriptan, relieves the pain \nassociated with attacks of migraine. \tThe\tgraph \tis \ta \tKaplan\u2013\nMeir\tplot\tshowing \tthe \tprobability \tof \texperiencing \trelief \tfrom \tthe \t\npain\tof\tthe \tattack \tafter \ttreatment \twith \tplacebo \tor \twith \t10 \tmg \t\nrizatriptan. \t(Modified \tfrom \tDahlof \tet \tal., \t1999).5-Hydroxytryptamine (5-HT) \nreceptors \n\u2022\tThere\tare \tseven \tfamilies \t(5-HT1\u20137),\twith\tfurther \t\nsubtypes\tof \t5-HT1\t(A\u2013F)\tand \t5-HT 2\t(A\u2013C).\tMany \t\npolymorphisms \tand \tsplice \tvariants \thave \talso \tbeen \t\nobserved.\n\u2022\tAll\tare\tG \tprotein\u2013coupled \treceptors, \texcept \t5-HT 3,\t\nwhich\tare \tligand-gated \tcation \tchannels.\n\u2013\t5-HT 1\treceptors \toccur \tmainly \tin \tthe \tcentral \tnervous \t\nsystem\t(CNS) \t(all \tsubtypes) \tand \tsome \tblood \tvessels \t\n(5-HT1B/D\tsubtypes). \tSome \teffects \tare \tmediated \t\nthrough\tinhibition \tof \tadenylyl \tcyclase, \tinclude \tneural \t\ninhibition\tand \tvasoconstriction. \tSpecific \tagonists \t\ninclude\ttriptans \t(used \tin \tmigraine \ttherapy) \tand \t\nbuspirone \t(used\tin\tanxiety). \tSpecific \tantagonists \t\ninclude\tspiperone \tand\tmethiothepin.\n\u2013\t5-HT 2\treceptors \toccur \tin \tthe \tCNS \tand \tmany \t\nperipheral \tsites \t(especially \tblood \tvessels, \tplatelets, \t\nautonomic \tneurons). \tNeuronal \tand \tsmooth \tmuscle \t\neffects\tare \texcitatory \tand \tsome \tblood \tvessels \tare \t\ndilated\tas \ta \tresult \tof \tnitric \toxide \trelease \tfrom \t\nendothelial \tcells. \t5-HT 2\treceptors \tact \tthrough \tthe \t\nphospholipase \tC/inositol \ttrisphosphate \tpathway. \t\nLigands\tinclude \tlysergic \tacid \tdiethylamide \t(LSD;\t\nagonist\tin \tCNS, \tantagonist \tin \tperiphery). \tSpecific \t\nantagonists \tinclude \tketanserin.\n\u2013\t5-HT 3\treceptors \toccur \tin \tthe \tperipheral \tnervous \t\nsystem,\tespecially \tnociceptive \tafferent \tneurons \tand \t\nenteric\tneurons, \tand \tin \tthe \tCNS. \tEffects \tare \t\nexcitatory, \tmediated \tthrough \tdirect \treceptor-coupled \t\nion\tchannels. \t2-Methyl-5-HT \tis\ta\tspecific \tagonist. \t\nSpecific\tantagonists \tinclude \tondansetron \tand\t\npalonosetron .\tAntagonists \tare \tused \tmainly", "start_char_idx": 3255, "end_char_idx": 5372, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aecf4001-6a3e-48e1-91a4-13d84799ba31": {"__data__": {"id_": "aecf4001-6a3e-48e1-91a4-13d84799ba31", "embedding": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a5b4439a-e942-4634-99b3-45a57ba89e28", "node_type": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "441cc69136937dc667b5dd20daa9336b80c4554c98a0e16f8d3dfb4cb3b41530"}, "2": {"node_id": "743358ca-5775-43a6-a553-51840100d806", "node_type": null, "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fcf52cfed645d37a40b2a45e829b6a5e8d4fea2217cbea5679f72d3cf71034f8"}}, "hash": "ef9e05f71054114e82c69691a81ed2e60a5256488fd028a3bcdf4bd37390edff", "text": "\tas \t\nantiemetic \tdrugs \tbut \tmay \talso \tbe \tanxiolytic.\n\u2013\t5-HT 4\treceptors \toccur \tmainly \tin \tthe \tenteric \tnervous \t\nsystem\t(also \tin \tthe \tCNS). \tEffects \tare \texcitatory, \t\nthrough\tstimulation \tof \tadenylyl \tcyclase, \tcausing \t\nincreased\tgastrointestinal \tmotility. \tSpecific \tagonists \t\ninclude\tmetoclopramide \t(used\tto\tstimulate \tgastric \t\nemptying).\n\u2013\t5-HT 5\treceptors \t(one \tsubtype \tin \thumans) \tare \t\nlocated\tin \tthe \tCNS. \tLittle \tis \tknown \tabout \ttheir \trole \t\nin\thumans.\n\u2013\t5-HT 6\treceptors \tare \tlocated \tin \tthe \tCNS \tand \ton \t\nleukocytes. \tLittle \tis \tknown \tabout \ttheir \trole \tin \t\nhumans.\n\u2013\t5-HT 7\treceptors \tare \tlocated \tin \tthe \tCNS \tand \tthe \t\ngastrointestinal \ttract. \tLittle \tis \tknown \tabout \ttheir \trole \t\nin\thumans \tbut \temerging \tdata \tshows \tthey \tmay \talso \t\nbe\timportant \tin \tmigraine.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5412, "end_char_idx": 6709, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "58b0b0fe-ca45-46b8-b85e-0ce8aafcacca": {"__data__": {"id_": "58b0b0fe-ca45-46b8-b85e-0ce8aafcacca", "embedding": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bb3a579e-f618-418a-bf1a-74d40ad6fd53", "node_type": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "868a233866306b92f539f61b0f2858bbfcf6c24d051063d2575300987cbd903e"}, "3": {"node_id": "803a9e21-eb58-48ae-b348-1814de902c9a", "node_type": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "178f1d91ccf40bcda9482dbf61a63707e536fd8787a1600241b7b6627137fba1"}}, "hash": "d6b6be8bb3ef9413d6344d3e4f9628d2e8366559124aa5d7123bfd359b2725df", "text": "16 5-Hy DRO xyTRypTAMI nE A n D THE p HARMACOLO gy O f MI g RAI n E\n221Ergot alkaloids \n\u2022\tThese\tactive \tsubstances \tare \tproduced \tby \ta \tfungus \t\nthat\tinfects \tcereal \tcrops \tand \tare \tresponsible \tfor \t\noccasional \tpoisoning \tincidents. \tThe \tmost \timportant \t\ncompounds \tare:\n\u2013 ergotamine \tused\tin\tmigraine \tprophylaxis, \tand \t\ndihydroergotamine\n\u2013 ergometrine ,\tused\tin\tobstetrics \tto \tprevent \t\npostpartum \thaemorrhage\n\u2013 methysergide ,\tformerly\tused \tto \ttreat \tcarcinoid \t\nsyndrome, \tand \tmigraine \tprophylaxis\n\u2013 bromocriptine ,\tused\tin\tparkinsonism \tand \t\nendocrine \tdisorders.\n\u2022\tMain\tsites \tof \taction \tare \t5-hydroxytryptamine \t(5-HT) \t\nreceptors, \tdopamine \treceptors \tand \tadrenoceptors \t\n(mixed\tagonist, \tantagonist \tand \tpartial \tagonist \teffects).\n\u2022\tUnwanted \teffects \tinclude \tnausea \tand \tvomiting, \t\nvasoconstriction \t(ergot \talkaloids \tare \tcontraindicated \tin \t\npatients\twith \tperipheral \tvascular \tdisease).PHARMACOLOGICAL EFFECTS\nThe actions of 5-HT are numerous and complex and there \nis considerable species variation. This complexity reflects \nthe profusion of 5-HT receptor subtypes. The main sites \nof action are as follows.\nGastrointestinal tract. Most 5-HT receptor subtypes are \npresent in the gut with the exception of those of the 5-HT 5/6 \nfamily. Only about 10% of 5-HT in the intestine is located \nin neurons, where it acts as a neurotransmitter, while the \nremainder is located in the enterochromaffin cells, which act as sensors to transduce information about the state of \nthe gut, and release 5-HT into the lamina propria. Broadly \nspeaking, 5-HT receptors are present on most neuronal \ncomponents of the enteric nervous system as well as smooth \nmuscle, secretory and other cells. Their main function is \nto regulate peristalsis, intestinal motility, secretion and visceral sensitivity; the responses observed are complex and the reader is referred to Beattie and Smith (2008) for \na more comprehensive account.\nThe importance of 5-HT in the gut is underlined by the \nwidespread distribution in the enteric nervous system and the intestinal mucosa, of the serotonin uptake transporter \n(SERT) which rapidly and efficiently removes extracellular 5-HT, thus limiting its action. Inhibitors of this transporter \nsuch as the SSRIs (Ch. 48) exaggerate the action of 5-HT \nin the gut, explaining some of the common side effects of these drugs, which include diarrhoea. Interestingly, there \nis evidence for genetic defects in this reuptake system in \nirritable bowel syndrome, which might explain the rather bewildering symptoms of the disease (Ch. 31).\nSmooth muscle. In many species (although only to a \nminor extent in humans), smooth muscle outside of the \ngastrointestinal tract (e.g. uterus and bronchial tree) is also \ncontracted by 5-HT.\nBlood vessels. The effect of 5-HT on blood vessels \ndepends on various factors, including the size of the vessel, \nthe species and the prevailing sympathetic activity. Large \nvessels, both arteries and veins, are usually constricted by 5-HT, although the sensitivity varies greatly. This is the \nresult of a direct action on vascular smooth muscle cells, \nmediated through 5-HT\n2A", "start_char_idx": 0, "end_char_idx": 3163, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "803a9e21-eb58-48ae-b348-1814de902c9a": {"__data__": {"id_": "803a9e21-eb58-48ae-b348-1814de902c9a", "embedding": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bb3a579e-f618-418a-bf1a-74d40ad6fd53", "node_type": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "868a233866306b92f539f61b0f2858bbfcf6c24d051063d2575300987cbd903e"}, "2": {"node_id": "58b0b0fe-ca45-46b8-b85e-0ce8aafcacca", "node_type": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6b6be8bb3ef9413d6344d3e4f9628d2e8366559124aa5d7123bfd359b2725df"}, "3": {"node_id": "b2aaac40-91cc-4432-b2ea-bd5dfa64d183", "node_type": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95be378f2138c386857a407297c1632ae9fc8a180775bd22bff353333a782cec"}}, "hash": "178f1d91ccf40bcda9482dbf61a63707e536fd8787a1600241b7b6627137fba1", "text": "direct action on vascular smooth muscle cells, \nmediated through 5-HT\n2A receptors. Dilatation of large \nintracranial vessels contributes to headache whereas activa -\ntion of 5-HT 1 receptors causes constriction, perhaps con -\ntributing to the antimigraine action of these drugs. 5-HT \ncan also cause vasodilatation indirectly by releasing nitric \noxide from vascular endothelial cells (see Ch. 21) and inhibiting noradrenaline release from sympathetic nerve \nterminals. If 5-HT is injected intravenously, the blood \npressure initially rises, owing to the constriction of large vessels, and then falls, owing to arteriolar dilatation. 5-HT \nmay play a role in the pathology of pulmonary hypertension \n(see later in this chapter and Ch. 23).\nPlatelets. 5-HT causes platelet aggregation (see Ch. 25) \nby acting on 5-HT 2A receptors, and the platelets that collect \nin the vessel release further 5-HT. If the endothelium is intact, 5-HT release from adherent platelets causes vasodila -\ntation, which helps to sustain blood flow; if it is damaged \n(e.g. by atherosclerosis), 5-HT causes constriction and \nimpairs blood flow further. These effects of platelet-derived \n5-HT are thought to be important in vascular disease.\nNerve endings. 5-HT stimulates nociceptive (pain-mediating) \nsensory nerve endings, an effect mediated mainly by 5-HT 3 \nreceptors. If injected into the skin, 5-HT causes pain; when \ngiven systemically, it elicits a variety of autonomic reflexes through stimulation of afferent fibres in the heart and lungs, which further complicate the cardiovascular response. In some \nspecies, mast cells release 5-HT when stimulated and nettle stings contain 5-HT among other mediators. 5-HT also inhibits \ntransmitter release from adrenergic neurons in the periphery.\nCentral nervous system. 5-HT is an important neurotrans -\nmitter in the CNS and several important antipsychotic and antidepressant drugs act on these pathways (Chs 47 and \n48). LSD is a relatively non-selective 5-HT receptor agonist/partial agonist, which acts centrally as a potent hallucinogen. \nHowever, its actions are complex: 5-HT excites some neurons \nand inhibits others; it also acts presynaptically to inhibit transmitter release from nerve terminals and this might \nunderlie some of the actions of serotonergic drugs in migraine. \nDifferent receptor subtypes mediate these effects. The role of 5-HT in the CNS is discussed in Chapter 40.\nDRUGS ACTING AT 5-HT RECEPTORS\nTable 16.1 lists some significant agonists and antagonists at the different receptor types. Many are only partly selec -\ntive. Our increasing understanding of the location and function of the different receptor subtypes has raised the possibility of developing compounds with improved recep-\ntor selectivity.\nImportant drugs that act on 5-HT receptors in the \nperiphery include the following:\n\u2022\tAlthough \tnot \tclinically \tuseful, \tselective \t5-HT 1A \nagonists, such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), are potent hypotensive agents, \nacting through a central mechanism. They are useful experimental drugs.\n\u2022\t5-HT1\nB/D-receptor agonists (e.g. the triptans) are used \nfor treating migraine.\n\u2022\t5-HT 2-receptor antagonists (e.g. methysergide, \nketanserin) act mainly on 5-HT 2A receptors but may \nalso block other 5-HT receptors, as well as \u03b1 \nadrenoceptors and histamine receptors (Ch. 27).", "start_char_idx": 3101, "end_char_idx": 6468, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b2aaac40-91cc-4432-b2ea-bd5dfa64d183": {"__data__": {"id_": "b2aaac40-91cc-4432-b2ea-bd5dfa64d183", "embedding": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bb3a579e-f618-418a-bf1a-74d40ad6fd53", "node_type": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "868a233866306b92f539f61b0f2858bbfcf6c24d051063d2575300987cbd903e"}, "2": {"node_id": "803a9e21-eb58-48ae-b348-1814de902c9a", "node_type": null, "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "178f1d91ccf40bcda9482dbf61a63707e536fd8787a1600241b7b6627137fba1"}}, "hash": "95be378f2138c386857a407297c1632ae9fc8a180775bd22bff353333a782cec", "text": "well as \u03b1 \nadrenoceptors and histamine receptors (Ch. 27). \nErgotamine and methysergide belong to the ergot family and have been used mainly for migraine \nprophylaxis (although methysergide is rarely used mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6473, "end_char_idx": 7157, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3ebb9065-2204-4fc0-96ce-0021965159b6": {"__data__": {"id_": "3ebb9065-2204-4fc0-96ce-0021965159b6", "embedding": null, "metadata": {"page_label": "228", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1a9a28bb-86ed-4570-bb88-f3ee8b13fc81", "node_type": null, "metadata": {"page_label": "228", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c15260faff2e29b969d1dad6c93affa2aa8002ae1db5704cf741b7f6f213d7c4"}, "3": {"node_id": "409925ec-eace-4a01-a97a-44c4ab9704e2", "node_type": null, "metadata": {"page_label": "228", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "daf09af0bf69510e340bc62c8d5a8d89559cb886d46bfbe1a213fd76a5c8c1e1"}}, "hash": "25cad638711a61fc6d63d2399e56631f4456fb2635b584c442e41e182c65f8bd", "text": "16 SECTION 2 CHEMICAL MEDIATORS\n222important members of the group (Table 16.2) include various naturally \noccurring and synthetic derivatives with different substituent groups \narranged around a common nucleus. These compounds display diverse \npharmacological actions and it is difficult to discern any clear relation -\nship between chemical structure and pharmacological properties.\nActions\nMost of the effects of ergot alkaloids appear to be mediated \nthrough adrenoceptors, 5-HT or dopamine receptors, \nalthough some may be produced through other mechanisms. \nAll alkaloids stimulate smooth muscle, some being relatively selective for vascular smooth muscle while others act mainly \non the uterus. Ergotamine and dihydroergotamine are, \nrespectively, a partial agonist and an antagonist at \u03b1 \nadrenoceptors. Bromocriptine is an agonist of dopamine \nreceptors, particularly in the CNS (Ch. 40), and methysergide is an antagonist at 5-HT\n2A receptors.\nThe clinical use of ergot agents has diminished as more \nselective and safer drugs have been introduced but never -\ntheless, they remain important for pharmacologists. Their main actions and uses are summarised in Table 16.2. As one \nwould expect of agents having so many actions, their \nphysiological effects are complex and often rather poorly understood. Ergotamine, dihydroergotamine and methy-\nsergide are discussed here; further information on ergometrine \nand bromocriptine is given in Chapters 34, 36 and 41.\nVascular effects. When injected into an anaesthetised \nanimal, ergotamine activates \u03b1 adrenoceptors, causing \nvasoconstriction and a sustained rise in blood pressure. \nAt the same time, ergotamine reverses the pressor effect of adrenaline (epinephrine; see Ch. 15). The vasoconstric -\ntor effect of ergotamine is responsible for the peripheral gangrene of St Anthony\u2019s fire, and probably also for some of the effects of ergot on the CNS. Methysergide \nand dihydroergotamine have much less vasoconstrictor \neffect. Methysergide is a potent 5-HT\n2A-receptor antagonist, these days). Other 5-HT 2 antagonists are used to \ncontrol the symptoms of carcinoid tumours.\n\u2022\t5-HT 3-receptor antagonists (e.g. granisetron, \nondansetron, palonosetron) are used as antiemetic \ndrugs (see Chs 31 and 57), particularly for controlling the severe nausea and vomiting that occurs with many forms of cancer chemotherapy.\n\u2022\t5-HT\n4-receptor agonists that stimulate coordinated \nperistaltic activity (known as a \u2018prokinetic action\u2019) could \nbe used for treating gastrointestinal disorders (see Ch. \n31). Metoclopramide acts in this way, as well as by \nblocking dopamine receptors. Similar but more selective \ndrugs such as cisapride and tegaserod were introduced \nto treat irritable bowel syndrome, but were withdrawn \non account of adverse cardiovascular side effects.\nERGOT ALKALOIDS\nErgot alkaloids have preoccupied pharmacologists for more than a century. As a group, they stubbornly resist classifica -\ntion. Many act on 5-HT receptors, but not selectively, so that their effects are complex and diverse.\n\u25bc Ergot, an extract of the fungus Claviceps purpurea that infests cereal \ncrops, contains many active substances, and it was the study of their \npharmacological properties that led Dale to many important discoveries \nconcerning acetylcholine, histamine and catecholamines. Epidemics of ergot poisoning have occurred, and still occur, when contaminated \ngrain is used for food. The symptoms include mental disturbances and \nintensely painful peripheral vasoconstriction leading to", "start_char_idx": 0, "end_char_idx": 3542, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "409925ec-eace-4a01-a97a-44c4ab9704e2": {"__data__": {"id_": "409925ec-eace-4a01-a97a-44c4ab9704e2", "embedding": null, "metadata": {"page_label": "228", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1a9a28bb-86ed-4570-bb88-f3ee8b13fc81", "node_type": null, "metadata": {"page_label": "228", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c15260faff2e29b969d1dad6c93affa2aa8002ae1db5704cf741b7f6f213d7c4"}, "2": {"node_id": "3ebb9065-2204-4fc0-96ce-0021965159b6", "node_type": null, "metadata": {"page_label": "228", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "25cad638711a61fc6d63d2399e56631f4456fb2635b584c442e41e182c65f8bd"}}, "hash": "daf09af0bf69510e340bc62c8d5a8d89559cb886d46bfbe1a213fd76a5c8c1e1", "text": "mental disturbances and \nintensely painful peripheral vasoconstriction leading to gangrene\n1.\nErgot alkaloids are complex molecules derived from lysergic acid. The \n1This came to be known in the Middle Ages as St Anthony\u2019s fire, because \nit was believed that it could be cured by a visit to the Shrine of St \nAnthony (which conveniently happened to be in an ergot-free region of \nFrance).Table 16.2 Properties of ergot alkaloids and related compounds\nDrugActions at receptors\nUterus Main uses Side effects, etc. 5-HT \u03b1 Adrenoceptor Dopamine\nErgotamineAntagonist/\npartial agonist (5-HT\n1)\nAntagonist (other sites)Partial agonist (blood vessels)InactiveContracts ++Migraine (largely \nobsolete)Emesis, vasospasm (avoid in peripheral vascular disease and pregnancy)\nDihydroergotamineAntagonist/partial agonist (5-HT\n1)Antagonist InactiveContracts +Migraine (largely \nobsolete)Less emesis than with ergotamine\nErgometrineWeak antagonist/partial agonist (5-HT\n1)Weak antagonist/ \npartial agonistWeakContracts +++Prevention of \npostpartum \nhaemorrhage (Ch. 36)Nausea, vomiting\nBromocriptine Inactive Weak antagonistAgonist/partial agonist\u2014Parkinson's disease (Ch. 41)Endocrine disorders (Ch. 32)Drowsiness, emesis\nMethysergideAntagonist/partial agonist at several subtypes\u2014 \u2014 \u2014Carcinoid syndrome Migraine prophylaxis (rarely used)Retroperitoneal and mediastinal fibrosisEmesis\n5-HT,\n\t5-hydroxytryptamine.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3461, "end_char_idx": 5338, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "08f04a69-466a-4c22-b549-d13067fb098b": {"__data__": {"id_": "08f04a69-466a-4c22-b549-d13067fb098b", "embedding": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "71f73ac9-92f9-45b7-9dc3-f726ffc23d08", "node_type": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e98d164442e5af84a0d62f8ec30a75545a5829761ea1c8961fa861207ff72cf"}, "3": {"node_id": "01404040-3fc6-4c0c-8aa0-0258b49f04ee", "node_type": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01554f2a4e711255b48cbdfc9dc3f881f9550fa0ae09276275dfa90ed2652c87"}}, "hash": "ace49b65b5c16cf36a213d9f500fd4f514ce7795220de882f58ec096e25a6c7f", "text": "16 5-Hy DRO xyTRypTAMI nE A n D THE p HARMACOLO gy O f MI g RAI n E\n223Migraine can be differentiated from other types of head -\nache (e.g. cluster headaches, tension headaches) based on \nstrict diagnostic guidelines. The onset of an attack is heralded \nby a premonitory phase, with symptoms including nausea, \nmood changes and often sensitivity to light and sound \n(photophobia and phonophobia). These may occur hours \nbefore the onset, in some patients, of the aura phase during \nwhich phonophobia and photophobia are more common, and \nmay be accompanied by more specific visual symptoms such \nas a slowly moving blind spot with associated flashing lights (\u2018scintillating scotoma\u2019) or geometric patterns of coloured lights (\u2018fortification spectra\u2019) or the illusion of looking \nthrough the wrong end of a telescope. The headache phase \nproper is characterised by a moderate or severe headache, \nstarting unilaterally, but then usually spreading to both \nsides of the head. It may have a pulsating or throbbing \nquality accompanied by nausea, vomiting and prostration. This phase may persist for hours or even days. Following \nresolution of the headache, postdromal phase. may include \nfeelings of fatigue, altered cognition or mood changes. Whilst \nthese different phases probably represent discrete biological \nevents, in practice they overlap and may run in parallel. A \ngood account of these is given by Charles (2013).\nPATHOPHYSIOLOGY\nThe causes of migraine are incompletely understood. Histori -\ncally there have been three main hypotheses advanced to \naccount for the symptoms (see Eadie, 2005).\nThe classic \u2018vascular\u2019 theory, first proposed around 50 \nyears ago by Wolff, implicated an initial humorally medi -\nated intracerebral vasoconstriction as the cause of the \naura, followed by an extracerebral vasodilatation causing the headache. This idea is not supported by the current \nevidence, although vascular events are certainly involved \nin the disease.\nThe \u2018brain\u2019 hypothesis (see Lauritzen, 1987) linked the \nsymptoms to the phenomenon of cortical spreading depres-\nsion. This is a dramatic, although poorly understood, phenomenon, triggered in experimental animals by local application of K\n+ to the cortex and also thought to occur \nin humans after (for example) concussion. An advancing \nwave of profound neural inhibition progresses slowly over \nthe cortical surface at a rate of about 2 mm/min. In the \naffected area, the ionic balance is grossly disturbed, with \nan extremely high extracellular K+ concentration, and the \nblood flow is reduced.\nThe inflammation hypothesis (see Waeber & Moskowitz, \n2005) proposes that activation of trigeminal nerve terminals in the meninges and extracranial vessels is the primary event \nin a migraine attack. This would cause pain directly and \nalso induce inflammatory changes through the release of neuropeptides and other inflammatory mediators from the \nsensory nerve terminals (neurogenic inflammation; see Chs \n19 and 43). One such peptide ( calcitonin gene-related peptide \n(CGRP); see Ch. 19) is indeed released into the meningeal circulation during a migraine attack and an antagonist of this \npeptide, telcagepant \u2013 an investigational drug (discontinued \nbecause of liver toxicity) \u2013 as well as a CGRP-neutralising \nmonoclonal antibody were extremely effective in aborting \nattacks (Farinelli et al., 2008; Dodick et al., 2014; Pellesi \net al., 2017; Hershey, 2017).\nIn practice, elements of all these phenomena seem to play \na role in the pathogenesis of migraine but increasingly, \nattention is focusing on the trigeminovascular system \u2013 the", "start_char_idx": 0, "end_char_idx": 3616, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "01404040-3fc6-4c0c-8aa0-0258b49f04ee": {"__data__": {"id_": "01404040-3fc6-4c0c-8aa0-0258b49f04ee", "embedding": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "71f73ac9-92f9-45b7-9dc3-f726ffc23d08", "node_type": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e98d164442e5af84a0d62f8ec30a75545a5829761ea1c8961fa861207ff72cf"}, "2": {"node_id": "08f04a69-466a-4c22-b549-d13067fb098b", "node_type": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ace49b65b5c16cf36a213d9f500fd4f514ce7795220de882f58ec096e25a6c7f"}, "3": {"node_id": "d1f0aa77-8fb7-4e86-9035-de332f668197", "node_type": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3756bbe7f769ef94da7962b0d30b44efd3f1823ee453ad48c42ed0758536f2f"}}, "hash": "01554f2a4e711255b48cbdfc9dc3f881f9550fa0ae09276275dfa90ed2652c87", "text": "but increasingly, \nattention is focusing on the trigeminovascular system \u2013 the \nsensory neurones that innervate the cerebral vessels (see whereas ergotamine and dihydroergotamine act on 5-HT 1 \nreceptors, which may account for their antimigraine activity.\nClinical use. The only use of ergotamine is in the treatment \nof attacks of migraine unresponsive to simple analgesics (see Chs 27 and 43). Methysergide was formerly used for \nmigraine prophylaxis, and for treating the symptoms of carcinoid tumours, but is seldom used today. All these \ndrugs can be used orally or by injection.\nUnwanted effects. Ergotamine often causes nausea \nand vomiting, and it must be avoided in patients with peripheral vascular disease because of its vasoconstrictor \naction. Methysergide also causes nausea and vomiting, but its most serious side effect, which considerably restricts its \nclinical usefulness, is retroperitoneal and mediastinal fibrosis , \nwhich impairs the functioning of the gastrointestinal tract, \nkidneys, heart and lungs. The mechanism of this is unknown, \nbut it is noteworthy that similar fibrotic reactions also occur \nin carcinoid syndrome, in which there is a high circulating level of 5-HT.\nMIGRAINE AND OTHER CLINICAL \nCONDITIONS IN WHICH 5-HT PLAYS \nA ROLE\nIn this section, we discuss three situations where the periph -\neral actions of 5-HT are believed to be important, namely \nmigraine , carcinoid syndrome and pulmonary hypertension . The \nuse of 5-HT 3 antagonists for treating drug-induced emesis \nis discussed in Chapter 31. Modulation of 5-HT-mediated transmission in the CNS is an important mechanism of \naction of antidepressant and antipsychotic drugs (see Chs 40, 45 and 48).\nMIGRAINE AND ANTIMIGRAINE DRUGS\nMigraine2 is a common and debilitating condition affecting \n10%\u201315% of people and is often stated to be the third most \ncommon disease in the world. Although the causes are not \nwell understood, both genetic and environmental factors seem to be important. The frequency of attacks varies, with \nabout three-quarters of migraineurs (as they are called) \nhaving more than one episode per month. Generally, the \nonset of attacks begins at puberty and wanes with increasing \nage. Women are twice as likely as men to suffer from the \ndisorder and the attacks are often linked to the menstrual cycle or other reproductive events. It appears that rapidly falling oestrogen levels can precipitate bouts of migraine \nin susceptible subjects.\nMigraine can be episodic, when the attacks are relatively \ninfrequent, or chronic, when the frequency and severity become a major burden to the patient and is possibly \naccompanied by comorbidities such as gastrointestinal problems or mental health issues. The treatment of the two \nmanifestations is a little different. It is likely that episodic \nattacks eventually transform into a more chronic illness unless treated.\nIn the United Kingdom, some 25 million work or school \ndays are lost each year because of the incapacitating effects of the disease, with an economic cost of more than \u00a33 billion. \nThe WHO has classified migraine as amongst the 20 most \ndisabling lifetime conditions.\n2The word is apparently of French origin and is probably a corruption \nof hemicrania, the Latin name for the disease.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3549, "end_char_idx": 7130, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d1f0aa77-8fb7-4e86-9035-de332f668197": {"__data__": {"id_": "d1f0aa77-8fb7-4e86-9035-de332f668197", "embedding": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "71f73ac9-92f9-45b7-9dc3-f726ffc23d08", "node_type": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e98d164442e5af84a0d62f8ec30a75545a5829761ea1c8961fa861207ff72cf"}, "2": {"node_id": "01404040-3fc6-4c0c-8aa0-0258b49f04ee", "node_type": null, "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01554f2a4e711255b48cbdfc9dc3f881f9550fa0ae09276275dfa90ed2652c87"}}, "hash": "f3756bbe7f769ef94da7962b0d30b44efd3f1823ee453ad48c42ed0758536f2f", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7151, "end_char_idx": 7374, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d71ca1c6-c347-4859-96bd-aa22af6fc9f0": {"__data__": {"id_": "d71ca1c6-c347-4859-96bd-aa22af6fc9f0", "embedding": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "111b4a9c-dbca-4a85-ad54-c6d023df7d32", "node_type": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79b37d5b6d86a71d9b00e3879150fff010ea9aeaca62f84944a2bbc939f1b937"}, "3": {"node_id": "c747535a-e722-4d7c-bc99-2f3f7df99a66", "node_type": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1206389e802e03977f42ad9c1ea1c06abbc578086f0fd3aff651251a508ec6b3"}}, "hash": "3b838a9f16fc9606822f9a886bf2684541cfe23099d77969a3cbc735c681f7b0", "text": "16 SECTION 2 CHEMICAL MEDIATORS\n224Sumatriptan also has high affinity for the 5-HT 1F receptor \n(see Agosti, 2007) and lasmiditan, an investigational non-\ntriptan drug that is a selective 5HT 1F-receptor agonist, is \nhighly effective in aborting migraine attacks (Tfelt-Hansen, \n2012). Interestingly, this receptor subtype is scarce in the \nvasculature, casting further doubt on the role of vascular changes per se in the pain experienced by patients. This is \nsignificant because a major drawback to triptan therapy is vasoconstriction in other peripheral vascular beds, includ -\ning the heart. Lasmiditan would be expected to be free of \nsuch effects; however, it commonly causes other adverse \neffects (e.g. dizziness and nausea) that can be severe. It is postulated that the antimigraine action of the triptans is through activation of presynaptic 5-HT\n1 receptors which \ninhibit the release of CGRP (and other neuropeptides) from \nneurones of the trigeminovascular system (Juhasz et al., \n2015). This theory is consistent with the reported efficacy of telagepant and anti-CGRP antibodies mentioned above.\nCARCINOID SYNDROME\nCarcinoid syndrome (see Creutzfeld & Stockmann, 1987) is a rare disorder associated with malignant tumours of \nenterochromaffin cells, which usually arise in the small \nintestine and metastasise to the liver. These tumours secrete a variety of chemical mediators: 5-HT is the most \nimportant, but neuropeptides such as substance P (Ch. 19), \nand other agents such as prostaglandins and bradykinin (Ch. 18), are also produced. The sudden release of these \nsubstances (carcinoid crisis) into the bloodstream results in \nseveral unpleasant symptoms, including flushing, abdominal cramps, diarrhoea, bronchoconstriction and hypotension, which may cause dizziness or fainting. More insidiously, \ncognitive impairment may develop and sometimes fibrotic \nstenosis of heart valves, leading to cardiac failure. It is reminiscent of the retroperitoneal and mediastinal fibrosis \nseen with methysergide and some other serotonergic agents, \nand appears to be related to overproduction of 5-HT acting Charles, 2013; Buture et al., 2016; Aurora & Brin, 2017) as \nthe source of the pain. The symptoms associated with the premonitory phase are largely dopaminergic in origin. The \nonset of the aura phase coincides with the cortical spreading \ndepression and imaging studies have indicated widespread changes in brain perfusion during this phase. There may be \nhypoperfusion of some brain areas as well as hyperperfusion \nin others, suggesting that the physiological mechanisms that normally regulate the relationship between brain activity and \nblood flow become disengaged. Such neurovascular uncoupling \nis a feature of cortical spreading depression.\nDuring the headache phase, there are again vascular \nchanges in (for example) the meningeal and middle cerebral arteries, but once again, these are not consistent and in \nany case not directly responsible for the pain and other symptoms. What does seem to be important is central \nsensitisation, which increases the migraineur\u2019s sensitivity \nto sound, light, cutaneous sensations and other normally non-painful stimuli. This is accompanied by a release of \ninflammatory or nociceptive mediators such as CGRP, nitric \noxide (NO) and prostaglandins. Many of the observed vascular and other changes may persist into the postdromal \nphase, which may last for hours or days.\nIt is noteworthy that none of these mechanisms offer a \ntotally conclusive explanation, at the biochemical level, for what initiates a migraine attack", "start_char_idx": 0, "end_char_idx": 3595, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c747535a-e722-4d7c-bc99-2f3f7df99a66": {"__data__": {"id_": "c747535a-e722-4d7c-bc99-2f3f7df99a66", "embedding": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "111b4a9c-dbca-4a85-ad54-c6d023df7d32", "node_type": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79b37d5b6d86a71d9b00e3879150fff010ea9aeaca62f84944a2bbc939f1b937"}, "2": {"node_id": "d71ca1c6-c347-4859-96bd-aa22af6fc9f0", "node_type": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b838a9f16fc9606822f9a886bf2684541cfe23099d77969a3cbc735c681f7b0"}, "3": {"node_id": "28e78f40-9d3e-400d-b3c1-e25561d04681", "node_type": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a2e8ba72a4691abca67ff6300646975253e9478abeef71db7d3432c83e0074e8"}}, "hash": "1206389e802e03977f42ad9c1ea1c06abbc578086f0fd3aff651251a508ec6b3", "text": "explanation, at the biochemical level, for what initiates a migraine attack or define the underlying \nabnormality that predisposes particular individuals to suffer such attacks. In some rare types of familial migraine, \ninherited mutations affecting calcium channels and Na\n+-\nK+-ATPase have been found, suggesting that abnormal \nmembrane function may be responsible, but in most forms of migraine there is no clear genetic cause.\nWhether one inclines to the view that migraine is primarily \na vascular disorder, a type of spontaneous concussion, an inflammatory disease or just a bad headache, there are two \nimportant factors that implicate 5-HT in its pathogenesis:\n1. There is a sharp increase in the urinary excretion of \nthe main 5-HT metabolite, 5-HIAA, during the attack. The blood concentration of 5-HT falls, probably \nbecause of depletion of platelet 5-HT.\n2. Many of the drugs that are effective in treating \nmigraine are 5-HT receptor agonists or antagonists. \nSee Fig. 16.3 and the clinical box below for further \ninformation.\nANTIMIGRAINE DRUGS\nThe main drugs currently used to treat migraine are sum-\nmarised in Table 16.3, and their postulated sites of action \nare shown in Fig. 16.3. It is important to distinguish between \ndrugs used therapeutically to treat acute attacks of migraine \n(appropriate when the attacks are fairly infrequent) and \ndrugs that are used prophylactically . Apart from 5-HT 2 recep -\ntor antagonists, the drugs used prophylactically are rather a mixed bag, and include the anticonvulsant agent topimarate \n(not UK), the potassium-sparing diuretic amiloride and \nbotulinum toxin . Non-steroidal anti-inflammatory drugs \n(NSAIDs) (Ch. 27) seem to have a variable effect, being \nuseful for some patients but not others.\nThe most important agents for the treatment of acute \nattacks are currently the triptans. These are 5-HT\n1 agonists \nand are usually classified as 5-HT 1B/1D agonists, largely \nbecause it is difficult to distinguish between actions at \nthese two receptors. However, selective high-affinity 5-HT 1D \nsubtype agonists have proved disappointing in the clinic. Drugs used for migraine \nAcute attack\n\u2022\tSimple\tanalgesics \t(e.g. \taspirin,\tparacetamol ;\tsee\t\nCh.\t27)\twith \tor \twithout \tmetoclopramide \t(see\tCh.\t31) \t\nto\thasten\tabsorption.\n\u2022\tErgotamine \t(5-HT1D\treceptor\tpartial \tagonist).\n\u2022\tSumatriptan ,\tzolmitriptan \t(5-HT1D\tagonists).\nProphylaxis\n\u2022\t\u03b2-Adrenoceptor \tantagonists \t(e.g. \tpropranolol ,\t\nmetoprolol ;\tsee\tCh.\t15).\n\u2022\tPizotifen\t(5-HT 2\treceptor\tantagonist).\n\u2022\tOther\t5-HT 2\treceptor\tantagonists:\n\u2013 cyproheptadine :\talso\thas \tantihistamine \tactions\n\u2013 methysergide :\trarely\tused \tbecause \tof \trisk \tof \t\nretroperitoneal \tfibrosis.\n\u2022\tTricyclic \tantidepressants \t(e.g. \tamitriptyline ;\tsee\t \nCh.\t48).\n\u2022\tClonidine ,\tan\t\u03b12\tadrenoceptor \tagonist \t(see \tCh. \t15).\n\u2022\tCalcium \tantagonists \t(e.g. \tdihydropyridines, \tverapamil ;\t\nsee\tCh.\t22): \theadache \tis \ta \tside \teffect \tof \tthese \tdrugs \t\nbut,\tparadoxically, \tthey \tmay \treduce \tfrequency \tof", "start_char_idx": 3531, "end_char_idx": 6534, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "28e78f40-9d3e-400d-b3c1-e25561d04681": {"__data__": {"id_": "28e78f40-9d3e-400d-b3c1-e25561d04681", "embedding": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "111b4a9c-dbca-4a85-ad54-c6d023df7d32", "node_type": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "79b37d5b6d86a71d9b00e3879150fff010ea9aeaca62f84944a2bbc939f1b937"}, "2": {"node_id": "c747535a-e722-4d7c-bc99-2f3f7df99a66", "node_type": null, "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1206389e802e03977f42ad9c1ea1c06abbc578086f0fd3aff651251a508ec6b3"}}, "hash": "a2e8ba72a4691abca67ff6300646975253e9478abeef71db7d3432c83e0074e8", "text": "\tthey \tmay \treduce \tfrequency \tof \t\nmigraine\tattacks.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6566, "end_char_idx": 7098, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9ff2cf88-c722-4cb9-82b1-4fd82abcb335": {"__data__": {"id_": "9ff2cf88-c722-4cb9-82b1-4fd82abcb335", "embedding": null, "metadata": {"page_label": "231", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "51dd85c2-1bf8-4238-a955-1bc44a65b4ce", "node_type": null, "metadata": {"page_label": "231", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "516cd9fa5c486d7391373bc0285e8e568b37b5c7d2142278d1c058d442562f7a"}, "3": {"node_id": "f8c81eb4-0413-4939-8db0-b880e2910b22", "node_type": null, "metadata": {"page_label": "231", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b9587b4d7f67e2a870b30712fe0a79885a410c5ca3c3b00db6fc398978e05f6"}}, "hash": "4df7188cfd5a595c9573da262cb769716ddfd150c3dc4dcd9725435238399048", "text": "16 5-Hy DRO xyTRypTAMI nE A n D THE p HARMACOLO gy O f MI g RAI n E\n225treatment is difficult), inevitably leads to right heart failure \nand death. There are several types of pulmonary hyperten -\nsion and the role of 5-HT was suggested by the fact that at least one form of the condition was precipitated by appetite suppressants (e.g. dexfenfluramine and fenfluramine) \nthat were at one time widely prescribed as \u2018weight loss\u2019 or \u2018slimming\u2019 aids. These drugs apparently blocked SERT and since 5-HT promotes the growth and proliferation of \npulmonary arterial smooth muscle cells and also produces a \nnet vasoconstrictor effect in this vascular bed, the hypothesis seemed reasonable. The use of SSRI antidepressants (Ch. 48) in late pregnancy may lead to pulmonary hypertension \nin the newborn (Grigoriadis et al., 2014).\nSome types of pulmonary hypertension (idiopathic and \nfamilial) are more prevalent in females and sex hormones \nmay therefore be of relevance in the pathogenesis. The \ninterested reader is referred to MacLean and Dempsie (2010) for an accessible account of the current thinking in this \narea, and to Chapter 23, where this topic is also discussed.through 5-HT\n2B receptors to drive the proliferation of con -\nnective tissue (Mota et al., 2016).\nClinical diagnosis can be confirmed by measuring the \nurinary excretion of the main metabolite of 5-HT, 5-HIAA. This may increase by as much as 20-fold when the disease is \nactive and is raised even when the tumour is asymptomatic. 5-HT\n2 antagonists, and the mixed 5-HT/histamine antagonist \ncyproheptadine, are effective in controlling some of the \nsymptoms of carcinoid syndrome, but a more useful drug is \noctreotide (a long-acting agonist at somatostatin receptors), \nwhich suppresses hormone secretion from neuroendocrine, \nincluding carcinoid, cells (see Ch. 34).\nPULMONARY HYPERTENSION\nPulmonary hypertension (see also Ch. 23) is an extremely \nserious disease characterised by the progressive remodelling \nof the pulmonary vascular tree leading to stiffening and \nnarrowing of the vascular tree. This leads to an inexorable rise in pulmonary arterial pressure which, if untreated (and Vascular\nendothelium\nNSAIDs\nTopiramate5-HT 1B/D/F\nantagonists\nbotulinum toxin5-HT 2\nantagonists5-HT\nNO\nTrigeminovascular\nnerve discharge\nPain and auraDilatation of cerebral\nvessels and sensitisation\nof nerve endingsRelease of mediators,\nkinins, prostaglandins,\netc.\nNeuroinflammation\nCentral pain sensitisation Cortical spreading\ndepressionNeuropeptide\nrelease\nCGRP, SP\nFig. 16.3 Postulated sites of drug action in migraine pain. \tThe\tinitiating \tevent \tis \tuncertain \tbut \tmay \tbe \tan \tabnormal \tneuronal \t\ndischarge \tset \toff \tby \temotional \tor \tbiochemical \tdisturbances. \tThe \trelease \tof \t5-HT, \tdirectly \tor \tindirectly, \tdilates \tcranial \tvessels \tand \tstimulates \t\ntrigeminovascular \tnerve \tterminals \tin \tthe \tmeningeal \tvessels. \tThis \ttriggers \ta \tcycle \tof \tneurogenic \tinflammation, \tproducing \ta \tcortical \t\u2018spreading \t\ndepression\u2019, \tan \tuncoupling \tof \tneurovascular \tperfusion \tand \tsensitisation \tof \tcentral \tpain \tpathways. \t5-HT,\t5-hydroxytryptamine;", "start_char_idx": 0, "end_char_idx": 3136, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f8c81eb4-0413-4939-8db0-b880e2910b22": {"__data__": {"id_": "f8c81eb4-0413-4939-8db0-b880e2910b22", "embedding": null, "metadata": {"page_label": "231", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "51dd85c2-1bf8-4238-a955-1bc44a65b4ce", "node_type": null, "metadata": {"page_label": "231", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "516cd9fa5c486d7391373bc0285e8e568b37b5c7d2142278d1c058d442562f7a"}, "2": {"node_id": "9ff2cf88-c722-4cb9-82b1-4fd82abcb335", "node_type": null, "metadata": {"page_label": "231", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4df7188cfd5a595c9573da262cb769716ddfd150c3dc4dcd9725435238399048"}}, "hash": "6b9587b4d7f67e2a870b30712fe0a79885a410c5ca3c3b00db6fc398978e05f6", "text": "\tpain \tpathways. \t5-HT,\t5-hydroxytryptamine; \tCGRP, \ncalcitonin\tgene-related \tpeptide; \tNO,\tnitric\toxide; \tNSAIDs,\tnon-steroidal \tanti-inflammatory \tdrugs; \tSP,\tsubstance \tP. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3092, "end_char_idx": 3747, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "817f4c23-57b0-465a-bcaf-be2cda2e9347": {"__data__": {"id_": "817f4c23-57b0-465a-bcaf-be2cda2e9347", "embedding": null, "metadata": {"page_label": "232", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b091c834-b87e-4f0c-91e2-27636541094b", "node_type": null, "metadata": {"page_label": "232", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9e1aadcff9781a851365856540195cd5db58e1ec6f9886d54e073fd84c7b779"}, "3": {"node_id": "59497e1c-e285-4a18-9ef8-95bb25bd8d92", "node_type": null, "metadata": {"page_label": "232", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e69b3d54730ca2db5f57c55b93cb54425b65bea7d17395166de5dd4d9deda7b7"}}, "hash": "0f1f52557d85ff9393a655b5ef44971a7c5c9f44da08b0188763309b91d2d5a3", "text": "16 SECTION 2 CHEMICAL MEDIATORS\n226Table 16.3 Antimigraine drugsa\nUse Drug(s) Mode of action Side effectsPharmacokinetic \naspects Notes\nAcute Sumatriptan5-HT 1B/1D/1F receptor agonist.\nConstricts large arteries, \ninhibits trigeminal nerve transmission.Coronary vasoconstriction, dysrhythmias.Poor oral absorption, hence delayed response.Can be given s.c.Does not cross blood\u2013brain barrier.\nPlasma half-life 1.5 h.Effective in ~70% of migraine attacks.Short duration of action is a drawback.Contraindicated in coronary disease.\nAcuteAlmotriptanEletriptanFrovatriptanNaratriptanRizatriptanZolmitriptanAs above; additional actions on CNS.sSide effects less than with sumatriptan.Improved bioavailability and duration of action.Able to cross blood\u2013brain barrier.Similar to sumatriptan; but improved pharmacokinetics and reduced cardiac side effects.\nAcute Ergotamine5-HT\n1 receptor partial \nagonist; also affects \u03b1 \nadrenoceptors.\nVasoconstrictor.\nBlocks trigeminal nerve \ntransmission.Peripheral \nvasoconstriction, including coronary vessels.Nausea and vomiting.Contracts uterus and may damage fetus.Poorly absorbed.\nCan be given by \nsuppository, \ninhalation, etc.\nDuration of action \n12\u201324 h.Effective, but use limited by side effects.\nProphylaxis Methysergide5-HT\n2 receptor antagonist/\npartial agonist.Nausea, vomiting, \ndiarrhoea.Retroperitoneal or mediastinal fibrosis (rare but serious).Used orallyEffective, but rarely \nused because of side \neffects and insidious \ntoxicity.\nProphylaxis Pizotifen5-HT\n2 and histamine \nreceptor antagonist.Weight gain, anti-\nmuscarinic side effects.Used orally _\nProphylaxis TopiramateActs on ion channels (e.g. \nNa+) and possibly the \nGABA A receptor (see Ch. 46)Sedation, dizziness, weight loss, nausea, paraesthesia, diarrhoea.Used orallyUsed for treating \nchronic migraine\nProphylaxisPropranolol and similar drugs.\u03b2-adrenoceptor antagonists.\nMechanism of antimigraine \neffect not clear.Fatigue, bronchoconstriction.Used orallyEffective and widely \nused for migraine. \nOther anti-epileptics \nmay also be of value.\nProphylaxisBotulinum toxin AProbably acts by preventing \nthe neuronal release of \nCGRP and other \nneuropeptides.Muscle paralysis and \nother neuromuscular disorders if used incorrectly.Administered by s.c., \ni.m. or i.d. injection.A single treatment can \nact for up to a year.\naOther\tdrugs \tused \tfor \tthe \tacute\ttreatment \tof \tmigraine \tinclude \tnon-steroidal \tanti-inflammatory \tdrugs \t(NSAIDs) \tor \topiate \tanalgesic \tdrugs \t\n(see\tChs\t27, \t43 \tand \t48). \tOther \tdrugs \tused \tfor \tmigraine \tprophylaxis \tinclude\tcalcium \tchannel \tblockers \t(e.g. \tnifedipine, \tsee \tCh. \t23), \t\nantidepressants \t(e.g. \tamitriptyline; \tsee \tCh. \t48), \tand \tthe \tantihypertensives, \tclonidine \tand \tamiloride \t(Ch. \t15). \tTheir \tefficacy \tis \tlimited.\n5-HT,\t5-hydroxytryptamine; \tCNS,\tcentral\tnervous \tsystem. \tCGRP,\tcalcitonin \tgene-related \tpeptide.\nREFERENCES AND FURTHER", "start_char_idx": 0, "end_char_idx": 2915, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "59497e1c-e285-4a18-9ef8-95bb25bd8d92": {"__data__": {"id_": "59497e1c-e285-4a18-9ef8-95bb25bd8d92", "embedding": null, "metadata": {"page_label": "232", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b091c834-b87e-4f0c-91e2-27636541094b", "node_type": null, "metadata": {"page_label": "232", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9e1aadcff9781a851365856540195cd5db58e1ec6f9886d54e073fd84c7b779"}, "2": {"node_id": "817f4c23-57b0-465a-bcaf-be2cda2e9347", "node_type": null, "metadata": {"page_label": "232", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f1f52557d85ff9393a655b5ef44971a7c5c9f44da08b0188763309b91d2d5a3"}}, "hash": "e69b3d54730ca2db5f57c55b93cb54425b65bea7d17395166de5dd4d9deda7b7", "text": "\tgene-related \tpeptide.\nREFERENCES AND FURTHER READING\n5-Hydroxytryptamine\nAgosti, R.M., 2007. 5HT 1F- and 5HT 7-receptor agonists for the treatment \nof migraines. CNS Neurol. Disord. Drug Targets 6, 235\u2013237. (Describes \nresearch in the field of migraine treatment utilising agonists at cloned 5-HT \nreceptors)\nBarnes, N.M., Sharp, T., 1999. A review of central 5-HT receptors and \ntheir function. Neuropharmacology 38, 1083\u20131152. (Useful general review focusing on CNS)\nBeattie, D.T., Smith, J.A., 2008. Serotonin pharmacology in the \ngastrointestinal tract: a review. Naunyn Schmiedebergs Arch. Pharmacol. 377, 181\u2013203. (Very comprehensive review dealing with a complex topic. Easy to read)\nBonasera, S.J., Tecott, L.H., 2000. Mouse models of serotonin receptor \nfunction: towards a genetic dissection of serotonin systems. Pharmacol. Ther. 88, 133\u2013142. (Review of studies on transgenic mice \nlacking 5-HT\n1 or 5-HT 2 receptors; shows how difficult it can be to interpret \nsuch experiments)\nBranchek, T.A., Blackburn, T.P., 2000. 5-HT 6 receptors as emerging \ntargets for drug discovery. Annu. Rev. Pharmacol. Toxicol. 40, 319\u2013334. (Emphasises potential therapeutic opportunities in this \narea)\nGershon, M.D., 2004. Review article: serotonin receptors and \ntransporters \u2013 roles in normal and abnormal gastrointestinal motility. Aliment. Pharmacol. Ther. 20 (Suppl. 7), 3\u201314.\nSpiller, R., 2008. Serotonergic agents and the irritable bowel syndrome: \nwhat goes wrong? Curr. Opin. Pharmacol. 8, 709\u2013714. (A very interesting account of the development \u2013 and withdrawl \u2013 of 5-HT\n3/4 \nantagonists in irritable bowel syndrome and a discussion of the role of SERT mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2869, "end_char_idx": 5007, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2ab7290f-395a-4036-8bfb-83e73a4ac9f4": {"__data__": {"id_": "2ab7290f-395a-4036-8bfb-83e73a4ac9f4", "embedding": null, "metadata": {"page_label": "233", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "01d36b75-6e23-4975-b146-80c29c49fb53", "node_type": null, "metadata": {"page_label": "233", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9821b167b12322e702e325c6e06963b9196d70907e137ddae7b4ee7024fb638b"}, "3": {"node_id": "330bde62-e44d-4b67-8b69-b1f929d44880", "node_type": null, "metadata": {"page_label": "233", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "612544b68511e381adead6f87d7589a6d33d08a86e44090cb9d6417ee8a15e8f"}}, "hash": "e6ad469a15d30dfb39ed368dc5e5ce4ed68414e1444f6f217aafa64c867eb6cd", "text": "16 5-HyDROxyTRypTAMInE AnD THE pHARMACOLOgy Of MIgRAInE\n227polymorphisms in the disease. Illustrates the type of problems encountered \nwhen trying to develop useful drugs that act at 5-HT receptors )\nMigraine and other pathologies\nAurora, S.K., Brin, M.F., 2017. Chronic migraine: an update on \nphysiology, imaging, and the mechanism of action of two available \npharmacologic therapies. Headache 57, 109\u2013125. ( This paper, together \nwith the one below, summarise recent views on the causes of migraine and \ndiscuss the mechanism of action of some drugs. Both are quite clinical in \noutlook but easy to read )\nButure, A., Gooriah, R., Nimeri, R., Ahmed, F., 2016. Current \nunderstanding on pain mechanism in migraine and cluster headache. \nAnesth. Pain. Med. 6, e35190. ( Excellent concise review of these two \npathologies focusing on the latest ideas about pain mechanisms )\nCharles, A., 2013. The evolution of a migraine attack \u2013 a review of \nrecent evidence. Headache 53, 413\u2013419. ( An excellent and easily readable \naccount of modern thinking about the causes of migraine )\nCreutzfeld, W., Stockmann, F., 1987. Carcinoids and carcinoid \nsyndrome. Am. J. Med. 82 (Suppl. 58), 4\u201316.\nDahlof, C.G., Rapoport, A.M., Sheftell, F.D., Lines, C.R., 1999. \nRizatriptan in the treatment of migraine. Clin. Ther. 21, 1823\u20131836.\nDodick, D.W., Goadsby, P.J., Spierings, E.L., Scherer, J.C., Sweeney, S.P., \nGrayzel, D.S., 2014. Safety and efficacy of LY2951742, a monoclonal \nantibody to calcitonin gene-related peptide, for the prevention of \nmigraine: a phase 2, randomised, double-blind, placebo-controlled \nstudy. Lancet Neurol. 13, 885\u2013892.\nEadie, M.J., 2005. The pathogenesis of migraine \u2013 17th to early 20th \ncentury understandings. J. Clin. Neurosci. 12, 383\u2013388. ( Fascinating \naccount of the historical development of theories of causes of migraine. Good \nif you are interested in the history of medicine! )\nFarinelli, I., Missori, S., Martelletti, P., 2008. Proinflammatory mediators \nand migraine pathogenesis: moving towards CGRP as a target for a \nnovel therapeutic class. Expert Rev. Neurother. 8, 1347\u20131354.\nGrigoriadis, S., Vonderporten, E.H., Mamisashvili, L., et al., 2014. \nPrenatal exposure to antidepressants and persistent pulmonary \nhypertension of the newborn: systematic review and meta-analysis. \nBMJ 348, f6932.\nGoadsby, P.J., 2005. Can we develop neurally acting drugs for the \ntreatment of migraine? Nat. Rev. Drug Discov. 4, 741\u2013750. ( Useful \nreview of the causes and treatments of migraine )Hershey, A.D., 2017. CGRP - the next frontier for migraine. N. Engl. J. \nMed. 377, 2190\u20132191.\nJuhasz, G., Zsombok, T., Jakab, B., Nemeth, J., Szolcsanyi, J., Bagdy, G., \n2005. Sumatriptan causes parallel decrease in plasma calcitonin \ngene-related peptide (CGRP) concentration and migraine headache \nduring nitroglycerin induced migraine attack. Cephalalgia 25,", "start_char_idx": 0, "end_char_idx": 2874, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "330bde62-e44d-4b67-8b69-b1f929d44880": {"__data__": {"id_": "330bde62-e44d-4b67-8b69-b1f929d44880", "embedding": null, "metadata": {"page_label": "233", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "01d36b75-6e23-4975-b146-80c29c49fb53", "node_type": null, "metadata": {"page_label": "233", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9821b167b12322e702e325c6e06963b9196d70907e137ddae7b4ee7024fb638b"}, "2": {"node_id": "2ab7290f-395a-4036-8bfb-83e73a4ac9f4", "node_type": null, "metadata": {"page_label": "233", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e6ad469a15d30dfb39ed368dc5e5ce4ed68414e1444f6f217aafa64c867eb6cd"}}, "hash": "612544b68511e381adead6f87d7589a6d33d08a86e44090cb9d6417ee8a15e8f", "text": "headache \nduring nitroglycerin induced migraine attack. Cephalalgia 25, \n179\u2013183.\nLauritzen, M., 1987. Cerebral blood flow in migraine and cortical \nspreading depression. Acta Neurol. Scand. Suppl. 113, 1\u201340. ( Review of \nclinical measurements of cerebral blood flow in migraine, which overturned \nearlier hypotheses )\nMaclean, M.R., Dempsie, Y., 2010. The serotonin hypothesis of \npulmonary hypertension revisited. Adv. Exp. Med. Biol. 661, 309\u2013322. \n(An account of the evidence supporting a role for 5-HT in pulmonary \nhypertension by one of the leaders in this field )\nMota, J.M., Sousa, L.G., Riechelmann, R.P., 2016. Complications from \ncarcinoid syndrome: review of the current evidence. \nEcancermedicalscience 10, 662. ( Good account of carcinoid syndrome \nwritten from a clinical viewpoint. Easy to read )\nPellesi, L., Guerzoni, S., Pini, L.A., 2017. Spotlight on anti-CGRP \nmonoclonal antibodies in migraine: the clinical evidence to date. Clin. \nPharmacol. Drug Dev. 6, 534\u2013547. ( Lists a number of anti-CGRP \nmonoclonals undergoing clinical trials for migraine treatment )\nTfelt-Hansen, P., 2012. Clinical pharmacology of current and future \ndrugs for the acute treatment of migraine: a review and an update. \nCurr. Clin. Pharmacol. 7, 66\u201372. ( A good account of anti-migraine drugs. \nRecommended )\nWaeber, C., Moskowitz, M.A., 2005. Migraine as an inflammatory \ndisorder. Neurology 64, S9\u2013S15. ( Useful review of the \u2018inflammation\u2019 \nhypothesis of migraine )\nBooks\nSjoerdsma, A.G., 2008. Starting With Serotonin: How a High-Rolling \nFather of Drug Discovery Repeatedly Beat the Odds. Improbable \nBooks, Silver Spring, MD. ( Biography of an astonishing pharmacologist, by \nhis daughter. Very well reviewed )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2803, "end_char_idx": 4999, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "847eba8d-ad44-4119-bfed-e196044505f7": {"__data__": {"id_": "847eba8d-ad44-4119-bfed-e196044505f7", "embedding": null, "metadata": {"page_label": "234", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7bf89b04-ee20-46cd-a8bd-ab1cc29f3360", "node_type": null, "metadata": {"page_label": "234", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "02a983427710d659bf4e9af61f1c82a4b268855b250835acdc3b2ae02dc3b15c"}, "3": {"node_id": "5edab9ce-9687-4135-adb2-8609267b36d5", "node_type": null, "metadata": {"page_label": "234", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42418153b9b6ec104a6fb0565647f159ece0b67ff1cf0c975d536563fbb4662b"}}, "hash": "03a5bd9f00661bbe33b2ba6e24c991b7c323bac7bce932cfa4919fbb82c7db42", "text": "228\nPurines17\u2003CHEMICAL MEDIATORS SECTION \u20032\nOVERVIEW\nIn\u2003addition \u2003to\u2003their\u2003role\u2003in\u2003the\u2003energy \u2003economy \u2003of\u2003the\u2003\ncell,\u2003purine \u2003nucleosides \u2003and \u2003nucleotides \u2003function \u2003as\u2003\nextracellular \u2003chemical \u2003mediators \u2003subserving \u2003a \u2003wide \u2003\nrange \u2003of \u2003functions. \u2003In \u2003this \u2003chapter \u2003we \u2003describe \u2003the\u2003\nmechanisms \u2003responsible \u2003for \u2003their \u2003synthesis \u2003and\u2003\nrelease, \u2003the\u2003drugs \u2003that\u2003act\u2003through \u2003purinergic \u2003signalling \u2003\npathways \u2003and \u2003the \u2003receptors \u2003that \u2003transduce \u2003these \u2003\neffects.\nINTRODUCTION\nNucleosides (especially adenosine) and nucleotides (espe -\ncially ADP and ATP) will already be familiar to you because \nof their crucial role in DNA/RNA synthesis and energy \nmetabolism, but it may come as a surprise to learn that they also function extracellularly as signalling molecules \nthat produce a wide range of unrelated pharmacological \neffects.\nThe finding, in 1929, that adenosine injected into anaes -\nthetised animals caused bradycardia, hypotension, vasodila -\ntation and inhibition of intestinal movements, foreshadowed the current interest in purines. But the true origins of the field can really be traced to the crucial observations in 1970 \nby Burnstock and his colleagues, who provided strong \nevidence that ATP is a neurotransmitter (see Ch. 2). After a period during which this radical idea was treated with \nscepticism, it has become clear that the \u2018purinergic\u2019 signalling \nsystem is not only of ancient evolutionary origin but participates in many physiological control mechanisms, \nincluding the regulation of coronary blood flow and \nmyocardial function (Chs 22 and 23), platelet aggregation and immune responses (Chs 18 and 25), as well as neuro -\ntransmission in both the central and peripheral nervous system (Chs 13 and 40).\nThe full complexity of purinergic control systems, their \nimportance in many pathophysiological mechanisms and the therapeutic relevance of the various receptor subtypes is now emerging. As a result, there is an increas -\ning interest in purine pharmacology and the prospect of developing \u2018purinergic\u2019 drugs for the treatment of pain and a variety of other disorders, particularly of thrombotic and inflammatory origin. There is no doubt \nthat such drugs will assume growing significance but, \nrecognising that the overall picture is still developing, we will focus our discussion in this chapter on a few \nprominent areas.\nFig. 17.1 summarises the mechanisms by which purines \nare stored, released and interconverted, and the main \nreceptor types on which they act.PURINERGIC \u2003RECEPTORS\nPurines exert their biological actions through three families of \nreceptors. Table 17.1 (and the Box on p. 229) list these and sum -\nmarises what is currently known about their signalling systems, their endogenous ligands and antagonists of pharmacological interest. It should be noted, however, that the action of \ndrugs and ligands at purinergic receptors can be confusing. \nIn part, this is because nucleotides are rapidly degraded by ecto-enzymes and there is also evidence of interconversion \nby phosphate exchange. Thus ATP may produce effects at \nall three receptor subclasses depending upon the extent of its enzymatic conversion to ADP, AMP and adenosine.\nThe three main families of purine receptor are:\n\u2022\tAdenosine \treceptors \t(A1, A 2A, A 2B and A 3), formerly \nknown as P1 receptors before", "start_char_idx": 0, "end_char_idx": 3332, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5edab9ce-9687-4135-adb2-8609267b36d5": {"__data__": {"id_": "5edab9ce-9687-4135-adb2-8609267b36d5", "embedding": null, "metadata": {"page_label": "234", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7bf89b04-ee20-46cd-a8bd-ab1cc29f3360", "node_type": null, "metadata": {"page_label": "234", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "02a983427710d659bf4e9af61f1c82a4b268855b250835acdc3b2ae02dc3b15c"}, "2": {"node_id": "847eba8d-ad44-4119-bfed-e196044505f7", "node_type": null, "metadata": {"page_label": "234", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "03a5bd9f00661bbe33b2ba6e24c991b7c323bac7bce932cfa4919fbb82c7db42"}}, "hash": "42418153b9b6ec104a6fb0565647f159ece0b67ff1cf0c975d536563fbb4662b", "text": "2A, A 2B and A 3), formerly \nknown as P1 receptors before the agonist was \ndiscovered to be adenosine. These are G protein\u2013\ncoupled receptors that act through adenylyl cyclase/cAMP, or by direct effects on Ca\n2+ and K+ channels, as \ndescribed in Ch 3.\n\u2022\tP2Y\tmetabotropic \treceptors \t(P2Y 1\u201314), which are G \nprotein\u2013coupled receptors that utilise either \nphospholipase C activation or cAMP as their \nsignalling system (see Ch. 3); they respond to various adenine nucleotides, generally preferring ATP over \nADP or AMP. Some also recognise pyrimidines such \nas UTP.\n\u2022\tP2X\tionotropic \treceptors \t(P2X 1\u20137) which are trimeric (in \nmany cases heterotrimeric) ATP-gated cation channels. \nIn the presence of ATP, the channels become permeable \nto Ca2+ and Na+ ions, activating Ca2+-sensitive pathways \nand causing membrane depolarisation.\nThe subtypes in each family are distinguished on the basis of their molecular structure as well as their agonist and \nantagonist \tselectivity. \tThe\tP2Y\tgroup\tis\tparticularly \tprob -\nlematic: several receptors have been cloned on the basis of \nhomology with other family members, but their ligands \nhave yet to be identified (in other words they are \u2018orphan receptors\u2019). In addition, since some members of this group \nalso recognise pyrimidines such as UTP and UDP as well \nas purines, they are sometimes classed as pyrimidinoceptors. However, little is currently known about the role of pyri-\nmidines in cell signalling.\nWe will now discuss some prominent and interesting \naspects of purinergic pharmacology; the reading list provides \nfurther information.\nADENOSINE \u2003AS \u2003A \u2003MEDIATOR\nThe simplest of the purines, adenosine, is found in biological fluids throughout the body. It exists free in the cytosol \u2003\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3275, "end_char_idx": 5494, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "73c57b23-38f5-47ee-ad3d-d9b932b9d64d": {"__data__": {"id_": "73c57b23-38f5-47ee-ad3d-d9b932b9d64d", "embedding": null, "metadata": {"page_label": "235", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6b383ff1-bdbb-477d-b5ff-577d8598dfac", "node_type": null, "metadata": {"page_label": "235", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1b5facf000086cd7e555f3f94d38dc1185c3dca7ae33d47ab7a4717f7d38bb7e"}, "3": {"node_id": "70fd9e77-a5ff-401c-bfdc-dcda4a5967a3", "node_type": null, "metadata": {"page_label": "235", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d09ea1e62c9bf1c5f9aed8b406c9544daad43a54b3265363921e547e3a775cef"}}, "hash": "ce4c83f0524923ef2dd5dd555b9c9b885de466f1027a9b834af2401d70fc80dc", "text": "17 PuRInES\n229Purines as mediators \n\u2022\tAdenosine \tacts\tthrough\tA1,\tA2A,\tA2B\tand\tA3\tG\tprotein\t\nreceptors,\t coupled\tto\tinhibition\tor\tstimulation\t of\tadenylyl\t\ncyclase.\tAdenosine\t receptors\t are\tblocked\tby\t\nmethylxanthines\t such\tas\tcaffeine\tand\ttheophylline .\t\nDipyramidole \tblocks\tadenosine\t uptake.\n\u2013\tAdenosine \taffects\tmany\tcells\tand\ttissues,\tincluding\t\nsmooth\tmuscle\tand\tnerve\tcells.\tIt\tis\tnot\ta\tconventional\t\ntransmitter\t but\tmay\tbe\timportant\t as\ta\tlocal\thormone\t\nand\t\u2018homeostatic\t modulator\u2019.\n\u2013\tImportant\t sites\tof\taction\tinclude\tthe\theart\tand\tthe\t\nlung.\tAdenosine\t is\tvery\tshort-acting\t and\tis\tsometimes\t\nused\tfor\tits\tantidysrhythmic\t effect.\n\u2022\tADP\tacts\tthrough\tthe\tP2Y 1\u201314\t\u2018metabotropic\u2019\t G\tprotein\u2013\nreceptor\tfamily.\tThese\tare\tcoupled\tto\tcAMP\tor\tPLC\u03b2.\n\u2013\tImportant\t sites\tof\taction\tinclude\tplatelets\twhere\tADP\t\nreleased\tfrom\tgranules\tpromotes\t aggregation\t by\tacting\ton\tthe\tPY12\treceptor.\t This\tis\tantagonised\t by\tthe\t\ndrugs\t clopidogrel ,\tprasugrel, ticagrelor \tand\t\ncangrelor .\n\u2022\tATP\tis\tstored\tin\tvesicles\tand\treleased\tby\texocytosis\t or\t\nthrough\tmembrane\t channels\twhen\tcells\tare\tdamaged.\t It\t\nalso\tfunctions\t as\tan\tintracellular\t mediator,\t inhibiting\tthe\t\nopening\tof\tmembrane\t potassium\t channels.\n\u2013\tATP\tacts\ton\tP2X\treceptors:\t these\tare\tligand-gated\t ion\t\nchannels.\t It\tcan\talso\tact\ton\tP2Y\treceptors.\n\u2013\tSuramin\tblocks\tthe\tATP\tactions\tat\tmost\treceptors.\n\u2013\tImportant\t sites\tof\tATP\taction\tinclude\tthe\tcentral\t\nnervous\tsystem\t(CNS),\tperipheral\t and\tcentral\t\npathways\t and\tinflammatory\t cells.\n\u2013\tWhen\treleased,\t ATP\tis\trapidly\tconverted\t to\tADP\tand\t\nadenosine\t yielding\tproducts\t that\tmay\tact\ton\tother\t\npurinergic\t receptors.ATP vesicles\nVNUT ATPP2X receptor\n(ligand-gated\nion channel)\nP2Y receptor\n(GPCR)\nA(P1) receptor\n(GPCR)ATP\nADP vesicles ADP\nAdenosine\nInosineEcto\nEctoNucleotidases\nNucleotidases\nAdenosineAdenosine\nDeaminaseNtT\nNsTExocytosis\nExocytosis\nFig. 17.1 \tPurines as mediators. \tATP\t(and,\tin\tplatelets,\t ADP)\tis\tpresent\tin\tthe\tcytosol\tof\tcells\t(and\treleased\tfollowing\tcellular\tdamage)\tor\t\nconcentrated\t into\tvesicles\tby\tthe\tvesicular\tnucleotide\t transporter\t (VNUT).\tNucleotides\t may\tbe\treleased\tby\texocytosis\t or\tthrough\tmembrane\t\nchannels\tsuch\tan\tpannexins\t (Pnx)\tor\ttransporters\t (NtT).\tOnce\treleased,\t ATP\tcan\tbe\tconverted\t to\tADP\tand\tto\tadenosine\t", "start_char_idx": 0, "end_char_idx": 2270, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "70fd9e77-a5ff-401c-bfdc-dcda4a5967a3": {"__data__": {"id_": "70fd9e77-a5ff-401c-bfdc-dcda4a5967a3", "embedding": null, "metadata": {"page_label": "235", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6b383ff1-bdbb-477d-b5ff-577d8598dfac", "node_type": null, "metadata": {"page_label": "235", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1b5facf000086cd7e555f3f94d38dc1185c3dca7ae33d47ab7a4717f7d38bb7e"}, "2": {"node_id": "73c57b23-38f5-47ee-ad3d-d9b932b9d64d", "node_type": null, "metadata": {"page_label": "235", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce4c83f0524923ef2dd5dd555b9c9b885de466f1027a9b834af2401d70fc80dc"}}, "hash": "d09ea1e62c9bf1c5f9aed8b406c9544daad43a54b3265363921e547e3a775cef", "text": "to\tADP\tand\tto\tadenosine\t by\tthe\taction\tof\t\nectonucleotidases.\t Adenosine\t is\tpresent\tin\tthe\tcytosol\tof\tall\tcells\tand\tis\treleased\tand\ttaken\tup\tvia\ta\tspecific\tmembrane\t transporter(s)\t\n(NsT),\twhich\tis\tblocked\tby\tdipyramidole.\t Adenosine\t itself\tcan\tbe\thydrolysed\t to\tinosine\tby\tthe\tenzyme\tadenosine\t deaminase.\t ATP\tacts\t\ndirectly\tupon\tthe\tP2X\treceptors\t (ligand-gated\t ion\tchannels)\t but\talso\tupon\tP2Y\treceptors\t (GPCRs;\tG\tprotein\tcoupled\treceptors),\t the\t\nprincipal\ttarget\tfor\tADP.\tAdenosine\t itself\tacts\ton\tA\treceptors\t (also\tcalled\tP1\treceptors),\t which\tare\talso\tGPCRs.\tCh.\t4\tcontains\tmore\t\ndetails\tof\texocytotic\t and\tother\tsecretory\t mechanisms.\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2246, "end_char_idx": 3374, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "69ee1921-1ce7-486b-a6be-80573b9ae7c2": {"__data__": {"id_": "69ee1921-1ce7-486b-a6be-80573b9ae7c2", "embedding": null, "metadata": {"page_label": "236", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7a06d8aa-b385-4082-b494-79734de3d953", "node_type": null, "metadata": {"page_label": "236", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2478669a8d3ec83dae57b1b1fe173e0aa495b0f66c493c38232bbced5f810fdf"}, "3": {"node_id": "65d6683d-2b50-49ab-a557-239107980867", "node_type": null, "metadata": {"page_label": "236", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0918d577828257b3c18efb466270e5a4d35e6ad0d537fd9d22faaed6905843d0"}}, "hash": "59a07ce6ad268c0d130b66c0a5e63ce9a3727c2631d565aaeae04b93b908c3d2", "text": "17 SECTION \u20032\u2003\u2003CHEMICAL MEDIATORS\n230ischaemia; see Chs 22 and 41). Under less extreme conditions, \nvariations in adenosine release play a role in controlling \nblood flow and (through effects on the carotid bodies) \nrespiration, matching them to the metabolic needs of the tissues.\nADENOSINE \u2003AND \u2003THE\u2003\u2003\nCARDIOVASCULAR \u2003SYSTEM\nAdenosine inhibits cardiac pacemaker activity and atrio -\nventricular node conduction and it is likely that all four of \nthe adenosine receptors are involved in these effects. Because \nof this, adenosine is used therapeutically, being given as an intravenous bolus injection to terminate supraventricular \ntachycardia (Ch. 22). Because of its short duration of action \n(it is destroyed or taken up within a few seconds of intravenous administration) it is considered safer than \nalternatives such as \u03b2-adrenoceptor antagonists or vera-\npamil. Regadenoson, a powerful vasodilator used for \ndiagnostic tests of cardiac function, is a selective A\n2A agonist. \nDipyramidole (a vasodilator and antiplatelet drug: Ch. 25) of all cells and is transported in (by active transport \nagainst a concentration gradient) and out mainly by a \nmembrane transporter (of which there are several types). Little is known about the way in which this is controlled, \nbut the extracellular concentrations are usually quite \nlow compared with intracellular levels. Extracellular adenosine in tissues comes partly from this intracellular \nsource and partly from hydrolysis of released ATP or \nADP by nucleotidases such as CD39 and CD73 (see Fig. 17.1). Adenosine can be inactivated by adenosine deaminase , \nyielding inosine, providing yet another level of control of \nthis biologically active molecule, and another potential \ndrug target.\nVirtually all cells express one or more adenosine receptors \nand so adenosine produces many pharmacological effects, both in the periphery and in the central nervous system (CNS). Based on its ability to minimise the metabolic \nrequirements of cells, one of its functions may be as an \n\u2018acute\u2019 defensive agent that is released immediately when tissue integrity is threatened (e.g. by coronary or cerebral Table 17.1 Purinergic receptors\nReceptor subtype Mechanism Principal endogenous ligands Notes\nAdenosine (also called P1)\nA1 G protein coupled (G i/o)\nLowers cAMP\nAdenosine (high affinity)\nCaffeine, theophylline (antagonists)A2A G protein coupled (G s)\nRaises cAMP\nA2B G protein coupled (G s)\nRaises cAMP\nAdenosine (low affinity)\nA3 G protein coupled (G i/o)\nLowers cAMP\nP2Y \u2018metabotropic\u2019a\nP2Y 1\nG protein coupled (mainly G q/11). \nActivates PLC\u03b2 mobilises Ca2+\nSometimes alters cAMPATP (antagonist or partial agonist)\nADP (agonist)Suramin (antagonist)\nP2Y 2 UTP and ATP Suramin (antagonist)\nP2Y 4 ATP, GTP, UTP (partial agonists) Pyrimidinoceptor\nP2Y 6 UDP Pyrimidinoceptor\nP2Y 11 ATP > ADP Suramin (antagonist)\nP2Y 12\nG protein coupled (mainly G i/o)\nReduces cAMPADP>ATPPlatelet ADP receptor.Clopidigrel, prasugrel, cangrelor and ticagrelor (antagonists)\nP2Y\n13 ADP Suramin\nP2Y 14 UDP-glucose UDP\nP2X \u2018ionotropic\u2019\nP2X 1\nReceptor-gated cation-selective \nion channelsATPSuramin", "start_char_idx": 0, "end_char_idx": 3128, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "65d6683d-2b50-49ab-a557-239107980867": {"__data__": {"id_": "65d6683d-2b50-49ab-a557-239107980867", "embedding": null, "metadata": {"page_label": "236", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7a06d8aa-b385-4082-b494-79734de3d953", "node_type": null, "metadata": {"page_label": "236", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2478669a8d3ec83dae57b1b1fe173e0aa495b0f66c493c38232bbced5f810fdf"}, "2": {"node_id": "69ee1921-1ce7-486b-a6be-80573b9ae7c2", "node_type": null, "metadata": {"page_label": "236", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59a07ce6ad268c0d130b66c0a5e63ce9a3727c2631d565aaeae04b93b908c3d2"}}, "hash": "0918d577828257b3c18efb466270e5a4d35e6ad0d537fd9d22faaed6905843d0", "text": "1\nReceptor-gated cation-selective \nion channelsATPSuramin (antagonist; rather non-selective)P2X\n2\nP2X 3\nP2X 4\nP2X 5\nP2X 6\nP2X 7\naOnly\tfunctional \thuman \treceptors \tare \tlisted. \tThe \tmissing \tnumbers \tin \tthe \tsequence \tindicate \tthat \tthese \treceptors \thave \tbeen \tcloned, \tbut \t\ntheir\tligands \thave \tnot \tyet \tbeen \tidentified. \tA \tfurther \tfamily \tof \trelated \treceptors \tthat \tbinds \textracellular \tcAMP \t(CAR 1\u20134)\tis\tomitted \tas \tlittle \tis \t\nknown\tabout \ttheir \tbiology.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3071, "end_char_idx": 4026, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a6dc7ecc-2b94-490e-99a7-f229bc9b0518": {"__data__": {"id_": "a6dc7ecc-2b94-490e-99a7-f229bc9b0518", "embedding": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9ca4f025-d915-40c5-a850-d0548f4e4f2e", "node_type": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a3b63ee4e3d7fb1fa32e181686cb6f12612e69e304c102e3cf6950c552c52c8"}, "3": {"node_id": "6d1350e7-b6de-442f-9bb1-110f6389493a", "node_type": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b7e845d040c42473334fb3b70133002ac6a8683335238e09a8605bdc7b359e6"}}, "hash": "3079077a912caf7a0949959fda673aeb6a971d264399456d4cde9827fd966421", "text": "17 PuRInES\n231the platelets are activated (see Ch 25). One of the many \neffects of ADP is to promote platelet aggregation, so this \nsystem provides positive feedback \u2013 an important mecha-\nnism for controlling this process. The receptor involved is P2Y\n12. Exploitation of this finding has provided the best \nexamples to date of the value of purinergic drugs. Ticlo-\npidine (no longer used in UK), clopidogrel and prasugrel \n(prodrugs), cangrelor and ticagrelor (allosteric antagonist), \nall\tantagonise \tplatelet\tP2Y 12 receptors inhibiting the aggrega -\ntion response. They are used, often alongside aspirin, for \npreventing arterial thromboembolic disorders (Ch. 25). The \nP2Y 1 receptor may also play a part in the regulation of \nplatelet reactivity (Hechler & Gachet, 2015).\nATP\u2003AS \u2003A \u2003MEDIATOR\nATP\texerts\tits\taction\tprimarily \tthrough\tthe\tP2X\treceptors. \t\nThe extracellular domain of these trimeric receptors can bind three molecules of ATP. When activated by binding \nof two or three ATP molecules, the receptor gates the \ncation-selective ion channels that trigger ongoing intracellular signalling. Some other actions of ATP in mammals are \nmediated \tthrough \tthe \tP2Y \treceptors. \tSuramin (a drug \noriginally developed to treat trypanosome infections) \nantagonises ATP and has broad-spectrum inhibitory activity \nat\tP2X\tand\tP2Y\treceptors. \tMore\tselective \tATP\tantagonists \t\nare in development.\nATP is present in all cells in millimolar concentrations \nand is released if the cells are damaged (e.g. by ischaemia). \nThe mechanism of release can be through exocytosis of vesicles containing ATP, through ATP transporters or \nthrough pannexin or connexin channels in the cell membrane. \nDying cells may release ATP, which may serve as a \u2018danger \nsignal\u2019 alerting immune cells to potential local tissue damage \n(see Ch. 7).\nATP released from cells is rapidly dephosphorylated by \ntissue-specific nucleotidases, producing ADP and adenosine \n(see Fig. 17.1), both of which may produce further receptor-\nmediated effects. The role of intracellular ATP in regulating \nmembrane potassium channels to control vascular smooth muscle (Ch. 23) and insulin secretion (Ch. 32), is quite \ndistinct from this transmitter function.\nATP\u2003AS \u2003A \u2003NEUROTRANSMITTER\nThe idea that such a workaday metabolite as ATP might \nbe a member of the neurotransmitter elite was resisted \nfor a long time, but is now firmly established. ATP is a \ntransmitter in the periphery, both as a primary mediator and as a co-transmitter in noradrenergic nerve terminals. \nP2X\n2,\tP2X 4\tand\tP2X 6 are the predominant receptor subtypes \nexpressed \tin\tneurons.\tP2X 1 predominates in smooth muscle.\nATP is contained in synaptic vesicles of both adrenergic \nand cholinergic neurons, and it accounts for many of the \nactions produced by stimulation of autonomic nerves that are not caused by acetylcholine or noradrenaline (see Ch. \n13). These effects include the relaxation of intestinal smooth \nmuscle evoked by sympathetic stimulation, and contraction of the bladder produced by parasympathetic nerves. Burnstock \nand his colleagues have shown that ATP is released on nerve \nstimulation in a Ca\n2+-dependent fashion, and that exogenous \nATP, in general, mimics the effects of nerve stimulation in \nvarious preparations. ATP", "start_char_idx": 0, "end_char_idx": 3286, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d1350e7-b6de-442f-9bb1-110f6389493a": {"__data__": {"id_": "6d1350e7-b6de-442f-9bb1-110f6389493a", "embedding": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9ca4f025-d915-40c5-a850-d0548f4e4f2e", "node_type": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a3b63ee4e3d7fb1fa32e181686cb6f12612e69e304c102e3cf6950c552c52c8"}, "2": {"node_id": "a6dc7ecc-2b94-490e-99a7-f229bc9b0518", "node_type": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3079077a912caf7a0949959fda673aeb6a971d264399456d4cde9827fd966421"}, "3": {"node_id": "9dc2a7b1-e999-4e12-808b-7baa59f4e1da", "node_type": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "74da91043babf85352e3b53aeb4e71a831e30814d485c986987560fe4c475f0f"}}, "hash": "6b7e845d040c42473334fb3b70133002ac6a8683335238e09a8605bdc7b359e6", "text": "mimics the effects of nerve stimulation in \nvarious preparations. ATP may function as a conventional \n\u2018fast\u2019 transmitter in autonomic ganglia and possibly the CNS, or as an inhibitory presynaptic transmitter.blocks adenosine uptake by cells, thus effectively increasing its extracellular concentration.\nADENOSINE \u2003IN \u2003ASTHMA\nAdenosine receptors are found on all the cell types involved in asthma (Ch. 29) and the overall pharmacol -\nogy is complex. For example, activation of the A\n2A subtype \nexerts a largely protective and anti-inflammatory effect, but \nacting through its A 1 receptor, adenosine promotes media -\ntor release from mast cells, and causes enhanced mucus secretion, bronchoconstriction and leukocyte activation. \nMethylxanthines, especially analogues of theophylline \n(Ch. 29), are adenosine receptor antagonists. Theophylline \nhas been used for the treatment of asthma and part of its \nbeneficial activity may be ascribed to its antagonism of the A\n1 receptor; however, methylxanthines also increase cAMP \nby inhibiting phosphodiesterase, which underwrites some \nof their pharmacological actions independently of adenosine \nreceptor antagonism. Certain derivatives of theophylline are claimed to show greater selectivity for adenosine receptors \nover phosphodiesterase.\nActivation of the A\n2B receptor also promotes mast cell \nmediator release, while the role of the A 3 receptor has yet \nto be fully elucidated. An antagonist of the A 1 and A 2B \nreceptor or an agonist of the A 2A receptor could therefore \nrepresent a significant advance in this therapeutic area (see \nBrown et al., 2008; Burnstock et al., 2012).\nADENOSINE \u2003IN \u2003INFLAMMATION\nAdenosine also regulates the inflammatory response \nelsewhere and A receptors at various locations in the eye \n(particularly A 2A receptors) have been identified as potential \ntargets in ocular diseases (Guzman-Aranguez et al., 2014 ). \nExperimental A 3 antagonists have been observed to produce \na beneficial effect in experimental models of colitis and may be useful in other inflammatory disorders, including \nrheumatoid arthritis, psoriasis and dry eye syndrome \n(Ochoa-Cortes et al., 2014). Interestingly, sulfasalazine and \nmethotrexate , which are used to treat inflammatory bowel \ndisease (Ch. 31) and have other anti-inflammatory proper -\nties, stimulate the hydrolysis of ATP and AMP by ectonu -\ncleotidases to produce adenosine thereby increasing its \neffective local concentration.\nADENOSINE \u2003IN \u2003THE \u2003CNS\nActing through A 1 and A 2A receptors, adenosine has an \ninhibitory effect on many CNS neurons, and the stimulation experienced after consumption of methylxanthines such \nas caffeine and theophylline. Antagonism of adenosine \nreceptors by the methylxanthines, (which share the purine \nstructure), explains part of their stimulatory effects (see \nCh. 49).\nADP\u2003AS \u2003A \u2003MEDIATOR\nADP is usually stored in vesicles in cells and released by exocytosis (see Ch. 4). It exerts its direct biological effects \npredominantly \tthrough \tthe \tP2Y \tfamily \tof \treceptors \tbut \t\nonce released it can be converted to adenosine by ectonucleotidases.\nADP\u2003AND \u2003PLATELETS\nThe secretory vesicles of blood platelets store both ATP and ADP in high concentrations, and release them when mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3227, "end_char_idx": 6649, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9dc2a7b1-e999-4e12-808b-7baa59f4e1da": {"__data__": {"id_": "9dc2a7b1-e999-4e12-808b-7baa59f4e1da", "embedding": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9ca4f025-d915-40c5-a850-d0548f4e4f2e", "node_type": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a3b63ee4e3d7fb1fa32e181686cb6f12612e69e304c102e3cf6950c552c52c8"}, "2": {"node_id": "6d1350e7-b6de-442f-9bb1-110f6389493a", "node_type": null, "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b7e845d040c42473334fb3b70133002ac6a8683335238e09a8605bdc7b359e6"}}, "hash": "74da91043babf85352e3b53aeb4e71a831e30814d485c986987560fe4c475f0f", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6662, "end_char_idx": 7013, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "398fd14f-c80b-4a0c-a77c-cfb0b5d4cdb5": {"__data__": {"id_": "398fd14f-c80b-4a0c-a77c-cfb0b5d4cdb5", "embedding": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ae98b6f9-d8d1-4d53-afdc-f65c649d45bb", "node_type": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "958f6fbbe3e133c88024c598f214d264d1a649692f57ae735915d2cbb2f30b06"}, "3": {"node_id": "b62899a2-d644-4de8-bbff-16253f60bbce", "node_type": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3011e0ca148eb9c1c201eb823210d7f81af36a11b7995b11c36a7a252574a332"}}, "hash": "d37c3770aed3d4d5f7b7c5acd5edc2bf26d4c3f8f2fdd5cb01f3adb103440115", "text": "17 SECTION \u20032\u2003\u2003CHEMICAL MEDIATORS\n232ATP\u2003IN \u2003INFLAMMATION\nATP is released from stimulated, damaged or dying cells \nand\tP2X \treceptors \tare \twidely \tdistributed \ton \tcells \tof \tthe \t\nimmune\tsystem;\tP2Y\treceptors \tless\tso.\tActing\tthrough\tthese\t\nreceptors, ATP can regulate neutrophil and phagocyte \nchemotaxis and provoke the release from macrophages and \nmast cells of cytokines and other mediators of the inflam -\nmatory response (Hechler & Gachet, 2015). Mice in which \nthe\tP2X 7 receptor is deleted show a reduced capacity to \ndevelop chronic inflammation. Purinergic signalling also plays an important role in T-cell signalling. A good account \nof the role of autocrine signalling in the immune system \nis given by Junger (2011).\nFUTURE \u2003PROSPECTS\nThe area of purinergic pharmacology as a whole holds \nconsiderable promise for future therapeutic exploitation. \nSpace does not permit a comprehensive listing but some \nof the papers cited below will enable the reader to follow up these.Adenosine, produced following hydrolysis of ATP, exerts \npresynaptic inhibitory effects on the release of excitatory transmitters in the CNS and periphery.\nATP\u2003IN \u2003NOCICEPTION\nATP causes pain when injected (for example) subdermally, \nas\ta\tresult \tof \tactivation \tof \tP2X 2\tand/or\tP2X 3 heteromeric \nreceptors on afferent neurons involved in the transduction \nof nociception (see Ch. 43). The pain can be blocked by \naspirin (see Ch. 27) suggesting the involvement of prosta -\nglandins. There is considerable interest in the potential role \nof\tpurinergic \treceptors \t(mainly \tP2Y \tand \tP2X \treceptors), \t\nin various aspects of nociceptive pain transmission and in particular the development of neuropathic pain, which is \ndifficult to treat (see Ch. 43). Interestingly, purinergic \nreceptors are found not just on neurons, but also on glial cells, suggesting a role for these \u2018support\u2019 cells in modulating \nthe chain of nociceptive transmission. It has been suggested \nthat both types of receptors could be useful targets for \nanalgesic and anti-migraine drugs (Tsuda et al., 2012; Magni \n& Ceruti, 2013).\nOddly, perhaps, the same receptors seem to be involved \nin taste perception on the tongue.\nREFERENCES \u2003AND \u2003FURTHER \u2003READING\n(A note of caution: the nomenclature of these receptors has changed \nseveral times and this can make for difficulties when reading some \nolder papers. For the latest version of the nomenclature, as well as \ninformation about ligands etc., always refer to www.guidetopharmacology.org/)\nAntonioli, L., Colucci, R., Pellegrini, C., et al., 2013. The role of \npurinergic pathways in the pathophysiology of gut diseases: pharmacological modulation and potential therapeutic applications. \nPharmacol. Ther. 139, 157\u2013188. (Very comprehensive survey of the \ndistribution and function of purinergic receptors in the gut and their relevance to normal physiological function and disease)\nBrown, R.A., Spina, D., Page, C.P., 2008. Adenosine receptors and \nasthma. Br. J. Pharmacol. 153 (Suppl. 1), S446\u2013S456. (Excellent review of the pharmacology of adenosine in the lung. Very accessible)\nBurnstock, G., 2006. Purinergic P2 receptors as targets for novel", "start_char_idx": 0, "end_char_idx": 3165, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b62899a2-d644-4de8-bbff-16253f60bbce": {"__data__": {"id_": "b62899a2-d644-4de8-bbff-16253f60bbce", "embedding": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ae98b6f9-d8d1-4d53-afdc-f65c649d45bb", "node_type": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "958f6fbbe3e133c88024c598f214d264d1a649692f57ae735915d2cbb2f30b06"}, "2": {"node_id": "398fd14f-c80b-4a0c-a77c-cfb0b5d4cdb5", "node_type": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d37c3770aed3d4d5f7b7c5acd5edc2bf26d4c3f8f2fdd5cb01f3adb103440115"}, "3": {"node_id": "e35ae7ab-4226-4917-8f45-fe67f476b802", "node_type": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6972d74f84f82542993e71333e7d3306f1ae2907565dec35946b87480a819c8"}}, "hash": "3011e0ca148eb9c1c201eb823210d7f81af36a11b7995b11c36a7a252574a332", "text": "G., 2006. Purinergic P2 receptors as targets for novel \nanalgesics. Pharmacol. Ther. 110, 433\u2013454. (This paper, and the reviews that follow by the same author, cover various aspects of purinergic signalling \nand its therapeutic application)\nBurnstock, G., 2008. Purinergic receptors as future targets for treatment \nof functional GI disorders. Gut 57, 1193\u20131194.\nBurnstock, G., 2012. Purinergic signalling: Its unpopular beginning, \nits acceptance and its exciting future. Bioessays 34, 218\u2013225. \n(Interesting account of the entire field of purinergic signalling \nwritten by the scientist who really pioneered the field. Easy to read and \ninformative)\nBurnstock, G., Brouns, I., Adriaensen, D., Timmermans, J.P., 2012. \nPurinergic signalling in the airways. Pharmacol. Rev. 64, 834\u2013868. ( A \nsubstantial and authoritative review for those who want to delve into this area of purinergic pharmacology)\nBurnstock, G., 2017. Purinergic signalling: therapeutic developments. \nFront. Pharmacol. 8, 1\u201355. (A very comprehensive review of this area highlighting the potential therapeutic opportunities for purinergic agents in \nmany therapeutic areas)\nChen, J.F., Eltzschig, H.K., Fredholm, B.B., 2013. Adenosine \nreceptors as drug targets\u2013what are the challenges? Nat. Rev. Drug Discov. 12, 265\u2013286. (Excellent and comprehensive coverage of adenosine \nreceptors)Cunha, R.A., 2001. Adenosine as a neuromodulator and as a \nhomeostatic regulator in the nervous system: different roles, different \nsources and different receptors. Neurochem. Int. 38, 107\u2013125. \n(Speculative review on the functions of adenosine in the nervous system)\nGuzman-Aranguez, \tA., \tGasull, \tX., \tDiebold, \tY., \tPintor, \tJ., \t2014. \t\nPurinergic receptors in ocular inflammation. Mediators Inflamm. 2014, 320906. (This is a relatively new area and this paper details receptor \ndistribution in the eye and discusses the potential therapeutic uses of \npurinergic agents in ocular disorders. Some diagrams. A bit specialised, but interesting)\nHechler, B., Gachet, C., 2015. Purinergic receptors in thrombosis and \ninflammation. Arterioscler. Thromb. Vasc. Biol. 35, 2307\u20132315. (An excellent review of the role of purinergic receptors in these particular \nindications and prospects for future drug therapy. Focuses mainly on P2X \nreceptors. Well written, useful diagrams. Recommended)\nJunger, W.G., 2011. Immune cell regulation by autocrine purinergic \nsignalling. Nat. Rev. Immunol. 11, 201\u2013212. (An excellent, and well illustrated, overview of the role of the pruinergic system in immune cells. Focuses on T cells and neutrophil autocrine signalling. Recommended \nreading)\nKhakh,\tB.S., \tNorth, \tR.A., \t2006. \tP2X \treceptors \tas \tcell-surface \tATP \t\nsensors in health and disease. Nature 442, 527\u2013532. (Excellent and very \nreadable review on P2X receptors. Recommended)\nMagni,\tG., \tCeruti, \tS., \t2013. \tP2Y \tpurinergic \treceptors: \tnew \ttargets \tfor \t\nanalgesic and antimigraine drugs. Biochem. Pharmacol. 85, 466\u2013477. (Very thorough review of the potential for new analgesics that act at these \nreceptors. Useful diagrams and structural information about P2Y receptor", "start_char_idx": 3120, "end_char_idx": 6249, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e35ae7ab-4226-4917-8f45-fe67f476b802": {"__data__": {"id_": "e35ae7ab-4226-4917-8f45-fe67f476b802", "embedding": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ae98b6f9-d8d1-4d53-afdc-f65c649d45bb", "node_type": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "958f6fbbe3e133c88024c598f214d264d1a649692f57ae735915d2cbb2f30b06"}, "2": {"node_id": "b62899a2-d644-4de8-bbff-16253f60bbce", "node_type": null, "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3011e0ca148eb9c1c201eb823210d7f81af36a11b7995b11c36a7a252574a332"}}, "hash": "d6972d74f84f82542993e71333e7d3306f1ae2907565dec35946b87480a819c8", "text": "\nreceptors. Useful diagrams and structural information about P2Y receptor \nagonists)\nOchoa-Cortes, F., Linan-Rico, A., Jacobson, K.A., Christofi, F.L., 2014. \nPotential for developing purinergic drugs for gastrointestinal diseases. Inflamm. Bowel Dis. 20, 1259\u20131287. (Comprehensive and easy-to-read review of this topic. Includes data on herbal products containing purinergic \ndrugs also. Recommended)\nTsuda, M., Tozaki-Saitoh, H., Inoue, K., 2012. Purinergic system, \nmicroglia and neuropathic pain. Curr. Opin. Pharmacol. 12, 74\u201379. (A short overview of the role of the purinergic system in microglia and the \nimplications for the pathogenesis and treatment of neuropathic pain)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6222, "end_char_idx": 7381, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "277d381b-a684-4b7d-aded-7c5c6e782d07": {"__data__": {"id_": "277d381b-a684-4b7d-aded-7c5c6e782d07", "embedding": null, "metadata": {"page_label": "239", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ab09283d-70ae-47de-b6cf-9bcd570b5983", "node_type": null, "metadata": {"page_label": "239", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f920af89e157c8591d04bb29bce761d76f5341b56f97cbceef99f54f6019f45f"}, "3": {"node_id": "bc2ca772-79b7-47cf-8a59-8da822ed0f3f", "node_type": null, "metadata": {"page_label": "239", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff60690e9b1856ef97e3d8c1e78ad12cc6f940eebf7ced36485cd57231e447e7"}}, "hash": "da2e7d7dfa3a2307bb3097ed652f980432efce290ed5deea22242fae154a9f39", "text": "233\nLocal hormones 1: \nhistamine and the \nbiologically active lipids18 CHEMICAL MEDIATORS SECTION 2 \nOVERVIEW\nIn Chapter 7 we discussed the function of cellular \nplayers in host defence and alluded to the crucial \nrole of soluble chemical regulators of inflammation. \nIn this chapter, and the next, we take a closer look at these substances. We begin with some small molecule \nmediators. While also having a physiological role, \nthese are also pressed into service by host defence mechanisms when necessary, and are therefore \nimportant targets for anti-inflammatory drug action.\nINTRODUCTION\nThe growth of pharmacology as a discipline was attended \nby the discovery of numerous biologically active substances. \nMany were initially described as uncharacterised smooth \nmuscle contracting (or relaxing) \u2018factors\u2019, which appeared in blood or tissues during particular physiological or \npathological events. Sometimes, these factors were identified \ncomparatively quickly but others resisted analysis for many years and so the development of a particular pharmacological \narea was often tied to progress in analytical methodology. \nFor example, 5-hydroxytryptamine (5-HT; Ch. 16) and histamine, which are quite simple compounds, were identi -\nfied soon after their biological properties were described. \nHowever, the structural elucidation of the more complex \nprostaglandins, which were first discovered in the 1930s, had to await the development of the mass spectrometer \nsome 30 years later before the field could really progress. \nPeptide and protein structures took even longer to solve. Substance P (11 amino acids) was also discovered in the \n1930s, but was not characterised until 1970 when peptide \nsequencing techniques had been developed. By the 1980s however, molecular biology had greatly enhanced our \nanalytical proficiency; for example, the 21 amino acid \npeptide, endothelin, was discovered and fully characterised, with the sequences of the gene and peptide published within \nabout a year and the complete information published in a \nsingle paper (Yanagisawa et al., 1988).\nWHAT IS A \u2018MEDIATOR\u2019?\nLike regular hormones, such as thyroxine (Ch. 35) or insulin \n(Ch. 32), a local hormone is simply a chemical messenger \nthat conveys information from one cell to another.1 Hormones such as thyroxine and insulin are released from a single endocrine gland, circulate in the blood and produce \ntheir action on other \u2018target\u2019 tissues. In contrast, local \nhormones are usually produced by cells to operate within their immediate microenvironment. The distinction is not \nactually completely clear-cut however. For example, one \nof the \u2018classical\u2019 hormones, hydrocortisone, is normally released by the adrenal gland but, surprisingly, can also \nbe produced by, and act locally upon, some other tissues \nsuch as the skin. Conversely, some cytokines (see Ch. 19), which are usually regarded as local hormones, can circulate in the blood and produce systemic actions as well.\nWhen, in response to a stimulus of some kind, a local \nhormone is released and produces a particular biological effect (such as contraction of smooth muscle in response \nto allergen challenge), it is said to be a mediator of this \nresponse. Traditionally, a putative mediator\n2 had to satisfy \ncertain criteria before gaining official recognition. In the 1930s, Sir Henry Dale proposed a set of five rules to validate \nthe credentials of mediators and these guidelines have been used as a point of reference ever since. Originally formulated \nas a test for putative neurotransmitters however, these \ncriteria cannot easily be applied to mediators of other responses and have been modified on several occasions.\nCurrently, the experimental criteria that establish a \nsubstance as a mediator are:\n\u2022\tthat\tit\tis \treleased \tfrom \tlocal \tcells \tin \tsufficient", "start_char_idx": 0, "end_char_idx": 3835, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bc2ca772-79b7-47cf-8a59-8da822ed0f3f": {"__data__": {"id_": "bc2ca772-79b7-47cf-8a59-8da822ed0f3f", "embedding": null, "metadata": {"page_label": "239", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ab09283d-70ae-47de-b6cf-9bcd570b5983", "node_type": null, "metadata": {"page_label": "239", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f920af89e157c8591d04bb29bce761d76f5341b56f97cbceef99f54f6019f45f"}, "2": {"node_id": "277d381b-a684-4b7d-aded-7c5c6e782d07", "node_type": null, "metadata": {"page_label": "239", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "da2e7d7dfa3a2307bb3097ed652f980432efce290ed5deea22242fae154a9f39"}}, "hash": "ff60690e9b1856ef97e3d8c1e78ad12cc6f940eebf7ced36485cd57231e447e7", "text": "\treleased \tfrom \tlocal \tcells \tin \tsufficient \tamounts \t\nto produce a biological action on the target cells within an appropriate time frame;\n\u2022\tthat\tapplication \tof \tan \tauthentic \tsample \tof \tthe \t\nmediator reproduces the original biological effect;\n\u2022\tthat\tinterference \twith \tthe \tsynthesis, \trelease \tor \taction \t\n(e.g. using receptor antagonists, enzyme inhibitors, \u2018knock-down\u2019 or \u2018knock-out\u2019 techniques) ablates or \nmodulates the original biological response.\nHISTAMINE\nIn a classic study, Dale and his colleagues demonstrated \nthat a local anaphylactic reaction (a type I or \u2018immediate \nhypersensitivity reaction\u2019 such as the response to egg \nalbumin in a previously sensitised animal; see Ch. 7) was caused by antigen\u2013antibody reactions in sensitised tissue, \nand found that histamine mimicked this effect both in vitro \nand in vivo. Later studies confirmed that histamine is present in tissues, and released (along with other mediators) during \nanaphylaxis.\n1The term \u2018autocrine\u2019 is sometimes used to denote a local mediator that \nacts on the cell from which it is released, whereas a \u2018paracrine\u2019 mediator \nacts on other neighbouring cells.2To add to the lexicographical confusion, the term \u2018bioregulator\u2019 has \nrecently crept into use. As this portmanteau word could cover just about any biologically active substance, it is not much use for our \npurposes.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3790, "end_char_idx": 5634, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "647cf8e1-85b6-46f0-b27c-408994810ef2": {"__data__": {"id_": "647cf8e1-85b6-46f0-b27c-408994810ef2", "embedding": null, "metadata": {"page_label": "240", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "24859742-b485-48e8-ba7b-39a823af7e05", "node_type": null, "metadata": {"page_label": "240", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9ea9ba3f4b5f9e688f1e2116ae6be59e097609b7e26cbdeda7d3fe23a85f0491"}, "3": {"node_id": "75b5e800-fc7c-4ade-93ea-a6c3fd7201b7", "node_type": null, "metadata": {"page_label": "240", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7fcabdd967500d0e0a67e6d18a5ca472a005b54f4de863717ef5e29ba642ba21"}}, "hash": "c000676ef63e2c2df1981c52b3aa6646c29835b677523d29c84b0b96593afcb6", "text": "18 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n234Selective antagonists at H 1, H 2 and H 3 receptors include \nmepyramine, cimetidine and thioperamide, respectively. \nSelective agonists for H 2 and H 3 receptors are, respectively, \ndimaprit and (R)-methylhistamine. Histamine H 1 antagonists \nare the principal antihistamines used in the treatment or prevention of inflammation (notably allergic inflammation \nsuch as hay fever). Other clinical uses of subtype antagonists may be found in Chapters 27, 28 and 40. The pharmacology \nof H\n4 receptors is less well developed but strongly suggests \nthat the receptor has a significant role in the inflammatory response. Eosinophils seem to be a prominent target. Panula \net al. (2015) have compiled a comprehensive review of \nhistamine receptors and their pharmacology.\nACTIONS\nSmooth muscle effects. Histamine, acting on H 1 receptors, \ncontracts the smooth muscle of the ileum, bronchi, bron -\nchioles and uterus. The effect on the ileum is not as marked \nin humans as it is in the guinea pig (this tissue remains the de facto standard preparation for histamine bioassay). \nHistamine reduces air flow in the first phase of bronchial asthma (see Ch. 29) but H\n1 antagonists are not of much \nbenefit in the human disease. It is possible that H 4 receptors \nare more important (Thurmond, 2015) in mediating these \nresistant histamine effects.\nCardiovascular effects. Histamine dilates human blood \nvessels and increases permeability of postcapillary venules, by an action on H\n1 receptors, the effect being partly \nendothelium-dependent in some vascular beds. It also increases the rate and the output of the heart mainly by \nan action on cardiac H\n2 receptors. It seems that this mediator \nis involved mainly in regulation of cardiovascular system \nin pathological, rather than physiological, states. Hattori \net al. (2017) have reviewed the area in detail.\nGastric secretion. Histamine stimulates the secretion of \ngastric acid by action on H 2 receptors. In clinical terms, \nthis is the most important action of histamine, because it is implicated in the pathogenesis of peptic ulcer. It is \nconsidered in detail in Chapter 31.\nEffects on skin. When injected intradermally, histamine \ncauses a reddening of the skin, accompanied by a weal \nwith a surrounding flare. This mimics the triple response to \nscratching of the skin, described by Sir Thomas Lewis over \n80 years ago. The reddening reflects vasodilatation of the \nsmall arterioles and precapillary sphincters and the weal, \nthe increased permeability of the postcapillary venules. These effects are mainly mediated through activation of \nH\n1 receptors. The flare is an axon reflex : stimulation of sensory \nnerve fibres evokes antidromic impulses through neighbour -\ning branches of the same nerve, releasing vasodilators such \nas calcitonin gene-related peptide (CGRP; see Chs 19 and 27). Histamine causes intense itch if injected into the skin \nor applied to a blister base, because it stimulates sensory \nnerve endings through an H\n1-dependent mechanism. H 1 \nantagonists are used to control itch caused by allergic \nreactions, insect bites, etc.\nEven though histamine release is manifestly capable of \nreproducing many of the inflammatory signs and symptoms, H\n1 antagonists do not have much clinical utility in the acute \ninflammatory response per se, because other mediators are more important. Histamine is, however, important in type \nI hypersensitivity reactions such as allergic rhinitis and urticaria. Other significant actions of histamine in inflam-\nmation include effects on B and T cells, modulating the", "start_char_idx": 0, "end_char_idx": 3617, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "75b5e800-fc7c-4ade-93ea-a6c3fd7201b7": {"__data__": {"id_": "75b5e800-fc7c-4ade-93ea-a6c3fd7201b7", "embedding": null, "metadata": {"page_label": "240", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "24859742-b485-48e8-ba7b-39a823af7e05", "node_type": null, "metadata": {"page_label": "240", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9ea9ba3f4b5f9e688f1e2116ae6be59e097609b7e26cbdeda7d3fe23a85f0491"}, "2": {"node_id": "647cf8e1-85b6-46f0-b27c-408994810ef2", "node_type": null, "metadata": {"page_label": "240", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c000676ef63e2c2df1981c52b3aa6646c29835b677523d29c84b0b96593afcb6"}}, "hash": "7fcabdd967500d0e0a67e6d18a5ca472a005b54f4de863717ef5e29ba642ba21", "text": "histamine in inflam-\nmation include effects on B and T cells, modulating the \nacquired immune response (Jutel et al., 2009). The use of SYNTHESIS AND STORAGE OF HISTAMINE\nHistamine is a basic amine formed from histidine by histidine \ndecarboxylase (Fig. 18.1). It is found in most tissues but is \npresent in high concentrations in tissues in contact with the \noutside world (lungs, skin and gastrointestinal tract). At the cellular level, it is found largely in mast cells (approximately \n0.1\u20130.2 pmol/cell) and basophils (0.01 pmol/cell), but non-\nmast cell histamine also occurs in \u2018histaminocytes\u2019 in the stomach and in histaminergic neurons in the brain (see Ch. \n40). In mast cells and basophils, histamine is complexed \nin intracellular granules with an acidic protein and a high molecular-weight heparin termed macroheparin.\nHISTAMINE RELEASE\nHistamine is released from mast cells by exocytosis during inflammatory or allergic reactions. Stimuli include comple -\nment components C3a and C5a (see Ch. 7), which interact with specific surface receptors, and the combination of antigen with cell-fixed immunoglobulin (Ig)E antibodies. \nIn common with many secretory processes (Ch. 4), histamine \nrelease is initiated by a rise in cytosolic [Ca\n2+]. Various \nbasic drugs, such as morphine and tubocurarine, release \nhistamine, as does compound 48/80, an experimental tool often used to investigate mast cell biology. Agents that increase cAMP formation (e.g. \u03b2-adrenoceptor agonists; see \nCh. 15) inhibit histamine secretion. Replenishment of secreted histamine by mast cells or basophils is a slow process, which may take days or weeks, whereas turnover \nof histamine in the gastric histaminocyte is very rapid. \nHistamine is metabolised by histaminase and/or by the methylating enzyme imidazole N-methyltransferase.\nHISTAMINE RECEPTORS\nFour types of histamine receptor have been identified, H 1-4. \nAll are G protein\u2013coupled receptors but their downstream \nsignalling systems differ. H 1 and H 3 receptors, for example, \nelevate cAMP, whereas H 2 and H 4 receptors stimulate PLC. \nSplice variants of H 3 and H 4 receptors have been reported. \nAll four are implicated in the inflammatory response in some capacity. A good account of the role of histamine in \ninflammation has been given by Jutel et al. (2009).\nH3N+ HN\nHNNO\nOC\nNNH2Histidine decarboxylase\nHistamine\nFig. 18.1 The synthesis of histamine. Histamine is \nsynthesised by histidine decarboxylas, which removes the \ncarboxyl group (in shaded box) from histidine. Histamine can be metabolised to inactive products by several enzymes, including histaminase (diamine oxidase), and/or by the methylating enzyme imidazole N-methyltransferase. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3541, "end_char_idx": 6727, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bff04dfe-4731-48a5-8f80-ea134fcc931c": {"__data__": {"id_": "bff04dfe-4731-48a5-8f80-ea134fcc931c", "embedding": null, "metadata": {"page_label": "241", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ffc575a-d1ea-44f7-ad42-a8f43388f91b", "node_type": null, "metadata": {"page_label": "241", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdea8ccf3468dbac97a6008b2e4c7c8c2a2d463acca780768c1e254a6017a135"}, "3": {"node_id": "7817b001-d62f-4a0e-a70e-6e7e5f868223", "node_type": null, "metadata": {"page_label": "241", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8398df3066379798d8b0ca48660894629735eaff14201c17de651aaa6a3998b3"}}, "hash": "ccf17a2c8c2386c782ffdf3e644f14fbea7e449c37290ff214556985e2cb80ea", "text": "18 LOCAL HORMO n ES 1: HISTAMI n E A n D THE b IOLO g ICALL y ACTI v E LI p IDS \n235STRUCTURE AND BIOSYNTHESIS\nIn land-dwelling mammals, the main eicosanoid precursor \nis arachidonic acid (5,8,11,14-eicosatetraenoic acid), a \n20-carbon unsaturated fatty acid containing four unsaturated \ndouble bonds (hence the prefix eicosa-, referring to the 20 carbon atoms, and tetra-enoic, referring to the four double \nbonds; see Fig. 18.2). The principal groups of eicosanoids \nare prostaglandins, thromboxanes, leukotrienes, lipoxins and \nresolvins. The common term prostanoids refers to prosta-\nglandins and thromboxanes only.\nIn most cell types, arachidonic acid is a component of \nphospholipids and the intracellular concentration of the \nfree acid is low. Eicosanoids are not stored in cells (like \nhistamine, for example) but are synthesised and released \nimmediately. The initial and rate-limiting step in eicosanoid synthesis is therefore the liberation of arachidonate. Usually \nthis is a one-step process catalysed by the enzyme phospho -\nlipase A\n2 (PLA 2; see Fig. 18.3) but an alternative multi-step \nprocess involving phospholipases C or D in conjunction with diacylglycerol lipase is sometimes utilised. Several \ntypes of PLA\n2 exist, but the most important is probably \nthe highly-regulated cytosolic PLA 2 (cPLA 2). This enzyme \nnot only generates arachidonic acid (and thus eicosanoids) \nbut also lysoglyceryl-phosphorylcholine (lyso-PAF), the \nprecursor of platelet-activating factor (PAF), another inflam -\nmatory mediator (see Figs 18.2 and 18.3).\nCytosolic PLA 2 is activated by phosphorylation and this \nmay be triggered by signal transduction systems activated \nby many stimuli, such as thrombin action on platelets, C5a \non neutrophils, bradykinin on fibroblasts and antigen\u2013antibody reactions on mast cells. General cell damage also \ntriggers cPLA\n2 activation. The free arachidonic acid (which \nnormally exists as arachidonate in solution) is metabolised \nseparately (or sometimes jointly) by several pathways, \nincluding the following.\n\u2022\tFatty acid cyclo-oxygenase (COX). Two main isoforms \nexist, COX-1 and COX-2. These are highly \nhomologous enzymes but are regulated in different and tissue-specific ways. They enzymatically combine \narachidonic (and some other unsaturated fatty acid) \nsubstrates with molecular oxygen to form unstable intermediates, cyclic endoperoxides, which can \nsubsequently be transformed by other enzymes to different prostanoids.\n\u2022\tLipoxygenases. There are several subtypes, which often \nwork sequentially, to synthesise leukotrienes, lipoxins \nand other compounds (Figs 18.2\u201318.4).\nChapter 27 deals in detail with the way inhibitors of these \npathways (including non-steroidal anti-inflammatory \ndrugs [NSAIDs] and glucocorticoids) produce their anti-inflammatory effects.\nPROSTANOIDS\nCOX-1 is present in most cells as a constitutive enzyme. It produces prostanoids that act mainly as homeostatic regula -\ntors (e.g. modulating vascular responses, regulating gastric acid secretion). COX-2 is not normally present (at least in most tissues \u2013 CNS and renal tissue are important excep -\ntions) but it is strongly induced by inflammatory stimuli and therefore believed to be more relevant as a target", "start_char_idx": 0, "end_char_idx": 3254, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7817b001-d62f-4a0e-a70e-6e7e5f868223": {"__data__": {"id_": "7817b001-d62f-4a0e-a70e-6e7e5f868223", "embedding": null, "metadata": {"page_label": "241", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ffc575a-d1ea-44f7-ad42-a8f43388f91b", "node_type": null, "metadata": {"page_label": "241", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdea8ccf3468dbac97a6008b2e4c7c8c2a2d463acca780768c1e254a6017a135"}, "2": {"node_id": "bff04dfe-4731-48a5-8f80-ea134fcc931c", "node_type": null, "metadata": {"page_label": "241", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ccf17a2c8c2386c782ffdf3e644f14fbea7e449c37290ff214556985e2cb80ea"}}, "hash": "8398df3066379798d8b0ca48660894629735eaff14201c17de651aaa6a3998b3", "text": "is strongly induced by inflammatory stimuli and therefore believed to be more relevant as a target for anti-inflammatory drugs (see Ch. 27). Both enzymes catalyse \nthe incorporation of two molecules of oxygen into two of \nthe unsaturated double bonds in each arachidonate molecule, H\n1 antagonists in these conditions is dealt with in Chapter \n27. It is possible that the developing field of H 4 receptor \npharmacology will fill in some significant gaps in our \nunderstanding of the role of histamine in inflammation in \nthe near future (Thurmond, 2015).\nHistamine \n\u2022\tHistamine \tis \ta \tbasic \tamine, \tstored \tin \tmast \tcell \tand \t\nbasophil granules, and secreted when C3a and C5a \ninteract with specific membrane receptors or when antigen interacts with IgE fixed on cells triggering the \nhigh affinity IgE receptor.\n\u2022\tHistamine \tproduces \teffects \tby \tacting \ton \tH1, H 2, H 3 or \nH4 receptors on target cells.\n\u2022\tThe\tmain \tactions \tin \thumans \tare:\n\u2013 stimulation of gastric secretion (H 2)\n\u2013 contraction of most smooth muscle, except blood \nvessels (H 1)\n\u2013 cardiac stimulation (H 2)\n\u2013 vasodilatation (H1)\n\u2013 increased vascular permeability (H 1)\n\u2022\tInjected \tintradermally, \thistamine \tcauses \tthe \t\u2018triple \t\nresponse\u2019: \treddening (local vasodilatation), weal \n(increased permeability of postcapillary venules) and \nflare\t(from\tan\t\u2018axon\u2019 \treflex \tin \tsensory \tnerves \treleasing \t\na peptide mediator).\n\u2022\tThe\tmain \tpathophysiological \troles \tof \thistamine \tare:\n\u2013 as a stimulant of gastric acid secretion (treated with \nH2-receptor antagonists)\n\u2013 as a mediator of type I hypersensitivity reactions \nsuch as urticaria and hay fever (treated with H\n1-receptor antagonists)\n\u2013 CNS functions (see Ch. 40).\n3The name arose through an anatomical error. In some species it is \ndifficult to differentiate the prostaglandin-rich seminal vesicles from the \nprostate gland which (ironically as we now know) contains relatively \nlittle. Nevertheless, the name stuck, outlasting the more appropriate term vesiglandin, which was suggested later.EICOSANOIDS\nGENERAL REMARKS\nThe term eicosanoid refers to a group of mediators that are \ngenerated from specific fatty acid precursors. They are \nimplicated in the control of many physiological processes, \nare among the most important mediators and modulators of the inflammatory reaction (Figs 18.2 and 18.3) and are \na significant target for drug action.\nInterest in eicosanoids first arose in the 1930s after reports \nthat semen contained a lipid substance, apparently originat -\ning from the prostate gland, which contracted uterine \nsmooth muscle. Later, it became clear that prostaglandin (as \nthe factor was named\n3) was not a single substance but a \nwhole family of compounds generated by virtually all cells \nfrom 20-carbon unsaturated fatty acid precursors.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3156, "end_char_idx": 6430, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5edb0697-e73d-4844-a291-da6e3849917f": {"__data__": {"id_": "5edb0697-e73d-4844-a291-da6e3849917f", "embedding": null, "metadata": {"page_label": "242", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0e1c5a7d-7ae5-41a9-9d0d-59a0dc9b9b3b", "node_type": null, "metadata": {"page_label": "242", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e7b4c29f266a4d0c02e53d6769b5433ea72c0516f6cc804095b4baa80615b4ea"}}, "hash": "e7b4c29f266a4d0c02e53d6769b5433ea72c0516f6cc804095b4baa80615b4ea", "text": "18 SECTION 2 \u2003\u2003CHEMICAL MEDIATORS\n236COOH1\n2\n3\n14\n15\n13COOH\nOHO\nO\nO\nHOCOOH\nOH\nHOHO\nCOOH\nOH\nOHO\nCOOH\nOHCH\nO\u2013OOPR\nCH3COO\nCH2CH2N(CH3)3OCH2O\nCH2+\nCOOH\nOHOOCOOH\nO\nOHHOOH OH\nCOOHOH\nSC ys Gly\nGluCOOHO\nOH\nCOOH\nOHOHCOOHArachidonic acid Platelet Activating Factor (PAF)\nLTB4PGH2\nPGE2\nPGF2\u03b1\nPGD2\nLTC4LXA4\nRVE4\nThromboxane (TX)A2Prostacyclin (PGI2)A\nC\nE\nGI\nJB\nD\nF\nHK\nL\nFig. 18.2 Some key lipid mediators involved in the host defence response. (A) Arachidonic acid, an important precursor of \nprostanoids,\t leukotrienes\t and\t(some)\tlipoxins\tand\tresolvins.\t Note\tthe\tconjugated\t double\tbonds\t (in shaded box) . (B) Platelet-activating factor \n(PAF):\tthe\tlocation\tof\tthe\tacetyl\tgroup\tat\tC2\tis\tshown\tin\tthe\tshaded box . R is a 6- or 8-carbon saturated fatty acid attached by an ether \nlinkage to the carbon backbone. (C) Prostaglandin (PG)H 2, one of the labile intermediates in the synthesis of prostaglandins; note unstable \nring structure (in shaded box) \twhich\tcan\tspontaneously\t hydrolyse\t in\tbiological\t fluids\tif\tnot\tenzymatically\t changed.\t (D)\tPGE 2, the 15-hydroxyl \ngroup (in shaded box) is crucial for the biological activity of prostaglandins and its removal is the first step in their inactivation. (E) and (F) \nPGF 2\u03b1\tand\tPGD 2. (G) Prostacyclin (PGI 2); note unstable ring structure (in shaded box) .\t(H)\tThromboxane\t (TX)A 2; note unstable oxane \nstructure (in shaded box) .\t(I)\tLeukotriene\t (LT)B 4.\t(J)\tLipoxin\t(LX)A 4; note unstable and highly reactive oxygen bridge structure (in shaded \nbox).\t(K)\tLeukotriene\t (LT)C 4;\tnote\tconjugated\t glutathione\t moiety\t (in shaded box) . (L) Resolvin (Rv)E 4. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2086, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "94960a13-8409-4406-9fe1-14cc54908185": {"__data__": {"id_": "94960a13-8409-4406-9fe1-14cc54908185", "embedding": null, "metadata": {"page_label": "243", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2e7abd4b-d20b-44b9-a395-51382fea4aaf", "node_type": null, "metadata": {"page_label": "243", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3c802be2aa93b50ae0770508fb07796505404401458c5350442a938ded37b000"}, "3": {"node_id": "841ad537-bc1b-4386-9b55-2ec3349f249c", "node_type": null, "metadata": {"page_label": "243", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f5cf4ec7d9a084b03bc9bc88d4951e6660ce04ccab0655c2bb1b0cfd28fb0d1"}}, "hash": "14cf4b13c380a85b89436aeabf471d93b84c731c2104145cfb768e6bcb902bbd", "text": "18 LOCAL HORMOnES 1: HISTAMInE AnD THE bIOLOgICALLy ACTIvE LIpIDS \n237Glucocorticoids\n(induce annexin 1)\nNSAIDs\nTXA 2\nsynthase\ninhibitors5-Lipoxygenase\ninhibitors\n(e.g. zileutin)\nPG\nantagonistsLyso-glyceryl-\nphosphorylcholinePhospholipid\nPhospholipase A2 activation\n12-Lipoxygenase\n15-LipoxygenaseCyclo-oxygenase 5-LipoxygenaseArachidonate\nPGE2\n(vasodilator;\nhyperalgesic)PGD2\n(inhibits platelet\naggregation;\nvasodilator)PGF2\u03b1\n(bronchoconstrictor;\nmyometrial\ncontraction)LTC4\nLTD4\nLTE4(bronchoconstrictors;\nincrease vascular\npermeability)LTB4 (chemotaxin)LTA4PAF\n(vasodilator;\nincreases vascular\npermeability;\nbronchoconstrictor;\nchemotaxin)5-HPETECyclic\nendoperoxides\nTXA2\n(thrombotic;\nvasoconstrictor)PGI2\n(vasodilator;\nhyperalgesic;\nstops platelet\naggregation)Lipoxins\nA and B12-HETE\n(chemotaxin)\nLeukotriene\nreceptor\nantogonists\n(e.g.\nzafirukast,\nmontelukast) TXA 2\nantagonistsGlucocorticoids\ninhibit\ninductionPAF\nantagonists\nFig. 18.3 Summary diagram of the inflammatory mediators derived from phospholipids, with an outline of their actions and the \nsites of action of anti-inflammatory drugs. \tArachidonate\t metabolites\t are\tknown\tas\teicosanoids.\t The\tglucocorticoids\t inhibit\ttranscription\t\nof\tthe\tgene\tfor\tcyclo-oxygenase\t (COX)-2,\twhich\tis\tinduced\tin\tcells\tby\tinflammatory\t mediators\t and\tinduce\tand\trelease\tAnnexin\tA1\twhich\t\ndown-regulates phospholipase A 2\tactivity\tthereby\tlimiting\tarachidonate\t release.\tThe\teffects\tof\tprostaglandin\t (PG)E 2 depend on which of the \nfour receptors it activates. HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LT, leukotriene; NSAID, \nnon-steroidal\t anti-inflammatory\t drug;\t PAF, platelet-activating factor; PGI 2, prostacyclin; TX, thromboxane. \nGlutathioneS-\ntransferase\nH2O\nLeukotriene B 4Leukotriene D 4\n(structure includes \nglycine and cysteine)15-HPETE\n15-HETE\nLipoxins\nA and B12-HPETE\n12-HETE\n5-HETE\nGlycine \u03b3-Glutamic\nacid\u03b3-Glutamic\nacid5-HPETEArachidonic acid\nLeukotriene F 4\n(structure includes cysteine \nand \u03b3-glutamic acid)Leukotriene E 4\n(structure includes cysteine)Leukotriene C 4\n(structure includes cysteine,\nglycine and\n\u03b3-glutamic acid)Leukotriene A 45-Lipoxygenase inhibitors\n(e.g. zileutin)12-Lipoxygenase 15-Lipoxygenase\n5-Lipoxygenase 5-Lipoxygenase\nDipeptidase\u03b3-Glutamyl-\ntranspeptidase\u03b3-Glutamyl-\ntranspeptidaseHydrolase\nFig. 18.4 The biosynthesis of", "start_char_idx": 0, "end_char_idx": 2358, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "841ad537-bc1b-4386-9b55-2ec3349f249c": {"__data__": {"id_": "841ad537-bc1b-4386-9b55-2ec3349f249c", "embedding": null, "metadata": {"page_label": "243", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2e7abd4b-d20b-44b9-a395-51382fea4aaf", "node_type": null, "metadata": {"page_label": "243", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3c802be2aa93b50ae0770508fb07796505404401458c5350442a938ded37b000"}, "2": {"node_id": "94960a13-8409-4406-9fe1-14cc54908185", "node_type": null, "metadata": {"page_label": "243", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14cf4b13c380a85b89436aeabf471d93b84c731c2104145cfb768e6bcb902bbd"}}, "hash": "8f5cf4ec7d9a084b03bc9bc88d4951e6660ce04ccab0655c2bb1b0cfd28fb0d1", "text": "18.4 The biosynthesis of leukotrienes from arachidonic acid. Compounds with biological action are shown in grey boxes . HETE, \nhydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2333, "end_char_idx": 3014, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ca932626-3910-4e21-b8fe-184e507f6353": {"__data__": {"id_": "ca932626-3910-4e21-b8fe-184e507f6353", "embedding": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d2741b24-047b-4d6b-8c52-0b318da87c8b", "node_type": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b7c8297c14a21a86d9289b7842be2870c3a4cc94d2aedab0896ef2111179a67c"}, "3": {"node_id": "4a800351-2dbf-4224-b217-72ca67d09284", "node_type": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d6d80a75fc6d488a58d64fdf7459c38cc5f21199520f19e68cdadd341c00925"}}, "hash": "e604dfcb78726f082b058f163eeb0d2903f682e373b7bb533a9336ca9c5495a1", "text": "18 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n238in the lung, and 95% of infused PGE 2, PGE 1 or PGF 2\u03b1 is \ninactivated after a single passage through the lungs, meaning \nthat little normally reaches the arterial circulation and for \nthis reason the half-life of most prostaglandins in the circula -\ntion is less than 1 minute.\nTXA 2 and PGI 2 are slightly different. Both are inherently \nunstable and decay rapidly and spontaneously (within 30 s \nand 5 min, respectively) in biological fluids into inactive \nTXB 2 and 6-keto-PGF 1\u03b1, respectively. Further metabolism \nthen occurs, but it is not really relevant to us here.\nPROSTANOID \u2003RECEPTORS\nThere are five main classes of prostanoid receptor (Wood -\nward et al., 2011), all of which are G protein\u2013coupled \nreceptors ( Table 18.1). They are termed DP, FP, IP, EP and \nTP receptors, respectively, depending on whether their \nligands are PGD, PGF, PGI, PGE or TXA species. Some \nhave further subtypes; for example, there are four EP receptors. Polymorphisms and other variants of these \nenzymes have been implicated in the pathogenesis of various \ndiseases (see Cornejo-Garcia et al., 2016).\nACTIONS \u2003OF \u2003THE \u2003PROSTANOIDS\nThe prostanoids can affect most tissues and exert a bewilder -\ning variety of effects.\n\u2022\tPGD 2 causes vasodilatation in many vascular beds, \ninhibition of platelet aggregation, relaxation of \ngastrointestinal and uterine muscle, and modification \nof release of hypothalamic/pituitary hormones. It has a bronchoconstrictor effect through a secondary action \non TP receptors. It may also activate chemoattractant \nreceptors on some leukocytes.\n\u2022\tPGF\n2\u03b1 causes uterine contraction in humans (see Ch. \n36), luteolysis in some species (e.g. cattle) and \nbronchoconstriction in others (e.g. cats and dogs).\n\u2022\tPGI 2 causes vasodilatation, inhibition of platelet \naggregation (see Ch. 25), renin release and natriuresis through effects on tubular reabsorption of Na\n+.\n\u2022\tTXA 2 causes vasoconstriction, platelet aggregation (see \nCh. 25) and bronchoconstriction (more marked in guinea pig than in humans).\n\u2022\tPGE\n2, the predominant \u2018inflammatory\u2019 prostanoid has \nthe following actions:\n\u2022\tat\tEP 1 receptors, it causes contraction of bronchial \nand gastrointestinal smooth muscle;\n\u2022\tat\tEP 2 receptors, it causes bronchodilatation, \nvasodilatation, stimulation of intestinal fluid secretion and relaxation of gastrointestinal smooth \nmuscle;\n\u2022\tat\tEP 3 receptors, it causes contraction of intestinal \nsmooth muscle, inhibition of gastric acid (see Ch. \n31) with increased mucus secretion, inhibition of \nlipolysis, inhibition of autonomic neurotransmitter release and contraction of the pregnant human \nuterus (Ch. 36);\n\u2022\tat\tEP 4 receptors, it causes similar effects to those of \nEP 2 stimulation (these were originally thought to be \na single receptor). Vascular relaxation is one consequence of receptor activation, as is cervical \n\u2018ripening\u2019. Some inhibitory effects of PGE\n2 on \nleukocyte activation are probably mediated through \nthis receptor.\nSeveral clinically useful drugs act at prostanoid receptors. \nThese include misoprostol, an EP 2/EP 3 agonist that forming the highly unstable endoperoxides prostaglandin (PG)G\n2 and PGH 2 (see Fig.", "start_char_idx": 0, "end_char_idx": 3201, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4a800351-2dbf-4224-b217-72ca67d09284": {"__data__": {"id_": "4a800351-2dbf-4224-b217-72ca67d09284", "embedding": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d2741b24-047b-4d6b-8c52-0b318da87c8b", "node_type": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b7c8297c14a21a86d9289b7842be2870c3a4cc94d2aedab0896ef2111179a67c"}, "2": {"node_id": "ca932626-3910-4e21-b8fe-184e507f6353", "node_type": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e604dfcb78726f082b058f163eeb0d2903f682e373b7bb533a9336ca9c5495a1"}, "3": {"node_id": "43c9c3f3-fc47-4914-89eb-e08eefb28648", "node_type": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c573edd00010b3b268e5f5f255b8eec2d58ab3594564732f043d0be3ed9aaf04"}}, "hash": "5d6d80a75fc6d488a58d64fdf7459c38cc5f21199520f19e68cdadd341c00925", "text": "prostaglandin (PG)G\n2 and PGH 2 (see Fig. 18.2). The suffix \u20182\u2019 indicates \nthat the product contains only two double bonds. PGG 2 \nand PGH 2 are rapidly transformed in a tissue-specific \nmanner by endoperoxide isomerase or synthase enzymes to \nPGE 2, PGI 2 (prostacyclin), PGD 2, PGF 2\u03b1 and thromboxane \n(TX)A 2, which are the principal bioactive end products of \nthis reaction. The mix of eicosanoids thus produced varies \nbetween cell types, depending on the particular endoper -\noxide isomerases or synthases present. In platelets, for \nexample, TXA 2 predominates, whereas in vascular endothe -\nlium PGI 2 is the main product. Macrophages, neutrophils \nand mast cells synthesise a mixture of products. If eicosa-\ntrienoic acid (three double bonds) rather than arachidonic acid is the substrate for these enzymes, the resulting prostanoids have only a single double bond, for example \nPGE\n1, while eicosapentaenoic acid , which contains five double \nbonds, yields PGE 3. Eicosapentaenoic acid is abundant in \ndiets rich in oily fish and may, if present in sufficient amounts, represent a significant fraction of cellular fatty \nacids and thus constitute the major source of precursors for the COX enzyme. When this occurs, the production of \nthe pro-inflammatory PGE\n2 is diminished and, more sig-\nnificantly, the generation of TXA 2 as well. This may partly \nunderlie the beneficial anti-inflammatory and cardiovascular actions that are ascribed to diets rich in this type of marine \nproduct (see also Resolvins, later).\nThe endocannabinoid anandamide (see Ch. 20) is an etha -\nnolamine derivative of arachidonic acid and, surprisingly, it can also be oxidised by COX-2 to form a range of pros-\ntamides. These substances are of increasing interest. They \nact at prostanoid receptors but often exhibit a unique \npharmacology (see Urquhart et al., 2015).\nCATABOLISM \u2003OF \u2003THE \u2003PROSTANOIDS\nThis is a multi-step process. After carrier-mediated uptake, \nmost prostaglandins are rapidly inactivated by prostaglandin \ndehydrogenase and reductase enzymes. These enzymes oxidise \nthe 15-hydroxyl group (see Fig. 18.2) and the 13-14 double \nbond, both of which are important for biological activity. \nThe inactive products are further degraded by general fatty \nacid-oxidising enzymes and excreted in the urine. These dehydrogenase enzymes are present in high concentration Mediators derived from \nphospholipids \n\u2022\tThe\tprincipal \tphospholipid-derived \tmediators \tare \tthe \t\neicosanoids (prostanoids and leukotrienes) and \nplatelet-activating factor (PAF).\n\u2022\tThe\teicosanoids \tare \tsynthesised \tfrom \tarachidonic \tacid \t\nreleased directly from phospholipids by phospholipase A\n2, or by a two-step process involving phospholipase \nC and diacylglycerol lipase.\n\u2022\tArachidonate \tis \tmetabolised \tby \tcyclo-oxygenases \t\n(COX)-1\tor \tCOX-2 \tto \tprostanoids, \tby \t5-lipoxygenase \t\nto leukotrienes and, after further conversion, to lipoxins and other compounds.\n\u2022\tPAF\tis\tderived \tfrom \tphospholipid \tprecursors \tby \t\nphospholipase A 2, giving rise to lyso-PAF, which is \nthen acetylated to give PAF.mebooksfree.net mebooksfree.net", "start_char_idx": 3167, "end_char_idx": 6283, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "43c9c3f3-fc47-4914-89eb-e08eefb28648": {"__data__": {"id_": "43c9c3f3-fc47-4914-89eb-e08eefb28648", "embedding": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d2741b24-047b-4d6b-8c52-0b318da87c8b", "node_type": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b7c8297c14a21a86d9289b7842be2870c3a4cc94d2aedab0896ef2111179a67c"}, "2": {"node_id": "4a800351-2dbf-4224-b217-72ca67d09284", "node_type": null, "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d6d80a75fc6d488a58d64fdf7459c38cc5f21199520f19e68cdadd341c00925"}}, "hash": "c573edd00010b3b268e5f5f255b8eec2d58ab3594564732f043d0be3ed9aaf04", "text": "\nthen acetylated to give PAF.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6258, "end_char_idx": 6766, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "164ed92a-57a2-425e-84f6-65ca0bc690fb": {"__data__": {"id_": "164ed92a-57a2-425e-84f6-65ca0bc690fb", "embedding": null, "metadata": {"page_label": "245", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "170f7225-61a9-48f5-92ae-9601012ba88c", "node_type": null, "metadata": {"page_label": "245", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07b1776dbca22c478c25513f7c77ed36d98bb4b47797b10c1ea6eaaf59cace64"}, "3": {"node_id": "fbf49f7d-7b53-4845-b635-61576c933b6f", "node_type": null, "metadata": {"page_label": "245", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5c4582c0d1cda19e4f0dc1cde09fdc8c0836b7ba18e5ec5f780f047ebf72b57"}}, "hash": "44f3622ac39e2f33fc88eb356f9b2004491e231671eec964e41929ebe0c4f388", "text": "18 LOCAL HORMO n ES 1: HISTAMI n E A n D THE b IOLO g ICALL y ACTI v E LI p IDS \n239yin\u2013yang effect in inflammation, stimulating some responses \nand decreasing others. The most striking effects are as \nfollows.\n\u2022\tPGE 2, PGI 2 and PGD 2 are themselves powerful \nvasodilators but they also synergise with other \ninflammatory vasodilators, such as histamine and \nbradykinin. It is this combined dilator action on precapillary arterioles that contributes to the redness \nand increased blood flow in areas of acute \ninflammation. Prostanoids do not directly increase the permeability of the postcapillary venules, but \npotentiate the effects on vascular leakage caused by \nhistamine and bradykinin. Similarly, they do not themselves produce pain, but sensitise afferent C fibres (see Ch. 43) to the effects of bradykinin and \nother noxious stimuli. The anti-inflammatory and \nanalgesic effects of aspirin-like drugs (NSAIDs, see Ch. 27) stem largely from their ability to block these \nactions.suppresses gastric acid secretion (see Ch. 31), the FP agonists \nbimatoprost ,\n4 latanoprost, tafluprost and travoprost which \nare used for the treatment of glaucoma (see Ch. 14) and \niloprost and epoprostanol which are IP agonists used for \nthe treatment of pulmonary hypertension (see Ch. 23).\nTHE\u2003ROLE \u2003OF \u2003PROSTANOIDS \u2003IN \u2003INFLAMMATION\nThe inflammatory response is inevitably accompanied by \nthe release of prostanoids. PGE 2 predominates, although \nPGI 2 is also important. In areas of acute inflammation, PGE 2 \nand PGI 2 are generated by the local tissues and blood vessels, \nwhile mast cells release mainly PGD 2. In chronic inflam-\nmation, cells of the monocyte/macrophage series also release \nPGE 2 and TXA 2. Together, the prostanoids exert a sort of Table 18.1 A simplified scheme of prostanoid and leukotriene receptor classification based upon their physiological effects\nReceptorPhysiological \nligands Distribution General physiological effectsSignalling system\nIP PGI 2\u226b PGD 2 Abundant in cardiovascular system, \nplatelets, neurons and elsewhere\nGenerally inhibitory:e.g. smooth muscle relaxation, anti-inflammatory and anti-aggregatory effectsG\nS\n\u2191cAMPDP 1 PGD 2\u226b PGE 2 Low abundance; vascular smooth muscle, platelets, CNS, airways, the eye\nEP\n2 PGE 2>PG F 2\u03b1 Widespread distribution\nEP 4 PGE 2>PGF 2\u03b1 Widespread distribution\nTP TxA 2= H 2>D 2 Abundant in cardiovascular system, platelets and immune cells. Two subtypes known with opposing actionsGenerally excitatory:e.g. smooth muscle contraction, pro-inflammatory and platelet aggregatory actionsG\nq/G11\n[PLC]a\n\u2191Ca2+ FP PGF 2\u03b1>PGD 2 Very high expression in female reproductive organs\nEP\n1 PGE 2>PGF 2\u03b1 Myometrium, intestine and lung\nEP 3 PGE 2>PGF 2\u03b1 Widespread distribution throughout body; many isoforms with different G protein couplingGenerally inhibitory:e.g. smooth muscle relaxation, anti-inflammatory and anti-aggregatory effectsG\ni/Go\n\u2193cAMPDP 2 PGD 2>PGF 2\u03b1 Different structure to other prostanoid receptors. Widely distributed especially in immune cells\nBLT\n1 LTB 4>20 hydroxy \nLTB 4Widely distributed in leukocytes and in some endothelial cells\u2018High-affinity\u2019 LTB\n4 receptor. \nActivates leukocytes and \nstimulates chemotaxisGi/G0\u2193 \ncAMPG\nq/G11", "start_char_idx": 0, "end_char_idx": 3223, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fbf49f7d-7b53-4845-b635-61576c933b6f": {"__data__": {"id_": "fbf49f7d-7b53-4845-b635-61576c933b6f", "embedding": null, "metadata": {"page_label": "245", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "170f7225-61a9-48f5-92ae-9601012ba88c", "node_type": null, "metadata": {"page_label": "245", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07b1776dbca22c478c25513f7c77ed36d98bb4b47797b10c1ea6eaaf59cace64"}, "2": {"node_id": "164ed92a-57a2-425e-84f6-65ca0bc690fb", "node_type": null, "metadata": {"page_label": "245", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44f3622ac39e2f33fc88eb356f9b2004491e231671eec964e41929ebe0c4f388"}}, "hash": "f5c4582c0d1cda19e4f0dc1cde09fdc8c0836b7ba18e5ec5f780f047ebf72b57", "text": "chemotaxisGi/G0\u2193 \ncAMPG\nq/G11 \n\u2191PLC\nBLT 2 LTB 4>20 hydroxy \nLTB 4Several tissues intestine, skin and some lesions\u2018Low-affinity\u2019 LTB\n4 receptor. Maybe \nimportant in GI barrier formation and airway inflammationG\ni/Gq\u2193 \ncAMP\nCysLT 1 LTD 4>LTC 4>LTE 4 Several tissues including leukocytes, mast cells, lung, intestinal and vascular tissueBronchoconstriction and leukocyte activationG\nq/G11 \n\u2191PLC\nCysLT 2 LTC 4> LTD 4>LTE 4 Several tissues including leukocytes, mast cells, nasal mucosa and vascular tissuePMN activation, inflammation, contracts some vascular smooth muscleG\nq/G11 \n\u2191PLC\naPLC may not be involved in EP 1 signalling.\n(Data\tderived \tfrom \tWoodward \tet \tal., \t2011 \tand \tthe \tIUPHAR/BPS \tGuide \tto \tPharmacology.)\n4Women being treated with bimatoprost eye drops for glaucoma were \ndelighted with a side effect of this drug \u2013 stimulation of eyelash \ngrowth. It wasn\u2019t long before a thriving \u2018off-label\u2019 market had been \nestablished for its use in beauty spas. Eventually, the FDA licensed a preparation specifically for this cosmetic indication.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3194, "end_char_idx": 4725, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "085126dc-f72c-47f0-86c2-0a2d56185848": {"__data__": {"id_": "085126dc-f72c-47f0-86c2-0a2d56185848", "embedding": null, "metadata": {"page_label": "246", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c7aed488-8077-41d9-96e1-36d35d3d5c8c", "node_type": null, "metadata": {"page_label": "246", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84a7679379e3fbd025445aaf13b4755b1f9f6336c4b2cfa8d18d6a79cff06ae8"}, "3": {"node_id": "9cf43681-1e4d-4d97-b24f-21b156f28ef2", "node_type": null, "metadata": {"page_label": "246", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "326b73f7873a6742aa14d0d5eb9817a533667bdbf57b611c869ebe246c5a049b"}}, "hash": "6b49dd0684e91d696986b32912508c62b46c9466254b4f1985301965dbb6361a", "text": "18 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n240are synthesised from arachidonic acid by lipoxygenases. \nThese soluble cytosolic enzymes are mainly found in \nlung, platelets, mast cells and white blood cells. The main \nenzyme in this group is 5-lipoxygenase. On cell activation, this enzyme translocates to the nuclear membrane, where \nit associates with a crucial accessory protein, affectionately \ntermed FLAP ( Five-Lipoxygenase Activating Protein). The \n5-lipoxygenase incorporates a hydroperoxy group at C5 \nin arachidonic acid to form 5-hydroperoxytetraenoic acid \n(5-HPETE, see Fig. 18.4), which is further converted to \nthe unstable leukotriene (LT)A\n4. This may be converted \nenzymatically to LTB 4 or, utilising a separate pathway \ninvolving conjugation with glutathione, to the cysteinyl-\ncontaining leukotrienes LTC 4, LTD 4, LTE 4 and LTF 4. These \ncysteinyl leukotrienes are produced mainly by eosinophils, mast cells, basophils and macrophages. Mixtures of these \nsubstances constitute the biological activity historically ascribed to slow-reacting substance of anaphylaxis (SRS-A), \nan elusive bronchoconstrictor factor shown many years \nago to be generated in guinea pig lung during anaphylaxis, and consequently predicted to be important in asthma.\u2022\tProstaglandins \tof \tthe \tE \tseries \tare \talso \tpyrogenic \t(i.e. \t\nthey induce fever). High concentrations are found in cerebrospinal fluid during infection, and the increase \nin temperature (attributed to cytokines) is actually \nmediated by the release of PGE\n2. NSAIDs exert \nantipyretic actions (Ch. 27) by inhibiting PGE 2 \nsynthesis in the hypothalamus.\n\u2022\tSome\tprostaglandins \thave \tanti-inflammatory \teffects \t\nwhich are important during the resolution phase of inflammation. For example, PGE\n2 decreases lysosomal \nenzyme release and the generation of toxic oxygen \nmetabolites from neutrophils, as well as the release of \nhistamine from mast cells.\nProstanoids \n\u2022\tThe\tterm \tprostanoids encompass prostaglandins and \nthromboxanes.\n\u2022\tCyclo-oxygenases \t(COX) \toxidise \tarachidonate, \t\nproducing the unstable intermediates PGG 2 and PGH 2. \nThese\tare \tenzymatically \ttransformed \tto \tthe \tdifferent \t\nprostanoid species.\n\u2022\tThere\tare \ttwo \tmain \tCOX \tisoforms: \tCOX-1, \ta \t\nconstitutive \tenzyme, \tand \tCOX-2, \twhich \tis \toften \t\ninduced\tby \tinflammatory \tstimuli.\n\u2022\tThe\tprincipal \tprostanoids \tare:\n\u2013 PGI 2 (prostacyclin), predominantly from vascular \nendothelium, acts on IP receptors, producing \nvasodilatation and inhibition of platelet aggregation.\n\u2013\tThromboxane \t(TX)A 2, predominantly from platelets, \nacts\ton\tTP \treceptors, \tcausing \tplatelet \taggregation \t\nand vasoconstriction.\n\u2013 PGE 2\tis\tan\timportant \tmediator \tof \tthe \tinflammatory \t\nresponses and causes fever and pain.\n\u2022\tOther\teffects \tof \tPGE 2\tinclude:\n\u2013 at EP 1\treceptors: \tcontraction \tof \tbronchial \tand \t\ngastrointestinal (GI) tract smooth muscle;\n\u2013 at EP 2\treceptors: \trelaxation \tof \tbronchial, \tvascular \t\nand GI tract smooth muscle;\n\u2013 at EP 3\treceptors: \tinhibition \tof \tgastric", "start_char_idx": 0, "end_char_idx": 3012, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9cf43681-1e4d-4d97-b24f-21b156f28ef2": {"__data__": {"id_": "9cf43681-1e4d-4d97-b24f-21b156f28ef2", "embedding": null, "metadata": {"page_label": "246", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c7aed488-8077-41d9-96e1-36d35d3d5c8c", "node_type": null, "metadata": {"page_label": "246", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84a7679379e3fbd025445aaf13b4755b1f9f6336c4b2cfa8d18d6a79cff06ae8"}, "2": {"node_id": "085126dc-f72c-47f0-86c2-0a2d56185848", "node_type": null, "metadata": {"page_label": "246", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b49dd0684e91d696986b32912508c62b46c9466254b4f1985301965dbb6361a"}}, "hash": "326b73f7873a6742aa14d0d5eb9817a533667bdbf57b611c869ebe246c5a049b", "text": "at EP 3\treceptors: \tinhibition \tof \tgastric \tacid \tsecretion, \t\nincreased gastric mucus secretion, contraction of pregnant uterus and of gastrointestinal smooth muscle, inhibition of lipolysis and of autonomic \nneurotransmitter release.\n\u2022\tPGF\n2\u03b1 acts on FP receptors, found in uterine (and \nother) smooth muscle, and corpus luteum, producing \ncontraction of the uterus and luteolysis (in some \nspecies).\n\u2022\tPGD 2 is abundant in activated mast cells. It acts on \nDP\treceptors, \tcausing \tvasodilatation \tand \tinhibition \tof \t\nplatelet aggregation.Clinical uses of prostanoids \n\u2022\tGynaecological \tand \tobstetric \t(see \tCh. \t36):\n\u2013\ttermination \tof \tpregnancy: \tgemeprost or \nmisoprostol (a metabolically stable prostaglandin \n[PG]E analogue)\n\u2013\tinduction \tof \tlabour: \tdinoprostone or misoprostol\n\u2013\tpostpartum \thaemorrhage: \tcarboprost.\n\u2022\tGastrointestinal:\n\u2013 to prevent ulcers associated with non-steroidal \nanti-inflammatory \tdrug \tuse: misoprostol (see Ch. \n31).\n\u2022\tCardiovascular:\n\u2013 to maintain the patency of the ductus arteriosus until \nsurgical correction of the defect in babies with \ncertain\tcongenital \theart \tmalformations: \talprostadil \n(PGE 1);\n\u2013 to inhibit platelet aggregation (e.g. during \nhaemodialysis): \tepoprostenol (PGI 2), especially if \nheparin is contraindicated;\n\u2013\tprimary \tpulmonary \thypertension: \tepoprostenol (see \nCh. 23).\n\u2022\tOphthalmic:\n\u2013 open-angle \tglaucoma: latanoprost eye drops.\nLEUKOTRIENES\nLeukotrienes (leuko- because they are made by white \ncells, and -trienes because they contain a conjugated triene \nsystem of double bonds; see Fig. 18.2) comprise two main \ncategories, chemoattractant (LTB 4) and cysteinyl (or sufi-\ndopeptide) leukotrienes (LTC 4, D 4, E4 and F 4). Both types LTB 4 is produced mainly by neutrophils. Lipoxins and \nother active products, some of which have anti-inflammatory \nproperties, are also produced from arachidonate by this \npathway (see Figs 18.2 and 18.4).\nLTB 4 is metabolised by a unique membrane-bound \ncytochrome P450 enzyme in neutrophils, and then further \noxidised to 20-carboxy-LTB 4. LTC 4 and LTD 4 are metabolised \nto LTE 4, which is excreted in the urine.\nLEUKOTRIENE RECEPTORS\nLeukotriene receptors are all GPCRs. They are termed \nBLT (two subtypes) if the ligand is LTB 4, and CysLT (two \nsubtypes) for the cysteinyl leukotrienes (see Table 18.1). They \nare all of the G q/G 11 family that activates PLC signalling mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2969, "end_char_idx": 5840, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f4944ecc-4190-4182-9ae4-3f1378950935": {"__data__": {"id_": "f4944ecc-4190-4182-9ae4-3f1378950935", "embedding": null, "metadata": {"page_label": "247", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1261ef20-0455-42dc-b685-23b892763d57", "node_type": null, "metadata": {"page_label": "247", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "94159f449c84c50dbca5e083ba0c0859fc98bef0c54c81dbe71185908675cfe3"}, "3": {"node_id": "e45ce403-c30a-42b6-81b1-c2a83016652b", "node_type": null, "metadata": {"page_label": "247", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ba51430c500aefc5dbcf02ea24fc37ecbee0da7c5cf2ba088cf76d6e8f6a879"}}, "hash": "aefb83eb0a963b5f6af7fa3aea44e5b6aaf76654440b8ac487c3dd096bfe9c94", "text": "18 LOCAL HORMO n ES 1: HISTAMI n E A n D THE b IOLO g ICALL y ACTI v E LI p IDS \n241and tissues in many inflammatory conditions, including \nrheumatoid arthritis, psoriasis and ulcerative colitis.\nThe cysteinyl leukotrienes are present in the sputum of \nchronic bronchitis patients in amounts that are biologically active. On antigen challenge, they are released from samples \nof human asthmatic lung in vitro, and into nasal lavage \nfluid in subjects with allergic rhinitis. There is evidence that they contribute to the underlying bronchial hyper-\nreactivity in asthmatics, and it is thought that they are \namong the main mediators of both the early and late phases of asthma (see Fig. 29.2). Liu and Yokomizo (2015) have reviewed the role of these mediators in allergic diseases.mechanisms, although there may be further receptors that respond to these potent mediators. Genetic variations in \nthese receptors or the enzymes that synthesise leukotrienes \nmay contribute to allergy and asthma, or to the failure of \ndrug treatment in those disorders (Thompson et al., 2016).\nLEUKOTRIENE ACTIONS\nCysteinyl leukotrienes have important actions on the respira -\ntory and cardiovascular systems, and the CysLT-receptor \nantagonists zafirlukast and montelukast are now in use \nin the treatment of asthma (see Ch. 29), often in conjunction \nwith a corticosteroid. Cysteinyl leukotrienes may mediate \nthe cardiovascular changes of acute anaphylaxis. Agents \nthat inhibit 5-lipoxygenase are therefore obvious candidates for anti-asthmatic (see Ch. 29) and anti-inflammatory agents. \nOne such drug, zileuton, is available in some parts of the \nworld for the treatment of asthma.\nThe respiratory system. Cysteinyl leukotrienes are potent \nspasmogens, causing dose-related contraction of human bronchiolar muscle in vitro. LTE\n4 is less potent than LTC 4 \nand LTD 4, but its effect is much longer lasting. All cause \nan increase in mucus secretion. Given by aerosol to human volunteers, they reduce specific airway conductance and \nmaximum expiratory flow rate, the effect being more protracted than that produced by histamine (Fig. 18.5).\nThe cardiovascular system. Small amounts of LTC 4 or \nLTD 4 given intravenously cause a rapid, short-lived fall in \nblood pressure, and significant constriction of small coronary \nresistance vessels. Given subcutaneously, they are equipotent \nwith histamine in causing weal and flare. Given topically in the nose, LTD\n4 increases nasal blood flow and local \nvascular permeability.\nThe role of leukotrienes in inflammation. LTB 4 is a potent \nchemotactic agent for neutrophils and macrophages (see \nFig. 7.2). It upregulates membrane adhesion molecule \nexpression on neutrophils, and increases the production of superoxide anions and the release of granule enzymes. \nOn macrophages and lymphocytes, it stimulates proliferation \nand cytokine release. It is found in inflammatory exudates \nAirways conductance (% control)100\n90\n80706050\n00\nTime (min)HistamineLTD4\nLTC4\n10 20 30 40 50\nFig. 18.5 The time course of action on specific airways \nconductance of the cysteinyl leukotrienes and histamine, in \nsix normal subjects. Specific airways conductance was \nmeasured in a constant volume whole-body plethysmograph, \nand the drugs were given by inhalation. (From Barnes et al., \n1984.)Leukotrienes \n\u2022\t5-Lipoxygenase \toxidises \tarachidonate \tto", "start_char_idx": 0, "end_char_idx": 3381, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e45ce403-c30a-42b6-81b1-c2a83016652b": {"__data__": {"id_": "e45ce403-c30a-42b6-81b1-c2a83016652b", "embedding": null, "metadata": {"page_label": "247", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1261ef20-0455-42dc-b685-23b892763d57", "node_type": null, "metadata": {"page_label": "247", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "94159f449c84c50dbca5e083ba0c0859fc98bef0c54c81dbe71185908675cfe3"}, "2": {"node_id": "f4944ecc-4190-4182-9ae4-3f1378950935", "node_type": null, "metadata": {"page_label": "247", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aefb83eb0a963b5f6af7fa3aea44e5b6aaf76654440b8ac487c3dd096bfe9c94"}}, "hash": "3ba51430c500aefc5dbcf02ea24fc37ecbee0da7c5cf2ba088cf76d6e8f6a879", "text": "\toxidises \tarachidonate \tto \tgive \t\n5-hydroperoxyeicosatetraenoic \tacid \t(5-HPETE), \twhich \t\nis\tconverted \tto \tleukotriene \t(LT)A 4.\tThis,\tin\tturn, \tcan \tbe \t\nconverted \tto \teither \tLTB 4 or to a series of glutathione \nadducts,\tthe \tcysteinyl \tleukotrienes \tLTC 4,\tLTD 4 and \nLTE 4.\n\u2022\tLTB 4, acting on specific receptors, causes adherence, \nchemotaxis and activation of polymorphs and \nmonocytes, and stimulates proliferation and cytokine \nproduction from macrophages and lymphocytes.\n\u2022\tThe\tcysteinyl \tleukotrienes \tcause:\n\u2013 contraction of bronchial muscle\n\u2013 vasodilatation in most vessels, but coronary \nvasoconstriction\n\u2022\tLTB 4 is an important mediator in all types of \ninflammation; \tthe \tcysteinyl \tleukotrienes \tare \tof \t\nimportance in asthma.\nOTHER IMPORTANT FATTY \nACID DERIVATIVES\nUnsaturated fatty acids such as arachidonic acid, eicosap -\nentaenoic acid and docosahexaenoic acid can be enzymatically \ntransformed into other important lipid mediators. Trihy-\ndroxy arachidonate metabolites termed lipoxins (see Figs 18.2 \nand 18.4) are formed by the concerted action of the 5- and \nthe 12- or 15-lipoxygenase enzymes during inflammation. \nLipoxins (abbreviation Lx) act on polymorphonuclear leukocytes, through G protein\u2013coupled receptors such as \nALX (also known as formyl peptide receptor 2 (FPR2) this \nreceptor also recognises other anti-inflammatory factors such as annexin A1), to oppose the action of pro-inflammatory stimuli, providing what might be called \u2018stop signals\u2019 to \nhalt inflammation (see Chandrasekharan & Sharma-Walia, \n2015). Aspirin (a COX inhibitor, see Ch. 27) stimulates \nthe synthesis of lipoxins because COX-2 can still produce \nhydroxy fatty acids even when inhibited by aspirin and \nunable to synthesise prostaglandins. The formation of lipoxins probably contributes to aspirin\u2019s anti-inflammatory \neffects, some of which are not completely explained through \ninhibition of prostaglandin generation (see Gilroy & Perretti, \n2005; Serhan, 2005).\nResolvins (abbreviation Rv) are, as the name implies, a \nseries of compounds that fulfil a similar function, but unlike mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3354, "end_char_idx": 5942, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "738679ca-f6b6-4fb8-819e-4a2fd6c972f2": {"__data__": {"id_": "738679ca-f6b6-4fb8-819e-4a2fd6c972f2", "embedding": null, "metadata": {"page_label": "248", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2395193-c2ef-40a0-a452-b208e95c52a6", "node_type": null, "metadata": {"page_label": "248", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b99caa801dd12673047e3d7532b71769b03a2260076bfcbd5b01d6dd81bd00ae"}, "3": {"node_id": "1d016b09-0260-4238-95ad-a7ffd52cc768", "node_type": null, "metadata": {"page_label": "248", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b25be0110355ff72c5010b4730474d6da09d6d713afabaa003cd813ccad18321"}}, "hash": "bd7cf95779d8021662cba04707194e46e3c40a71dfd094c63fe4300a2215d970", "text": "18 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n242phase of asthma (see Fig. 29.3). PAF contracts both bronchial \nand ileal smooth muscle.\nActing through its receptor, PAF activates cPLA 2 and \nstimulates arachidonate turnover in many cells. In platelets \nit increases TXA 2 generation, producing a shape change \nand the release of the granule contents. This is important in haemostasis and thrombosis (see Ch. 25).\nThe anti-inflammatory actions of the glucocorticoids may \nbe caused, at least in part, by inhibition of PAF synthesis (see Fig. 18.2). Competitive antagonists of PAF and/or \nspecific inhibitors of lyso-PAF acetyltransferase could well \nbe useful anti-inflammatory drugs and/or anti-asthmatic \nagents. The PAF antagonist lexipafant is approved for the \ntreatment of acute pancreatitis in some countries (see Leveau \net al., 2005). Two other antagonists, modipafant and apafant \nare also undergoing trials. Rupatadine is a combined H 1 \nand PAF antagonist that is available in some parts of the world for treating allergic symptoms, but it is not clear \nwhat (if anything) its anti-PAF action adds clinically to its effect as an H\n1 antagonist.\nCONCLUDING REMARKS\nIn this chapter we have focused on histamine and lipid mediators, but in some species (i.e. rodents) 5-HT (Ch. 16) \nalso has pro-inflammatory properties. Other low molecular-\nweight factors also have inflammogenic actions, including some purines (Ch. 17) and nitric oxide (Ch. 21).\nPerhaps the most surprising development in this area is \nthe extraordinary proliferation of lipid mediators. It is a feature that would have surprised Dale and his colleagues, \nas lipids were regarded for many years simply as inert \nbuilding blocks for membranes or as a source of metabolic fuel. However, this has become one of the fastest growing and most exciting areas of small molecular-weight mediator \nresearch and has already yielded several novel therapeutic \nleads.lipoxins, their precursor fatty acid is eicosapentaenoic acid (RvE\n1-4) or docosahexaenoic acid (RvD 1-4). Fish oils are rich \nin these fatty acids and it is likely that at least some of their \nclaimed anti-inflammatory benefit is produced through \nconversion to these highly active species (see Zhang & Spite, 2012, for a review of this fascinating area). RvD\n1 acts \nthrough the ALX/FPR2 receptor system whereas RvE 1 acts \nthrough a GPCR called the chemerin receptor. This signals \nthrough the G1/Gq system to lower cAMP and release intracellular calcium. Resolvins can counteract inflammatory \npain (Xu et al., 2010) and analogues are undergoing trials \nfor the treatment of a variety of inflammatory conditions (Lee & Surh, 2012). Maresins (abbreviation Ma) and protectins \nare dihydroxy acids generated from docosahexaenoic acid, also by the actions of lipoxygenases. Maresins are predomi -\nnately synthesised by macrophages and have a role in \ninflammatory resolution. Protectins (abbreviation P) are \nproduced by lymphocytes and probably act to modulate the operation of the immune system amongst other func -\ntions. The area, which can be confusing until you come to terms with lipid structures, has been well reviewed by Sansbury and Spite (2016), Duvall and Levy (2016) and \nSerhan et al. (2015).\nPLATELET-ACTIVATING FACTOR\nPlatelet-activating factor , also variously termed PAF-acether \nand AGEPC (acetyl-glyceryl-ether-phosphorylcholine), is a \nbiologically active lipid that can produce effects at exceed -\ningly low", "start_char_idx": 0, "end_char_idx": 3460, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1d016b09-0260-4238-95ad-a7ffd52cc768": {"__data__": {"id_": "1d016b09-0260-4238-95ad-a7ffd52cc768", "embedding": null, "metadata": {"page_label": "248", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2395193-c2ef-40a0-a452-b208e95c52a6", "node_type": null, "metadata": {"page_label": "248", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b99caa801dd12673047e3d7532b71769b03a2260076bfcbd5b01d6dd81bd00ae"}, "2": {"node_id": "738679ca-f6b6-4fb8-819e-4a2fd6c972f2", "node_type": null, "metadata": {"page_label": "248", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bd7cf95779d8021662cba04707194e46e3c40a71dfd094c63fe4300a2215d970"}}, "hash": "b25be0110355ff72c5010b4730474d6da09d6d713afabaa003cd813ccad18321", "text": "is a \nbiologically active lipid that can produce effects at exceed -\ningly low concentrations (less than 10\u221210 mol/L) through \nits G protein\u2013coupled PAF receptor (G q/G 11; stimulates \ncAMP production). The name, PAF, is somewhat mislead -\ning because it acts on many different target cells and, in \nparticular, is believed to be an important mediator in both acute and chronic allergic and inflammatory phenomena.\nBIOSYNTHESIS\nPAF (see Fig. 18.2) is produced by platelets in response to thrombin, and also by activated inflammatory cells. It is \nsynthesised from phospholipids which have an ether-linked \nhexadecyl or octadecyl fatty acid at C1, an unsaturated fatty acid such as arachidonic acid ester-linked at C2 and \na phosphoryl choline base at C3. The action of PLA\n2 removes \nthe arachidonic acid yielding lyso-PAF, which is then \nacetylated by an acetyltransferase to yield the biologically \nactive PAF. The reaction is reversible and PAF, in turn, can be inactivated by an acetylhydrolase yielding lyso-PAF \nready for recycling.\nACTIONS AND ROLE IN INFLAMMATION\nPAF can reproduce many of the signs and symptoms of inflammation. Injected locally, it produces vasodilatation \n(and thus erythema), increased vascular permeability and \nweal formation. Higher doses produce hyperalgesia. It is a potent chemotaxin for neutrophils and monocytes, and \nrecruits eosinophils into the bronchial mucosa in the late Platelet-activating factor (PAF) \n\u2022\tPAF\tprecursors \tare \treleased \tfrom \tactivated \t\ninflammatory \tcells \tby \tphospholipase \tA2. After \nacetylation, the resultant PAF is released and acts on \nspecific receptors in target cells.\n\u2022\tPharmacological \tactions \tinclude \tvasodilatation, \t\nincreased vascular permeability, chemotaxis and activation of leukocytes (especially eosinophils), activation and aggregation of platelets, and smooth \nmuscle contraction.\n\u2022\tPAF\tis\timplicated \tin \tbronchial \thyper-responsiveness \t\nand in the delayed phase of asthma.\n\u2022\tA\tPAF\tantagonist, \tlexipafant, is used to treat \npancreatitis.\nREFERENCES AND FURTHER READING\nAriel, A., Serhan, C.N., 2007. Resolvins and protectins in the \ntermination program of acute inflammation. Trends Immunol. \n28, 176\u2013183. (Very accessible review on these unusual lipid mediators \nwhich promote inflammatory resolution and the link with fish oils)Barnes, N.C., Piper, P.J., Costello, J.F., 1984. Comparative effects of \ninhaled leukotriene C\n4, leukotriene D 4, and histamine in normal \nhuman subjects. Thorax 39, 500\u2013504.\nDi Gennaro, A., Haeggstrom, J.Z., 2012. The leukotrienes: \nimmune-modulating lipid mediators of disease. Adv. Immunol. 116, mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3382, "end_char_idx": 6486, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ab07b0a4-8ff8-49f8-a37c-a4a07eb9b148": {"__data__": {"id_": "ab07b0a4-8ff8-49f8-a37c-a4a07eb9b148", "embedding": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4fb92235-14fd-4d57-a4dd-2995bc5d91a8", "node_type": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "357ef7aed50ff498cc6f6c806b17b1750c3daa81420e9f77ded831139d10b418"}, "3": {"node_id": "f35810d3-a4c7-4dd1-8b74-222ef0941f26", "node_type": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fa5d34748effb70c8095017dc66fa83265e24212c189efee5629fc12aba0b870"}}, "hash": "0636cbfae8096f937cbeea882c7c7863c03d43013d08801b90bb1b73c3111e9e", "text": "18 LOCAL HORMOnES 1: HISTAMInE AnD THE bIOLOgICALLy ACTIvE LIpIDS \n243Pharmacol. Rev. 67, 601\u2013655. ( Very comprehensive review of histamine \npharmacology for those who want to dig deep into this area )\nSansbury, B.E., Spite, M., 2016. Resolution of acute inflammation and \nthe role of resolvins in immunity, thrombosis, and vascular biology. \nCirc. Res. 119, 113\u2013130.\nSerhan, C.N., 2005. Lipoxins and aspirin-triggered 15-epi-lipoxins are \nthe first lipid mediators of endogenous anti-inflammation and \nresolution. Prostaglandins Leukot. Essent. Fatty Acids 73, 141\u2013162. ( A \npaper reviewing the lipoxins \u2013 anti-inflammatory substances formed by the \n5-lipoxygenase enzyme; also discusses the action of aspirin in boosting the \nsynthesis of these compounds and the receptors on which they act. A good \nreview that summarises a lot of work )\nSerhan, C.N., Dalli, J., Colas, R.A., Winkler, J.W., Chiang, N., 2015. \nProtectins and maresins: New pro-resolving families of mediators in \nacute inflammation and resolution bioactive metabolome. Biochim. \nBiophys. Acta 1851, 397\u2013413. ( Very good account of these new families of \nmediators detailing their discovery, biosynthesis and biology. Many useful \ntables summarising their main actions for those who are intimidated by the, \noften complex, biochemistry )\nThompson, M.D., Capra, V., Clunes, M.T., et al., 2016. Cysteinyl \nleukotrienes pathway genes, atopic asthma and drug response: from \npopulation isolates to large genome-wide association studies. Front. \nPharmacol. 7, 1\u201317. ( This is for you if you want to know the latest thinking \non the genetic basis of atopic asthma and its relevance to leukotriene biology )\nThurmond, R.L., 2015. The histamine H4 receptor: from orphan to the \nclinic. Front. Pharmacol. 6, 65.\nUrquhart, P., Nicolaou, A., Woodward, D.F., 2015. Endocannabinoids \nand their oxygenation by cyclo-oxygenases, lipoxygenases and other \noxygenases. Biochim. Biophys. Acta 1851, 366\u2013376. ( The coming together \nof the cannabinoid and eicsanoid fields was unexpected and an exciting \ndevelopment. This is useful paper if you want to understand the biochemistry \nof these unusual compounds. Many pathway diagrams )\nWoodward, D.F., Jones, R.L., Narumiya, S., 2011. International Union of \nBasic and Clinical Pharmacology. LXXXIII: classification of prostanoid \nreceptors, updating 15 years of progress. Pharmacol. Rev. 63, 471\u2013538. \n(Definitive and comprehensive review by the leaders in the field )\nXu, Z.Z., Zhang, L., Liu, T., et al., 2010. Resolvins RvE 1 and RvD 1 \nattenuate inflammatory pain via central and peripheral actions. Nat. \nMed. 16, 592\u2013597. ( Fascinating paper reporting the ability of these \nanti-inflammatory lipids to reduce pain )\nYanagisawa, M., Kurihara, H., Kimura, S., et al., 1988. A novel potent \nvasoconstrictor peptide produced by vascular endothelial cells. \nNature 332, 411\u2013415. ( The discovery of endothelin \u2013 a remarkable tour de \nforce )\nZhang, M.J., Spite, M., 2012. Resolvins: anti-inflammatory and \nproresolving mediators derived from omega-3 polyunsaturated fatty \nacids. Annu. Rev. Nutr. 32, 203\u2013227. ( Explores", "start_char_idx": 0, "end_char_idx": 3119, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f35810d3-a4c7-4dd1-8b74-222ef0941f26": {"__data__": {"id_": "f35810d3-a4c7-4dd1-8b74-222ef0941f26", "embedding": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4fb92235-14fd-4d57-a4dd-2995bc5d91a8", "node_type": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "357ef7aed50ff498cc6f6c806b17b1750c3daa81420e9f77ded831139d10b418"}, "2": {"node_id": "ab07b0a4-8ff8-49f8-a37c-a4a07eb9b148", "node_type": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0636cbfae8096f937cbeea882c7c7863c03d43013d08801b90bb1b73c3111e9e"}, "3": {"node_id": "63ce22d3-a021-458e-8eaf-410b554d596f", "node_type": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "843b57bab781645a9ed31b69d2118b30ac94b0c9b00e5456f5a7afbe7df59928"}}, "hash": "fa5d34748effb70c8095017dc66fa83265e24212c189efee5629fc12aba0b870", "text": "Annu. Rev. Nutr. 32, 203\u2013227. ( Explores the link between \u2018fish oils\u2019 \nand anti-inflammatory resolving production )51\u201392. ( Useful update on leukotriene actions in inflammation. \nRecommended )\nChandrasekharan, J.A., Sharma-Walia, N., 2015. Lipoxins: nature\u2019s way \nto resolve inflammation. J Inflamm Res 8, 181\u2013192. ( Recent review and \nupdate on the role of these lipids in inflammatory resolution. A good \nintroduction and easy to read )\nCornejo-Garcia, J.A., Perkins, J.R., Jurado-Escobar, R., et al., 2016. \nPharmacogenomics of prostaglandin and leukotriene receptors. Front. \nPharmacol. 7, 316. ( This paper details some of the genetic variants of \neicosanoid receptors and reviews the evidence linking them to disease \npathologies )\nDuvall, M.G., Levy, B.D., 2016. DHA- and EPA-derived resolvins, \nprotectins, and maresins in airway inflammation. Eur. J. Pharmacol. \n785, 144\u2013155.\nGilroy, D.W., Perretti, M., 2005. Aspirin and steroids: new mechanistic \nfindings and avenues for drug discovery. Curr. Opin. Pharmacol. 5, \n405\u2013411. ( A very interesting review of the anti-inflammatory substances \nthat are released during the inflammatory response and that bring about \nresolution; it also deals with a rather odd effect of aspirin \u2013 its ability to \nboost the production of anti-inflammatory lipoxins. Easy to read and \ninformative )\nHattori, Y., Hattori, K., Matsuda, N., 2017. Regulation of the \ncardiovascular system by histamine. Handb. Exp. Pharmacol. 241, \n239\u2013258.\nJutel, M., Akdis, M., Akdis, C.A., 2009. Histamine, histamine receptors \nand their role in immune pathology. Clin. Exp. Allergy 39, 1786\u20131800. \n(Excellent review. Easy to read )\nKim, N., Luster, A.D., 2007. Regulation of immune cells by eicosanoid \nreceptors. ScientificWorld J. 7, 1307\u20131328. ( Useful overview of \neicosanoids, their biology and receptor family )\nLarsson, B.M., Kumlin, M., Sundblad, B.M., et al., 2006. Effects of \n5-lipoxygenase inhibitor zileuton on airway responses to inhaled \nswine house dust in healthy subjects. Respir. Med. 100, 226\u2013237. ( A \npaper describing the effects of zileuton, a 5-lipoxygenase inhibitor, on the \nallergic response in humans; the results are not unequivocally positive, but \nthe study is an interesting one )\nLee, H.N., Surh, Y.J., 2012. Therapeutic potential of resolvins in the \nprevention and treatment of inflammatory disorders. Biochem. \nPharmacol. 84, 1340\u20131350. ( Good review and easy to read )\nLeveau, P., Wang, X., Sun, Z., et al., 2005. Severity of \npancreatitis-associated gut barrier dysfunction is reduced following \ntreatment with the PAF inhibitor lexipafant. Biochem. Pharmacol. 69, \n1325\u20131331. ( An experimental study using a rat model but provides a useful \ninsight into the potential clinical role of such an antagonist in pancreatitis )\nLiu, M., Yokomizo, T., 2015. The role of leukotrienes in allergic diseases. \nAllergol. Int. 64, 17\u201326. ( Comprehensive and very readable account of this \narea. Some useful diagrams and tables. Recommended )\nPanula, P., Chazot, P.L., Cowart, M., et al., 2015. International Union of \nBasic and Clinical Pharmacology. XCVIII.", "start_char_idx": 3086, "end_char_idx": 6192, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "63ce22d3-a021-458e-8eaf-410b554d596f": {"__data__": {"id_": "63ce22d3-a021-458e-8eaf-410b554d596f", "embedding": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4fb92235-14fd-4d57-a4dd-2995bc5d91a8", "node_type": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "357ef7aed50ff498cc6f6c806b17b1750c3daa81420e9f77ded831139d10b418"}, "2": {"node_id": "f35810d3-a4c7-4dd1-8b74-222ef0941f26", "node_type": null, "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fa5d34748effb70c8095017dc66fa83265e24212c189efee5629fc12aba0b870"}}, "hash": "843b57bab781645a9ed31b69d2118b30ac94b0c9b00e5456f5a7afbe7df59928", "text": "al., 2015. International Union of \nBasic and Clinical Pharmacology. XCVIII. Histamine receptors. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6151, "end_char_idx": 6727, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "310ec046-7473-44b4-8a3d-b6b7bc7572f9": {"__data__": {"id_": "310ec046-7473-44b4-8a3d-b6b7bc7572f9", "embedding": null, "metadata": {"page_label": "250", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "83ff7cc8-5f61-4ec1-af6a-2861d462fffe", "node_type": null, "metadata": {"page_label": "250", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c7ce963cd6e9591d8bd4a55289ad35e86ce9cb8f18422d21b4e88675aac62c3"}, "3": {"node_id": "8f07c505-aeaf-4ec2-a8d5-7cdc4ad4e789", "node_type": null, "metadata": {"page_label": "250", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92a03f2fd423b0f0ff548433d6e45fe4a9ec935639acbbdbbe05fb011b6f3093"}}, "hash": "2f5d54063a3df85482eb9fad9b7d24fc57c7b0f901cd9568fd15b6faca762380", "text": "244\nLocal hormones 2: \npeptides and proteins19 CHEMICAL MEDIATORS SECTION 2 \nOVERVIEW\nHaving discussed small-molecule local hormones in \nthe previous chapter, we now turn our attention to \npeptides and proteins, which are orders of magnitude \nlarger in molecular terms. This constitutes a very diverse group and, unlike others described in Chapter \n18, includes compounds (e.g. cytokines) that seem to be exclusively concerned with host defence. We begin with some general introductory observations \non protein and peptide synthesis and secretion. We \nthen discuss bradykinin, neuropeptides, cytokines (interleukins, chemokines and interferons) in more \ndetail. Finally, we conclude with a few remarks \non other proteins and peptides that down-regulate inflammation.\nINTRODUCTION\nDespite the fact that several mediators discovered early in \nthe history of our discipline were recognised to be peptides, \nunderstanding of their pharmacology was limited until the \n1970s, when the techniques for purifying, sequencing and synthesising peptides and proteins were first developed. The \ndevelopment of high-performance liquid chromatography \nand solid-phase peptide synthesis, for example, have greatly accelerated the development of the area, and while proteins \ncontaining 50 or more amino acids were (and are still) dif -\nficult to synthesise chemically, molecular biology techniques \nhave provided a rapid alternative synthetic route. Indeed, the use of recombinant proteins as therapeutic agents \u2013 a \ndevelopment driven mainly by the emergent biotechnology \nindustry \u2013 is rapidly gaining ground (see Ch. 5).\nThe use of molecular biology has helped understanding \nof peptide and protein pharmacology in many other ways as well. The availability of monoclonal antibodies for radioimmunoassay and immunocytochemistry has solved \nmany quantitative problems. Transgenic animals with \npeptide or receptor genes deleted, overexpressed or mutated provide valuable clues about their functions, as has the \nuse of antisense oligonucleotides, siRNA and gene editing \n(CRISPR-Cas9 ) technologies (see also Ch. 5) to silence these genes for experimental purposes. The control of precursor \nsynthesis can be studied indirectly by measuring mRNA, \nfor which highly sensitive and specific assays have been developed, which are even able to analyse mRNA in a \nsingle cell. The technique of in situ hybridisation enables \nthe location and abundance of the mRNA to be mapped at microscopic resolution.\nIn summary, the molecular landscape has changed \ncompletely. Whereas the discovery of new \u2018small-molecule\u2019 mediators has slowed, the discovery of new protein and \npeptide mediators continues apace (Schulze et al., 2014). More than 100 cytokines have been discovered since \ninterleukin 2 (IL-2) was first characterised in 1982.\nGENERAL PRINCIPLES OF PROTEIN AND \nPEPTIDE PHARMACOLOGY\nSTRUCTURE\nPeptide and protein mediators generally vary from three \nto about 200 amino acid residues in length, the arbitrary \ndividing line between peptides and proteins being about \n50 residues. An important difference is that proteins need to adopt a complex folded structure to exert their specific \nfunction, whereas short peptides are in most cases flexible. \nSpecific residues in proteins and peptides often undergo post-translational modifications, such as amidation , glycosyla -\ntion, acetylation, carboxylation, sulfation or phosphorylation.\n1 \nThey also may contain intramolecular disulfide bonds, such \nthat the molecule adopts a partially cyclic conformation, or they may comprise two or more separate chains linked by intermolecular disulfide", "start_char_idx": 0, "end_char_idx": 3627, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8f07c505-aeaf-4ec2-a8d5-7cdc4ad4e789": {"__data__": {"id_": "8f07c505-aeaf-4ec2-a8d5-7cdc4ad4e789", "embedding": null, "metadata": {"page_label": "250", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "83ff7cc8-5f61-4ec1-af6a-2861d462fffe", "node_type": null, "metadata": {"page_label": "250", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c7ce963cd6e9591d8bd4a55289ad35e86ce9cb8f18422d21b4e88675aac62c3"}, "2": {"node_id": "310ec046-7473-44b4-8a3d-b6b7bc7572f9", "node_type": null, "metadata": {"page_label": "250", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f5d54063a3df85482eb9fad9b7d24fc57c7b0f901cd9568fd15b6faca762380"}}, "hash": "92a03f2fd423b0f0ff548433d6e45fe4a9ec935639acbbdbbe05fb011b6f3093", "text": "or they may comprise two or more separate chains linked by intermolecular disulfide bonds.\nGenerally speaking, larger proteins adopt restricted \nconformations that expose functional groups in fixed loca -\ntions on their surface, which interact with multiple sites on \ntheir receptors in \u2018lock-and-key\u2019 mode. To envisage flexible \npeptides fitting into a receptor site this way is to imagine that you can unlock your front door with a length of cooked spaghetti. These features have greatly impeded the rational \ndesign of non-peptide analogues that mimic the action of \nproteins and peptides at their receptors (peptidomimetics). The use of random screening methods has (somewhat to the \nchagrin of the rationalists) nevertheless led in recent years \nto the discovery of many non-peptide antagonists \u2013 although \nfew agonists \u2013 for peptide receptors.\nTYPES OF PROTEIN AND PEPTIDE MEDIATOR\nProtein and peptide mediators that are secreted by cells and act on surface receptors of the same or other cells can \nbe very broadly divided into four groups:\n\u2022\tneurotransmitters \t(e.g. \tendogenous \topioid \tpeptides, \t\nCh. 43) and neuroendocrine mediators (e.g. \nvasopressin, somatostatin, hypothalamic releasing \nhormones, adrenocorticotrophic hormone [ACTH], \nluteinising hormone (LH), follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH), see Chs \n34\u201336), not discussed further in this chapter);\n\u2022\thormones \tfrom \tnon-neural \tsources: \tthese \tcomprise \t\nplasma-derived peptides, notably angiotensin (Ch. 23) \nand bradykinin, as well as other hormones such as \ninsulin (Ch. 32), endothelin (Ch. 23), atrial natriuretic \npeptide (Ch. 22) and leptin (Ch. 33);\n1Bacteria are poor at post-translational modifications, hence over half of \nall protein drugs (biopharmaceuticals) are generated using mammalian \ncell cultures.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3544, "end_char_idx": 5853, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4061034a-68c0-4ea3-8f41-c3a4ac876411": {"__data__": {"id_": "4061034a-68c0-4ea3-8f41-c3a4ac876411", "embedding": null, "metadata": {"page_label": "251", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "072a67a1-3885-4e2e-b99f-75aec60378fb", "node_type": null, "metadata": {"page_label": "251", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "155d3bb813fd7600da08245e533621f32c67e3293d3b8adb623d6b6a191b83b6"}}, "hash": "155d3bb813fd7600da08245e533621f32c67e3293d3b8adb623d6b6a191b83b6", "text": "19 LOCAL HORMO n ES 2: p E p TIDES A n D p ROTEI n S \n245so intracellular manufacture is a matter of conventional \nprotein synthesis. This often begins with the manufacture \nof a precursor protein in which the desired final peptide \nsequence is embedded. Specific proteolytic enzymes excise the mature active peptide from within this peptide sequence, \na process of sculpture rather than synthesis. The precursor \nprotein is packaged into vesicles at the point of synthesis, and the active peptide is formed in situ ready for release \n(Fig. 19.1). Thus there is no need for specialised biosynthetic pathways, or for the uptake or recapturing mechanisms, that are important for the synthesis and release of most non-peptide mediators (e.g. 5-hydroxytryptamine [5-HT]; \nCh. 16).\u2022\tgrowth \tfactors: \tproduced \tby \tmany \tdifferent \tcells \tand \t\ntissues that control cell growth and differentiation \n(especially, in adults, in the haemopoietic system; see \nCh. 26);\n\u2022\tmediators \tof \tthe \timmune \tsystem \t(cytokines, \tsee \tlater).\nBIOSYNTHESIS AND REGULATION \nOF PEPTIDES\nPeptide structure is, of course, directly coded in the genome, \nin a manner that the structure of (say) acetylcholine is not, \nSYNTHESIS\nSORTING\nPROCESSING\nCleavage, amidation,\nsulfation, etc.Rough endoplasmic\nreticulum\nSmooth endoplasmic\nreticulum\nTransportvesicle\nGolgi\napparatusRibosomes\nRegulated secretion\n(e.g. neurotransmitter release)Continuous secretion\n(e.g. clotting factors)SECRETIONSecretory vesicles\nCell membraneCa2+\nFig. 19.1 Cellular mechanisms for peptide synthesis and release. Proteins synthesised by ribosomes are threaded through the \nmembrane of the rough endoplasmic reticulum, from where they are conveyed in transport vesicles to the Golgi apparatus. Here, they are \nsorted and packaged into secretory vesicles. Processing (cleavage, glycosylation, amidation, sulfation, etc.) occurs within the transport and secretory vesicles, and the products are released from the cell by exocytosis. Constitutive secretion (e.g. of plasma proteins and clotting factors by liver cells) occurs continuously, and little material is stored in secretory vesicles. Regulated secretion (e.g. of neuropeptides or cytokines) occurs in response to increased intracellular Ca\n2+ or other intracellular signals, and material is typically stored in significant \namounts in secretory vesicles awaiting release. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2862, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "087e1ea3-1584-4555-9928-c7eb5013da8c": {"__data__": {"id_": "087e1ea3-1584-4555-9928-c7eb5013da8c", "embedding": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cf430eb1-c967-4988-9f9d-7a4f01da9fb9", "node_type": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0734960fa29bb119a9066452c5d133dc679933c9a954650fee14b21b99766df3"}, "3": {"node_id": "ed391ff7-9e9c-4cbf-9f43-841f91215790", "node_type": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c527362c114271de8c4319aad6e2125ec483e4861651afaacfb0c772bdcab56a"}}, "hash": "0f7d941ce141db8a6216770e332dff2c3b1709b1d81aed1079a5302c414f88a3", "text": "19 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n246and when the gene is transcribed, the ensuing RNA \n(heterologous nuclear RNA [hnRNA]) is spliced to remove \nthe introns and some of the exons, forming the final mature \nmRNA that is translated. Control of the splicing process allows a measure of cellular control over the peptides that \nare produced.\nFor example, the calcitonin gene codes for calcitonin itself, \nimportant in bone metabolism (Ch. 37), and also for a completely dissimilar peptide (CGRP, involved in migraine \npathogenesis, Ch. 16). Alternative splicing allows cells to produce either pro-calcitonin (expressed in thyroid cells) or pro-CGRP (expressed in many neurons) from the same \ngene. Substance P and neurokinin A are two closely related \ntachykinins belonging to the same family, and are encoded on the same gene. Alternative splicing results in the produc -\ntion of two precursor proteins; one of these includes both peptides, the other includes only substance P. The ratio of the two varies widely between tissues, which correspond -\ningly produce either one or both peptides.\nPOST-TRANSLATIONAL \u2003MODIFICATIONS \u2003AS \u2003A\u2003\u2003\nSOURCE \u2003OF \u2003PEPTIDE \u2003DIVERSITY\nMany peptides, such as tachykinins and ACTH-related peptides (see Ch. 34), must undergo enzymatic amidation \nat the C-terminus to acquire full biological activity. Tissues \nmay also generate peptides of varying length from the same primary sequence by the action of specific peptidases \nthat cut the chain at different points. For example, pro-\ncholecystokinin (pro-CCK) contains the sequences of at least five CCK-like peptides ranging in length from 4 to \n58 amino acid residues, all with the same C-terminal \nsequence. CCK itself (33 residues) is the main peptide produced by the intestine, whereas the brain produces mainly CCK-8. The opioid precursor prodynorphin similarly \ngives rise to several peptides with a common terminal sequence, the proportions of which vary in different tissues and in different neurons in the brain. In some cases (e.g. \nthe inflammatory mediator bradykinin, see p. 247), peptide \ncleavage occurring after release generates a new active peptide (des-Arg\n9-bradykinin), which acts on a different \nreceptor, both peptides contributing differently to the \ncombined inflammatory response.\nPEPTIDE TRAFFICKING AND SECRETION\nThe basic mechanisms by which peptides are synthesised, \npackaged into vesicles, processed and secreted are sum-\nmarised in Fig. 19.1. Two secretory pathways exist, for \nconstitutive and regulated secretion, respectively. Constitu-\ntively secreted proteins (e.g. plasma proteins, some clotting \nfactors) are not stored in appreciable amounts, and secretion \nis coupled to synthesis. Regulated secretion is, as with many hormones and transmitters, controlled by receptor-activated \nsignals that lead to a rise in intracellular Ca\n2+ (see Ch. 4), \nand peptides awaiting release are stored in cytoplasmic vesicles. Specific protein\u2013protein interactions appear to be \nresponsible for the sorting of different proteins and their routing into different vesicles, and for choreographing their \nselective release. Identification of the specific \u2018trafficking\u2019 \nproteins involved in particular secretory pathways may eventually yield novel drug targets for the selective control \nof secretion.\nHaving described the general mechanisms by which \npeptides are synthesised, processed and released, we \nnow describe some significant mediators that fall into this \ncategory.PEPTIDE", "start_char_idx": 0, "end_char_idx": 3483, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ed391ff7-9e9c-4cbf-9f43-841f91215790": {"__data__": {"id_": "ed391ff7-9e9c-4cbf-9f43-841f91215790", "embedding": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cf430eb1-c967-4988-9f9d-7a4f01da9fb9", "node_type": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0734960fa29bb119a9066452c5d133dc679933c9a954650fee14b21b99766df3"}, "2": {"node_id": "087e1ea3-1584-4555-9928-c7eb5013da8c", "node_type": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f7d941ce141db8a6216770e332dff2c3b1709b1d81aed1079a5302c414f88a3"}, "3": {"node_id": "9e9f9d89-ae4c-4dbf-9e6c-b0a9aec5eb65", "node_type": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b687835c10d55d3c92949d18fdc5474b543339d91ea1299e194c0ec824eb873"}}, "hash": "c527362c114271de8c4319aad6e2125ec483e4861651afaacfb0c772bdcab56a", "text": "we \nnow describe some significant mediators that fall into this \ncategory.PEPTIDE PRECURSORS\nThe precursor protein, or pre-prohormone, usually 100\u2013250 \nresidues in length, consists of an N-terminal signal sequence \n(peptide), followed by a variable stretch of unknown func -\ntion, and a peptide-containing region that may contain \nseveral copies of active peptide fragments. Often, several \ndifferent peptides are found within one precursor, but \nsometimes there are multiple copies of a single peptide.2 \nThe signal sequence, which is strongly hydrophobic, facili -\ntates insertion of the protein into the endoplasmic reticu -\nlum and is then cleaved off at an early stage, yielding the \nprohormone.\nThe active peptides are usually demarcated within the \nprohormone sequence by pairs of basic amino acids (Lys-Lys or Lys-Arg), which are cleavage points for the trypsin-like proteases that release the peptides. This endoproteolytic \ncleavage generally occurs in the Golgi apparatus or the secretory vesicles. The enzymes responsible are known as prohormone convertases . Scrutiny of the prohormone sequence \noften reveals likely cleavage points that distinguish previ -\nously unknown peptides. In some cases (e.g. calcitonin gene-related peptide [CGRP]; see later), new peptide \nmediators have been discovered in this way, but there are \nmany examples where no function has yet been assigned. Whether these peptides are, like strangers at a funeral, \nwaiting to declare their purpose or merely functionless \nmournful relics, remains a mystery. There are also large stretches of the prohormone sequence of unknown function \nlying between the active peptide fragments.\n3\nThe abundance of mRNA coding for particular pre-\nprohormones, which reflects the level of gene expression, is very sensitive to physiological conditions. This type of \ntranscriptional control is one of the main mechanisms by which peptide expression and release are regulated over \nthe medium to long term. Inflammation, for example, \nincreases the expression, and hence the release, of various cytokines by immune cells (see Ch. 7). Sensory neurons \nrespond to peripheral inflammation by increased expression \nof tachykinins (substance P and neurokinins A and B), which is important in the genesis of inflammatory pain (see Ch. 43).\nDIVERSITY WITHIN PEPTIDE FAMILIES\nPeptides commonly occur in families with similar or related sequences and actions. For example, the pro-opiomelanocortin \n(POMC) serves as a source of ACTH, melanocyte-stimulating \nhormones (MSH) and \u03b2-endorphin, all of which have a role in controlling the inflammatory response (as well as \nother processes).\nGENE \u2003SPLICING \u2003AS \u2003A \u2003SOURCE \u2003OF \u2003DIVERSITY\nDiversity of members of a peptide family can also arise by \ngene splicing or during post-translational processing of \nthe prohormone. Genes contain coding regions ( exons) \ninterspersed with intervening non-coding regions ( introns ) \n2In the case of the invertebrate Aplysia, one protein precursor contains \nno fewer than 28 copies of the same short peptide.\n3When these large sequences of unknown function were discovered in \nour DNA, they were termed \u2018junk DNA\u2019, not because they were \nrubbish, but arrogantly because we didn\u2019t understand it. It turns out \n\u2018junk DNA\u2019 is actually very important in controlling cell function and in diseases, etc. Likewise with unknown function \u2018junk peptide\u2019, watch \nthis space for uncovering its true role.mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3413, "end_char_idx": 6897, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9e9f9d89-ae4c-4dbf-9e6c-b0a9aec5eb65": {"__data__": {"id_": "9e9f9d89-ae4c-4dbf-9e6c-b0a9aec5eb65", "embedding": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cf430eb1-c967-4988-9f9d-7a4f01da9fb9", "node_type": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0734960fa29bb119a9066452c5d133dc679933c9a954650fee14b21b99766df3"}, "2": {"node_id": "ed391ff7-9e9c-4cbf-9f43-841f91215790", "node_type": null, "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c527362c114271de8c4319aad6e2125ec483e4861651afaacfb0c772bdcab56a"}}, "hash": "8b687835c10d55d3c92949d18fdc5474b543339d91ea1299e194c0ec824eb873", "text": "its true role.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6907, "end_char_idx": 7400, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c978bf50-6b9a-4b67-a14d-81de40ef151d": {"__data__": {"id_": "c978bf50-6b9a-4b67-a14d-81de40ef151d", "embedding": null, "metadata": {"page_label": "253", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "709d1bcd-b04f-48a0-ab46-c5bda6fd2ed8", "node_type": null, "metadata": {"page_label": "253", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0b9c7f6ae5e5e89484060d37b3f9e5e7993962fa05389675b8acc58552e22bb"}, "3": {"node_id": "9235f740-7556-4018-a6f6-e1ef890d75ba", "node_type": null, "metadata": {"page_label": "253", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b34870ff2172daeab075199dafb718b113b9d0d3d04b35261c607027b1963b76"}}, "hash": "9e1aca83bd6247cd048fca797082a98a1153e30a6a3aa961abddf11d1976315c", "text": "19 LOCAL HORMO n ES 2: p E p TIDES A n D p ROTEI n S \n247which is bound to the luminal surface of endothelial cells, \nis identical to angiotensin-converting enzyme (ACE; see Ch. \n23), which cleaves the two C-terminal residues from the inactive peptide angiotensin I, converting it to the active vasoconstrictor peptide angiotensin II. Thus kininase II \ninactivates a vasodilator and activates a vasoconstrictor. \nPotentiation of bradykinin actions by ACE inhibitors may contribute to some side effects of these drugs (e.g. cough). \nKinins are also metabolised by various less specific pepti -\ndases, including a serum carboxypeptidase that removes \nthe C-terminal arginine, generating des-Arg\n9-bradykinin, \na specific agonist at one of the two main classes of bradykinin \nreceptor.\nBRADYKININ RECEPTORS\nThere are two bradykinin receptors, designated B 1 and B 2. \nBoth are G protein\u2013coupled receptors and mediate very similar effects. B\n1 receptors are normally expressed at very \nlow levels but are strongly induced in inflamed or damaged tissues by cytokines such as IL-1. B\n1 receptors respond to \ndes-Arg9-bradykinin but not to bradykinin itself. A number \nof selective peptide and non-peptide antagonists are known. It is likely that B\n1 receptors play a significant role in inflam -\nmation and hyperalgesia (see Ch. 43), and antagonists could \nbe used in cough and neurological disorders (Rodi et al., \n2005).\nB2 receptors are constitutively present in many normal \ncells and are activated by bradykinin and kallidin, but not by des-Arg\n9-bradykinin. Peptide and non-peptide antago -\nnists have been developed, the best known being the bradykinin analogue icatibant, used to treat acute attacks \nin patients with hereditary angio-oedema (an uncommon \ndisorder caused by deficiency of C1-esterase inhibitor that normally restrains complement activation).\nACTIONS AND ROLE IN INFLAMMATION\nBradykinin causes vasodilatation and increased vascular \npermeability. Its vasodilator action is partly a result of BRADYKININ\nBradykinin and lysyl-bradykinin ( kallidin ) are active peptides \nformed by proteolytic cleavage of circulating proteins termed \nkininogens through a protease cascade pathway (see Fig. 7.1).\nSOURCE AND FORMATION OF BRADYKININ\nAn outline of the formation of bradykinin from high \nmolecular-weight kininogen in plasma by the serine protease \nkallikrein is given in Fig. 19.2. Kininogen is a plasma \u03b1-globulin that exists in both high (M\nr 110,000) and low \n(M r 70,000) molecular-weight forms. Kallikrein is derived \nfrom the inactive precursor prekallikrein by the action of \nHageman factor (factor XII; see Fig. 7.1 and Ch. 25). Hageman \nfactor is activated by contact with negatively charged surfaces such as collagen, basement membrane, bacterial \nlipopolysaccharides, urate crystals and so on. Hageman \nfactor, prekallikrein and the kininogens leak out of the vessels during inflammation because of increased vascular \npermeability, and exposure to negatively charged surfaces \npromotes the interaction of Hageman factor with prekal -\nlikrein. The activated enzyme then \u2018clips\u2019 bradykinin from its kininogen precursor. Kallikrein can also activate the \ncomplement system and can convert", "start_char_idx": 0, "end_char_idx": 3218, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9235f740-7556-4018-a6f6-e1ef890d75ba": {"__data__": {"id_": "9235f740-7556-4018-a6f6-e1ef890d75ba", "embedding": null, "metadata": {"page_label": "253", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "709d1bcd-b04f-48a0-ab46-c5bda6fd2ed8", "node_type": null, "metadata": {"page_label": "253", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0b9c7f6ae5e5e89484060d37b3f9e5e7993962fa05389675b8acc58552e22bb"}, "2": {"node_id": "c978bf50-6b9a-4b67-a14d-81de40ef151d", "node_type": null, "metadata": {"page_label": "253", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e1aca83bd6247cd048fca797082a98a1153e30a6a3aa961abddf11d1976315c"}}, "hash": "b34870ff2172daeab075199dafb718b113b9d0d3d04b35261c607027b1963b76", "text": "Kallikrein can also activate the \ncomplement system and can convert plasminogen to plasmin \n(see Fig. 7.1 and Ch. 25).\nIn addition to plasma kallikrein, there are other kinin-\ngenerating isoenzymes found in pancreas, salivary glands, colon and skin. These tissue kallikreins act on both high and \nlow molecular-weight kininogens and generate mainly kalli -\ndin, a peptide with actions similar to those of bradykinin.\nMETABOLISM AND INACTIVATION \nOF BRADYKININ\nSpecific enzymes that inactivate bradykinin and related kinins are called kininases (see Fig. 19.2). One of these, \nkininase II , is a peptidyl dipeptidase that inactivates kinins \nby removing the two C-terminal amino acids. This enzyme, \nSites of cleavage for kinin formation\nLys-bradykinin\n(kallidin)\nBradykinin\nSites of cleavage for inactivationKininase I Kininase IICOOH Kininogen\nmolecule Kininogen\nmoleculeH2N MetL ys ArgP ro ProG ly Phe Ser ProP he Arg\nB2- receptor antagonist, Hoe 140: D-Arg \u2013 Arg \u2013 Pro \u2013 Hyp \u2013 Gly \u2013 Thi \u2013 Ser \u2013 D-Tic \u2013 Oic \u2013 Arg\nB1- receptor antagonist, des-Arg Hoe 140: D-Arg \u2013 Arg \u2013 Pro \u2013 Hyp \u2013 Gly \u2013 Thi \u2013 Ser \u2013 D-Tic \u2013 Oic\nFig. 19.2 The structure of bradykinin and some bradykinin antagonists. The sites of proteolytic cleavage of high molecular-weight \nkininogen by kallikrein involved in the formation of bradykinin are shown in the upper half of the figure; the sites of cleavage associated with \nbradykinin and kallidin inactivation are shown in the lower half. The B 2-receptor antagonist icatibant (Hoe 140) has a p A2 of 9, and the \ncompetitive B 1-receptor antagonist des-Arg Hoe 140 has a p A2 of 8. The Hoe compounds contain unnatural amino acids: Thi, \u03b4-Tic and \nOic, which are analogues of phenylalanine and proline. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3151, "end_char_idx": 5354, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "11df2f14-ec53-45b1-98f5-aa15a49b738c": {"__data__": {"id_": "11df2f14-ec53-45b1-98f5-aa15a49b738c", "embedding": null, "metadata": {"page_label": "254", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2542fe3e-cbef-459b-9d9d-742b13e42aac", "node_type": null, "metadata": {"page_label": "254", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "81e00f77bb02e1204352c68ec8d8873285c5e79ded821b9b918e4a1f50bf4f7b"}, "3": {"node_id": "a6304eb3-0330-49aa-9412-6784f38a5c24", "node_type": null, "metadata": {"page_label": "254", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "896df7e1484ac3ddbd502d21b841c23c99f5254c158156548cbedbbd9acf97e5"}}, "hash": "1bc90af0c073db5ab378d072009e7980acf7f58fdeb3cd32edf815eec003ec31", "text": "19 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n248central nervous system (CNS), the autonomic nervous \nsystem, and peripheral sensory neurons, as well as in many \nperipheral tissues. They are often released as co-transmitters \n(Chs 13, 40), along with non-peptide neurotransmitters.\nWhen released from peripheral endings of nociceptive \nsensory neurons (see Ch. 43), neuropeptides in some species cause neurogenic inflammation (Maggi, 1996). The main peptides involved are substance P, neurokinin A and \nCGRP. Substance P and neurokinin A are small (about \n1100 Da) members of the tachykinin family with partly \nhomologous structures, which act on mast cells, releasing \nhistamine and other mediators, and producing smooth \nmuscle contraction, neural activation, mucus secretion and vasodilatation. CGRP is a member of the calcitonin family \n(37 amino acids in length) shares these properties and is a \nparticularly potent vasodilator. Tachykinins released from the central endings of nociceptive neurons also modulate \ntransmission in the dorsal horn of the spinal cord, affecting \nsensitivity to pain (see Ch. 43). All these neuropeptides act on specific G protein\u2013coupled receptors to produce their \neffects.\nNeurogenic inflammation is implicated in the pathogenesis \nof several inflammatory conditions, including the delayed phase of asthma, allergic rhinitis, inflammatory bowel \ndisease and some types of arthritis as well as migraine (Ch. \n16 and Pisi et a l., 2009 ). Antagonists at the neurokinin NK 1 \nreceptor, such as aprepitant and fosaprepitant, are used to treat emesis, particularly that associated with some forms \nof cancer chemotherapy (see Ch. 57). Other important members of the neuropeptide family include enkephalins/\nendorphins (Ch. 43) and orexins (Ch. 33).\nCYTOKINES\n\u2018Cytokine\u2019 is an all-purpose functional term that is applied \nto protein or polypeptide mediators synthesised and released \nby cells of the immune system during inflammation. They \nare crucial for the overall coordination of the inflammatory response. Cytokines act locally by autocrine or paracrine \nmechanisms. Unlike conventional hormones such as insulin, \nconcentrations in blood and tissues are almost undetectable under normal circumstances, but are massively up-regulated \n(100\u20131000-fold) during inflammatory episodes. All these \nmediators are usually active at very low (sub-nanomolar) concentrations.\nOn the target cell, cytokines bind to and activate specific, \nhigh-affinity receptors that, in most cases, are also up-regulated during inflammation. Except for chemokines , which \nact on G protein\u2013coupled receptors, most cytokines act on \nkinase-linked receptors, regulating phosphorylation cascades \nthat affect gene expression, such as the Jak/Stat pathway (Chs 3 and 7).\nIn addition to their own direct actions on cells, some \ncytokines amplify inflammation by inducing the formation of other inflammatory mediators. Others can induce recep -\ntors for other cytokines on their target cell, or engage in synergistic or antagonistic interactions with other cytokines. Cytokines constitute a complex chemical signalling language, \nwith the final response of a particular cell involved being \ndetermined by the strength and number of different mes -\nsages received concurrently at the cell surface.\nSystems for classifying cytokines abound in the literature, \nas dodiagrams depicting complex networks of cytokines interacting with each other and with a range of target cells. generation of prostaglandin-I\n2 (PGI 2) and release of nitric \noxide (NO). It causes pain by stimulating", "start_char_idx": 0, "end_char_idx": 3574, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a6304eb3-0330-49aa-9412-6784f38a5c24": {"__data__": {"id_": "a6304eb3-0330-49aa-9412-6784f38a5c24", "embedding": null, "metadata": {"page_label": "254", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2542fe3e-cbef-459b-9d9d-742b13e42aac", "node_type": null, "metadata": {"page_label": "254", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "81e00f77bb02e1204352c68ec8d8873285c5e79ded821b9b918e4a1f50bf4f7b"}, "2": {"node_id": "11df2f14-ec53-45b1-98f5-aa15a49b738c", "node_type": null, "metadata": {"page_label": "254", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1bc90af0c073db5ab378d072009e7980acf7f58fdeb3cd32edf815eec003ec31"}}, "hash": "896df7e1484ac3ddbd502d21b841c23c99f5254c158156548cbedbbd9acf97e5", "text": "2) and release of nitric \noxide (NO). It causes pain by stimulating nociceptive \nnerve terminals, and its action here is potentiated by \nprostaglandins (Ch. 18), which are released by bradykinin. Bradykinin also contracts intestinal, uterine and bronchial \nsmooth muscle in some species. The contraction is slow and \nsustained in comparison with that produced by tachykinins such as substance P ( brady- means slow; tachy- means \nrapid).\nAlthough bradykinin reproduces many inflammatory \nsigns and symptoms, its role in inflammation and allergy is not clear, partly because its effects are often component \nparts of a complex cascade of events triggered by other \nmediators. However, excessive bradykinin production contributes to the diarrhoea of gastrointestinal disorders, \nand in allergic rhinitis it stimulates nasopharyngeal secre -\ntion. Bradykinin also contributes to the clinical picture \nin pancreatitis,\n4 although, disappointingly, B 2 antagonists \nworsen rather than alleviate this disorder. Physiologically, the release of bradykinin by tissue kallikrein may regulate \nblood flow to certain exocrine glands, and influence secre -\ntions. Bradykinin also stimulates ion transport and fluid \nsecretion by some epithelia, including intestine, airways \nand gall bladder.\nBradykinin \n\u2022\tBradykinin \t(BK) \tis \ta \tnonapeptide \t\u2018clipped\u2019 \tfrom \ta \t\nplasma \u03b1-globulin, kininogen, by kallikrein.\n\u2022\tIt\tis\tconverted \tby \tkininase I to an active octapeptide, \nBK 1\u20138 (des-Arg9-BK),\tand\tinactivated \tby \tthe \tremoval \tof \t\nan additional amino acid by kininase II (angiotensin-\nconverting enzyme) in the lung.\n\u2022\tPharmacological \tactions:\n\u2013 vasodilatation (largely dependent on endothelial cell \nnitric\toxide \tand \tPGI 2);\n\u2013 increased vascular permeability;\n\u2013 stimulation of pain nerve endings;\n\u2013 stimulation of epithelial ion transport and fluid \nsecretion in airways and gastrointestinal tract;\n\u2013 contraction of intestinal and uterine smooth muscle.\n\u2022\tThere\tare \ttwo \tmain \tsubtypes \tof \tBK \treceptors: \tB2, \nwhich is constitutively present, and B 1, which is \ninduced in inflammation.\n\u2022\tIcatibant ,\ta\tpeptide \tanalogue \tof \tBK, \tis \ta \tselective \t\ncompetitive antagonist for B 2 receptors and is used to \ntreat acute attacks of hereditary angioedema.\nOther, non-peptide antagonists for both B 1 and B 2 \nreceptors are known, and may be developed for treating inflammatory disorders.\n4A serious and painful condition in which proteolytic enzymes are \nreleased from damaged pancreatic cells, initiating cascades that release, \namong other things, bradykinin.NEUROPEPTIDES\nNeuropeptides constitute a large ( >100) and diverse family \nof small to medium-sized peptides. Many are found in the mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3507, "end_char_idx": 6677, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "68212f43-73b0-41e1-afa1-73df678a3419": {"__data__": {"id_": "68212f43-73b0-41e1-afa1-73df678a3419", "embedding": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "805483ce-1d91-4572-9b46-4ad9a52026e9", "node_type": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fcf4567948cbba9f20c22057cb50bf6c53cdb06c3b3d255d0f2eb09128ced9c6"}, "3": {"node_id": "fad17d10-c560-450f-b466-336dd696d1f8", "node_type": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c40ce0029563bbd94dffd3c578083677fe049a6eff08bda1b7b28144daa03d54"}}, "hash": "9da985706a279b1f6b404d0a10fb3d14d3e4ba719d3a5a6501e74da59346baa2", "text": "19 LOCAL HORMO n ES 2: p E p TIDES A n D p ROTEI n S \n249reactions. Again, the nomenclature (and the classification) \nis confusing, because some non-cytokine mediators also \ncontrol leukocyte movement (C5a, LTB 4, fMet-Leu-Phe, etc; \nsee Fig. 7.2) and many chemokines have more than one name. Furthermore, many chemokines have other actions, \ncausing mast cell degranulation or promoting angiogenesis, \nfor example.\nMore than 40 chemokines have been identified. They are \nall highly homologous peptides of 8\u201310 kDa, which are \nusually grouped according to the configuration of key cysteine residues in their polypeptide chain. Chemokines \nwith one cysteine are known as C chemokines. If there are \ntwo adjacent residues they are called C\u2013C chemokines . Other \nmembers have cysteines separated by one ( C\u2013X\u2013C chemokines ) \nor three other residues (C\u2013XXX\u2013C chemokines).\nThe C\u2013X\u2013C chemokines (main example IL-8; see Fig. 7.2) \nact on neutrophils and are predominantly involved in acute inflammatory responses. The C\u2013C chemokines (main \nexamples eotaxin, MCP-1 and RANTES)\n6 act on monocytes, \neosinophils and other cells, and are involved predominantly \nin chronic inflammatory responses.\n\u25bc Chemokines generally act through G protein\u2013coupled receptors, \nand alteration or inappropriate expression of these is implicated in \nmultiple sclerosis, cancer, rheumatoid arthritis and some cardiovascular \ndiseases (Gerard & Rollins, 2001). Some types of virus (herpes virus, \ncytomegalovirus, pox virus and members of the retrovirus family) can exploit the chemokine system and subvert the host\u2019s defences \n(Murphy, 2001). Some produce proteins that mimic host chemokines \nor chemokine receptors, some act as antagonists at chemokine receptors and some masquerade as growth or angiogenic factors. The AIDS-\ncausing HIV virus is responsible for the most audacious exploitation \nof the host chemokine system. This virus has a protein (gp120) in its \nenvelope that recognises and binds T-cell receptors for CD4 and a \nchemokine co-receptor that allows it to penetrate the T cell (see Ch. 53). These chemokine co-receptors, CCR5 (blocked by the HIV drug \nmaraviroc) and CXCR4, are hijacked by HIV virus to enter a cell.\nINTERFERONS\nSo called because they interfere with viral replication, there \nare three main types of interferon, termed IFN-\u03b1, IFN-\u03b2 \nand IFN-\u03b3. \u2018IFN-\u03b1\u2019 is not a single substance but a family \nof approximately 20 proteins with similar activities. IFN- \u03b1 \nand IFN-\u03b2 have antiviral activity whereas IFN- \u03b1 also has \nsome antitumour action. Both are released from virus-infected cells and activate antiviral mechanisms in neigh -\nbouring cells. IFN- \u03b3 has a role in induction of Th1 responses \n(Fig. 7.3).\nCLINICAL \u2003USE \u2003OF \u2003INTERFERONS\nIFN-\u03b1 is used in the treatment of chronic hepatitis B and C, and has some action against herpes zoster and in the \nprevention of the common cold. Antitumour action against \nsome lymphomas and solid tumours has been reported. Dose-related side effects, including influenza-like symptoms, \nmay occur. IFN-\u03b2 is used in patients with the relapsing\u2013\nremitting form of multiple sclerosis, whereas IFN- \u03b3 is used \nin chronic granulomatous disease, an uncommon chronic \ndisease of childhood in which neutrophil function is", "start_char_idx": 0, "end_char_idx": 3259, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fad17d10-c560-450f-b466-336dd696d1f8": {"__data__": {"id_": "fad17d10-c560-450f-b466-336dd696d1f8", "embedding": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "805483ce-1d91-4572-9b46-4ad9a52026e9", "node_type": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fcf4567948cbba9f20c22057cb50bf6c53cdb06c3b3d255d0f2eb09128ced9c6"}, "2": {"node_id": "68212f43-73b0-41e1-afa1-73df678a3419", "node_type": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9da985706a279b1f6b404d0a10fb3d14d3e4ba719d3a5a6501e74da59346baa2"}, "3": {"node_id": "dbb0b276-b2df-4676-99de-bb96c072d33b", "node_type": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2a81018b2d8eee9ada289c5618052e10fbafcae85611536f96378e047560663b"}}, "hash": "c40ce0029563bbd94dffd3c578083677fe049a6eff08bda1b7b28144daa03d54", "text": "an uncommon chronic \ndisease of childhood in which neutrophil function is \nimpaired, in conjunction with antibacterial drugs (see clinical \nbox below for more details).No one system of classification does justice to the complexity of cytokine biology. The terminology and nomenclature are horrendous, and a comprehensive coverage of this area is beyond the scope of this book. Table 19.1 lists some of \nthe more significant cytokines and their biological actions. \nThe would-be cytokine aficionado can find further classifica -\ntion tables in Murphy et al. (2011) and the IUPHAR/BPS \nGuide to Pharmacology.\nMore than 100 cytokines have been identified. These \nmay be broadly categorised into four main functional groups, namely interleukins, chemokines, interferons and \ncolony-stimulating factors (discussed separately in Ch. 26), \nbut these demarcations are of limited use because many \ncytokines have multiple roles.\nUsing biopharmaceuticals (see Ch. 5) to interfere with \ncytokine action has proved to be a particularly fertile area of drug development: several successful strategies have been adopted, including direct antibody neutralisation of cytokines or the use of \u2018decoy\u2019 receptor proteins that remove \nthe biologically active pool from the circulation (See Chs. \n5 and 27).\nINTERLEUKINS AND RELATED COMPOUNDS\nThe name was originally coined to describe mediators that signalled between leukocytes but, like so much else in the \ncytokine lexicography, it has become rather redundant, \nnot to say misleading. The primary pro-inflammatory species are tumour necrosis factor (TNF)-\u03b1 and interleukin 1 (IL-1). \nThe principal members of the latter cytokine group consist of two agonists, IL-1\u03b1, IL-1\u03b2 and, surprisingly, an endo -\ngenous IL-1-receptor antagonist (IL-1ra).\n5 Mixtures of these \nare released from macrophages and many other cells during \ninflammation and can initiate the synthesis and release of \na cascade of secondary cytokines, among which are the chemokines. TNF and IL-1 are key regulators of almost all \nmanifestations of the inflammatory response. A long-\nstanding debate about which of the two is really the prime mover of inflammation ended when it was found that this \nvaries according to the disease type. In auto- immune disease \n(e.g. rheumatoid arthritis, where the adaptive immune \nsystem is activated), TNF appears to be the predominant influence and blocking its action is therapeutically effective. \nIn auto-inflammatory diseases (e.g. gout, where only the \ninnate system is involved), IL-1 seems to be the key mediator \n(Dinarello et al., 2012). Both TNF- \u03b1 and IL-1 are important \ntargets for anti-inflammatory biopharmaceuticals (Chs 5 \nand 27).\nNot all interleukins are pro-inflammatory: some, including \ntransforming growth factor (TGF)- \u03b2, IL-4, IL-10 and IL-13 are \npotent anti-inflammatory substances. They inhibit chemokine \nproduction, and the responses driven by T-helper (Th) 1 cells, whose inappropriate activation is involved in the \npathogenesis of several diseases.\nCHEMOKINES\nChemokines are defined as chemoattractant cytokines \nthat control the migration of leukocytes, functioning as traffic coordinators during immune and inflammatory \n5One might have expected evolution to generate more examples of \nendogenous receptor antagonists as physiological regulators, but apart \nfrom IL-1ra, they are only exploited as toxins directed against other \nspecies.6MCP, monocyte chemoattractant protein; RANTES, Regulated on \nActivation Normal T cell Expressed and Secreted. (Don\u2019t blame us!)mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3197, "end_char_idx": 6786, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dbb0b276-b2df-4676-99de-bb96c072d33b": {"__data__": {"id_": "dbb0b276-b2df-4676-99de-bb96c072d33b", "embedding": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "805483ce-1d91-4572-9b46-4ad9a52026e9", "node_type": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fcf4567948cbba9f20c22057cb50bf6c53cdb06c3b3d255d0f2eb09128ced9c6"}, "2": {"node_id": "fad17d10-c560-450f-b466-336dd696d1f8", "node_type": null, "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c40ce0029563bbd94dffd3c578083677fe049a6eff08bda1b7b28144daa03d54"}}, "hash": "2a81018b2d8eee9ada289c5618052e10fbafcae85611536f96378e047560663b", "text": "blame us!)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6792, "end_char_idx": 7281, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "44f279d4-7a92-4186-9ed7-e27cc6d71dec": {"__data__": {"id_": "44f279d4-7a92-4186-9ed7-e27cc6d71dec", "embedding": null, "metadata": {"page_label": "256", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5dd18fb9-d145-4191-afe8-5cc39708c5c1", "node_type": null, "metadata": {"page_label": "256", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "212889d43fafc1698e9def0dcd43825eca1d410c6c5960c4f6a5ce0260fe0f2b"}, "3": {"node_id": "88ac092c-b9a0-4900-95b0-2de100fc83a9", "node_type": null, "metadata": {"page_label": "256", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce60fa19ab7fc149ffa17d2382e8cb24e67d02a30353430fd4707dcded7653ca"}}, "hash": "a3ab591b869402309d666512d77e400299380bad83186c8a8798e72cf4bfdc06", "text": "19 SECTION 2 \u2003\u2003CHEMICAL MEDIATORS\n250Table 19.1 Some examples of significant cytokines and their actions\nCytokine Main cell source Main target cell or biological effect Comments\nIL-1 Monocyte/macrophages, \ndendritic and other cellsRegulates cell migration to sites of infection, \nproduces inflammation, fever and painTwo original subtypes IL-1 \u03b1 and \nIL-1\u03b2, and IL-1ra \u2013 a receptor \nantagonist. Target for anti-\ninflammatory therapy (Ch. 27)\nIL-2 T cells Stimulates proliferation, maturation and \nactivation of T, B and NK cellsFirst interleukin to be discovered\nIL-4 Th2 cells Stimulates proliferation, maturation of T and \nB cells and promotes IgG and E synthesis. \nPromotes an anti-inflammatory phenotypeA key cytokine in the regulation of \nthe Th2 response (Ch. 27)\nIL-5 Th2 cells, mast cells Important for eosinophil activation. Stimulates \nproliferation, maturation of B cells and IgA \nsynthesisParticularly important in allergic \ndisease\nIL-6 Monocyte/macrophages and \nT cellsPro-inflammatory actions including fever. \nStimulation of osteoclast activityTarget for anti-inflammatory drugs \n(Ch. 27)\nIL-8 Macrophages, endothelial cells Neutrophil chemotaxis, phagocytosis and \nangiogenesisC\u2013X\u2013C chemokine (CXCL8)\nIL-10 Monocytes and Th2 cells Inhibits cytokine production and down-\nregulates inflammationA predominately anti-inflammatory \ncytokine\nIL-17 T cells and others Stimulates Th17 cells, involved in allergic \nresponse and autoimmunitySeveral subtypes. Target for \nanti-inflammatory drugs (Ch. 27)\nGM\u2013CSF Macrophages, T cells, mast \ncells and othersStimulates growth of leukocyte progenitor \ncells. Increases numbers of blood-borne \nleukocytesUsed therapeutically to stimulate \nmyeloid cell growth (e.g. after bone \nmarrow transplantation)\nMIP-1 Macrophages/lymphocytes Activation of neutrophils and other cells. \nPromotes cytokine releaseC\u2013C chemokine (CCL3). Two \nsubtypes\nTGF- \u03b2 T cells, monocytes Induces apoptosis. Regulates cell growth Three isoforms. Predominately \nanti-inflammatory action\nTNF- \u03b1 Mainly macrophages but also \nmany immune and other cellsKills tumour cells. Stimulates macrophage \ncytokine expression and is a key regulator of \nmany aspects of the immune responseA major target for anti-inflammatory \ndrugs (Ch. 7)\nTNF- \u03b2 Th1 cells Initiates a variety of immune-stimulatory and \npro-inflammatory actions in the host defence \nsystemNow often called lymphotoxin \u03b1 \n(LTA)\nEotaxin Airway epithelial and other \ncellsActivation and chemotaxis of eosinophils. \nAllergic inflammationC\u2013C chemokine (CCL11). Three \nsubtypes\nMCP-1 Monocytes, osteoblasts/clasts, \nneurons and other cellsPromotes recruitment of monocytes and T \ncells to sites of inflammationC\u2013C chemokine (CC2)\nRANTES T cells Chemotaxis of T cells. Chemotaxis and \nactivation of other leukocytes(CCL5)\nIFN-\u03b1 Leukocytes Activates NK cells and macrophages. Inhibits \nviral replication and has antitumour actionsMultiple molecular species\nIFN-\u03b3 Th1, NK cells Stimulates Th1, and inhibits Th2, cell \nproliferation. Activates NK cells and \nmacrophagesCrucial to the Th1 response (Ch. 7)\nGM\u2013CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; Ig, immunoglobulin; IL, interleukin; MCP, monocyte \nchemoattractant protein; MIP, macrophage inflammatory protein; NK, natural", "start_char_idx": 0, "end_char_idx": 3278, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "88ac092c-b9a0-4900-95b0-2de100fc83a9": {"__data__": {"id_": "88ac092c-b9a0-4900-95b0-2de100fc83a9", "embedding": null, "metadata": {"page_label": "256", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5dd18fb9-d145-4191-afe8-5cc39708c5c1", "node_type": null, "metadata": {"page_label": "256", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "212889d43fafc1698e9def0dcd43825eca1d410c6c5960c4f6a5ce0260fe0f2b"}, "2": {"node_id": "44f279d4-7a92-4186-9ed7-e27cc6d71dec", "node_type": null, "metadata": {"page_label": "256", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a3ab591b869402309d666512d77e400299380bad83186c8a8798e72cf4bfdc06"}}, "hash": "ce60fa19ab7fc149ffa17d2382e8cb24e67d02a30353430fd4707dcded7653ca", "text": "\nchemoattractant protein; MIP, macrophage inflammatory protein; NK, natural killer (cell); RANTES, regulated on activation normal T cell \nexpressed and secreted; TGF, transforming growth factor; Th, T-helper (cell); TNF, tumour necrosis factor.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3203, "end_char_idx": 3928, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "22a185eb-6a55-4b48-bd83-8fd10cd70f76": {"__data__": {"id_": "22a185eb-6a55-4b48-bd83-8fd10cd70f76", "embedding": null, "metadata": {"page_label": "257", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "06a752b8-8976-4f83-96e0-392c0bc480b0", "node_type": null, "metadata": {"page_label": "257", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d5697829da8a73367aa8456d7b2a7f2c7467d1552a1bc8bc84a300a09b7cf990"}, "3": {"node_id": "c70a7248-c5ea-4718-b2bb-480da2b15f18", "node_type": null, "metadata": {"page_label": "257", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "98c93ece404b71fd7457a32333a2cb02f118b195d48ca1edaac0745c63ea54b3"}}, "hash": "c3448d77a3639d2e637e00456a2fc12651bcacb15d7165e35a8b6efa2c0f7e48", "text": "19 LOCAL HORMO n ES 2: p E p TIDES A n D p ROTEI n S \n251THE \u2018CYTOKINE STORM\u2019\nMany cytokines release further cytokines in what is essen -\ntially a positive feedback loop. There are times when this \nfeedback system becomes unstable, perhaps as a result of \nthe absence of balancing anti-inflammatory factors. The result can be a massive overproduction of cytokines in \nresponse to infection or other injury. This is known as a \ncytokine storm (also called hypercytokinemia) and can lead \nto a particularly dangerous \u2013 potentially catastrophic \u2013 \ndevelopment called systemic inflammatory response syndrome \n(SIRS; Jaffer et al., 2010). Cytokine storms may be responsible \nfor deaths in septic shock as well as in some pandemic \ndiseases. A tragic case of volunteers suffering cytokine \nstorms after receiving an experimental drug is related in \nCh. 5.Clinical uses of interferons \n\u2022\t\u03b1: chronic hepatitis B or C (ideally combined with \nribavirin).\n\u2013 Malignant disease (alone or in combination with \nother drugs, e.g. cytarabine): chronic myelogenous \nleukaemia (CML), hairy cell leukaemia, follicular lymphoma, metastatic carcinoid, multiple myeloma, \nmalignant melanoma (as an adjunct to surgery), \nmyelodysplastic syndrome.\n\u2013\tConjugation \twith \tpolyethylene \tglycol \t(\u2018pegylation\u2019) \t\nresults in preparations that are more slowly eliminated and are administered intermittently subcutaneously.\n\u2022\t\u03b2: multiple sclerosis (especially the relapsing\u2013remitting form of this disease).\n\u2022\t\u03b3: to reduce infection in children with chronic granulomatous disease.\nCytokines \n\u2022\tCytokines \tare \tpolypeptides \tthat \tare \trapidly \tinduced \t\nand released during inflammation. They regulate the action of inflammatory and immune system cells.\n\u2022\tThe\tcytokine \tsuperfamily \tincludes \tthe \tinterferons, \ninterleukins, chemokines and colony-stimulating \nfactors.\n\u2022\tUtilising \tboth \tautocrine \tor \tparacrine \tmechanisms, \tthey \t\nexert complex effects on leukocytes, vascular endothelial cells, mast cells, fibroblasts, haemopoietic stem cells and osteoclasts, controlling proliferation, \ndifferentiation and/or activation.\n\u2022\tInterleukin \t1 \t(IL-1) \tand \ttumour \tnecrosis \tfactor \t\u03b1 \n(TNF-\u03b1) are important primary inflammatory cytokines, \ninducing the formation of other cytokines.\n\u2022\tChemokines, \tsuch \tas \tIL-8, \tare \tmainly \tinvolved \tin \tthe \t\nregulation of cell trafficking.\n\u2022\tInterferons \tIFN-\u03b1\tand\tIFN-\u03b2 have antiviral activity, and \nIFN-\u03b1 is used as an adjunct in the treatment of viral \ninfections. \tIFN-\u03b3 has significant immunoregulatory \nfunction and is used in the treatment of multiple sclerosis.PROTEINS AND PEPTIDES THAT \nDOWN-REGULATE INFLAMMATION\nInflammation is not regulated solely by factors that cause \nor enhance it: it has become increasingly evident that there \nis another panel of mediators that function at every step \nto down-regulate inflammation, to check its progress and limit its duration and scope. It is the dynamic balance \nbetween these two systems that regulates the onset and \nresolution of inflammatory episodes, and when this breaks down, may lead also to inflammatory disease or, in extreme \ncases, to the cytokine storm phenomenon. Some of these \nare peptidic in nature and we have already encountered IL-1ra, TGF-\u03b2 and IL-10, which are important negative regulators of inflammation. There are two other", "start_char_idx": 0, "end_char_idx": 3322, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c70a7248-c5ea-4718-b2bb-480da2b15f18": {"__data__": {"id_": "c70a7248-c5ea-4718-b2bb-480da2b15f18", "embedding": null, "metadata": {"page_label": "257", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "06a752b8-8976-4f83-96e0-392c0bc480b0", "node_type": null, "metadata": {"page_label": "257", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d5697829da8a73367aa8456d7b2a7f2c7467d1552a1bc8bc84a300a09b7cf990"}, "2": {"node_id": "22a185eb-6a55-4b48-bd83-8fd10cd70f76", "node_type": null, "metadata": {"page_label": "257", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3448d77a3639d2e637e00456a2fc12651bcacb15d7165e35a8b6efa2c0f7e48"}}, "hash": "98c93ece404b71fd7457a32333a2cb02f118b195d48ca1edaac0745c63ea54b3", "text": "and IL-10, which are important negative regulators of inflammation. There are two other systems \nthat are significant here because common anti-inflammatory \ndrugs exploit their action.\nAnnexin-A1\n (Anx-A1) is a 37 kDa protein produced by \nmany cells and especially abundant in cells of the myeloid lineage. When released, it exerts potent anti-inflammatory \nactions, down-regulating cell activation, cell transmigration \nand mediator release. It does this by acting through a G protein\u2013coupled receptor called ALX/FPR2 a member of \nthe formyl peptide receptor family: the same receptor that \nbinds the anti-inflammatory lipoxins (see Ch. 18).\nThe significance of the Anx-A1 system is that it is activated \nby anti-inflammatory glucocorticoids (see Ch. 27), which increase Anx-A1 gene transcription and promote its release from cells. Interestingly, the anti-allergic cromones (cro-moglicate, etc.; see Ch. 29) also promote the release of this \nprotein from cells. Anx-A1 gene \u2018knock-out\u2019 studies have \nshown that this protein is important for restraining the inflammatory response and for its timely resolution. The \nanti-inflammatory glucocorticoids cannot develop their full \ninhibitory actions without it. An account of this field is given by Perretti and D\u2019Acquisto (2009).\nThe melanocortin system also plays an important part in \nregulating inflammation. There are five G protein\u2013coupled melanocortin receptors, MC\n1-5. Endogenous ligands for these \nreceptors, such as MSH (three types), are derived from the \nPOMC gene, and serve a number of purposes, including \nregulating the development of a suntan, penile erection and the control of appetite through an action on various \nMC receptors.\nFrom the point of view of host defence, the MC\n3 receptor \nis the most important. Again, gene deletion studies have highlighted the importance of this receptor in a variety of \ninflammatory conditions. Interestingly, another product of the POMC gene, ACTH was formerly used as an anti-\ninflammatory agent, but it was thought that its action was \nsecondary to its ability to release endogenous cortisol from the adrenals (an MC\n2 action, see Ch. 34). It is now known \nthat it is a ligand at the MC 3 receptor and it is likely that \nit owes some of its activity to this action.\nAn account of the importance of this field is given by \nPatel et al. (2011).\nCONCLUDING REMARKS\nEven from the superficial sketch presented here and in Chapter 7 it must be evident that the host defence response \nis among the most intricate of all physiological responses. \nPerhaps that is not surprising, given its central importance mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3235, "end_char_idx": 6323, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "01ee1cb4-393e-4e47-9d97-ca343549a26b": {"__data__": {"id_": "01ee1cb4-393e-4e47-9d97-ca343549a26b", "embedding": null, "metadata": {"page_label": "258", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f3e5bdf3-5aeb-4ddb-bc93-cd9a0a727703", "node_type": null, "metadata": {"page_label": "258", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0a40f30358d432d3531709a0693bbebb3fc761affa5e2648346b55ad1e5c999"}, "3": {"node_id": "feabec87-faaa-470f-9ffe-d2f6684e0244", "node_type": null, "metadata": {"page_label": "258", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "322d3a9a02d6788ad2ce2cbb871a9d732b622aa9bce87ab2297cbc3429c258fe"}}, "hash": "59658d963653af41ecb720aebfa9d70c7ef2d9430b8c669e5840b34905c2eb4b", "text": "19 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n252to survival. For the same reason, it is also understandable \nthat so many different mediators orchestrate its operation. \nThat the activity of many of these mediators can be blocked \nin experimental models with little or no obvious effect on the initiation and outcome of inflammation points to redundancy amongst the many component systems and goes some way to explaining why, until the advent of highly \nspecific antibody-based therapies for inflammatory condi -\ntions (see Ch. 27), our ability to curb the worst ravages of \nchronic inflammatory disease was so limited.\nREFERENCES AND FURTHER READING\nChung, K.F., 2005. Drugs to suppress cough. Expert. Opin. Invest. \nDrugs 14, 19\u201327. (Useful review of cough treatments, including a section on \nthe role of neurokinin and bradykinin receptor antagonists)\nDinarello, C.A., Simon, A., van der Meer, J.W., 2012. Treating \ninflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug Discov. 11, 633\u2013652. (An extremely \ncomprehensive survey of the role of IL1 in disease and the therapeutic benefits that can be gained by blocking its action. Written by pioneers of the \nfield. Good diagrams)\nGerard, C., Rollins, B., 2001. Chemokines and disease. Nat. Immunol. 2, \n108\u2013115. (Discusses diseases associated with inappropriate activation of the chemokine network, and discusses some therapeutic implications; describes \nhow viruses evade the immune responses by mimicry of the chemokines or their receptors)\nHoruk, R., 2001. Chemokine receptors. Cytokine Growth Factor Rev. 12, \n313\u2013335. (Comprehensive review focusing on chemokine receptor research; describes the molecular, physiological and biochemical properties of each \nchemokine receptor)\nIUPHAR/BPS. Guide to Pharmacology. \nwww.guidetopharmacology.org/. (Comprehensive guide to pharmacological targets and the substances that act on them)\nJaffer, U., Wade, R.G., Gourlay, T., 2010. Cytokines in the systemic \ninflammatory response syndrome: a review. HSR Proc. Intensive Care Cardiovasc. Anesth. 2, 161\u2013175. (An easy to read review dealing mainly \nwith the role of cytokines in SIRS, but also has a good general review of cytokine biology. Some good diagrams)\nLuster, A.D., 1998. Mechanisms of disease: chemokines \u2013 chemotactic \ncytokines that mediate inflammation. N. Engl. J. Med. 338, 436\u2013445. (Excellent review; outstanding diagrams)\nMackay, C.R., 2001. Chemokines: immunology\u2019s high impact factors. \nNat. Immunol. 2, 95\u2013101. (Clear, elegant coverage of the role of chemokines in leukocyte\u2013endothelial interaction, control of primary immune responses \nand T/B cell interaction, T cells in inflammatory diseases and viral \nsubversion of immune responses)\nMaggi, C.A., 1996. Pharmacology of the efferent function of primary \nsensory neurones. In: Geppetti, P., Holzer, P. (Eds.), Neurogenic Inflammation. CRC Press, London. (Worthwhile. Covers neurogenic inflammation, the release of neuropeptides from sensory nerves and \ninflammatory mediators. Discusses agents that inhibit release and the \npharmacological modulation of receptor-mediated release)Murphy, P.M., 2001. Viral exploitation and subversion of the immune \nsystem through chemokine mimicry. Nat. Immunol. 2, 116\u2013122. \n(Excellent description of viral/immune system interaction)\nPatel,", "start_char_idx": 0, "end_char_idx": 3315, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "feabec87-faaa-470f-9ffe-d2f6684e0244": {"__data__": {"id_": "feabec87-faaa-470f-9ffe-d2f6684e0244", "embedding": null, "metadata": {"page_label": "258", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f3e5bdf3-5aeb-4ddb-bc93-cd9a0a727703", "node_type": null, "metadata": {"page_label": "258", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0a40f30358d432d3531709a0693bbebb3fc761affa5e2648346b55ad1e5c999"}, "2": {"node_id": "01ee1cb4-393e-4e47-9d97-ca343549a26b", "node_type": null, "metadata": {"page_label": "258", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59658d963653af41ecb720aebfa9d70c7ef2d9430b8c669e5840b34905c2eb4b"}}, "hash": "322d3a9a02d6788ad2ce2cbb871a9d732b622aa9bce87ab2297cbc3429c258fe", "text": "\n(Excellent description of viral/immune system interaction)\nPatel, H.B., Montero-Melendez, T., Greco, K.V., Perretti, M., 2011. \nMelanocortin receptors as novel effectors of macrophage responses in inflammation. Front. Immunol. 2, 41\u201346. (Succinct and easy-to-read \nreview of the role of melanocortins in inflammatory resolution focusing on the role of the MC3 receptor. Useful diagrams)\nPease, J.E., Williams, T.J., 2006. The attraction of chemokines as a target \nfor specific anti-inflammatory therapy. Br. J. Pharmacol. 147 (Suppl. 1), S212\u2013S221. (Very good review of the history of chemokine research with \nparticular emphasis on their potential role as drug targets)\nPerretti, M., D\u2019Acquisto, F., 2009. Annexin A1 and glucocorticoids as \neffectors of the resolution of inflammation. Nat. Rev. Immunol. 9, 62\u201370. (Explores the role of the glucocorticoid-regulated protein annexin 1 in \nthe control of inflammatory resolution. Easy to read and good diagrams )\nPisi, G., Olivieri, D., Chetta, A., 2009. The airway neurogenic \ninflammation: clinical and pharmacological implications. Inflamm. Allergy Drug Targets 8, 176\u2013181.\nRodi, D., Couture, R., Ongali, B., et al., 2005. Targeting kinin receptors \nfor the treatment of neurological diseases. Curr. Pharm. Des. 11, 1313\u20131326. (An overview of the potential role of kinin receptor antagonists \nin neurological diseases, dealing particularly with those of immunological \norigin)\nSchulze, U., Baedeker, M., Chen, Y.T., Greber, D., 2014. R&D \nproductivity: on the comeback trail. Nat. Rev. Drug Discov. 13, 331\u2013332. (Interesting overview of the decline of new small molecule drugs making it onto the market compared to biotherapeutics. Compares the \nhistorical cost effectiveness of the drug discovery process)\nSchulze-Topphoff, U., Prat, A., 2008. Roles of the kallikrein/kinin \nsystem in the adaptive immune system. Int. Immunopharmacol. 8, 155\u2013160. (Excellent overview of these mediators particularly with respect to \ntheir involvement in the adaptive response)\nBooks\nMurphy, K.M., Travers, P., Walport, M., 2011. Janeway\u2019s \nImmunobiology, eighth ed. Taylor & Francis, London. (A classic \ntextbook now completely updated and available as an e-book also. Excellent \ndiagrams)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3249, "end_char_idx": 5955, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bed56d60-530b-4b9e-a3f7-41b0d4a17c4a": {"__data__": {"id_": "bed56d60-530b-4b9e-a3f7-41b0d4a17c4a", "embedding": null, "metadata": {"page_label": "259", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6efde898-e39e-49fd-8923-b847e72a2500", "node_type": null, "metadata": {"page_label": "259", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f950d5b6283a218c9734201bd1b6fbaa7603715aa1628db75cbebca26554b8b8"}, "3": {"node_id": "aeeed7e0-503b-45b8-8962-b068c788aed4", "node_type": null, "metadata": {"page_label": "259", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8cce02659b5da55b2ba671d6c45a4d03cf9b24cd83b8742a157fe1b3148790d5"}}, "hash": "4f8c706a89197a49c8ff76fabb3bf4fbc2c0f76262913ca93335b23767e83f60", "text": "253\nCannabinoids 20\u2003CHEMICAL MEDIATORS SECTION \u20032\u2003\nOVERVIEW\nModern \u2003pharmacological \u2003interest \u2003in \u2003cannabinoids \u2003\ndates \u2003from \u2003the\u2003discovery \u2003that\u2003\u03949-tetrahydrocannabinol \u2003\n(THC) \u2003is \u2003the \u2003main \u2003active \u2003principle \u2003of \u2003cannabis, \u2003and\u2003\ntook\u2003off \u2003with \u2003the \u2003discovery \u2003of \u2003specific \u2003cannabinoid \u2003\nreceptors \u2003\u2013 \u2003termed \u2003CB \u2003receptors \u2003\u2013 \u2003and \u2003endogenous \u2003\nligands \u2003(endocannabinoids), \u2003together \u2003with\u2003mechanisms \u2003\nfor\u2003their \u2003synthesis \u2003and \u2003elimination. \u2003Drugs \u2003that \u2003act\u2003\non\u2003this \u2003endocannabinoid \u2003system \u2003have \u2003considerable \u2003\ntherapeutic \u2003potential. \u2003Here \u2003we\u2003consider \u2003plant-derived \u2003\ncannabinoids, \u2003cannabinoid \u2003receptors, \u2003endocan -\nnabinoids, \u2003physiological \u2003functions, \u2003pathological \u2003\nmechanisms, \u2003synthetic \u2003ligands \u2003and \u2003potential \u2003clinical \u2003\napplications. \u2003More \u2003detailed \u2003information \u2003is \u2003given \u2003by \nLigresti \u2003et\u2003al.\u2003(2016) and\u2003by Pertwee \u2003(2014; \u20032015) .\u2003The\u2003\npharmacology \u2003of\u2003cannabinoids \u2003in\u2003the\u2003central \u2003nervous \u2003\nsystem \u2003( CNS) \u2003i s \u2003d iscussed \u2003i n Chapters \u20034 0,\u20034 9 \u2003a nd\u20035 0.\nPLANT-DERIVED \u2003CANNABINOIDS \u2003AND \u2003\nTHEIR \u2003PHARMACOLOGICAL \u2003EFFECTS\nCannabis sativa , the hemp plant, has been used for its \npsychoactive properties for thousands of years (Ch. 49). \nIts medicinal use was advocated in antiquity, but serious \ninterest resurfaced only in 1964 with the identification of \u0394\n9-tetrahydrocannabinol (THC, Fig. 20.1) as the main psychoac -\ntive component. Cannabis extracts contain numerous related \ncompounds, called cannabinoids, most of which are \ninsoluble in water. The most abundant cannabinoids are THC, its precursor cannabidiol , and cannabinol , a breakdown \nproduct formed spontaneously from THC. Cannabidiol and cannabinol lack the psychoactive properties of THC, but can exhibit anticonvulsant activity (Ch. 46) and induce \nhepatic drug metabolism (see Ch. 10).\nPHARMACOLOGICAL \u2003EFFECTS\nTHC acts mainly on the CNS, producing a mixture of \npsychotomimetic and depressant effects, together with \nvarious centrally mediated autonomic effects. The main \nsubjective effects in humans consist of:\n\u2022\tSensations \tof \trelaxation \tand \twell-being, \tsimilar \tto \tthe \t\neffect of ethanol but without the accompanying recklessness and aggression. (Insensitivity to risk is an \nimportant feature of alcohol intoxication and is often a \nfactor in road accidents. Cannabis users are less accident prone in general \u2013 although cannabis does \ncontribute to a significant number of road deaths each \nyear \u2013 even though their motor performance is similarly impaired.)\u2022\tFeelings \tof \tsharpened \tsensory \tawareness, \twith \tsounds \t\nand sights seeming more intense and fantastic.\n\u2022\tThese\teffects \tare \tsimilar \tto, \tbut \tusually \tless \tpronounced \t\nthan, those produced by psychotomimetic drugs such", "start_char_idx": 0, "end_char_idx": 2708, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aeeed7e0-503b-45b8-8962-b068c788aed4": {"__data__": {"id_": "aeeed7e0-503b-45b8-8962-b068c788aed4", "embedding": null, "metadata": {"page_label": "259", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6efde898-e39e-49fd-8923-b847e72a2500", "node_type": null, "metadata": {"page_label": "259", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f950d5b6283a218c9734201bd1b6fbaa7603715aa1628db75cbebca26554b8b8"}, "2": {"node_id": "bed56d60-530b-4b9e-a3f7-41b0d4a17c4a", "node_type": null, "metadata": {"page_label": "259", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f8c706a89197a49c8ff76fabb3bf4fbc2c0f76262913ca93335b23767e83f60"}}, "hash": "8cce02659b5da55b2ba671d6c45a4d03cf9b24cd83b8742a157fe1b3148790d5", "text": "produced by psychotomimetic drugs such as lysergic acid diethylamide (LSD; see Ch. 49). Subjects \nreport that time passes extremely slowly. The alarming \nsensations and serious paranoid delusions that often occur with LSD are seldom experienced after cannabis, \nexcept in high doses. However epidemiological studies \nsupport a connection between heavy cannabis use in adolescence and subsequent psychiatric disorder \n(Rubino et al., 2012).\nCentral effects that can be directly measured in human and animal studies include:\n\u2022\timpairment \tof \tshort-term \tmemory \tand \tsimple \t\nlearning tasks \u2013 subjective feelings of confidence and heightened creativity are not reflected in actual \nperformance;\n\u2022\timpairment \tof \tmotor \tcoordination \t(e.g. \tdriving \t\nperformance);\n\u2022\tcatalepsy \t\u2013 \tthe \tadoption \tof \tfixed \tunnatural \tpostures;\n\u2022\thypothermia;\n\u2022\tanalgesia;\n\u2022\tantiemetic \taction \t(see \tCh. \t31);\n\u2022\tincreased \tappetite \t(see \tCh. \t33).\nThe main peripheral effects of cannabis are:\n\u2022\ttachycardia, \twhich \tcan \tbe \tprevented \tby \tdrugs \tthat \t\nblock sympathetic transmission;\n\u2022\tvasodilatation, \twhich \tis \tparticularly \tmarked \tin \t\nsuperficial blood vessels of the eye (scleral and conjunctival vessels), producing a bloodshot \nappearance which is characteristic of cannabis \nsmokers;\n\u2022\treduction \tof \tintraocular \tpressure;\n\u2022\tbronchodilatation.\nPHARMACOKINETIC \u2003ASPECTS\nThe effect of cannabis, taken by smoking, takes about 1 hour \nto\tdevelop \tfully \tand \tlasts \tfor \t2\u20133 \thours. \tA \tsmall \tfraction \t\nof THC is converted to 11-hydroxy-THC, which is more active than THC itself and probably contributes to the \npharmacological effect of smoking cannabis, but most is \nconverted to inactive metabolites that are subject to conjuga -\ntion and enterohepatic recirculation. Being highly lipophilic, \nTHC and its metabolites are sequestered in body fat, and \ndetectable urinary excretion continues for several weeks after a single dose.\nADVERSE \u2003EFFECTS\nIn overdose, THC is relatively safe, producing drowsi -\nness and confusion but not life-threatening respiratory or mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2670, "end_char_idx": 5212, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "db1725aa-2145-4e8c-9d7c-c7204cd9d267": {"__data__": {"id_": "db1725aa-2145-4e8c-9d7c-c7204cd9d267", "embedding": null, "metadata": {"page_label": "260", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1a101154-e58c-45f2-b6a1-32147d7510a1", "node_type": null, "metadata": {"page_label": "260", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2b79a8bdba753c2d90c095e22b8d0ea95c6f0473675f023af61b44d66a4934d"}, "3": {"node_id": "b2714eeb-1196-4a91-a0f2-f2e0fb3202a8", "node_type": null, "metadata": {"page_label": "260", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ff014bc4f9447014f1e5368199b81e2afc8e1abcf6fb20fbfda615ea7fdb011"}}, "hash": "d670dd49c8575657c72729639bde8ff5b01c4a36bbc40dc1eff8259101ac8938", "text": "20 SECTION \u20032\u2003\u2003CHEMICAL MEDIATORS\n254hallucinations. These effects, together with legal restric -\ntions on the use of cannabis1 have limited the widespread \ntherapeutic use of cannabinoids, although recent regulatory \napproval in several countries for a cannabis extract admin -\nistered by buccal spray as an adjunct in treating spasticity \nin multiple sclerosis may herald an expansion of potential \nclinical indications, several of which are being investigated.\nIn rodents, THC produces teratogenic and mutagenic \neffects, and an increased incidence of chromosome breaks in circulating white cells has been reported in humans. \nSuch breaks are, however, by no means unique to cannabis, and epidemiological studies have not shown an increased risk of fetal malformation or cancer among cannabis users.\nTOLERANCE \u2003AND \u2003DEPENDENCE\nTolerance to cannabis, and physical dependence, occur only \nto\ta\tminor \tdegree \tand \tmainly \tin \theavy \tusers. \tAbstinence \t\nsymptoms are similar to those of ethanol or opiate with -\ndrawal, namely nausea, agitation, irritability, confusion, \ntachycardia and sweating, but are relatively mild and do \nnot result in a compulsive urge to take the drug. Psychologi -\ncal dependence does occur with cannabis, but it is less \ncompelling than with the major drugs of addiction (Ch. \n50), although dependence is increasing in parallel with use \nof more potent material (Maldonado et al., 2011).\nCANNABINOID \u2003RECEPTORS\nCannabinoids, being highly lipid-soluble, were originally thought to act in a similar way to general anaesthetics. \nHowever, in 1988, saturable high-affinity binding of a triti -\nated cannabinoid was demonstrated in membranes prepared \nfrom homogenised rat brain. This led to the identification \nof specific cannabinoid receptors in brain. These are now \ntermed CB\n1 receptors to distinguish them from the CB 2 \nreceptors subsequently identified in peripheral tissues. \nCannabinoid receptors are typical members of the family \nof\tG\tprotein\u2013coupled \treceptors \t(Ch. \t3). \tCB 1 receptors are \nlinked via G i/o to inhibition of adenylyl cyclase and of \nvoltage-operated calcium channels, and to activation of G protein-sensitive inwardly rectifying potassium (GIRK) \nchannels, causing membrane hyperpolarisation (Fig. 20.2). These effects are similar to those mediated by opioid recep -\ntors\t(Ch. \t43). \tCB 1 receptors are located in the plasma \nmembrane of nerve endings and inhibit transmitter release \nfrom presynaptic terminals, which is caused by depolarisa -\ntion and Ca2+ entry (Ch. 4). CB receptors also influence \ngene expression, both directly by activating mitogen-activated protein kinase, and indirectly by reducing the \nactivity\tof\tprotein\tkinase\tA\tas\ta\tresult\tof\treduced\tadenylyl \t\ncyclase\tactivity \t(see \tCh. \t3).\nCB 1 receptors are abundant in the brain, with similar \nnumbers \tto\treceptors \tfor\tglutamate \tand\tGABA\t\u2013\tthe\tmain\t\ncentral\texcitatory \tand\tinhibitory \tneurotransmitters \t(Ch.\t39).\t\nThey are not homogeneously distributed, being concentrated \nin the hippocampus (relevant to effects of cannabinoids \non memory), cerebellum (relevant to loss of coordination), \nhypothalamus (important in control of appetite and body \ntemperature; \tsee \tCh. \t33 \tand \tfurther \tin \tthis \tchapter), \tsub-\nstantia nigra, mesolimbic dopamine pathways that have cardiovascular depression. In this respect, it is safer than most abused", "start_char_idx": 0, "end_char_idx": 3379, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b2714eeb-1196-4a91-a0f2-f2e0fb3202a8": {"__data__": {"id_": "b2714eeb-1196-4a91-a0f2-f2e0fb3202a8", "embedding": null, "metadata": {"page_label": "260", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1a101154-e58c-45f2-b6a1-32147d7510a1", "node_type": null, "metadata": {"page_label": "260", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2b79a8bdba753c2d90c095e22b8d0ea95c6f0473675f023af61b44d66a4934d"}, "2": {"node_id": "db1725aa-2145-4e8c-9d7c-c7204cd9d267", "node_type": null, "metadata": {"page_label": "260", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d670dd49c8575657c72729639bde8ff5b01c4a36bbc40dc1eff8259101ac8938"}}, "hash": "2ff014bc4f9447014f1e5368199b81e2afc8e1abcf6fb20fbfda615ea7fdb011", "text": "that have cardiovascular depression. In this respect, it is safer than most abused substances, particularly opiates and ethanol. \nEven in low doses, THC and synthetic derivatives such \nas nabilone (licensed for nausea and vomiting caused by \ncytotoxic chemotherapy) produce euphoria and drowsi-\nness, sometimes accompanied by sensory distortion and H3COHCH3\nOCH3 C5H11\n\u22069-Tetrahydrocannabinol (THC)\nAnandamideNOHO\n2-Arachidonoyl glycerol (2-AG)OCOOHC\nOHC\nFig. 20.1 Structures of \u03b49-tetrahydrocannabinol and two \nendocannabinoids. \nCannabis \n\u2022\tMain\tactive \tconstituent \tis \t\u03949-tetrahydrocannabinol \t\n(THC)\twhich \tgenerates \ta \tpharmacologically \tactive \t\n11-hydroxy \tmetabolite.\n\u2022\tActions \ton \tthe \tcentral \tnervous \tsystem \tinclude \tboth \t\ndepressant \tand \tpsychotomimetic \teffects.\n\u2022\tSubjective \texperiences \tinclude \teuphoria \tand \ta \tfeeling \t\nof\trelaxation, \twith \tsharpened \tsensory \tawareness.\n\u2022\tObjective \ttests \tshow \timpairment \tof \tlearning, \tmemory \t\nand\tmotor \tperformance, \tincluding \timpaired \tdriving \t\nability.\n\u2022\tTHC\talso \tshows \tanalgesic \tand \tantiemetic \tactivity, \tas \t\nwell\tas\tcausing \tcatalepsy \tand \thypothermia \tin \tanimal \t\ntests.\n\u2022\tPeripheral \tactions \tinclude \tvasodilatation, \treduction \tof \t\nintraocular \tpressure \tand \tbronchodilatation.\n\u2022\tCannabinoids \tare \tless \tliable \tthan \topiates, \tnicotine\tor\t\nalcohol\tto\tcause\tdependence \tbut \tmay \thave \tlong-\nterm\tpsychological \teffects.\n1Past\tlegal \trestrictions \ton \tthe \tpersonal \tuse \tof \tcannabis \tin \tthe \tUSA \thave \t\nbeen relaxed in some states, so this is an evolving scene.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3297, "end_char_idx": 5333, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e8660b83-019b-441a-a7fa-d1febd0772c0": {"__data__": {"id_": "e8660b83-019b-441a-a7fa-d1febd0772c0", "embedding": null, "metadata": {"page_label": "261", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5bb3759-1b12-4934-9e4a-948dbda45f87", "node_type": null, "metadata": {"page_label": "261", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "060a02d1ff84e000ac635148b8e11657beb32f25a1159330a2497caec1d905dd"}, "3": {"node_id": "273aa6cb-48bf-475b-a165-8751e0ae1901", "node_type": null, "metadata": {"page_label": "261", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e8d98c464b32f0afb1a7f4dcabb038b400353d60fb2e5c1d47623dcff09a78b"}}, "hash": "efa45ec90d1c4c6776dc6c9719a60dd7f9cb45e06d2c2d35bbfa123f648b3b5d", "text": "20 CAnnAbInOIDS\n255rather little is known about their function. They are present \nin atherosclerotic lesions (see Ch. 24), and CB 2 agonists \nhave potentially anti-atherosclerotic effects on macrophages \nand foam cells (Chiurchiu et al., 2014).\nSome endocannabinoids turned out, surprisingly,2 to bind \nto sites on the cytoplasmic side of transient receptor potential \nchannels (TRP channels), activating these ionotropic receptors \nand thereby stimulating nociceptive nerve endings (see Ch. \n43).\tOther\tas-yet-unidentified \tG\tprotein\u2013coupled \treceptors \t\nare also implicated, because cannabinoids exhibit analgesic actions and activate G proteins in the brain of CB\n1 knock-out \nmice, despite the absence of CB 1 receptors.\nENDOCANNABINOIDS\nThe discovery of specific cannabinoid receptors led to a search for endogenous mediators. The first success was \nchalked up by a team that screened fractions of extracted \npig brain for ability to compete with a radiolabelled can -\nnabinoid receptor ligand (Devane et al., 1992). This led to \nthe purification of N- arachidonylethanolamide , an eicosanoid \nmediator (see Ch. 19), the structure of which is shown in \nFig. 20.1. This was christened anandamide.3\tAnandamide \t\nnot only displaced labelled cannabinoid from synaptosomal \nmembranes in the binding assay, but also inhibited electri -\ncally evoked twitches of mouse vas deferens, a bioassay \nfor\tpsychotropic \tcannabinoids \t(Fig.\t20.3).\tA\tfew\tyears\tlater,\t\na second endocannabinoid, 2-arachidonoyl glycerol \t(2-AG,\t\nsee Fig. 20.1), was identified, and more recently at least three further endocannabinoid candidates \u2013 all arachidonic \nacid derivatives - with distinct CB\n1/CB 2 receptor selectivities \nhave been added to the list (see Table 20.1). Endocannabi -\nnoids are made \u2018on demand\u2019, like eicosanoids (see Ch. 19), \nrather than being presynthesised and stored for release when needed.\nBIOSYNTHESIS \u2003OF \u2003ENDOCANNABINOIDS\nBiosynthesis \tof \tanandamide \tand \tof \t2-AG \tis \tsummarised \t\nin\tFig.\t20.4.\tA\tfuller\taccount\tof\tbiosynthesis \tand\tdegradation \t\nis given by Di Marzo (2008).been implicated in psychological \u2018reward\u2019 (Ch.50), and in association areas of the cerebral cortex. There is a relative \npaucity of CB\n1 receptors in the brain stem, consistent with the \nlack of serious depression of respiratory or cardiovascular \nfunction\tby\tcannabinoids. \tAt\ta\tcellular\tlevel,\tCB 1 receptors \nare mainly localised presynaptically, and inhibit transmitter release as depicted in Fig. 20.2. Like opioids, they can, \nhowever, increase the activity of some neuronal pathways \nby\ti nhibiting \ti nhibitory \tc onnections, \ti ncluding \tG ABA-ergic \t\ninterneurons in the hippocampus and amygdala.\nIn addition to their well-recognised location in the CNS, \nCB 1 receptors are also expressed in peripheral tissues, for \nexample on endothelial cells, adipocytes and peripheral \nnerves. Cannabinoids promote lipogenesis through activa -\ntion of CB 1 receptors, an action that could contribute to \ntheir effect on body weight (see DiPatrizio & Piomele, 2012).\nThe CB 2 receptor has only approximately 45% amino \nacid homology with CB 1 and is located mainly in lymphoid \ntissue (spleen, tonsils and thymus as well as circulating", "start_char_idx": 0, "end_char_idx": 3217, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "273aa6cb-48bf-475b-a165-8751e0ae1901": {"__data__": {"id_": "273aa6cb-48bf-475b-a165-8751e0ae1901", "embedding": null, "metadata": {"page_label": "261", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5bb3759-1b12-4934-9e4a-948dbda45f87", "node_type": null, "metadata": {"page_label": "261", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "060a02d1ff84e000ac635148b8e11657beb32f25a1159330a2497caec1d905dd"}, "2": {"node_id": "e8660b83-019b-441a-a7fa-d1febd0772c0", "node_type": null, "metadata": {"page_label": "261", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "efa45ec90d1c4c6776dc6c9719a60dd7f9cb45e06d2c2d35bbfa123f648b3b5d"}}, "hash": "3e8d98c464b32f0afb1a7f4dcabb038b400353d60fb2e5c1d47623dcff09a78b", "text": "\ntissue (spleen, tonsils and thymus as well as circulating lymphocytes, monocytes and tissue mast cells). CB\n2 receptors \nare also present on microglia \u2013 immune cells in the CNS \nwhich,\twhen\tactivated, \tcontribute \tto\tchronic\tpain\t(Ch.\t38).\t\nThe localisation of CB 2 receptors on cells of the immune \nsystem was unexpected, but may account for inhibitory effects of cannabis on immune function. CB\n2 receptors differ \nfrom CB 1 receptors in their responsiveness to cannabinoid \nligands (see Table 20.1). They are linked via G i/o to adenylyl \ncyclase, GIRK channels and mitogen-activated protein kinase similarly to CB\n1, but not to voltage-operated calcium chan -\nnels (which are not expressed in immune cells). So far, Altered gene\nexpression\nVOC\nCannabinoidAdenylyl\ncyclase\nCBI receptor\nGIRK\nK+Ca2+\nCa2+\nK+cAMP\nATP//\nPKA\nMAPK\nFig. 20.2 Cellular actions of cannabinoids. CB 1\treceptor\t\nactivation\tinhibits \tneurotransmitter \trelease \tvia \tinhibition \tof \tCa2+ \nentry\tand\thyperpolarisation \tdue \tto \tactivation \tof \tpotassium \t\nchannels.\tIt \talso \talters \tgene \texpression. \tGIRK,\tG\tprotein-\nsensitive\tinward-rectifying \tpotassium \tchannel; \tMAPK,\tmitogen-\nactivated\tprotein \tkinase; \tPKA,\tprotein\tkinase \tA; \tVOC, \nvoltage-operated \tcalcium \tchannel. \t(Redrawn \tfrom \tDevane \tet \tal., \t\n1992.)Table 20.1 Definite and possible endocannabinoids\nEndocannabinoid Selectivity\nDefinite endocannabinoids\nAnandamide CB 1 > CB 2\n2-Arachidonoyl glycerol CB 1 = CB 2\nLess well-established endocannabinoid candidatesVirodhamine CB\n2 > CB 1\nNoladin CB 1 \u226b CB 2\nN-Arachidonoyl dopamine CB 1 \u226b CB 2\n2Surprising, because capsaicin, the active principle of chili peppers, \ncauses intense burning pain via activation of these receptors, whereas \nthe endocannabinoid anandamide is associated with pleasure, or even \nbliss \u2026 so perhaps not so surprising after all!\n3From a Sanskrit word meaning \u2018bliss\u2019 + amide.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3159, "end_char_idx": 5534, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d9d626f0-4692-4085-896b-ae380abad62c": {"__data__": {"id_": "d9d626f0-4692-4085-896b-ae380abad62c", "embedding": null, "metadata": {"page_label": "262", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d07c9ed3-871b-4ecb-a69e-bf56af097ac2", "node_type": null, "metadata": {"page_label": "262", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e7c9fe339484d35563fbfef8ec1311b184e644e8654962ab8801e06cb216a2f9"}, "3": {"node_id": "5bc0ed95-3dd6-4574-a521-6b373a120c33", "node_type": null, "metadata": {"page_label": "262", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fbda6357612f8198f3e8ccfb3b809f7b4a6433f5ed5f1efdb7d408fc07e3d706"}}, "hash": "fb0910444d26320bb9f32b9a40358b929a42fed83fc48af588a77a7d0d7fbcca", "text": "20 SECTION \u20032\u2003\u2003CHEMICAL MEDIATORS\n256\u25bc\tAnandamide \tis \tformed \tby \ta \tdistinct \tphospholipase \tD \t(PLD) \tselective\t\nfor N-acyl-phosphatidylethanolamine \t(NAPE)\tbut\twith\tlow\taffinity\tfor\t\nother\tmembran e \tphospholipids, \tand \tknown \tas \tNAPE-PLD. \tNAPE-PLD \t\nis a zinc metallohydrolase that is stimulated by Ca2+ and also by \npolyamines. \tSelective \tinhibitors \tfor\tNAPE-PLD \tare\tbeing\tsought.\tThe\t\nprecursors are produced by an as-yet-uncharacterised but Ca2+-sensitive \ntransacylase that transfers an acyl group from the sn-1 position of \nphospholipids to the nitrogen atom of phosphatidylethanolamine.\n2-AG\tis\talso \tproduced \tby \thydrolysis \tof \tprecursors \tderived \tfrom \t\nphospholipid metabolism. The key enzymes are two sn-1-selective \ndiacylglycerol \tlipases \t(DAGL- \u03b1\tand\tDAGL- \u03b2), which belong to the \nfamily\tof \tserine \tlipases. \tBoth \tthese \tenzymes, \tlike \tNAPE-PLD, \tare \t\nCa2+ sensitive, consistent with intracellular Ca2+ acting as the \nphysiological \tstimulus \tto \tendocannabinoid \tsynthesis. \tThe \tDAGLs \t\nare located in axons and presynaptic axon terminals during develop -\nment, but postsynaptically in dendrites and cell bodies of adult neurons, \nconsistent \twith \ta \trole \tfor \t2-AG \tin \tneurite \tgrowth, \tand \twith \ta \trole \tas \t\na retrograde mediator (see p. 257) in adult brain.\nLittle is known as yet about the biosynthesis of the more recent \nendocannabinoid candidates noladin, virodhamine and N-arachidonoyl \ndopamine. pH-dependent non-enzymatic interconversion of virod -\nhamine and anandamide is one possibility, and could result in a switch between CB\n2- and CB 1-mediated responses (see Table 20.1).\nTERMINATION \u2003OF \u2003THE\u2003\u2003\nENDOCANNABINOID \u2003SIGNAL\nEndocannabinoids are rapidly taken up from the extra-\ncellular space. Being lipid-soluble, they diffuse through \nplasma membranes down a concentration gradient. There \nis also evidence for a saturable, temperature-dependent, \nfacilitated \ttransport \tmechanism \tfor\tanandamide \tand\t2-AG,\t\ndubbed the \u2018endocannabinoid membrane transporter\u2019, for which selective uptake inhibitors (e.g. UCM-707) have been \ndeveloped. Pathways of endocannabinoid metabolism are \nsummarised in Fig. 20.4. The key enzyme for anandamide Anandamide (nM)Binding of HU-243 (%)405060708090100\n2030\n010\n1 1000 100 10 10000\nInhibition of twitch response (%)405060708090110\n100\n2030\n10\n0A\nB\nFig. 20.3 Anandamide as an endocannabinoid. \tAnandamide \t\nis\tan\tendogenous \tcannabinoid. \t(A) \tCompetitive \tinhibition \tof \ttritiated\t\nHU-243\t(a \tcannabinoid \treceptor \tligand) \tbinding \tto \tsynaptosomal \t\nmembranes \tfrom \trat \tbrain \tby \tnatural \tanandamide \t(red circles, \nleft-hand ordinate axis) .\t(B)\tInhibition \tof", "start_char_idx": 0, "end_char_idx": 2660, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5bc0ed95-3dd6-4574-a521-6b373a120c33": {"__data__": {"id_": "5bc0ed95-3dd6-4574-a521-6b373a120c33", "embedding": null, "metadata": {"page_label": "262", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d07c9ed3-871b-4ecb-a69e-bf56af097ac2", "node_type": null, "metadata": {"page_label": "262", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e7c9fe339484d35563fbfef8ec1311b184e644e8654962ab8801e06cb216a2f9"}, "2": {"node_id": "d9d626f0-4692-4085-896b-ae380abad62c", "node_type": null, "metadata": {"page_label": "262", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb0910444d26320bb9f32b9a40358b929a42fed83fc48af588a77a7d0d7fbcca"}}, "hash": "fbda6357612f8198f3e8ccfb3b809f7b4a6433f5ed5f1efdb7d408fc07e3d706", "text": "\tvas \tdeferens \ttwitch\t\nresponse\t(a \tbioassay \tfor \tcannabinoids) \tby \tnatural \tanandamide \t\n(blue symbols, right-hand ordinate) .\tNote\tthe \tsimilarity \tbetween \tthe\t\nbinding\tand \tbioactivity. \t(Redrawn \tfrom \tDevane \tet \tal., \t1992.)\nPresynaptic\nneuron2-AG\nG + A\nCBI\nreceptor Anandamide\nFAAHNAPE\nE + A2-AGPLCEMTEMT\nGPL\n+\nPESn-1-acyl-2-\narachidonoyl glycerolPostsynaptic\nneuronMAGLGPL\nNAPE-PLD\nNATDAGL\nFig. 20.4 Biosynthesis and inactivation of endocannabinoids. 2-AG,\t2-arachidonoyl \tglycerol; \tA,\tarachidonic \tacid; \tDAGL,\t\ndiacylglycerol \tlipase; \tE,\tethanolamine; \tEMT,\tendocannabinoid \tmembrane \ttransporter; \tFAAH,\tfatty\tacid \tamide \thydrolase; \tG,\tglycerol;\tGPL, \nglycerophospholipid; \tMAGL,\tmonoacyl \tglycerol \tlipase; \tNAPE, N-acyl-phosphatidylethanolamine; \tNAPE-PLD, N -acyl\t\nphosphatidylethanolamine-specific \tphospholipase \tD; \tNAT,\tN-acyl-transferase; \tPE,\tphosphatidylethanolamine; \tPLC,\tphospholipase \tC. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2661, "end_char_idx": 4064, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fb818fbf-85c5-4dbd-902d-177cdab20f47": {"__data__": {"id_": "fb818fbf-85c5-4dbd-902d-177cdab20f47", "embedding": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "be2f3034-7ccf-4a55-9adc-7bce860d4ff1", "node_type": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "63dfb21240bba2008ff475a4f716d01346517a287c1bc08ac62864850a855dbd"}, "3": {"node_id": "45ec4382-3cd2-401d-8409-f14acfa0eb0d", "node_type": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84aa873afb4259b85fa85f585e229b2c96be233a1c39e352b01a5d455e27d2cf"}}, "hash": "33645b1985b9162b9d0793ec619697a3d73c69ae4926bcef4ac461b818413063", "text": "20 CAnnAbInOIDS\n257are of particular interest, because of the importance of \nobesity\t(Ch. \t33).metabolism is a microsomal serine hydrolase known as fatty \nacid\tamide\thydrolase \t(FAAH).\tFAAH\tconverts\tanandamide \t\nto arachidonic acid plus ethanolamine and also hydrolyses \n2-AG,\tyielding \tarachidonic \tacid \tand \tglycerol.\nThe\tphenotype \tof \tFAAH \t\u2018knock-out\u2019 \tmice \tgives \tsome \t\nclues to endocannabinoid physiology; such mice have an \nincreased brain content of anandamide and an increased \npain\tthreshold. \tSelective\tinhibitors \tof\tFAAH4 have analgesic \nand anxiolytic properties in mice (see Ch. 45 for an explana -\ntion of how drugs are tested for anxiolytic properties in \nrodents). \tIn\tcontrast\tto\tanandamide, \tbrain\tcontent\tof\t2-AG\t\nis\tnot\tincreased \tin \tFAAH \tknock-out \tanimals, \tindicating \t\nthat\tanother \troute \tof \tmetabolism \tof \t2-AG \tis \tlikely \tto \tbe \t\nimportant. \tOther \tpossible \troutes \tof \tmetabolism \tinclude \t\nesterification, acylation and oxidation by cyclo-oxygenase-2 to prostaglandin ethanolamides (\u2018prostamides\u2019), or by 12- or \n15-lipoxygenase (see Ch. 18).\nPHYSIOLOGICAL \u2003MECHANISMS\nStimuli that release endocannabinoids, leading to activation \nof CB 1 receptors and the linkage to downstream events \nincluding behavioural or psychological effects, are incom -\npletely defined. Increased intracellular Ca2+ concentration is \nprobably an important cellular trigger because, as mentioned \non p. 256, Ca2+\tactivates \tNAPE-PLD \tand \tother \tenzymes \t\ninvolved in endocannabinoid biosynthesis.\nActivation \tof\tCB\treceptors \tis\timplicated \tin\ta\tphenomenon \t\nknown as depolarisation-induced suppression of inhibition (DSI). \nDSI occurs in hippocampal pyramidal cells; when these are depolarised by an excitatory input, this suppresses \nthe\tGABA-mediated \tinhibitory \tinput \tto \tthe \tpyramidal \t\ncells, implying a retrograde flow of information from the \ndepolarised pyramidal cell to inhibitory axons terminating \non it. Such a reverse flow of information from post- to \npresynaptic cell is a feature of other instances of neuronal plasticity, such as \u2018wind-up\u2019 in nociceptive pathways (Fig. \n43.2)\tand\tlong-term \tpotentiation \tin\tthe\thippocampus \t(Fig.\t\n39.7).\tDSI \tis \tblocked \tby \tthe \tCB 1 antagonist rimonabant. \nThe presynaptic location of CB 1 receptors and cellular \ndistributions \tof \tthe \tDAGL \tand \tmonoacyl \tglycerol \tlipase \t\n(MAGL) \tenzymes \t(see \tFig. \t20.4) \tfit \tnicely \twith \tthe \tidea \t\nthat\tthe\tendocannabinoid \t2-AG \tcould \tbe \ta \t\u2018retrograde\u2019 \t\nmessenger in DSI (see Fig. 40.7).\nNeuromodulatory actions of endocannabinoids could \ninfluence a wide range of physiological activities, including nociception, cardiovascular, respiratory and gastrointestinal function. Interactions of endocannabinoids with hypo -\nthalamic hormones are believed to influence food intake and reproductive function. Mouse models lacking CB receptors support important and balanced roles of endocan -\nnabinoid signalling in male and female fertility and such signalling is implicated in spermatogenesis,", "start_char_idx": 0, "end_char_idx": 3020, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "45ec4382-3cd2-401d-8409-f14acfa0eb0d": {"__data__": {"id_": "45ec4382-3cd2-401d-8409-f14acfa0eb0d", "embedding": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "be2f3034-7ccf-4a55-9adc-7bce860d4ff1", "node_type": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "63dfb21240bba2008ff475a4f716d01346517a287c1bc08ac62864850a855dbd"}, "2": {"node_id": "fb818fbf-85c5-4dbd-902d-177cdab20f47", "node_type": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33645b1985b9162b9d0793ec619697a3d73c69ae4926bcef4ac461b818413063"}, "3": {"node_id": "8c6312f3-b762-426c-a972-ef5c85acb921", "node_type": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ef2fcce697f4a4e91cd4357659258154826aad19af85cd05c9854100e62e3a2"}}, "hash": "84aa873afb4259b85fa85f585e229b2c96be233a1c39e352b01a5d455e27d2cf", "text": "is implicated in spermatogenesis, fertilisation, preimplantation development of the early embryo, implanta -\ntion and postimplantation growth of the embryo (see Battista \net al., 2012). Effects of endocannabinoids on food intake \n4Several such drugs have been administered to humans but none has \nprogressed \tin \tdevelopment. \tOne \tsuch \tdrug, \tBIA \t10-2474 \tcaused \tsudden \t\nsevere CNS damage during a trial involving repeated dosing of healthy \nvolunteers \tin \tRennes, \tFrance. \tBIA \t10-2474 \tis \tless \tselective \tthan \tanother \t\nFAAH\tinhibitor \twhich \twas \tinnocuous \tin \tearlier \ttrials, \tinhibiting \tseveral \t\nlipases that are not targeted by the more selective drug. This suggests \nthat promiscuous lipase inhibitors can cause metabolic dysregulation in \nthe nervous system due to off-target toxicity (see van Esbroeck et al., \n2017).The endocannabinoid system \n\u2022\tCannabinoid \treceptors \t(CB 1,\tCB 2)\tare\tG\tprotein \t\ncoupled\t(Gi/o).\n\u2022\tActivation \tof \tCB 1\tinhibits\tadenylyl \tcyclase \tand \tcalcium \t\nchannels,\tand \tactivates \tpotassium \tchannels, \tinhibiting \t\nsynaptic\ttransmission.\n\u2022\tThe\tCB 2\treceptor\tis \texpressed \tin \tcells \tof \tthe \timmune \t\nsystem,\tand \tits \texpression \tis \talso \tupregulated \tin \tthe \t\ncentral\tnervous \tsystem \t(CNS) \tin \tsome \tpathological \t\nconditions.\n\u2022\tSelective \tagonists \tand \tantagonists \thave \tbeen \t\ndeveloped.\n\u2022\tEndogenous \tligands \tfor \tCB \treceptors \tare \tknown \tas \t\nendocannabinoids. \tThey \tare \teicosanoid \tmediators \t(see \t\nCh.\t18).\n\u2022\tThe\tbest-established \tendocannabinoids \tare \t\nanandamide \tand \t2-arachidonoyl \tglycerol \t(2-AG), \twhich \t\nhave\tmany \troles, \tincluding \tfunctioning \tas \t\u2018retrograde\u2019 \t\nmediators \tpassing \tinformation \tfrom \tpostsynaptic \tto \t\npresynaptic \tneurons.\n\u2022\tThe\tmain \tenzyme \tthat \tinactivates \tanandamide \tis \tfatty \t\nacid\tamide \thydrolase \t(FAAH).\n\u2022\tA\tputative \t\u2018endocannabinoid \tmembrane \ttransporter\u2019 \t\nmay\ttransport \tcannabinoids \tfrom \tpostsynaptic \t\nneurons,\twhere \tthey \tare \tsynthesised, \tto \tthe \tsynaptic \t\ncleft,\twhere \tthey \taccess \tpresynaptic \tCB 1\treceptors, \t\nand\tinto\tpresynaptic \tterminals, \twhere \t2-AG \tis \t\nmetabolised.\n\u2022\tFAAH\t\u2018knock-out\u2019 \tmice \thave \tan \tincreased \tbrain \t\ncontent\tof \tanandamide \tand \tan \tincreased \tpain \t\nthreshold; \tselective \tinhibitors \tof \tFAAH \thave \tanalgesic \t\nand\tanxiolytic \tproperties, \timplicating \tendocannabinoids \t\nin\tnociception \tand \tanxiety. \tOne \tsuch \tdrug \tcaused \t\ncatastrophic \tCNS \tinjury", "start_char_idx": 2991, "end_char_idx": 5420, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8c6312f3-b762-426c-a972-ef5c85acb921": {"__data__": {"id_": "8c6312f3-b762-426c-a972-ef5c85acb921", "embedding": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "be2f3034-7ccf-4a55-9adc-7bce860d4ff1", "node_type": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "63dfb21240bba2008ff475a4f716d01346517a287c1bc08ac62864850a855dbd"}, "2": {"node_id": "45ec4382-3cd2-401d-8409-f14acfa0eb0d", "node_type": null, "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84aa873afb4259b85fa85f585e229b2c96be233a1c39e352b01a5d455e27d2cf"}}, "hash": "7ef2fcce697f4a4e91cd4357659258154826aad19af85cd05c9854100e62e3a2", "text": "\tin \thealthy \thuman \tvolunteers \t\nfor\tunknown \treasons.\nPATHOLOGICAL \u2003INVOLVEMENT\nThere is evidence, both from experimental animals and \nfrom human tissue, that endocannabinoid signalling is \nabnormal in various neurodegenerative diseases (see Ch. \n41).\tOther \tdiseases \twhere \tabnormalities \tof \tcannabinoid \t\nsignalling have been reported in human tissue as well as \nexperimental models include hypotensive shock (both \nhaemorrhagic \tand \tseptic; \tsee \tCh. \t23), \tadvanced \tcirrhosis \t\nof the liver (where there is evidence that vasodilatation is mediated by endocannabinoids acting on vascular CB\n1 \nreceptors \u2013 see B\u00e1tkai et al., 2001), miscarriage (see Battista \net al., 2012) and malignant disease. It seems likely that in \nsome disorders endocannabinoid activity is a compensatory mechanism limiting the progression of disease or occurrence \nof symptoms, whereas in others it may be \u2018too much of a \ngood thing\u2019 and actually contribute to disease progression. Consequently, there may be a place in therapeutics for \ndrugs that potentiate or inhibit the cannabinoid system \n(see Pertwee, 2015, for a fuller discussion).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5451, "end_char_idx": 7056, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "16ba4a63-7363-4d7a-89d4-793772ed3c6e": {"__data__": {"id_": "16ba4a63-7363-4d7a-89d4-793772ed3c6e", "embedding": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "90827983-ec76-4563-819a-add08efb3b8a", "node_type": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "72c236b75ec4e5cf6c06a05495d1b9d2b208b1cebf8e81666f42869e4e520549"}, "3": {"node_id": "e9cd2716-d6ba-4548-933f-6ff245d8871e", "node_type": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "adf130573c6e0fd5214c1a3f12c2aaf88b2f1acff37635089e4c0dd45779aa5b"}}, "hash": "2da6137be2895520eced0849a5c5cad0c10f218a87226966fc1ae8cc12d73a2f", "text": "20 SECTION \u20032\u2003\u2003CHEMICAL MEDIATORS\n258the United States, cannabinoids have been used as antiemet -\nics and to encourage weight gain in patients with chronic \ndisease\tsuch \tas \tHIV/AIDS \tand \tmalignancy. \tCannabis \textract\t\n(sativex) is used to treat spasticity in patients with multiple \nsclerosis\t(see \tBorgelt \tet \tal., \t2013). \tAdverse \tevents \twere \t\ngenerally mild at the doses used \u2013 see UK MS Research \nGroup\t(2003). \tEndocannabinoids \thave \tbeen \timplicated \tin \t\nshock and hypotension in liver disease (Malinowska et al., \n2008), and modulation of this system is a potential thera-\npeutic\ttarget. \tOther \tpotential \tclinical \tuses \tare \tgiven \tin \tthe \t\nclinical box below.SYNTHETIC \u2003CANNABINOIDS\nCannabinoid receptor agonists were developed in the 1970s \nin the hope that they would prove useful non-opioid/\nnon-NSAID \t(non-steroidal \tanti-inflammatory) \tanalgesics \t\n(cf.\tChs\t43 \tand \t27, \trespectively, \tfor \tlimitations \tof \topioids \t\nand\tNSAIDs), \tbut \tadverse \teffects, \tparticularly \tsedation \t\nand memory impairment, were problematic. Nevertheless, one such drug, nabilone, is sometimes used clinically for \nnausea and vomiting caused by cytotoxic chemotherapy \nif\tthis\tis\tunresponsive \tto\tconventional \tantiemetics \t(Ch.\t31).\t\nFurthermore, synthetic cannabinoid agonists (i.e. spice) \nhave been used as legal \u2018highs\u2019.5 More than 20 of these \nwere\tintroduced \tin \tthe \tUnited \tKingdom \tin \t2012\u201313 \tin \t\nattempts to circumvent the law on cannabis possession. The cloning of CB\n2 receptors, and their absence from healthy \nneuronal brain cells, led to the synthesis of CB 2-selective \nagonists in the hope that these would lack the CNS-related \nadverse effects of plant cannabinoids. Several such drugs \nare being investigated for possible use in inflammatory and neuropathic pain.\nThe first selective CB\n1 receptor antagonist, rimonabant, \nalso has inverse agonist properties in some systems. It was \nlicensed in Europe for treating obesity, and there were \nhopes that it would help promote abstinence from tobacco, but it was withdrawn because it caused psychiatric problems \nincluding depression. Synthetic inhibitors of endocan -\nnabinoid uptake and/or metabolism have shown potentially \nuseful effects in animal models of pain, epilepsy, multiple \nsclerosis, Parkinson\u2019s disease, anxiety and diarrhoea.\nIn addition to central CB\n1 receptors, hepatocyte CB 1 \nreceptors are also implicated in obesity and in non-alcoholic fatty liver disease, and research on selective peripheral \nantagonists \tcontinues \t(Klumpers \tet \tal., \t2013).\nCLINICAL \u2003APPLICATIONS\nClinical uses of drugs that act on the cannabinoid system \nremain controversial, but in both the United Kingdom and Potential and actual clinical uses \nof cannabinoid agonists and \nantagonists \nCannabis\textract \tis \tlicensed \tas \tan \tadjunct \tfor \texperts \t\ntreating\tspasticity \tin \tmultiple \tsclerosis \tand \tcannabinoid \t\nagonists\tand \tantagonists \tare \tundergoing \tevaluation \tfor \ta \t\nwide\trange \tof \tpossible \tindications, \tincluding:\n\u2022\tAgonists:\n\u2013\tnausea/vomiting \tassociated \twith \tcancer \t\nchemotherapy\n\u2013\tcancer\tand \tAIDS \t(to \treduce \tweight \tloss)\n\u2013\tneuropathic", "start_char_idx": 0, "end_char_idx": 3148, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e9cd2716-d6ba-4548-933f-6ff245d8871e": {"__data__": {"id_": "e9cd2716-d6ba-4548-933f-6ff245d8871e", "embedding": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "90827983-ec76-4563-819a-add08efb3b8a", "node_type": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "72c236b75ec4e5cf6c06a05495d1b9d2b208b1cebf8e81666f42869e4e520549"}, "2": {"node_id": "16ba4a63-7363-4d7a-89d4-793772ed3c6e", "node_type": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2da6137be2895520eced0849a5c5cad0c10f218a87226966fc1ae8cc12d73a2f"}, "3": {"node_id": "df96f13e-6fb3-40c8-a485-41be17aaae1f", "node_type": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01c4816de5e518fb220e3118ac63816a5cd4dd66fa3ae36afd360cec76ffa07e"}}, "hash": "adf130573c6e0fd5214c1a3f12c2aaf88b2f1acff37635089e4c0dd45779aa5b", "text": "\tAIDS \t(to \treduce \tweight \tloss)\n\u2013\tneuropathic \tpain\n\u2013\thead\tinjury\n\u2013\tglaucoma\n\u2013\tTourette \tsyndrome \t(to \treduce \ttics \t\u2013 \trapid \tinvoluntary \t\nmovements \tthat \tare \ta \tfeature \tof \tthis \tdisorder)\n\u2013\tParkinson\u2019s \tdisease \t(to \treduce \tinvoluntary \t\nmovements \tcaused \tas \tan \tadverse \teffect \tof \t\nlevodopa ;\tsee\tCh.\t41)\n\u2013\tseizures.\n\u2022\tAntagonists:\n\u2013\tobesity\n\u2013\ttobacco \tdependence\n\u2013\tdrug\taddiction\n\u2013\talcoholism.5Note the past tense: \u2018legal\u2019 highs are all illegal now \u2013 at least in the \nUnited Kingdom.\nREFERENCES \u2003AND \u2003FURTHER \u2003READING\nGeneral reading\nFreund,\tT.F., \tKatona, \tI., \tPiomelli, \tD., \t2003. \tRole \tof \tendogenous \t\ncannabinoids \tin \tsynaptic \tsignaling. \tPhysiol. \tRev. \t83, \t1017\u20131066. \t(The \nfine-grain anatomical distribution of the neuronal cannabinoid receptor CB 1 \nis described, and possible functions of endocannabinoids as retrograde \nsynaptic signal molecules discussed in relation to synaptic plasticity and \nnetwork activity patterns)\nLigresti,\tA., \tde \tPetrocellis, \tL., \tdi \tMarzo, \tV., \t2016. \tFrom \t\nphytocannabinoids to cannabinoid receptors and endocannabinoids: pleiotropic physiological and pathological roles through complex \npharmacology. \tPhysiol. \tRev. \t96, \t1593\u20131659. \t(Reviews the pharmacology \nof major phytocannabinoids, and physiological and pathological, roles of the \nendocannabinoid system in mammalian cells, tissues, and organs)\nPertwee, R.G. (Ed.), 2014. Handbook of Cannabis (Handbooks of \nPsychopharmacology). \tOxford \tUniversity \tPress. \t(Excellent textbook on \ncannabis)\nPertwee, R.G. (Ed.), 2015. Endocannabinoids and Their Pharmacological \nActions\t(Handbook \tof \tExperimental \tPharmacology). \tSpringer \t\nInternational Publications, Switzerland. (Excellent textbook on \nendocannabinoid pharmacology)Specific aspects\nB\u00e1tkai,\tS., \tJ\u00e1rai, \tZ., \tWagner, \tJ.A., \tet \tal., \t2001. \tEndocannabinoids \tacting \t\nat vascular CB 1 receptors mediate the vasodilated state in advanced \nliver\tcirrhosis. \tNat. \tMed. \t7, \t827\u2013832. \t(Rats with cirrhosis have low blood \npressure, which is elevated by a CB 1 receptor antagonist. Compared with \nnon-cirrhotic controls, in cirrhotic human livers there was a three-fold \nincrease in CB 1 receptors on isolated vascular endothelial cells)\nBattista, N., Meccariello, R., Cobellis, G., 2012. The role of \nendocannabinoids in gonadal function and fertility along the \nevolutionary \taxis. \tMol. \tCell. \tEndocrinol. \t355, \t1\u201314. \t(Reviews the actions \nof endocannabinoids on the main male and female reproductive events)\nBenyo, Z., Ruisanchez, E., Leszl-Ishiguro, M., 2016. Endocannabinoids \nin\tcerebrovascular \tregulation. \tAm. \tJ. \tPhysiol. \tHeart \tCirc. \tPhysiol. \t310, \t\nH785\u2013H801. (Reviews the complex ways in which the endocannabinoid \nsystem", "start_char_idx": 3106, "end_char_idx": 5830, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "df96f13e-6fb3-40c8-a485-41be17aaae1f": {"__data__": {"id_": "df96f13e-6fb3-40c8-a485-41be17aaae1f", "embedding": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "90827983-ec76-4563-819a-add08efb3b8a", "node_type": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "72c236b75ec4e5cf6c06a05495d1b9d2b208b1cebf8e81666f42869e4e520549"}, "2": {"node_id": "e9cd2716-d6ba-4548-933f-6ff245d8871e", "node_type": null, "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "adf130573c6e0fd5214c1a3f12c2aaf88b2f1acff37635089e4c0dd45779aa5b"}}, "hash": "01c4816de5e518fb220e3118ac63816a5cd4dd66fa3ae36afd360cec76ffa07e", "text": "modulates regulation of cerebral circulation)\nBorgelt,\tL.M., \tFranson, \tK.L., \tNussbaum, \tA.M., \tWang, \tG.S., \t2013. \tThe \t\npharmacologic and clinical effects of medical cannabis. \nPharmacotherapy \t33, \t195\u2013209.\nChiurchiu, V., Lanuti, M., Catanzaro, G., et al., 2014. Detailed \ncharacterization of the endocannabinoid system in human mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5874, "end_char_idx": 6688, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8d09f956-55b9-4ab0-8649-72fab8c903e0": {"__data__": {"id_": "8d09f956-55b9-4ab0-8649-72fab8c903e0", "embedding": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a296fb4a-5590-4c21-b40a-8c9e83748489", "node_type": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c6bde799d83a86c473e90312992b271139276b5b7d7f4709e19878d8e07f5fed"}, "3": {"node_id": "939770d1-7efb-4dd1-a69e-11020dcc3509", "node_type": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f04399870fd115989f9cc1835d7aaec444441cfaeea0284180264af7c2e5edb6"}}, "hash": "be49d7f6d9cd6206a59507645b309a8351f4072c24192733bb3e920a12271c6c", "text": "20 CAnnAbInOIDS\n259(Oxford)\t 26,\tSI177\u2013SI188.\t (Available data support the hypothesis that heavy \ncannabis use in adolescence increases the risk of developing psychiatric \ndisorders )\nSteffens, S., 2005. Low dose oral cannabinoid therapy reduces \nprogression\t of\tatherosclerosis\t in\tmice.\tNature\t434,\t782\u2013786.\t (Oral \nadministration of THC (1 mg/kg per day) inhibits atherosclerosis in a mouse \nmodel by an action on CB 2 receptors. See also News and Views, p. 708 of the \nsame issue, for comment by Roth, M.D. )\nTaber,\tK.H.,\tHurley,\tR.A.,\t2009.\tEndocannabinoids:\t stress,\tanxiety\tand\t\nfear.\tJ.\tNeuropsychiat.\t Clin.\tNeurosci.\t 21,\t108\u2013113.\t (Succinctly reviews \nthe involvement of the endocannabinoid system in brain function, and \npotential therapeutic applications in treating mood/anxiety, degenerative \ndisease and brain injury )\nUK\tMS\tResearch\t Group,\t2003.\tCannabinoids\t for\ttreatment\t of\tspasticity\t\nand\tother\tsymptoms\t related\tto\tmultiple\t sclerosis\t (CAMS\tstudy):\t\nmulticentre\t randomised\t placebo-controlled\t trial.\tLancet\t362,\t\n1517\u20131526. ( Randomised, placebo-controlled trial in 667 patients with stable \nmultiple sclerosis and muscle spasticity. Trial duration was 15 weeks. There \nwas no treatment effect of THC or cannabis extract on the primary outcome \nof spasticity assessed with a standard rating scale, but there was an \nimprovement in patient-reported spasticity and pain, which might be \nclinically useful )\nvan\tEsbroeck,\t A.C.M.,\tJanssen,\t A.P.A.,\tCognetta,\t A.B.,\tIII,\tet\tal.,\t2017.\t\nActivity-based\t protein\tprofiling\t reveals\toff-target\t proteins\t of\tthe\t\nFAAH\tinhibitor\t BIA\t10-2474.\t Science\t356,\t1084\u20131087.\t (BIA 10-2474 \ninhibits several lipases that are not targeted by a more selective FAAH \ninhibitor and alters lipid networks in human cortical neurons, suggesting \nthat promiscuous lipase inhibitors have the potential to cause metabolic \ndysregulation in the nervous system, possibly accounting for the serious \nadverse effects caused by BIA 10-2474 )\nVan\tGaal,\tL.F.,\tRissanen,\t A.M.,\tScheen,\tA.J.,\tet\tal.\tfor\tthe\tRIO-Europe\t\nStudy Group, 2005. Effects of the cannabinoid-1 receptor blocker \nrimonabant on weight reduction and cardiovascular risk factors in \noverweight\t patients:\t 1-year\texperience\t from\tthe\tRIO-Europe\t study.\t\nLancet\t365,\t1389\u20131397.\t (A total of 1507 overweight patients treated with \nrimonabant 5 or 20 mg or with placebo daily for 1 year in addition to dietary \nadvice: significant dose-related decrease in weight and improvement in \ncardiovascular risk factors in actively treated patients; adverse effects were \nmild, but subsequent work demonstrated that depression is an important \nadverse effect and the drug was withdrawn )macrophages and foam cells, and anti-inflammatory role of type-2 \ncannabinoid\t receptor.\t Atherosclerosis\t 233,\t55\u201363.\t(A fully active \nendocannabinoid system is present in human macrophages and foam cells. \nSelective activation of CB2R reduces CD36-dependent oxLDL accumulation \nand modulates production of inflammatory cytokines )\nDevane,\t", "start_char_idx": 0, "end_char_idx": 3028, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "939770d1-7efb-4dd1-a69e-11020dcc3509": {"__data__": {"id_": "939770d1-7efb-4dd1-a69e-11020dcc3509", "embedding": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a296fb4a-5590-4c21-b40a-8c9e83748489", "node_type": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c6bde799d83a86c473e90312992b271139276b5b7d7f4709e19878d8e07f5fed"}, "2": {"node_id": "8d09f956-55b9-4ab0-8649-72fab8c903e0", "node_type": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be49d7f6d9cd6206a59507645b309a8351f4072c24192733bb3e920a12271c6c"}, "3": {"node_id": "57770bff-358c-42a8-bbd7-f09e5f9c7ba7", "node_type": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2f949e1e220c023d1807f50c90fff7ddc9325db8f1b08e6fbfb9c042632aee0"}}, "hash": "f04399870fd115989f9cc1835d7aaec444441cfaeea0284180264af7c2e5edb6", "text": "accumulation \nand modulates production of inflammatory cytokines )\nDevane,\t W.A.,\tHanu,\tL.,\tBreurer,\t A.,\tet\tal.,\t1992.\tIsolation\t and\tstructure\t\nof a brain constituent that binds to the cannabinoid receptor. Science \n258, 1946\u20131949. ( Identification of arachidonylethanolamide, extracted from \npig brain, both chemically and via a bioassay, as a natural ligand for the \ncannabinoid receptor; the authors named it anandamide )\nDi Marzo, V., 2008. Endocannabinoids: synthesis and degradation. Rev. \nPhysiol. Biochem. Pharmacol. 160, 1\u201324. ( Reviews current knowledge )\nDi Marzo, V., Petrosino, S., 2007. Endocannabinoids and the regulation \nof\ttheir\tlevels\tin\thealth\tand\tdisease.\t Curr.\tOpin.\tLipidol.\t 18,\t129\u2013140.\t\n(Gastrointestinal disorders, inflammation, neurodegeneration )\nDiPatrizio, N.V., Piomele, D., 2012. The thrifty lipids: endocannabinoids \nand\tthe\tneural\tcontrol\tof\tenergy\tconservation.\t Trends\tNeurosci.\t 35,\t\n403\u2013411.\t (Endocannabinoids increase energy intake and decrease energy \nexpenditure by controlling the activity of peripheral and central neural \npathways involved in the sensing and hedonic processing of sweet and fatty \nfoods, as well as in the storage of their energy content for future use )\nKarst,\tM.,\tSalim,\tK.,\tBurstein,\t S.,\tet\tal.,\t2003.\tAnalgesic\t effect\tof\tthe\t\nsynthetic\t cannabinoid\t CT-3\ton\tchronic\tneuropathic\t pain.\tA\t\nrandomized\t controlled\t trial.\tJAMA\t290,\t1757\u20131762.\t (CT-3, a potent \ncannabinoid, produces marked antiallodynic and analgesic effects in animals. \nIn a preliminary randomised cross-over study in 21 patients with chronic \nneuropathic pain, CT-3 was effective in reducing chronic neuropathic pain \ncompared with placebo )\nKlumpers,\t L.E.,\tFridberg,\t M.,\tde\tKam,\tM.L.,\tet\tal.,\t2013.\tPeripheral\t\nselectivity\t of\tthe\tnovel\tcannabinoid\t receptor\t antagonist\t TM38837\t in\t\nhealthy subjects. Br. J. Clin. Pharmacol. 76, 846\u2013857.\nMaldonado,\t R.,\tBerrendero,\t F.,\tOzaita,\tA.,\tet\tal.,\t2011.\tNeurochemical\t\nbasis of cannabis addiction. Neuroscience 181, 1\u201317. ( Describes the \nexperimental methods now available to study the pharmacological responses \nof cannabinoids related to their addictive effects and the specific contribution \nof different neurochemical systems in cannabis addiction )\nMalinowska, B., Lupinski, S., Godlewski, G., et al., 2008. Role of \nendocannabinoids in cardiovascular shock. J. Physiol. Pharmacol. 59, \n91\u2013107.\nRubino,\t T.,\tZamberletti,\t E.,\tParolaro,\t D.,\t2012.\tAdolescent\t exposure\t to\t\ncannabis as a risk factor for psychiatric disorders. J. Psychopharmacol. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2961, "end_char_idx": 5867, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "57770bff-358c-42a8-bbd7-f09e5f9c7ba7": {"__data__": {"id_": "57770bff-358c-42a8-bbd7-f09e5f9c7ba7", "embedding": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a296fb4a-5590-4c21-b40a-8c9e83748489", "node_type": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c6bde799d83a86c473e90312992b271139276b5b7d7f4709e19878d8e07f5fed"}, "2": {"node_id": "939770d1-7efb-4dd1-a69e-11020dcc3509", "node_type": null, "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f04399870fd115989f9cc1835d7aaec444441cfaeea0284180264af7c2e5edb6"}}, "hash": "b2f949e1e220c023d1807f50c90fff7ddc9325db8f1b08e6fbfb9c042632aee0", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5904, "end_char_idx": 6047, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "72b4caf1-4d9c-424b-9dc3-16c6a7f19058": {"__data__": {"id_": "72b4caf1-4d9c-424b-9dc3-16c6a7f19058", "embedding": null, "metadata": {"page_label": "266", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "679606f7-c43d-46cc-8790-86b178958081", "node_type": null, "metadata": {"page_label": "266", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8af4af0cab33bb91f79400437e5584da53fa0a5ad969e21707b4c7db0f35d6e4"}, "3": {"node_id": "b7faf5f0-c887-479d-98dd-6bb56f8fdfe0", "node_type": null, "metadata": {"page_label": "266", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44bdec6d9cedea27feb9ae9276ca45faadf99787dafc65bb2c8cac106823a2fc"}}, "hash": "e6a346d281d086b4b4541e1c43daa58e442328ba008903700e3e7bb4562da86b", "text": "260\nNitric oxide and \nrelated mediators21 CHEMICAL MEDIATORS SECTION 2 \nOVERVIEW\nNitric oxide (NO) is a ubiquitous mediator with diverse \nfunctions. It is generated from L-arginine by nitric \noxide synthase (NOS), an enzyme that occurs in \nendothelial, neuronal and inducible isoforms. In this chapter, we concentrate on general aspects of NO, \nespecially its biosynthesis, degradation and effects. \nWe touch on evidence that it can act as a circulating as well as local mediator, and conclude with a brief \nconsideration of the therapeutic potential of drugs \nthat act on the L-arginine/NO pathway. Other gaseous mediators (carbon monoxide, hydrogen sulfide)\n1 are \ndescribed briefly: while they have yet to yield thera -\npeutic drugs, their pathways are tempting drug targets.\nINTRODUCTION\nNO, a free radical gas, is formed in the atmosphere during \nlightning storms. Less dramatically, but with far-reaching \nbiological consequences, it is also formed in an enzyme-\ncatalysed reaction between molecular oxygen and L-arginine. The convergence of several lines of research led to the \nrealisation that NO is a key signalling molecule in the \ncardiovascular and nervous systems, and that it has a role in host defence.\nA physiological function of NO emerged when biosyn -\nthesis of this gas was shown to account for the endothelium-\nderived relaxing factor described by Furchgott and Zawadzki \n(1980) (Figs 21.1 and 21.2). NO is the endogenous activator \nof soluble guanylyl cyclase, leading to the formation of \ncyclic guanosine monophosphate (cGMP), an important \u2018second messenger\u2019 (Ch. 3) in many cells, including neurons, \nsmooth muscle, monocytes and platelets. Nitrogen and \noxygen are neighbours in the periodic table, and NO shares several properties with O\n2, in particular a high affinity for \nhaem and other iron\u2013sulfur groups. This is important for \nactivation of guanylyl cyclase, which contains a haem group, \nfor the inactivation of NO by haemoglobin and for the regulation of diffusion of NO from endothelial cells (which \nexpress the alpha chain of haemoglobin) to vascular smooth \nmuscle.\nThe role of NO in specific settings is described in other \nchapters: the endothelium in Chapter 23, the autonomic nervous system (Ch. 13), and as a chemical transmitter and mediator of excitotoxicity in the central nervous system (CNS) in Chapters 38\u201340. Therapeutic uses of organic nitrates and of nitroprusside (NO donors) are described in Chapters \n22 and 23.\nBIOSYNTHESIS OF NITRIC OXIDE \nAND ITS CONTROL\nNOS enzymes are central to the control of NO biosynthesis. There are three isoforms: an inducible form (iNOS or NOS2) \nwhich is expressed in macrophages and Kupffer cells, neutrophils, fibroblasts, vascular smooth muscle and endothelial cells in response to pathological stimuli such \nas invading microorganisms; and two constitutive forms, \nwhich are present under physiological conditions in \nendothelium (eNOS or NOS3)\n2 and in neurons (nNOS or \nNOS1).3 The constitutive enzymes generate small amounts \nof NO, whereas NOS2 produces much greater amounts, \nboth because of its high activity and because of its abundance \nin pathological states associated with cytokine release.\n\u25bc All three NOS isoenzymes are dimers. They are structurally and \nfunctionally complex, bearing similarities to the cytochrome P450 \nenzymes (described in Ch. 10) that are so important in drug metabolism. \nEach isoform contains iron protoporphyrin IX (haem), flavin adenine \ndinucleotide", "start_char_idx": 0, "end_char_idx": 3486, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b7faf5f0-c887-479d-98dd-6bb56f8fdfe0": {"__data__": {"id_": "b7faf5f0-c887-479d-98dd-6bb56f8fdfe0", "embedding": null, "metadata": {"page_label": "266", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "679606f7-c43d-46cc-8790-86b178958081", "node_type": null, "metadata": {"page_label": "266", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8af4af0cab33bb91f79400437e5584da53fa0a5ad969e21707b4c7db0f35d6e4"}, "2": {"node_id": "72b4caf1-4d9c-424b-9dc3-16c6a7f19058", "node_type": null, "metadata": {"page_label": "266", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e6a346d281d086b4b4541e1c43daa58e442328ba008903700e3e7bb4562da86b"}}, "hash": "44bdec6d9cedea27feb9ae9276ca45faadf99787dafc65bb2c8cac106823a2fc", "text": "iron protoporphyrin IX (haem), flavin adenine \ndinucleotide (FAD), flavin mononucleotide (FMN) and tetrahydro -\nbiopterin (H 4B) as bound prosthetic groups. They also bind L-arginine, \nreduced nicotinamide adenine dinucleotide phosphate (NADPH) and \ncalcium\u2013calmodulin. These prosthetic groups and ligands control the \nassembly of the enzyme into the active dimer. NOS3 is doubly acylated by N-myristoylation and cysteine palmitoylation; these post-\ntranslational modifications lead to its association with membranes in the Golgi apparatus and in caveolae, specialised cholesterol-rich \nmicrodomains in the plasma membrane derived from the Golgi \napparatus. In the caveolae, NOS3 is held as an inactive complex with \ncaveolin, the main membrane protein of caveolae. Dissociation from \ncaveolin activates the enzyme.\nThe nitrogen atom in NO is derived from the terminal guanidino \ngroup of L-arginine. NOS enzymes combine oxygenase and reductase \nactivities. The oxygenase domain contains haem, while the reductase \ndomain binds calcium\u2013calmodulin. In pathological states, the enzyme can undergo structural change leading to electron transfer between \nsubstrates, enzyme co-factors and products becoming \u2018uncoupled\u2019, \nso that electrons are transferred to molecular oxygen, leading to the \nsynthesis of superoxide anion (O\n2\u2212) rather than NO. This is important, \nas superoxide anion reacts with NO to form a toxic product (perox -\nynitrite anion; see p. 263). Reactive nitrogen species such as perox -\nynitrite act together with reactive oxygen species (ROS) to damage \ncells, causing nitrosative stress.\n1The pure substances (NO, CO and H 2S) are gases at room temperature \nand usual atmospheric pressure, and when pure NO is administered \ntherapeutically (see p. 265 and clinical box, p. 267), it is in the form of a \ngas; when formed endogenously, the gases are, of course, dissolved in intra- and extracellular fluids.2NOS3 is not restricted to endothelium. It is also present in cardiac \nmyocytes, renal mesangial cells, osteoblasts and osteoclasts, airway \nepithelium and, in small amounts, platelets, so the term eNOS is \nsomewhat misleading.\n3It is possible that some of the NO made in healthy animals under basal \nconditions is derived from the action of NOS2, just as the inducible form \nof cyclo-oxygenase is active under basal conditions (Ch. 18) \u2013 whether \nthis is because there is some NOS2 expressed even when there is no pathology, or because there is enough \u2018pathology\u2019 in healthy mammals, \nfor example in relation to gut microflora, to induce it, is a moot point.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3427, "end_char_idx": 6485, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4a3f9c60-0e4c-4d17-ae5c-34a986ae9679": {"__data__": {"id_": "4a3f9c60-0e4c-4d17-ae5c-34a986ae9679", "embedding": null, "metadata": {"page_label": "267", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b82c8bf2-5027-4eb8-8a41-8fafd5622f5e", "node_type": null, "metadata": {"page_label": "267", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cddc8a047825ec02f601185afb12ca0f13bc41fbfed33a99b1bf333e93bf1b75"}, "3": {"node_id": "b436f740-9208-45e3-864d-d4a16ae46fa0", "node_type": null, "metadata": {"page_label": "267", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9888b0970e7e61e9540f07a2996971d61ebe9bb048c74b2d10ad2edd2406b2a7"}}, "hash": "fe2c40126a65b234973f1b3fc7a3ad61573c456cd2c3898f1964ec3e9ae50688", "text": "21 NITRIC O x IDE AND RELATED MEDIATORS\n261The activity of constitutive isoforms of NOS is controlled \nby intracellular calcium\u2013calmodulin (Fig. 21.3). L-Arginine, \nthe substrate of NOS, is usually present in excess in \nendothelial cell cytoplasm, so the rate of production of NO is determined by the activity of the enzyme rather than by \nsubstrate availability. Nevertheless, very high doses of \nL-arginine can restore endothelial NO biosynthesis in some pathological states (e.g. hypercholesterolaemia) in which \nendothelial function is impaired. Possible explanations for \nthis paradox include:\n\u2022\tcompartmentation: \ti.e. \texistence \tof \ta \tdistinct \tpool \tof \t\nsubstrate in a cell compartment with access to NOS, which can become depleted despite apparently \nplentiful total cytoplasmic arginine concentrations;\n\u2022\tcompetition \tby \thigh \tconcentrations \tof \tL-arginine \twith \t\nendogenous competitive inhibitors of NOS such as \nasymmetric dimethylarginine (ADMA; see p. 265 and \nFig. 21.4), which is elevated in plasma from patients \nwith hypercholesterolaemia;\n\u2022\trecoupling \tof \telectron \ttransfer \tto \tL-arginine.\nControl of constitutive NOS activity by calcium\u2013calmodulin is exerted in two ways:\n1. Many endothelium-dependent agonists (e.g. \nacetylcholine, bradykinin, substance P) increase the cytoplasmic concentration of calcium ions [Ca\n2+]i; the \nconsequent increase in calcium\u2013calmodulin activates \nNOS1 and NOS3.Unrubbed\nNA -7.7\nNA -7.7ACh\nACh-6\n-6-7\n-7-8\n-85 min2 g\nRubbed\nW\nW\nFig. 21.1 Endothelium-derived relaxing factor. \nAcetylcholine (ACh) relaxes a strip of rabbit aorta precontracted \nwith noradrenaline (NA) if the endothelium is intact (\u2018unrubbed\u2019: \nupper panel), but not if it has been removed by gentle rubbing (\u2018rubbed\u2019: lower panel). The numbers are logarithms of molar concentrations of drugs. (From Furchgott & Zawadzki, 1980.)\nHb + ACh\nHb + ACh\n+ ECHb + NOHb\n10 min2 cm10 min\n0.67\n0.670.22 \n0.22 0.07 \n0.07 100 \n100 30 \n30 10 \n10 3\n3 EDRF from BK nmol/L TC\nEDRF from BK nmol/L TCNO nmol\nNO nmol0.6\n0.50.40.3\n0.2\n0.1\n0Absorbance\n400 425 450 400 425 450\nWavelength (nm)A B\nC\nFig. 21.2 Endothelium-derived relaxing factor (EDRF) is closely related to nitric oxide (NO). (A) EDRF released from aortic \nendothelial cells (EC) by acetylcholine (ACh) (right panel) has the same effect on the absorption spectrum of deoxyhaemoglobin (Hb) as \ndoes authentic NO (left panel) . (B) EDRF is released from a column of cultured ECs by bradykinin (BK 3\u2013100 nmol) applied through the \ncolumn of cells (TC) and relaxes a de-endothelialised precontracted bioassay strip, as does authentic NO (upper trace). (C) A chemical \nassay of NO based on chemiluminescence shows that similar concentrations of NO are present in the EDRF released from the column of \ncells as in equiactive authentic NO solutions. (From Ignarro, L.J., Byrns,. RE., Buga, G.M. et al., 1987. Circ. Res.", "start_char_idx": 0, "end_char_idx": 2892, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b436f740-9208-45e3-864d-d4a16ae46fa0": {"__data__": {"id_": "b436f740-9208-45e3-864d-d4a16ae46fa0", "embedding": null, "metadata": {"page_label": "267", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b82c8bf2-5027-4eb8-8a41-8fafd5622f5e", "node_type": null, "metadata": {"page_label": "267", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cddc8a047825ec02f601185afb12ca0f13bc41fbfed33a99b1bf333e93bf1b75"}, "2": {"node_id": "4a3f9c60-0e4c-4d17-ae5c-34a986ae9679", "node_type": null, "metadata": {"page_label": "267", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe2c40126a65b234973f1b3fc7a3ad61573c456cd2c3898f1964ec3e9ae50688"}}, "hash": "9888b0970e7e61e9540f07a2996971d61ebe9bb048c74b2d10ad2edd2406b2a7", "text": "RE., Buga, G.M. et al., 1987. Circ. Res. 61, 866\u2013879; and Palmer, \nR.M.J., Ferrige, A.G., Moncada, S. et al., 1987. Nature 327, 524\u2013526.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2851, "end_char_idx": 3469, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5259ef40-939e-4b53-8771-d4124fad0d97": {"__data__": {"id_": "5259ef40-939e-4b53-8771-d4124fad0d97", "embedding": null, "metadata": {"page_label": "268", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a1285979-8783-4eac-87ef-5ab5a642135f", "node_type": null, "metadata": {"page_label": "268", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "104da0dba6e19b02d9b03f8ce57704cc8e89de2dcdf0d1591474400039f83a36"}, "3": {"node_id": "e7aab2a8-cf64-4b1a-abb9-7d60e8b26c1b", "node_type": null, "metadata": {"page_label": "268", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "70b785adc9d68fb5d827882479bae230da89a86c7adc41c1ebb5a5fd486a24ac"}}, "hash": "1ec42722436fc769d0bc4d57b3ea3c225ddadb0130a7d2f3aa3387563e015ad6", "text": "21 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n262lipopolysaccharide and inflammatory cytokines, notably \ninterferon-\u03b3, the antiviral effect of which is due to this. \nTumour necrosis factor- \u03b1 and interleukin-1 do not alone \ninduce NOS2, but they each synergise with interferon- \u03b3 in \nthis regard (see Ch. 18). Induction of NOS2 is inhibited by glucocorticoids and by several cytokines, including trans -\nforming growth factor-\u03b2. There are important species differences in the inducibility of NOS2, which is less readily induced in human than in mouse cells.\nDEGRADATION AND CARRIAGE \nOF NITRIC OXIDE\nNO reacts with oxygen to form N 2O4, which combines with \nwater to produce a mixture of nitric and nitrous acids. \nNitrite ions are oxidised to nitrate by oxyhaemoglobin. \nThese reactions are summarised as follows:\n 2 22 4 NO ON O +\u2192 (21.1)\n NO HO NO NO H 24 23 22 +\u2192 ++\u2212\u2212 + (21.2)\n NO HbON OH b 23\u2212\u2212+\u2192 + (21.3)2. Phosphorylation of specific residues on NOS3 controls \nits sensitivity to calcium\u2013calmodulin; this can alter NO synthesis in the absence of any change in [Ca\n2+]i.\nShear stress is an important physiological stimulus to endothelial NO synthesis in resistance vessels. This is sensed \nby endothelial mechanoreceptors and transduced via a \nserine\u2013threonine protein kinase called Akt (see Ch. 3) which is also known as protein kinase B. Agonists that increase cAMP in endothelial cells (e.g. \u03b2\n2-adrenoceptor agonists) \nincrease NOS3 activity, via protein kinase A-mediated \nphosphorylation4 whereas protein kinase C reduces NOS3 \nactivity by phosphorylating residues in the calmodulin-binding domain, thereby reducing the binding of calmodulin. \nInsulin increases NOS3 activity via tyrosine kinase activation (and also increases the expression of NOS1 in diabetic mice).\nIn contrast to constitutive NOS isoforms, the activity of \nNOS2 is effectively independent of [Ca\n2+]i, being fully \nactivated even at the low values of [Ca2+]i present under \nresting conditions. The enzyme is induced by bacterial [Ca2+]ia\nb020406080100\n0102030405060\n1.6 0.5 0.4 0.3 0.2 0.1 Citrulline synthesis (fmol/min per mL) Guanylyl cyclase stimulation (%)Calmodulin Ca2+-calmodulin\nENDOTHELIAL\nCELL\nSMOOTH\nMUSCLE\nCELLNOS\n(active)NOS\n(inactive)\nArginine Citrulline + NO\nGC\n(basal)GC\n(activated)\ncGMP GTP\nRELAXATIONAktReceptors\n(acetylcholine, bradykinin, \nsubstance P, etc.) Mechanical shear stress\nFree Ca2+ concentration (\u00b5mol/L)A B\nFig. 21.3 Control of constitutive nitric oxide synthase (NOS) by calcium\u2013calmodulin. (A) Dependence on Ca2+ of nitric oxide (NO) \nand citrulline synthesis from L-arginine by rat brain synaptosomal cytosol. Rates of synthesis of NO from L-arginine were determined by \nstimulation of guanylyl cyclase (GC) (upper panel) or by synthesis of [3H]-citrulline from L-[3H]-arginine (lower panel) . (B) Regulation of GC in \nsmooth muscle by NO formed in adjacent endothelium. Akt is a protein kinase that phosphorylates NOS, making it more sensitive to", "start_char_idx": 0, "end_char_idx": 2961, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e7aab2a8-cf64-4b1a-abb9-7d60e8b26c1b": {"__data__": {"id_": "e7aab2a8-cf64-4b1a-abb9-7d60e8b26c1b", "embedding": null, "metadata": {"page_label": "268", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a1285979-8783-4eac-87ef-5ab5a642135f", "node_type": null, "metadata": {"page_label": "268", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "104da0dba6e19b02d9b03f8ce57704cc8e89de2dcdf0d1591474400039f83a36"}, "2": {"node_id": "5259ef40-939e-4b53-8771-d4124fad0d97", "node_type": null, "metadata": {"page_label": "268", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ec42722436fc769d0bc4d57b3ea3c225ddadb0130a7d2f3aa3387563e015ad6"}}, "hash": "70b785adc9d68fb5d827882479bae230da89a86c7adc41c1ebb5a5fd486a24ac", "text": "is a protein kinase that phosphorylates NOS, making it more sensitive to \ncalcium\u2013calmodulin. (Panel [A] from Knowles, R.G. et al., 1989. Proc. Natl. Acad. Sci. U. S. A. 86, 5159\u20135162.) \n4As explained in Chapter 4, \u03b2 2 agonists also act directly on smooth \nmuscle cells, causing relaxation via cAMP.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2889, "end_char_idx": 3668, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d5afa1a4-3fa9-4f9a-87a3-30a66d2f11ee": {"__data__": {"id_": "d5afa1a4-3fa9-4f9a-87a3-30a66d2f11ee", "embedding": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "93aa463c-e0ba-43fc-93a0-8d937e112bf3", "node_type": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "098f438970d7b60cb750116b3fa7429e99fb3a43f202226e8a2b82cd536947b9"}, "3": {"node_id": "40d56eef-c52c-4f21-92ed-c8d8f2e677bc", "node_type": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d12898d350b9351aaa85fa26592fa174c71a28bb2fb86202946543041517679c"}}, "hash": "ea767f56e7e3903d6ce9d94516e22618773695a46a99a31fc1239cab774fa6b1", "text": "21 NITRIC O x IDE AND RELATED MEDIATORS\n263muscle cells kiss, forming a corridor along which NO can diffuse. \nHaemoglobin alpha is concentrated in these junctions and acts as a \nredox-sensitive stop/go signal. When the haem iron is in the oxidised \nFe3+ state (methaemoglobin), NO can diffuse along the corridor and \ninto the smooth muscle cell on which it acts; when the haem iron is \nin the Fe2+ state, however, NO is rapidly converted to nitrate and the \ndiffusion pathway is effectively closed. Conversion of methaemoglobin to haemoglobin, preventing NO from crossing the barrier, is brought \nabout by the enzyme cytochrome b5 reductase3 (also known as methaemoglobin reductase) and inhibition of this enzyme increases \nNO bioactivity in small arteries (Straub et al., 2012).\nDistinct from the inactivation reaction between NO and haem, a specific cysteine residue (cys 93 of the \u03b2-chain) in globin combines \nreversibly with NO under physiological conditions. The resulting S-nitrosylated haemoglobin acts as a circulating oxygen-sensitive NO \ncarrier that releases biologically active nitrosothiol (SNO) compounds \nsuch as cysteinyl-NO or glutathionyl-NO to mediate vasodilatation \nwhen haemoglobin transitions from the R (oxygenated) to the T (deoxygenated) state, thereby contributing to hypoxic vasodilatation. \nThe biological importance of this mechanism is attested to by observa -\ntions in mutant mice expressing humanised haemoglobin and lacking \u03b2-cys93 S-nitrosylation. Such mice are more susceptible to myocardial \ndamage in experimental myocardial ischaemia and heart failure models \nthan controls with humanised haemoglobin but intact \u03b2-cys93 \nS-nitrosylation (Zhang et al., 2015).\nEFFECTS OF NITRIC OXIDE\nNO reacts with various metals, thiols and oxygen species, \nthereby modifying proteins, DNA and lipids. One of its \nmost important biochemical effects (see Ch. 3) is activation \nof soluble guanylyl cyclase, a heterodimer present in vascular and nervous tissue as two distinct isoenzymes. \nGuanylyl cyclase synthesises the second messenger cGMP. \nNO activates the enzyme by combining with its haem group, and many physiological effects of low concentrations of \nNO are mediated by cGMP. These effects are prevented \nby inhibitors of guanylyl cyclase (e.g. 1H-[1,2,4]-oxadiazole-[4,3-\u03b1]-quinoxalin-1-one, better known as \u2018ODQ\u2019), which are useful investigational tools. NO activates soluble \nguanylyl cyclase in intact cells (neurons and platelets) \nextremely rapidly, and activation is followed by desensitisa -\ntion to a steady-state level. This contrasts with its effect on \nthe isolated enzyme, which is slower but more sustained. \nGuanylyl cyclase contains another regulatory site, which is NO independent. This is activated by riociguat, used to \ntreat some forms of pulmonary hypertension (see Ch. 23).\nEffects of cGMP are terminated by phosphodiesterase \nenzymes. Sildenafil and tadalafil are inhibitors of phos-\nphodiesterase type V. They are used to treat erectile dysfunc -\ntion and work by potentiating NO actions in the corpora \ncavernosa of the penis by this mechanism (see Ch. 36). NO \nalso combines with haem groups in other biologically \nimportant proteins, notably cytochrome c oxidase, where it competes with oxygen, contributing to the control of \ncellular respiration (see Erusalimsky & Moncada, 2007).", "start_char_idx": 0, "end_char_idx": 3347, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "40d56eef-c52c-4f21-92ed-c8d8f2e677bc": {"__data__": {"id_": "40d56eef-c52c-4f21-92ed-c8d8f2e677bc", "embedding": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "93aa463c-e0ba-43fc-93a0-8d937e112bf3", "node_type": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "098f438970d7b60cb750116b3fa7429e99fb3a43f202226e8a2b82cd536947b9"}, "2": {"node_id": "d5afa1a4-3fa9-4f9a-87a3-30a66d2f11ee", "node_type": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea767f56e7e3903d6ce9d94516e22618773695a46a99a31fc1239cab774fa6b1"}, "3": {"node_id": "19d21ec3-3841-4c4a-af65-e983fbab3692", "node_type": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "802420256b38b3ae942260d3df6e3fd194e3f78d4d313bdf9f3f1bc69a98c29c"}}, "hash": "d12898d350b9351aaa85fa26592fa174c71a28bb2fb86202946543041517679c", "text": "control of \ncellular respiration (see Erusalimsky & Moncada, 2007). \nCytotoxic and/or cytoprotective effects of higher concentra -\ntions of NO relate to its chemistry as a free radical (see Ch. 41). Some physiological and pathological effects of NO are \nshown in Table 21.1.\nBIOCHEMICAL AND CELLULAR ASPECTS\nPharmacological effects of NO can be studied with NO gas \ndissolved in deoxygenated salt solution. More conveniently, \nbut less directly, various donors of NO, such as nitroprus-\nside, S-nitrosoacetylpenicillamine (SNAP) or S- nitrosoglutathione Low concentrations of NO are relatively stable in air, because the rate of reaction shown in Eq. 21.1 depends on the square \nof the NO concentration, so small amounts of NO produced \nin the lung escape degradation and can be detected in \nexhaled air. Exhaled NO is increased in patients with lung \ndiseases such as bronchitis, and is used as a biomarker of airway inflammation (Ch. 29). In contrast, NO reacts very rapidly with even low concentrations of superoxide anion \n(O\n2\u2212) to produce peroxynitrite anion (ONOO\u2212), which is \nresponsible for some of its toxic effects.\n\u25bc H aem has an affinity for NO >10,000 times greater than for oxygen. \nIn the absence of oxygen, NO bound to haem is relatively stable, but \nin the presence of oxygen NO is converted to nitrate and the haem \niron (Fe2+) oxidised to form methaemoglobin (Fe3+).\nEndothelium-derived NO acts locally on underlying vascular smooth muscle or on adherent monocytes or platelets. The internal elastic lamina of small arteries is a layer of elastic fibres between the endothelium \nand the smooth muscle, which represents a barrier to diffusion. It is \npenetrated by myoendothelial junctions where endothelial and smooth Nitric oxide: synthesis, inactivation \nand carriage \n\u2022\tNitric\toxide \t(NO) \tis \tsynthesised \tfrom \tL-arginine \tand \t\nmolecular O 2 by NO synthase (NOS).\n\u2022\tNOS\texists \tin \tthree \tisoforms: \tinducible \t(NOS2), \tand \t\nconstitutive \u2018endothelial\u2019 (NOS3, which is not restricted \nto endothelial cells) and neuronal (NOS1) forms. NOSs are dimeric flavoproteins, contain tetrahydrobiopterin \nand have homology with cytochrome P450. The \nconstitutive enzymes are activated by calcium\u2013calmodulin. Sensitivity to calcium\u2013calmodulin is controlled by phosphorylation of specific residues on \nthe enzymes.\n\u2022\tNOS2\tis \tinduced \tin \tmacrophages \tand \tother \tcells \tby \t\ninflammatory cytokines, especially interferon- \u03b3.\n\u2022\tNOS1\tis \tpresent \tin \tthe \tcentral \tnervous \tsystem \t(see \t\nChs 38\u201341) and in some autonomic nerves.\n\u2022\tNOS3\tis \tpresent \tin \tplatelets \tand \tother \tcells \tin \taddition \t\nto endothelium.\n\u2022\tNO\tdiffuses \tto \tsites \tof \taction \tin \tneighbouring \tcells. \t\nThis is regulated by the redox state of haemoglobin \nalpha which is present in the myoendothelial junctions that act as diffusion corridors across the internal \nelastic\tlamina \t(and \tin \tother \tcells): \tsignalling \tcan \toccur \t\nwhen the haem is in the Fe3+ state, but is stopped \n\u2013 like at a red traffic light \u2013 when haem is in the Fe2+ \nstate.\n\u2022\tNO\tis\tinactivated \tby \tcombination \twith \tthe \thaem \tof", "start_char_idx": 3289, "end_char_idx": 6387, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "19d21ec3-3841-4c4a-af65-e983fbab3692": {"__data__": {"id_": "19d21ec3-3841-4c4a-af65-e983fbab3692", "embedding": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "93aa463c-e0ba-43fc-93a0-8d937e112bf3", "node_type": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "098f438970d7b60cb750116b3fa7429e99fb3a43f202226e8a2b82cd536947b9"}, "2": {"node_id": "40d56eef-c52c-4f21-92ed-c8d8f2e677bc", "node_type": null, "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d12898d350b9351aaa85fa26592fa174c71a28bb2fb86202946543041517679c"}}, "hash": "802420256b38b3ae942260d3df6e3fd194e3f78d4d313bdf9f3f1bc69a98c29c", "text": "\tby \tcombination \twith \tthe \thaem \tof \t\nhaemoglobin or by oxidation to nitrite and nitrate, which are excreted in urine; it is also present in exhaled air, especially in patients with inflammatory \nlung diseases such as bronchitis.\n\u2022\tNO\tcan \treact \treversibly \twith \tcysteine \tresidues \t(e.g. \tin \t\nglobin or albumin) to form stable nitrosothiols; as a \nresult, red cells can act as an O 2-regulated source of \nNO. NO released in this way escapes inactivation by haem by being exported via cysteine residues in the \nanion exchange protein in red cell membranes.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6409, "end_char_idx": 7449, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8d9e67b4-ba5b-496e-9568-bb1fc127d52a": {"__data__": {"id_": "8d9e67b4-ba5b-496e-9568-bb1fc127d52a", "embedding": null, "metadata": {"page_label": "270", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c1784347-127a-488d-8348-de75e2a7de63", "node_type": null, "metadata": {"page_label": "270", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ff2284bf96b7909caee376c5fb9feb1260b445fd514561790712fe879a9feb5"}, "3": {"node_id": "0b60ad39-cfb0-40e2-b550-4725c0083455", "node_type": null, "metadata": {"page_label": "270", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3146cb9d5dc6a9b43cb70c41a3ebb9b0186a3cb287d17068d6ba21b2dbc82e6"}}, "hash": "d86bb77b9d199f467c6e828fec1b5a4cb0c6386cb230492e61e5a5d9467ba1ca", "text": "21 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n264vasodilatation that occurs during pregnancy. In addition \nto effects on basal resistance vessel tone and mediating the \neffects of endothelium-dependent vasodilator agonists such \nas acetylcholine and substance P, it has more recently been appreciated that NO promotes new vessel formation \n(\u2018angiogenesis\u2019) and vascular remodelling (Kraehling & \nSessa, 2017; Ghimire et al., 2017).\nNEURONAL EFFECTS (see also Ch. 13)\nNO is a non-noradrenergic non-cholinergic (NANC) \nneurotransmitter in many tissues (see Fig. 13.5), including \nthe upper airways, gastrointestinal tract and corpora \ncavernosa of the penis (Chs 29, 31 and 36). It is implicated in the control of neuronal development and of synaptic \nplasticity in the CNS (Chs 38 and 41). Mice carrying a \nmutation that disrupts the gene coding NOS1 have grossly distended stomachs similar to those seen in human hyper -\ntrophic pyloric stenosis (a disorder in which deficient NO production has been implicated, characterised by pyloric hypertrophy causing gastric outflow obstruction, which occurs in approximately 1 in 150 male infants and is cor -\nrected surgically). NOS1 knock-out mice resist stroke damage caused by middle cerebral artery ligation but are aggressive and oversexed (characteristics that may not be \nunambiguously disadvantageous, at least in the context of \nnatural selection!).\nHOST DEFENCE (see Ch. 7)\nCytotoxic and/or cytostatic effects of NO are implicated in primitive non-specific host defence mechanisms against \nnumerous pathogens, including viruses, bacteria, fungi, \nprotozoa and parasites, and against tumour cells. The importance of this is evidenced by the susceptibility of \nmice lacking NOS2 to Leishmania major (to which wild-type \nmice are highly resistant). Mechanisms whereby NO \ndamages invading pathogens include nitrosylation of nucleic \nacids and combination with haem-containing enzymes, \nincluding the mitochondrial enzymes involved in cell respiration.(SNOG), have been used as surrogates. This has pitfalls; for example, ascorbic acid potentiates SNAP but inhibits \nresponses to authentic NO.\n5\nNO can activate guanylyl cyclase in the same cells that \nproduce it, giving rise to autocrine effects, for example on the barrier function of the endothelium. NO also diffuses \nfrom its site of synthesis and activates guanylyl cyclase in neighbouring cells. The resulting increase in cGMP affects \nprotein kinase G, ion channels and possibly other proteins, \ninhibiting [Ca\n2+]i-induced smooth muscle contraction and \nplatelet aggregation. NO hyperpolarises vascular smooth \nmuscle as a consequence of potassium-channel activation, \nand inhibits monocyte adhesion and migration, adhesion and aggregation of platelets, and smooth muscle and \nfibroblast proliferation. These cellular effects probably \nunderlie the anti-atherosclerotic action of NO (see Ch. 24).\nLarge amounts of NO (released following induction of \nNOS or excessive stimulation of NMDA receptors in the brain, see Chs 40 and 41) cause cytotoxic effects, either directly or via formation of peroxynitrite. Such cytotoxicity contributes to host defence, but also to the neuronal cell \ndeath that occurs when there is overstimulation of NMDA \nreceptors by glutamate (see Chs 39 and 41). Paradoxically, NO is also cytoprotective under some circumstances (see Ch. 41).\nVASCULAR EFFECTS (see also Ch. 23)\nThe L-arginine/NO pathway is tonically active in resistance vessels, reducing", "start_char_idx": 0, "end_char_idx": 3477, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0b60ad39-cfb0-40e2-b550-4725c0083455": {"__data__": {"id_": "0b60ad39-cfb0-40e2-b550-4725c0083455", "embedding": null, "metadata": {"page_label": "270", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c1784347-127a-488d-8348-de75e2a7de63", "node_type": null, "metadata": {"page_label": "270", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ff2284bf96b7909caee376c5fb9feb1260b445fd514561790712fe879a9feb5"}, "2": {"node_id": "8d9e67b4-ba5b-496e-9568-bb1fc127d52a", "node_type": null, "metadata": {"page_label": "270", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d86bb77b9d199f467c6e828fec1b5a4cb0c6386cb230492e61e5a5d9467ba1ca"}}, "hash": "f3146cb9d5dc6a9b43cb70c41a3ebb9b0186a3cb287d17068d6ba21b2dbc82e6", "text": "pathway is tonically active in resistance vessels, reducing peripheral vascular resistance and hence \nsystemic blood pressure. Mutant mice that lack the gene \ncoding NOS3 are hypertensive, consistent with a role for NO biosynthesis in the physiological control of blood \npressure. In addition, NO derived from NOS1 is implicated \nin the control of basal resistance vessel tone in human \nforearm and cardiac muscle vascular beds (Seddon et al., \n2008, 2009). NO is believed to contribute to the generalised Table 21.1 Postulated roles of endogenous nitric oxide\nSystem Physiological rolePathological role\nExcess production Inadequate production or action\nCardiovascular\nEndothelium/vascular \nsmooth muscleControl of blood pressure and regional blood flowHypotension (septic shock) Atherogenesis, thrombosis (e.g. in hypercholesterolaemia, diabetes mellitus)\nPlatelets Limitation of adhesion/aggregation \u2014 \u2014\nHost defence\nMacrophages, \nneutrophils, leukocytesDefence against viruses, bacteria, fungi, protozoa, parasites\u2014 \u2014\nNervous system\nCentral Neurotransmission, long-term \npotentiation, plasticity (memory, appetite, nociception)Excitotoxicity (Ch. 41) (e.g. ischaemic stroke, Huntington's disease, AIDS, dementia)\u2014\nPeripheral Neurotransmission (e.g. gastric emptying, penile erection)\u2014 Hypertrophic pyloric stenosis, erectile dysfunction\n5Ascorbic acid releases NO from SNAP but accelerates NO degradation \nin solution, which could explain this divergence.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3418, "end_char_idx": 5357, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cff8110f-fc40-465a-a90c-390d34ae6c9c": {"__data__": {"id_": "cff8110f-fc40-465a-a90c-390d34ae6c9c", "embedding": null, "metadata": {"page_label": "271", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d0aca54a-e8bd-44ca-8884-405fd1af4ad1", "node_type": null, "metadata": {"page_label": "271", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "83080ada1a5f3d98fd1b53cd5eb2c871bf83fb7f581a23f383c56ae6f2bb1e43"}, "3": {"node_id": "64fba9ee-9450-443a-b380-d26a6c69b1e8", "node_type": null, "metadata": {"page_label": "271", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9d13ef6a79ad7c769d3f850da1a1c27c8c958672bac0627571e538c1a00d7eb"}}, "hash": "2acf4d87ab2fdb13440f5f81c969705ff966c9d4a9dc7cd1a724ab9c730d3814", "text": "21 NITRIC O x IDE AND RELATED MEDIATORS\n265than on platelets, whereas SNOG (see p. 264) selectively \ninhibits platelet aggregation. It was shown recently that \ndietary inorganic nitrate ions (contained in beetroot juice) \nacutely lower arterial blood pressure in parallel with a rise in plasma nitrite concentration and improved endothelial \nand platelet function. Interruption of the enterosalivary \nconversion of nitrate to nitrite prevents the rise in plasma nitrite, blocks the fall in blood pressure and abolishes the \ninhibitory effect on platelet aggregation (see review by \nLidder & Webb, 2013).\nINHIBITION OF NITRIC OXIDE SYNTHESIS\n\u25bc Drugs can i nhibit NO synthesis or action by several mechanisms. \nCertain arginine analogues compete with arginine for NOS. Several \nsuch compounds, for example, NG-monomethyl-L-arginine (L-NMMA) \nand NG-nitro-L-arginine methyl ester (L-NAME), have proved of great \nvalue as experimental tools. One such endogenous compound, ADMA \n(see earlier), is approximately equipotent with L-NMMA. It is present \nin human plasma and is excreted in urine. Its plasma concentration correlates with vascular mortality in patients receiving haemodialysis \nfor chronic renal failure, and is increased in people with hypercho -\nlesterolaemia, possibly via changes in gene expression rather than \ndirect inhibition (Caplin & Leiper, 2012). In addition to urinary \nexcretion, ADMA is also eliminated by metabolism to a mixture of \ncitrulline and methylamine by dimethylarginine dimethylamino hydrolase \n(DDAH), an enzyme that exists in two isoforms, each with a reactive cysteine residue in the active site that is subject to control by nitrosyla -\ntion. Inhibition of DDAH by NO causes feedback inhibition of the \nL-arginine/NO pathway by allowing cytoplasmic accumulation of \nADMA. Conversely, activation of DDAH could potentiate the L-arginine/NO pathway; see Fig. 21.4.\nInfusion of the non-selective NOS inhibitor L-NMMA into the brachial \nartery causes local vasoconstriction (Fig. 21.5), owing to inhibition \nof the basal production of NO in the infused arm, probably partly \nby inhibiting NOS1 in autonomic nerve fibres (Seddon et al., 2008). \nA contribution of NOS3-derived NO to basal vasodilator tone is also \npossible, since NOS3 knock-out mice are hypertensive, as mentioned \npreviously (p. 264). Intravenous L-NMMA causes vasoconstriction THERAPEUTIC ASPECTS\nNovel therapeutic approaches under investigation to \nincrease bioavailability of NO include new ways to increase \nNO synthase activity, ways to amplify the nitrate-nitrite-NO \npathway, novel classes of NO donors; drugs that limit NO inactivation by ROS; and ways to modulate phosphodies -\nterases and soluble guanylyl cyclases (reviewed by Lundberg \net al. 2015).\nNITRIC OXIDE\nInhaling high concentrations of NO (as occurred when cylinders of nitrous oxide, N\n2O, for anaesthesia were \naccidentally contaminated) causes acute pulmonary oedema \nand methaemoglobinaemia, but concentrations below \n50 ppm (parts per million) are not toxic. NO (5\u2013300 ppm) \ninhibits bronchoconstriction (at least in guinea pigs), but \nthe main action of low concentrations of inhaled NO in \nman is pulmonary vasodilatation. Inspired NO acts pref -\nerentially on ventilated alveoli, and is used therapeutically \nin", "start_char_idx": 0, "end_char_idx": 3296, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "64fba9ee-9450-443a-b380-d26a6c69b1e8": {"__data__": {"id_": "64fba9ee-9450-443a-b380-d26a6c69b1e8", "embedding": null, "metadata": {"page_label": "271", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d0aca54a-e8bd-44ca-8884-405fd1af4ad1", "node_type": null, "metadata": {"page_label": "271", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "83080ada1a5f3d98fd1b53cd5eb2c871bf83fb7f581a23f383c56ae6f2bb1e43"}, "2": {"node_id": "cff8110f-fc40-465a-a90c-390d34ae6c9c", "node_type": null, "metadata": {"page_label": "271", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2acf4d87ab2fdb13440f5f81c969705ff966c9d4a9dc7cd1a724ab9c730d3814"}}, "hash": "c9d13ef6a79ad7c769d3f850da1a1c27c8c958672bac0627571e538c1a00d7eb", "text": "-\nerentially on ventilated alveoli, and is used therapeutically \nin respiratory distress syndrome, including acute hypoxic \nrespiratory failure in newborn babies for which NO has \nbeen approved by the FDA. This is characterised by intrapulmonary \u2018shunting\u2019, that is, pulmonary arterial blood \npassing through non-ventilated alveoli and remaining \ndeoxygenated. This causes arterial hypoxaemia, and, because hypoxaemia causes pulmonary arterial vasoconstriction, acute pulmonary arterial hypertension. Inhaled NO dilates \nblood vessels in ventilated alveoli (which are exposed to \nthe inspired gas) and thus reduces shunting. NO is used in intensive care units to reduce pulmonary hypertension \nand to improve oxygen delivery in patients with respiratory \ndistress syndrome, but it is not known whether this improves long-term survival in these severely ill patients.\nNITRIC OXIDE DONORS/PRECURSORS\nNitrovasodilators have been used therapeutically for over a century. The common mode of action of these drugs is \nas a source of NO (Chs 22 and 23). There is interest in the \npotential for selectivity of nitrovasodilators; for instance, glyceryl trinitrate is more potent on vascular smooth muscle R\nR\nRR\nR\nRR\nADMA\nNOSDDAHMethylated arginine\nresidues in cell protein\nProteolysis\nCitrulline\nNO + CitrullineL-arginine\n+\nO2(CH3)2\nFig. 21.4 Control of NO synthesis by asymmetric \ndimethylarginine (ADMA). DDAH, dimethylarginine \ndimethylamino hydrolase; NO, nitric oxide; NOS, nitric oxide \nsynthase. Actions of nitric oxide \n\u2022\tNitric\toxide \t(NO) \tacts \tby:\n\u2013 combining with haem in guanylyl cyclase, activating \nthe enzyme, increasing cGMP and thereby lowering \n[Ca2+]I;\n\u2013 combining with haem groups in other proteins (e.g. \ncytochrome C oxidase);\n\u2013 combining with superoxide anion to yield the \ncytotoxic peroxynitrite anion;\n\u2013 nitrosation of proteins, lipids and nucleic acids.\n\u2022\tEffects\tof \tNO \tinclude:\n\u2013 vasodilatation, inhibition of platelet and monocyte \nadhesion and aggregation, inhibition of smooth muscle proliferation, protection against atheroma, vascular remodelling and angiogenesis;\n\u2013 synaptic effects in the peripheral and central nervous \nsystem;\n\u2013 host defence and cytotoxic effects on pathogens;\n\u2013 cytoprotection.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3229, "end_char_idx": 5938, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "58ddaee7-d5d5-4201-8a3d-e80d3a30432e": {"__data__": {"id_": "58ddaee7-d5d5-4201-8a3d-e80d3a30432e", "embedding": null, "metadata": {"page_label": "272", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f480beaf-4895-44ab-a422-6dd3a9a90b03", "node_type": null, "metadata": {"page_label": "272", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d753a0def9ca152d4a61a7e42178ead4018c70ccb599edc01090689c8952a0b8"}, "3": {"node_id": "fc9d41ec-8a68-4782-b2f9-ad5902ad0ec7", "node_type": null, "metadata": {"page_label": "272", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f192a964f97759eaa899b3719a83151d73352c220b1d9cb34885b447dc65a9af"}}, "hash": "6f9dcebd91169c4899553bebfe44a9f159692aabcf7e3ac32f4e92d20f0973e9", "text": "21 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n266on existing drugs of proven value in other contexts. The \nhope (as yet unproven) is that, by potentiating NO, they \nwill prevent atherosclerosis or its thrombotic complications \nor have other beneficial effects attributed to NO. Possibilities \ninclude:\n\u2022\tselective \tNO \tdonors \tas \t\u2018replacement\u2019 \ttherapy \t(see \t\nclinical box, p. 267) or to protect against unwanted aspects of the action of another drug (e.g. naproxinod, \nCh. 27);\n\u2022\tdietary \tsupplementation \twith \tL-arginine \tor \tinorganic \t\nnitrate (see clinical box, p. 267);\n\u2022\tantioxidants \t(to \treduce \tconcentrations \tof \tROS \tand \t\nhence stabilise NO and reduce toxic reaction products; \nCh. 23);\n\u2022\tdrugs\tthat \trestore \tendothelial \tfunction \tin \tpatients \twith \t\nmetabolic risk factors for vascular disease (e.g. angiotensin-converting enzyme inhibitors, statins, \ninsulin, oestrogens; Chs 23, 24, 32 and 36);\n\u2022\t\u03b2\n2-adrenoceptor agonists and related drugs (e.g. \nnebivolol, a \u03b2 1-adrenoceptor antagonist that is \nmetabolised to an active metabolite that potentiates the L-arginine/NO pathway);\n\u2022\tphosphodiesterase \ttype \tV \tinhibitors \t(e.g. \tsildenafil; \nsee clinical box, p. 267 and Ch. 36).\nCLINICAL CONDITIONS IN WHICH NITRIC \nOXIDE MAY PLAY A PART\nThe wide distribution of NOS enzymes and diverse actions \nof NO suggest that abnormalities in the L-arginine/NO \npathway could be important in disease. Either increased \nor reduced production could play a part, and hypotheses abound. Evidence is harder to come by but has been sought \nusing various indirect approaches, including:\n\u2022\tAnalysing \tnitrate \tand/or \tcGMP \tin \turine: \tthese \tstudies \t\nare bedevilled, respectively, by dietary nitrate and by \ncGMP produced by membrane-bound guanylyl \ncyclase (which is stimulated by endogenous natriuretic \npeptides independently of NO; see Ch. 22).\n\u2022\tA\trefinement \tis \tto \tadminister \t[15N]-arginine and use \nmass spectrometry to measure the enrichment of 15N \nover naturally abundant [14N]-nitrate in urine.\n\u2022\tMeasuring \tNO \tin \texhaled \tair.\n\u2022\tMeasuring \teffects \tof \tNOS \tinhibitors \t(e.g. \tL-NMMA),\n\u2022\tComparing \tresponses \tto \tendothelium-dependent \t\nagonists (e.g. acetylcholine) and endothelium-independent agonists that act by \nproviding NO (e.g. nitroprusside).\n\u2022\tMeasuring \tresponses \tto \tincreased \tblood \tflow \t\n(\u2018flow-mediated dilatation\u2019), which are largely \nmediated by NO.\n\u2022\tComparing \tin \tvitro \tresponses \tto \tpharmacological \t\nprobes of tissue obtained at operation (e.g. coronary artery surgery) with histochemical data from the \ntissue (e.g. anatomical distribution of NOS isoforms).\nAll these methods have limitations, and the dust is far from \nsettled. Nevertheless, it seems clear that the L-arginine/\nNO pathway is indeed a player in the pathogenesis of \nseveral important diseases, opening the way to new thera -\npeutic approaches. Some pathological roles of excessive or \nreduced NO production are summarised in Table 21.1. We \ntouch only briefly on these clinical conditions, and would in renal, mesenteric,", "start_char_idx": 0, "end_char_idx": 3029, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fc9d41ec-8a68-4782-b2f9-ad5902ad0ec7": {"__data__": {"id_": "fc9d41ec-8a68-4782-b2f9-ad5902ad0ec7", "embedding": null, "metadata": {"page_label": "272", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f480beaf-4895-44ab-a422-6dd3a9a90b03", "node_type": null, "metadata": {"page_label": "272", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d753a0def9ca152d4a61a7e42178ead4018c70ccb599edc01090689c8952a0b8"}, "2": {"node_id": "58ddaee7-d5d5-4201-8a3d-e80d3a30432e", "node_type": null, "metadata": {"page_label": "272", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f9dcebd91169c4899553bebfe44a9f159692aabcf7e3ac32f4e92d20f0973e9"}}, "hash": "f192a964f97759eaa899b3719a83151d73352c220b1d9cb34885b447dc65a9af", "text": "only briefly on these clinical conditions, and would in renal, mesenteric, cerebral and striated muscle resistance vessels, \nincreases blood pressure and causes reflex bradycardia.\nThere is therapeutic interest in selective inhibitors of different isoforms \nof NOS. Selective inhibitors of NOS2 versus the constitutive enzymes have been described (e.g. N-iminoethyl-l-lysine), and have potential \nfor the treatment of inflammatory and other conditions in which NOS2 has been implicated (e.g. asthma). 7-Nitroindazole selectively inhibits NOS1, the mechanism of selectivity being uncertain. S-methyl-\nL-thiocitrulline is a potent and selective inhibitor of human NOS1 \n(Furfine et al., 1994), and has recently provided new understanding \nof the importance of NOS1 in control of human resistance vessel tone \nin vivo as mentioned earlier.405060708090100110\n0 20 40 60 80 100\nMinutes after cannulationForearm blood flow (% of control)D-NMA L-NMA\nL-Arg\nFig. 21.5 Basal blood flow in the human forearm is \ninfluenced by nitric oxide (NO) biosynthesis. Forearm blood \nflow is expressed as a percentage of the flow in the non-\ncannulated control arm (which does not change). Brachial artery infusion of the D-isomer of the arginine analogue N\nG-\nmonomethyl-L-arginine (D-NMA) has no effect, while the L-isomer (L-NMA) causes vasoconstriction. L-Arginine (L-Arg) accelerates recovery from such vasoconstriction (dashed line). \n(From Vallance, P., Bhagat, K., MacAllister, R. et al., 1989. \nLancet ii, 997\u20131000.)\nInhibition of the L-arginine/nitric \noxide pathway \n\u2022\tGlucocorticoids \tinhibit \tbiosynthesis \tof \tnitric \toxide \t\nsynthase 2 (NOS2).\n\u2022\tSynthetic \targinine \tand \tcitrulline \tanalogues \t(e.g. \t\nL-NMMA, L-NAME; see text) compete with arginine \nand are useful experimental tools. Isoform-selective inhibitors include S-methyl-L-thiocitrulline (selective for \nNOS1).\n\u2022\tADMA\t(asymmetric \tdimethylarginine) \tis \tan \tendogenous \t\ninhibitor of NOS.\nNITRIC OXIDE REPLACEMENT OR POTENTIATION\nSeveral means whereby the L-arginine/NO pathway could \nbe enhanced are under investigation. Some of these rely mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2955, "end_char_idx": 5534, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c81736b7-f2c3-48e6-918f-f0e0b14d2842": {"__data__": {"id_": "c81736b7-f2c3-48e6-918f-f0e0b14d2842", "embedding": null, "metadata": {"page_label": "273", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "717887a0-3f1f-4590-af1c-d188db215b32", "node_type": null, "metadata": {"page_label": "273", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "214098459f9a03b8094a479c0056ee5f367149511a866c82aa304ffd68d7fb47"}, "3": {"node_id": "279feb6a-1486-48db-8fae-b01adb80e5cc", "node_type": null, "metadata": {"page_label": "273", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8bae53ac2faf32a2587a91b255de319841c4f68567b5c0196934e427706fdb6d"}}, "hash": "805f887b483575207f234ae34c9af0e9acc160d962a58165c916559459850367", "text": "21 NITRIC O x IDE AND RELATED MEDIATORS\n267RELATED MEDIATORS\nNO, promoted from pollutant to \u2018molecule of the year\u2019,6 \nwas joined, similarly implausibly, by carbon monoxide (CO) \n\u2013 a potentially lethal exhaust gas \u2013 and by hydrogen sulfide Sepsis can cause multiple organ failure. Whereas NO benefits \nhost defence by killing invading organisms, excessive NO causes harmful hypotension. Disappointingly, however, \nL-NMMA worsens survival in sepsis.\nChronic low-grade endotoxaemia occurs in patients with \nhepatic cirrhosis. Systemic vasodilatation is typical in such patients. Urinary excretion of cGMP is increased, and it is plausible (but unproven) that vasodilatation is a conse-\nquence of induction of NOS leading to increased NO \nsynthesis.\nNitrosative stress (see earlier, p. 260) and nitration of \nproteins in airway epithelium are believed to contribute to steroid resistance in asthma, and the ineffectiveness of \nglucocorticoids in chronic obstructive pulmonary disease (see Ch. 29).\nNO biosynthesis is reduced in patients with hypercholes-\nterolaemia and some other precursors of atheromatous disease, including cigarette smoking and diabetes mellitus. \nIn hypercholesterolaemia, evidence of blunted NO release \nin forearm and coronary vascular beds is supported by evidence that this can be corrected by lowering plasma \ncholesterol with a statin (see Ch. 25).\nEndothelial dysfunction in individuals (e.g. diabetic \npatients) with erectile dysfunction occurs in tissue from \nthe corpora cavernosum of the penis, as evidenced by \nblunted relaxation to acetylcholine despite preserved responses to nitroprusside (Fig. 21.6). Vasoconstrictor \nresponses to intra-arterial L-NMMA are reduced in forearm \nvasculature of insulin-dependent diabetics, especially in patients with traces of albumin in their urine (\u2018microal -\nbuminuria\u2019 \u2013 early evidence of glomerular endothelial \ndysfunction).\nIt is thought that failure to increase endogenous NO \nbiosynthesis during pregnancy contributes to eclampsia. \nThis is a hypertensive disorder that accounts for many \nmaternal deaths and in which the normal vasodilatation seen in healthy pregnancy fails to manifest itself.\nExcessive NMDA receptor activation increases NO \nsynthesis, contributing to consequent neurological damage (see Ch. 41).\nNOS1 is absent in pyloric tissue from babies with idio -\npathic hypertrophic pyloric stenosis.\nEstablished clinical uses of drugs that influence the \nL-arginine/NO system are summarised in the clinical box.Nitric oxide in pathophysiology \n\u2022\tNitric\toxide \t(NO) \tis \tsynthesised \tunder \tphysiological \t\nand pathological circumstances.\n\u2022\tEither\treduced \tor \tincreased \tNO \tproduction \tcan \t\ncontribute to disease.\n\u2022\tUnderproduction \tof \tneuronal \tNO \tis \treported \tin \tbabies \t\nwith hypertrophic pyloric stenosis. Endothelial NO \nproduction is reduced in patients with hypercholesterolaemia and some other risk factors for \natherosclerosis, and this may contribute to \natherogenesis.\n\u2022\tOverproduction \tof \tNO \tmay \tbe \timportant \tin \t\nneurodegenerative diseases (see Ch. 41) and in septic shock (Ch. 23).Diabetic\nNon-diabetic\n1009080706050403020100\n\u22124 \u22125 \u22126 \u22127 \u22128 \u22129 \nAcetylcholine concentration (log mol/L)Percent of maximal relaxation\nFig. 21.6 Impaired endothelium-mediated relaxation of", "start_char_idx": 0, "end_char_idx": 3287, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "279feb6a-1486-48db-8fae-b01adb80e5cc": {"__data__": {"id_": "279feb6a-1486-48db-8fae-b01adb80e5cc", "embedding": null, "metadata": {"page_label": "273", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "717887a0-3f1f-4590-af1c-d188db215b32", "node_type": null, "metadata": {"page_label": "273", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "214098459f9a03b8094a479c0056ee5f367149511a866c82aa304ffd68d7fb47"}, "2": {"node_id": "c81736b7-f2c3-48e6-918f-f0e0b14d2842", "node_type": null, "metadata": {"page_label": "273", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "805f887b483575207f234ae34c9af0e9acc160d962a58165c916559459850367"}}, "hash": "8bae53ac2faf32a2587a91b255de319841c4f68567b5c0196934e427706fdb6d", "text": "21.6 Impaired endothelium-mediated relaxation of \npenile smooth muscle from diabetic men with erectile \ndysfunction. Mean ( \u00b1SE) relaxation responses to acetylcholine \nin corpora cavernosa tissue (obtained at the time of performing surgical implants to treat impotence) from 16 diabetic men and 22 non-diabetic subjects. (Data from Saenz de Tejada, I., \nCarson, M.P., de las Morenas, A. et al., 1989. N. Engl. J. Med. \n320, 1025\u20131030.)caution the reader that not all of these exciting possibilities \nare likely to withstand the test of time!\nNitric oxide in therapeutics \n\u2022\tNitric\toxide \t(NO) \tdonors \t(e.g. \tnitroprusside and \norganic nitrovasodilators) are well established (see Chs \n22 and 23).\n\u2022\tType\tV\tphosphodiesterase \tinhibitors \t(e.g. \tsildenafil, \ntadalafil) potentiate the action of NO. They are used \nto treat erectile dysfunction (Ch. 36).\n\u2022\tOther\tpossible \tindications \t(e.g. \tpulmonary \t\nhypertension, gastric stasis) are being investigated.\n\u2022\tInhaled\tNO \tis \tused \tin \tintensive \tcare \tof \tadult \tand \t\nneonatal respiratory distress syndrome.\n\u2022\tInhibition \tof \tNO \tbiosynthesis \tis \tbeing \tinvestigated \tin \t\ndisorders where there is overproduction of NO (e.g. inflammation and neurodegenerative disease). Disappointingly, N\nG-monomethyl-L-arginine \n(L-NMMA) increases mortality in one such condition (sepsis).\n6By the American Association for the Advancement of Science in 1992.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3238, "end_char_idx": 5114, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0ebc1a54-33b3-456b-915c-16c71081aa31": {"__data__": {"id_": "0ebc1a54-33b3-456b-915c-16c71081aa31", "embedding": null, "metadata": {"page_label": "274", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0df4b4e8-3bab-4d7a-b235-a392e6b6a045", "node_type": null, "metadata": {"page_label": "274", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b6b247295ef843bc1a95e6baf31c18ec5fa1d562ca6adfc212a6b62d53cece8d"}, "3": {"node_id": "2831c48f-ed44-43df-9eae-1214bcfa33af", "node_type": null, "metadata": {"page_label": "274", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "588841bf5fdde3728b28b7ab361fdfb48e1446d4f0ac45388e4c618a532ee1f3"}}, "hash": "71f0fe8106e7c89539dc1d6ada71447e0da11024aea8ad9f35baff00a16b7507", "text": "21 SECTION 2\u2003\u2003 CHEMICAL MEDIATORS\n268mediator was met with some scepticism. Its toxicology includes actions \non enzymes including monoamine oxidase and carbonic anhydrase, \nbut more recent work has demonstrated a diverse pharmacology \nconsistent with functions as a signalling molecule under physiological conditions.\nEndogenous H\n2S is produced from l-cysteine by cystathionine \u03b3-lyase \n(also known as cystathionase or CSE) and cystathionine \u03b2-synthase \n(CBS). Large amounts of CBS occur in mammalian brain (especially \nhippocampus and cerebellar Purkinje cells), whereas CSE activity is greatest in liver, kidney and media of blood vessels. These enzymes \nare regulated by lipopolysaccharide and by tumour necrosis factor \n\u03b1 (TNF- \u03b1) and their expression is altered in pancreatitis and diabetes. \nPharmacological inhibitors of H\n2S synthesis are so far only of modest \npotency and specificity and have been of limited use in elucidating \nits physiological role. Several assays of H 2S in biological fluids grossly \noverestimate the true concentrations. Measuring thiosulfate excretion (see Fig. 21.7) may represent a better analytical approach than plasma \nsulfide to estimating overall turnover of H\n2S; sulfite and sulfate (to \nwhich thiosulfate is converted) are not satisfactory, as their production \nfrom other sources of sulfur swamps the contribution of H 2S.\nPharmacological effects and therapeutic potential. H2S \nhas potent pharmacological effects in the cardiovascular \nsystem, including vasorelaxation secondary to activation \nof vascular smooth muscle K ATP channels (see Ch. 4). It also \nacts on the nervous system and influences nociception, \nselectively modulating voltage dependent T-type Ca2+ \nchannels (Elies et al., 2016). It also influences inflammatory \nprocesses. For a review of the effects of H 2S on ion channels \nand intracellular transduction systems see Li et al., 2011. Endocrine effects include inhibition of glucose-stimulated \ninsulin secretion; actions on K\nATP channels may be important \nhere also (see Ch. 32). One of the most striking effects of (H 2S), which are also formed in mammalian tissues. There \nare striking similarities between these three gases, as well \nas some contrasts. All three are highly diffusible labile \nmolecules that are rapidly eliminated from the body: NO as nitrite and nitrate in urine as well as NO in exhaled air \n(see pp. 262\u2013263); CO in exhaled air; H\n2S as thiosulfate, \nsulfite and sulfate in urine (Fig. 21.7) as well as in exhaled breath. All three react with haemoglobin, and all three affect \ncellular energetics via actions on cytochrome C oxidase. All have vasodilator effects (although chronic exposure to \nCO can cause vasoconstriction), and all have anti-inflam-\nmatory and cytoprotective effects at low concentrations but cause cellular injury at higher concentrations.\nCARBON \u2003MONOXIDE \u2003(CO)\n\u25bc CO is synthesised, together with biliverdin, by inducible and/or \nconstitutive forms of haem oxygenase, and has been implicated as a \nsignalling molecule in the cardiovascular and central nervous systems \n(especially olfactory pathways) and in controlling respiratory, \ngastrointestinal, endocrine and reproductive functions (see Wu & Wang, 2005). There is evidence that prostanoid-induced cerebral \nvasodilatation is mediated by CO, and that CO also interacts with \nNO in modulating cerebral vascular tone (Leffler et al., 2011). There \nare as yet no therapeutic drugs acting via this pathway, but CO", "start_char_idx": 0, "end_char_idx": 3484, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2831c48f-ed44-43df-9eae-1214bcfa33af": {"__data__": {"id_": "2831c48f-ed44-43df-9eae-1214bcfa33af", "embedding": null, "metadata": {"page_label": "274", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0df4b4e8-3bab-4d7a-b235-a392e6b6a045", "node_type": null, "metadata": {"page_label": "274", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b6b247295ef843bc1a95e6baf31c18ec5fa1d562ca6adfc212a6b62d53cece8d"}, "2": {"node_id": "0ebc1a54-33b3-456b-915c-16c71081aa31", "node_type": null, "metadata": {"page_label": "274", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "71f0fe8106e7c89539dc1d6ada71447e0da11024aea8ad9f35baff00a16b7507"}}, "hash": "588841bf5fdde3728b28b7ab361fdfb48e1446d4f0ac45388e4c618a532ee1f3", "text": "There \nare as yet no therapeutic drugs acting via this pathway, but CO \n(perhaps surprisingly for a gas associated with lethal effects in a \ndomestic setting) has potentially beneficial effects on cell survival \nand CO-releasing molecules are under investigation (Motterlini & Foresti, 2017).\nHYDROGEN \u2003SULFIDE \u2003(H2S)\n\u25bc H2S has been known to generations of schoolboys as the source \nof the odour of rotten eggs and the proposal that it too is a gaseous Haemoglobin\nCytochrome C oxidaseK\nATP channels\nMonoamine oxidaseCarbonic anhydrase\nExhaled H\n2S\nOther pathwaysMethionine Homocysteine\n+\nL-serine CBS\nCSE\nCSE\nCBSCystathionine\nL-cysteine\nThiosulfate\nSulfite\nSulfateH2SH S\u2013 + H+Sulfide salts;\nother sulfide\nderivatives\nFig. 21.7 Synthesis, sites of action and disposition of H 2S. Endogenous biosynthesis from sulfur-containing amino acids (methionine, \ncycteine) via actions of the regulated enzymes methionine cystathionine \u03b3-lyase (CSE) and cystathionine \u03b2-synthase (CBS) is shown; \npharmacological H 2S donors (red-rimmed box) may be administered exogenously. Most H 2S is probably renally excreted as sulfate (yellow \nbox). Some is eliminated in exhaled air (green box) . Some molecular targets of H 2S are indicated in the blue box. (Adapted with permission \nfrom\tRitter, \tJ.M., \t2010. \tHuman \tpharmacology \tof \thydrogen \tsulfide: \tputative \tgaseous \tmediator. \tBr. \tJ. \tClin. \tPharmacol. \t69, \t573\u2013575.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3414, "end_char_idx": 5303, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "56fbf341-b84d-43c8-8f35-60f849a7da4c": {"__data__": {"id_": "56fbf341-b84d-43c8-8f35-60f849a7da4c", "embedding": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d9d5661d-0a9e-4e66-8c62-3bc58315541d", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6d6702aa198386d59660ffbd6675b8fc6c96aedf6dd82b768453d132a245c137"}, "3": {"node_id": "2b6ad75c-5fdc-434a-ab59-141da865c8d0", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53432d9e69839fa1e44c4eb0cea23691485f10c3c1635c78d857573896c7c6d9"}}, "hash": "965dbff01fadec0a80fd32ec71ee5c9ace54d85392f56b008742f2452b67d0aa", "text": "21 NITRIC O x IDE AND RELATED MEDIATORS\n269as diverse as pulmonary vasoconstriction, ischaemic heart \ndisease, pulmonary fibrosis and stroke. The results have \nbeen sufficiently encouraging to provide a rationale for \nstudying H 2S donors in man. Several sulfide-releasing \nderivatives based on naproxen, diclofenac (Ch. 27) and \non mesalazine (Ch. 31), as well as inorganic sodium sulfide, \nare under investigation as potential therapeutic agents. Again, a case of \u2018watch this space\u2019.H\n2S is to induce a state of suspended animation and \nhypothermia, described first in nematode worms, but then \nalso in rodents. Subsequently, a whole range of cytotoxic \n(high concentration) and cytoprotective (low concentration) effects of H\n2S and H 2S donors have been described in a \nwide variety of cell types in many different tissues (reviewed \nby Szabo, 2007). These findings provided a rationale for \nstudies of effects of H 2S donors in animal models of diseases \nREFERENCES AND FURTHER READING\nBiochemical aspects\nDerbyshire, E.R., Marletta, M.A., 2012. Structure and regulation of \nsoluble guanylate cyclase. Annu. Rev. Biochem. 81, 533\u2013559. \n(Summarises sGC structure and regulation)\nFurfine, E.S., Harmon, M.F., Paith, J.E., et al., 1994. Potent and selective \ninhibition of human nitric oxide synthases: selective inhibition of \nneuronal nitric oxide synthase by S-methyl-L-thiocitrulline and \nS-ethyl-L-thiocitrulline. J. Biol. Chem. 269, 26677\u201326683.\nHill, B.G., Dranka, B.P., Shannon, M., et al., 2010. What part of NO \ndon\u2019t you understand? Some answers to the cardinal questions in nitric oxide biology. J. Biol. Chem. 285, 19699\u201319704. (Biochemistry of \nNO in a biological context)\nKim-Shapiro, D.B., Schechter, A.N., Gladwin, M.T., 2006. Unraveling the \nreactions of nitric oxide, nitrite, and hemoglobin in physiology and therapeutics. Arterioscler. Thromb. Vasc. Biol. 26, 697\u2013705. (Reviews \nevidence that nitrite anion may be the main intravascular NO storage molecule; cf. Singel & Stamler, 2005)\nMatsubara, M., Hayashi, N., Jing, T., Titani, K., 2003. Regulation of \nendothelial nitric oxide synthase by protein kinase C. J. Biochem. 133, 773\u2013781. (Protein kinase C inhibits NOS3 activity by altering the affinity of \ncalmodulin for the enzyme)\nPawloski, J.R., Hess, D.T., Stamler, J.S., 2001. Export by red cells of nitric \noxide bioactivity. Nature 409, 622\u2013626. (Movement of NO from red blood cells via anion exchange protein AE1; see also editorial by Gross, S.S., pp. \n577\u2013578)\nRibiero, J.M.C., Hazzard, J.M.H., Nussenzveig, R.H., et al., 1993. \nReversible binding of nitric oxide by a salivary haem protein from a blood sucking insect. Science 260, 539\u2013541. (Action at a distance)\nShaul, P.W., 2002. Regulation of endothelial nitric oxide synthase: \nlocation, location, location. Annu. Rev. Physiol. 64, 749\u2013774.\nZhang, R., Hess, D.T., Reynolds, J.D., Stamler, J.S., 2015. Hemoglobin", "start_char_idx": 0, "end_char_idx": 2910, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2b6ad75c-5fdc-434a-ab59-141da865c8d0": {"__data__": {"id_": "2b6ad75c-5fdc-434a-ab59-141da865c8d0", "embedding": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d9d5661d-0a9e-4e66-8c62-3bc58315541d", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6d6702aa198386d59660ffbd6675b8fc6c96aedf6dd82b768453d132a245c137"}, "2": {"node_id": "56fbf341-b84d-43c8-8f35-60f849a7da4c", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "965dbff01fadec0a80fd32ec71ee5c9ace54d85392f56b008742f2452b67d0aa"}, "3": {"node_id": "74d5fb38-ccba-418a-a638-8988ad5a2da1", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "509ff10350c970b0802e042fe8d64d13952b3a18e4bccd0ea72ff339747a74ff"}}, "hash": "53432d9e69839fa1e44c4eb0cea23691485f10c3c1635c78d857573896c7c6d9", "text": "J.D., Stamler, J.S., 2015. Hemoglobin \nS-nitrosylation plays and essential role in cardioprotection. J. Clin. Invest. 126, 4654\u20134658. (Cardiac injury and mortality were substantially increased in models of myocardial infarction and heart failure in mice lacking \n\u03b2-cys93 S-nitrosylation. See also accompanying commentary on the \ncardioprotective role of S-nitrosylated haemoglobin from red blood cells aby Piantadosi C.A. pp. 4402\u20134403)\nPhysiological aspects\nCoggins, M.P., Bloch, K.D., 2007. Nitric oxide in the pulmonary \nvasculature. Arterioscler. Thromb. Vasc. Biol. 27, 1877\u20131885.\nDiesen, D.L., Hess, D.T., Stamler, J.S., 2008. Hypoxic vasodilation by red \nblood cells evidence for an S-nitrosothiol-based signal. Circ. Res. 103, \n545\u2013553. (An S-nitrosothiol originating from RBCs mediates hypoxic \nvasodilatation by RBCs)\nErusalimsky, J.D., Moncada, S., 2007. Nitric oxide and mitochondrial \nsignalling from physiology to pathophysiology. Arterioscler. Thromb. Vasc. Biol. 27, 2524\u20132531. (Reviews the evidence that binding of NO to \ncytochrome c oxidase elicits intracellular signalling events)\nFurchgott, R.F., Zawadzki, J.V., 1980. The obligatory role of endothelial \ncells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288, 3734ess reClassic.\nGarthwaite, J., 2008. Concepts of neural nitric oxide-mediated \ntransmission. Eur. J. Neurosci. 27, 2783\u20132802. (Diverse ways in which NO receptor activation initiates changes in neuronal excitability and synaptic strength by acting at pre- and/or postsynaptic locations)\nGhimire, K., et al., 2017. Nitric oxide: what\u2019s new to NO? Am. J. \nPhysiol. Cell Physiol. 312, C254\u2013C262. (Wide-ranging discussion including vessel wall remodeling. \u201cIn microvessels and particularly \ncapillaries, NO, along with growth factors, is important in promoting new \nvessel formation, a process termed angiogenesis.\u201d)\nKraehling, J.R., Sessa, W.C., 2017. Contemporary approaches to \nmodulating the nitric oxide-cGMP pathway in cardiovascular disease. Circ. Res. 120, 1174\u20131182. (Discusses remodeling of blood vessels and approaches to improve endothelial NO generation and bioavailability. Also discusses therapeutic opportunities aimed at activation of soluble guanylate \ncyclase)\nNelson, R.J., Demas, G.E., Huang, P.L., et al., 1995. Behavioural \nabnormalities in male mice lacking neuronal nitric oxide synthase. \nNature 378, 383\u2013386. (\u2018A large increase in aggressive behaviour and excess, \ninappropriate sexual behaviour in nNOS knock-out mice\u2019)\nSeddon, M.D., Chowienczyk, P.J., Brett, S.E., et al., 2008. Neuronal nitric \noxide synthase regulates basal microvascular tone in humans in vivo . \nCirculation 117, 1991\u20131996. (Paradigm shift? \u2013 very possibly; see next reference)\nSeddon, M., Melikian, N., Dworakowski, R., et al., 2009. Effects of \nneuronal nitric oxide synthase on human coronary artery diameter \nand blood flow in vivo . Circulation 119, 2656\u20132662. (Local \nnNOS-derived NO regulates basal blood flow in the human coronary \nvascular bed, whereas substance", "start_char_idx": 2878, "end_char_idx": 5908, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "74d5fb38-ccba-418a-a638-8988ad5a2da1": {"__data__": {"id_": "74d5fb38-ccba-418a-a638-8988ad5a2da1", "embedding": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d9d5661d-0a9e-4e66-8c62-3bc58315541d", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6d6702aa198386d59660ffbd6675b8fc6c96aedf6dd82b768453d132a245c137"}, "2": {"node_id": "2b6ad75c-5fdc-434a-ab59-141da865c8d0", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53432d9e69839fa1e44c4eb0cea23691485f10c3c1635c78d857573896c7c6d9"}, "3": {"node_id": "bfb74446-5a60-446c-ab35-1808c1431451", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6d1dadb586eb8ef320f2b1a2b45de8ec22771063cb3fdbe301ff2639c17ecab1"}}, "hash": "509ff10350c970b0802e042fe8d64d13952b3a18e4bccd0ea72ff339747a74ff", "text": "basal blood flow in the human coronary \nvascular bed, whereas substance P-stimulated vasodilatation is NOS3 \nmediated)\nStraub, A.C., Lohman, A.W., Billaud, M., et al., 2012. Endothelial cell \nexpression of haemoglobin \u03b1 regulates nitric oxide signalling. Nature 491, 473\u2013477. (See also accompanying editorial Gladwyn, M.T., \nKim-Shapiro, D.B., 2012. Nitric oxide caught in traffic. Nature 491, \n344\u2013345)\nToda, N., Okamura, T., 2003. The pharmacology of nitric oxide in the \nperipheral nervous system of blood vessels. Pharmacol. Rev. 55, 271\u2013324.\nVallance, P., Leiper, J., 2004. Cardiovascular biology of the asymmetric \ndimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler. Thromb. Vasc. Biol. 24, 1023\u20131030.\nVictor, V.M., N\u00fa\u00f1ez, C., D\u2019Oc\u00f3n, P., et al., 2009. Regulation of oxygen \ndistribution in tissues by endothelial nitric oxide. Circ. Res. 104, 1178\u20131183. (Endogenously released endothelial NO inhibits cytochrome c \noxidase and can modulate tissue O\n2 consumption and regulates O 2 \ndistribution to the surrounding tissues)\nPathological aspects\nCaplin, B., Leiper, J., 2012. Endogenous nitric oxide synthase inhibitors \nin the biology of disease: markers, mediators, and regulators? Arterioscler. Thromb. Vasc. Biol. 32, 1343\u20131353. (Review outlining the \nbasic biochemistry and physiology of endogenous methylarginines, examining their role in disease pathogenesis, and the potential for therapeutic regulation \nof these molecules)\nRicciardolo, F.L.M., Sterk, P.J., Gaston, B., et al., 2004. Nitric oxide in \nhealth and disease of the respiratory system. Physiol. Rev. 84, \n731\u2013765.\nClinical and therapeutic aspects\nGriffiths, M.J.D., Evans, T.W., 2005. Drug therapy: inhaled nitric oxide \ntherapy in adults. N. Engl. J. Med. 353, 2683\u20132695. (Concludes that, on \nthe available evidence, inhaled NO is not effective in patients with acute \nlung injury, but that it may be useful as a short-term measure in acute hypoxia \u00b1 pulmonary hypertension)\nLidder, S., Webb, A.J., 2013. Vascular effects of dietary nitrate (as found \nin green leafy vegetables and beetroot) via the nitrate\u2013nitrite\u2013nitric oxide pathway. Br. J. Clin. Pharmacol. 75, 677\u2013696.\nLundberg, J.O., Gladwin, M.T., Weitzberg, E., 2015. Strategies to \nincrease nitric oxide signalling in cardiovascular disease. Nat. Rev. Drug Discov. 14, 623\u2013641. (Discusses new pathways for enhancing NO \nsynthase activity; ways to amplify the nitrate-nitrite-NO pathway; novel \nclasses of NO-donating drugs; drugs that limit NO metabolism through effects on reactive oxygen species; and ways to modulate downstream \nphosphodiesterases and soluble guanylyl cyclises, focusing on cardiovascular \ndisease)\nMalmstr\u00f6m, R.E., T\u00f6rnberg, D.C., Settergren, G., et al., 2003. \nEndogenous nitric oxide release by vasoactive drugs monitored in mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 5881, "end_char_idx": 8872, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bfb74446-5a60-446c-ab35-1808c1431451": {"__data__": {"id_": "bfb74446-5a60-446c-ab35-1808c1431451", "embedding": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d9d5661d-0a9e-4e66-8c62-3bc58315541d", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6d6702aa198386d59660ffbd6675b8fc6c96aedf6dd82b768453d132a245c137"}, "2": {"node_id": "74d5fb38-ccba-418a-a638-8988ad5a2da1", "node_type": null, "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "509ff10350c970b0802e042fe8d64d13952b3a18e4bccd0ea72ff339747a74ff"}}, "hash": "6d1dadb586eb8ef320f2b1a2b45de8ec22771063cb3fdbe301ff2639c17ecab1", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 8886, "end_char_idx": 9237, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e6008c04-48ea-47ad-b6a9-d2d16e810bab": {"__data__": {"id_": "e6008c04-48ea-47ad-b6a9-d2d16e810bab", "embedding": null, "metadata": {"page_label": "276", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "de184d90-8a77-4d83-a264-83f1a1d8bd84", "node_type": null, "metadata": {"page_label": "276", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "088d9d6501b8942bd79b5a1567e76d2cf2cd6886c0012b3f9b6838165703fd49"}, "3": {"node_id": "6040bc08-06d9-4ce6-9b26-d45176267882", "node_type": null, "metadata": {"page_label": "276", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a531114b8a146550c841e9069b47338927cfb8114f44989a3cf63306292da106"}}, "hash": "78ece5cddb4f128a122890e1d455339c635af7d3e747f5412036dd14f2b53ed2", "text": "21 SECTION 2 \u2003\u2003 CHEMICAL MEDIATORS\n270Hydrogen sulfide as possible mediator\nElies, J., Scragg, J.L., Boyle, J.P., 2016. Regulation of the T-type Ca2+ \nchannel Cav3.2 by hydrogen sulfide: emerging controversies \nconcerning the role of H 2S in nociception. J. Physiol. (Lond.) 594, \n4119\u20134129. ( Evidence that H 2S modulates low voltage-activated T-type Ca2+ \nchannels, and discriminates between the different subtypes of T-type Ca2+ \nchannel, selectively modulating Cav3.2, whilst Cav3.1 and Cav3.3 are \nunaffected )\nLi, L., Rose, P., Moore, P.K., 2011. Hydrogen sulfide and cell signaling. \nAnnu. Rev. Pharmacol. Toxicol. 51, 169\u2013187. ( H2S inhibits cytochrome c \noxidase and reduces cell energy production; it also activates K-ATP, and \ntransient receptor potential (TRP) channels but usually inhibits big \nconductance Ca2+-sensitive K+ (BKCa) channels, T- and M-type calcium \nchannels. H 2S may inhibit or activate NF-kappa B nuclear translocation \nwhile affecting the activity of numerous kinases including p38 \nmitogen-activated protein kinase (p38 MAPK), extracellular signal-regulated \nkinase (ERK), and Akt )\nReiffenstein, R.J., Hulbert, W.C., Roth, S.H., 1992. Toxicology of \nhydrogen sulfide. Annu. Rev. Pharmacol. Toxicol. 32, 109\u2013134.\nSzabo, C., 2007. Hydrogen sulphide and its therapeutic potential. Nat. \nRev. Drug Discov. 6, 917\u2013935.exhaled air. Am. J. Respir. Crit. Care Med. 168, 114\u2013120. ( In humans, \nacetylcholine evokes a dose-dependent increase of NO in exhaled air; NO \nrelease by vasoactive agonists can be measured online in the exhaled air of \npigs and humans )\nMiller, M.R., Megson, I.L., 2007. Review \u2013 Recent developments in nitric \noxide donor drugs. Br. J. Pharmacol. 151, 305\u2013321. ( Explores some of the \nmore promising recent advances in NO donor drug development and \nchallenges associated with NO as a therapeutic agent )\nPawloski, J.R., Hess, D.T., Stamler, J.S., 2005. Impaired vasodilation by \nred blood cells in sickle cell disease. Proc. Natl. Acad. Sci. U.S.A. 102, \n2531\u20132536. ( Sickle red cells are deficient in membrane S-nitrosothiol and \nimpaired in their ability to mediate hypoxic vasodilation; the magnitudes of \nthese impairments correlate with the clinical severity of disease )\nCarbon monoxide as possible mediator\nLeffler, C.W., Parfenova, H., Jaggar, J.H., 2011. Carbon monoxide as an \nendogenous vascular modulator. Am. J. Physiol. 301, H1\u2013H11.\nMotterlini, R., Foresti, R., 2017. Biological signaling by carbon monoxide \nand carbon monoxide-releasing molecules. Am. J. Physiol. Cell \nPhysiol. 312, C302\u2013C313.\nWu, L., Wang, R., 2005. Carbon monoxide: endogenous production, \nphysiological functions and pharmacological applications. Pharmacol. \nRev. 57, 585\u2013630.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2938, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6040bc08-06d9-4ce6-9b26-d45176267882": {"__data__": {"id_": "6040bc08-06d9-4ce6-9b26-d45176267882", "embedding": null, "metadata": {"page_label": "276", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "de184d90-8a77-4d83-a264-83f1a1d8bd84", "node_type": null, "metadata": {"page_label": "276", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "088d9d6501b8942bd79b5a1567e76d2cf2cd6886c0012b3f9b6838165703fd49"}, "2": {"node_id": "e6008c04-48ea-47ad-b6a9-d2d16e810bab", "node_type": null, "metadata": {"page_label": "276", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "78ece5cddb4f128a122890e1d455339c635af7d3e747f5412036dd14f2b53ed2"}}, "hash": "a531114b8a146550c841e9069b47338927cfb8114f44989a3cf63306292da106", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2891, "end_char_idx": 3194, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "044917f7-4322-4510-875c-68fa43cc5cc2": {"__data__": {"id_": "044917f7-4322-4510-875c-68fa43cc5cc2", "embedding": null, "metadata": {"page_label": "277", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5342547c-59cf-4c84-a929-cdd4be65305a", "node_type": null, "metadata": {"page_label": "277", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69a8cb9f3072dd75b19a938dca014dfdeec2031b43be3f3cf11943ec06be495b"}, "3": {"node_id": "c47e6e0b-8b97-433e-95ce-d6a007e55e55", "node_type": null, "metadata": {"page_label": "277", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc95ef371d6925d15af842dbf4fb0b1a44b7e935ac03893fad9e11584db40105"}}, "hash": "177549e017d42ed3408fa35d76e68ecd5f3345344e51ca5b07f7fa9ac547dafd", "text": "271\nThe heart22 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3 \nOVERVIEW\nThis chapter presents an overview of cardiac function \nin terms of electrophysiology, contraction, oxygen \nconsumption and coronary blood flow, autonomic \ncontrol and natriuretic peptides as a basis for under -\nstanding effects of drugs on the heart and their place \nin treating cardiac disease. We concentrate on drugs \nthat act directly on the heart, namely antidysrhythmic drugs and drugs that increase the force of contraction \n(especially digoxin), as well as anti-anginal drugs \nthat act indirectly by reducing cardiac work. The commonest form of heart disease is caused by ath -\neroma in the coronary arteries, complicated by thrombosis on ruptured atheromatous plaques; drugs to treat and prevent these are considered in Chapters \n24 and 25. Heart failure is mainly treated by drugs \nthat work indirectly on the heart via actions on vascular smooth muscle, discussed in Chapter 23 , by \ndiuretics (Ch. 30) and \u03b2-adrenoceptor antagonists \n(Ch. 15).\nINTRODUCTION\nIn this chapter we consider effects of drugs on the heart \nunder three main headings:\n1. Rate and rhythm.\n2. Myocardial contraction.\n3. Metabolism and blood flow.\nThe effects of drugs on these aspects of cardiac function are not, of course, independent of each other. For example, \nif a drug affects the electrical properties of the myocardial \ncell membrane, it is likely to influence both cardiac rhythm and myocardial contraction. Similarly, a drug that affects \ncontraction will inevitably alter metabolism and blood \nflow as well. Nevertheless, from a therapeutic point of view, these three classes of effect represent distinct clinical \nobjectives in relation to the treatment, respectively, of \ncardiac dysrhythmias, cardiac failure and coronary insuf -\nficiency (as occurs during angina pectoris or myocardial \ninfarction).\nPHYSIOLOGY OF CARDIAC FUNCTION\nCARDIAC RATE AND RHYTHM\nThe chambers of the heart normally contract in a coordinated manner, pumping blood efficiently by a route determined \nby the valves. Coordination of contraction is achieved by \na specialised conducting system. Normal sinus rhythm is \ngenerated by pacemaker impulses that arise in the sinoatrial \n(SA) node and are conducted in sequence through the atria, \nthe atrioventricular (AV) node, bundle of His, Purkinje fibres and ventricles. Cardiac cells owe their electrical excitability to voltage-sensitive plasma membrane channels selective for various ions, including Na\n+, K+ and Ca2+, the \nstructure and function of which are described in Chapter \n4. Electrophysiological features of cardiac muscle that \ndistinguish it from other excitable tissues include:\n\u2022\tpacemaker \tactivity\n\u2022\tabsence \tof \tfast \tNa+ current in SA and AV nodes, \nwhere slow inward Ca2+ current initiates action \npotentials\n\u2022\tlong\taction \tpotential \t(\u2018plateau\u2019) \tand \trefractory \tperiod\n\u2022\tinflux\tof \tCa2+ during the plateau\nSeveral of these special features of cardiac rhythm relate \nto Ca2+ currents. The heart contains intracellular calcium \nchannels (i.e. ryanodine receptors and inositol trisphosphate-activated calcium channels described in Chapter 4, which \nare important in myocardial contraction) and voltage-dependent calcium channels in the plasma membrane, which \nare important in controlling cardiac rate and rhythm. The \nmain type of voltage-dependent calcium channel in adult working myocardium is the L-type channel, which is also \nimportant in vascular smooth muscle; L-type channels are \nimportant in specialised conducting regions as well as in working myocardium.\nThe action potential", "start_char_idx": 0, "end_char_idx": 3607, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c47e6e0b-8b97-433e-95ce-d6a007e55e55": {"__data__": {"id_": "c47e6e0b-8b97-433e-95ce-d6a007e55e55", "embedding": null, "metadata": {"page_label": "277", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5342547c-59cf-4c84-a929-cdd4be65305a", "node_type": null, "metadata": {"page_label": "277", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69a8cb9f3072dd75b19a938dca014dfdeec2031b43be3f3cf11943ec06be495b"}, "2": {"node_id": "044917f7-4322-4510-875c-68fa43cc5cc2", "node_type": null, "metadata": {"page_label": "277", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "177549e017d42ed3408fa35d76e68ecd5f3345344e51ca5b07f7fa9ac547dafd"}}, "hash": "bc95ef371d6925d15af842dbf4fb0b1a44b7e935ac03893fad9e11584db40105", "text": "specialised conducting regions as well as in working myocardium.\nThe action potential of an idealised cardiac muscle cell \nis shown in Fig. 22.1A and is divided into five phases: 0 (fast depolarisation), 1 (partial repolarisation), 2 (plateau), 3 (repolarisation) and 4 (pacemaker).\n\u25bc Ionic mechanisms underlying these phases can be summarised as \nfollows.\nPhase 0, rapid depolarisation, occurs when the membrane potential \nreaches a critical firing threshold (about \u221260 mV), at which the inward \ncurrent of Na+ flowing through the voltage-dependent sodium channels \nbecomes \tlarge \tenough \tto \tproduce \ta \tregenerative \t(\u2018all-or-nothing\u2019) \t\ndepolarisation. This mechanism is the same as that responsible for \naction potential generation in neurons (see Ch. 4). Activation of sodium \nchannels by membrane depolarisation is transient, and if the membrane \nremains depolarised for more than a few milliseconds, they close again (inactivation). They are therefore closed during the plateau of \nthe action potential and remain unavailable for the initiation of another \naction potential until the membrane repolarises.\nPhase 1, partial repolarisation, occurs as the Na\n+ current is inactivated. \nThere may also be a transient voltage-sensitive outward current.Phase 2, the plateau, results from an inward Ca\n2+ current. Calcium \nchannels show a pattern of voltage-sensitive activation and inactivation \nqualitatively similar to sodium channels, but with a much slower time \ncourse. The plateau is assisted by a special property of the cardiac muscle membrane known as inward-going rectification , which means \nthat the K\n+ conductance falls to a low level when the membrane is \ndepolarised. Because of this, there is little tendency for outward K+ \ncurrent to restore the resting membrane potential during the plateau, \nso a relatively small inward Ca2+ current suffices to maintain the plateau. \nA persistent sodium current ( INap) also contributes to the plateau; it is \nvery small compared with the fast component of sodium current, but as it flows throughout the action potential it makes a substantial contribu -\ntion to sodium loading during each cardiac cycle, and is a major contribu -\ntor to ischaemic arrhythmias and a drug target (see p. 284).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3522, "end_char_idx": 6253, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9e4a00f9-ab38-4a45-91f1-5ae5774c0f1c": {"__data__": {"id_": "9e4a00f9-ab38-4a45-91f1-5ae5774c0f1c", "embedding": null, "metadata": {"page_label": "278", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1afcf0bb-0c68-4bb8-8602-3ba2ca328169", "node_type": null, "metadata": {"page_label": "278", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b5af879bd500a7c5e1a60428c9ec74567f74e934132d7d8203c1d6779926ae24"}, "3": {"node_id": "d55e0371-0ca8-4958-8a72-2c5481b25d97", "node_type": null, "metadata": {"page_label": "278", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a20e916dddac21b95f7b85e55350c030a1b7a09f097433b407adefa60ee98aee"}}, "hash": "203692f6feb0b25b7bf2e1bb786f96be221d9cd561d06f069a43028a90901a7c", "text": "22 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n272(~5 cm/s) compared with other regions such as the Purkinje \nfibres (conduction velocity ~200 cm/s), which propagate \nthe action potential rapidly to the ventricles. Regions that \nlack a fast inward current have a much longer refractory \nperiod than fast-conducting regions. This is because recovery \nof the slow inward current following its inactivation during the action potential takes a considerable time (a few hundred \nmilliseconds), and the refractory period outlasts the action \npotential. With fast-conducting fibres, inactivation of the Na\n+ current recovers rapidly, and the cell becomes excitable \nagain almost as soon as it is repolarised.\nThe orderly pattern of sinus rhythm can be disrupted \neither by heart disease or by the action of drugs or circulating hormones, and an important therapeutic use of drugs is \nto restore a normal cardiac rhythm where it has become \ndisturbed. The commonest cause of cardiac dysrhythmia is ischaemic heart disease, and many deaths following \nmyocardial infarction result from ventricular fibrillation rather \nthan directly from failure of the contractile machinery due \nto death of cardiac myocytes. Fibrillation is a state where heart chambers stop contracting in a coordinated way \nbecause the rhythm is replaced by chaotic electrical activity, \ncausing rapid uncoordinated contractions within ventricles or atria that do not support cardiac output from the affected \nchambers.\nDISTURBANCES \u2003OF \u2003CARDIAC \u2003RHYTHM\nClinically, dysrhythmias are classified according to:\n\u2022\tthe\tsite \tof \torigin \tof \tthe \tabnormality \t\u2013 \tatrial, \tjunctional \t\nor ventricular;\n\u2022\twhether \tthe \trate \tis \tincreased \t(tachycardia) or decreased \n(bradycardia).\nThey may cause palpitations (awareness of the heartbeat) \nor symptoms from cerebral hypoperfusion (faintness or Phase 3, repolarisation, occurs as the Ca2+ current inactivates and a \ndelayed outwardly rectifying K+ current (analogous to, but much \nslower than, the K+ current that causes repolarisation in nerve fibres; \nCh. 4) activates, causing outward K+ current. This is augmented by \nanother K+ current, which is activated by high intracellular Ca2+ \nconcentrations, [Ca2+]i during the plateau, and sometimes also by \nother K+ currents, including one through channels activated by \nacetylcholine (see p. 277) and another that is activated by arachidonic \nacid, which is liberated under pathological conditions such as \nmyocardial infarction.\nPhase 4, the pacemaker potential , is a gradual depolarisation during \ndiastole. Pacemaker activity is normally found only in nodal and \nconducting tissue. The pacemaker potential is caused by a combination \nof increasing inward currents and declining outward currents during \ndiastole. It is usually most rapid in cells of the SA node, which therefore acts as pacemaker for the whole heart. Cells in the SA node have \na greater background Na\n+-conductance than do atrial or ventricular \nmyocytes, leading to a greater background inward current. In addition, inactivation of voltage-dependent calcium channels wears off during \ndiastole, resulting in increasing inward Ca\n2+ current during late diastole. \nActivation of T-type calcium channels during late diastole contributes \nto pacemaker activity in the SA node. The negative membrane potential \nearly in diastole activates a cation channel that is permeable to Na+ and \nK+, giving rise to another inward current, called If.1 An inhibitor of this \ncurrent, ivabradine, slows the heart and is used therapeutically (see", "start_char_idx": 0, "end_char_idx": 3563, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d55e0371-0ca8-4958-8a72-2c5481b25d97": {"__data__": {"id_": "d55e0371-0ca8-4958-8a72-2c5481b25d97", "embedding": null, "metadata": {"page_label": "278", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1afcf0bb-0c68-4bb8-8602-3ba2ca328169", "node_type": null, "metadata": {"page_label": "278", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b5af879bd500a7c5e1a60428c9ec74567f74e934132d7d8203c1d6779926ae24"}, "2": {"node_id": "9e4a00f9-ab38-4a45-91f1-5ae5774c0f1c", "node_type": null, "metadata": {"page_label": "278", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "203692f6feb0b25b7bf2e1bb786f96be221d9cd561d06f069a43028a90901a7c"}}, "hash": "a20e916dddac21b95f7b85e55350c030a1b7a09f097433b407adefa60ee98aee", "text": "ivabradine, slows the heart and is used therapeutically (see \nlater). Several voltage- and time-dependent outward currents play a part as well: delayed rectifier K\n+ current ( IK), which is activated during \nthe action potential, is turned off by the negative membrane potential \nearly in diastole. Current from the electrogenic Na+/K+ pump also \ncontributes to the outward current during the pacemaker potential.\nFig. 22.1B shows the action potential configuration in different \nparts of the heart. Phase 0 is absent in the nodal regions, \nwhere the conduction velocity is correspondingly slow Na+\nCa2+ K+Membrane potential (mV) \nTime (s)4321\n0\n0.1110100\u2212100\u221250050\n1.0 0.5 0 0.6 0.4 0.2 0 TQRS\nPSA node \nSA node\nAtrium\nAV node \nPurkinje fibre\nVentricleSA node \nAtrium\nVentriclePurkinje\nfibreAV node AV node \nECG trace \nTime (s) Membrane\nconductance\n(arbitrary units)A B\nFig. 22.1 The cardiac action potential. (A) Phases of the action potential: (0) rapid depolarisation; (1) partial repolarisation; (2) plateau; \n(3) repolarisation; (4) pacemaker depolarisation. The lower panel shows the accompanying changes in membrane conductance for Na+, K+ \nand Ca2+. (B) Conduction of the impulse through the heart, with the corresponding electrocardiogram (ECG) trace. Note that the longest \ndelay occurs at the atrioventricular (AV) node, where the action potential has a characteristically slow waveform. SA, sinoatrial. \n1\u2018f\u2019\tfor\t\u2018funny\u2019, \tbecause \tit \tis \tunusual \tfor \tcation \tchannels \tto \tbe \tactivated \t\nby hyperpolarisation; cardiac electrophysiologists have a peculiar sense \nof humour!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3503, "end_char_idx": 5573, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7531f3db-e115-4dfb-afd5-a70fb60ed18f": {"__data__": {"id_": "7531f3db-e115-4dfb-afd5-a70fb60ed18f", "embedding": null, "metadata": {"page_label": "279", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d70c1bfe-e16e-4ce0-a658-57419ecb6553", "node_type": null, "metadata": {"page_label": "279", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff29d283d6e480ab8e52533418a67ab8ce685d4a526963d4724638f8398b9be6"}, "3": {"node_id": "a1c52e32-8920-472a-8379-330d8f5be91c", "node_type": null, "metadata": {"page_label": "279", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "005d7d2e73ae9b321d83144daa45975e358a7a980390f8f5ea2352e763995388"}}, "hash": "6e6a8da968ae5e8f52dcc8b831716d2a6effdaa47e1fd801c9d2662cd44c6cdc", "text": "22 ThE hEART\n273other organs, delay cardiac repolarisation by binding to \npotassium or other cardiac channels or by influencing \nelectrolyte concentrations (see Roden, 2008). Delayed \nrepolarisation, evidenced by prolongation of the QT interval on the ECG, increases Ca\n2+ entry during the prolonged \naction potential, leading to after-depolarisation, which \ncarries a risk of causing dangerous ventricular dysrhythmias. \nQT prolongation is a concern in drug development (see \nsection\ton \tantidysrhythmic \tdrugs, \tpp. \t279\u2013283, \tand \tsee \t \nCh. 60).\nNormally, a cardiac action potential dies out after it has \nactivated the ventricles because it is surrounded by refractory tissue, which it has just traversed. Re-entry (Fig. 22.3) describes \na situation in which the impulse re-excites regions of the \nmyocardium after the refractory period has subsided, causing continuous circulation of action potentials. It can result from \nanatomical anomalies or, more commonly, from myocardial \ndamage. Re-entry underlies many types of dysrhythmia, the pattern depending on the site of the re-entrant circuit, which may be in the atria, ventricles or nodal tissue. A simple \nring of tissue can give rise to a re-entrant rhythm if a transient \nor unidirectional conduction block is present. Normally, an impulse originating at any point in the ring will propagate \nin both directions and die out when the two impulses meet, \nbut if a damaged area causes either a transient block (so that one impulse is blocked but the second can get through; \nsee Fig. 22.3) or a unidirectional block, continuous circulation \nof the impulse can occur. This is known as circus movement \nand was demonstrated experimentally on rings of jellyfish tissue many years ago.\nAlthough the physiological pacemaker resides in the SA \nnode, other cardiac tissues can take on pacemaker activity. This provides a safety mechanism in the event of failure \nof the SA node but can also trigger tachyarrhythmias. Ectopic pacemaker activity is encouraged by sympathetic activity \nand by partial depolarisation, which may occur during \nischaemia. Catecholamines, acting on \u03b2\n1 adrenoceptors (see \np. 276), increase the rate of depolarisation during phase 4 \nand can cause normally quiescent parts of the heart to take loss of consciousness). Their diagnosis depends on the \nsurface electrocardiogram (ECG), and details are beyond \nthe\tscope \tof \tthis \tbook \t\u2013 \tsee \tOpie \tand \tGersh \t(2013). \tThe \t\ncommonest types of tachyarrhythmia are atrial fibrillation, \nwhere the heartbeat is completely irregular, and supraven-\ntricular tachycardia (SVT), where the heartbeat is rapid but \nregular.\tOccasional \tectopic \tbeats \t(ventricular \tas \twell \tas \t\nsupraventricular) are common. Sustained ventricular tachyarrhythmias are much less common but more serious; \nthey include ventricular tachycardia , and ventricular fibrillation \nwhere the electrical activity in the ventricles is completely \nchaotic and cardiac output ceases. Bradyarrhythmias include \nvarious kinds of heart block (e.g. at the AV or SA node) and \ncomplete \tcessation \tof \telectrical \tactivity \t(\u2018asystolic arrest \u2019).\t\nIt is often unclear which of the various mechanisms dis -\ncussed below are responsible. These cellular mechanisms nevertheless provide a useful starting point for understand -\ning how antidysrhythmic drugs work. Four basic phenomena \nunderlie disturbances of cardiac rhythm:\n1. Delayed after-depolarisation.\n2. Re-entry.\n3. Ectopic pacemaker activity.\n4. Heart block.\nThe main cause of", "start_char_idx": 0, "end_char_idx": 3523, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a1c52e32-8920-472a-8379-330d8f5be91c": {"__data__": {"id_": "a1c52e32-8920-472a-8379-330d8f5be91c", "embedding": null, "metadata": {"page_label": "279", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d70c1bfe-e16e-4ce0-a658-57419ecb6553", "node_type": null, "metadata": {"page_label": "279", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff29d283d6e480ab8e52533418a67ab8ce685d4a526963d4724638f8398b9be6"}, "2": {"node_id": "7531f3db-e115-4dfb-afd5-a70fb60ed18f", "node_type": null, "metadata": {"page_label": "279", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6e6a8da968ae5e8f52dcc8b831716d2a6effdaa47e1fd801c9d2662cd44c6cdc"}}, "hash": "005d7d2e73ae9b321d83144daa45975e358a7a980390f8f5ea2352e763995388", "text": "Ectopic pacemaker activity.\n4. Heart block.\nThe main cause of delayed after-depolarisation is abnormally raised [Ca\n2+]i, which triggers inward current and hence a \ntrain of abnormal action potentials (Fig. 22.2). After-\ndepolarisation is the result of a net inward current, known \nas the transient inward current. A rise in [Ca2+]i activates \nNa+/Ca2+ exchange. This transfers one Ca2+ ion out of the \ncell in exchange for entry of three Na+ ions, resulting in a \nnet influx of one positive charge and hence membrane \ndepolarisation. Raised [Ca2+]i also contributes to the depo -\nlarisation by opening non-selective cation channels in the plasma membrane. Consequently, hypercalcaemia (which \nincreases the entry of Ca\n2+) promotes after-depolarisation. \nHypokalaemia also influences repolarisation, via an effect \non the gating of cardiac delayed rectifier potassium channels. \nMany drugs, including ones whose principal effects are on \nS3 S2 S1 1 s\n*\n*\n*\u2020\n\u2020\n\u2021\nFig. 22.2 After-depolarisation in cardiac muscle recorded \nfrom a dog coronary sinus in the presence of noradrenaline \n(norepinephrine). The first stimulus (S1) causes an action \npotential followed by a small after-depolarisation. As the interval S2\u2013S3 is decreased, the after-depolarisation gets larger (\u2020) until \nit triggers an indefinite train of action potentials (\u2021). (Adapted \nfrom Wit, A.L., Cranefield, P.F., 1977. Circ. Res. 41, 435.)Normal Damaged\nAnterograde \nimpulse \nblockedCircus \nmovement\nFig. 22.3 Generation of a re-entrant rhythm by a damaged \narea of myocardium. The damaged area (brown) conducts in \none direction only. This disturbs the normal pattern of conduction and permits continuous circulation of the impulse to occur. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3462, "end_char_idx": 5654, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9cb42c91-ff17-4fd4-a6aa-533a2bae6729": {"__data__": {"id_": "9cb42c91-ff17-4fd4-a6aa-533a2bae6729", "embedding": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f7751953-61be-4c38-87d5-3296b3de73ed", "node_type": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c8c22126d08daf0b8a5a3372025e02f9e1a37a01616bd2983dac02314181644"}, "3": {"node_id": "3676a575-787a-4028-860d-92317bd836d2", "node_type": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "47b2adb05022a82cb183a06af2caa6121fdcfb04b966e83aa90bb67e31a28c8f"}}, "hash": "d427149995a58a34455636db5c9ef1b652e9b33fe075478f7f5ce4fb943f28cf", "text": "22 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n274the conformation of the troponin complex, permitting \ncross-bridging of myosin to actin and initiating contraction. \nLevosimendan (a drug used in some countries to treat \nacute decompensated heart failure; Ch. 23), increases the force of contraction of the heart by binding troponin C and \nsensitising it to the action of Ca\n2+.\n\u25bc Many effects of drugs on cardiac contractility can be explained in \nterms of actions on [Ca2+]i, via effects on calcium channels in plasma \nmembrane or sarcoplasmic reticulum, or on the Na+/K+ pump, which \nindirectly influences the Na+/Ca2+\tpump\t(see \tp. \t283). \tOther \tfactors \t\nthat affect the force of contraction are the availability of oxygen and \na source of metabolic energy such as free fatty acids. Myocardial \nstunning \u2013 contractile dysfunction that persists after ischaemia and \nreperfusion despite restoration of blood flow and absence of cardiac \nnecrosis\t\u2013\tis\tincompletely \tunderstood \tbut\tcan\tbe\tclinically \timportant. \t\nIts converse is known as ischaemic preconditioning; this refers to an \nimproved ability to withstand ischaemia following previous ischaemic \nepisodes. This potentially beneficial state could be clinically important. \nThere is some evidence that it is mediated by adenosine (see Ch. 17), \nwhich accumulates as ATP is depleted. Exogenous adenosine affords \nprotection similar to that caused by ischaemic preconditioning, and \nblockade of adenosine receptors prevents the protective effect of \npreconditioning (see Eltzschig et al., 2012). There is considerable \ninterest in developing strategies to minimise harmful effects of ischaemia while maximising preconditioning, but clinical trials have \nso far been negative and translation into therapeutics is fraught with \ndifficulty (Heusch, 2017).\nVENTRICULAR \u2003FUNCTION \u2003CURVES \u2003AND \u2003HEART \u2003FAILURE\nThe force of contraction of the heart is determined partly \nby its intrinsic contractility (which, as described above, \ndepends on [Ca2+]i and availability of ATP), and partly by \nextrinsic haemodynamic factors that affect end-diastolic volume and hence the resting length of the muscle fibres. \nThe end-diastolic volume is determined by the end-diastolic pressure, and its effect on stroke work is expressed in the \nFrank\u2013Starling \tl aw \to f\tt he\th eart,\tw hich\tr eflects\ta n\ti nherent\t\nproperty \tof\tthe\tcontractile \tsystem.\tThe\tFrank\u2013Starling \tlaw\t\ncan be represented as a ventricular function curve (Fig. \n22.4).\tThe \tarea \tenclosed \tby \tthe \tpressure\u2013volume \tcurve \t\nduring the cardiac cycle provides a measure of ventricular stroke work. It is approximated by the product of stroke \nvolume and mean arterial pressure. As Starling showed, \nfactors extrinsic to the heart affect its performance in various ways, two patterns of response to increased load being \nparticularly important:\n1. Increased cardiac filling pressure ( preload), whether \ncaused by increased blood volume or by venoconstriction, increases ventricular end-diastolic \nvolume. This increases stroke volume and hence cardiac output and mean arterial pressure. Cardiac \nwork and cardiac oxygen consumption both increase.\n2. Resistance vessel vasoconstriction increases afterload. \nEnd-diastolic volume and, hence, stroke work are initially unchanged, but constant stroke work in the \nface of increased vascular resistance causes reduced stroke volume and hence increased end-diastolic \nvolume. This in turn increases stroke work, until a \nsteady state is", "start_char_idx": 0, "end_char_idx": 3497, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3676a575-787a-4028-860d-92317bd836d2": {"__data__": {"id_": "3676a575-787a-4028-860d-92317bd836d2", "embedding": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f7751953-61be-4c38-87d5-3296b3de73ed", "node_type": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c8c22126d08daf0b8a5a3372025e02f9e1a37a01616bd2983dac02314181644"}, "2": {"node_id": "9cb42c91-ff17-4fd4-a6aa-533a2bae6729", "node_type": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d427149995a58a34455636db5c9ef1b652e9b33fe075478f7f5ce4fb943f28cf"}, "3": {"node_id": "419990c3-1ac8-4f06-8849-e2e7e27a8fb4", "node_type": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8dacd1d78ee3377328d2311d3831889d5ebe91ab05aeece6557433b593c0c13"}}, "hash": "47b2adb05022a82cb183a06af2caa6121fdcfb04b966e83aa90bb67e31a28c8f", "text": "\nvolume. This in turn increases stroke work, until a \nsteady state is re-established with increased end-diastolic volume and the same cardiac output as \nbefore. As with increased preload, cardiac work and \ncardiac oxygen consumption both increase.\nNormal ventricular filling pressure is only a few centimetres \nof water, on the steep part of the ventricular function curve, \nso a large increase in stroke work can be achieved with CARDIAC CONTRACTION\nCardiac output is the product of heart rate and mean left ventricular stroke volume (i.e. the volume of blood ejected \nfrom the ventricle with each heartbeat). Heart rate is \ncontrolled \tby \tthe \tautonomic \tnervous \tsystem \t(Chs \t13\u201315, \t\nand\tsee\tpp. \t276\u2013277). \tStroke \tvolume \tis \tdetermined \tby \ta \t\ncombination of factors, including some intrinsic to the heart \nitself and other haemodynamic factors extrinsic to the heart. \nIntrinsic factors regulate myocardial contractility via [Ca2+]i \nand ATP, and are sensitive to various drugs and pathological processes. Extrinsic circulatory factors include the elasticity \nand contractile state of arteries and veins, and the volume and viscosity of the blood, which together determine cardiac \nload (preload and afterload, see further). Drugs that influ -\nence these circulatory factors are of paramount importance \nin treating patients with heart failure. They are covered in \nChapter 23.\nMYOCARDIAL \u2003CONTRACTILITY \u2003AND \u2003VIABILITY\nThe contractile machinery of myocardial striated muscle \nis basically the same as that of voluntary striated muscle \n(Ch. 4). It involves binding of Ca2+ to troponin C; this changes Cardiac dysrhythmias \n\u2022\tDysrhythmias \tarise \tbecause \tof:\n\u2013 delayed after-depolarisation, which triggers ectopic \nbeats\n\u2013 re-entry, resulting from partial conduction block\n\u2013 ectopic pacemaker activity\n\u2013 heart block.\n\u2022\tDelayed \tafter-depolarisation \tis \tcaused \tby \tan \tinward \t\ncurrent associated with abnormally raised intracellular \nCa2+.\n\u2022\tRe-entry \tis \tfacilitated \twhen \tparts \tof \tthe \tmyocardium \t\nare depolarised as a result of disease.\n\u2022\tEctopic \tpacemaker \tactivity \tis \tencouraged \tby \t\nsympathetic activity.\n\u2022\tHeart\tblock \tresults \tfrom \tdisease \tin \tthe \tconducting \t\nsystem, especially the atrioventricular node.\n\u2022\tClinically, \tdysrhythmias \tare \tdivided:\n\u2013 according to their site of origin (supraventricular and \nventricular)\n\u2013 according to whether the heart rate is increased or \ndecreased (tachycardia or bradycardia).on a spontaneous rhythm. Several tachyarrhythmias (e.g. \nparoxysmal atrial fibrillation) can be triggered by circum -\nstances associated with increased sympathetic activity. Pain \n(e.g. during myocardial infarction) triggers sympathetic \ndischarge and release of adrenaline (epinephrine) from the adrenal gland increasing myocardial excitability. Partial \ndepolarisation resulting from ischaemic damage can also \ncause abnormal pacemaker activity.\nHeart block results from fibrosis of, or ischaemic damage to, \nthe conducting system (often in the AV node). In complete heart block, the atria and ventricles beat independently of one another, the ventricles beating at a slow rate determined by whatever pacemaker picks up distal to the block. Sporadic \ncomplete failure of AV conduction causes sudden periods \nof\tunconsciousness \t(Stokes\u2013Adams \tattacks)\tand\tis\ttreated\t\nby implanting an artificial pacemaker.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3440, "end_char_idx": 6861, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "419990c3-1ac8-4f06-8849-e2e7e27a8fb4": {"__data__": {"id_": "419990c3-1ac8-4f06-8849-e2e7e27a8fb4", "embedding": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f7751953-61be-4c38-87d5-3296b3de73ed", "node_type": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c8c22126d08daf0b8a5a3372025e02f9e1a37a01616bd2983dac02314181644"}, "2": {"node_id": "3676a575-787a-4028-860d-92317bd836d2", "node_type": null, "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "47b2adb05022a82cb183a06af2caa6121fdcfb04b966e83aa90bb67e31a28c8f"}}, "hash": "b8dacd1d78ee3377328d2311d3831889d5ebe91ab05aeece6557433b593c0c13", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6872, "end_char_idx": 7335, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8b7d0e5b-4651-4bf3-b0d8-d6a5503d69b2": {"__data__": {"id_": "8b7d0e5b-4651-4bf3-b0d8-d6a5503d69b2", "embedding": null, "metadata": {"page_label": "281", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "01a39b72-8bc8-414d-ac57-b166f28a2544", "node_type": null, "metadata": {"page_label": "281", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a4713be9654a6654fedc197b1a8384bbda32169829e5357b59f4f014411fb2c"}, "3": {"node_id": "2c53765a-56c1-48ed-9d78-7d879d512cd7", "node_type": null, "metadata": {"page_label": "281", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "491e9349959bdccfdac447d9a4158380b7ff8136b904b6cc199dca3085204642"}}, "hash": "383989435406c003259a468c4d11ccb60fa8944571176e5fdddf2a1d31d1f128", "text": "22 ThE hEART\n275at greater risk of ischaemic damage. Coronary flow is, under \nnormal circumstances, closely related to myocardial oxygen \nconsumption, and both change over a nearly 10-fold range \nbetween conditions of rest and maximal exercise. Most drugs that influence cardiac metabolism do so indirectly \nby influencing coronary blood flow.\n2\nPHYSIOLOGICAL \u2003FACTORS\nThe main physiological factors that regulate coronary flow \nare:\n\u2022\tphysical \tfactors\n\u2022\tvascular \tcontrol \tby \tmetabolites\n\u2022\tneural \tand \thumoral \tcontrol\nPhysical factors\nDuring systole, the pressure exerted by the myocardium on vessels that pass through it equals or exceeds the perfu -\nsion pressure, so coronary flow occurs only during diastole. Diastole is shortened more than systole during tachycardia, reducing the period available for myocardial perfusion. \nDuring diastole, the effective perfusion pressure is equal \nto the difference between the aortic and ventricular pressures (Fig. 22.5). If diastolic aortic pressure falls or diastolic \nventricular pressure increases, perfusion pressure falls and \nso (unless other control mechanisms can compensate) does coronary blood flow. Stenosis of the aortic valve reduces aortic pressure but increases left ventricular pressure \nupstream of the narrowed valve and hence reducing coro -\nnary perfusion pressure and often causes ischaemic chest \npain (angina), even in the absence of coronary artery disease, \nby this mechanism.\nVascular control by metabolites/mediators\nVascular control by metabolites is the most important \nmechanism by which coronary flow is regulated. A reduction only a small increase in filling pressure. The Starling \nmechanism plays little part in controlling cardiac output \nin healthy subjects (e.g. during exercise), because changes in contractility, mainly as a result of changes in sympathetic \nnervous activity, achieve the necessary regulation without \nany increase in ventricular filling pressure (see Fig. 22.4). In contrast, the denervated heart in patients who have \nreceived a heart transplant relies on the Starling mechanism \nto increase cardiac output during exercise.\nIn heart failure, the cardiac output is insufficient to meet \nthe needs of the body, initially only when these are increased during exercise but ultimately, as disease progresses, also at rest. It has many causes, most commonly ischaemic heart \ndisease. In patients with heart failure (see Ch. 23), the heart \nmay be unable to deliver as much blood as the tissues require, even when its contractility is increased by sympa -\nthetic activity. Under these conditions, the basal (i.e. at \nrest) ventricular function curve is greatly depressed, and \nthere is insufficient reserve, in the sense of extra contractility that can be achieved by sympathetic activity, to enable \ncardiac output to be maintained during exercise without \na large increase in central venous pressure (see Fig. 22.4). \nOedema\tof\tperipheral \ttissues\t(causing\tswelling\tof\tthe\tlegs)\t\nand the lungs (causing breathlessness) is an important consequence of cardiac failure. It is caused by the increased \nvenous pressure, and retention of Na\n+ (see Ch. 23).\nMYOCARDIAL OXYGEN CONSUMPTION \nAND CORONARY BLOOD FLOW\nRelative to its large metabolic needs, the heart is one of \nthe most poorly perfused tissues in the body, and is therefore 0.6\n0.4\n0.2\n0Stroke work (J)\nEnd-diastolic pressure (kPa)4 3 2 1 0Vehicle\ninfusionNoradrenalineinfusion\nFig. 22.4 Ventricular function curves in the dog. Infusion of \nphysiological saline increases blood volume and", "start_char_idx": 0, "end_char_idx": 3549, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2c53765a-56c1-48ed-9d78-7d879d512cd7": {"__data__": {"id_": "2c53765a-56c1-48ed-9d78-7d879d512cd7", "embedding": null, "metadata": {"page_label": "281", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "01a39b72-8bc8-414d-ac57-b166f28a2544", "node_type": null, "metadata": {"page_label": "281", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a4713be9654a6654fedc197b1a8384bbda32169829e5357b59f4f014411fb2c"}, "2": {"node_id": "8b7d0e5b-4651-4bf3-b0d8-d6a5503d69b2", "node_type": null, "metadata": {"page_label": "281", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "383989435406c003259a468c4d11ccb60fa8944571176e5fdddf2a1d31d1f128"}}, "hash": "491e9349959bdccfdac447d9a4158380b7ff8136b904b6cc199dca3085204642", "text": "curves in the dog. Infusion of \nphysiological saline increases blood volume and hence \nend-diastolic pressure. This increases stroke work (\u2018extrinsic\u2019 control) by increasing the force of contraction of the heart. This relationship is called the Starling curve. Noradrenaline has a direct action on the heart (\u2018intrinsic\u2019 control), increasing the slope \nof the Starling curve. (Redrawn from Sarnoff, S.J. et al., 1960. \nCirc. Res. 8, 1108.)Myocardial contraction \n\u2022\tControlling \tfactors \tare:\n\u2013 intrinsic myocardial contractility\n\u2013 extrinsic circulatory factors.\n\u2022\tMyocardial \tcontractility \tdepends \tcritically \ton \t\nintracellular Ca2+, and hence on:\n\u2013 Ca2+ entry across the cell membrane\n\u2013 Ca2+ storage in the sarcoplasmic reticulum.\n\u2022\tThe\tmain \tfactors \tcontrolling \tCa2+ entry are:\n\u2013 activity of voltage-gated calcium channels\n\u2013 intracellular Na+, which affects Ca2+/Na+ exchange.\n\u2022\tCatecholamines, \tcardiac \tglycosides \tand \tother \t\nmediators and drugs influence these factors.\n\u2022\tExtrinsic \tcontrol \tof \tcardiac \tcontraction \tis \tthrough \tthe \t\ndependence of stroke work on the end-diastolic \nvolume, expressed in the Frank\u2013Starling law.\n\u2022\tCardiac \twork \tis \taffected \tindependently \tby \tafterload \t\n(i.e. peripheral resistance and arterial compliance) and preload (i.e. central venous pressure).\n2Trimetazidine, used to treat angina in some European countries, is \nclaimed to improve cardiac metabolism by blocking fatty acid \noxidation, thereby increasing the use of glucose as an energy source, \nwhich requires less oxygen per unit of energy generated.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3469, "end_char_idx": 5509, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b41f6a80-4a3e-412b-8814-b69b97401683": {"__data__": {"id_": "b41f6a80-4a3e-412b-8814-b69b97401683", "embedding": null, "metadata": {"page_label": "282", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6873dfdb-094a-49ad-90df-453be6c00b8a", "node_type": null, "metadata": {"page_label": "282", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe4ef9be5c92074295d66652825451d4a76aa520b74dd68cb8a3c03ad08046ce"}, "3": {"node_id": "a80438bc-0369-47cb-94b2-53fb835987d7", "node_type": null, "metadata": {"page_label": "282", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0942497be1b1fc519b62569e5d31d092c3d6b9317241792de4a455ec772e7ca"}}, "hash": "3cf442d4ef112e1d73da1a961209dad1cd1cf141f6b25c307a3f4a5860903053", "text": "22 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n276\u2022\trepolarisation \tand \trestoration of function following \ngeneralised cardiac depolarisation\n\u2022\treduced \tcardiac \tefficiency (i.e. oxygen consumption is \nincreased more than cardiac work);\n\u2022\tcardiac \thypertrophy \t(which \tseems \tto \tbe \tdirectly \t\nmediated by stimulation of myocardial \u03b1 and \u03b2 \nadrenoceptors rather than by haemodynamic \nchanges).\n\u25bc These effects mainly result from activation of \u03b21 adrenoceptors. \nThe \u03b21 effects of catecholamines on the heart, although complex, \nprobably all occur through activation of adenylyl cyclase resulting \nin increased intracellular cAMP (see Ch. 3). cAMP activates protein \nkinase A, which phosphorylates sites on the \u03b11 subunits of calcium \nchannels. This increases the probability that the channels will open, \nincreasing inward Ca2+ current and hence force of cardiac contraction \n(see Fig. 22.6). Activation of \u03b21 adrenoceptors also increases the Ca2+ \nsensitivity of the contractile machinery, possibly by phosphorylating troponin C; furthermore, it facilitates Ca\n2+ capture by the sarcoplasmic \nreticulum, thereby increasing the amount of Ca2+ available for release in arterial partial pressure of oxygen ( PO2) causes marked \nvasodilatation of coronary vessels in situ but has little effect \non isolated strips of coronary artery, suggesting that it is \na change in the metabolites produced by the myocardial cells, rather than the change in P\nO2 per se, that controls the \nstate of the coronary vessels. Adenosine is a popular candidate \nfor the dilator metabolite (see Ch. 17).\nNeural and humoral control\nCoronary vessels have a dense sympathetic innervation, but sympathetic nerves (like circulating catecholamines) \nexert only a small direct effect on the coronary circulation. \nLarge coronary vessels possess \u03b1 adrenoceptors that mediate \nvasoconstriction, whereas smaller vessels have \u03b2\n2 adrenocep -\ntors that have a dilator effect. Coronary vessels are also \ninnervated by purinergic, peptidergic and nitrergic nerves, \nand basal coronary blood flow in patients with angiographi -\ncally normal coronary arteries is reduced by about one-third \nby\tselective\tinhibition \tof\tNOS1\t(Seddon\tet\tal., \t 2009). \t Coro -\nnary vascular responses to altered mechanical and metabolic \nactivity during exercise or pathological events overshadow \nneural and endocrine effects.\nAUTONOMIC CONTROL OF THE HEART\nThe sympathetic and parasympathetic systems (see Chs \n13\u201315)\teach \texert \ta \ttonic \teffect \ton \tthe \theart \tat \trest \tand \t\ninfluence each of the aspects of cardiac function discussed above, namely rate and rhythm, myocardial contraction, \nand myocardial metabolism and blood flow.\nSYMPATHETIC SYSTEM\nThe main effects of sympathetic activity on the heart are:\n\u2022\tincreased \tforce \tof \tcontraction \t(positive \tinotropic effect; \nFig. 22.6);\n\u2022\tincreased \theart \trate \t(positive \tchronotropic effect; Fig. \n22.7);\n\u2022\tincreased \tautomaticity (i.e. tendency to generate ectopic \nbeats);VentricleAorta20\n10\n0Pressure (kPa)3\n21Window for \ncoronary flow\n(aortic pressure > \nventricular pressure)Systole Diastole Systole\n0.5 s\nFig. 22.5 Mechanical factors affecting coronary blood \nflow. The \u2018window\u2019 for coronary flow may be encroached on by:", "start_char_idx": 0, "end_char_idx": 3245, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a80438bc-0369-47cb-94b2-53fb835987d7": {"__data__": {"id_": "a80438bc-0369-47cb-94b2-53fb835987d7", "embedding": null, "metadata": {"page_label": "282", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6873dfdb-094a-49ad-90df-453be6c00b8a", "node_type": null, "metadata": {"page_label": "282", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe4ef9be5c92074295d66652825451d4a76aa520b74dd68cb8a3c03ad08046ce"}, "2": {"node_id": "b41f6a80-4a3e-412b-8814-b69b97401683", "node_type": null, "metadata": {"page_label": "282", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3cf442d4ef112e1d73da1a961209dad1cd1cf141f6b25c307a3f4a5860903053"}}, "hash": "d0942497be1b1fc519b62569e5d31d092c3d6b9317241792de4a455ec772e7ca", "text": "The \u2018window\u2019 for coronary flow may be encroached on by: \n(1) shortening diastole, when heart rate increases; (2) increased \nventricular end-diastolic pressure and (3) reduced diastolic \narterial pressure. \nCoronary flow, ischaemia and \ninfarction \n\u2022\tThe\theart \thas \ta \tsmaller \tblood \tsupply \tin \trelation \tto \tits \t\noxygen consumption than most organs.\n\u2022\tCoronary \tflow \tis \tcontrolled \tmainly \tby:\n\u2013 physical factors, including transmural pressure \nduring systole\n\u2013 vasodilator metabolites.\n\u2022\tAutonomic \tinnervation \tis \tless \timportant.\n\u2022\tCoronary \tischaemia \tis \tusually \tthe \tresult \tof \t\natherosclerosis and causes angina. Sudden ischaemia \nis usually caused by thrombosis and may result in cardiac infarction (death of a region of the \nmyocardium).\n\u2022\tCoronary \tspasm \tsometimes \tcauses \tangina \t(variant \t\nangina).\n\u2022\tCellular\tCa2+ overload results from ischaemia and may \nbe responsible for:\n\u2013 cell death\n\u2013 dysrhythmias.Tension 2.5 nmol/L Isoprenaline Control \n1 s0.2 mN\n[Ca2+]i\nFig. 22.6 The calcium transient in frog cardiac muscle. A \ngroup of cells was injected with the phosphorescent Ca2+ \nindicator aequorin, which allows [Ca2+]i to be monitored optically. \nIsoprenaline causes a large increase in the tension and in the \n[Ca2+]i transient caused by an electrical stimulus (\u25b2). (From Allen, \nD.G.,\tBlinks, \tJ.R., \t1978. \tNature \t273, \t509.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3190, "end_char_idx": 5026, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "56a0e6b9-b839-4d33-b3db-8d51255697f0": {"__data__": {"id_": "56a0e6b9-b839-4d33-b3db-8d51255697f0", "embedding": null, "metadata": {"page_label": "283", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "97497838-610a-45cd-9620-2a36d02d869f", "node_type": null, "metadata": {"page_label": "283", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69f26d1aa9d42583ca0e853561e131a68e941324989918e29798e2eb25803107"}, "3": {"node_id": "21b54023-5f78-4403-932e-fbb9c9664fc2", "node_type": null, "metadata": {"page_label": "283", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "83a7ba44a92fd48e3ece0db048bc22b12ff8c763d59aaf915d6a54217f07a201"}}, "hash": "de270c333b364eeb638382e45cb0da0abb58daab8005bec3faf7ade8b12f4eee", "text": "22 ThE hEART\n277by the action potential. The net result of catecholamine action is to \nelevate and steepen the ventricular function curve (see Fig. 22.4). The \nincrease in heart rate results from an increased slope of the pacemaker \npotential (see Figs 22.1 and 22.7A). Increased Ca2+ entry also increases \nautomaticity because of the effect of [Ca2+]i on the transient inward \ncurrent, which can result in a train of action potentials following a \nsingle stimulus (see Fig. 22.2).\nActivation of \u03b2 1 adrenoceptors repolarises damaged or hypoxic \nmyocardium by stimulating the Na+/K+ pump. This can restore function \nif asystole has occurred following myocardial infarction, and adrenaline \nis one of the most important drugs used during cardiac arrest.The reduction of cardiac efficiency by catecholamines is important \nbecause it means that the oxygen requirement of the myocardium \nincreases. This limits the use of \u03b2 agonists such as adrenaline and \ndobutamine for circulatory shock (Ch. 23). Myocardial infarction \nactivates the sympathetic nervous system (see Fig. 22.8), which has \nthe undesirable effect of increasing the oxygen needs of the damaged myocardium.\nPARASYMPATHETIC SYSTEM\nParasympathetic activity produces effects that are, in general, \nopposite to those of sympathetic activation. However, in \ncontrast to sympathetic activity, the parasympathetic \nnervous system has little effect on contractility, its main effects being on rate and rhythm, namely:\n\u2022\tcardiac \tslowing \tand \treduced \tautomaticity\n\u2022\tinhibition \tof \tAV \tconduction\n\u25bc These effects result from activation of muscarinic (M 2) acetylcholine \nreceptors, which are abundant in nodal and atrial tissue but spares \nin the ventricles. These receptors are negatively coupled to adenylyl ControlControl 10 s NA \nACh10 sSympathetic stimulation\nVagal stimulationAction\npotential\nAction\npotential400 ms\n400 msA B\nC D\nFig. 22.7 Autonomic regulation of the heartbeat. (A) and \n(B) Effects of sympathetic stimulation and noradrenaline (NA). (C \nand\tD)\tEffects \tof \tparasympathetic \tstimulation \tand \tacetylcholine \t\n(ACh). Sympathetic stimulation (A) increases the slope of the \npacemaker potential and increases heart rate, whereas parasympathetic stimulation (C) abolishes the pacemaker potential, hyperpolarises the membrane and temporarily stops the heart (frog sinus venosus). NA (B) prolongs the action \npotential,\twhile \tACh \t(D) \tshortens \tit \t(frog \tatrium). \t([A] \tand \t[C] \t\nfrom\tHutter, \tO.F., \tTrautwein, \tW., \t1956. \tJ. \tGen. \tPhysiol. \t39, \t\n715;\t[B]\tfrom \tReuter, \tH., \t1974. \tJ. \tPhysiol. \t242, \t429; \t[D] \tfrom \t\nGiles, W.R., Noble, S.J., 1976. J. Physiol. 261, 103.)\nARB\nACEI\nNecrosis Apoptosis\nCell\nDeathATP\nIon pumps\n[Ca2+]i\nProtease activation\nMembrane damageReceptor activation (e.g. TNF-\u03b1)\nICE-related protease activation\nPARP inactivation\nDNA fragmentationMyocardial\nischaemia\nDysrhythmiasCardiac work\nCardiac efficiencySympathetic\nactivityPAIN Opioids\n\u03b2-Adrenoceptor \nantagonistsThrombolytic drugs\nAspirinOxygenNitrates\nFig. 22.8 Effects of myocardial ischaemia. This leads to cell death by one of two pathways: necrosis or apoptosis. ACEI,", "start_char_idx": 0, "end_char_idx": 3142, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "21b54023-5f78-4403-932e-fbb9c9664fc2": {"__data__": {"id_": "21b54023-5f78-4403-932e-fbb9c9664fc2", "embedding": null, "metadata": {"page_label": "283", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "97497838-610a-45cd-9620-2a36d02d869f", "node_type": null, "metadata": {"page_label": "283", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69f26d1aa9d42583ca0e853561e131a68e941324989918e29798e2eb25803107"}, "2": {"node_id": "56a0e6b9-b839-4d33-b3db-8d51255697f0", "node_type": null, "metadata": {"page_label": "283", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "de270c333b364eeb638382e45cb0da0abb58daab8005bec3faf7ade8b12f4eee"}}, "hash": "83a7ba44a92fd48e3ece0db048bc22b12ff8c763d59aaf915d6a54217f07a201", "text": "to cell death by one of two pathways: necrosis or apoptosis. ACEI, angiotensin-\nconverting enzyme inhibitor; ARB, angiotensin AT 1 receptor antagonist; ICE, interleukin-1-converting enzyme; PARP,\tpoly-[ADP-ribose]-\npolymerase; TNF-\u03b1, tumour necrosis factor- \u03b1. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3076, "end_char_idx": 3816, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f51487ec-4c73-4110-b1c0-881f0be33cc2": {"__data__": {"id_": "f51487ec-4c73-4110-b1c0-881f0be33cc2", "embedding": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ade2c52b-f06e-46de-b11a-eb18896fc798", "node_type": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d76c65d4ffd3eb066c18e4e3f5314f8f24c5290fe5f5c6ea26bfc526d66b5781"}, "3": {"node_id": "666233cf-c6ce-453d-9a60-c6bb4c27f83c", "node_type": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce90fafe504b5b09acc64353dabbf58c7536327678479e6cd8f049eefdee6a8e"}}, "hash": "02b1e9ebb26f311cc91c782c6ed3fcb73922dde404b1163a19a070abc21b6665", "text": "22 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n278\u25bc Both NPR-A and NPR-B incorporate a catalytic guanylyl cyclase \nmoiety (see Ch. 3), and, when activated, increase intracellular cGMP. \nOrganic\tnitrates \t(discussed \tlater) \tand \tendogenous \tnitric \toxide \t(Ch. \t\n21) also increase cGMP, though they interact with soluble rather than \nmembrane-bound guanylyl cyclase. Renal glomerular afferent arterioles \nare dilated by ANP but efferent arterioles are constricted, so filtration \npressure is increased, leading to increased glomerular filtration and enhanced Na\n+ excretion. Elsewhere in the vasculature, natriuretic \npeptides cause vasorelaxation and reduce blood pressure. Recombinant \nBNP (nesiritide) had a yo-yo ride as a potential therapy for acute \nheart failure. After initial regulatory rejection, it was approved in 2001 by the US FDA. However, in 2011 a large study showed that it \ndid not increase life expectancy or improve symptoms requiring \nre-hospitalisation \tin \tsuch \tacutely \till \tpatients \t(O\u2019Connor \tet \tal., \t2011). \t\nThis line of investigation took a happier turn when it was found that \nsacubitril , an inhibitor of neprilysin (see earlier), increases circulating \nBNP and ANP and, in fixed combination with valsartan, is effective \nin treating chronic heart failure (see Ch.23).\nISCHAEMIC HEART DISEASE\nAtheromatous deposits are ubiquitous in the coronary \narteries of adults living in developed countries. They are \nasymptomatic for most of the natural history of the disease \n(see Ch. 24), but can progress insidiously, culminating in acute myocardial infarction and its complications, including \ndysrhythmia and heart failure. Details of ischaemic heart \ndisease are beyond the scope of this book, and excellent \naccounts (e.g. Mann et al., 2014) are available for those \nseeking pathological and clinical information. Here, we merely set the scene for understanding the place of drugs \nthat affect cardiac function in treating this most common \nform of heart disease.\nImportant consequences of coronary atherosclerosis \ninclude:\n\u2022\tangina \t(chest \tpain \tcaused \tby \tcardiac \tischaemia)\n\u2022\tmyocardial \tinfarction\nANGINA\nAngina occurs when the oxygen supply to the myocardium is insufficient for its needs. The pain has a characteristic \ndistribution in the chest, arm and neck, and is brought on \nby exertion, cold or excitement. A similar type of pain occurs in skeletal muscle when it is made to contract while its \nblood supply is interrupted, and Lewis showed many years \nago that chemical factors released by ischaemic muscle are responsible. Possible candidates include K\n+, H+ and adeno -\nsine (Ch. 17), all of which sensitise or stimulate nociceptors \n(see Ch. 43). It is possible that the same mediator that causes \ncoronary vasodilatation is responsible, at higher concentra -\ntion, for initiating pain.\nThree kinds of angina are recognised clinically: stable, \nunstable and variant.\nStable angina. This is predictable chest pain on exertion. \nIt is produced by an increased demand on the heart and is \nusually caused by fixed narrowing(s) of the coronary vessels cyclase and thus reduce cAMP formation, acting to inhibit the opening \nof L-type Ca2+ channels and reduce the slow Ca2+ current, in opposition \nto \u03b21 adrenoceptors. M 2 receptors also open a type of K+ channel known \nas\tGIRK\t(G\tprotein\u2013activated \tinward\trectifying \tK+ channel) via produc", "start_char_idx": 0, "end_char_idx": 3399, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "666233cf-c6ce-453d-9a60-c6bb4c27f83c": {"__data__": {"id_": "666233cf-c6ce-453d-9a60-c6bb4c27f83c", "embedding": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ade2c52b-f06e-46de-b11a-eb18896fc798", "node_type": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d76c65d4ffd3eb066c18e4e3f5314f8f24c5290fe5f5c6ea26bfc526d66b5781"}, "2": {"node_id": "f51487ec-4c73-4110-b1c0-881f0be33cc2", "node_type": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "02b1e9ebb26f311cc91c782c6ed3fcb73922dde404b1163a19a070abc21b6665"}, "3": {"node_id": "621a0770-1a93-4d19-a02f-458780730291", "node_type": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50bfe73ce7e8af92ca8d3d6eaf5751b3e5ed569bb1ae131b3ce9ad15c988ff85"}}, "hash": "ce90fafe504b5b09acc64353dabbf58c7536327678479e6cd8f049eefdee6a8e", "text": "\tinward\trectifying \tK+ channel) via produc -\ntion of G \u03b2/\u03b3 subunits (see Ch. 3). The resulting increase in K+ perme -\nability produces a hyperpolarising current that opposes the inward \npacemaker current, slowing the heart and reducing automaticity (see \nFig. 22.7C). Vagal activity is often increased during myocardial infarction, both in association with vagal afferent stimulation and as a side effect \nof opioids used to control the pain, and parasympathetic effects are \nimportant in predisposing to acute dysrhythmias.\nVagal stimulation decreases the force of contraction of the atria \nassociated with marked shortening of the action potential (see Fig. \n22.7D). Increased K\n+ permeability and reduced Ca2+ current both \ncontribute to conduction block at the AV node, where propagation \ndepends on the Ca2+ current. Shortening the atrial action potential \nreduces the refractory period, which can lead to re-entrant arrhythmias. Coronary vessels lack cholinergic innervation; consequently, the \nparasympathetic nervous system has little effect on coronary artery tone (see Ch. 14).\nAutonomic control of the heart \n\u2022\tSympathetic \tactivity, \tacting \tthrough \t\u03b21 adrenoceptors, \nincreases heart rate, contractility and automaticity, but \nreduces cardiac efficiency (in relation to oxygen \nconsumption).\n\u2022\tThe\t\u03b21\tadrenoceptors \tact \tby \tincreasing \tcAMP \t\nformation, which increases Ca2+ currents.\n\u2022\tParasympathetic \tactivity, \tacting \tthrough \tmuscarinic \tM2 \nreceptors, causes cardiac slowing, decreased force of \ncontraction (atria only) and inhibition of atrioventricular \nconduction.\n\u2022\tM 2\treceptors \tinhibit \tcAMP \tformation \tand \talso \topen \t\npotassium channels, causing hyperpolarisation.\n3The nomenclature of natriuretic peptides and their receptors is \npeculiarly \tobtuse. \tThe \tpeptides \tare \tnamed \t\u2018A\u2019 \tfor \tatrial, \t\u2018B\u2019 \tfor \tbrain \t\n\u2013\tdespite \tbeing \tpresent \tmainly \tin \tcardiac \tventricle \t\u2013 \tand \t\u2018C\u2019 \tfor \tA, \tB, \tC \t\n\u2026; NPRs are named NPR-A, which preferentially binds ANP; NPR-B, \nwhich\tbinds \tCNP \tpreferentially; \tand \tNPR-C \tfor \t\u2018clearance\u2019 \treceptor, \t\nbecause until recently clearance via cellular uptake and degradation by \nlysosomal enzymes was the only definite known function of this \nbinding site.CARDIAC NATRIURETIC PEPTIDES\nCardiac natriuretic peptides are an important family of \nmediators (see Potter et al., 2009, for a review). Atrial cells \ncontain secretory granules, and store and release atrial \nnatriuretic peptide (ANP). This has powerful effects on the \nkidney and vascular system. Release of ANP occurs during \nvolume overload in response to stretching of the atria, and intravenous saline infusion is sufficient to stimulate its \nrelease. B-natriuretic peptide (BNP) is released from ven -\ntricular muscle and opposes ventricular fibrosis; its plasma \nconcentration is increased in patients with heart failure \nand this (or the concentration of its precursor, N-terminal \npro-BNP) is used as an aid to diagnosis. C-natriuretic peptide (CNP) is stored in endothelium and, in addition to vascular actions, influences the development of long bones. Both \nANP and BNP are inactivated by neprilysin, also known \nas neutral endopeptidase (NEP) (see Ch. 23).\nThe main effects of natriuretic peptides are to increase", "start_char_idx": 3362, "end_char_idx": 6621, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "621a0770-1a93-4d19-a02f-458780730291": {"__data__": {"id_": "621a0770-1a93-4d19-a02f-458780730291", "embedding": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ade2c52b-f06e-46de-b11a-eb18896fc798", "node_type": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d76c65d4ffd3eb066c18e4e3f5314f8f24c5290fe5f5c6ea26bfc526d66b5781"}, "2": {"node_id": "666233cf-c6ce-453d-9a60-c6bb4c27f83c", "node_type": null, "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce90fafe504b5b09acc64353dabbf58c7536327678479e6cd8f049eefdee6a8e"}}, "hash": "50bfe73ce7e8af92ca8d3d6eaf5751b3e5ed569bb1ae131b3ce9ad15c988ff85", "text": "Ch. 23).\nThe main effects of natriuretic peptides are to increase \nNa\n+ and water excretion by the kidney; relax vascular \nsmooth muscle (except efferent arterioles of renal glomeruli; \nsee below); increase vascular permeability; and inhibit the \nrelease and/or actions of several vasoconstrictor or salt-retaining hormones and mediators, including aldosterone, \nangiotensin II, endothelin and antidiuretic hormone. They \nexert their effects by combining with membrane receptors (natriuretic peptide receptors, NPRs, which exist in at least \ntwo subtypes, designated A and B).\n3mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6594, "end_char_idx": 7651, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9dd422ae-18f5-47e1-9718-cfec930ea23f": {"__data__": {"id_": "9dd422ae-18f5-47e1-9718-cfec930ea23f", "embedding": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "62807d3a-5e23-487b-b916-94a21a8f6499", "node_type": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1636d64415339b6c3893fca13894eeec4f47c325fec28f887380bc8f16a5466e"}, "3": {"node_id": "78b5686a-65fb-49f6-a8fe-3f0056af5bc2", "node_type": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b5876122e6d524de9e5fd761ed0b3124d2a0925946f8bb6a10fd2b438ad61c1"}}, "hash": "fdf649ec37e4ca498bfd949426f0e8036a7e3a855feaa0488b64c5ddb24d2236", "text": "22 ThE hEART\n279cardiac function by maintaining oxygenation and reducing \ncardiac work, as well as treating pain and preventing further \nthrombosis. They are used in combination, and include:\n\u2022\tcombinations \tof \tthrombolytic, \tantiplatelet \t(aspirin \tand \t\nclopidogrel) and antithrombotic (a heparin \npreparation) drugs to open the blocked artery and \nprevent reocclusion (see Ch. 25)\n\u2022\toxygen \tif \tthere \tis \tarterial \thypoxia;\n\u2022\topioids \t(given \twith \tan \tantiemetic) \tto \tprevent \tpain \tand \t\nreduce excessive sympathetic activity;\n\u2022\torganic \tnitrate;\n\u2022\t\u03b2-adrenoceptor antagonists;\n\u2022\tangiotensin-converting \tenzyme \tinhibitors \t(ACEIs) \tor\t\nangiotensin AT 1 receptor antagonists (ARBs; see Ch. 23).\n\u03b2-Adrenoceptor antagonists reduce cardiac work and thereby the metabolic needs of the heart, and are used as \nsoon as the patient is stable. ACEIs and ARBs also reduce cardiac work and improve survival, as does opening the \ncoronary artery (with angioplasty or thrombolytic drug) \nand antiplatelet treatment.\nDRUGS THAT AFFECT \nCARDIAC FUNCTION\nDrugs that have a major action on the heart can be divided into three groups.\n1. Drugs that affect myocardial cells directly. These include:\n a. autonomic neurotransmitters and related drugs\n b. antidysrhythmic drugs\n c. cardiac glycosides and other inotropic drugs\n d. miscellaneous drugs and hormones; these are dealt \nwith elsewhere (e.g. doxorubicin, Ch. 57; thyroxine, Ch. 35; glucagon, Ch. 32)\n2. Drugs that affect cardiac function indirectly. These have actions elsewhere in the vascular system. Some \nanti-anginal drugs (e.g. nitrates) fall into this category, \nas do many drugs that are used to treat heart failure (e.g. diuretics and ACEIs).\n3. Calcium antagonists. These affect cardiac function by a direct action on myocardial cells and also indirectly \nby relaxing vascular smooth muscle.\nANTIDYSRHYTHMIC DRUGS\nA classification of antidysrhythmic drugs based on their \nelectrophysiological effects was proposed by Vaughan \nWilliams in 1970 (Table 22.1). It provides a good starting \npoint for discussing mechanisms, although many useful drugs do not fit neatly into this classification (Table 22.2). \nFurthermore, emergency treatment of serious dysrhythmias \nis usually by physical means (e.g. pacing or electrical cardioversion by applying a direct current shock to the \nchest or via an implanted device) rather than drugs.\nThere are four classes (see Table 22.1).\n\u2022\tClass\tI: \tdrugs \tthat \tblock \tvoltage-sensitive \tsodium \t\nchannels. They are subdivided: Ia, Ib and Ic.\n\u2022\tClass\tII: \t\u03b2-adrenoceptor antagonists.\n\u2022\tClass\tIII: \tdrugs \tthat \tsubstantially \tprolong \tthe \tcardiac \t\naction potential.\n\u2022\tClass\tIV: \tcalcium \tantagonists.\nThe phase of the action potential on which each of these \nclasses of drug have their main effect is shown in Fig. 22.9.by atheroma, although, as explained above, narrowing of \nthe\taortic \tvalve \t(\u2018aortic \tstenos is\u2019)\tcan \tcause \tangina \tby \treducin g\t\ncoronary blood flow even in the absence of coronary artery narrowing. Symptomatic therapy is directed at reducing \ncardiac work with organic nitrates, \u03b2-adrenoceptor antago -\nnists and/or calcium", "start_char_idx": 0, "end_char_idx": 3140, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "78b5686a-65fb-49f6-a8fe-3f0056af5bc2": {"__data__": {"id_": "78b5686a-65fb-49f6-a8fe-3f0056af5bc2", "embedding": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "62807d3a-5e23-487b-b916-94a21a8f6499", "node_type": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1636d64415339b6c3893fca13894eeec4f47c325fec28f887380bc8f16a5466e"}, "2": {"node_id": "9dd422ae-18f5-47e1-9718-cfec930ea23f", "node_type": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fdf649ec37e4ca498bfd949426f0e8036a7e3a855feaa0488b64c5ddb24d2236"}, "3": {"node_id": "4829c3e4-24ac-4cf5-8cfe-61db4b1f5f7f", "node_type": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc88af35d68efe6020207a2f552424fecc30b5dc7caab9d515b23d50512dbc2a"}}, "hash": "4b5876122e6d524de9e5fd761ed0b3124d2a0925946f8bb6a10fd2b438ad61c1", "text": "nitrates, \u03b2-adrenoceptor antago -\nnists and/or calcium antagonists, together with treatment \nof the underlying atheromatous disease, usually including \na statin (Ch. 24), and prophylaxis against thrombosis with \nan antiplatelet drug, such as aspirin (Ch. 25).\nUnstable angina. This is characterised by pain that occurs \nwith less and less exertion, culminating in pain at rest. The \npathology is similar to that involved in myocardial infarc -\ntion,\tnamely \tplatelet\u2013fibrin \tthrombus \tassociated \twith \ta \t\nruptured atheromatous plaque, but without complete \nocclusion of the vessel. Treatment is similar to that for \nmyocardial infarction and includes imaging and considera -\ntion of revascularisation procedures. Antiplatelet drugs \n(aspirin and/or an ADP antagonist such as clopidogrel or \nprasugrel , see Ch. 17) reduce the risk of myocardial infarc -\ntion in this setting, and antithrombotic drugs add to this benefit (Ch. 25) at the cost of increased risk of haemorrhage. \nOrganic\tnitrates \t(see \tlater) \tare \tused \tto \trelieve \tischaemic \t\npain.\nVariant angina. This is relatively uncommon. It can occur \nat rest and is caused by coronary artery spasm, often in \nassociation with atheromatous disease. Therapy is with \ncoronary artery vasodilators (e.g. organic nitrates, calcium antagonists).\nMYOCARDIAL INFARCTION\nMyocardial infarction occurs when a coronary artery has been blocked by thrombus. This may be fatal and is a \ncommon cause of death, usually as a result of mechanical \nfailure of the ventricle or from dysrhythmia. Cardiac myocytes rely on aerobic metabolism. If the supply of oxygen \nremains below a critical value, a sequence of events leading \nto cell death ensues, detected clinically by an elevation of circulating troponin (a biochemical marker of myocardial \ninjury) as well as of cardiac enzymes (e.g. the cardiac isoform of creatinine kinase) and changes in the surface ECG. The sequences leading from vascular occlusion to cell death via necrosis or apoptosis (see Ch. 6) are illustrated in Fig. \n22.8. The relative importance of these two pathways in \ncausing myocardial cell death is unknown, but apoptosis may be an adaptive process in hypoperfused regions, \nsacrificing some jeopardised myocytes and thereby avoiding \nthe disturbance of membrane function and risk of dys -\nrhythmia inherent in necrosis. Consequently, it is currently \nunknown if pharmacological approaches to promote or \ninhibit this pathway could be clinically beneficial.\nPrevention of irreversible ischaemic damage\n4 following \nan\tepisode \tof \tcoronary \tthrombosis \tis \tcrucial. \tOpening \tthe \t\noccluded artery must be achieved as fast as possible. If logistically possible, angioplasty (performed using a catheter \nwith an inflatable balloon near its tip, with administration \nof\ta\tglycoprotein \tIIb/IIIa \tantagonist \t\u2013 \tsee \tChapter \t25 \t\u2013 \tto \t\nprevent reocclusion) is somewhat more effective than thrombolytic drugs, which are an effective alternative if \nangioplasty is unavailable. The main therapeutic drugs for \nmyocardial infarction (see Fig. 22.8) include drugs to improve \n4\u2018Irreversible\u2019 \tby \tpresent \ttechnologies; \tcell \ttherapies \tbased \ton \tcardiac \t\nstem cells have been attempted therapeutically, and are a beacon of \nhope for the future.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3092, "end_char_idx": 6421, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4829c3e4-24ac-4cf5-8cfe-61db4b1f5f7f": {"__data__": {"id_": "4829c3e4-24ac-4cf5-8cfe-61db4b1f5f7f", "embedding": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "62807d3a-5e23-487b-b916-94a21a8f6499", "node_type": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1636d64415339b6c3893fca13894eeec4f47c325fec28f887380bc8f16a5466e"}, "2": {"node_id": "78b5686a-65fb-49f6-a8fe-3f0056af5bc2", "node_type": null, "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b5876122e6d524de9e5fd761ed0b3124d2a0925946f8bb6a10fd2b438ad61c1"}}, "hash": "bc88af35d68efe6020207a2f552424fecc30b5dc7caab9d515b23d50512dbc2a", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6423, "end_char_idx": 6886, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "254862c7-9e13-4df1-b217-f64ca03fc5e3": {"__data__": {"id_": "254862c7-9e13-4df1-b217-f64ca03fc5e3", "embedding": null, "metadata": {"page_label": "286", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "965806fe-f867-4cb4-8531-b9cf2577130e", "node_type": null, "metadata": {"page_label": "286", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ae8b97cb1cc2511c117b82702c09d8dbf6d937de1b30d5c043fbe618db5dd1d"}, "3": {"node_id": "56a39164-b80f-485f-b1d7-0372c18fd5b4", "node_type": null, "metadata": {"page_label": "286", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b9f2c77737a54373932675ee93e5552488141bf8e10bfd2bea5b1f19bf980733"}}, "hash": "d5bed146dc17ff5cda1990c2f4d3f358fda071f336ac410a7a3324fc8dedaa25", "text": "22 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n280depolarisation, as in ischaemic muscle, causes channels to change \nmore slowly from open to inactivated, and the membrane, which is \nthen refractory, must then be repolarised for a time to restore the \nchannel to the resting state before it can be activated again. Class I drugs bind to channels most strongly when they are in either the \nopen or the inactivated state, less strongly to channels in the resting \nstate.\tTheir \taction \ttherefore \tshows \tthe \tproperty \tof \t\u2018use \tdependence\u2019 \t\n(i.e. the more frequently the channels are activated, the greater the \ndegree of block produced).\nClass Ib drugs, for example, lidocaine , associate and dissociate rapidly \nwithin the timeframe of the normal heartbeat. The drug binds to \nopen channels during phase 0 of the action potential (affecting the \nrate of rise very little, but leaving many of the channels blocked by the time the action potential reaches its peak). Dissociation occurs in \ntime for the next action potential, provided the cardiac rhythm is \nnormal. A premature beat, however, will be aborted because the channels are still blocked. Furthermore, class Ib drugs bind selectively \nto inactivated channels and thus block preferentially when the cells \nare depolarised, for example, in ischaemia.\nClass Ic drugs, such as flecainide and encainide, associate and dis-\nsociate much more slowly, thus reaching a steady-state level of block that does not vary appreciably during the cardiac cycle. They markedly \ninhibit\tconduction \tthrough \tthe \tHis\u2013Purkinje \tsystem.\nClass Ia, the oldest group (e.g. quinidine, procainamide, disopyra-\nmide ), lies midway in its properties between Ib and Ic but, in addition, \nprolongs repolarisation, albeit less markedly than class III drugs (see later).\nClass II drugs\nClass II drugs comprise the \u03b2-adrenoceptor antagonists \n(e.g. metoprolol).\nAdrenaline can cause dysrhythmias by its effects on the \npacemaker potential and on the slow inward Ca2+ current \n(see\tpp.\t276\u2013277). \tVentricular \tdysrhythmias \tfollowing \t\nmyocardial infarction are partly the result of increased \nsympathetic activity (see Fig. 22.8), providing a rationale \nfor using \u03b2-adrenoceptor antagonists in this setting. AV \nconduction depends critically on sympathetic activity; \n\u03b2-adrenoceptor antagonists increase the refractory period MECHANISMS \u2003OF \u2003ACTION\nClass I drugs\nClass I drugs block sodium channels, just as local anaesthet -\nics do, by binding to sites on the \u03b1 subunit (see Chs 4 and \n44). Because this inhibits action potential propagation in \nmany\texcitable\tcells,\tit\thas\tbeen\treferred\tto\tas\ta\t\u2018membrane-\nstabilising\u2019 \tactivity, \ta \tphrase \tbest \tavoided \tnow \tthat \tthe \t\nionic mechanism is understood. The characteristic effect \non the action potential is to reduce the maximum rate of \ndepolarisation during phase 0.\n\u25bc The reason for further subdivision of these drugs into classes Ia, \nIb and Ic is that the earliest examples, quinidine and procainamide \n(class Ia), have different effects from many of the more recently \ndeveloped drugs, even though all share the same basic mechanism \nof action. A partial explanation for these functional differences comes from electrophysiological studies of the characteristics of the sodium-\nchannel block produced by different class I drugs.\nThe central concept is of use-dependent channel block. It is this charac -\nteristic that enables all class I drugs to block the high-frequency \nexcitation of the myocardium that occurs in", "start_char_idx": 0, "end_char_idx": 3513, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "56a39164-b80f-485f-b1d7-0372c18fd5b4": {"__data__": {"id_": "56a39164-b80f-485f-b1d7-0372c18fd5b4", "embedding": null, "metadata": {"page_label": "286", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "965806fe-f867-4cb4-8531-b9cf2577130e", "node_type": null, "metadata": {"page_label": "286", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ae8b97cb1cc2511c117b82702c09d8dbf6d937de1b30d5c043fbe618db5dd1d"}, "2": {"node_id": "254862c7-9e13-4df1-b217-f64ca03fc5e3", "node_type": null, "metadata": {"page_label": "286", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d5bed146dc17ff5cda1990c2f4d3f358fda071f336ac410a7a3324fc8dedaa25"}}, "hash": "b9f2c77737a54373932675ee93e5552488141bf8e10bfd2bea5b1f19bf980733", "text": "drugs to block the high-frequency \nexcitation of the myocardium that occurs in tachyarrhythmias, without preventing the heart from beating at normal frequencies. Sodium \nchannels exist in three distinct functional states: resting, open and \ninactivated (see Ch. 4). Channels switch rapidly from resting to open in response to depolarisation; this is known as activation . Maintained Table 22.2 Antidysrhythmic drugs unclassified in the \nVaughan Williams system\nDrug Use\nAtropine Sinus bradycardia\nAdrenaline (epinephrine) Cardiac arrest\nIsoprenaline Heart block\nDigoxin Rapid atrial fibrillation\nAdenosine Supraventricular tachycardia\nCalcium chloride Ventricular tachycardia due to \nhyperkalaemia\nMagnesium chloride Ventricular fibrillation, digoxin toxicityRapid\ndepolarisation\n(phase 0)b-Agonists\nClass II\nPlateau\n(phase 2)Pacemaker\npotential\n(phase 4)\nRepolarisation\n(phase 3)Class IV Class I\nClass III\n(and Ia)\nFig. 22.9 Effects of antidysrhythmic drugs on the different \nphases (as defined in Fig. 22.1) of the cardiac action \npotential. Table 22.1 Summary of antidysrhythmic drugs (Vaughan \nWilliams classification)\nClass Example(s) Mechanism\nIa Disopyramide Sodium-channel block (intermediate dissociation)\nIb Lidocaine Sodium-channel block (fast dissociation)\nIc Flecainide Sodium-channel block (slow dissociation)\nII Propranolol \u03b2-Adrenoceptor antagonism\nIII Amiodarone, sotalolPotassium-channel block\nIV Verapamil Calcium-channel blockmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3435, "end_char_idx": 5363, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fa4ff7ac-be03-4a2e-bed2-19cb38f85302": {"__data__": {"id_": "fa4ff7ac-be03-4a2e-bed2-19cb38f85302", "embedding": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d36bd17-f2bb-444f-b35f-6cfb23804a5f", "node_type": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16f9bd81a8063e62df42a2cd2a069793e2cd560066f974fb73ff44f7cb163645"}, "3": {"node_id": "9df91b08-b219-4ea3-9db2-04ab844fa90b", "node_type": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2eaa7eb896abf6d08c433fff0b88d2d031e6d8ef62d2db950ff3949738a46d79"}}, "hash": "3b61cd67cc217d457642675fdbd656514e0dd93e8ef0426feab0909b6be93c74", "text": "22 ThE hEART\n281DETAILS \u2003OF \u2003INDIVIDUAL \u2003DRUGS\nQuinidine, procainamide and disopyramide \n(class Ia)\nQuinidine and procainamide, now mainly of historical \ninterest, are pharmacologically similar. Disopyramide \nresembles quinidine, possessing an atropine-like effect, \ndistinct from its class Ia action, which can cause blurred vision, dry mouth, constipation and urinary retention. It \nhas more negative inotropic action than quinidine but is \nless likely to cause hypersensitivity reactions.\nLidocaine (class Ib)\nLidocaine, also well known as a local anaesthetic (see Ch. 43), has been given by intravenous infusion, to treat and \nprevent ventricular dysrhythmias in the immediate after-\nmath of myocardial infarction, but is now seldom used. It is almost completely extracted from the portal circulation \nby hepatic presystemic metabolism (Ch. 10), and so cannot \nusefully be swallowed (although if administered into the mouth to produce local anaesthesia it can be absorbed \ndirectly into the systemic circulation and cause systemic \neffects). Its plasma half-life is normally about 2 h, but its \nelimination is slowed if hepatic blood flow is reduced, for \nexample by reduced cardiac output following myocardial \ninfarction or by drugs that reduce cardiac output (e.g. \n\u03b2-adrenoceptor antagonists). Dosage must be reduced accordingly to prevent accumulation and toxicity. Indeed, \nits clearance has been used to estimate hepatic blood flow, \nanalogous to the use of para-aminohippurate (PAH) clear -\nance to measure renal blood flow (Ch. 10).\nThe adverse effects of lidocaine are mainly due to its \nactions on the central nervous system and include drowsi -\nness, disorientation and convulsions. Because of its relatively short half-life, the plasma concentration can be adjusted \nfairly rapidly by varying the infusion rate.\nFlecainide and encainide (class Ic)\nFlecainide and encainide suppress ventricular ectopic beats. \nThey are long-acting and reduce the frequency of ventricular ectopic beats when administered orally. However, in clinical \ntrials, they unexpectedly increased the incidence of sudden death associated with ventricular fibrillation after myocardial \ninfarction, so they are no longer used in this setting. This \ncounterintuitive result had a profound impact on the way clinicians and drug regulators view the use of seemingly \nreasonable intermediate end points (in this case, reduction \nof frequency of ventricular ectopic beats) as evidence of efficacy in clinical trials.\n\u03b2-Adrenoceptor antagonists (class II)\n\u03b2-Adrenoceptor antagonists are described in Chapter 15. Their clinical use for rhythm disorders is shown in the \nclinical box. Propranolol, like several other drugs of this \ntype, has some class I action in addition to blocking \u03b2 \nadrenoceptors. This may contribute to its antidysrhythmic effects, although probably not very much, because an isomer \nwith little \u03b2-antagonist activity has little antidysrhythmic activity, despite similar activity as a class I agent.\nAdverse effects include worsening bronchospasm in \npatients with asthma, a negative inotropic effect, bradycardia and fatigue. It was hoped that the use of \u03b2\n1-selective drugs \n(e.g. metoprolol, atenolol) would remove the risk of \nbronchospasm, but their selectivity is insufficient to achieve this goal in clinical practice, although the once-a-day of the AV node and can therefore prevent recurrent attacks of SVT. The \u03b2-adrenoceptor antagonists are also used to \nprevent paroxysmal attacks of atrial fibrillation when these \noccur in the setting of sympathetic activation.\nClass III drugs\nThe class III category was originally based on the unusual", "start_char_idx": 0, "end_char_idx": 3658, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9df91b08-b219-4ea3-9db2-04ab844fa90b": {"__data__": {"id_": "9df91b08-b219-4ea3-9db2-04ab844fa90b", "embedding": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d36bd17-f2bb-444f-b35f-6cfb23804a5f", "node_type": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16f9bd81a8063e62df42a2cd2a069793e2cd560066f974fb73ff44f7cb163645"}, "2": {"node_id": "fa4ff7ac-be03-4a2e-bed2-19cb38f85302", "node_type": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b61cd67cc217d457642675fdbd656514e0dd93e8ef0426feab0909b6be93c74"}, "3": {"node_id": "22dc2746-df01-45fb-ac99-a26114bae1d7", "node_type": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b24b55e985960171cc8de086c3a6feffca1b7c5728fac6b867a05378fe1e77f8"}}, "hash": "2eaa7eb896abf6d08c433fff0b88d2d031e6d8ef62d2db950ff3949738a46d79", "text": "activation.\nClass III drugs\nThe class III category was originally based on the unusual \nbehaviour of a single drug, amiodarone (see p. 282), although \nothers with similar properties (e.g. sotalol ) have since been \ndescribed. Both amiodarone and sotalol have more than one mechanism of antidysrhythmic action. The special feature \nthat defines them as class III drugs is that they substantially \nprolong the cardiac action potential. The mechanism of this effect is not fully understood, but it involves block -\ning some of the potassium channels involved in cardiac repolarisation, including the outward (delayed) rectifier. Action potential prolongation increases the refractory period, accounting for powerful and varied antidysrhythmic activity, \nfor example, by interrupting re-entrant tachycardias and \nsuppressing ectopic activity. However, drugs that prolong the cardiac action potential (detected clinically as prolonged \nQT interval on the ECG; see earlier) can paradoxically also \nhave proarrhythmic effects, notably a polymorphic form of \nventricular tachycardia called (somewhat whimsically) \ntorsade de pointes (because the appearance of the ECG \ntrace is said to be reminiscent of this ballet sequence). This occurs particularly in patients taking other drugs that can \nprolong QT, including several antipsychotic drugs; those \nwith disturbances of electrolytes involved in repolarisation (e.g. hypokalaemia, hypercalcaemia); or individuals with \nhereditary \tprolonged \tQT \t(Ward\u2013Romano \tsyndrome).5 The \nmechanism of the dysrhythmia is not fully understood; \npossibilities include increased dispersion of repolarisation \n(i.e. lack of spatial homogeneity) and increased Ca2+ entry \nduring the prolonged action potential, leading to increased \nafter-depolarisation.\nClass IV drugs\nClass IV agents act by blocking voltage-sensitive calcium \nchannels. Class IV drugs in therapeutic use as antidysrhythmic \ndrugs (e.g. verapamil) act on L-type channels. Class IV \ndrugs slow conduction in the SA and AV nodes where \naction potential propagation depends on inward Ca2+ current, \nslowing the heart and terminating SVT by causing partial \nAV block. They shorten the plateau of the action potential \nand reduce the force of contraction. Decreased Ca2+ entry \nreduces after-depolarisation and thus suppresses premature \nectopic beats. Functionally distinct classes of L-type voltage-\ngated calcium channels are expressed in heart and vascular smooth muscle, and L-type calcium-channel blockers that \nact mainly on vascular smooth muscle (e.g. nifedipine) \nindirectly increase sympathetic tone via their hypotensive \neffect, causing reflex tachycardia.\n5A 3-year-old girl began to have blackouts, which decreased in \nfrequency with age. Her ECG showed a prolonged QT interval. When \n18 years of age, she lost consciousness running for a bus. When she was \n19, she became quite emotional as a participant in a live television audience and died suddenly. The molecular basis of this rare inherited \ndisorder is now known. It is caused by a mutation in either the gene \ncoding\tfor \ta \tparticular \tpotassium \tchannel \t\u2013 \tcalled \tHERG \u2013 or another \ngene, SCN5A, which codes for the sodium channel and disruption of \nwhich results in a loss of inactivation of the Na+ current (see Welsh & \nHoshi, 1995, for a commentary).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3584, "end_char_idx": 7113, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "22dc2746-df01-45fb-ac99-a26114bae1d7": {"__data__": {"id_": "22dc2746-df01-45fb-ac99-a26114bae1d7", "embedding": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d36bd17-f2bb-444f-b35f-6cfb23804a5f", "node_type": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16f9bd81a8063e62df42a2cd2a069793e2cd560066f974fb73ff44f7cb163645"}, "2": {"node_id": "9df91b08-b219-4ea3-9db2-04ab844fa90b", "node_type": null, "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2eaa7eb896abf6d08c433fff0b88d2d031e6d8ef62d2db950ff3949738a46d79"}}, "hash": "b24b55e985960171cc8de086c3a6feffca1b7c5728fac6b867a05378fe1e77f8", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7157, "end_char_idx": 7460, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "88b9b458-3d2a-4970-b35d-b8664498bda5": {"__data__": {"id_": "88b9b458-3d2a-4970-b35d-b8664498bda5", "embedding": null, "metadata": {"page_label": "288", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e18a258b-3ab4-4693-b182-f2336d0bf7e6", "node_type": null, "metadata": {"page_label": "288", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2294d4d703a429a8bcf0ae1dd5c212b7e0fab831f65e3f86783103a3923a9eb6"}, "3": {"node_id": "be376c17-09de-4d91-992c-f8ed41f18c4b", "node_type": null, "metadata": {"page_label": "288", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9551aa928526f1da72f0469ce22d40e9cf708fb9deaa4555a4973124365fa2ef"}}, "hash": "5cc1603da08e57b7c725e55cb69a26ec482bf0be4e2dc1a909e40068fe9555d2", "text": "22 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n282convenience of several such drugs has led to their wide -\nspread use.\nClinical uses of class II \nantidysrhythmic drugs (e.g. \npropranolol, timolol) \n\u2022\tTo\treduce \tmortality \tfollowing \tmyocardial \tinfarction.\n\u2022\tTo\tprevent \trecurrence \tof \ttachyarrhythmias \t(e.g. \t\nparoxysmal atrial fibrillation) provoked by increased \nsympathetic activity.\n\u2022\tIn\tmanaging \thyperthyroidism \twhile \tcontrol \twith \t\nantithyroid drugs is being established (Ch. 35).Clinical uses of class III \nantidysrhythmic drugs \n\u2022\tAmiodarone: tachycardia associated with the Wolff\u2013Parkinson\u2013White syndrome. It is also effective in many other supraventricular and ventricular \ntachyarrhythmias but has serious adverse effects.\n\u2022\t(Racemic) \tsotalol combines class III with class II \nactions. It is used in paroxysmal supraventricular \ndysrhythmias and suppresses ventricular ectopic beats \nand short runs of ventricular tachycardia.patients with permanent atrial fibrillation and risk factors \nfor vascular events and is hazardous in such patients \n(Connolly et al., 2011).\nSotalol is a non-selective \u03b2-adrenoceptor antagonist, this \nactivity residing in the L isomer. Unlike other \u03b2 antagonists, \nit prolongs the cardiac action potential and the QT interval \nby delaying the slow outward K+ current. This class III \nactivity is present in both L and D isomers. Racemic sotalol \n(the form prescribed) appears to be somewhat less effective \nthan amiodarone in preventing chronic life-threatening ventricular tachyarrhythmias. It can cause torsades de \npointes; it is valuable in patients in whom \u03b2-adrenoceptor \nantagonists are not contraindicated. Close monitoring of \nplasma K\n+ is important.Clinical uses of class I \nantidysrhythmic drugs \n\u2022\tClass\tIa \t(e.g. \tdisopyramide)\n\u2013 ventricular dysrhythmias\n\u2013 prevention of recurrent paroxysmal atrial fibrillation \ntriggered by vagal overactivity.\n\u2022\tClass Ib (e.g. intravenous lidocaine)\n\u2013 now seldom used.\n\u2022\tClass Ic\n\u2013 to prevent paroxysmal atrial fibrillation ( flecainide)\n\u2013 recurrent tachyarrhythmias associated with abnormal \nconducting pathways (e.g. Wolff\u2013Parkinson\u2013White \nsyndrome).\nClass III\nAmiodarone is highly effective at suppressing dysrhythmias \n(see the clinical box below). Like other drugs that interfere \nwith cardiac repolarisation, it is important to monitor plasma \nelectrolyte concentrations (especially of K+). Unfortunately, \nseveral peculiarities complicate its use. It is extensively \nbound\tin \ttissues, \thas \ta \tlong \telimination \thalf-life \t(10\u2013100 \t\ndays) and accumulates in the body during repeated dosing. For this reason, a loading dose is used, and for life-\nthreatening dysrhythmias this is given intravenously via \na central vein (it causes phlebitis if given into a peripheral vessel). Adverse effects are numerous and important; they \ninclude photosensitive rashes and a slate-grey/bluish \ndiscoloration of the skin; thyroid abnormalities (hypo- and hyper-, connected with its iodine content); pulmonary \nfibrosis, which is late in onset but may be irreversible; \ncorneal deposits; and neurological and gastrointestinal disturbances, including hepatitis. Surprisingly (since it delays repolarisation and prolongs the QT interval) reports \nof", "start_char_idx": 0, "end_char_idx": 3250, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "be376c17-09de-4d91-992c-f8ed41f18c4b": {"__data__": {"id_": "be376c17-09de-4d91-992c-f8ed41f18c4b", "embedding": null, "metadata": {"page_label": "288", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e18a258b-3ab4-4693-b182-f2336d0bf7e6", "node_type": null, "metadata": {"page_label": "288", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2294d4d703a429a8bcf0ae1dd5c212b7e0fab831f65e3f86783103a3923a9eb6"}, "2": {"node_id": "88b9b458-3d2a-4970-b35d-b8664498bda5", "node_type": null, "metadata": {"page_label": "288", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5cc1603da08e57b7c725e55cb69a26ec482bf0be4e2dc1a909e40068fe9555d2"}}, "hash": "9551aa928526f1da72f0469ce22d40e9cf708fb9deaa4555a4973124365fa2ef", "text": "it delays repolarisation and prolongs the QT interval) reports \nof torsades de pointes and ventricular tachycardia are very \nunusual. Dronedarone is a related benzofuran with some -\nwhat different effects on individual ion channels. It does not incorporate iodine and was designed to be less lipophilic \nthan amiodarone in hopes of reducing thyroid and pul -\nmonary toxicities. Its elimination t\n1/2 is shorter than that \nof amiodarone and it is indicated to maintain sinus rhythm \nafter cardioversion of atrial fibrillation, but only as a last \nresort, due to safety concerns: it increased the rates of stroke, heart failure, and death from cardiovascular causes in Verapamil and diltiazem (class IV)\nVerapamil is given by mouth. (Intravenous preparations are available but are dangerous and almost never needed.) \nIt\thas\ta\tplasma \thalf-life \tof \t6\u20138 \th \tand \tis \tsubject \tto \tquite \t\nextensive first-pass metabolism, which is more marked for the isomer that is responsible for its cardiac effects. A \nslow-release preparation is available for once-daily use, \nbut it is less effective when used for prevention of dys -\nrhythmia than the regular preparation because the bio -\navailability of the cardioactive isomer is reduced through the presentation of a steady low concentration to the drug-metabolising enzymes in the liver. If verapamil is \nadded to digoxin in patients with poorly controlled atrial \nfibrillation, the dose of digoxin should be reduced and \nplasma digoxin concentration checked after a few days, because verapamil both displaces digoxin from tissue-\nbinding sites and reduces its renal elimination, hence \npredisposing to digoxin accumulation and toxicity.\n\u25bc\tVerapamil \tis \tcontraindicated \tin \tpatients \twith \tWolff\u2013Parkinson\u2013\nWhite syndrome (a pre-excitation syndrome caused by a rapidly \nconducting pathway between atria and ventricles, anatomically distinct \nfrom the physiological conducting pathway, that predisposes to re-\nentrant tachycardia), and is ineffective and dangerous in ventricular dysrhythmias. Adverse effects of verapamil and diltiazem are described \nbelow in the section on calcium-channel antagonists.\nDiltiazem is similar to verapamil but has relatively more \neffect on smooth muscle while producing less bradycardia \n(said\tto\tbe \t\u2018rate \tneutral\u2019).\nAdenosine (unclassified in the Vaughan \nWilliams classification)\nAdenosine is produced endogenously and is an important chemical mediator (Ch. 17) with effects on breathing, cardiac \nand smooth muscle, vagal afferent nerves and on platelets, \nin addition to the effects on cardiac conducting tissue that mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3184, "end_char_idx": 6266, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9d59313e-e667-4254-bfa6-42b8b511ca23": {"__data__": {"id_": "9d59313e-e667-4254-bfa6-42b8b511ca23", "embedding": null, "metadata": {"page_label": "289", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b8b8ee3d-f697-4b26-813f-020c6807c013", "node_type": null, "metadata": {"page_label": "289", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca05de68630f6d3da24cdefb4bbb8bfc2185524f13f5204e330785d46e144e72"}, "3": {"node_id": "4e50a060-3d75-4e0d-8911-b5acbfc10efb", "node_type": null, "metadata": {"page_label": "289", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "da7e8d71fb89b9cca3dc9a397bf05c1fdf0ed3a5c62c218e1e36a3697e6c55d1"}}, "hash": "474062d9a99596bf61b08416a7e05dfeb4570a0e19f9bb9b7101fd111066c0b8", "text": "22 ThE hEART\n283molecule mainly determining potency and pharmacokinetic \nproperties. Therapeutically the most important cardiac \nglycoside is digoxin.\nEndogenous digitalis-like factors, have been mooted for \nnearly half a century. There is evidence in mammals of an endogenous digitalis-like factor closely similar to ouabain, \na short-acting cardiac glycoside implicated in cardiovascular function (see Schoner & Scheiner-Bobis, 2007; Blaustein \net al., 2016). Endogenous cardiotonic steroids were first \nconsidered important in the regulation of renal sodium transport and arterial pressure, but have also been implicated \nin the regulation of cell growth, differentiation, apoptosis, \nfibrosis, the modulation of immunity and of carbohydrate metabolism, and the control of various central nervous \nfunctions (Bagrov et al., 2009).\nActions and adverse effects\nThe main actions of glycosides are on the heart, but some of their adverse effects are extracardiac, including nausea, \nvomiting, diarrhoea and confusion. The cardiac effects are:\n\u2022\tcardiac \tslowing \tand \treduced \trate \tof \tconduction \t\nthrough the AV node, due to increased vagal activity;\n\u2022\tincreased \tforce \tof \tcontraction;\n\u2022\tdisturbances \tof \trhythm, \tespecially:\n\u2022\tblock\tof \tAV \tconduction\n\u2022\tincreased \tectopic \tpacemaker \tactivity.\nAdverse\teffects\tare\tcommon \tand\tcan\tbe\tsevere.\tOne\tof\tthe\t\nmain drawbacks of glycosides in clinical use is the narrow \nmargin between effectiveness and toxicity.\nMechanism\nThe mechanism whereby cardiac glycosides increase the force of cardiac contraction (positive inotropic effect) is \ninhibition of the Na\n+/K+ pump in the cardiac myocytes. \nThis causes increased [Na+ ]i, and a secondary rise in [Ca2+]i \n(see later). Cardiac glycosides bind to a site on the extracel -\nlular aspect of the \u03b1 subunit of the Na+-K+-ATPase, and \nare useful experimental tools for studying this important transporter. The molecular mechanism underlying increased \nvagal tone (negative chronotropic effect) is unknown, but could also be due to inhibition of the Na\n+/K+ pump.\nRate and rhythm\nCardiac glycosides slow, and in higher concentrations may block, AV conduction by increasing vagal outflow. Their \nbeneficial effect in established rapid atrial fibrillation results \npartly from this. If ventricular rate is excessively rapid, the time available for diastolic filling is inadequate, so slowing \nheart rate by partly blocking AV conduction increases stroke \nvolume and cardiac efficiency even if atrial fibrillation persists. Digoxin can terminate paroxysmal atrial tachycardia \nby its effect on AV conduction, although adenosine (see \nabove) is usually preferred for this indication.\nToxic concentrations of glycosides disturb sinus rhythm. \nThis can occur at plasma concentrations of digoxin within, \nor only slightly above, the therapeutic range. AV block can \noccur, and also ectopic beats. Because Na\n+/K+ exchange is \nelectrogenic, inhibition of the pump by glycosides causes \ndepolarisation, predisposing to disturbances of cardiac \nrhythm. Furthermore, the increased [Ca2+]i causes increased \nafter-depolarisation, leading first to coupled beats \n(bigeminy), in which a normal ventricular beat is followed \nby an ectopic beat; ventricular tachycardia and eventually ventricular fibrillation may ensue.underlie its therapeutic use. The A\n1 receptor is responsible \nfor its effect on the AV node. These receptors are linked to \nthe same cardiac potassium channel that is activated by \nacetylcholine, and adenosine hyperpolarises cardiac conduct -\ning tissue and slows the rate of", "start_char_idx": 0, "end_char_idx": 3576, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4e50a060-3d75-4e0d-8911-b5acbfc10efb": {"__data__": {"id_": "4e50a060-3d75-4e0d-8911-b5acbfc10efb", "embedding": null, "metadata": {"page_label": "289", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b8b8ee3d-f697-4b26-813f-020c6807c013", "node_type": null, "metadata": {"page_label": "289", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca05de68630f6d3da24cdefb4bbb8bfc2185524f13f5204e330785d46e144e72"}, "2": {"node_id": "9d59313e-e667-4254-bfa6-42b8b511ca23", "node_type": null, "metadata": {"page_label": "289", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "474062d9a99596bf61b08416a7e05dfeb4570a0e19f9bb9b7101fd111066c0b8"}}, "hash": "da7e8d71fb89b9cca3dc9a397bf05c1fdf0ed3a5c62c218e1e36a3697e6c55d1", "text": "hyperpolarises cardiac conduct -\ning tissue and slows the rate of rise of the pacemaker potential \naccordingly. It is administered intravenously to terminate \nSVT if this rhythm persists despite manoeuvres such as carotid artery massage to increase vagal tone. It has largely \nreplaced verapamil for this purpose, because it is safer owing \nto its effect being short-lived. This is a consequence of its pharmacokinetics: it is taken up via a specific nucleoside transporter by red blood cells and is metabolised by enzymes \non the lumenal surface of vascular endothelium. Conse-\nquently, the effects of an intravenous bolus dose of adenosine \nlast\tonly \t20\u201330 \ts. \tOnce \tSVT \thas \tterminated, \tthe \tpatient \t\nusually remains in sinus rhythm, even though adenosine is no longer present in plasma. Its short-lived unwanted \neffects include chest pain, shortness of breath, dizziness \nand nausea. Regadenoson is an A\n2A adenosine receptor \nagonist that is used diagnostically in pharmacological cardiac \nstress testing (mentioned later, p. 285). It is claimed that its \nselectivity and short duration of action are advantages over adenosine for this indication. It has a 2- to 3-minute biological \nhalf-life and is administered as a bolus,\nTheophylline and other xanthines (Chs 17 and 28) block \nadenosine receptors and inhibit the actions of intravenous adenosine, whereas dipyridamole (a vasodilator and \nantiplatelet drug; see p. 285 and Ch. 24) blocks the nucleoside uptake mechanism, potentiating adenosine and prolonging its adverse effects. Both these interactions are clinically \nimportant.\nClinical uses of class IV \nantidysrhythmic drugs \n\u2022\tVerapamil is the main drug. It is used:\n\u2013 to prevent recurrence of paroxysmal supraventricular \ntachycardia (SVT)\n\u2013 to reduce the ventricular rate in patients with atrial \nfibrillation, provided they do not have Wolff\u2013\nParkinson\u2013White or a related disorder.\n\u2022\tDiltiazem is similar\n\u2022\tVerapamil was previously given intravenously to terminate SVT; it is now seldom used for this because adenosine is safer. (A slow-release preparation of verapamil is sometimes used to treat hypertension \nand/ or angina, especially where it is desired to slow \nthe heart rate but a \u03b2-adrenoceptor antagonist is \ncontraindicated.)\nDRUGS THAT INCREASE MYOCARDIAL \nCONTRACTION\nCARDIAC \u2003GLYCOSIDES\nCardiac glycosides come from foxgloves ( Digitalis spp.) \nand related plants. Withering wrote on the use of the \nfoxglove \tin \t1775: \t\u2018it \thas \ta \tpower \tover \tthe \tmotion \tof \tthe \t\nheart to a degree yet unobserved in any other medicine \n\u2026\u2019\tFoxgloves \tcontain\tseveral\tcardiac\tglycosides \twith\tsimilar\t\nactions. Their basic chemical structure consists of three \ncomponents: a sugar moiety, a steroid and a lactone ring. \nThe lactone is essential for activity, the other parts of the mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3511, "end_char_idx": 6798, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "22e2fa36-bab5-4101-baf6-7bbcdc85497f": {"__data__": {"id_": "22e2fa36-bab5-4101-baf6-7bbcdc85497f", "embedding": null, "metadata": {"page_label": "290", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8a890c37-be29-45d8-b10b-7c6eacd772e8", "node_type": null, "metadata": {"page_label": "290", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7427a64090147992b686973ac96116a91c728996c64cfd4d8813fa2b05821aaf"}, "3": {"node_id": "840df9c1-8d6a-489b-98d1-f40f1e9b59e8", "node_type": null, "metadata": {"page_label": "290", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1f8b33fd512d6bb29e8f297a93ee5397ac24f6b36d898da8cc3686f59aaa8323"}}, "hash": "c703814e85e897d15398344e731622aed3f4fd205e4c73e585106721b607f44a", "text": "22 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n284OTHER \u2003DRUGS \u2003THAT \u2003INCREASE \u2003\u2003\nMYOCARDIAL \u2003CONTRACTION\nCertain \u03b21-adrenoceptor agonists, for example dobutamine , \nare used to treat acute but potentially reversible heart failure \n(e.g. following cardiac surgery or in some cases of cardio -\ngenic or septic shock) because of their positive inotropic action. Dobutamine, for reasons that are not well understood, produces less tachycardia than other \u03b2\n1 agonists. It is used \nintravenously for short-term treatment of acute heart failure, or for pharmacological cardiac stress testing and echocar -\ndiography. Glucagon also increases myocardial contractility \nby increasing synthesis of cAMP, and has been used in patients with acute cardiac dysfunction caused by overdos -\nage of \u03b2-adrenoceptor antagonists.\nInhibitors of the heart-specific subtype (type III) of phos -\nphodiesterase, the enzyme responsible for the intracellular degradation of cAMP, increase myocardial contractility. Consequently, like \u03b2-adrenoceptor agonists, they increase \nintracellular cAMP and can cause dysrhythmias for the same reason. Compounds in this group include amrinone \nand milrinone. They improve haemodynamic indices in \npatients with heart failure but paradoxically worsen sur -\nvival, presumably because of dysrhythmias. As with the encainide/flecainide example (see p. 281) this disparity has had a sobering effect on clinicians and drug regulatory authorities.\nANTI-ANGINAL DRUGS\nThe mechanism of anginal pain is discussed previously. Angina is managed by using drugs that improve perfusion of the myocardium or reduce its metabolic demand, or both. Two of the main groups of drugs, organic nitrates and calcium antagonists, are vasodilators and produce both these effects. The third group, \u03b2-adrenoceptor \nantagonists, slow the heart and hence reduce metabolic \ndemand. \tOrganic\tnitrates\tand\tcalcium\tantagonists \tare\t\ndescribed below. The \u03b2-adrenoceptor antagonists are \ncovered in Chapter 15, and their antidysrhythmic actions are described above. Ivabradine slows the heart by inhibiting the sinus node I\nf current (see p. 272), and is an alterna -\ntive to \u03b2-adrenoceptor antagonists in patients in whom these are not tolerated or are contraindicated. Combined use of ivabradine with a \u03b2-adrenoceptor antagonist is \nindicated in patients whose symptoms are not adequately controlled despite an optimal dose of the \u03b2-adrenoceptor \nantagonist. Ranolazine was introduced as an adjunct to \nother anti-anginal drugs: it inhibits late sodium current and hence indirectly reduces intracellular calcium and force of contraction (the opposite of the effects of cardiac glycosides), without affecting heart rate; more potent and selective inhibitors of the persistent sodium current are in development. Newer anti-anginal drugs are described by \nJones et al. (2013).Force of contraction\nGlycosides cause a large increase in twitch tension in isolated preparations of cardiac muscle. Unlike catecholamines, they do not accelerate relaxation (compare Fig. 22.6 with Fig. 22.10). Increased tension is caused by an increased [Ca\n2+]i \ntransient (see Fig. 22.10). The action potential is only slightly affected and the slow inward current little changed, so the increased [Ca\n2+]i transient probably reflects a greater release \nof Ca2+ from intracellular stores. The most likely mechanism \nis as follows (see also Ch. 4):\n1. Glycosides inhibit the Na+/K+ pump.\n2. Increased [Na+]i slows", "start_char_idx": 0, "end_char_idx": 3477, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "840df9c1-8d6a-489b-98d1-f40f1e9b59e8": {"__data__": {"id_": "840df9c1-8d6a-489b-98d1-f40f1e9b59e8", "embedding": null, "metadata": {"page_label": "290", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8a890c37-be29-45d8-b10b-7c6eacd772e8", "node_type": null, "metadata": {"page_label": "290", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7427a64090147992b686973ac96116a91c728996c64cfd4d8813fa2b05821aaf"}, "2": {"node_id": "22e2fa36-bab5-4101-baf6-7bbcdc85497f", "node_type": null, "metadata": {"page_label": "290", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c703814e85e897d15398344e731622aed3f4fd205e4c73e585106721b607f44a"}}, "hash": "1f8b33fd512d6bb29e8f297a93ee5397ac24f6b36d898da8cc3686f59aaa8323", "text": "the Na+/K+ pump.\n2. Increased [Na+]i slows extrusion of Ca2+ via the Na+/\nCa2+ exchange transporter since increasing [Na+]i \nreduces the inwardly directed gradient for Na+ which \ndrives extrusion of Ca2+ by Na+/Ca2+ exchange.\n3. Increased [Ca2+]i is stored in the sarcoplasmic \nreticulum, and thus increases the amount of Ca2+ \nreleased by each action potential.\nThe effect of extracellular potassium\nEffects of cardiac glycosides are increased if plasma [K+] \ndecreases, because of reduced competition at the K+-binding \nsite on the Na+-K+-ATPase. This is clinically important, \nbecause many diuretics, which are often used to treat heart failure (Ch. 30), decrease plasma [K\n+] thereby increasing \nthe risk of glycoside-induced dysrhythmia.\nPharmacokinetic aspects\nDigoxin is administered by mouth or, in urgent situations, intravenously. It is a polar molecule; elimination is mainly by renal excretion and involves P-glycoprotein (Ch. 9), leading to clinically significant interactions with other drugs used to treat heart failure, such as spironolactone, and \nwith antidysrhythmic drugs such as verapamil and ami-\nodarone\n. Elimination half-time is approximately 36 h in \npatients with normal renal function, but considerably longer in elderly patients and those with overt renal failure, for whom the dose must be reduced. A loading dose is used in urgent situations. The therapeutic range of plasma concentrations, below which digoxin is unlikely to be effective and above which the risk of toxicity increases \nsubstantially, \tis\tra ther\tna rrow\t(1 \u20132.6\tnm ol/L).\tDe termina -\ntion of plasma digoxin concentration is useful when lack of efficacy or toxicity is suspected.\nTension Control \n1 s0.2 mN\n[Ca2+]iAcetylstrophanthidin 0.75 \u00b5mol/L \nFig. 22.10 Effect of a cardiac glycoside \n(acetylstrophanthidin) on the Ca2+ transient and tension \nproduced by frog cardiac muscle. The effect was recorded as \nin\tFig.\t22.6.\t(From\tAllen,\tD.G.,\tBlinks,\tJ.R.,\t1978.\tNature\t273,\t\n509.)Clinical uses of cardiac glycosides \n(e.g. digoxin) \n\u2022\tTo\tslow\tventricular \trate\tin\trapid\tpersistent \tatrial\t\nfibrillation.\n\u2022\tTreatment \tof\theart\tfailure\tin\tpatients\twho\tremain\t\nsymptomatic despite optimal use of diuretics and \nangiotensin-converting enzyme inhibitors (Ch. 23).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3435, "end_char_idx": 6174, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "22486a56-2c49-4545-b5f1-13e0c51c9de7": {"__data__": {"id_": "22486a56-2c49-4545-b5f1-13e0c51c9de7", "embedding": null, "metadata": {"page_label": "291", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d3f734f-7aa8-4cc4-8305-11ce4ace3134", "node_type": null, "metadata": {"page_label": "291", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d3a4cc4e386a84006c7dfbe2a74c1d9fc86bfd8f81cb70c76dc1a810138e9eea"}, "3": {"node_id": "876bd4db-8406-437f-adab-46e582d5ada3", "node_type": null, "metadata": {"page_label": "291", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8170616905bfedd0b44fd95cb22366eb7fc06c80bdd4667d9ad32d228b0ab8eb"}}, "hash": "82c9158607675342ac622a4b090a3897191ddc356b2bcd70a8cbf88ffc2d62c9", "text": "22 ThE hEART\n285consequently reduces central (aortic) pressure and cardiac \nafterload (see Ch. 23 for the role of these factors in determin -\ning cardiac work). The direct dilator effect on coronary arteries opposes coronary artery spasm in variant angina. With larger doses, resistance arteries and arterioles dilate, \nand arterial pressure falls. Nevertheless, coronary flow \nincreases because of coronary vasodilatation. Myocardial oxygen consumption is reduced because of the reductions \nin cardiac preload and afterload. This, together with the \nincreased coronary blood flow, causes a large increase in the oxygen content of coronary sinus blood. Studies in experimental animals have shown that glyceryl trinitrate \ndiverts blood from normal to ischaemic areas of myocar -\ndium. The mechanism involves dilatation of collateral vessels \nthat bypass narrowed coronary artery segments (Fig. 22.11).\n\u25bc It is interesting to compare this effect with that of other vasodila -\ntors, notably dipyridamole , which dilate arterioles but not collaterals. \nDipyridamole is at least as effective as nitrates in increasing coronary \nflow in normal subjects but actually worsens angina. This is probably because arterioles in an ischaemic region are fully dilated by the \nischaemia, and drug-induced dilatation of the arterioles in normal \nareas has the effect of diverting blood away from the ischaemic areas (see Fig. 22.11), producing what is termed a vascular steal. This effect is \nexploited \tin\ta\tpharmacological \t\u2018stress\ttest\u2019\tfor\tcoronary \tarterial\tdisease,\t\nin which dipyridamole is administered intravenously to patients in whom this diagnosis is suspected but who cannot exercise, while \nmonitoring myocardial perfusion and the ECG. Regadenoson is an A\n2A \nadenosine receptor agonist that is used similarly in pharmacological cardiac stress testing (see earlier, p. 283).\nIn summary, the anti-anginal action of nitrates involves:\n\u2022\treduced \tcardiac \twork, \tbecause \tof \treduced \tcardiac \t\npreload (venodilatation) and afterload (reduced \narterial wave reflection), leading to reduced \nmyocardial oxygen requirement;ORGANIC \u2003NITRATES\nThe ability of organic nitrates (see also Chs 21 and 24) to \nrelieve angina was discovered by Lauder Brunton, a dis-\ntinguished British physician, in 1867. He had found that \nangina could be partly relieved by bleeding, and knew that amyl nitrite, which had been synthesised 10 years earlier, \ncaused flushing and tachycardia with a fall in blood pressure \nwhen its vapour was inhaled. He thought that the effect of bleeding resulted from hypotension, and found that amyl \nnitrite inhalation worked much better. Amyl nitrite has \nnow been replaced by glyceryl trinitrate (GTN).\n6 Several \nrelated organic nitrates, of which the most important is \nisosorbide mononitrate, have a prolonged action. Nico-\nrandil, a potassium-channel activator with additional \nnitrovasodilator activity, is sometimes combined with other \nanti-anginal treatment in resistant cases.\nActions\nOrganic\tnitrates \trelax \tsmooth \tmuscle \t(especially \tvascular \t\nsmooth muscle, but also oesophageal and biliary smooth \nmuscle). They relax veins, with a consequent reduction in \ncentral venous pressure (reduced preload). In healthy \nsubjects, this reduces stroke volume; venous pooling occurs on standing and can cause postural hypotension and diz -\nziness. Therapeutic doses have less effect on small resistance arteries than on veins, but there is a marked effect on larger", "start_char_idx": 0, "end_char_idx": 3482, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "876bd4db-8406-437f-adab-46e582d5ada3": {"__data__": {"id_": "876bd4db-8406-437f-adab-46e582d5ada3", "embedding": null, "metadata": {"page_label": "291", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d3f734f-7aa8-4cc4-8305-11ce4ace3134", "node_type": null, "metadata": {"page_label": "291", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d3a4cc4e386a84006c7dfbe2a74c1d9fc86bfd8f81cb70c76dc1a810138e9eea"}, "2": {"node_id": "22486a56-2c49-4545-b5f1-13e0c51c9de7", "node_type": null, "metadata": {"page_label": "291", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82c9158607675342ac622a4b090a3897191ddc356b2bcd70a8cbf88ffc2d62c9"}}, "hash": "8170616905bfedd0b44fd95cb22366eb7fc06c80bdd4667d9ad32d228b0ab8eb", "text": "on small resistance arteries than on veins, but there is a marked effect on larger muscular arteries. This reduces pulse wave reflection from \narterial branches (as appreciated in the 19th century by \nMurrell but neglected for many years thereafter), and \n6Nobel discovered how to stabilise GTN with kieselguhr, enabling him \nto exploit its explosive properties in dynamite, the manufacture of \nwhich earned him the fortune with which he endowed the eponymous \nprizes.Effect of nitrate\nBlood flow to \nischaemic area \nINCREASEDCollateral\ndilatedEffect of dipyridamole\nCollateral \nnot dilated\nBlood flow to \nischaemic area \nREDUCEDBlood flow to \nnormal area \nINCREASEDAtheromatous\nplaqueControl (no drug) in a patient with CAD\nFully\ndilated arterioles\nBlood flow to \nischaemic area of \nmyocardiumBlood flow to \nnormal area of \nmyocardiumNormal \narteriolar\ntoneCollateralA C B\nFig. 22.11 Comparison of the effects of organic nitrates and an arteriolar vasodilator (dipyridamole) on the coronary circulation. \n(A) Control. (B) Nitrates dilate the collateral vessel, thus allowing more blood through to the underperfused region (mostly by diversion from \nthe\tadequately \tperfused \tarea). \t(C) \tDipyridamole \tdilates \tarterioles, \tincreasing \tflow \tthrough \tthe \tnormal \tarea \tat \tthe \texpense \tof \tthe \tischaemic \t\narea (in which the arterioles are anyway fully dilated). CAD, coronary artery disease. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3400, "end_char_idx": 5278, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "97ba3211-56cf-40f2-9b8b-2e73982ee48b": {"__data__": {"id_": "97ba3211-56cf-40f2-9b8b-2e73982ee48b", "embedding": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d0d00bb-5ec9-4fac-9b5e-5806eeb67be2", "node_type": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0676bcad4d54a148f4ad28ad673d6a42cf9547ef791cb36c0e5bff0d15d44199"}, "3": {"node_id": "24803293-5e0c-4788-9bb1-14cd7e359145", "node_type": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9520a4371512beb5d4424e8f14c43a25cd783f66c9378bd90566b206141150e1"}}, "hash": "1352868de11682a4aefdad3a2e837d95af1b773ff03b42976ba0467d6e3138e4", "text": "22 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n286to allow a nitrate-free period during the night, when patients \nare not exerting themselves, to avoid tolerance). It is also \navailable in slow-release form for once-daily use in the \nmorning.\u2022\tredistribution\t of\tcoronary\t flow\ttowards\t ischaemic\t\nareas via collaterals;\n\u2022\trelief\tof\tcoronary\t spasm.\n\u25bc\tIn\taddition\t to\tits\teffects\ton\tsmooth\t muscle,\t nitric\toxide\t(NO)\t\nincreases\tthe\trate\tof\trelaxation\tof\tcardiac\tmuscle\t(dubbed\ta\t\u2018 lusiotropic \u2019\t\naction). It is probable that organic nitrates mimic this action, which \ncould be important in patients with impaired diastolic function, a \ncommon accompaniment of hypertension and of heart failure.\nMechanism of action\nOrganic\t nitrates\tare\tmetabolised\t with\trelease\tof\tNO.\tAt\t\nconcentrations achieved during therapeutic use, this involves \nan enzymic step and possibly a reaction with tissue sulf -\nhydryl\t(\u2013SH)\tgroups.\tNO\tactivates\tsoluble\tguanylyl\tcyclase \t\n(see Ch. 21), increasing formation of cGMP, which activates \nprotein kinase G (Ch. 4) and leads to a cascade of effects \nin smooth muscle culminating in dephosphorylation of \nmyosin light chains, sequestration of intracellular Ca2+ and \nconsequent relaxation.\nTolerance and unwanted effects\nRepeated administration of nitrates to smooth muscle \npreparations in vitro results in diminished relaxation, \npossibly\t partly\tbecause\t of\tdepletion\t of\tfree\t\u2013SH\tgroups,\t\nalthough attempts to prevent tolerance by agents that restore \ntissue\t\u2013SH\tgroups\thave\tnot\tbeen\tclinically \tuseful.\tTolerance \t\nto the anti-anginal effect of nitrates does not occur to a \nclinically important extent with ordinary formulations of \nshort-acting drugs (e.g. glyceryl trinitrate), but does occur \nwith longer-acting drugs (e.g. isosorbide mononitrate) or \nwhen glyceryl trinitrate is administered by prolonged \nintravenous infusion or by frequent application of slow-\nrelease transdermal patches (see later).\nThe main adverse effects of nitrates are a direct conse -\nquence of their main pharmacological actions, and include \npostural hypotension and headache. This was the cause of \n\u2018Monday\t morning\t sickness\u2019\t among\tworkers\t in\texplosives\t\nfactories. Tolerance to these effects develops quite quickly \nbut wears off after a brief nitrate-free interval (which is \nwhy the symptoms appeared on Mondays and not later \nin the week). Formation of methaemoglobin , an oxidation \nproduct of haemoglobin that is ineffective as an oxygen \ncarrier, seldom occurs when nitrates are used clinically but \nis induced deliberately with amyl nitrite in the treatment \nof cyanide poisoning , because methaemoglobin binds and \ninactivates cyanide ions.\nPharmacokinetic and pharmaceutical aspects\nGlyceryl trinitrate is rapidly inactivated by hepatic metabo -\nlism. It is well absorbed from the mouth and is taken as a \ntablet under the tongue or as a sublingual spray, producing \nits effects within a few minutes. If swallowed, it is ineffective \nbecause of presystemic metabolism in the liver. Given \nsublingually, the trinitrate is converted to di- and mononi -\ntrates. Its effective duration of action is approximately \n30 min. It is appreciably absorbed through the skin, and a \nmore sustained effect can be achieved by applying it as a", "start_char_idx": 0, "end_char_idx": 3263, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "24803293-5e0c-4788-9bb1-14cd7e359145": {"__data__": {"id_": "24803293-5e0c-4788-9bb1-14cd7e359145", "embedding": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d0d00bb-5ec9-4fac-9b5e-5806eeb67be2", "node_type": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0676bcad4d54a148f4ad28ad673d6a42cf9547ef791cb36c0e5bff0d15d44199"}, "2": {"node_id": "97ba3211-56cf-40f2-9b8b-2e73982ee48b", "node_type": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1352868de11682a4aefdad3a2e837d95af1b773ff03b42976ba0467d6e3138e4"}, "3": {"node_id": "f4c3c32a-f6af-4649-a12d-4a7fdd93a32a", "node_type": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2339c05625d187801368adcc8129e0348a0b8098fdab188d3d82c5beea58c4f0"}}, "hash": "9520a4371512beb5d4424e8f14c43a25cd783f66c9378bd90566b206141150e1", "text": "skin, and a \nmore sustained effect can be achieved by applying it as a \ntransdermal\t patch.\tOnce\ta\tbottle\tof\tthe\ttablets\thas\tbeen\t\nopened, its shelf-life is quite short because the volatile active \nsubstance evaporates; spray preparations avoid this problem.\nIsosorbide mononitrate is longer acting than glyceryl \ntrinitrate because it is absorbed and metabolised more \nslowly, but has similar pharmacological actions. It is swal -\nlowed rather than taken sublingually, and is taken twice \na day for prophylaxis (usually in the morning and at lunch, Organic nitrates \n\u2022\tImportant\t compounds\t include\t glyceryl trinitrate and \nlonger-acting isosorbide mononitrate .\n\u2022\tThese\tdrugs\tare\tpowerful\tvasodilators,\t acting\ton\tveins\t\nto reduce cardiac preload and on arteries to reduce \narterial wave reflection and hence afterload.\n\u2022\tAct\tvia\tnitric\toxide,\tto\twhich\tthey\tare\tmetabolised.\t\nNitric\toxide\tstimulates\t formation\t of\tcGMP\tand\thence\t\nactivates protein kinase G, affecting contractile \nproteins (myosin light chains) and Ca2+ regulation.\n\u2022\tTolerance\t occurs\texperimentally\t and\tis\timportant\t\nclinically with frequent use of long-acting drugs or \nsustained-release preparations.\n\u2022\tEffectiveness\t in\tangina\tresults\tpartly\tfrom\treduced\t\ncardiac load and partly from dilatation of collateral \ncoronary vessels, causing more effective distribution of \ncoronary\tflow.\tDilatation\t of\tconstricted\t coronary\t\nvessels is particularly beneficial in variant angina.\n\u2022\tSerious\t unwanted\t effects\tare\tuncommon;\t headache\t\nand\tpostural\thypotension\t may\toccur\tinitially.\tOverdose\t\ncan, rarely, cause methaemoglobinaemia.\nClinical uses of organic nitrates \n\u2022\tStable\tangina:\n\u2013 prevention (e.g. daily isosorbide mononitrate , or \nglyceryl trinitrate sublingually immediately before \nexertion);\n\u2013 treatment (sublingual glyceryl trinitrate ).\n\u2022\tUnstable\t angina:\tintravenous\t glyceryl trinitrate .\n\u2022\tAcute\theart\tfailure:\tintravenous\t glyceryl trinitrate .\n\u2022\tChronic\t heart\tfailure:\t isosorbide mononitrate , with \nhydralazine in patients of African origin (Ch. 23).\nPOTASSIUM-CHANNEL\u2003 ACTIVATORS\nNicorandil combines activation of the potassium K ATP \nchannel\t(see\tCh.\t4)\twith \tnitrovasodilator\t(NO\tdonor)\tactions. \t\nIt is both an arterial and a venous dilator, and causes the \nexpected unwanted effects of headache, flushing and diz -\nziness. It is used for patients who remain symptomatic \ndespite optimal management with other drugs, often while \nthey await surgery or angioplasty.\n\u03b2-ADRENOCEPTOR\u2003 ANTAGONISTS\n\u03b2-Adrenoceptor antagonists (see Ch. 15) are important in \nprophylaxis of stable angina, and in treating patients with \nunstable angina, acting by reducing cardiac oxygen con -\nsumption. They reduce the risk of death following myo -\ncardial infarction, possibly via their antidysrhythmic action. \nAny effects on coronary vessel diameter are of minor \nimportance, although these drugs are avoided in variant \nangina because of the theoretical risk that they will increase \ncoronary spasm. Their astonishingly diverse clinical uses mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3207, "end_char_idx": 6294, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f4c3c32a-f6af-4649-a12d-4a7fdd93a32a": {"__data__": {"id_": "f4c3c32a-f6af-4649-a12d-4a7fdd93a32a", "embedding": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d0d00bb-5ec9-4fac-9b5e-5806eeb67be2", "node_type": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0676bcad4d54a148f4ad28ad673d6a42cf9547ef791cb36c0e5bff0d15d44199"}, "2": {"node_id": "24803293-5e0c-4788-9bb1-14cd7e359145", "node_type": null, "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9520a4371512beb5d4424e8f14c43a25cd783f66c9378bd90566b206141150e1"}}, "hash": "2339c05625d187801368adcc8129e0348a0b8098fdab188d3d82c5beea58c4f0", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6288, "end_char_idx": 6767, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d8866ee8-c843-4e1e-b26a-d124967f0357": {"__data__": {"id_": "d8866ee8-c843-4e1e-b26a-d124967f0357", "embedding": null, "metadata": {"page_label": "293", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dc809377-d7d4-4a32-97ce-dca18a43d36c", "node_type": null, "metadata": {"page_label": "293", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6997f5d45dd55133346f8e837568e0c278d5fec4bf204e19387d863662a46101"}, "3": {"node_id": "278c11b5-cc1c-4dd2-9ace-7967b1d979c6", "node_type": null, "metadata": {"page_label": "293", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b08b661a1040c6710b7f4fa328c4ca9742e6e6267cc3f6c82bfcf650563b1b6"}}, "hash": "fbe0f662890337e10de330c8795cc24817aa4ac36e5289e01d7011b9e7d7cf22", "text": "22 ThE hEART\n287this non-opening state, whereas agonists bind selectively to channels \nin mode 2 (see Fig. 22.12). This type of two-directional modulation \nresembles the phenomenon seen with the GABA/benzodiazepine \ninteraction (Ch. 45), and invites speculation about possible endogenous dihydropyridine-like mediator(s) with a regulatory effect on Ca\n2+ \nentry.\nMibefradil blocks T- as well as L-type channels at therapeutic con-\ncentrations, but was withdrawn from therapeutic use because it caused adverse drug interactions by interfering with drug metabolism. \nEthosuximide (a carbonic anhydrase inhibitor used to treat absence \nseizures, Ch. 46) also blocks T channels in thalamic and reticular neurones.\nPharmacological effects\nThe main effects of calcium antagonists, as used therapeuti-\ncally, are on cardiac and smooth muscle. Verapamil \npreferentially affects the heart, whereas most of the \ndihydropyridines (e.g. nifedipine) exert a greater effect on smooth muscle than on the heart. Diltiazem is intermediate \nin its actions.\nCardiac actions\nThe antidysrhythmic effects of verapamil and diltiazem \nhave been discussed earlier. Calcium antagonists can cause \nAV block and cardiac slowing by their actions on conducting \ntissues, but this is offset by a reflex increase in sympathetic activity secondary to their vasodilator action. For example, \nnifedipine typically causes reflex tachycardia; diltiazem \ncauses little or no change in heart rate and verapamil slows the heart rate. Calcium antagonists also have a negative \ninotropic effect, from their inhibition of Ca\n2+ entry during \nthe action potential plateau. Verapamil has the most marked negative inotropic action, and is contraindicated in heart \nfailure, whereas amlodipine does not worsen cardiovascular mortality in patients with severe but stable chronic heart \nfailure.\nVascular smooth muscle\nCalcium antagonists cause generalised arterial/arteriolar \ndilatation, thereby reducing blood pressure, but do not \nmuch affect the veins. They affect all vascular beds, although \nregional effects vary considerably between different drugs. They cause coronary vasodilatation and are used in patients \nwith\tcoronary \tartery \tspasm \t(variant \tangina). \tOther \ttypes \t\nDHP antagonists DHP agonistsMode\nChannel closed\nChannel open\nDepolarising\nstepDepolarising\nstepDepolarising\nstepMode 0 Mode 1 Mode 2\nZero\n~30%Low\n~70%High\n<1%Opening probability\nFavoured by\n% of time normally \nspent in this mode\nFig. 22.12 Mode behaviour of calcium channels. The traces are patch clamp recordings (see Ch. 3) of the opening of single calcium \nchannels (downward deflections) in a patch of membrane from a cardiac muscle cell. A depolarising step is imposed close to the start of \neach trace, causing an increase in the opening probability of the channel. When the channel is in mode 1 (centre), this causes a few brief \nopenings to occur; in mode 2 (right), the channel stays open for most of the time during the depolarising step; in mode 0 (left), it fails to \nopen\tat\tall. \tUnder \tnormal \tconditions, \tin \tthe \tabsence \tof \tdrug, \tthe \tchannel \tspends \tmost \tof \tits \ttime \tin \tmodes \t1 \tand \t2, \tand \tonly \trarely \tenters \t\nmode 0. DHP,\tdihydropyridine. \t(Redrawn \tfrom \tHess, \tet \tal., \t1984. \tNature \t311, \t538\u2013544.)are summarised in the clinical boxes earlier (p. 282) and \nin Chapter 15.\nCALCIUM", "start_char_idx": 0, "end_char_idx": 3358, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "278c11b5-cc1c-4dd2-9ace-7967b1d979c6": {"__data__": {"id_": "278c11b5-cc1c-4dd2-9ace-7967b1d979c6", "embedding": null, "metadata": {"page_label": "293", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dc809377-d7d4-4a32-97ce-dca18a43d36c", "node_type": null, "metadata": {"page_label": "293", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6997f5d45dd55133346f8e837568e0c278d5fec4bf204e19387d863662a46101"}, "2": {"node_id": "d8866ee8-c843-4e1e-b26a-d124967f0357", "node_type": null, "metadata": {"page_label": "293", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fbe0f662890337e10de330c8795cc24817aa4ac36e5289e01d7011b9e7d7cf22"}}, "hash": "7b08b661a1040c6710b7f4fa328c4ca9742e6e6267cc3f6c82bfcf650563b1b6", "text": "clinical boxes earlier (p. 282) and \nin Chapter 15.\nCALCIUM \u2003ANTAGONISTS\nThe\tterm \t\u2018calcium \tantagonist\u2019 \tis \tused \tfor \tdrugs \tthat \tblock \t\ncellular entry of Ca2+ through calcium channels rather than \npreventing its intracellular actions (Ch. 4). Some authors \nuse\tthe\tterm \t\u2018Ca2+\tentry\tblockers\u2019 \tto \tmake \tthis \tdistinction \t\nclearer. Therapeutically important calcium antagonists act \non L-type channels. L-type calcium antagonists comprise \nthree chemically distinct classes: phenylalkylamines (e.g. \nverapamil ), dihydropyridines (e.g. nifedipine , amlodipine ) \nand benzothiazepines (e.g. diltiazem).\nMechanism of action: types of calcium channel\nThe properties of voltage-gated calcium channels have been \nstudied by voltage clamp and patch clamp techniques (see \nCh. 3). Drugs of each of the three chemical classes mentioned \nabove all bind the \u03b11 subunit of the L-type calcium channel \nbut at distinct sites. These interact allosterically with each \nother and with the gating machinery of the channel to \nprevent its opening (see later and Fig. 22.12), thus reducing Ca\n2+ entry. Many calcium antagonists show properties of \nuse dependence (i.e. they block more effectively in cells in \nwhich the calcium channels are most active; see the discus -\nsion of class I antidysrhythmic drugs earlier). For the same \nreason, they also show voltage-dependent blocking actions, \nblocking more strongly when the membrane is depolarised, \ncausing calcium-channel opening and inactivation.\n\u25bc Dihydropyridines affect calcium-channel function in a complex \nway, not simply by physical plugging of the pore. This became clear \nwhen some dihydropyridines, exemplified by BAY K 8644, were found \nto bind to the same site but to do the opposite; that is, to promote \nthe opening of voltage-gated calcium channels. Thus BAY K 8644 increases the force of cardiac contraction, and constricts blood vessels; \nit is competitively antagonised by nifedipine. Calcium channels can \nexist\tin\tone \tof \tthree \tdistinct \tstates, \ttermed \t\u2018modes\u2019 \t(see \tFig. \t22.12). \t\nWhen a channel is in mode 0, it does not open in response to depolarisa -\ntion; in mode 1, depolarisation produces a low opening probability, \nand each opening is brief. In mode 2, depolarisation produces a very \nhigh opening probability, and single openings are prolonged. Under normal conditions, about 70% of the channels at any one moment \nexist in mode 1, with only 1% or less in mode 0; each channel switches \nrandomly and quite slowly between the three modes. Dihydropyridine antagonists bind selectively to channels in mode 0, thus favouring mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3299, "end_char_idx": 6381, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7c77754d-8247-4327-8f32-8b3dd61908fe": {"__data__": {"id_": "7c77754d-8247-4327-8f32-8b3dd61908fe", "embedding": null, "metadata": {"page_label": "294", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f725e3e0-f87c-483e-b003-1dd81349d039", "node_type": null, "metadata": {"page_label": "294", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c1d7b81766d376450da5ed8c1d3853de60059bae6eb17791effce76aefeafc8"}, "3": {"node_id": "098ca88f-aade-46a3-ac1e-c3393817f27b", "node_type": null, "metadata": {"page_label": "294", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9a8f735c1c848a2742057289bebd264251363a194eb170b04d2470929890667a"}}, "hash": "9f7a75a2424dcc78a1e658af4c2a3b77572d3b8564ffac4572fc0e880d1d0133", "text": "22 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n288of smooth muscle (e.g. biliary tract, urinary tract and uterus) \nare also relaxed by calcium antagonists, but these effects \nare less important therapeutically than their actions on \nvascular smooth muscle.\nProtection of ischaemic tissues\nThere are theoretical reasons (see Fig. 22.8) why calcium antagonists might exert a cytoprotective effect in ischaemic \ntissues (see Ch. 41) and thus be of use in treating heart \nattack and stroke. However, randomised clinical trials have been disappointing, with little or no evidence of beneficial \n(or harmful) effects of calcium antagonists on cardiovascular \nmorbidity or mortality in patient groups other than patients with hypertension, in whom calcium antagonists have \nbeneficial effects comparable with those of other drugs that \nlower blood pressure to similar extents (see Ch. 23). Nimodipine is partly selective for cerebral vasculature and \nthere is some evidence that it reduces cerebral vasospasm \nfollowing subarachnoid haemorrhage.\nPharmacokinetics\nCalcium antagonists in clinical use are well absorbed from \nthe gastrointestinal tract, and are given by mouth except \nfor some special indications, such as following subarachnoid \nhaemorrhage, for which intravenous preparations are available. They are extensively metabolised. Pharmacokinetic \ndifferences between different drugs and different pharma -\nceutical preparations are clinically important, because they \ndetermine the dose interval and the intensity of some of \nthe unwanted effects, such as headache and flushing. \nAmlodipine has a long elimination half-life and is given once daily, whereas nifedipine, diltiazem and verapamil have shorter elimination half-lives and are either given \nmore frequently or are formulated in various slow-release \npreparations to permit once-daily dosing.\nUnwanted effects\nMost of the unwanted effects of calcium antagonists are extensions of their main pharmacological actions. Short-\nacting dihydropyridines cause flushing and headache \nbecause of their vasodilator action, and in chronic use dihydropyridines often cause ankle swelling (oedema) \nrelated to arteriolar dilatation and increased permeability \nof postcapillary venules. Verapamil can cause constipation, probably because of effects on calcium channels in \ngastrointestinal nerves or smooth muscle. Effects on cardiac \nrhythm (e.g. heart block) and force of contraction (e.g. worsening heart failure) are discussed earlier.\nApart from these predictable effects, calcium-channel \nantagonists, as a class, have few idiosyncratic adverse effects.Calcium antagonists \n\u2022\tBlock\tCa2+ entry by preventing opening of voltage-\ngated L-type calcium channels.\n\u2022\tThere\tare \tthree \tmain \tL-type \tantagonists, \ttypified \tby \t\nverapamil, diltiazem and dihydropyridines (e.g. \nnifedipine).\n\u2022\tMainly\taffect \theart \tand \tsmooth \tmuscle, \tinhibiting \tthe \t\nCa2+ entry caused by depolarisation in these tissues.\n\u2022\tSelectivity \tbetween \theart \tand \tsmooth \tmuscle \tvaries: \t\nverapamil is relatively cardioselective, nifedipine is \nrelatively smooth muscle selective, and diltiazem is \nintermediate.\n\u2022\tVasodilator \teffect \t(mainly \tdihydropyridines) \tis \tmainly \ton \t\nresistance vessels, reducing afterload. Calcium antagonists dilate coronary vessels, which is important in variant angina.\n\u2022\tEffects\ton \theart \t(verapamil, diltiazem): \nantidysrhythmic", "start_char_idx": 0, "end_char_idx": 3403, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "098ca88f-aade-46a3-ac1e-c3393817f27b": {"__data__": {"id_": "098ca88f-aade-46a3-ac1e-c3393817f27b", "embedding": null, "metadata": {"page_label": "294", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f725e3e0-f87c-483e-b003-1dd81349d039", "node_type": null, "metadata": {"page_label": "294", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c1d7b81766d376450da5ed8c1d3853de60059bae6eb17791effce76aefeafc8"}, "2": {"node_id": "7c77754d-8247-4327-8f32-8b3dd61908fe", "node_type": null, "metadata": {"page_label": "294", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f7a75a2424dcc78a1e658af4c2a3b77572d3b8564ffac4572fc0e880d1d0133"}}, "hash": "9a8f735c1c848a2742057289bebd264251363a194eb170b04d2470929890667a", "text": "\t(verapamil, diltiazem): \nantidysrhythmic action (mainly atrial tachycardias), because of impaired atrioventricular conduction; \nreduced contractility.\n\u2022\tClinical\tuses:\n\u2013 antidysrhythmic (mainly verapamil)\n\u2013 angina (e.g. diltiazem)\n\u2013 hypertension (mainly dihydropyridines).\n\u2022\tUnwanted \teffects \tinclude \theadache, \tconstipation \t\n(verapamil) and ankle oedema (dihydropyridines). \nThere is a risk of causing cardiac failure or heart block, especially with verapamil.\nClinical uses of calcium \nantagonists \n\u2022\tDysrhythmias \t(verapamil):\n\u2013 to slow ventricular rate in rapid atrial fibrillation\n\u2013 to prevent recurrence of supraventricular tachycardia \n(SVT) (intravenous administration of verapamil to \nterminate SVT attacks has been replaced by use of adenosine).\n\u2022\tHypertension: \tusually \ta \tdihydropyridine \tdrug \t(e.g. \t\namlodipine or slow-release nifedipine; Ch. 23).\n\u2022\tTo\tprevent \tangina \t(e.g. \ta \tdihydropyridine \tor \tdiltiazem).\nREFERENCES AND FURTHER READING\nFurther reading\nFink, M., Noble, D., 2010. Pharmacodynamic effects in the \ncardiovascular \tsystem: \tthe \tmodeller\u2019s \tview. \tBasic \tClin. \tPharmacol. \t\nToxicol.\t106, \t243\u2013249.\nJones, D.A., Timmis, A., Wragg, A., 2013. Novel drugs for treating \nangina.\tBMJ \t347, \t34\u201337. \t(Useful summary)\nMann,\tD.L., \tZipes, \tD.P., \tLibby, \tP., \tBonow, \tR.O., \t2014. \tBraunwald\u2019s \t\nHeart Disease: A Textbook of Cardiovascular Medicine, tenth ed. \nSaunders/Elsevier, Philadelphia.\nOpie,\tL.H., \tGersh, \tB.J., \t2013. \tDrugs \tfor \tthe \tHeart, \teighth \ted. \tSaunders/\nElsevier, Philadelphia.Specific aspects\nPhysiological and pathophysiological aspects\nBagrov,\tA.Y., \tShapiro, \tJ.I., \tFedorova, \tO.V., \t2009. \tEndogenous \t\ncardiotonic steroids: physiology, pharmacology, and novel therapeutic \ntargets.\tPharmacol. \tRev. \t61, \t9\u201338. \t(Reviews physiological interactions \nbetween CTS and other regulatory systems that may be important in the \npathophysiology of essential hypertension, pre-eclampsia, end-stage renal \ndisease, congestive heart failure and diabetes)\nBlaustein, M.P., Chen, L., Hamlyn, J.M., 2016. Pivotal role of alpha 2 \nNa+ pumps and their high affinity ouabain binding site in \ncardiovascular \thealth \tand \tdisease. \tJ. \tPhysiol. \t594, \t6079\u20136103. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3362, "end_char_idx": 6048, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1c4435d3-3d05-4f8e-91ad-7d3ef857edc5": {"__data__": {"id_": "1c4435d3-3d05-4f8e-91ad-7d3ef857edc5", "embedding": null, "metadata": {"page_label": "295", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dff9fe2c-8751-475b-9c0d-d75a78f3d941", "node_type": null, "metadata": {"page_label": "295", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5aa68f9f35d7dcfba20f3fdd1d6673c9d8b68e3d20eb526abb55863d870b01a3"}, "3": {"node_id": "c2d90c87-bd25-4292-807f-c11c5a900fa4", "node_type": null, "metadata": {"page_label": "295", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "56fd5a1909797bdbf27ce955e1cc47c7f454d28f0a9e84694c3f990f68e6b996"}}, "hash": "77dd4c78bcf4db45a115d59ab6087ddf2931204dc0a29e40d420e35bc3cefe0a", "text": "22 ThE hEART\n289Connolly, S.J., Camm, J., Halperin, J.L., et al., 2011. Dronedarone in \nhigh-risk\t permanent\t atrial\tfibrillation.\t N.\tEngl.\tJ.\tMed.\t365,\t2268\u20132276.\t\n(Dronedarone increased the rates of stroke, heart failure, and death from \ncardiovascular causes in patients with permanent atrial fibrillation and risk \nfactors for vascular events and is hazardous in such patients )\nFox, K., Ford, I., Steg, P.G., et al., 2008. Ivabradine for patients with \nstable coronary artery disease and left-ventricular systolic dysfunction \n(BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. \nLancet\t372,\t807\u2013816.\t (Ivabradine does not improve cardiac outcomes in all \npatients with stable coronary artery disease and left-ventricular systolic \ndysfunction, but improved outcome in patients with heart rates >70 bpm. See \nalso adjacent paper: Fox, K., et al., 2008. Heart rate as a prognostic risk \nfactor in patients with coronary artery disease and left-ventricular systolic \ndysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled \ntrial. Lancet 372, 817\u2013821 )\nHeusch, G., 2017. Critical issues for the translation of cardioprotection. \nCirc.\tRes.\t120,\t1477\u20131486.\t (\u201cFuture trials must focus on interventions/\nagents with robust preclinical evidence, have solid phase II dosing and \ntiming data, and recruit patients who have truly a chance to benefit from \nadjunct cardioprotection\u201d )\nISIS-4 Collaborative Group, 1995. ISIS-4: a randomised factorial trial \nassessing early oral captopril, oral mononitrate, and intravenous \nmagnesium sulphate in 58 050 patients with suspected acute \nmyocardial\t infarction.\t Lancet\t345,\t669\u2013685.\t (Impressive trial: \ndisappointing results! Magnesium was ineffective; oral nitrate did not reduce \n1-month mortality )\nO\u2019Connor,\t C.M.,\tStarling,\t R.C.,\tHernandez,\t A.F.,\tet\tal.,\t2011.\tEffect\tof\t\nnesiritide in patients with acute decompensated heart failure. N. Engl. \nJ.\tMed.\t365,\t32\u201343.\t(see also Topol, E.T., 2011. The lost decade of nesiritide. \nN. Engl. J. Med. 365, 81\u201382 )\nRahimtoola, S.H., 2004. Digitalis therapy for patients in clinical heart \nfailure.\tCirculation\t 109,\t2942\u20132946.\t (Review )\nRoden, D.M., 2008. Cellular basis of drug-induced torsades de pointes. \nBr.\tJ.\tPharmacol.\t 154,\t1502\u20131507.\t (This adverse drug reaction occurs \nduring therapy with some antidysrhythmic drugs and also several drugs not \nused for cardiovascular indications, including certain antibiotics, \nantipsychotics and antihistamines. The common mechanism is inhibition of a \nspecific repolarizing potassium current, I-Kr )\nRuskin, J.N., 1989. The cardiac arrhythmia suppression trial (CAST). N. \nEngl.\tJ.\tMed.\t321,\t386\u2013388.\t (Enormously influential trial showing \nincreased mortality with active treatment despite suppression of \ndysrhythmia )(\u201cCirculating endogenous ouabain modulates ouabain-sensitive 2 Na+ pump \nactivity and Ca2+ transporter expression and, via Na+/Ca2+ exchange, Ca2+ \nhomeostasis. This regulates sensitivity to sympathetic activity, Ca2+ \nsignalling and arterial and cardiac", "start_char_idx": 0, "end_char_idx": 3048, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c2d90c87-bd25-4292-807f-c11c5a900fa4": {"__data__": {"id_": "c2d90c87-bd25-4292-807f-c11c5a900fa4", "embedding": null, "metadata": {"page_label": "295", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dff9fe2c-8751-475b-9c0d-d75a78f3d941", "node_type": null, "metadata": {"page_label": "295", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5aa68f9f35d7dcfba20f3fdd1d6673c9d8b68e3d20eb526abb55863d870b01a3"}, "2": {"node_id": "1c4435d3-3d05-4f8e-91ad-7d3ef857edc5", "node_type": null, "metadata": {"page_label": "295", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "77dd4c78bcf4db45a115d59ab6087ddf2931204dc0a29e40d420e35bc3cefe0a"}}, "hash": "56fd5a1909797bdbf27ce955e1cc47c7f454d28f0a9e84694c3f990f68e6b996", "text": "sensitivity to sympathetic activity, Ca2+ \nsignalling and arterial and cardiac contraction.\u201d )\nEltzschig, H.K., Sitkovsky, M.V., Robson, S.C., 2012. Purinergic \nsignaling\t during\tinflammation.\t N.\tEngl.\tJ.\tMed.\t367,\t2322\u20132333.\nNoble, D., 2008. Computational models of the heart and their use in \nassessing\t the\tactions\tof\tdrugs.\tJ.\tPharmacol.\t Sci.\t107,\t107\u2013117.\t (Models \nof cardiac cells are sufficiently well developed to answer questions concerning \nthe actions of drugs such as ranolazine, a recently introduced blocker of \nperisistent sodium current, on repolarisation and the initiation of \narrhythmias )\nPotter, L.R., Yoder, A.R., Flora, D.R., et al., 2009. Natriuretic peptides: \ntheir structures, receptors, physiologic functions and therapeutic \napplications.\t Handb.\tExp.\tPharmacol.\t 191,\t341\u2013366.\t (Reviews the \nhistory, structure, function and clinical applications of natriuretic peptides \nand their receptors )\nRockman, H.A., Koch, W.J., Lefkowitz, R.J., 2002. \nSeven-transmembrane-spanning receptors and heart function. Nature \n415,\t206\u2013212.\nSchoner, W., Scheiner-Bobis, G., 2007. Endogenous and exogenous \ncardiac glycosides: their roles in hypertension, salt metabolism, and \ncell\tgrowth.\t Am.\tJ.\tPhysiol.\t Cell\tPhysiol.\t 293,\tC509\u2013C536.\t (Review: \ntouches on anticancer potential also )\nSeddon, M., Melikian, N., Dworakowski, R., et al., 2009. Effects of \nneuronal nitric oxide synthase on human coronary artery diameter \nand\tblood\tflow\tin\tvivo.\tCirculation\t 119,\t2656\u20132662.\t (Local \nnNOS-derived NO regulates basal blood flow in the human coronary \nvascular bed, whereas substance P-stimulated vasodilatation is eNOS \nmediated )\nWelsh, M.J., Hoshi, T., 1995. Molecular cardiology \u2014 ion channels lose \nthe\trhythm.\t Nature\t376,\t640\u2013641.\t (Commentary on Ward\u2013Romano \nsyndrome )\nTherapeutic aspects\nCOMMIT\t Collaborative\t Group,\t2005.\tEarly\tintravenous\t then\toral\t\nmetoprolol in 45 852 patients with acute myocardial infarction: \nrandomised\t placebo-controlled\t trial.\tLancet\t366,\t1622\u20131632.\t (Early \u03b2 \nblockade reduced ventricular fibrillation and reinfarction, benefits that were \noffset by increased cardiogenic shock in patients with signs of heart failure; \nsee accompanying comment by Sabatine, M.S., pp. 1587\u20131589 in the same \nissue )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2970, "end_char_idx": 5707, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "000cadd2-701d-430e-817e-fb533c5d2013": {"__data__": {"id_": "000cadd2-701d-430e-817e-fb533c5d2013", "embedding": null, "metadata": {"page_label": "296", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "00b9e78e-cb31-47ec-b5e1-60073983b237", "node_type": null, "metadata": {"page_label": "296", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f79a156affb214b8610e28bcf6b2cae5897e8d72733dbb4aaac59514fb9afdf"}, "3": {"node_id": "cbea3a24-a0ae-4a76-9605-a52e91a7108f", "node_type": null, "metadata": {"page_label": "296", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10905dd4963c61b332375b84c11e0df88eef668b4f7b70f45d6d33ef70acc5e6"}}, "hash": "8efe2f035724596fba6a1c2fce654991709ef62de6349f79b36985637e89a6fd", "text": "290\nThe vascular system23 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3 \nOVERVIEW\nThis chapter is concerned with the pharmacology of \nblood vessels. The walls of arteries, arterioles, venules \nand veins contain smooth muscle, the contractile state \nof which is controlled by circulating hormones and by mediators released locally from sympathetic nerve \nterminals (Ch. 15), endothelial cells and other cells \nresident in the vessel wall or visiting it from the circulating blood. These work mainly by regulating \nCa\n2+ in vascular smooth muscle cells, as described in \nChapter 4. In the present chapter, we first consider the control of vascular smooth muscle by the endothe -\nlium and by the renin\u2013angiotensin system, followed \nby the actions of vasoconstrictor and vasodilator drugs. \nFinally, we consider briefly some of the clinical uses \nof vasoactive drugs in selected important diseases, namely hypertension (pulmonary as well as systemic), \nheart failure, shock, peripheral vascular disease and \nRaynaud\u2019s disease. The use of vasoactive drugs to treat angina is covered in Chapter 22.\nINTRODUCTION\nActions of drugs on the vascular system can be broken \ndown into effects on:\n\u2022\ttotal\tsystemic \t(\u2018peripheral\u2019) \tvascular \tresistance, \tone \tof \t\nthe main determinants of arterial blood pressure;\n\u2022\tthe\tresistance \tof \tindividual \tvascular \tbeds, \twhich \t\ndetermines the local distribution of blood flow to and within different organs; such effects are relevant to the \ndrug treatment of angina (Ch. 22), Raynaud\u2019s \nphenomenon, pulmonary hypertension and circulatory shock\n\u2022\taortic\tcompliance \tand \tpulse \twave \treflection, \twhich \t\nare relevant to the treatment of hypertension, cardiac failure and angina;\n\u2022\tvenous \ttone \tand \tblood \tvolume \t(the \t\u2018fullness\u2019 \tof \tthe \t\ncirculation), which together determine the central venous pressure and are relevant to the treatment of \ncardiac failure and angina; diuretics (which reduce \nblood volume) are discussed in Chapter 30;\n\u2022\tatheroma \t(Ch. \t24) \tand \tthrombosis \t(Ch. \t25);\n\u2022\tnew\tvessel \tformation \t(angiogenesis) \t\u2013 \timportant, \tfor \t\nexample, in diabetic retinopathy (Ch. 32) and in treating malignant disease (Ch. 57).\nDrug effects considered in this chapter are caused by actions on vascular smooth muscle cells. Like other muscles, vascular smooth muscle contracts when cytoplasmic Ca\n2+ \n([Ca2+]i) rises, but the coupling between [Ca2+]i and contrac -\ntion is less tight than in striated voluntary or cardiac muscle \n(Ch. 4). Vasoconstrictors and vasodilators act by increasing or reducing [Ca2+]i, and/or by altering the sensitivity of \nthe contractile machinery to [Ca2+]i. Fig. 4.10 (see Ch. 4) \nsummarises cellular mechanisms that are involved in the control of smooth muscle contraction and relaxation. The \ncontrol of vascular smooth muscle tone by various mediators is described in other chapters (noradrenaline in Ch. 15, \n5-HT in Ch. 16, prostanoids in Ch. 18, nitric oxide [NO] in \nCh. 21, cardiac natriuretic peptides in Ch. 22, antidiuretic hormone in Ch. 34). Here we focus on endothelium-derived \nmediators and on the renin\u2013angiotensin\u2013aldosterone system, \nbefore describing the actions of vasoactive drugs and their uses in some important clinical disorders (hypertension, heart failure, shock, peripheral vascular disease and \nRaynaud\u2019s disease).\nVASCULAR", "start_char_idx": 0, "end_char_idx": 3332, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cbea3a24-a0ae-4a76-9605-a52e91a7108f": {"__data__": {"id_": "cbea3a24-a0ae-4a76-9605-a52e91a7108f", "embedding": null, "metadata": {"page_label": "296", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "00b9e78e-cb31-47ec-b5e1-60073983b237", "node_type": null, "metadata": {"page_label": "296", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f79a156affb214b8610e28bcf6b2cae5897e8d72733dbb4aaac59514fb9afdf"}, "2": {"node_id": "000cadd2-701d-430e-817e-fb533c5d2013", "node_type": null, "metadata": {"page_label": "296", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8efe2f035724596fba6a1c2fce654991709ef62de6349f79b36985637e89a6fd"}}, "hash": "10905dd4963c61b332375b84c11e0df88eef668b4f7b70f45d6d33ef70acc5e6", "text": "disease and \nRaynaud\u2019s disease).\nVASCULAR STRUCTURE AND FUNCTION\nBlood is ejected with each heartbeat from the left ventricle \ninto the aorta, whence it flows rapidly to the organs via large \nconduit arteries. Successive branching leads via muscular \narteries to arterioles (endothelium surrounded by a layer of smooth muscle only one cell thick) and capillaries (naked \ntubes of endothelium), where gas and nutrient exchanges \noccur. Capillaries coalesce to form postcapillary venules, venules and progressively larger veins leading, via the vena \ncava, to the right heart. Deoxygenated blood ejected from \nthe right ventricle travels through the pulmonary artery, pulmonary capillaries and pulmonary veins back to the left atrium.\n1 Small muscular arteries and arterioles are the main \nresistance vessels, while veins are capacity vessels that contain \na large fraction of the total blood volume. In terms of cardiac \nfunction, therefore, arteries and arterioles regulate the afterload , \nwhile veins and pulmonary vessels regulate the preload of \nthe ventricles (see Ch. 22).\nViscoelastic properties of large arteries determine arterial \ncompliance (i.e. the degree to which the volume of the \narterial system increases as the pressure increases). This is \nan important factor in a circulatory system that is driven by an intermittent pump such as the heart. Blood ejected from the left ventricle is accommodated by distension of \nthe aorta, which absorbs the pulsations and delivers a \nrelatively steady flow to the tissues. The greater the compli -\nance of the aorta, the more effectively are fluctuations \ndamped out,\n2 and the smaller the oscillations of arterial \n1William Harvey (physician to King Charles I) inferred the circulation of \nthe blood on the basis of superbly elegant quantitative experiments long \nbefore the invention of the microscope enabled visual confirmation of \nthe tiny vessels he had predicted. This intellectual triumph did his \nmedical\tstanding \tno \tgood \tat \tall, \tand \tAubrey \twrote \tthat \t\u2018he \tfell \tmightily \t\nin\this\tpractice, \tand \twas \tregarded \tby \tthe \tvulgar \tas \t\u2018crack-brained\u2019. \tPlus \n\u00e7a change \u2026\n2This\tcushioning \taction \tis \tcalled \tthe \t\u2018windkessel\u2019 \teffect. \tThe \tsame \t\nprinciple was used to deliver a steady rather than intermittent flow from old-fashioned fire pumps.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3291, "end_char_idx": 6090, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a9c00889-77c7-4399-8a1d-e54b58327241": {"__data__": {"id_": "a9c00889-77c7-4399-8a1d-e54b58327241", "embedding": null, "metadata": {"page_label": "297", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b3fc432a-d74f-428e-9dce-e4cb4ae4bf08", "node_type": null, "metadata": {"page_label": "297", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "34bdf9f0587f7fb8a45cc845ca001008397711cc3ba421f055a2a8f248e954f0"}, "3": {"node_id": "8616bfec-2715-4f5d-b091-0144b21d50cb", "node_type": null, "metadata": {"page_label": "297", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "afc9ee9784bb7ae97f4044c387307e743c476591383f97f78bc9000199324b96"}}, "hash": "ffc80f48c3cb20f2bf58683027aacaf9c3be22a02d57d261faaf932cca8bca4a", "text": "23 ThE vASCU lAR SYSTEM\n291CONTROL OF VASCULAR SMOOTH \nMUSCLE TONE\nIn addition to the sympathetic nervous system (Ch. 15), \ntwo important physiological systems that regulate vascular \ntone, namely the vascular endothelium and the renin\u2013\nangiotensin system, deserve special attention.\nTHE VASCULAR ENDOTHELIUM\nA new chapter in our understanding of vascular control opened with the discovery that vascular endothelium acts \nnot only as a passive barrier between plasma and extracel -\nlular fluid, but also as a source of numerous potent media -\ntors. These actively control the underlying smooth muscle as well as influencing platelet and mononuclear cell function: \nthe roles of the endothelium in haemostasis and thrombosis are discussed in Chapter 25. Several distinct classes of \nmediator are involved (Fig. 23.1).\n\u2022\tProstanoids (see Ch. 18). The discovery by Bunting, \nGryglewski, Moncada and Vane (1976) of \nprostaglandin PGI\n2 (prostacyclin) ushered in this era. \nThis mediator, acting on IP receptors (Ch. 18), relaxes smooth muscle and inhibits platelet aggregation by \nactivating adenylyl cyclase. Endothelial cells from pressure with each heartbeat (i.e. the difference between \nthe\tsystolic \tand \tdiastolic \tpressure, \tknown \tas \tthe \t\u2018pulse \t\npressure\u2019). Reflection3 of the pressure wave from branch \npoints in the vascular tree also sustains arterial pressure \nduring diastole. In young people, this helps to preserve a \nsteady perfusion of vital organs, such as the kidneys, during diastole.\nHowever, excessive reflection can pathologically augment \naortic systolic pressure, because the less compliant the aorta, the greater the pulse wave velocity. Consequently, returning \n(reflected) pressure waves collide with the forward-going \npulse wave from the next heartbeat earlier in the cardiac cycle. This results from stiffening of the aorta due to loss of elastin during ageing, especially in people with hyperten -\nsion. Elastin is replaced by inelastic collagen. Cardiac work (see Ch. 22) can be reduced by increasing arterial compliance or by reducing arterial wave reflection (both of which \ndecrease the pulse pressure), even if the cardiac output \nand mean arterial pressure are unchanged. Over the age of around 55 years, pulse pressure and aortic stiffness are \nimportant risk factors for cardiac disease.[Ca2+]i\n[Ca2+]i [Ca2+]iAT1 ETA/(B)\nCONTRACTION RELAXATIONGq/IP3/ \nDAGTP NPR IP\ncGMP cAMP\nHyperpolarisationNa+/K+\nATPaseKIR\nK+\nVASCULAR\nSMOOTH\nMUSCLEGAP JUNCTION\n\u2013 electrotonic \nspread of \nendothelial \nhyperpolarisationEDHF\n?EET\n?K+PGl2ENDOTHELIAL\nCELLET-1 PGG2\nPGH2\nNO CNPAII AI\nACEShear\nstressVarious\n(thrombin, \nIL-1, \nendotoxin)Agonists\n(ACh, BK, 5-HT, etc.)\nFig. 23.1 Endothelium-derived mediators. The schematic shows some of the more important endothelium-derived contracting and \nrelaxing mediators; many (if not all) of the vasoconstrictors also cause smooth muscle mitogenesis, while vasodilators commonly inhibit \nmitogenesis. 5-HT, 5-hydroxytryptamine; A, angiotensin; ACE, angiotensin-converting enzyme; ACh, acetylcholine; AT1, angiotensin AT 1 \nreceptor; BK, bradykinin; CNP, C-natriuretic peptide; DAG,", "start_char_idx": 0, "end_char_idx": 3146, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8616bfec-2715-4f5d-b091-0144b21d50cb": {"__data__": {"id_": "8616bfec-2715-4f5d-b091-0144b21d50cb", "embedding": null, "metadata": {"page_label": "297", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b3fc432a-d74f-428e-9dce-e4cb4ae4bf08", "node_type": null, "metadata": {"page_label": "297", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "34bdf9f0587f7fb8a45cc845ca001008397711cc3ba421f055a2a8f248e954f0"}, "2": {"node_id": "a9c00889-77c7-4399-8a1d-e54b58327241", "node_type": null, "metadata": {"page_label": "297", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ffc80f48c3cb20f2bf58683027aacaf9c3be22a02d57d261faaf932cca8bca4a"}}, "hash": "afc9ee9784bb7ae97f4044c387307e743c476591383f97f78bc9000199324b96", "text": "CNP, C-natriuretic peptide; DAG, diacylglycerol; EDHF, endothelium-derived hyperpolarising factor; EET, \nepoxyeicosatetraenoic acid; ET-1, endothelin-1; ETA/(B), endothelin A (and B) receptors; Gq, G protein; IL-1, interleukin-1; IP, I prostanoid \nreceptor; IP3, inosinol 1,4,5-trisphosphate; KIR, inward rectifying potassium channel; Na+/K+ ATPase, electrogenic pump; NO, nitric oxide; \nNPR, natriuretic peptide receptor; PG, prostaglandin; TP, T prostanoid receptor. \n3Think of the waves in your bath as you sit up: down the tub, a splash \ndown the overflow but most comes back as reflections from the foot \nend under the taps and interferes with the forward waves.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3114, "end_char_idx": 4260, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a7dc427-d4da-4a0a-ad3b-736d2cb2c643": {"__data__": {"id_": "7a7dc427-d4da-4a0a-ad3b-736d2cb2c643", "embedding": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dd1a954d-5089-464f-a52d-920c8ba7a668", "node_type": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9da9004e2ee0ee77e4f4322b7d8817aa8975d6d381a826aee4e9b471d50b0ee2"}, "3": {"node_id": "c43c89b0-9c2c-4cf3-8820-6cddd54b1061", "node_type": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c4a5c59f01e5890c8582f4b3bee1e0508fb21181dfe2733944616bed9fef03dc"}}, "hash": "b0b5c8e60917b2c5552da63b63f0f4bb6eb70958a1e828b045f42da448977eda", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n292\u2022\tEndothelium-derived hyperpolarisation factors (EDHFs). \nPGI 2 and NO each hyperpolarise vascular smooth \nmuscle cells, which contributes to their relaxant \neffects. Endothelium-dependent dilatation and \nhyperpolarisation in response to several mediators (including acetylcholine and bradykinin) persists in \nsome vessels in the absence of prostaglandin and NO \nsynthesis. Several endothelium-derived mediators have been implicated, including epoxyeicosatrienoic \nacids (EETs \u2013 derived from endothelial cytochrome \nP450 enzymes), various lipoxygenase (LOX) products, hydrogen peroxide (H\n2O2), carbon monoxide (CO), \nhydrogen sulfide (H 2S), and CNP \u2013 see F\u00e9l\u00e9tou and \nVanhoutte (2009). These authors define an additional \nEDHF distinct from these mediators, and dependent \non calcium-activated potassium (K Ca) channels in \nendothelial cells. As the name implies, these channels \nare activated by an increase in endothelial cell [Ca2+]i.\nIn addition to secreting vasoactive mediators, endothelial \ncells express several enzymes and transport mechanisms \nthat act on circulating hormones and are important targets \nof drug action. ACE is a particularly important example (see pp. 295\u2013296, including Figs 23.4 and 23.5).\nMany endothelium-derived mediators are mutually \nantagonistic, conjuring an image of opposing rugby football players swaying back and forth in a scrum; in moments of exasperation, one sometimes wonders whether all this \nmakes sense or whether the designer simply could not make \nup their mind! An important distinction is made between mechanisms that are tonically active in resistance vessels \nunder basal conditions, as is the case with the noradrenergic \nnervous system (Ch. 15), NO (Ch. 21) and endothelin (see pp. 292\u2013294), and those that operate mainly in response to \ninjury, inflammation, etc., as with PGI\n2. Some of the latter \ngroup may be functionally redundant, perhaps represent-ing vestiges of mechanisms that were important to our \nevolutionary forebears, or they may simply be taking a breather on the touchline and are ready to rejoin the fray \nif called on by the occurrence of some vascular insult. \nEvidence \tfor \tsuch \ta \t\u2018back-up\u2019 \trole \tcomes, \tfor \texample, \t\nfrom mice that lack the IP receptor for PGI 2; they have a \nnormal blood pressure and do not develop spontaneous thrombosis, but are more susceptible to vasoconstrictor \nand thrombotic stimuli than their wild-type litter mates \n(Murata et al., 1997).\nTHE\u2003ENDOTHELIUM \u2003IN \u2003ANGIOGENESIS\nAs touched on in Chapter 9, the barrier function of vascular endothelium differs markedly in different organs, and its \ndevelopment during angiogenesis is controlled by several \ngrowth factors, including vascular endothelial growth factor \n(VEGF) and various tissue-specific factors such as endocrine \ngland VEGF. These are involved in repair processes and \nin pathogenesis (e.g. tumour growth and in neovascularisa -\ntion in the eye \u2013 an important cause of blindness in patients \nwith diabetes mellitus). These factors and their receptors \nare potentially fruitful targets for drug development and new therapies (including gene therapies; Ch. 5).\nENDOTHELIN\nDiscovery, biosynthesis and secretion\nHickey et al. described a vasoconstrictor factor produced \nby cultured endothelial cells in 1985. This was identified as endothelin (ET), a 21-residue peptide, by Yanagisawa microvessels also", "start_char_idx": 0, "end_char_idx": 3441, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c43c89b0-9c2c-4cf3-8820-6cddd54b1061": {"__data__": {"id_": "c43c89b0-9c2c-4cf3-8820-6cddd54b1061", "embedding": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dd1a954d-5089-464f-a52d-920c8ba7a668", "node_type": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9da9004e2ee0ee77e4f4322b7d8817aa8975d6d381a826aee4e9b471d50b0ee2"}, "2": {"node_id": "7a7dc427-d4da-4a0a-ad3b-736d2cb2c643", "node_type": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0b5c8e60917b2c5552da63b63f0f4bb6eb70958a1e828b045f42da448977eda"}, "3": {"node_id": "4d6eb0de-40b6-4b98-9228-d3a544d99de3", "node_type": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f3ba127f2ffe307bc69929237117157481ce84b863adfad3d0761defc97bca7"}}, "hash": "c4a5c59f01e5890c8582f4b3bee1e0508fb21181dfe2733944616bed9fef03dc", "text": "a 21-residue peptide, by Yanagisawa microvessels also synthesise PGE\n2, which is a direct \nvasodilator and additionally inhibits noradrenaline \nrelease from sympathetic nerve terminals, while \nlacking the effect of PGI 2 on platelets. Prostaglandin \nendoperoxide intermediates (PGG 2, PGH 2) are \nendothelium-derived contracting factors acting via \nthromboxane (TX) T prostanoid (TP) receptors.\n\u2022\tNO (see Ch. 21). Endothelium-derived relaxing factor \n(EDRF) was described by Furchgott and Zawadzki in \n1980, and identified as NO by the groups of Moncada \nand of Ignarro (see Fig. 21.2). These discoveries enormously expanded our understanding of the role \nof the endothelium. NO activates guanylyl cyclase. It \nis released continuously in resistance vessels, giving rise to vasodilator tone and contributing to the physiological control of blood pressure. As well as \ncausing vascular relaxation, it inhibits vascular smooth \nmuscle cell proliferation, inhibits platelet adhesion and aggregation, and inhibits monocyte adhesion and \nmigration; consequently, it may protect blood vessels \nfrom atherosclerosis and thrombosis (see Chs 24 and 25).\n\u2022\tPeptides. The endothelium secretes several vasoactive peptides (see Ch. 19 for general mechanisms of peptide secretion). C-natriuretic peptide (CNP) (Ch. 22) \nand adrenomedullin (a vasodilator peptide originally \ndiscovered in an adrenal tumour \u2013 \nphaeochromocytoma \u2013 but expressed in many tissues, \nincluding vascular endothelium) are vasodilators \nworking, respectively, through cGMP and cAMP. Angiotensin II, formed by angiotensin-converting \nenzyme (ACE) on the surface of endothelial cells (see \np. 295), and endothelin are potent endothelium-derived vasoconstrictor peptides.Vascular smooth muscle \n\u2022\tVascular \tsmooth \tmuscle \tis \tcontrolled \tby \tmediators \t\nsecreted by sympathetic nerves (Ch. 15) and vascular \nendothelium, and by circulating hormones.\n\u2022\tSmooth \tmuscle \tcell \tcontraction \tis \tinitiated \tby \ta \trise \tin \t\n[Ca2+]i, which activates myosin light-chain kinase, \ncausing phosphorylation of myosin, or by sensitisation of the myofilaments to Ca\n2+ by inhibition of myosin \nphosphatase (see Ch. 4).\n\u2022\tAgents\tcause \tcontraction \tvia \tone \tor \tmore \tmechanism:\n\u2013 release of intracellular Ca2+ via inositol trisphosphate\n\u2013 depolarising the membrane, opening voltage-gated \ncalcium channels and causing Ca2+ entry\n\u2013 increasing sensitivity to Ca2+ via actions on myosin \nlight-chain kinase and/or myosin phosphatase (Ch. 4, Fig. 4.9)\n\u2022\tAgents\tcause \trelaxation \tby:\n\u2013 inhibiting Ca2+ entry through voltage-gated calcium \nchannels either directly (e.g. nifedipine) or indirectly \nby hyperpolarising the membrane (e.g. potassium-channel activators such as the active metabolite of minoxidil)\n\u2013 increasing intracellular cAMP or cGMP; cAMP \ninactivates myosin light-chain kinase and facilitates Ca\n2+ efflux, cGMP opposes agonist-induced \nincreases in [Ca2+]i.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3395, "end_char_idx": 6487, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4d6eb0de-40b6-4b98-9228-d3a544d99de3": {"__data__": {"id_": "4d6eb0de-40b6-4b98-9228-d3a544d99de3", "embedding": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dd1a954d-5089-464f-a52d-920c8ba7a668", "node_type": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9da9004e2ee0ee77e4f4322b7d8817aa8975d6d381a826aee4e9b471d50b0ee2"}, "2": {"node_id": "c43c89b0-9c2c-4cf3-8820-6cddd54b1061", "node_type": null, "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c4a5c59f01e5890c8582f4b3bee1e0508fb21181dfe2733944616bed9fef03dc"}}, "hash": "8f3ba127f2ffe307bc69929237117157481ce84b863adfad3d0761defc97bca7", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6487, "end_char_idx": 6838, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2f68fe2e-5dbe-4506-a6c1-c18a22574f4b": {"__data__": {"id_": "2f68fe2e-5dbe-4506-a6c1-c18a22574f4b", "embedding": null, "metadata": {"page_label": "299", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "34449fc1-fa4f-4a77-ad27-a3b3ffd96108", "node_type": null, "metadata": {"page_label": "299", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a03f33f9f84f5b9feece3d05cd88104fa727e215d187ad748eec94ae7ff2ecf"}, "3": {"node_id": "6fd8f0fa-78c8-4f88-a6d8-c46f1ba2bd64", "node_type": null, "metadata": {"page_label": "299", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b054fe1fb0fada4aea0f1ac307da323c8d7bdfd4e27d6276eddf1da9618d666"}}, "hash": "0b7bb5720c6ff44d37e1cf44ece47b107f1f706f8347bb91726f500eadb18311", "text": "23 ThE vASCU lAR SYSTEM\n293vascular smooth muscle are presumably much higher, since \nendothelin receptor antagonists (see later) cause vasodilata -\ntion when infused directly into the brachial artery, implying tonic ET-1-mediated vasoconstrictor activity in resistance vasculature. ET-1 has a plasma elimination half-life of less \nthan 5 min, despite a much longer duration of action fol-\nlowing intravenous administration, and clearance occurs \nmainly in the lung and kidneys.\nEndothelin receptors and responses\nThere are two types of endothelin receptor, designated ET A \nand ET B (Table 23.2), both of which are G protein\u2013coupled (Ch. et al. (1988), who achieved the isolation, analysis and cloning \nof the gene for this peptide, which at that time was the \nmost potent vasoconstrictor known,4 in an impressively \nshort space of time.\n\u25bc Three genes encode different sequences (ET-1, ET-2 and ET-3), \neach\twith\ta\tdistinctive \t\u2018shepherd\u2019s \tcrook\u2019\tstructure \tproduced \tby\ttwo\t\ninternal disulfide bonds. These isoforms are differently expressed in \norgans such as brain and adrenal glands (Table 23.1), suggesting that \nendothelins have functions beyond the cardiovascular system and \nthis is supported by observations of mice in which the gene coding for ET-1 is disrupted (see later). ET-1 is the only endothelin present \nin endothelial cells, and is also expressed in many other tissues. Its \nsynthesis and actions are summarised schematically in Fig. 23.2. ET-2 is much less widely distributed: it is present in kidney and intestine. \nET-3 is present in brain, lung, intestine and adrenal gland. ET-1 is \nsynthesised from a 212-residue precursor molecule (prepro-ET), which \nis\tprocessed \tto \t\u2018big \tET-1\u2019 \tand \tfinally \tcleaved \tby \tan \tendothelin-\nconverting enzyme to yield ET-1. Cleavage occurs not at the usual Lys\u2013Arg or Arg\u2013Arg position (see Ch. 19), but at a Trp\u2013Val pair, \nimplying a very atypical endopeptidase. The converting enzyme is \na metalloprotease and is inhibited by phosphoramidon (a pharm-acological tool but not used therapeutically). Big ET-1 is converted \nto ET-1 intracellularly and also on the surface of endothelial and \nsmooth muscle cells.\nStimuli of endothelin synthesis include many vasoactive \nmediators released by trauma or inflammation, including \nactivated platelets, endotoxin, thrombin, various cytokines \nand growth factors, angiotensin II, antidiuretic hormone (ADH), adrenaline, insulin, hypoxia and low shear stress. \nInhibitors of endothelin synthesis include NO, natriuretic \npeptides, PGE\n2, PGI 2, heparin and high shear stress.\nRelease of ET-1 is poorly understood. Preformed ET-1 \ncan be stored in endothelial cells, although probably not in granules. ET-1 concentration in plasma is too low (<\n5 pmol/L) to activate endothelin receptors, but concentra -\ntions in the extracellular space between endothelium and Table 23.1 Distribution of endothelins and endothelin \nreceptors in various tissuesa\nTissuesEndothelin Endothelin receptor\n1 2 3 ET AET B\nVascular tissue\nEndothelium++++ \u2014 \u2014 +\nSmooth muscle + \u2014 \u2014 ++ \u2014\nBrain +++ + + +++\nKidney ++ ++ + + ++\nIntestines + + +++ + +++\nAdrenal gland + \u2014 +++ + ++\naLevels of expression of", "start_char_idx": 0, "end_char_idx": 3180, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6fd8f0fa-78c8-4f88-a6d8-c46f1ba2bd64": {"__data__": {"id_": "6fd8f0fa-78c8-4f88-a6d8-c46f1ba2bd64", "embedding": null, "metadata": {"page_label": "299", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "34449fc1-fa4f-4a77-ad27-a3b3ffd96108", "node_type": null, "metadata": {"page_label": "299", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7a03f33f9f84f5b9feece3d05cd88104fa727e215d187ad748eec94ae7ff2ecf"}, "2": {"node_id": "2f68fe2e-5dbe-4506-a6c1-c18a22574f4b", "node_type": null, "metadata": {"page_label": "299", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b7bb5720c6ff44d37e1cf44ece47b107f1f706f8347bb91726f500eadb18311"}}, "hash": "4b054fe1fb0fada4aea0f1ac307da323c8d7bdfd4e27d6276eddf1da9618d666", "text": "+ +++\nAdrenal gland + \u2014 +++ + ++\naLevels of expression of endothelins or the receptor mRNA and/\nor\timmunoreactive \tendothelins: \t++++, highest; +++, high; ++, \nmoderate; +, low.\n(Adapted from Masaki, T., 1993. Endocr. Rev. 14, 256\u2013268.)Stimulation\nPromoter\nET-1 gene\nPrepro-ET-1\nmRNA\nPrepro-ET-1\nBIG ET-1\nET-1\nETA / ETBReceptors\n(lungs, kidneys)Clearance\nSignal transduction EffectsET-1Inhibition\nAdrenaline\nAngiotensin IIVasopressinInsulinCortisolIL-1ThrombinGlucoseOxidised LDLHypoxiaCiclosporinShear stressPGl\n2\nNONatriuretic\n peptides (A, B, C)\nTyrosine kinase/MAPK\nPhospholipase A2, C, D\nInositol trisphosphate\nCa2+\nProtein kinase CGene\nexpression\nMitogenesisContraction Blood pressure\nVasospasm\nSmooth muscle proliferationActivation of hypothalamic\n\u2013\n pituitary axis\nFig. 23.2 Endothelin-1 (ET-1) synthesis and actions. The \nschematic shows some of the more important actions only. IL-1, \ninterleukin-1; LDL, low-density lipoprotein; MAPK, mitogen-\nactivated protein kinase; NO, nitric oxide; PGI 2, prostaglandin I 2. \nTable 23.2 Endothelin receptors\nReceptor Affinity Pharmacological response\nETA ET-1 = ET-2 \n> ET-3Vasoconstriction, \nbronchoconstriction, stimulation of aldosterone secretion\nET\nB ET-1 = ET-2 \n= ET-3Vasodilatation, inhibition of ex vivo platelet aggregation\n(From Masaki, T., 1993. Endocr. Rev. 14, 256\u2013268.)\n4Subsequently, an 11-amino acid peptide (urotensin) was isolated from \nthe brains of bony fish and found to be 50\u2013100 times more potent than \nendothelin in some blood vessels. It and its receptor are expressed in \nhuman tissue but its function, if any, in man remains enigmatic.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3123, "end_char_idx": 5230, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c9ac673e-8fa3-42c7-8f73-291dedce7034": {"__data__": {"id_": "c9ac673e-8fa3-42c7-8f73-291dedce7034", "embedding": null, "metadata": {"page_label": "300", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "30b2a322-3cb2-4dea-af94-10276e2e1991", "node_type": null, "metadata": {"page_label": "300", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8c9757a351d9f334740a6022b156fa973d5c9055457002eb302b3d66fa0c132"}, "3": {"node_id": "f3acde98-db65-45a7-b85d-eea928c2dcd3", "node_type": null, "metadata": {"page_label": "300", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a42aa078f3cf16c9716057fd5f0a0b7ef2c6f7bd1b78534d4c0c715538b00fa"}}, "hash": "81caad49cfcfabf253ce20ccfcb50b09848491fe5136cd5ec6c967d1cdc75b3d", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n2943). The predominant overall response is vasoconstriction. A \nkey unresolved question is the precise molecular mechanism \nof the protracted vasoconstrictor response mentioned above; \ndissociation of labelled ET-1 from ET A receptors is slow \ncompared with other peptide agonist/receptor dissociation, \nwith a half-life of about 6 hours, as expected if long-lasting \nconstrictor responses are due to slow agonist dissociation. However, binding is not irreversible \u2013 important when \nconsidering possible therapeutic indications for antagonists \n(Davenport et al., 2016).\n\u25bc ET-1 preferentially activates ET A receptors. Messenger RNA for \nthe ET A receptor is expressed in many human tissues, including \nvascular smooth muscle, heart, lung and kidney. It is not expressed \nin endothelium. ET A-mediated responses include vasoconstriction, \nbronchoconstriction and aldosterone secretion. ET A receptors are \ncoupled to phospholipase C, which stimulates Na+/H+ exchange, \nprotein kinase C and mitogenesis, as well as causing vasoconstriction through inositol trisphosphate-mediated Ca\n2+ release (Ch. 3). There \nare several partially selective ET A-receptor antagonists, including \nBQ-123 (a cyclic pentapeptide) and several orally active non-peptide drugs (e.g. bosentan , a mixed ET\nA/ET B antagonist, and ambrasentan , \nET A-selective, both of which are used in treating pulmonary arterial \nhypertension \u2013 see pp. 307\u2013308). ET B receptors are activated to a \nsimilar extent by each of the three endothelin isoforms, but sarafotoxin \nS6c (a 21-residue peptide that shares the shepherd\u2019s crook structure \nof the endothelins and was isolated from the venom of the burrowing asp) is a selective agonist and has proved useful as a pharmacological \ntool for studying the ET\nB receptor. Messenger RNA for the ET B receptor \nis mainly expressed in brain (especially cerebral cortex and cerebellum), with moderate expression in aorta, heart, lung, kidney and adrenals. \nIn contrast to the ET\nA receptor, it is highly expressed in endothelium, \nwhere it causes vasodilatation by stimulating NO and PGI 2 production, \nbut it is also present in vascular smooth muscle, where it initiates \nvasoconstriction like the ET A receptor. ET B receptors play a part in \nclearing ET-1 from the circulation, and ET antagonists with appreciable affinity for ET\nB receptors consequently increase plasma concentrations \nof ET-1, complicating interpretation of such concentrations during experiments with these drugs.\nFunctions of endothelin\nET-1 is a local mediator rather than a circulating hormone, \nalthough it stimulates secretion of several hormones (see \nTable 23.1). Administration of an ET A-receptor antagonist \nor of phosphoramidon into the brachial artery increases forearm blood flow, and ET\nA-receptor antagonists lower \narterial blood pressure, suggesting that ET-1 contributes to vasoconstrictor tone and the control of peripheral vascular \nresistance in man. Endothelins have several other possible functions, including roles in:\n\u2022\trelease \tof \tvarious \thormones, \tincluding \tatrial \t\nnatriuretic peptide, aldosterone, adrenaline, and hypothalamic and pituitary hormones;\n\u2022\tnatriuresis \tand \tdiuresis \tvia \tactions \tof \tcollecting \t\nduct-derived ET-1 on ET B receptors on tubular \nepithelial cells;\n\u2022\tthyroglobulin \tsynthesis \t(the", "start_char_idx": 0, "end_char_idx": 3379, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f3acde98-db65-45a7-b85d-eea928c2dcd3": {"__data__": {"id_": "f3acde98-db65-45a7-b85d-eea928c2dcd3", "embedding": null, "metadata": {"page_label": "300", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "30b2a322-3cb2-4dea-af94-10276e2e1991", "node_type": null, "metadata": {"page_label": "300", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8c9757a351d9f334740a6022b156fa973d5c9055457002eb302b3d66fa0c132"}, "2": {"node_id": "c9ac673e-8fa3-42c7-8f73-291dedce7034", "node_type": null, "metadata": {"page_label": "300", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "81caad49cfcfabf253ce20ccfcb50b09848491fe5136cd5ec6c967d1cdc75b3d"}}, "hash": "6a42aa078f3cf16c9716057fd5f0a0b7ef2c6f7bd1b78534d4c0c715538b00fa", "text": "cells;\n\u2022\tthyroglobulin \tsynthesis \t(the \tconcentration \tof \tET-1 \tin \t\nthyroid follicles is extremely high)\n\u2022\tcontrol \tof \tuteroplacental \tblood \tflow \t(ET-1 \tis \tabundant \t\nin amniotic fluid)\n\u2022\trenal\tand \tcerebral \tvasospasm \t(Fig. \t23.3);\n\u2022\tdevelopment \tof \tthe \tcardiorespiratory \tsystems \t(if \tthe \t\nET-1 gene is disrupted in mice, pharyngeal arch tissues develop abnormally and homozygotes die of \nrespiratory failure at birth, and ET receptor \nantagonists are teratogenic, causing cardiorespiratory developmental disorders).403020100Renal blood flow (% decrease)Ro 46\u20132005 (mg/kg)\n3 0 \n50250Cerebral blood flow (% decrease)\n120 90 60 30 Baseline \nTime after SAH (min)SAH\n-40-30-20-100Mean arterial pressure (\u2206 mmHg)\n8 7 6 5 4 3 2 1 0\nTime (h)A\nCB\nFig. 23.3 In vivo effects of a potent non-peptide \nendothelin-1 ET A- and ET B-receptor antagonist, Ro 46-2005, \nin three animal models. (A) Prevention by Ro 46-2005 of \npost-ischaemic renal vasoconstriction in rats. (B) Prevention by \nRo 46-2005 of the decrease in cerebral blood flow after \nsubarachnoid \thaemorrhage \t(SAH) \tin \trats \ttreated \twith \tplacebo \t\n(blue) or with Ro 46-2005 (red). (C) Effect of orally administered \nRo 46-2005 on mean arterial pressure in sodium-depleted squirrel monkeys treated with placebo (blue) or increasing doses \nof antagonist (red:\n\t\u2022\t< \u25b2 < \u25c6). (From Clozel, M., et al., 1993. \nNature 365, 759\u2013761.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3340, "end_char_idx": 5214, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ebc3e9b-3df0-475c-8f39-557486261b2d": {"__data__": {"id_": "8ebc3e9b-3df0-475c-8f39-557486261b2d", "embedding": null, "metadata": {"page_label": "301", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e15bedf3-1b5c-4cb4-a145-db3f7620034f", "node_type": null, "metadata": {"page_label": "301", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "96231a9462fc8901c06db480f63e1bac11e4d3d7658b0ff1f67e3fc82306e473"}, "3": {"node_id": "865b6145-d42d-4006-8dc5-7683f6e905b2", "node_type": null, "metadata": {"page_label": "301", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "41401f69607fc55764fc45d74872146916a9cb09f70cd22b2f2528dde5f7c28d"}}, "hash": "e279d13636f2b2065a8716bcfc16bc386b248b056cc4fb079eaa74bbfa6c2102", "text": "23 ThE vASCU lAR SYSTEM\n295THE RENIN\u2013ANGIOTENSIN SYSTEM\nThe renin\u2013angiotensin system synergises with the sympa -\nthetic nervous system, for example, by increasing the release \nof noradrenaline from sympathetic nerve terminals. It \nstimulates aldosterone secretion and plays a central role in the control of Na\n+ excretion and fluid volume, as well \nas of vascular tone.\nThe control of renin secretion (Fig. 23.4) is only partly \nunderstood. It is a proteolytic enzyme that is secreted by the juxtaglomerular apparatus (see Ch. 30, Fig. 30.2) in \nresponse to various physiological stimuli including reduced renal perfusion pressure, or reduced Na\n+ concentration in \ndistal tubular fluid, which is sensed by the macula densa (a \nspecialised part of the distal tubule apposed to the juxtaglo -\nmerular apparatus). Renal sympathetic nerve activity, \u03b2-adrenoceptor agonists and PGI\n2 all stimulate renin \nsecretion directly, whereas angiotensin II causes feedback \ninhibition. Atrial natriuretic peptide (Ch. 22) also inhibits \nrenin secretion. Renin is cleared rapidly from plasma. It acts on angiotensinogen (a plasma globulin made in the liver), \nsplitting off a decapeptide, angiotensin I.\nAngiotensin I is inactive, but is converted by ACE to an \noctapeptide, angiotensin II , which is a potent vasoconstrictor. \nAngiotensin II is a substrate for enzymes (aminopeptidase A and N) that remove single amino acid residues, giving rise, respectively, to angiotensin III and angiotensin IV (Fig. \n23.5). Angiotensin III stimulates aldosterone secretion and \nis involved in thirst. Angiotensin IV also has distinct actions, \nprobably via its own receptor, including release of plasmi-\nnogen activator inhibitor-1 from the endothelium (Ch. 25). \nReceptors for angiotensin IV have a distinctive distribution, \nincluding the hypothalamus.\nACE is a membrane-bound enzyme on the surface of \nendothelial cells, and is particularly abundant in the lung, which has a vast surface area of vascular endothelium.\n5 The role of the endothelium in \ncontrolling vascular smooth \nmuscle \n\u2022\tEndothelial \tcells \trelease \tvasoactive \tmediators \tincluding \t\nprostacyclin (PGI 2), nitric oxide (NO) and distinct but \nincompletely characterised hyperpolarising factor(s) \n\u2018EDHF\u2019\t(vasodilators), \tand \tendothelin \tand \t\nendoperoxide thromboxane receptor agonists \n(vasoconstrictors).\n\u2022\tMany\tvasodilators \t(e.g. \tacetylcholine \tand \tbradykinin) \t\nact via endothelial NO production. The NO derives from arginine and is produced when [Ca\n2+]i increases \nin the endothelial cell, or the sensitivity of endothelial NO synthase to Ca\n2+ is increased (see Fig. 21.3).\n\u2022\tNO\trelaxes \tsmooth \tmuscle \tby \tincreasing \tcGMP \t\nformation.\n\u2022\tEndothelin \tis \ta \tpotent \tand \tlong-acting \tvasoconstrictor \t\npeptide released from endothelial cells by many chemical and physical factors. It is not confined to blood vessels, and it has several functional roles.Renin releaseGlomerular \nfiltrationRenal \nsympathetic \nnerve activityRenal perfusion \npressure \u2193\nAtrial natriuretic \npeptide\u03b2-Agonists\nPGl2\nAngiotensinogen\nAngiotensin I\nAngiotensin IIACE\nAT1\nreceptorsACE inhibitors\nAngiotensin II\nAT1", "start_char_idx": 0, "end_char_idx": 3151, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "865b6145-d42d-4006-8dc5-7683f6e905b2": {"__data__": {"id_": "865b6145-d42d-4006-8dc5-7683f6e905b2", "embedding": null, "metadata": {"page_label": "301", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e15bedf3-1b5c-4cb4-a145-db3f7620034f", "node_type": null, "metadata": {"page_label": "301", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "96231a9462fc8901c06db480f63e1bac11e4d3d7658b0ff1f67e3fc82306e473"}, "2": {"node_id": "8ebc3e9b-3df0-475c-8f39-557486261b2d", "node_type": null, "metadata": {"page_label": "301", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e279d13636f2b2065a8716bcfc16bc386b248b056cc4fb079eaa74bbfa6c2102"}}, "hash": "41401f69607fc55764fc45d74872146916a9cb09f70cd22b2f2528dde5f7c28d", "text": "inhibitors\nAngiotensin II\nAT1 subtype\nreceptor\nantagonists\nVascular growth:\n1. Hyperplasia2. HypertrophyVasoconstriction:1. Direct2. Via increased \nnoradrenaline release from sympathetic nervesSalt retention:1. Aldosterone \nsecretion\n2. Tubular Na\n+ \nreabsorption\nFig. 23.4 Control of renin release and formation, and \naction of angiotensin II. \tSites\tof\taction \tof \tdrugs \tthat \tinhibit \tthe \t\ncascade are shown. ACE, angiotensin-converting enzyme; AT1, \nangiotensin II receptor subtype 1; PGI 2, prostaglandin I 2. \nV etc. LL HF PH IY VR NC-terminal N-terminalRenin\nACEACE2\nAminopeptidase N\nAminopeptidase A\nAngiotensin III\nAngiotensin IV\nAngiotensin IIAngiotensin 1-7\nAngiotensin I\nAngiotensinogen\nFig. 23.5 Formation of angiotensins I\u2013IV from the \nN-terminal of the precursor protein angiotensinogen. Also \nshown is angiotensin 17 which is a product of the action of \nangiotensin-converting enzyme 2 (ACE2) and opposing actins to angiotensin II. \n5Approximately that of a football field.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3122, "end_char_idx": 4595, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "538ca174-8aa1-4bd8-97e6-cd4adcfbde2c": {"__data__": {"id_": "538ca174-8aa1-4bd8-97e6-cd4adcfbde2c", "embedding": null, "metadata": {"page_label": "302", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d152b95-1f45-4b8d-bedb-d001a7b105d9", "node_type": null, "metadata": {"page_label": "302", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "03de8e1a4a83bfd281e0a27904cbc88f23147775416e3e7f6824d28b090c3083"}, "3": {"node_id": "aa7b47e7-098b-4ada-97bc-4edf5251c059", "node_type": null, "metadata": {"page_label": "302", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "372020daf72e80e9d4c3e808ce3d90f6e8c04e5814e0c262dcd1fe2d65155400"}}, "hash": "6178407939178e713c0e1ce158eed59d4abc15950832e4a865087dbb8f6e8390", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n296The renin\u2013angiotensin\u2013aldosterone pathway contributes \nto the pathogenesis of heart failure, and several leading \nclasses of therapeutic drug act on it at different points (see \nFig. 23.4).\nVASOACTIVE DRUGS\nDrugs can affect vascular smooth muscle by acting either directly on smooth muscle cells, or indirectly, for example, \non endothelial cells, on sympathetic nerve terminals or on \nthe central nervous system (CNS) (Table 23.3). Mechanisms of directly acting vasoconstrictors and vasodilators are \nsummarised in Fig. 4.10 (Ch. 4). Many indirectly acting \ndrugs are discussed in other chapters (see Table 23.3). We concentrate here on agents that are not covered \nelsewhere.\nVASOCONSTRICTOR DRUGS\nThe \u03b11-adrenoceptor agonists and drugs that release \nnoradrenaline from sympathetic nerve terminals or inhibit its reuptake (sympathomimetic amines) are discussed in \nChapter 15. Some eicosanoids (e.g. thromboxane A\n2; see Chs \n18 and 25) and several peptides, notably endothelin, angio-\ntensin and ADH, are also predominantly vasoconstrictor. Sumatriptan and ergot alkaloids acting on certain 5-hydroxytryptamine receptors (5-HT\n2 and 5-HT 1D) also \ncause vasoconstriction (Ch. 16).\nANGIOTENSIN \u2003II\nThe physiological role of the renin\u2013angiotensin system is described previously. Angiotensin II is roughly 40 times \nas potent as noradrenaline in raising blood pressure. Like \n\u03b1\n1-adrenoceptor agonists, it constricts mainly cutaneous, \nsplanchnic and renal vasculature, with less effect on blood \nflow to brain and skeletal muscle. It has no routine clinical \nuses, although it has promise in the treatment of vasodilatory \nshock (Khanna et al., 2017), its main therapeutic importance \nlying in the fact that other drugs (e.g. captopril and losartan , \nsee pp. 300\u2013301) affect the cardiovascular system by reducing \nits production or action.\nANTIDIURETIC \u2003HORMONE\nADH (also known as vasopressin) is a posterior pituitary \npeptide hormone (Ch. 34). It is physiologically important The common isoform of ACE is also present in other \nvascularised tissues, including heart, brain, striated muscle \nand kidney, and is not restricted to endothelial cells. Consequently, local formation of angiotensin II can occur \nin different vascular beds, and it provides local control \nindependent of blood-borne angiotensin II. ACE inactivates bradykinin (see Ch. 19) and several other peptides. This \nmay contribute to the pharmacological actions of ACE \ninhibitors (ACEIs), as discussed below.\n\u25bc AC E2, a homologue of ACE, converts angiotensin II to angiotensin \n1-7 (Ang 1-7) as shown in Fig. 23.5. Ang 1-7 acts on the Mas receptor \n(a G-protein\u2013coupled receptor coded by the MAS1 oncogene) opposing \nthe effects of angiotensin II. ACE2 is widely expressed, including in \ncardiomyocytes and endothelial cells, and potentially protects against heart failure. Recombinant human ACE2 has been tested in humans \nwithout adverse effects while lowering plasma angiotensin II and \nincreasing Ang 1-7 concentration. For a recent review of the therapeutic potential of enhancing ACE2/Ang 1-7 action for heart failure see \nPatel et al. (2016). ACE2 is expressed in Leydig cells of the testis and \nmale mice lacking this ACE isoform have markedly reduced", "start_char_idx": 0, "end_char_idx": 3292, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aa7b47e7-098b-4ada-97bc-4edf5251c059": {"__data__": {"id_": "aa7b47e7-098b-4ada-97bc-4edf5251c059", "embedding": null, "metadata": {"page_label": "302", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d152b95-1f45-4b8d-bedb-d001a7b105d9", "node_type": null, "metadata": {"page_label": "302", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "03de8e1a4a83bfd281e0a27904cbc88f23147775416e3e7f6824d28b090c3083"}, "2": {"node_id": "538ca174-8aa1-4bd8-97e6-cd4adcfbde2c", "node_type": null, "metadata": {"page_label": "302", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6178407939178e713c0e1ce158eed59d4abc15950832e4a865087dbb8f6e8390"}}, "hash": "372020daf72e80e9d4c3e808ce3d90f6e8c04e5814e0c262dcd1fe2d65155400", "text": "of the testis and \nmale mice lacking this ACE isoform have markedly reduced fertility. ACE2 is insensitive to conventional ACE inhibitors.\nThe main actions of angiotensin II are mediated via AT 1 \nand/or AT 2 receptors, which belong to the family of G \nprotein\u2013coupled receptors. Effects mediated by AT 1 receptors \ninclude:\n\u2022\tgeneralised \tvasoconstriction, \tespecially \tmarked \tin \t\nefferent arterioles of the renal glomeruli;\n\u2022\tincreased \tnoradrenaline \trelease, \treinforcing \t\nsympathetic effects;\n\u2022\tproximal \ttubular \treabsorption \tof \tNa+;\n\u2022\tsecretion \tof \taldosterone \tfrom \tthe \tadrenal \tcortex \t(see \t\nCh. 34);\n\u2022\tgrowth \tof \tcardiac \tand \tvascular \tcells.6\nAT 2 receptors are expressed during fetal life and in distinct \nbrain regions in adults. They are believed to be involved \nin growth, development and exploratory behaviour. \nCardiovascular effects of AT 2 receptors (inhibition of cell \ngrowth and lowering of blood pressure) are relatively subtle \nand oppose those of AT 1 receptors.Table 23.3 Classification of vasoactive drugs that act indirectly\nSite Mechanism Examples See chapter\nVasoconstrictors\nSympathetic nerves Noradrenaline (norepinephrine) release\nBlocks noradrenaline reuptakeTyramineCocaine1515\nEndothelium Endothelin release Angiotensin II (in part) This chapter\nVasodilators\nSympathetic nerves Inhibits noradrenaline release Prostaglandin E\n2, \nguanethidine18\n15\nEndothelium Nitric oxide release Acetylcholine, substance P 21\nCentral nervous system Vasomotor inhibition Anaesthetics 42\nEnzymes ACE inhibition Captopril This chapter\n6These effects are initiated by the G protein\u2013coupled AT 1 receptor acting \nvia the same intracellular tyrosine phosphorylation pathways as are \nused by cytokines, for example, the Jak/Stat pathway (Ch. 3).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3217, "end_char_idx": 5466, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e2e74ca3-63a9-4386-8939-b3d312085092": {"__data__": {"id_": "e2e74ca3-63a9-4386-8939-b3d312085092", "embedding": null, "metadata": {"page_label": "303", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3cb4c5bb-bf97-4956-8549-2a1bef7d6fe2", "node_type": null, "metadata": {"page_label": "303", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "70d01db503015e401fc64145d1295157e6302997edba39dde0061895365d1a16"}, "3": {"node_id": "27ccde05-4595-4107-9273-4fad0ee8cd92", "node_type": null, "metadata": {"page_label": "303", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d48773ddd3127790772840c0718117d7e226af0051f99e00310a8c706902cb29"}}, "hash": "c9205c4488758c3d837262179a3ef6bff477bc6b277dcc4541a712992efc43b8", "text": "23 ThE vASCU lAR SYSTEM\n297reuptake) and enzymes that determine Ca2+ sensitivity of \nthe contractile proteins (see Fig. 4.10).\nCalcium antagonists\nL-type calcium antagonists are discussed in Chapter 22. \nDrugs that activate potassium channels\nSome drugs (e.g. minoxidil, diazoxide) relax smooth muscle \nby opening K ATP channels (Fig. 23.6). This hyperpolarises \nthe cells and switches off voltage-dependent calcium chan -\nnels. Potassium-channel activators work by antagonising \nthe action of intracellular ATP on these channels.\nMinoxidil (acting through an active sulfate metabolite) \nis an especially potent and long-acting vasodilator, used as a drug of last resort in treating severe hypertension unresponsive to other drugs. It causes hirsutism (the active \nmetabolite is actually used as a rub-on cream to treat bald -\nness, see Ch. 28). It causes marked salt and water retention, for its antidiuretic action on the kidney (Ch. 30) but is also \na powerful vasoconstrictor. Its effects are initiated by two \ndistinct receptors (V\n1 and V 2). Water retention is mediated \nthrough V 2 receptors, occurs at low plasma concentrations \nof ADH and involves activation of adenylyl cyclase in renal collecting ducts. Vasoconstriction is mediated through \nV\n1 receptors (two subtypes, see Ch. 34), requires higher \nconcentrations of ADH and involves activation of phos -\npholipase C (see Ch. 3). ADH causes generalised vasocon -\nstriction, including the skin, coeliac, mesenteric and coronary \nvessels. It also affects other (e.g. gastrointestinal and uterine) \nsmooth muscle and causes abdominal cramps for this reason. \nVasopressin or its analogue, terlipressin , is commonly used \nto treat patients with bleeding oesophageal varices and \nportal hypertension before more definitive endoscopic \ntreatment; although gastroenterologists also have the option of using octreotide (unlicensed indication; see Ch. 34) for \nthis. It may also have a place in treating vasodilatory shock \n(see p. 307).\nENDOTHELIN\nEndothelins are discussed earlier in the context of their \nphysiological roles; as explained above, they have vasodila -\ntor and vasoconstrictor actions, but vasoconstriction pre-dominates. Intravenous administration causes transient vasodilatation followed by profound and long-lived \nvasoconstriction. The endothelins are even more potent \nvasoconstrictors than angiotensin II. As yet, they have no clinical uses, and endothelin antagonists are licensed only \nfor primary pulmonary hypertension (see p. 308).\nVASODILATOR DRUGS\nVasodilator drugs play a major role in the treatment of \ncommon conditions, including hypertension, cardiac failure \nand angina pectoris, as well as several less common but \nserious diseases, including pulmonary hypertension and Raynaud\u2019s disease.\nDIRECT \u2003ACTING \u2003VASODILATORS\nTargets on which drugs act to relax vascular smooth muscle include plasma membrane voltage-dependent calcium \nchannels, sarcoplasmic reticulum channels (Ca\n2+ release or Vasoconstrictor substances \n\u2022\tThe\tmain \tgroups \tare \tsympathomimetic \tamines \t(direct \t\nand indirect; Ch. 15), certain eicosanoids (especially \nthromboxane A 2; Ch. 18), peptides (angiotensin II, \nantidiuretic \thormone \t[ADH] \tand \tendothelin; \tCh. \t19) \t\nand a group of miscellaneous drugs (e.g. ergot alkaloids; Ch.", "start_char_idx": 0, "end_char_idx": 3298, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "27ccde05-4595-4107-9273-4fad0ee8cd92": {"__data__": {"id_": "27ccde05-4595-4107-9273-4fad0ee8cd92", "embedding": null, "metadata": {"page_label": "303", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3cb4c5bb-bf97-4956-8549-2a1bef7d6fe2", "node_type": null, "metadata": {"page_label": "303", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "70d01db503015e401fc64145d1295157e6302997edba39dde0061895365d1a16"}, "2": {"node_id": "e2e74ca3-63a9-4386-8939-b3d312085092", "node_type": null, "metadata": {"page_label": "303", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9205c4488758c3d837262179a3ef6bff477bc6b277dcc4541a712992efc43b8"}}, "hash": "d48773ddd3127790772840c0718117d7e226af0051f99e00310a8c706902cb29", "text": "a group of miscellaneous drugs (e.g. ergot alkaloids; Ch. 16).\n\u2022\tClinical\tuses \tinclude \tlocal \tapplications \t(e.g. \tnasal \t\ndecongestion, co-administration with local \nanaesthetics). \tSympathomimetic \tamines \tand \tADH are \nused in circulatory shock. Adrenaline is life-saving in \nanaphylactic shock and in cardiac arrest. ADH or \nterlipressin (an analogue) has been infused intravenously to stop bleeding from oesophageal varices before surgery in patients with portal hypertension caused by liver disease.\n100 \u00b5mol/L diazoxide0.5 mmol/L ATP\nSaponin\n20 s5 pA\nFig. 23.6 ATP-sensitive potassium channels. \tPatch\tclamp \t(see \tCh. \t3) \trecord \tfrom \tinsulin-secreting \tpancreatic \tB \tcell: \tsaponin \t\npermeabilised the cell, with loss of intracellular ATP, causing the channels to open (upward deflection) until they were inhibited by ATP. \nAddition of diazoxide, a vasodilator drug (which also inhibits insulin secretion; see text) reopens the channels. In smooth muscle, this \ncauses hyperpolarisation and relaxation. (Redrawn from Dunne, et al., 1990. Br. J. Pharmacol. 99, 169.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3241, "end_char_idx": 4801, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6b090398-4e3a-4ff9-b534-169fe23c5e2f": {"__data__": {"id_": "6b090398-4e3a-4ff9-b534-169fe23c5e2f", "embedding": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1f6a82bb-5f49-4ac7-acf1-88fdcda8a3cd", "node_type": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aed025fb0a5124bccc3f28148d5c2705e30b5a1ebf83766076aec0490702a4e5"}, "3": {"node_id": "24c18645-dc96-419a-be4b-a3985fb9b47e", "node_type": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ae6513995954b714dda7e46ca204d953b17f1c1df7761205ed60a93660424629"}}, "hash": "4f0aa16bb7377900ee49da2c2af58ead41adf73712c411ce09bbef157b9cad22", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n298discussed in Chapters 29 and 49. In addition to inhibiting \nPDE, some methylxanthines are also purine receptor \nantagonists (Ch. 17). Papaverine is produced by opium \npoppies (see Ch. 43) and relaxes vascular smooth muscle. Its mechanism is poorly understood but seems to involve \na combination of PDE inhibition and block of calcium \nchannels. Selective PDE type III inhibitors (e.g. milrinone ) \nincrease cAMP in cardiac muscle. They have a positive \ninotropic effect but, despite short-term haemodynamic \nimprovement, increase mortality in patients with heart failure, possibly by causing dysrhythmias. Dipyridamole , \nas well as enhancing the actions of adenosine (see Ch. 17), \nalso causes vasodilatation by inhibiting PDE. Selective PDE \ntype V inhibitors (e.g. sildenafil) inhibit the breakdown of \ncGMP, thereby potentiating NO signalling. It revolutionised treatment of erectile dysfunction (see Ch. 36) and has \ntherapeutic potential in other situations, including pulmo -\nnary hypertension (see clinical box, p. 308).so is usually prescribed with a loop diuretic. It causes reflex tachycardia, and a \u03b2-adrenoceptor antagonist is used to \nprevent this. Nicorandil (Ch. 22) combines K\nATP channel \nactivation with NO donor activity, and is used in refractory angina.\nDrugs that act via cyclic nucleotides\nCyclase activation\nMany drugs relax vascular smooth muscle by increasing \nthe cellular concentration of either cGMP or cAMP. For \nexample, NO, nitrates and the natriuretic peptides act through cGMP (see Chs 21 and 22); BAY41-2272, a pyra -\nzolopyridine, activates soluble guanylyl cyclase via an NO-independent site (see Ch. 21). The \u03b2\n2 agonists , adenosine \nand PGI 2 increase cytoplasmic cAMP (see Chs 15, 17, 18). \nDopamine has mixed vasodilator and vasoconstrictor actions. \nIt selectively dilates renal vessels, where it increases cAMP by activating adenylyl cyclase. Dopamine, when adminis -\ntered as an intravenous infusion, produces a mixture of \ncardiovascular effects resulting from agonist actions on \u03b1 \nand \u03b2 adrenoceptors, as well as on dopamine receptors. \nBlood pressure increases slightly, but the main effects are \nvasodilatation in the renal circulation and increased cardiac \noutput. Dopamine was widely used in intensive care units in patients in whom renal failure associated with decreased renal perfusion appeared imminent; despite its beneficial \neffect on renal haemodynamics, clinical trials have shown \nthat it does not improve survival in these circumstances and this use is obsolete. Nesiritide , a recombinant form of \nhuman B-type natriuretic peptide (BNP) (see Ch. 22), was widely used in the United States for the treatment of acutely decompensated heart failure, but efficacy data have not \nbeen impressive (O\u2019Connor et al., 2011). However, sacubitril, \nprodrug of an active metabolite sacubitilat, an inhibitor of \nneprilysin (which is also known as neutral endopeptidase, \nNEP), increases circulating natriuretic peptides (BNP and ANP) and, in fixed combination with valsartan , is effective \nin treating chronic heart failure (see later, p. 305).\nNitroprusside (nitroferricyanide) is a powerful vasodila -\ntor which acts by releasing NO (Ch. 21). Unlike the organic \nnitrates, it", "start_char_idx": 0, "end_char_idx": 3294, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "24c18645-dc96-419a-be4b-a3985fb9b47e": {"__data__": {"id_": "24c18645-dc96-419a-be4b-a3985fb9b47e", "embedding": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1f6a82bb-5f49-4ac7-acf1-88fdcda8a3cd", "node_type": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aed025fb0a5124bccc3f28148d5c2705e30b5a1ebf83766076aec0490702a4e5"}, "2": {"node_id": "6b090398-4e3a-4ff9-b534-169fe23c5e2f", "node_type": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f0aa16bb7377900ee49da2c2af58ead41adf73712c411ce09bbef157b9cad22"}, "3": {"node_id": "39058389-376e-416e-8f24-f205c62f4051", "node_type": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdf6f9d05affd08d7e55e899d0390719e2e4e738da165368ff1a563ca4f4b057"}}, "hash": "ae6513995954b714dda7e46ca204d953b17f1c1df7761205ed60a93660424629", "text": "which acts by releasing NO (Ch. 21). Unlike the organic \nnitrates, it acts equally on arterial and venous smooth \nmuscle. Its clinical usefulness is limited because it must be given intravenously. In solution, particularly when exposed to light, nitroprusside hydrolyses with formation \nof cyanide. The intravenous solution must therefore be \nmade up freshly from dry powder and protected from light. Nitroprusside is rapidly converted to thiocyanate in \nthe body, its plasma half-life being only a few minutes, so \nit must be given as a continuous infusion with careful monitoring to avoid hypotension. Prolonged use causes \nthiocyanate accumulation and toxicity (weakness, nausea \nand inhibition of thyroid function); consequently, nitroprus -\nside is useful only for short-term treatment (usually up to \n72 h maximum). It is used in intensive care units for \nhypertensive emergencies, to produce controlled hypoten -\nsion during surgery, and to reduce cardiac work during \nthe reversible cardiac dysfunction that occurs after \ncardiopulmonary bypass surgery.\nPhosphodiesterase inhibition\nPhosphodiesterases (PDEs; see Ch. 3) include at least 14 distinct isoenzymes. Methylxanthines (e.g. theophylline) \nand papaverine are non-selective PDE inhibitors (and have \nadditional actions). Methylxanthines exert their main effects on bronchial smooth muscle and on the CNS, and are Vasodilator drugs \n\u2022\tVasodilators \tact:\n\u2013 to increase local tissue blood flow\n\u2013 to reduce arterial pressure\n\u2013 to reduce central venous pressure\n\u2022\tReduce \tcardiac \twork \tby \treducing \tcardiac \tpreload \t\n(reduced filling pressure) and afterload (reduced \nvascular resistance).\n\u2022\tMain\tuses \tare:\n\u2013 antihypertensive therapy (e.g. angiotensin II type 1 \n[AT 1] antagonists, calcium antagonists and \u03b11-\nadrenoceptor antagonists)\n\u2013 treatment/prophylaxis of angina (e.g. calcium \nantagonists, nitrates)\n\u2013 treatment of cardiac failure (e.g. angiotensin-\nconverting enzyme inhibitors, AT 1 antagonists)\n\u2013 treatment of erectile dysfunction.\n7An autoimmune disease affecting one or more tissues, including joints, \nkidneys, brain, blood platelets, skin and pleural membranes (Chs 27 \nand 58). The autoantibodies are directed against antigens that are \nintracellular in healthy cells but which become clustered in blebs at the surface of apoptotic cells. In SLE apoptotic waste may present these \nmultiple antigens to cells of the immune system; hydralazine is one of \nseveral drugs that can mimic SLE but the mechanism is incompletely understood.VASODILATORS \u2003WITH \u2003UNCERTAIN \u2003MECHANISM \u2003\u2003\nOF\u2003ACTION\nHydralazine\nHydralazine acts mainly by relaxing arteries and arterioles, \ncausing a fall in blood pressure accompanied by reflex \ntachycardia and increased cardiac output. It interferes with \nthe action of inositol trisphosphate on Ca2+ release from \nthe sarcoplasmic reticulum. Its original clinical use was in \nhypertension, and is still used for short-term treatment of \nsevere hypertension in pregnancy but it can cause an immune disorder resembling systemic lupus erythematosus \n(SLE),\n7 so alternative agents are now preferred for long-term \ntreatment of hypertension. It has a place in treating heart failure in patients of African origin in combination with a \nlong-acting organic nitrate (see clinical box, p. 306).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3237, "end_char_idx": 6639, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "39058389-376e-416e-8f24-f205c62f4051": {"__data__": {"id_": "39058389-376e-416e-8f24-f205c62f4051", "embedding": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1f6a82bb-5f49-4ac7-acf1-88fdcda8a3cd", "node_type": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aed025fb0a5124bccc3f28148d5c2705e30b5a1ebf83766076aec0490702a4e5"}, "2": {"node_id": "24c18645-dc96-419a-be4b-a3985fb9b47e", "node_type": null, "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ae6513995954b714dda7e46ca204d953b17f1c1df7761205ed60a93660424629"}}, "hash": "cdf6f9d05affd08d7e55e899d0390719e2e4e738da165368ff1a563ca4f4b057", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6650, "end_char_idx": 7065, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bb21f84f-7208-43e3-8283-a671f57102eb": {"__data__": {"id_": "bb21f84f-7208-43e3-8283-a671f57102eb", "embedding": null, "metadata": {"page_label": "305", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1e1f477d-b3e4-4339-aaef-e19072eabc45", "node_type": null, "metadata": {"page_label": "305", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cf0c804abaf25434cf0392310918cd380ea324aca02637d684d0166ae335ebc4"}, "3": {"node_id": "b3ce1938-bf63-4ff0-b72d-d1ca3046b59c", "node_type": null, "metadata": {"page_label": "305", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f05b449216ea469cb3fdabaeacf70716ead5c0c1a9233e4d4df230bccc2473d0"}}, "hash": "3da0f6307599fae467d890f059836106915b7f0b22aaba38598b65d5253f5087", "text": "23 ThE vASCU lAR SYSTEM\n299acetylcholine, bradykinin, substance P) exert some or all \nof their effects by stimulating biosynthesis of vasodilator \nprostaglandins or of NO (or of both) by vascular endothe -\nlium (see previously and Ch. 21), thereby causing functional \nantagonism of the constrictor tone caused by sympathetic \nnerves and angiotensin II.\nMany useful drugs block the renin\u2013angiotensin\u2013aldos -\nterone system (RAAS; see Table 23.4 for a summary of \nselective antagonists) at one of several points:\n\u2022\trenin\trelease: \t\u03b2-adrenoceptor antagonists inhibit renin \nrelease (Ch. 15)\n\u2022\trenin\tactivity: \trenin \tinhibitors \tinhibit \tconversion \tof \t\nangiotensinogen to angiotensin I\n\u2022\tACE:\tACEIs \t(see \tlater) \tblock \tconversion \tof \tangiotensin \t\nI to angiotensin II\n\u2022\tangiotensin \tII \treceptors: \tAT 1-receptor antagonists \n(ARBs, see later)\n\u2022\taldosterone \treceptors: \taldosterone-receptor \t\nantagonists (see later)Ethanol\nEthanol (see Ch. 50) dilates cutaneous vessels, causing the \nfamiliar drunkard\u2019s flush. Several general anaesthetics (e.g. \npropofol ) cause vasodilatation as an unwanted effect (Ch. 42).\nINDIRECTLY \u2003ACTING \u2003VASODILATOR \u2003DRUGS\nIndirectly acting vasodilator drugs work by inhibiting \nvasoconstrictor systems, namely the sympathetic nervous \nsystem (see Ch. 15) and the renin\u2013angiotensin\u2013aldosterone \nand endothelin systems or by potentiating endogenous vasodilators such as the natriuretic peptides (see Ch.22 \nand further in this chapter, p. 305).\nThe central control of sympathetically mediated vaso -\nconstriction involves \u03b1\n2 adrenoceptors and another class \nof receptor, termed the imidazoline I 1 receptor , present in the \nbrain stem in the rostral ventrolateral medulla. Clonidine \n(an \u03b12-adrenoceptor agonist, now largely obsolete as an \nantihypertensive drug) and moxonodine, an I 1-receptor \nagonist, lower blood pressure by reducing sympathetic activity centrally. In addition, many vasodilators (e.g. \nTable 23.4 Summary of drugs that inhibit the renin\u2013angiotensin\u2013aldosterone system\nClass DrugaPharmacokinetics Adverse effectsbUses Notes\nACE inhibitors Captopril Short acting\nt1/2 \u223c2 h\nDose 2\u20133 times dailyCoughHypotensionProteinuriaTaste disturbanceHypertensionHeart failureAfter MIACEIs are cleared mainly by renal excretion\nEnalapril Prodrug \u2013 active metabolite enalaprilatt\n1/2 \u223c11 h\nDose 1\u20132 times dailyCoughHypotensionReversible renal impairment (in patients with renal artery stenosis)As captopril Lisinopril, perindopril, ramipril, trandolapril are similarSome are licensed for distinct uses (e.g. stroke, left ventricular hypertrophy)\nARBs Valsartan t\n1/2 \u223c6 h HypotensionReversible renal impairment (in patients with renal artery stenosis)HypertensionHeart failureARBs are cleared by hepatic metabolism\nLosartan Long-acting metabolitet\n1/2 \u223c8 hAs valsartan As valsartanDiabetic nephropathyIrbesartan is similar, with t\n1/2 \n\u223c10\u201315 h\nCandesartan t1/2 5\u201310 h\nLong-acting because receptor complex is stableAs valsartan As valsartan Given as prodrug ester (candesartan", "start_char_idx": 0, "end_char_idx": 3016, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b3ce1938-bf63-4ff0-b72d-d1ca3046b59c": {"__data__": {"id_": "b3ce1938-bf63-4ff0-b72d-d1ca3046b59c", "embedding": null, "metadata": {"page_label": "305", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1e1f477d-b3e4-4339-aaef-e19072eabc45", "node_type": null, "metadata": {"page_label": "305", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cf0c804abaf25434cf0392310918cd380ea324aca02637d684d0166ae335ebc4"}, "2": {"node_id": "bb21f84f-7208-43e3-8283-a671f57102eb", "node_type": null, "metadata": {"page_label": "305", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3da0f6307599fae467d890f059836106915b7f0b22aaba38598b65d5253f5087"}}, "hash": "f05b449216ea469cb3fdabaeacf70716ead5c0c1a9233e4d4df230bccc2473d0", "text": "is stableAs valsartan As valsartan Given as prodrug ester (candesartan cilexetil)\nRenin inhibitor Aliskiren Low oral bioavailabilityt\n1/2 24 hAs valsartan, also diarrhoeaEssential hypertensionThe FDA has warned against combining with ACEI or ARB in patients with renal impairment + \ndiabetes mellitus\nAldosterone antagonistsEplerenone t\n1/2 3\u20135 h As valsartan, especially hyperkalaemiaNausea, diarrhoeaHeart failure after MICaution in renal impairment; monitor plasma potassium\nSpironolactone Prodrug converted to canrenone, which has t\n1/2 \u223c24 hAs eplerenoneAlso oestrogenic effects (gynaecomastia, menstrual irregularity, erectile dysfunction)Primary hyperaldosteronismHeart failureOedema and ascites (e.g. in hepatic cirrhosis)\naAll drugs listed are orally active.\nbAdverse effects common to all drugs listed include hyperkalaemia (especially in patients with impaired renal function) and teratogenesis.\nACE, angiotensin-converting enzyme; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; MI, myocardial infarction.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2946, "end_char_idx": 4476, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1f4ef9e6-281d-4a8b-8099-bf3295bfa2ba": {"__data__": {"id_": "1f4ef9e6-281d-4a8b-8099-bf3295bfa2ba", "embedding": null, "metadata": {"page_label": "306", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "74241bfb-346c-4263-b1d3-c3a60eb1faff", "node_type": null, "metadata": {"page_label": "306", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb9f73d50634280384ecf30d98471ceb83fba58ca7cef7a10145dd13edfa91ba"}, "3": {"node_id": "6baea516-1503-41f1-bd98-7fd0e636c04b", "node_type": null, "metadata": {"page_label": "306", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f84c04f01f9c2912a6f15b7539e989f63de92cf454a419293fd93897c694eb50"}}, "hash": "5bc1791af63fe5e1ad34134bd7509926c1d6d1a6ce089dd6c9ef220bea1fbf46", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n300ACEIs affect capacitance and resistance vessels, and reduce \ncardiac load as well as arterial pressure. They act prefer-\nentially on angiotensin-sensitive vascular beds, which \ninclude those of the kidney, heart and brain. This selectivity may be important in sustaining adequate perfusion of these \nvital organs in the face of reduced perfusion pressure. \nCritical renal artery stenosis\n9 represents an exception to \nthis, where ACE inhibition results in a fall in glomerular \nfiltration rate (see later).\nClinical uses of ACEIs are summarised in the clinical \nbox.Renin inhibitors\nAliskiren , an orally active non-peptide renin inhibitor, was \ndeveloped and registered as an antihypertensive drug. It is a triumph of drug design and lowers blood pressure, \nbut has adverse effects that include diarrhoea (common), acute renal failure, cardiovascular events in patients with \ndiabetes mellitus, and, rarely, angioedema and severe \nallergic reactions.\nAngiotensin-converting enzyme inhibitors\nThe first ACEI to be marketed was captopril (Fig. 23.7), an \nearly example of successful drug design based on a chemical \nknowledge of the target molecule. Various small peptides \nhad been found to be weak inhibitors of the enzyme.8 \nCaptopril was designed to combine the steric properties of \nsuch peptide antagonists in a non-peptide molecule that \nwas active when given by mouth. Captopril has a short \nplasma half-life (about 2 h) and must be given 2 or 3 times \ndaily. Many of the ACEIs developed subsequently (see Table \n23.4), which are widely used in the clinic, have a longer \nduration of action and are administered once daily.\nPharmacological effects\nACEIs cause only a small fall in arterial pressure in healthy \nhuman subjects who are consuming the amount of salt contained in a usual Western diet, but a much larger fall \nin hypertensive patients, particularly those in whom renin \nsecretion is enhanced (e.g. in patients receiving diuretics). Active site\nACE\nPLASMA MEMBRANEBinding\nsites\nC-terminal of\nangiotensin I\nZn2+\nO\u2212CHCH3CH3\nCH2CH2H\nH\nHNNO\nO OCC\nC\nCNN\nH\nNH XNH2 HN\nC H\nNH XNH2 HN\nCCleavage\npointCOOHNH2\nZn2+\nO\nO\u2212OCH2C\nHS\nCHCH3CH2\nCH2 N\nCC\nCCaptopril\nAB\nFig. 23.7 The active site of angiotensin-converting enzyme. (A) Binding of angiotensin I. (B) Binding of the inhibitor captopril, which is \nan analogue of the terminal dipeptide of angiotensin I. \nClinical uses of angiotensin-\nconverting enzyme inhibitors \n\u2022\tHypertension\n\u2022\tCardiac \tfailure\n\u2022\tFollowing \tmyocardial \tinfarction \t(especially \twhen \tthere \t\nis ventricular dysfunction)\n\u2022\tIn\tpeople \tat \thigh \trisk \tof \tischaemic \theart \tdisease\n\u2022\tDiabetic \tnephropathy\n\u2022\tChronic \trenal \tinsufficiency \tto \tprevent \tprogression\n8The lead compound was a nonapeptide derived from the venom of \nBothrops jacaraca \u2013 a South American snake. It was originally \ncharacterised as a bradykinin-potentiating peptide (ACE inactivates \nbradykinin, Ch. 19).9Severe narrowing of the renal artery caused, for example, by atheroma \n(Ch. 24).Unwanted effects\nAdverse effects (see Table 23.4) directly related to ACE \ninhibition are common to all drugs of this class. These \ninclude hypotension, especially", "start_char_idx": 0, "end_char_idx": 3214, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6baea516-1503-41f1-bd98-7fd0e636c04b": {"__data__": {"id_": "6baea516-1503-41f1-bd98-7fd0e636c04b", "embedding": null, "metadata": {"page_label": "306", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "74241bfb-346c-4263-b1d3-c3a60eb1faff", "node_type": null, "metadata": {"page_label": "306", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb9f73d50634280384ecf30d98471ceb83fba58ca7cef7a10145dd13edfa91ba"}, "2": {"node_id": "1f4ef9e6-281d-4a8b-8099-bf3295bfa2ba", "node_type": null, "metadata": {"page_label": "306", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5bc1791af63fe5e1ad34134bd7509926c1d6d1a6ce089dd6c9ef220bea1fbf46"}}, "hash": "f84c04f01f9c2912a6f15b7539e989f63de92cf454a419293fd93897c694eb50", "text": "are common to all drugs of this class. These \ninclude hypotension, especially after the first dose and especially in patients with heart failure who have been mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3137, "end_char_idx": 3775, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b50f958e-797c-4e6a-b905-551cb15ce276": {"__data__": {"id_": "b50f958e-797c-4e6a-b905-551cb15ce276", "embedding": null, "metadata": {"page_label": "307", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f9a9d6f-fef1-4373-a7cd-3c799f648cb7", "node_type": null, "metadata": {"page_label": "307", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "745d113fd563ed623abc9b08adc8ec86ffbac323aaece178db84fbe5a4df220f"}, "3": {"node_id": "44ccfb8f-4598-4ccc-a577-111fd7d4bb04", "node_type": null, "metadata": {"page_label": "307", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "038d2c449696bb9fef132e698a38dedbca58a0afc2e02dd4dcd905553b11c087"}}, "hash": "0d07894abf5bd8f324c193efdc4c0eab8b92a50bc7e60ee838c5c8436cae7f93", "text": "23 ThE vASCU lAR SYSTEM\n301nonetheless useful to consider briefly the treatment of certain \nimportant disorders, namely:\n\u2022\tsystemic \thypertension\n\u2022\theart\tfailure\n\u2022\tvasodilatory \tshock\n\u2022\tperipheral \tvascular \tdisease\n\u2022\tRaynaud\u2019s \tdisease\n\u2022\tpulmonary \thypertension\nSYSTEMIC HYPERTENSION\nSystemic hypertension is a common disorder that, if not effectively treated, increases the risk of coronary thrombosis, \nstrokes and renal failure. Until about 1950, there was no \neffective treatment, and the development of antihypertensive treated with loop diuretics, in whom the renin\u2013angiotensin system is activated. A dry cough, possibly the result of \naccumulation of bradykinin (Ch. 19), is the commonest \npersistent adverse effect. Kinin accumulation may also underlie angioedema (painful swelling in tissues which \ncan be life-threatening if it involves the airway); this adverse effect aborted the introduction of omapatrilat, \na combined ACEI/ NEP inhibitor, and can also occur, \nalbeit less frequently, during treatment with sacubitril, \na selective NEP inhibitor used for chronic heart failure \n(see later). Patients with severe bilateral renal artery stenosis predictably develop renal failure if treated with \nACEIs, because glomerular filtration is normally main -\ntained, in the face of low afferent arteriolar pressure, by \nangiotensin II, which selectively constricts efferent \narterioles; hyperkalaemia may be severe owing to reduced aldosterone secretion. Such renal failure is reversible provided that it is recognised promptly and ACEI treat -\nment discontinued.\nAngiotensin II receptor antagonists\nLosartan, candesartan, valsartan and irbesartan (sartans) \nare non-peptide, orally active AT 1 receptor antagonists \n(ARBs). ARBs differ pharmacologically from ACEIs (Fig. \n23.8) but behave similarly to ACEIs apart from not causing \ncough\t\u2013\tconsistent \twith \tthe \t\u2018bradykinin \taccumulation\u2019 \t\nexplanation of this side effect, mentioned above; however, \nACEIs have a more robust evidence base than ARBs, reduc -\ning cardiovascular morbidity and mortality (including stroke) compared with placebo in hypertension. For ethical reasons placebo-controlled outcome data are not available \nfor ARBs used as single agents, since these were introduced \nafter incontrovertible evidence was available for the efficacy of other drug classes. The situation has been clouded by \nevidence of fabricated clinical trial data in several studies \nof valsartan.\nACE is not the only enzyme capable of forming \nangiotensin II, chymase (which is not inhibited by ACEIs) \nproviding one alternative route. It is not known if alterna -\ntive pathways of angiotensin II formation are important in vivo, but if so, then ARBs could be more effective than \nACEIs when such alternative pathways are active. Again, \nit is not known whether any of the beneficial effects of ACEIs are bradykinin/NO mediated. It is therefore unwise \nto assume that ARBs will necessarily share all the thera -\npeutic properties of ACEIs, although there is considerable \noverlap in the clinical indications for these drugs (see \nTable 23.4).\nNeutral endopeptidase (NEP, neprilysin) inhibition\n\u25bc NEP (see also Ch. 22) is a zinc-dependent metalloprotease that \ninactivates several peptide mediators including not only natriuretic \npeptides (ANP and BNP) but also glucagon, enkephalins, substance \nP, neurotensin, oxytocin and bradykinin. It also degrades amyloid \nbeta peptide (a suspect in the pathogenesis of", "start_char_idx": 0, "end_char_idx": 3463, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "44ccfb8f-4598-4ccc-a577-111fd7d4bb04": {"__data__": {"id_": "44ccfb8f-4598-4ccc-a577-111fd7d4bb04", "embedding": null, "metadata": {"page_label": "307", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f9a9d6f-fef1-4373-a7cd-3c799f648cb7", "node_type": null, "metadata": {"page_label": "307", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "745d113fd563ed623abc9b08adc8ec86ffbac323aaece178db84fbe5a4df220f"}, "2": {"node_id": "b50f958e-797c-4e6a-b905-551cb15ce276", "node_type": null, "metadata": {"page_label": "307", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0d07894abf5bd8f324c193efdc4c0eab8b92a50bc7e60ee838c5c8436cae7f93"}}, "hash": "038d2c449696bb9fef132e698a38dedbca58a0afc2e02dd4dcd905553b11c087", "text": "amyloid \nbeta peptide (a suspect in the pathogenesis of Alzheimer\u2019s disease, see Ch 41). In health it is expressed in many tissues including kidney \nand lung. Several NEP inhibitors have been developed for possible \nindications including analgesia and hypertension; as mentioned above one such drug, omapatrilat, is a combined ACEI/ NEP inhibitor \nwhich was not introduced because it caused angioedema.\nCLINICAL USES OF VASOACTIVE DRUGS\nIt is beyond the scope of this book to provide a detailed \naccount of the clinical uses of vasoactive drugs, but it is A\nBPlacebo\nEnalapril\nLosartan\nAngiotensin II (pmol/min)\u221280\u221260\u221240\u221220020Change in flow (%) Change in flow (%)103102101\nBradykinin (pmol/min)Placebo\nEnalapril\nLosartan\n102 101 600\n400200\n0\nFig. 23.8 Comparison of effects of angiotensin-converting \nenzyme inhibition and angiotensin receptor blockade in the \nhuman forearm vasculature. (A) Effect of brachial artery \ninfusion of angiotensin II on forearm blood flow after oral \nadministration of placebo, enalapril (10 mg) or losartan (100 mg). \n(B) Effect of brachial artery infusion of bradykinin, as in (A). (From \nCockcroft, J.R. et al., 1993. J. Cardiovasc. Pharmacol. 22, \n579\u2013584.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3408, "end_char_idx": 5082, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "56635e51-559c-42da-935e-7104ac375746": {"__data__": {"id_": "56635e51-559c-42da-935e-7104ac375746", "embedding": null, "metadata": {"page_label": "308", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e18459e0-d931-4f4c-970a-459a840b1730", "node_type": null, "metadata": {"page_label": "308", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db25389879c9e3a9f830bae0bff5aba02c1e8e46ec287a5d4d001f25b7af816c"}, "3": {"node_id": "4e38276f-346e-4461-ba58-a19ec2fb1b7c", "node_type": null, "metadata": {"page_label": "308", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "954878b52e6a23600add4fb0d92e1e902144fc52223157da4acac59343a81d91"}}, "hash": "744b3f91de886a4db18ee5194c883748ac37d98b5f5e456708975f6b3214a2c3", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n302drugs has been a major success story. Systemic blood pressure \nis\tan\texcellent \t\u2018surrogate \tmarker\u2019 \tfor \tincreased \tcardiovascular \t\nrisk in that there is good evidence from randomised con -\ntrolled trials that common antihypertensive drugs (diuretics, \nACEIs, calcium antagonists) combined with lifestyle changes \nnot only lower blood pressure but also prolong life and reduce the extra risks of heart attacks and, especially, strokes \nassociated with high blood pressure.\nCorrectable causes of hypertension include phaeochro -\nmocytoma,\n10 steroid-secreting tumours of the adrenal cortex \nand narrowing (coarctation) of the aorta, but most cases involve no obvious cause and are grouped as essential \nhypertension (so-called because it was originally, albeit \nincorrectly, thought that the raised blood pressure was \n\u2018essential\u2019 \tto\tmaintain \tadequate \ttissue\tperfusion). \tIncreased \t\ncardiac output may be an early feature, but by the time essential hypertension is established (commonly in middle \nlife) there is usually increased peripheral resistance and \nthe cardiac output is normal. Blood pressure control is intimately related to the kidneys, as demonstrated in humans \nrequiring \trenal \ttransplantation: \thypertension \t\u2018goes \twith\u2019 \t\nthe kidney from a hypertensive donor, and donating a kidney from a normotensive to a hypertensive corrects \nhypertension in the recipient (see also Ch. 30). It seems \nlikely that the cause of most cases of essential hypertension is a combination of inherited variations in renal tubular \nsodium ion handling and of dietary salt consumption \n(Meneton et a l., 2005). Persistently raised arterial pressure \nleads to hypertrophy of the left ventricle and remodelling \nof resistance arteries, with narrowing of the lumen, and \npredisposes to atherosclerosis in larger conduit arteries.\nFig. 23.9 summarises physiological mechanisms that \ncontrol arterial blood pressure and shows sites at which antihypertensive drugs act, notably the sympathetic nervous \nsystem, the renin\u2013angiotensin\u2013aldosterone system and endothelium-derived mediators. Remodelling of resistance \narteries in response to raised pressure reduces the ratio of \nlumen diameter to wall thickness and increases the periph -\neral vascular resistance. The role of cellular growth factors (including angiotensin II) and inhibitors of growth (e.g. \nNO) in the evolution of these structural changes is of great \ninterest to vascular biologists, and is potentially important for ACEIs and ARBs.\nReducing arterial blood pressure greatly improves the \nprognosis of patients with hypertension. Controlling hypertension (which is asymptomatic) without producing \nunacceptable side effects is therefore an important clinical \nneed, which is, in general, well catered for by modern drugs. Treatment involves non-pharmacological measures (e.g. \nincreased exercise, reduced dietary salt and saturated fat \nwith increased fruit and fibre, and weight and alcohol reduction) followed by the staged introduction of drugs, \nstarting with those of proven benefit and least likely to \nproduce side effects. Some of the drugs that were used to lower blood pressure in the early days of antihypertensive \ntherapy, including ganglion blockers , adrenergic neuron blockers \nand reserpine (see Ch. 15), produced a fearsome array of \nadverse effects and are now obsolete. The preferred regimens \nhave changed progressively as better-tolerated drugs have \nbecome available. A rational strategy is to start treatment Types of vasodilator drug \nDirectly acting vasodilators\n\u2022\tCalcium \tantagonists \t(e.g. \tnifedipine, diltiazem, \nverapamil", "start_char_idx": 0, "end_char_idx": 3675, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4e38276f-346e-4461-ba58-a19ec2fb1b7c": {"__data__": {"id_": "4e38276f-346e-4461-ba58-a19ec2fb1b7c", "embedding": null, "metadata": {"page_label": "308", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e18459e0-d931-4f4c-970a-459a840b1730", "node_type": null, "metadata": {"page_label": "308", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db25389879c9e3a9f830bae0bff5aba02c1e8e46ec287a5d4d001f25b7af816c"}, "2": {"node_id": "56635e51-559c-42da-935e-7104ac375746", "node_type": null, "metadata": {"page_label": "308", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "744b3f91de886a4db18ee5194c883748ac37d98b5f5e456708975f6b3214a2c3"}}, "hash": "954878b52e6a23600add4fb0d92e1e902144fc52223157da4acac59343a81d91", "text": "\tnifedipine, diltiazem, \nverapamil ):\tblock\tCa2+ entry in response to \ndepolarisation. Common adverse effects include ankle \nswelling and (especially with verapamil) constipation.\n\u2022\tK ATP channel activators (e.g. minoxidil ):\topen\t\npotassium channels, hyperpolarising vascular smooth muscle cells. Ankle swelling and increased hair growth are common.\n\u2022\tDrugs\tthat \tincrease \tcytoplasmic \tcyclic \tnucleotide \t\nconcentrations \tby:\n\u2013 increasing adenylyl cyclase activity, for example \nprostacyclin (epoprostenol), \u03b22-adrenoceptor \nagonists, adenosine\n\u2013\tincreasing \tguanylyl \tcyclase \tactivity: \tnitrates \t(e.g. \t\nglyceryl trinitrate , nitroprusside)\n\u2013 inhibiting phosphodiesterase activity (e.g. sildenafil)\nIndirectly acting vasodilators\n\u2022\tDrugs\tthat \tinterfere \twith \tthe \tsympathetic \tnervous \t\nsystem (e.g. \u03b11-adrenoceptor antagonists). Postural \nhypotension is a common adverse effect.\n\u2022\tDrugs\tthat \tblock \tthe \trenin\u2013angiotensin \tsystem:\n\u2013 renin inhibitors (e.g. aliskiren)\n\u2013 angiotensin-converting enzyme inhibitors (e.g. \nramipril); dry cough may be troublesome\n\u2013 AT1 receptor antagonists (e.g. losartan).\n\u2022\tDrugs\tor \tmediators \tthat \tstimulate \tendothelial \tnitric \t\noxide release (e.g. acetylcholine, bradykinin).\n\u2022\tDrugs\tthat \tblock \tthe \tendothelin \tsystem:\n\u2013 endothelin synthesis (e.g. phosphoramidon)\n\u2013 endothelin receptor antagonists (e.g. bosentan)\n\u2022\tDrugs\tthat \tpotentiate \tvasodilator \tpeptides \tby \tblocking \t\ntheir breakdown (e.g. sacubitril).\nVasodilators whose mechanism is uncertain\n\u2022\tMiscellaneous \tdrugs \tincluding \talcohol, \tpropofol (Ch. \n42) and hydralazine.\n10Catecholamine-secreting tumours of chromaffin tissue, usually the \nadrenal medulla (Ch. 13).Clinical uses of angiotensin II \nsubtype 1 receptor antagonists \n(sartans) \nThe AT 1 antagonists are extremely well tolerated but are \nteratogenic. \tTheir \tuses \tinclude \tthe \tfollowing:\n\u2022\tHypertension, \tespecially \tin:\n\u2013 young men (circulating renin decreases with \nincreasing age, and sartans are avoided during \npregnancy)\n\u2013 diabetic patients\n\u2013 hypertension complicated by left ventricular \nhypertrophy\n\u2013 as an additional agent in hypertensive patients \ninsufficiently responsive to a thiazide diuretic.\n\u2022\tHeart\tfailure; \tespecially \tthe \tcombination \tof \tvalsartan \t\nwith sacubitril (NEP inhibitor).\n\u2022\tDiabetic \tnephropathy.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3641, "end_char_idx": 6426, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1864cf02-c775-4040-bd6b-593d60ed50fb": {"__data__": {"id_": "1864cf02-c775-4040-bd6b-593d60ed50fb", "embedding": null, "metadata": {"page_label": "309", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "202f634d-ec7e-4f70-b38d-eb484183b4a8", "node_type": null, "metadata": {"page_label": "309", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9c942558cdb2e5cc07ef9686a0cbc6b0a7ef3c6e7f24fd5339cda8ad26c86e7"}}, "hash": "c9c942558cdb2e5cc07ef9686a0cbc6b0a7ef3c6e7f24fd5339cda8ad26c86e7", "text": "23 ThE vASCUlAR SYSTEM\n303drugs. They are useful for hypertensive patients with some \nadditional indication for \u03b2 blockade, such as angina or \nheart failure.\nAddition of a third or fourth drug (e.g. to ARB/diuretic \nor ARB/calcium antagonist combination) is often needed, \nand a long-acting \u03b11-adrenoceptor antagonist (Ch. 15) such \nas once daily doxazosin is one option in this setting. The \n\u03b11 antagonists additionally improve symptoms of prostatic \nhyperplasia (also known as benign prostatic hypertrophy) \n(Chs 15, 30 and 36), which is common in older men, albeit \nat the risk of postural hypotension, which is the main \nunwanted effect of these agents. Spironolactone , whose \nactive metabolite canrenone is a competitive antagonist of \naldosterone (Ch. 30), has staged something of a comeback with either an ACEI or an ARB in patients who are likely \nto have normal or raised plasma renin (i.e. younger white \npeople), and with either a thiazide diuretic or a calcium \nantagonist in older people and people of African origin \n(who are more likely to have low plasma renin). If the \ntarget blood pressure is not achieved but the drug is well \ntolerated, then a drug of the other group is added. It is \nbest not to increase the dose of any one drug excessively, \nas this often causes adverse effects and engages homeostatic \ncontrol mechanisms (e.g. renin release by a diuretic) that \nlimit efficacy.\n\u03b2-Adrenoceptor antagonists are less well tolerated than \nACEIs or ARBs, and the evidence supporting their routine \nuse is less strong than for other classes of antihypertensive Aldosterone\nAI AngiotensinogenCaptopril AliskirenNANA NA\nACE ReninArterial\npressurePeripheral\nresistanceCardiac\noutputBaroreceptor\ndischarge\nGanglion-\nblocking\ndrugs\nb-Blockers\nb-Blockers\nSpironolactoneDiureticsNa+ excretionBlood volumeMoxonidine\nClonidine\nMethyldopa\nLosartanAII\nAIIAII\nAII AIIa-Blockers\nNO\nET-1Vasodilators\nCa2+ blockers\nAII\nFig. 23.9 Main mechanisms involved in arterial blood pressure regulation (black lines) , and the sites of action of antihypertensive \ndrugs (hatched boxes + orange lines) . ACE, angiotensin-converting enzyme; AI, angiotensin I; AII, angiotensin II; ET-1, endothelin-1; NA, \nnoradrenaline; NO, nitric oxide. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2714, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "50550adb-59d8-4fda-ac3b-196af774fa62": {"__data__": {"id_": "50550adb-59d8-4fda-ac3b-196af774fa62", "embedding": null, "metadata": {"page_label": "310", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54451b4b-0434-4f6d-8060-c2d71fa15224", "node_type": null, "metadata": {"page_label": "310", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51a8830f4e77c8cba1b7e6643271f9acf0cbf28be27caf726e0ffa8ced2f32c4"}, "3": {"node_id": "f3c866ac-2c2e-4e76-8cf0-0fe1e9da24b6", "node_type": null, "metadata": {"page_label": "310", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a0da0dc83915a51782ed11167ed2ea44fbbb28c07c3161118620a910e3df7bb"}}, "hash": "6eb1aec24d25b9e95e91791bd87ecbd0d0f959371df72170503843c26dd37529", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n304including cardiotoxic drugs such as doxorubicin and \ntrastuzumab \u2013 Ch. 57), or by circulatory factors such as \nvolume overload (e.g. leaky valves, or arteriovenous shunts \ncaused by congenital defects) or pressure overload (e.g. stenosed \u2013 i.e. narrowed \u2013 valves, systemic or pulmonary \nhypertension). Some of these underlying causes are surgi -\ncally correctable, and in some either the underlying disease \n(e.g. hyperthyroidism; Ch. 35), or an aggravating factor \nsuch as anaemia (Ch. 26) or atrial fibrillation (Ch. 22), is \ntreatable with drugs. Here, we focus on drugs used to treat heart failure per se, irrespective of the underlying cause.\nWhen cardiac output is insufficient to meet metabolic \ndemand, an increase in fluid volume occurs, partly because increased venous pressure increases capillary pressure and hence formation of tissue fluid, and partly because reduced \nrenal blood flow activates the renin\u2013angiotensin\u2013aldosterone \nsystem, causing Na\n+ and water retention. Irrespective of \nthe cause, the outlook for adults with cardiac failure is \ngrim: 50% of those with the most severe grade are dead in \n6\tmonths,\tand\tof\tthose\twith\t\u2018mild/moderate\u2019 \tdisease,\t50%\t\nare dead in 5 years. Non-drug measures, including dietary \nsalt restriction and exercise training in mildly affected \npatients,11 are important, but drugs are needed to improve \nsymptoms of oedema, fatigue and breathlessness, and to improve prognosis.\nA simplified diagram of the sequence of events is shown \nin Fig. 23.10. A common theme is that several of the \nfeedbacks \tthat\tare\tactivated \tare\t\u2018counter-regulatory\u2019 \t\u2013\tthat\t\nis, they make the situation worse not better. This occurs \nbecause the body fails to distinguish the haemodynamic \nstate of heart failure from haemorrhage, in which release \nof vasoconstrictors such as angiotensin II and ADH would as an additional agent in treating severe hypertension. Careful monitoring of plasma K\n+ concentration is required, \nbecause spironolactone inhibits urinary K+ excretion as well \nas causing oestrogen-related adverse effects, but it is usually \nwell tolerated in low doses. Methyldopa is now used mainly \nfor hypertension during pregnancy because of the lack of \ndocumented adverse effects on the baby (in contrast to \nACEIs, ARBs and standard \u03b2-adrenoceptor antagonists, \nwhich are contraindicated during pregnancy and therefore \noften avoided in women of child-bearing potential). Clo-\nnidine (a centrally acting \u03b12 agonist) is now seldom used. \nMoxonidine, a centrally acting agonist at imidazoline I 1 \nreceptors that causes less drowsiness than \u03b12 agonists, is \nlicensed for mild or moderate hypertension, but there is \nlittle evidence from clinical end-point trials to support its \nuse. Minoxidil , combined with a diuretic and \u03b2-adrenoceptor \nantagonist, is sometimes effective where other drugs have \nfailed in severe hypertension resistant to other drugs. \nFenoldopam, a selective dopamine D 1 receptor agonist, is \napproved in the United States for the short-term manage -\nment in hospital of severe hypertension. Its effect is similar in magnitude to that of intravenous nitroprusside, but it lacks thiocyanate-associated toxicity and is slower in onset \nand offset.\nCommonly used antihypertensive drugs and their main \nadverse effects are summarised in Table 23.5.\nHEART FAILURE\nHeart failure is a clinical syndrome characterised by", "start_char_idx": 0, "end_char_idx": 3441, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f3c866ac-2c2e-4e76-8cf0-0fe1e9da24b6": {"__data__": {"id_": "f3c866ac-2c2e-4e76-8cf0-0fe1e9da24b6", "embedding": null, "metadata": {"page_label": "310", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54451b4b-0434-4f6d-8060-c2d71fa15224", "node_type": null, "metadata": {"page_label": "310", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51a8830f4e77c8cba1b7e6643271f9acf0cbf28be27caf726e0ffa8ced2f32c4"}, "2": {"node_id": "50550adb-59d8-4fda-ac3b-196af774fa62", "node_type": null, "metadata": {"page_label": "310", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6eb1aec24d25b9e95e91791bd87ecbd0d0f959371df72170503843c26dd37529"}}, "hash": "8a0da0dc83915a51782ed11167ed2ea44fbbb28c07c3161118620a910e3df7bb", "text": "FAILURE\nHeart failure is a clinical syndrome characterised by \nsymptoms of breathlessness and/or fatigue, usually with \nsigns of fluid overload (oedema, raised venous pressure \nand crackles heard when listening to the chest). The underlying physiological abnormality (see also Ch. 22) is \na cardiac output that is inadequate to meet the metabolic \ndemands of the body, initially during exercise but, as the syndrome progresses, also at rest. It may be caused by \ndisease of the myocardium itself (most commonly secondary \nto coronary artery disease but also other pathologies Table 23.5 Common antihypertensive drugs and their adverse effects\nDrugAdverse effectsa\nPostural hypotension Impotence Other\nThiazide (e.g. bendroflumethiazide) \nand related (e.g. chlortalidone) diuretics\u00b1 ++ Urinary frequency, gout, glucose intolerance, hypokalaemia, hyponatraemia\nACE inhibitors (e.g. enalapril) \u00b1 \u2014 Cough, first-dose hypotension, teratogenicity, reversible renal dysfunction (in presence of renal artery stenosis)\nAT\n1 antagonists (e.g. losartan) \u2014 \u2014 Teratogenicity, reversible renal dysfunction (in presence of renal artery stenosis)\nCa\n2+ antagonists (e.g. nifedipine) \u2014 \u00b1 Ankle oedema\n\u03b2-Adrenoceptor antagonists \n(e.g. metoprolol)\u2014 + Bronchospasm, fatigue, cold hands and feet, bradycardia\n\u03b1\n1-Adrenoceptor antagonists \n(e.g. doxazosin)++ \u2014 First-dose hypotension\na\u00b1 indicates that the adverse effect occurs in special circumstances only (e.g. postural hypotension occurs with a thiazide diuretic only if \nthe patient is dehydrated for some other reason, is taking some additional drug or suffers from some additional disorder).ACE, angiotensin-converting enzyme; AT\n1, angiotensin II type 1 receptor.\n11Bed rest used to be recommended but results in deconditioning, and \nregular exercise has been shown to be beneficial in patients who can \ntolerate it.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3380, "end_char_idx": 5715, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bbfc5d51-4b8d-4533-956d-819c6d9490cb": {"__data__": {"id_": "bbfc5d51-4b8d-4533-956d-819c6d9490cb", "embedding": null, "metadata": {"page_label": "311", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "84b84774-dd69-4949-831b-ceb576285395", "node_type": null, "metadata": {"page_label": "311", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8f497ea781452ab133ec701482759e44633f964a2fa945304e17edcfbbc7aa1"}, "3": {"node_id": "40b8f786-635d-411d-a4a5-ff9a9bcb7acb", "node_type": null, "metadata": {"page_label": "311", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7bf2c7869189bb9fe638aca7a56b5ce6d6eeaea388df2d420a9ad867ca04fa86"}}, "hash": "cf99f24fd97078c31357b13be35bd6450e1cf91fea1bbceef6f23d568da34c06", "text": "23 ThE vASCU lAR SYSTEM\n305thereby reducing vascular resistance, improving tissue \nperfusion and reducing cardiac afterload. They also cause \nnatriuresis by inhibiting secretion of aldosterone and by \nreducing the direct stimulatory effect of angiotensin II on reabsorption of Na\n+ and HCO 3\u2212 in the early part of the \nproximal convoluted tubule. Most important of all, they \nprolong life.\n\u25bc Differences in the pharmacology of ACEIs and ARBs led to the \nhypothesis \tthat \tco-administration \tof \tthese \tdrugs \t(\u2018dual \tblockade\u2019) \t\ncould confer additional benefit over increasing the dose of either \ngiven as a single agent. However, two large randomised controlled \ntrials comparing monotherapy with ACEI or ARB with combined \ntherapy both showed that the combined treatment produced more symptoms attributable to hypotension, and no survival benefit \ncompared with monotherapy in patients with acute myocardial \ninfarction (Pfeffer et al., 2003).\nIn contrast to the disappointing experience of combin -\ning ARBs with ACEI, a fixed combination of sacubitril \nwith valsartan is used in patients symptomatic with \nchronic heart failure and reduced cardiac ejection. In comparison to an ACEI (enalapril), sacubitril/valsartan \nusefully reduced cardiac and all-cause mortality in \nsuch patients and Jhund and McMurray (2016) argue \nthat this combination should therefore replace an ACEI \nas the foundation of treatment of symptomatic heart \nfailure.\n\u25bc The choice of valsartan as ARB in this combination is supported \nby its pharmacokinetic similarity to sacubitril. Sacubitril, sacubitrilat \nand valsartan are highly bound to plasma proteins (94%\u201397%) but \nsacubitril does cross the blood\u2013brain barrier to a limited extent (0.28%). \nCerebrospinal fluid (CSF) A \u03b2 clearance in young cynomolgus monkeys \nis reduced by sacubitril/ valsartan. Administration of the combination \nfor two weeks to healthy subjects increased CSF A \u03b21-38 without \nchange in A \u03b21-40 and 1-42. The clinical relevance of this is not known, \nand the product is subject to ongoing safety monitoring.\nAdverse effects and drug interactions observed during \ntreatment with valsartan/sacubitril are in line with those \nof its two components. Hypotension, hyperkalaemia and \nrenal impairment are the commonest observed adverse effects. Angioedema occurred during the pivotal controlled \ntrial in 0.5% of patients treated with the combination, \ncompared with 0.2% of patients treated with enalapril. Concomitant use of sacubitril with ACEIs is contraindicated \nsince, consistent with the experience with omapatrilat \nmentioned above, the concomitant inhibition of NEP and ACE increases the risk of angioedema. PDE5 inhibitors \n(Ch. 22) including sildenafil that work through cGMP \nsignalling are potentiated by sacubitril.\nAngiotensin II is not the only stimulus to aldosterone \nsecretion, and during chronic treatment with ACEIs, circulat -\ning aldosterone concentrations return towards pretreatment \nvalues\t(a\tphenomenon \tknown\tas\t\u2018aldosterone \tescape\u2019).\tThis\t\nprovides a rationale for combining spironolactone (an \naldosterone antagonist; see Ch. 34) with ACEI treatment, which further reduces mortality. Eplerenone is an aldos -\nterone antagonist with less oestrogen-like adverse effects \nthan spironolactone; it too has been shown to improve \nsurvival in patients with heart failure when added to \nconventional therapy. Patients with impaired renal function were excluded from these trials, and careful monitoring of \nplasma K\n+ concentration is important when they", "start_char_idx": 0, "end_char_idx": 3532, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "40b8f786-635d-411d-a4a5-ff9a9bcb7acb": {"__data__": {"id_": "40b8f786-635d-411d-a4a5-ff9a9bcb7acb", "embedding": null, "metadata": {"page_label": "311", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "84b84774-dd69-4949-831b-ceb576285395", "node_type": null, "metadata": {"page_label": "311", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8f497ea781452ab133ec701482759e44633f964a2fa945304e17edcfbbc7aa1"}, "2": {"node_id": "bbfc5d51-4b8d-4533-956d-819c6d9490cb", "node_type": null, "metadata": {"page_label": "311", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cf99f24fd97078c31357b13be35bd6450e1cf91fea1bbceef6f23d568da34c06"}}, "hash": "7bf2c7869189bb9fe638aca7a56b5ce6d6eeaea388df2d420a9ad867ca04fa86", "text": "and careful monitoring of \nplasma K\n+ concentration is important when they are treated \nwith an ACEI or an ARB in combination with an aldosterone antagonist.be appropriate.\n12 ACEIs and ARBs, \u03b2-adrenoceptor and \naldosterone antagonists interrupt these counter-regulatory neurohormonal mechanisms and have each been shown \nto prolong life in heart failure, although prognosis remains poor despite optimal management.\nDrugs used to treat heart failure act in various comple -\nmentary ways to do the following.\nIncrease natriuresis. Diuretics, especially loop diuretics \n(Ch. 30), are important in increasing salt and water excretion, \nespecially if there is pulmonary oedema. In chronic heart \nfailure, drugs that have been shown to improve survival were studied mainly in patients treated with diuretics.\nInhibit the renin\u2013angiotensin\u2013aldosterone system/\npotentiate NEP. The renin\u2013angiotensin\u2013aldosterone system \nis inappropriately activated in patients with cardiac failure, \nespecially when they are treated with diuretics. The \n\u03b2-adrenoceptor antagonists inhibit renin secretion and are \nused in clinically stable patients with chronic heart failure \n(see clinical box, p. 306). ACEIs and ARBs block the forma -\ntion of angiotensin II and inhibit its action, respectively, Tissue\nperfusionPathological factors\nPreload Afterload Heart disease\nCardiac output\nOedemaNa+/water\nretentionRelease of\naldosteroneRenin releaseRenal\nblood flowCentral venous\npressure\nFormation of\nangiotensin IIVasodilator\ndrugs\nACE\ninhibitors\nDiureticsPositive\ninotropes\nFig. 23.10 Simplified scheme showing the pathogenesis \nof heart failure, and the sites of action of some of the drugs \nused to treat it. The symptoms of heart failure are produced by \nreduced tissue perfusion, oedema and increased central venous pressure. ACE, angiotensin-converting enzyme. \n12Natural selection presumably favoured mechanisms that would benefit \nyoung hunter\u2013gatherers at risk of haemorrhage; middle-aged or elderly \npeople at high risk of heart failure are past their reproductive prime.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3458, "end_char_idx": 5994, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "281b1df8-8953-4e05-aea2-0624b46acbca": {"__data__": {"id_": "281b1df8-8953-4e05-aea2-0624b46acbca", "embedding": null, "metadata": {"page_label": "312", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c1b3f474-9f24-48a5-8ee0-f0ad0726b314", "node_type": null, "metadata": {"page_label": "312", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0a4415ecf0a10d940154a3458ea8d5dcca4c98c97f85702cf547d2839dbcc30"}, "3": {"node_id": "7e8fd38c-0cb0-46ca-9ba4-d7b81ab66c3b", "node_type": null, "metadata": {"page_label": "312", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e35b35e7584a9cf9a7c1a03c3ba092afa0fff37ca0b9205d8f3e53381d3d1e6"}}, "hash": "a87e92530919e8aa041b0d8e7c7fed96699823523403d8034ee604847b2a26c8", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n306VASODILATORY SHOCK AND \nHYPOTENSIVE STATES\nShock is a medical emergency characterised by inadequate \nperfusion of vital organs, usually because of a very low \narterial blood pressure. This leads to anaerobic metabolism \nand hence to increased lactate production. Mortality is very high, even with optimal treatment in an intensive care unit. \nShock can be caused by various insults, including haemor -\nrhage, burns, bacterial infections, anaphylaxis (Ch. 18) and \nmyocardial infarction (Fig. 23.11). The common factor is \nreduced effective circulating blood volume (hypovolaemia) \ncaused either directly by bleeding or by movement of fluid from the plasma to the gut lumen or extracellular fluid. The physiological (homeostatic) response to this is complex: \nvasodilatation in a vital organ (e.g. brain, heart or kidney) \nfavours perfusion of that organ, but at the expense of a further reduction in blood pressure, which leads to reduced \nperfusion of other organs. Survival depends on a balance \nbetween vasoconstriction in non-essential vascular beds and vasodilatation in vital ones. The dividing line between the \nnormal physiological response to blood loss and clinical shock \nis that in shock tissue hypoxia produces secondary effects that magnify rather than correct the primary disturbance. \nTherefore patients with established shock have profound \nand inappropriate vasodilatation in non-essential organs, \nDrugs used in chronic heart failure \n\u2022\tLoop\tdiuretics, \tfor \texample \tfurosemide (Ch. 30).\n\u2022\tAngiotensin-converting \tenzyme \tinhibitors \t(e.g. \t\nramipril).\n\u2022\tAngiotensin \tII \tsubtype \t1 \treceptor \tantagonists \t(e.g. \t\nvalsartan, candesartan) alone or, increasingly, in \ncombination with an neutral endopeptidase (NEP) \ninhibitor (valsartan/sacubitril).\n\u2022\t\u03b2-adrenoceptor antagonists (e.g. metoprolol, bisoprolol, carvedilol), introduced in low dose in \nstable patients.\n\u2022\tAldosterone-receptor \tantagonists \t(e.g. \t\nspironolactone, Ch. 30; and eplerenone).\n\u2022\tDigoxin (see Ch. 22), especially for heart failure associated with established rapid atrial fibrillation. It is \nalso indicated in patients who remain symptomatic \ndespite optimal treatment.\n\u2022\tOrganic \tnitrates \t(e.g. \tisosorbide mononitrate ) \nreduce preload, and hydralazine reduces afterload. \nUsed in combination, these prolong life in African-\nAmericans with heart failure.Haemorrhage\nMyocardial\ndamage\nRenal\nfailureRenin\nrelease\nDEATH\nAllergenRelease of\nmediatorsTissue\nhypoxiaVasoconstriction\nBacterial\nendotoxinAcidosisCirculating\nvolume\nCardiac\noutput\nArterial\npressureRenal\nblood flow\nArteriolar and\ncapillary dilatation\nCorticosteroids\nAdrenalineDobutamine\nAdrenalineTransfusion\n(fluid\nreplacement)\nAdrenaline*\nProstacyclin\n(epoprostenol)\nandl eakiness\nBurns,\ntrauma\nFig. 23.11 Simplified scheme showing the pathogenesis \nof hypovolaemic shock. *Adrenaline causes vasodilatation in \nsome vascular beds, vasoconstriction in others. Block \u03b2 adrenoceptors. Heart failure is accompanied by \npotentially harmful activation of the sympathetic nervous \nsystem as well as of the renin\u2013angiotensin system, providing \na rationale for using \u03b2-adrenoceptor antagonists. Most", "start_char_idx": 0, "end_char_idx": 3209, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7e8fd38c-0cb0-46ca-9ba4-d7b81ab66c3b": {"__data__": {"id_": "7e8fd38c-0cb0-46ca-9ba4-d7b81ab66c3b", "embedding": null, "metadata": {"page_label": "312", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c1b3f474-9f24-48a5-8ee0-f0ad0726b314", "node_type": null, "metadata": {"page_label": "312", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0a4415ecf0a10d940154a3458ea8d5dcca4c98c97f85702cf547d2839dbcc30"}, "2": {"node_id": "281b1df8-8953-4e05-aea2-0624b46acbca", "node_type": null, "metadata": {"page_label": "312", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a87e92530919e8aa041b0d8e7c7fed96699823523403d8034ee604847b2a26c8"}}, "hash": "4e35b35e7584a9cf9a7c1a03c3ba092afa0fff37ca0b9205d8f3e53381d3d1e6", "text": "system, providing \na rationale for using \u03b2-adrenoceptor antagonists. Most \nclinicians were very wary of this approach because of the \nnegative inotropic action of these drugs, but when started \nin low doses that are increased slowly, metoprolol, carve-\ndilol and bisoprolol each improve survival when added \nto optimal treatment in clinically stable patients with chronic \nheart failure.\nGlyceryl trinitrate (Ch. 22) is infused intravenously to \ntreat acute cardiac failure. Its venodilator effect reduces \nvenous pressure, and its effects on arterial compliance and \nwave reflection further reduce cardiac work. The combina -\ntion of hydralazine (to reduce afterload) with a long-acting \norganic nitrate (to reduce preload) in patients with chronic heart failure improved survival in a North American randomised controlled trial, but the results suggested that \nthe benefit was restricted to patients of African origin. This \nethnic group is genetically very heterogeneous, and it is unknown what other groups will benefit from such treat -\nment, which is underutilised in African-origin patients \n(Taylor et al., 2004; Cole et al., 2014).\nIncrease the force of cardiac contraction. Cardiac gly-\ncosides (Ch. 22) are used either in patients with heart failure \nwho also have chronic rapid atrial fibrillation (in whom it \nimproves cardiac function by slowing ventricular rate and hence ventricular filling in addition to any benefit from \nits positive inotropic action), or in patients who remain symptomatic despite treatment with a diuretic and ACEI. Digoxin does not reduce mortality in heart failure patients \nin sinus rhythm who are otherwise optimally treated, but does improve symptoms and reduce the need for hospital admission. In contrast, PDE inhibitors (see Ch. 22) increase cardiac output, but increase mortality in heart failure, \nprobably through cardiac dysrhythmias. Dobutamine (a \n\u03b2\n1-selective adrenoceptor agonist; see Ch. 22) is used \nintravenously when a rapid response is needed in the short term, for example following heart surgery.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3136, "end_char_idx": 5679, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "02f2bf07-52c5-494d-ae2c-15c3c16a6640": {"__data__": {"id_": "02f2bf07-52c5-494d-ae2c-15c3c16a6640", "embedding": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "51a8a76e-df44-45b9-80e5-dad1255fa4f5", "node_type": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f26edaa022c1c7f360e9c5740091e494dbf57bdb12bef6d3ca9be32bf157553"}, "3": {"node_id": "8b398b2c-91e4-4c35-a00d-5589db0564f5", "node_type": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ed269780642befcfb2498b06b312511c62780b933c942ffcd48deeddb0756aa"}}, "hash": "5508fe223c8755a969f9095df396a5bdec5c4f67a6cc721fa87cdb1b1b00bd62", "text": "23 ThE vASCU lAR SYSTEM\n307This can be mild, but if severe causes ulceration and \ngangrene of the fingers. It can occur in isolation (Raynaud\u2019s \ndisease) or in association with a number of other diseases, \nincluding several so-called connective tissue diseases (e.g. systemic sclerosis, systemic lupus erythematosus). Treatment \nof Raynaud\u2019s phenomenon hinges on stopping smoking \n(crucially) and on avoiding the cold; \u03b2-adrenoceptor antagonists are contraindicated. Vasodilators (e.g. nifedi-\npine; see Ch. 22) are of some benefit in severe cases, and evidence from several small studies suggests sildenafil is helpful, as well as other vasodilators (e.g. PGI\n2, calcitonin \ngene-related peptide (CGRP)) which can have surprisingly \nprolonged effects long outlasting their presence in the \ncirculation, but are difficult to administer.\nPULMONARY HYPERTENSION\nAfter birth, pulmonary vascular resistance becomes much lower than systemic vascular resistance, and systolic \npulmonary artery pressure in adults is normally approxi -\nmately 20 mmHg.13\nPulmonary artery pressure is much less easy to measure \nthan is systemic pressure, often requiring cardiac catheterisa -\ntion, so only severe and symptomatic pulmonary hyperten -\nsion tends to be diagnosed. Pulmonary hypertension usually \ncauses some regurgitation of blood from the right ventricle \nto the right atrium. This tricuspid regurgitation can be used \nto estimate the pulmonary artery pressure indirectly by ultrasonography. Pulmonary hypertension may rarely be \nidiopathic (i.e. of unknown cause, a severe and progressive \nform), but is more commonly associated with some other \ndisease. It can result from an increased cardiac output (such as occurs, for example, in patients with hepatic cirrhosis \n\u2013 where vasodilatation may accompany intermittent subclini -\ncal exposure to bacterial endotoxin \u2013 or in patients with \ncongenital connections between the systemic and pulmonary \ncirculations). Vasoconstriction and/or structural narrowing \nof the pulmonary resistance arteries increase pulmonary arterial pressure, even if cardiac output is normal. In some \nsituations, both increased cardiac output and increased \npulmonary vascular resistance are present.\nEndothelial dysfunction (see pp. 291\u2013295, and also Chs \n24 and 25) is implicated in the aetiology of pulmonary hypertension. Drugs (e.g. anorexic drugs including dexfen -\nfluramine , now withdrawn) and toxins (e.g. monocrotaline ) \ncan cause pulmonary hypertension. Occlusion of the pulmonary arteries, for example with recurrent pulmonary \nemboli (Ch. 25), is a further primary cause or exacerbating \nfactor, and anticoagulation (see Ch. 25) is an important part \nof treatment. Aggregates of deformed red cells in patients \nwith sickle cell anaemia (Ch. 26) can occlude small pulmonary \narteries.\nIncreased pulmonary vascular resistance may, alterna-\ntively, result from vasoconstriction and/or structural changes in the walls of pulmonary resistance arteries. Many \nof the diseases (e.g. systemic sclerosis) associated with \nRaynaud\u2019s phenomenon mentioned in the section above and this is difficult to correct with vasoconstrictor drugs. The release of mediators (e.g. histamine, 5-hydroxytryptamine, bradykinin, prostaglandins, cytokines including interleu -\nkins and tumour necrosis factor, NO and undoubtedly many more as-yet-unidentified substances) that cause capillary dilatation and", "start_char_idx": 0, "end_char_idx": 3413, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8b398b2c-91e4-4c35-a00d-5589db0564f5": {"__data__": {"id_": "8b398b2c-91e4-4c35-a00d-5589db0564f5", "embedding": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "51a8a76e-df44-45b9-80e5-dad1255fa4f5", "node_type": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f26edaa022c1c7f360e9c5740091e494dbf57bdb12bef6d3ca9be32bf157553"}, "2": {"node_id": "02f2bf07-52c5-494d-ae2c-15c3c16a6640", "node_type": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5508fe223c8755a969f9095df396a5bdec5c4f67a6cc721fa87cdb1b1b00bd62"}, "3": {"node_id": "45687dde-01c8-40a5-a0f6-970816d61147", "node_type": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a69bcd203fa388e484547a90f117269faad966abef04621abac023f5a140c18"}}, "hash": "4ed269780642befcfb2498b06b312511c62780b933c942ffcd48deeddb0756aa", "text": "more as-yet-unidentified substances) that cause capillary dilatation and leakiness is the opposite of what \nis required to improve function in this setting. Mediators \npromoting vasodilatation in shock converge on two main \nmechanisms:\n1. Activation of ATP-sensitive potassium channels in \nvascular smooth muscle by reduced cytoplasmic ATP and increased lactate and protons.\n2. Increased synthesis of NO, which activates myosin \nlight-chain phosphatase and activates K Ca channels.\nA third important mechanism seems to be a relative deficiency \nof ADH, which is secreted acutely in response to haemor-rhage but subsequently declines, probably because of depletion within the neurohypophysis (see Ch. 34).\nPatients with shock are not a homogeneous population, \nmaking it hard to perform valid clinical trials, and in contrast to hypertension and heart failure there is very little evidence \nto support treatment strategies based on hard clinical end \npoints (such as improved survival). Volume replacement is of benefit if there is hypovolaemia; antibiotics are essential \nif there is persistent bacterial infection; adrenaline can be \nlife-saving in anaphylactic shock and is also used by intensivists in managing circulatory shock of other aetiolo -\ngies. Hypoperfusion leads to multiple organ failure (includ -\ning renal failure), and intensive therapy specialists spend much effort supporting the circulations of such patients \nwith cocktails of vasoactive drugs in attempts to optimise \nflow to vital organs. Trials of antagonists designed to block or neutralise endotoxin, interleukins, tumour necrosis factor and the inducible form of NO synthase, and of recombinant \nhuman protein C have shown them to be ineffective or \nactually harmful. Vasopressin or angiotensin II may increase \nblood pressure even when there is resistance to adrenaline; \ncorticosteroids suppress the formation of NO and of pros -\ntaglandins but are not of proven benefit once shock is \nestablished; epoprostenol (PGI\n2) may be useful in patients \nwith inappropriate platelet activation (e.g. meningococcal \nsepsis ); positive inotropic agents, including adrenaline and \ndobutamine, may help in individual patients.\nPERIPHERAL VASCULAR DISEASE\nWhen atheroma involves peripheral arteries, the first symptom is usually pain in the calves on walking (claudica -\ntion), followed by pain at rest, and in severe cases gangrene of the feet or legs. Other vascular beds (e.g. coronary, cerebral and renal) are often also affected by atheromatous \ndisease in patients with peripheral vascular disease. Treat -\nment is mainly mechanical (open surgery or endovascular \nprocedures to open the stenosed artery), combined with \ndrugs that reduce the risk of ischaemic heart disease and \nstrokes. Drug treatment includes antiplatelet drugs (e.g. aspirin , clopidogrel ; see Ch. 25), a statin (e.g. simvastatin ; \nsee Ch. 24) and an ACEI (e.g. ramipril; see p. 300).\nRAYNAUD\u2019S DISEASE\nInappropriate vasoconstriction of small arteries and arte -\nrioles gives rise to Raynaud\u2019s phenomenon (blanching of \nthe fingers during vasoconstriction, followed by blueness \nowing to deoxygenation of the static blood and redness from reactive hyperaemia following return of blood flow). 13In fetal life, pulmonary vascular resistance is high; failure to adapt \nappropriately at birth is associated with prematurity, lack of pulmonary \nsurfactant and hypoxaemia. The resulting pulmonary hypertension is \ntreated by paediatric intensive care specialists with measures including replacement of surfactant and ventilatory support, sometimes including", "start_char_idx": 3349, "end_char_idx": 6949, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "45687dde-01c8-40a5-a0f6-970816d61147": {"__data__": {"id_": "45687dde-01c8-40a5-a0f6-970816d61147", "embedding": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "51a8a76e-df44-45b9-80e5-dad1255fa4f5", "node_type": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f26edaa022c1c7f360e9c5740091e494dbf57bdb12bef6d3ca9be32bf157553"}, "2": {"node_id": "8b398b2c-91e4-4c35-a00d-5589db0564f5", "node_type": null, "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ed269780642befcfb2498b06b312511c62780b933c942ffcd48deeddb0756aa"}}, "hash": "8a69bcd203fa388e484547a90f117269faad966abef04621abac023f5a140c18", "text": "care specialists with measures including replacement of surfactant and ventilatory support, sometimes including \ninhaled NO \u2013 see Chapter 21.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6903, "end_char_idx": 7523, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "13b59beb-f4a9-4707-809c-69f260fb0bb8": {"__data__": {"id_": "13b59beb-f4a9-4707-809c-69f260fb0bb8", "embedding": null, "metadata": {"page_label": "314", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8a8ec880-be50-4c33-ac3e-f94994930d49", "node_type": null, "metadata": {"page_label": "314", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cde69a19ff2ec11732f1a6405f2fd25adc28f779cd116f48274ece4914baa155"}, "3": {"node_id": "3cc186d2-a8f4-4817-aa1f-b7491ee2d583", "node_type": null, "metadata": {"page_label": "314", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b5da670462bd7e67842a27d8f90ab54ed1c0f3f0cbd6d24b3592478f23806c79"}}, "hash": "2dea5b7220143ffc33f44a0c4bcd0bebb205da3ec88550fe1e05a6394d7195e1", "text": "23 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n308are also associated with pulmonary hypertension. Vaso -\nconstriction may precede cellular proliferation and medial \nhypertrophy which causes wall thickening in the pulmonary \nvasculature. Calcium antagonists (e.g. nifedipine) are used, but benefit is limited. Vasodilators with an antiproliferative \naction (e.g. epoprostenol, Fig. 23.12), drugs that potentiate \nNO such as riociguat, an allosteric activator of soluble guanylyl cyclase (see Ch. 21), approved for this indication \nin Europe and the United States, or antagonise endothelin \n\u2013 for example bosentan and ambrisentan \u2013 are considered \nto yield greater benefit.\nDrugs used in treating pulmonary arterial hypertension \nand clinical disorders for which vasoactive drugs are important are shown in the clinical boxes.\nCumulative survival\n(Months)Historical controlIV epoprostenol\np < 0.0001 (Cox-Mantel log-rank test)00.20.40.60.81\n01 22 43 64 86 07 28 49 6108 12 0\nFig. 23.12 Survival in primary pulmonary hypertension. \nSurvival\tin \t178 \tpatients \ttreated \twith \tintravenous \tepoprostenol \t\nversus a historical control group of 135 patients matched for \ndisease\tseverity. \t(Adapted \tfrom \tSitbon, \tO. \tet \tal., \t2002 \tProg. \t\nCardiovasc. Dis. 45, 115.)\nDrugs used in pulmonary arterial hypertension \nDrugs are used where indicated to treat any underlying \ncause;\tin\taddition, \tconsider \tthe \tfollowing:\n\u2022\tOral\tanticoagulants \t(Ch. \t25).\n\u2022\tDiuretics \t(Ch. \t30).\n\u2022\tOxygen.\n\u2022\tDigoxin (Ch. 22).\n\u2022\tCalcium-channel \tblockers.\n\u2022\tEndothelin \treceptor \tantagonists \t(e.g. \tbosentan, \nambrisentan, sitaxentan) by mouth for less severe \nstages of disease.\n\u2022\tProstanoid \tanalogues \t(iloprost, treprostinil, \nberaprost), subcutaneous or inhaled, are used for more \nsevere stages of disease.\u2022\tEpoprostenol (Ch. 18) is given as a long-term intravenous infusion, and improves survival (see Fig. 23.12).\n\u2022\tInhaled\tNO is administered in intensive care, for example \nfor pulmonary hypertensive crises in newborn babies.\n\u2022\tPhosphodiesterase \tV \tinhibitor: \tsildenafil and tadalafil \nby mouth are licensed for pulmonary arterial hypertension (PAH)\n\u2022\tRiociguat \t(activator \tof \tguanylyl \tcyclase).\nClinical disorders for which vasoactive drugs are important \n\u2022\tSystemic \thypertension:\n\u2013 secondary to underlying disease (e.g. renal or \nendocrine)\n\u2013\tprimary \t\u2018essential\u2019 \thypertension, \tan \timportant \trisk \t\nfactor for atheromatous disease (Ch. 24). Treatment reduces the excess risk of stroke or myocardial infarction, the main classes of drugs being (a) \nangiotensin-converting enzyme inhibitor (ACEI) or AT\n1 \nreceptor antagonists; (b) \u03b2-adrenoceptor antagonists; \n(c) calcium antagonists; and (d) diuretics.\n\u2022\tCardiac \tfailure. \tSeveral \tdiseases \t(most \tcommonly \t\nischaemic heart disease) impair the ability of the heart to \ndeliver an output adequate to meet metabolic needs. Oedema can be improved with diuretics. Life expectancy \nis reduced", "start_char_idx": 0, "end_char_idx": 2947, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3cc186d2-a8f4-4817-aa1f-b7491ee2d583": {"__data__": {"id_": "3cc186d2-a8f4-4817-aa1f-b7491ee2d583", "embedding": null, "metadata": {"page_label": "314", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8a8ec880-be50-4c33-ac3e-f94994930d49", "node_type": null, "metadata": {"page_label": "314", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cde69a19ff2ec11732f1a6405f2fd25adc28f779cd116f48274ece4914baa155"}, "2": {"node_id": "13b59beb-f4a9-4707-809c-69f260fb0bb8", "node_type": null, "metadata": {"page_label": "314", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2dea5b7220143ffc33f44a0c4bcd0bebb205da3ec88550fe1e05a6394d7195e1"}}, "hash": "b5da670462bd7e67842a27d8f90ab54ed1c0f3f0cbd6d24b3592478f23806c79", "text": "Oedema can be improved with diuretics. Life expectancy \nis reduced but can be improved by treatment of \nhaemodynamically \tstable \tpatients \twith:\n\u2013 ACEIs and/or AT 1 receptor antagonists\n\u2013 \u03b2-adrenoceptor antagonists (e.g. carvedilol, \nbisoprolol)\u2013 aldosterone antagonists (e.g. spironolactone).\n\u2022\tShock.\tSeveral \tdiseases \t(e.g. \toverwhelming \tbacterial \t\ninfections, Ch. 52; anaphylactic reactions, Ch. 28) lead to inappropriate vasodilatation, hypotension and reduced tissue perfusion with raised circulating concentrations of \nlactic acid. Pressors (e.g. adrenaline) are used.\n\u2022\tPeripheral \tvascular \tdisease. \tAtheromatous \tplaques \tin \tthe \t\narteries of the legs are often associated with atheroma in \nother\tvascular \tterritories. \tStatins \t(Ch. \t23) \tand \tantiplatelet \t\ndrugs (Ch. 24) are important.\n\u2022\tRaynaud\u2019s \tdisease. \tInappropriate \tvasoconstriction \tin \t\nsmall arteries in the hands causes blanching of the \nfingers followed by blueness and pain. Nifedipine or \nother vasodilators are used.\n\u2022\tPulmonary \thypertension, \twhich \tcan \tbe:\n\u2013\tidiopathic \t(a \trare \tdisorder): \tepoprostenol, iloprost, \nbosentan and sildenafil are of benefit in selected \npatients\n\u2013 associated with hypoxic lung disease.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2881, "end_char_idx": 4569, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4493a09c-59dd-40cb-a3f3-c0cc1376ec6e": {"__data__": {"id_": "4493a09c-59dd-40cb-a3f3-c0cc1376ec6e", "embedding": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c4638a2-db7f-4a28-805e-c633176a6859", "node_type": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5fb9c59698ac5d36afcfda0e788cefc5d73b5e415f16f3a2178fa4f284dc8b4e"}, "3": {"node_id": "f479fec0-999f-40a7-aee7-3bf1810cfc34", "node_type": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "078473ca1b7802df13b22054442e2c44c1f25042c33a85a1dca6d0d3313f15ec"}}, "hash": "8643c77ac3cf051ab5fa210cad5f70293f487e487f366ce2d5ac9e98c3964408", "text": "23 ThE vASCUlAR SYSTEM\n309REFERENCES AND FURTHER READING\nVascular endothelium (see Ch. 21 for further reading \non nitric oxide)\nProstacyclin\nBunting, S., Gryglewski, R., Moncada, S., Vane, J.R., 1976. Arterial walls \ngenerate from prostaglandin endoperoxides a substance ( prostaglandin \nX) which relaxes strips of mesenteric and celiac arteries and inhibits \nplatelet aggregation. Prostaglandins 12, 897\u2013913. ( Classic )\nMurata, T., Ushikubi, F., Matsuoka, T., et al., 1997. Altered pain \nperception and inflammatory response in mice lacking prostacyclin \nreceptor. Nature 388, 678\u2013682. ( I prostanoid receptor-deficient mice are \nviable, reproductive and normotensive; however, their susceptibility to \nthrombosis is increased \u2026 the results establish that prostacyclin is an \nendogenous antithrombotic agent )\nEndothelium-derived hyperpolarising factor\nEllinsworth, D.C., Sandow, S.L., Shukla, N., et al., 2016. \nEndothelium-derived hyperpolarization and coronary vasodilation: \ndiverse and integrated roles of epoxyeicosatrienoic acids, hydrogen \nperoxide, and gap junctions. Micorocirculation 23, 15\u201332. ( Reviews the \nmechanisms by which EETs and H 2O2 regulate vessel tone and examines the \nhypothesis that myoendothelial microdomain signaling facilitates EDH \nactivity in the human heart )\nEndothelin\nHickey, K.A., Rubanyi, G., Paul, R.J., Highsmith, R.F., 1985. \nCharacterization of a coronary vasoconstrictor produced by cultured \nendothelial cells. Am. J. Physiol. 248 (Pt 1), C550\u2013C556. ( Key discovery )\nYanagisawa, M., Kurihara, H., Kimura, S., et al., 1988. A novel potent \nvasoconstrictor peptide produced by vascular endothelial cells. \nNature 332, 411\u2013415. ( Tour de force )\nDavenport, A.P., Hyndman, K.A., Dhaun, N., et al., 2016. Endothelin. \nPharmacol. Rev. 68, 357\u2013418. ( Excellent review )\nRenin\u2013angiotensin system\nLang, C.C., Struthers, A.D., 2013. Targeting the renin-angiotensin-\naldosterone system in heart failure. Nat. Rev. Cardiol. 10, 125\u2013134.\nONTARGET Investigators, 2008. Telmisartan, ramipril or both in \npatients at high risk for vascular events. N. Engl. J. Med. 358, \n1547\u20131559.\nPatel, V.B., Zhong, J.C., Grant, M.B., et al., 2016. Role of the ACE2/\nangiotensin 1-7 axis of the renin-angiotensin system in heart failure. \nCirc. Res. 118, 1313\u20131326. ( Reviews ACE2/Ang 1-7 limb of the \nrenin-angiotensin axis and its therapeutic potential for heart failure )\nCirculation research\nPfeffer, M.A., McMurray, J.J.V., Velasquez, E.J., et al., 2003. The \nValsartan in Acute Myocardial Infarction Trial I. Valsartan, captopril \nor both in myocardial infarction complicated by heart failure, left \nventricular dysfunction, or both. N. Engl. J. Med. 349, 1839\u20131906.\nVasodilator drugs (see Ch. 22 for further reading on calcium \nantagonists)\nChan, C.K.S., Burke, S.L., Zhu, H., et al., 2005. Imidazoline receptors \nassociated", "start_char_idx": 0, "end_char_idx": 2851, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f479fec0-999f-40a7-aee7-3bf1810cfc34": {"__data__": {"id_": "f479fec0-999f-40a7-aee7-3bf1810cfc34", "embedding": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c4638a2-db7f-4a28-805e-c633176a6859", "node_type": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5fb9c59698ac5d36afcfda0e788cefc5d73b5e415f16f3a2178fa4f284dc8b4e"}, "2": {"node_id": "4493a09c-59dd-40cb-a3f3-c0cc1376ec6e", "node_type": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8643c77ac3cf051ab5fa210cad5f70293f487e487f366ce2d5ac9e98c3964408"}, "3": {"node_id": "399b2ce1-297f-4042-9c19-a989cc33d029", "node_type": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a3d5042a62ec110e05a91722092f97153e1390853ef3eee65140dac25b5eb818"}}, "hash": "078473ca1b7802df13b22054442e2c44c1f25042c33a85a1dca6d0d3313f15ec", "text": "Zhu, H., et al., 2005. Imidazoline receptors \nassociated with noradrenergic terminals in the rostral ventrolateral \nmedulla mediate the hypotensive responses of moxonidine but not \nclonidine. Neuroscience 132, 991\u20131007. ( The hypotensive and bradycardic \nactions of moxonidine but not clonidine are mediated through imidazoline \nreceptors and depend on noradrenergic CNS pathways; noradrenergic \ninnervation may be associated with imidazoline receptor protein )\nHypertension\nMeneton, P., Jeunemaitre, X., de Wardener, H.E., MacGregor, G.A., \n2005. Links between dietary salt intake, renal salt handling, blood \npressure, and cardiovascular diseases. Physiol. Rev. 85, 679\u2013715. (\u201c The \nmechanisms by which dietary salt increases arterial pressure are not fully \nunderstood, but they seem related to the inability of the kidneys to excrete large amounts of salt. From an evolutionary viewpoint, the human species is \nadapted to ingest and excrete <1 g of salt per day, at least 10 times less than \nthe average values currently observed in industrialized and urbanized \ncountries.\u201d )\nHeart failure\nCole, R.T., Gupta, D., Butler, J., 2014. Current perspectives in \nhydralazine and nitrate therapies in heart failure. Heart Fail Clin 10, \n565\u2013575. ( Underutilised ) \nJhund, P.S., McMurray, J.J.V., 2016. The neprilysin pathway in heart \nfailure: a review and guide on the use of sacubitril/valsartan. Heart \n102, 1342\u20131347. ( Reviews the background to neprilysin inhibition in heart \nfailure, the results of the PARADIGM-HF trial and describes the use of \nsacubitril/valsartan in clinical practice )\nO\u2019Connor, C.M., Starling, R.C., Hernandez, A.F., et al., 2011. Effect of \nnesiritide in patients with acute decompensated heart failure. N. Engl. \nJ. Med. 365, 32\u201343. ( see also Topol, E.T., 2011. The lost decade of nesiritide. \nN. Engl. J. Med. 365, 81\u201382 )\nTask Force for the diagnosis and treatment of acute and chronic heart \nfailure of the European Society of Cardiology (ESC), 2016. 2016 ESC \nGuidelines for the diagnosis and treatment of acute and chronic heart \nfailure. Eur. Heart J. 37 (2016), 2129\u20132200.\nTaylor, A.L., Ziesche, S., Yancy, C., et al., 2004. Combination of \nisosorbide dinitrate and hydralazine in blacks with heart failure. N. \nEngl. J. Med. 351, 2049\u20132057. ( Addition of a fixed dose of isosorbide \ndinitrate plus hydralazine to standard therapy for heart failure including \nneurohormonal blockers increased survival among black patients with \nadvanced heart failure )\nShock\nHolmes, C.L., Russell, J.A., 2004. Vasopressin. Semin. Respir. Crit. Care \nMed. 25, 705\u2013711. ( \u2018A deficiency of vasopressin exists in some shock states \nand replacement of physiological levels of vasopressin can restore vascular \ntone. Vasopressin is therefore emerging as a rational therapy for vasodilatory \nshock.\u2019 Reviews rationale, evidence and uncertainties for using vasopressin \nin shock )\nKhanna, A., English, S.W., Wang, X.S., et al., for the ATHOS3 \ninvestigators, 2017. Angiotensin II for the treatment of vasodilatory \nshock. N. Engl. J. Med. 377, 419\u2013430. (\u201c Angiotensin II effectively \nincreased blood pressure in patients with vasodilatory shock that did", "start_char_idx": 2803, "end_char_idx": 5975, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "399b2ce1-297f-4042-9c19-a989cc33d029": {"__data__": {"id_": "399b2ce1-297f-4042-9c19-a989cc33d029", "embedding": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c4638a2-db7f-4a28-805e-c633176a6859", "node_type": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5fb9c59698ac5d36afcfda0e788cefc5d73b5e415f16f3a2178fa4f284dc8b4e"}, "2": {"node_id": "f479fec0-999f-40a7-aee7-3bf1810cfc34", "node_type": null, "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "078473ca1b7802df13b22054442e2c44c1f25042c33a85a1dca6d0d3313f15ec"}}, "hash": "a3d5042a62ec110e05a91722092f97153e1390853ef3eee65140dac25b5eb818", "text": "II effectively \nincreased blood pressure in patients with vasodilatory shock that did not \nrespond to high doses of conventional vasopressors \u201d)\nLandry, D.W., Oliver, J.A., 2001. Mechanisms of disease: the \npathogenesis of vasodilatory shock. N. Engl. J. Med. 345, 588\u2013595. \n(Reviews mechanisms promoting inappropriate vasodilation in shock, \nincluding activation of ATP-sensitive potassium channels, increased \nsynthesis of NO and depletion of ADH )\nPulmonary arterial hypertension (PAH)\nHigenbottam, T., Laude, L., Emery, C., Essener, M., 2004. Pulmonary \nhypertension as a result of drug therapy. Clin. Chest Med. 25, \n123\u2013131. ( Reviews anorectic drug-induced pulmonary arterial hypertension \nand considers mechanisms )\nHumbert, M., Ghofrani, H.A., 2016. The molecular targets of approved \ntreatments for pulmonary arterial hypertension. Thorax 71, 73\u201383. \n(This review describes how the four currently approved drug classes \n- prostanoids, endothelin receptor antagonists, phosphodiesterase type 5 \ninhibitors and the soluble guanylate cyclase stimulator riociguat - target the \ncomplex pathobiology of PAH )\nMann, D.L., Zipes, D.P., Libby, P., Bonow, R.O. (Eds.), 2015. \nBraunwald\u2019s Heart Disease, tenth ed. Elsevier, Philadelphia. Ch. 74, \nPulmonary hypertension.\nTaichman, D.B., Ornelas, J., Chung, L., et al., 2014. Pharmacologic \ntherapy for pulmonary arterial hypertension in adults: CHEST \nguideline and expert panel report. Chest 146, 449\u2013475. ( Provides advice \non drug therapy for adult patients with PAH based on available evidence )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5939, "end_char_idx": 7968, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "70e1d3bc-8661-4eed-b19e-0963fa8bda60": {"__data__": {"id_": "70e1d3bc-8661-4eed-b19e-0963fa8bda60", "embedding": null, "metadata": {"page_label": "316", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e9fe91ec-1a3f-42fc-b243-3b9b66880a54", "node_type": null, "metadata": {"page_label": "316", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ddb8d21f279d907c25ed81f5fda0aa30382a4950329965511e421d17a211cc5"}, "3": {"node_id": "0c75b4df-f82e-404e-b1b1-e0a57a483bf6", "node_type": null, "metadata": {"page_label": "316", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "531012ea33579109f53b53d871364b8c786c2f4a7ba756d44044f17ffa0c9a39"}}, "hash": "0027043a9cd25c8d7800bb7451066b34402af38082f6952f811386fa8bf5e9ae", "text": "310\nAtherosclerosis and lipoprotein \nmetabolism24 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3 \nOVERVIEW\nAtheromatous disease is ubiquitous and underlies \nthe commonest causes of death (myocardial infarction \ncaused by thrombosis \u2013 Ch. 25 \u2013 on ruptured ather-\nomatous plaque in a coronary artery) and disability \n(stroke, heart failure) in industrial societies. Hyperten -\nsion is one of the most important risk factors for atheroma, and is discussed in Chapter 23. Here, we \nconsider other risk factors, especially dyslipidaemia,\n1 \nwhich, like hypertension, is amenable to drug therapy. \nWe describe briefly the processes of atherogenesis \nand of lipid transport as a basis for understanding the actions of lipid-lowering drugs. Agents employed \ntherapeutically (statins, inhibitors of PCSK9,\n2 fibrates, \ncholesterol absorption inhibitors, nicotinic acid deriva -\ntives) are described, with emphasis on the statins \nwhich, in selected patients, reduce the incidence of arterial disease and prolong life.\nINTRODUCTION\nIn this chapter we summarise the pathological process of \natherogenesis and approaches to the prevention of athero -\nsclerotic disease. Lipoprotein transport forms the basis for understanding drugs used to treat dyslipidaemia. We emphasise the statins, which have been a major success \nstory, not only lowering plasma cholesterol but also reducing cardiovascular events by approximately 25%\u201350% and prolonging life in people at increased risk of vascular \ndisease. However, some patients do not tolerate them, and \nothers fail to respond. Evidence that other drugs that influence dyslipidaemia improve clinical outcomes is less secure than for the statins, and there have been setbacks, \ndescribed later, that call into question the universal reliability \nof changes in circulating lipid concentrations in response to drugs as surrogates predicting clinical improvement. In \nthe absence of hard evidence of clinical improvement, other \nclasses of lipid-lowering drugs remain second line to statins, so there is rather a lot of \u2018small print\u2019 in this section.\nATHEROGENESIS\nAtheroma is a focal disease of the intima of large and medium-sized arteries. Lesions evolve over decades, during most \nof which time they are clinically silent, the occurrence of \nsymptoms signalling advanced disease. Presymptomatic lesions are often difficult to detect non-invasively, although ultrasound is useful in accessible arteries (e.g. the carotids), \nand associated changes such as reduced aortic compliance \nand arterial calcification can be detected by measuring, respectively, aortic pulse wave velocity and coronary artery \ncalcification. There were no good animal models until trans -\ngenic mice (see Ch. 8) deficient in apolipoproteins or receptors \nthat play key roles in lipoprotein metabolism transformed \nthe scene. Nevertheless, most of our current understanding \nof atherogenesis comes from human epidemiology and pathology, and from clinical investigations.\nEpidemiological studies have identified numerous risk \nfactors for atheromatous disease. Some of these cannot be altered (e.g. a family history of ischaemic heart disease\n3), \nbut others are modifiable (Table 24.1) and are potential \ntargets for therapeutic drugs. Clinical trials have shown \nthat improving risk factors can reduce the consequences of atheromatous disease. Many risk factors (e.g. type 2 \ndiabetes, dyslipidaemia, cigarette smoking) cause endothelial \ndysfunction (see Ch. 23), evidenced by reduced vasodilator responses to acetylcholine or to increased blood flow (so-\ncalled flow-mediated dilatation), responses that are inhibited \nby drugs that block nitric oxide", "start_char_idx": 0, "end_char_idx": 3660, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0c75b4df-f82e-404e-b1b1-e0a57a483bf6": {"__data__": {"id_": "0c75b4df-f82e-404e-b1b1-e0a57a483bf6", "embedding": null, "metadata": {"page_label": "316", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e9fe91ec-1a3f-42fc-b243-3b9b66880a54", "node_type": null, "metadata": {"page_label": "316", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ddb8d21f279d907c25ed81f5fda0aa30382a4950329965511e421d17a211cc5"}, "2": {"node_id": "70e1d3bc-8661-4eed-b19e-0963fa8bda60", "node_type": null, "metadata": {"page_label": "316", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0027043a9cd25c8d7800bb7451066b34402af38082f6952f811386fa8bf5e9ae"}}, "hash": "531012ea33579109f53b53d871364b8c786c2f4a7ba756d44044f17ffa0c9a39", "text": "dilatation), responses that are inhibited \nby drugs that block nitric oxide (NO) synthesis (Ch. 21). Healthy endothelium produces NO and other mediators that protect against atheroma, so it is likely that metabolic \ncardiovascular risk factors act by causing endothelial \ndysfunction.\nAtherogenesis involves:\n1. Endothelial dysfunction, with altered NO (Ch. 21) biosynthesis which predisposes to atherosclerosis.\n2. Injury of dysfunctional endothelium, which leads to \nexpression of adhesion molecules. This encourages \nmonocyte attachment and migration of monocytes \nfrom the lumen into the intima. Lesions have a predilection for regions of disturbed flow such as the \norigins of aortic branches.\n3. Low-density lipoprotein (LDL) cholesterol transport into \nthe vessel wall. Endothelial cells and monocytes/\nmacrophages generate free radicals that oxidise LDL \n(oxLDL), resulting in lipid peroxidation.\n4. oxLDL uptake by macrophages via \u2018scavenger\u2019 receptors. Such macrophages are called foam cells \nbecause of their \u2018foamy\u2019 histological appearance, \nresulting from accumulation of cytoplasmic lipid, and are characteristic of atheroma. Uptake of oxLDL \nactivates macrophages which release proinflammatory \ncytokines.\n5. Subendothelial accumulation of foam cells and T \nlymphocytes to form fatty streaks.\n6. Protective mechanisms, for example cholesterol \nmobilisation from the artery wall and transport in \n1The term dyslipidaemia is preferred to hyperlipidaemia because a low \nplasma concentration of high-density lipoprotein cholesterol is believed \nto be harmful and is a potential therapeutic target.\n2PCSK9 stands for proprotein convertase subtilisin/kexin type 9.3As we learn how to tinker with the expression of genes even this \nseeming truism may turn out to be less immutable than it seemed (see Ch. 5 and later, p. 317.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3585, "end_char_idx": 5898, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8907c030-fd56-437b-b4f5-9046b326f91b": {"__data__": {"id_": "8907c030-fd56-437b-b4f5-9046b326f91b", "embedding": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fbbafa90-14ef-47d0-a3da-80dbe4fe6404", "node_type": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bec9aff667cd2c4cb47a5276d71b7722522f2e791f3a8ef43560225b5f535e4d"}, "3": {"node_id": "bef1a3e4-dc92-41d3-aa90-35260885285c", "node_type": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c26738a31481ec4b2fd0f023cd6024a5df5b98bc9e631e1f3848c202514d30a6"}}, "hash": "ad75a4bc463bf45f1dd56c812a22659c7505d5b64af5b9b98d2279b818dc8da5", "text": "24 AThEROSC lEROSIS AND l I p O p ROTEIN META b O l ISM\n311\u2022\tvery-low-density \tlipoprotein \t(VLDL) \tparticles \t(contain \t\napoB-100), diameter 30\u201380 nm\n\u2022\tchylomicrons \t(contain \tapoB-48), \tdiameter \t100\u20131000 \tnm\nEach class of lipoprotein has a specific role in lipid transport, \nand there are different pathways for exogenous and \nendogenous lipids, as well as a pathway for reverse cho-\nlesterol transport (Fig. 24.1). In the exogenous pathway, \ncholesterol and triglycerides absorbed from the ileum are \ntransported as chylomicrons in lymph and then blood, to \ncapillaries in muscle and adipose tissue. Here, triglycerides are hydrolysed by lipoprotein lipase, and the tissues take \nup the resulting free fatty acids and glycerol. The chylomi -\ncron remnants, still containing their full complement of \ncholesteryl esters, pass to the liver, bind to receptors on hepatocytes and undergo endocytosis. Cholesterol liberated \nin hepatocytes is stored, oxidised to bile acids, secreted \nunaltered in bile, or can enter the endogenous pathway.\nIn the endogenous pathway, cholesterol and newly syn-\nthesised\ttriglycerides \tare\ttransported \tfrom\tthe\tliver\tas\tVLDL\t\nto muscle and adipose tissue, where triglyceride is hydro-lysed to fatty acids and glycerol; these enter the tissues as \ndescribed above. During this process, the lipoprotein \nparticles become smaller but retain a full complement of cholesteryl esters and become LDL particles. LDL provides \nthe source of cholesterol for incorporation into cell mem-\nbranes and for synthesis of steroids (see Chs 34 and 36) but is also key in atherogenesis. Cells take up LDL by \nendocytosis via LDL receptors that recognise apoB-100. LDL \nreceptors are critically important in determining the con -\ncentration of circulating LDL, and hence the development \nand progression of atheromatous disease; the most widely \nused drugs for the prevention of such disease, the statins, \nact by blocking the synthesis of cholesterol within hepato -\ncytes which respond by increasing LDL receptor expression \non their surface membranes (see later, p. 312). A new class \nof drugs, the PCSK9 inhibitors, also influence LDL receptor density but by a different mechanism, namely reduced \nlysosomal degradation of internalised LDL receptors leading \nto increased recycling of functional LDL receptors to the surface membrane (see later, p. 315).\nCholesterol can return to plasma from the tissues in HDL \nparticles (reverse cholesterol transport). Cholesterol is esterified with long-chain fatty acids in HDL particles, and \nthe\tresulting \tcholesteryl \testers \tare \ttransferred \tto \tVLDL \tor \t\nLDL particles by a transfer protein present in the plasma and known as cholesteryl ester transfer protein (CETP). \nLipoprotein(a), or Lp(a), is a species of LDL that is associated with atherosclerosis and is localised in atherosclerotic lesions. Lp(a) contains a unique apoprotein, apo(a), with \nstructural similarities to plasminogen (Ch. 25). Lp(a) \ncompetes with plasminogen for its receptor on endothelial cells. Plasminogen is the substrate for plasminogen activator, \nwhich is secreted by, and bound to endothelial cells, generat -\ning the fibrinolytic enzyme plasmin (see Fig. 25.10). The \neffect of the binding of Lp(a) is that less plasmin is generated, \nfibrinolysis is inhibited and thrombosis", "start_char_idx": 0, "end_char_idx": 3328, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bef1a3e4-dc92-41d3-aa90-35260885285c": {"__data__": {"id_": "bef1a3e4-dc92-41d3-aa90-35260885285c", "embedding": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fbbafa90-14ef-47d0-a3da-80dbe4fe6404", "node_type": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bec9aff667cd2c4cb47a5276d71b7722522f2e791f3a8ef43560225b5f535e4d"}, "2": {"node_id": "8907c030-fd56-437b-b4f5-9046b326f91b", "node_type": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad75a4bc463bf45f1dd56c812a22659c7505d5b64af5b9b98d2279b818dc8da5"}, "3": {"node_id": "3b7083b4-0398-4516-8955-56aa3f11c5f3", "node_type": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9927aaa63ca7327c8753bff2f3a9cf6fa386d10a7e13a5967a37efac466b2b86"}}, "hash": "c26738a31481ec4b2fd0f023cd6024a5df5b98bc9e631e1f3848c202514d30a6", "text": "plasmin is generated, \nfibrinolysis is inhibited and thrombosis promoted.\n\u25bc Lipid transfer proteins have been implicated in atherogenesis (Stein \n& Stein, 2005). ACAT (acyl coenzyme A: cholesterol acyltransferase), \nwhich is expressed in two forms, catalyses the intracellular synthesis \nof cholesteryl ester in macrophages, adrenal cortex, gut and liver. \nTamoxifen, used in the treatment and prevention of breast cancer \n(Chs 36 and 57), is a potent ACAT inhibitor (de Medina et al., 2004). \nCETP is involved in transfer of cholesterol between different classes of lipoprotein particle in plasma. Microsomal triglyceride transport plasma as high-density lipoprotein (HDL) cholesterol, \ntermed \u2018reverse cholesterol transport\u2019.\n7. Cytokine and growth factor release by activated \nplatelets, macrophages and endothelial cells, causing proliferation of smooth muscle and deposition of \nconnective tissue components. This inflammatory \nfibroproliferative response leads to a dense fibrous cap overlying a lipid-rich core, the whole structure \ncomprising the atheromatous plaque.\n8. Plaque rupture, which provides a substrate for \nthrombosis (see Ch. 25, Figs 25.1 and 25.10). The presence of large numbers of macrophages predisposes \nto plaque rupture, whereas vascular smooth muscle and matrix proteins stabilise the plaque.\nTo understand how drugs prevent atheromatous disease, \nit is necessary briefly to review lipoprotein transport.\nLIPOPROTEIN TRANSPORT\nLipids and cholesterol are transported in the bloodstream \nas complexes of lipid and protein known as lipoproteins. \nThese consist of a central core of hydrophobic lipid (includ -\ning triglycerides and cholesteryl esters) encased in a hydrophilic coat of polar phospholipid, free cholesterol \nand apoprotein. There are four main classes of lipoprotein, \ndiffering in the relative proportion of the core lipids and \nin the type of apoprotein (various kinds of apoA and apoB). \nApoproteins bind to specific receptors that mediate uptake \nof lipoprotein particles into liver, blood or other tissues. Lipoproteins differ in size and density, and this latter property, measured originally by ultracentrifugation but \nnow commonly estimated by simpler methods, is the basis \nfor their classification into:\n\u2022\tHDL\tparticles \t(contain \tapoA1 \tand \tapoA2), \tdiameter \t\n7\u201320 nm\n\u2022\tLDL\tparticles \t(contain \tapoB-100), \tdiameter \t20\u201330 \tnmTable 24.1 Modifiable risk factors for atheromatous \ndisease\nRaised low-density lipoprotein cholesterol\nReduced high-density lipoprotein cholesterolHypertension (Ch. 23)Diabetes mellitus (Ch. 32)Cigarette smoking (Ch. 50)Obesity (Ch. 33)Physical inactivityRaised C-reactive protein\na\nRaised coagulation factors (e.g. factor VII, fibrinogen)Raised homocysteineRaised lipoprotein(a)\nb\naStrongly associated with atheromatous disease but not causal \nof it.\nbPotentially modifiable but strongly genetically determined: \nnicotinic acid does lower lipoprotein(a).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3273, "end_char_idx": 6551, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3b7083b4-0398-4516-8955-56aa3f11c5f3": {"__data__": {"id_": "3b7083b4-0398-4516-8955-56aa3f11c5f3", "embedding": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fbbafa90-14ef-47d0-a3da-80dbe4fe6404", "node_type": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bec9aff667cd2c4cb47a5276d71b7722522f2e791f3a8ef43560225b5f535e4d"}, "2": {"node_id": "bef1a3e4-dc92-41d3-aa90-35260885285c", "node_type": null, "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c26738a31481ec4b2fd0f023cd6024a5df5b98bc9e631e1f3848c202514d30a6"}}, "hash": "9927aaa63ca7327c8753bff2f3a9cf6fa386d10a7e13a5967a37efac466b2b86", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6560, "end_char_idx": 6751, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "144548b5-8573-4810-9ae8-35ae6826e923": {"__data__": {"id_": "144548b5-8573-4810-9ae8-35ae6826e923", "embedding": null, "metadata": {"page_label": "318", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54427b83-c87e-441c-879b-063731937468", "node_type": null, "metadata": {"page_label": "318", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1eb06d47e721a545a9fe66f78e8ab5f826479db1404b614f928872c13579bf45"}, "3": {"node_id": "21c8694d-d5d4-4fc2-a155-301f54e018b5", "node_type": null, "metadata": {"page_label": "318", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "94ed6bccf10b31e965c0009a8f81e604f4233580dadf3ee6e67790790b3a3d85"}}, "hash": "cc9be581d3eebf5f2a50a12ef2c1c61d7003ad8256c2b30e915eb64a41a50caf", "text": "24 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n312familial hypercholesterolaemia (FH), and the plasma total \ncholesterol concentration, normally <5 mmol/L, in affected \nadults is typically >8 mmol/L in heterozygotes and \n12\u201325 mmol/L in homozygotes. Study of FH enabled Brown \nand Goldstein (1986) to define the LDL receptor pathway \nof cholesterol homeostasis (for which they shared a Nobel \nPrize). Further investigation of people with very low or \nvery high circulating LDL cholesterol concentrations led to the discovery of inactivating and gain-of-function variants \nof the PCSK9 gene (see Hall, 2013 for a popular account, \nand later, p. 315). Drugs used to treat primary dyslipidaemia are described below.\nSecondary forms of dyslipidaemia are a consequence of \nother conditions, such as diabetes mellitus, alcoholism, nephrotic syndrome, chronic renal failure, hypothyroidism, protein (MTP) is a lipid-transfer protein present in the lumen of the \nendoplasmic reticulum responsible for binding and transfer of lipids \nbetween membranes. Inhibition of MTP interferes with apoB secretion \nand LDL assembly and lomitapide, one such inhibitor, is used in \naddition to diet and other measures in homozygous familial \nhypercholesterolaemia.\nDYSLIPIDAEMIA\nDyslipidaemia may be primary or secondary. The primary \nforms are due to a combination of diet and genetics (often \nbut not always polygenic). They are classified into six \nphenotypes (the Frederickson classification; Table 24.2). An especially great risk of ischaemic heart disease occurs \nin a subset of primary type IIa hyperlipoproteinaemia caused \nby single-gene defects of LDL receptors; this is known as Alirocumab,\nevolocumab\nBILE DUCT\nPORTAL VEINBile acids\nand CHEPATOCYTE\nCExogenous pathway\nHMG CoA HMG CoA\nreductase\nMVA\n\u2018Coated pit\u2019Resins bind\nBile acids\nFree fatty\nacidsFree fatty\nacidsUptake\nof CC from cell\nturnoverFat + C\nin diet\nChylomicron\nremnant\nChylomicronsVLDL\nCETPNPC1L1\nLDL HDLLIVEREndogenous pathway\nPERIPHERAL TISSUES\n(FAT, MUSCLE)INTESTINE\nVASCULAR ENDOTHELIUMFatty acids\n+\nGlycerol\n+\nCLDL\nreceptors\nFibrates\nenhance\nLipoprotein lipaseFibrates\ndecrease\nsecretion\nEzetimibe reduces\nabsorption of CStatins, resins,\nfibrates increase\nuptakeStatins decrease\nsynthesis of C\nFaecal \nelimination of \nbile acidsPCSK9\nFig. 24.1 Schematic diagram of cholesterol transport in the tissues, with sites of action of the main drugs affecting lipoprotein \nmetabolism. C, cholesterol; CETP, cholesteryl ester transport protein; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-\nmethylglutaryl-coenzyme A; LDL, low-density lipoprotein; MVA, mevalonate; NPC1L1, a cholesterol transporter in the brush border of \nenterocytes; PCSK9, proprotein convertase subtilisin/kexin 9; VLDL, very-low-density lipoprotein. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3012, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "21c8694d-d5d4-4fc2-a155-301f54e018b5": {"__data__": {"id_": "21c8694d-d5d4-4fc2-a155-301f54e018b5", "embedding": null, "metadata": {"page_label": "318", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54427b83-c87e-441c-879b-063731937468", "node_type": null, "metadata": {"page_label": "318", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1eb06d47e721a545a9fe66f78e8ab5f826479db1404b614f928872c13579bf45"}, "2": {"node_id": "144548b5-8573-4810-9ae8-35ae6826e923", "node_type": null, "metadata": {"page_label": "318", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cc9be581d3eebf5f2a50a12ef2c1c61d7003ad8256c2b30e915eb64a41a50caf"}}, "hash": "94ed6bccf10b31e965c0009a8f81e604f4233580dadf3ee6e67790790b3a3d85", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2965, "end_char_idx": 3268, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2ac00aa5-cf80-458c-9adc-8af22595ffa8": {"__data__": {"id_": "2ac00aa5-cf80-458c-9adc-8af22595ffa8", "embedding": null, "metadata": {"page_label": "319", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f36cf705-0214-4c5d-aa90-3f7e277e3148", "node_type": null, "metadata": {"page_label": "319", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fd6d8b73b24514cdc80fe5bc0854ad713a046d58bcdde8453d74ea149f6a5460"}, "3": {"node_id": "174d1584-ebfd-4a81-92b9-d44872301c8f", "node_type": null, "metadata": {"page_label": "319", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "64673a667f1ef98e393ca0ce7626e03e98854dadde89a1ef5ce0fb7536902a97"}}, "hash": "a5e2098e959ee00663e1f87bcb47c7b363bbfe12fb524b4c15a302d9625ad48a", "text": "24 AThEROSC lEROSIS AND l I p O p ROTEIN META b O l ISM\n313PREVENTION OF ATHEROMATOUS \nDISEASE\nDrug treatment is often justified, to supplement healthy \nhabits. Treatment of hypertension (Ch. 23) and, to a lesser \nextent, diabetes mellitus (Ch. 32) reduces the incidence of \nsymptomatic atheromatous disease, and antithrombotic drugs (Ch. 25) reduce arterial thrombosis. Reducing LDL \nis also effective and is the main subject of this present \nchapter, but several other steps in atherogenesis are also potential targets for pharmacological attack.\n\u25bc Angiotensin-converting enzyme inhibitors (Ch. 23) improve \nendothelial function and prolong life in patients with atheromatous \ndisease. Other drugs that also increase NO biosynthesis or availability \nare under investigation.\nMeasures to increase HDL : moderate alcohol consumption increases \nHDL, and epidemiological evidence favours moderate alcohol con -\nsumption in older people. Regular exercise also increases circulating \nHDL; drug treatment to increase HDL is of uncertain benefit. Fibrates \nand nicotinic acid derivatives \u2013 see below \u2013 modestly increase HDL, and reduce LDL and triglycerides. In subjects with low HDL, inhibition \nof CETP can markedly increase circulating HDL, but three such drugs \nhave failed because of lack of clinical efficacy or adverse outcomes. Trials of a fourth, anacetrapib, showed that it increases HDL and \nlowers LDL, and is associated with a modest reduction in major coronary events, compared with placebo in patients at risk for cardiac events already receiving a statin, though no effect on overall mortality, \nand its development has been discontinued.\nApoA-I Milano is a variant of apolipoprotein A-I identified in individuals \nin rural Italy with very low levels of HDL but almost no cardiovascular \ndisease. Infusion of recombinant ApoA-I Milano\u2013phospholipid complexes causes rapid regression of atherosclerosis in animal models. \nIt is expensive to produce and must be administered intravenously, \nbut the strategy remains a possible future approach (see review by \nIkenaga et al., 2016).\nAntioxidants (e.g. vitamin C and vitamin E) are of interest, because of reports that they improve endothelial function in patients with \nincreased oxidant stress, and because of epidemiological evidence \nthat a diet rich in antioxidants is associated with reduced risk of coronary artery disease. Results from clinical trials have been negative, \nhowever, and several antioxidants reduce HDL. Oestrogen, used to \nprevent symptoms of the menopause (Ch. 36) and to prevent post -\nmenopausal osteoporosis, has antioxidant properties and exerts other vascular effects that could be beneficial. Epidemiological evidence \nsuggested that women who use such hormone replacement might \nbe at reduced risk of atheromatous disease, but controlled trials showed \nsignificant adverse effects on cardiovascular mortality (Ch. 36).liver disease and administration of drugs, for example \nisotretinoin (an isomer of vitamin A given by mouth as \nwell as topically in the treatment of severe acne, see Ch. \n28), tamoxifen , ciclosporine (Ch. 27) and protease inhibitors \nused to treat infection with human immunodeficiency virus \n(Ch. 53). Secondary forms are treated where possible by \ncorrecting the underlying cause.Table 24.2 Frederickson/World Health Organization classification of hyperlipoproteinaemia\nType Lipoprotein elevated Cholesterol Triglycerides Atherosclerosis risk Drug treatment\nI Chylomicrons + +++ NE None\nIIa LDL ++ NE High Statin \u00b1 ezetimibe\nIIb LDL + VLDL ++ ++ High", "start_char_idx": 0, "end_char_idx": 3566, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "174d1584-ebfd-4a81-92b9-d44872301c8f": {"__data__": {"id_": "174d1584-ebfd-4a81-92b9-d44872301c8f", "embedding": null, "metadata": {"page_label": "319", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f36cf705-0214-4c5d-aa90-3f7e277e3148", "node_type": null, "metadata": {"page_label": "319", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fd6d8b73b24514cdc80fe5bc0854ad713a046d58bcdde8453d74ea149f6a5460"}, "2": {"node_id": "2ac00aa5-cf80-458c-9adc-8af22595ffa8", "node_type": null, "metadata": {"page_label": "319", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a5e2098e959ee00663e1f87bcb47c7b363bbfe12fb524b4c15a302d9625ad48a"}}, "hash": "64673a667f1ef98e393ca0ce7626e03e98854dadde89a1ef5ce0fb7536902a97", "text": "High Statin \u00b1 ezetimibe\nIIb LDL + VLDL ++ ++ High Fibrates, statin, nicotinic acid\nIII \u03b2VLDL ++ ++ Moderate Fibrates\nIV VLDL + ++ Moderate Fibrates\nV Chylomicrons + VLDL + ++ NE Fibrate, niacin, fish oil and \nstatin combinations\n+, increased concentration; LDL, low-density lipoprotein; NE, not elevated; VLDL, very-low-density lipoprotein; \u03b2VLDL, a qualitatively \nabnormal form of VLDL identified by its pattern on electrophoresis.\nLipoprotein metabolism and \ndyslipidaemia \nLipids, including cholesterol and triglycerides, are \ntransported in the plasma as lipoproteins, of which there are four classes:\n\u2022\tChylomicrons \ttransport \ttriglycerides \tand \tcholesterol \t\nfrom the gastrointestinal tract to the tissues, where triglyceride is split by lipoprotein lipase, releasing free fatty acids and glycerol which are taken up in muscle \nand\tadipose \ttissue. \tChylomicron \tremnants \tare \ttaken \t\nup in the liver, where cholesterol is stored, secreted in bile, oxidised to bile acids or converted into:\n\u2013 very-low-density lipoproteins (VLDLs), which \ntransport cholesterol and newly synthesised triglycerides to the tissues, where triglycerides are removed as before, leaving:\n\u2013 intermediate-density and low-density lipoprotein \n(LDL) particles with a large component of cholesterol; some LDL cholesterol is taken up by the tissues and some by the liver, by endocytosis via \nspecific LDL receptors.\n\u2022\tHigh-density \tlipoprotein \t(HDL) \tparticles \tadsorb \t\ncholesterol derived from cell breakdown in tissues \n(including arteries) and transfer it to VLDL and LDL \nparticles\tvia \tcholesterol \tester \ttransport \tprotein \t(CETP).\n\u2022\tDyslipidaemias \tcan \tbe \tprimary, \tor \tsecondary \tto \ta \t\ndisease\t(e.g. \thypothyroidism). \tThey \tare \tclassified \t\naccording to which lipoprotein particle is abnormal into \nsix\tphenotypes \t(the \tFrederickson \tclassification). \tThe \t\nhigher\tthe \tLDL \tcholesterol \tand \tthe \tlower \tthe \tHDL \t\ncholesterol, the higher the risk of ischaemic heart disease.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3517, "end_char_idx": 5970, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "591b2554-9a04-4264-9a54-e2696fff63ec": {"__data__": {"id_": "591b2554-9a04-4264-9a54-e2696fff63ec", "embedding": null, "metadata": {"page_label": "320", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9f7980e6-ef40-45b8-96aa-eef217c39644", "node_type": null, "metadata": {"page_label": "320", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ff3716e815ee4e99772fe0e8535fbd5e3e91c0b7dc84d4e2eb82c17bd988e9a"}, "3": {"node_id": "8aa2132b-d0c9-4c83-b653-71b316d799ad", "node_type": null, "metadata": {"page_label": "320", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9872d8626e3d0e8b0aefd28d304547e6421194f42f3898ff7152fd396530dbc0"}}, "hash": "b620c57e4550855d8f21cb16808002a64f740a8f5d317e8206bf7971887e63c2", "text": "24 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n314inhibitors. Decreased hepatic cholesterol synthesis upregu -\nlates LDL receptor synthesis, increasing LDL clearance from \nplasma into liver cells. The main biochemical effect of statins \nis therefore to reduce plasma LDL. There is also some reduc -\ntion in plasma triglyceride and increase in HDL. Several \nlarge randomised placebo-controlled trials of the effects of \nHMG-CoA reductase inhibitors on morbidity and mortality have been positive.\n\u25bc The Scandinavian Simvastatin Survival Study (4S) recruited patients \nwith ischaemic heart disease and plasma cholesterol of 5.5\u20138.0 mmol/L: \nsimvastatin lowered serum LDL by 35% and death by 30% ( Fig. 24.2 ). \nThere was a 42% reduction in death from coronary disease. Other \nlarge trials have confirmed reduced mortality both in patients with \nestablished ischaemic heart disease and in apparently healthy people at high risk of coronary disease, with a wide range of plasma cholesterol \nvalues and other risk factors, and treated with different statins. \nIntensive lowering of LDL with atorvastatin 80 mg had a greater \neffect on event rate than did a 10-mg dose, but with a greater incidence \nof abnormally raised plasma transaminase activity (evidence of liver \ndamage). In secondary prevention trials of statins, cardiovascular \nevent rate has been approximately linearly related to the achieved plasma LDL over a concentration range from approximately \n1.8\u20134.9 m mol/L, and the event rate falls on the same line in placebo- \nand statin-treated patients, suggesting that plasma LDL is a valid surrogate marker of cardiovascular risk in this context.\nOther actions of statins\nProducts of the mevalonate pathway react with protein \n(\u2018lipidation\u2019, which is the addition to a protein of hydro -\nphobic groups such as prenyl or farnesyl moieties). Several important membrane-bound enzymes (e.g. endothelial NO synthase; see Ch. 21) are modified in this way. The fatty \ngroups serve as anchors, localising the enzyme in organelles \nsuch as caveoli and Golgi apparatus. Consequently, there is interest in actions of statins that are unrelated, or indirectly \nrelated, to their effect on plasma LDL (sometimes referred \nto as pleiotropic effects). Some of these actions are undesirable \n(e.g. HMG-CoA reductase guides migrating primordial germ cells, and statin use is contraindicated during Anti-inflammatory approaches: drug treatment to lower C-reactive \nprotein (see Ch. 7) has been mooted, but it is likely that, while elevated \nC-reactive protein is a marker of vascular inflammation, it does not \nitself play a direct part in atherogenesis. Other anti-inflammatory measures are being investigated; for example, ACAT inhibitors.\nAtheromatous disease \n\u2022\tAtheroma \tis \ta \tuniquely \thuman \tfocal \tdisease \tof \tlarge \t\nand medium-sized arteries. Atheromatous plaques \noccur in most people, progress insidiously over many decades, and underlie the commonest causes of \ndeath (myocardial infarction) and disability (e.g. stroke) \nin industrialised countries.\n\u2022\tFatty\tstreaks \tare \tthe \tearliest \tstructurally \tapparent \t\nlesion and progress to fibrous and/or fatty plaques. Symptoms such as angina occur only when blood flow through the vessel is reduced below that needed to \nmeet the metabolic demands of tissues downstream \nfrom the obstruction.\n\u2022\tImportant \tmodifiable \trisk \tfactors \tinclude \thypertension \t\n(Ch.\t23),\tdyslipidaemia", "start_char_idx": 0, "end_char_idx": 3445, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8aa2132b-d0c9-4c83-b653-71b316d799ad": {"__data__": {"id_": "8aa2132b-d0c9-4c83-b653-71b316d799ad", "embedding": null, "metadata": {"page_label": "320", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9f7980e6-ef40-45b8-96aa-eef217c39644", "node_type": null, "metadata": {"page_label": "320", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ff3716e815ee4e99772fe0e8535fbd5e3e91c0b7dc84d4e2eb82c17bd988e9a"}, "2": {"node_id": "591b2554-9a04-4264-9a54-e2696fff63ec", "node_type": null, "metadata": {"page_label": "320", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b620c57e4550855d8f21cb16808002a64f740a8f5d317e8206bf7971887e63c2"}}, "hash": "9872d8626e3d0e8b0aefd28d304547e6421194f42f3898ff7152fd396530dbc0", "text": "\tinclude \thypertension \t\n(Ch.\t23),\tdyslipidaemia \t(this \tchapter) \tand \tsmoking \t(Ch. \t\n50).\n\u2022\tThe\tpathophysiology \tis \tof \tchronic \tinflammation \tin \t\nresponse\tto \tinjury. \tEndothelial \tdysfunction \tleads \tto \t\nloss of protective mechanisms, monocyte/macrophage \nand\tT-cell \tmigration, \tuptake \tof \tlow-density \tlipoprotein \t\n(LDL) cholesterol and its oxidation, uptake of oxidised LDL by macrophages, smooth muscle cell migration and proliferation, and deposition of collagen.\n\u2022\tPlaque\trupture \tleads \tto \tplatelet \tactivation \tand \t\nthrombosis \t(Ch. \t25) \twith \tthe \tpotential \tto \tcause \t\ndownstream infarction of, for example, heart muscle or brain.\nProportion alive\n0.000.800.850.900.951.00\n6 5 4 3 2 1 0\nYears since randomisationp = 0.0003PlaceboSimvastatin\nFig. 24.2 Survival in patients with coronary heart disease \nand serum cholesterol 5.5\u20138.0 mmol/L treated either with \nplacebo or with simvastatin. \tThe\trelative \trisk \tof \tdeath \tin \tthe \t\nsimvastatin group was 0.70 (95% confidence intervals 0.58\u2013\n0.85). (Based on 4S Study, 1994. Lancet 344, 1383\u20131389.)LIPID-LOWERING DRUGS\nSeveral drugs decrease plasma lipoprotein concentrations. \nDrug therapy is used in addition to dietary measures and \ncorrection of other modifiable cardiovascular risk factors.\nThe main agents used clinically are:\n\u2022\tstatins: \t3-hydroxy-3-methylglutaryl-coenzyme \tA \t\n(HMG-CoA) reductase inhibitors\n\u2022\tPCSK9 \tinhibitors\n\u2022\tfibrates\n\u2022\tinhibitors \tof \tcholesterol \tabsorption\n\u2022\tnicotinic \tacid \tor \tits \tderivatives\nSTATINS: HMG-COA REDUCTASE INHIBITORS\nThe rate-limiting enzyme in cholesterol synthesis is HMG-CoA \nreductase, which catalyses the conversion of HMG-CoA to \nmevalonic acid (see Fig. 24.1). Simvastatin, lovastatin and \npravastatin are specific, reversible, competitive HMG-CoA \nreductase inhibitors with K i values of approximately \n1 nmol/L. Atorvastatin and rosuvastatin are long-lasting mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3397, "end_char_idx": 5768, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ff885003-9c67-451c-bbe8-223a505f745f": {"__data__": {"id_": "ff885003-9c67-451c-bbe8-223a505f745f", "embedding": null, "metadata": {"page_label": "321", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "730e17c9-c104-432f-aeb9-78e71b942c2d", "node_type": null, "metadata": {"page_label": "321", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2b3f3a4ba1e6b6864ade13872a3a0611307e42e8ed98a277fd2b328bde8d0f33"}, "3": {"node_id": "7a0876d5-265a-4fb5-8964-478ce5bdbb80", "node_type": null, "metadata": {"page_label": "321", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b8aae94340eb37bd5394ffd61f10b35ab2bc9fcd9ba7b52dc3aaa96de638f13"}}, "hash": "ed2e873329ad85d6ae066a5057e0346e7a3172a8326104c5c659bbf322394ba0", "text": "24 AThEROSC lEROSIS AND l I p O p ROTEIN META b O l ISM\n315PROPROTEIN CONVERTASE SUBTILISIN/KEXIN \nTYPE-9 (PCSK9) INHIBITORS\nPCSK9 is synthesised in inactive form by many tissues, \nincluding brain and liver. It is activated autocatalytically \nby proteolytic cleavage, which removes a section of its \npeptide chain that blocks its activity. When activated, it binds to LDL receptors and promotes their lysosomal \ndegradation following LDL uptake into hepatocyte cyto -\nplasm (see Fig. 24.1), thereby preventing recycling of LDL \nreceptors to the surface membrane and diminishing their \nability to sequester LDL. Family members who inherit a \nhyperactive form of the PCSK9 gene suffer from severe hypercholesterolaemia; conversely individuals with inac-tivating mutations in this gene have low circulating LDL \nand a low incidence of atheromatous disease. Individuals \nhomozygous for inactivated PCSK9 have very low plasma concentrations of LDL and are healthy. This encouraged \nthe development of monoclonal antibodies that block PCSK9, \nthereby preventing it from combining with LDL receptors and marking them down for lysosomal destruction. Evo-\nlocumab and alirocumab are now licensed in the United \nStates and Europe for the treatment of primary hypercho-lesterolaemia in patients whose circulating LDL is not \nadequately controlled by a statin or statin/ezetimibe \ncombination, as additional agents (or given alone to patients who do not tolerate treatment with a statin). Evolocumab \nis administered subcutaneously every 2\u20134 weeks, alirocumab \nevery 2 weeks. Nasopharyngitis and influenza-like symp -\ntoms are common adverse effects of both agents. Other \nagents that work by inhibiting this pathway, for example, \na small interfering RNA that causes long-lasting block of PCSK9 synthesis, are also being developed.\nFIBRATES\nSeveral fibric acid derivatives (fibrates) are available, includ -\ning bezafibrate, ciprofibrate, gemfibrozil, fenofibrate and \nclofibrate .\tThese\tmarkedly \treduce \tcirculating \tVLDL, \tand \t\nhence triglyceride, with a modest (approximately 10%) reduction in LDL and an approximately 10% increase in \nHDL. Their mechanism of action is complex (see Fig. 24.1). \nThey are agonists at PPAR \u03b1 nuclear receptors\n5 (Ch. 3); in \nhumans, the main effects are to increase transcription of the genes for lipoprotein lipase, apoA1 and apoA5. They \nincrease hepatic LDL uptake. In addition to effects on lipoproteins, fibrates reduce plasma C-reactive protein and \nfibrinogen, improve glucose tolerance and inhibit vascular \nsmooth muscle inflammation by inhibiting the expression of the transcription factor nuclear factor \u03baB (see Ch. 3). The \nrelative importance of these effects is uncertain, and fibrates have not been demonstrated to improve survival.\nAdverse effects\nRhabdomyolysis is unusual but severe, giving rise to acute renal failure associated with excretion of muscle proteins, \nespecially myoglobin, by the kidney. It occurs particularly \nin patients with renal impairment, because of reduced protein binding and impaired drug elimination. Fibrates \nshould be avoided in such patients and also in alcoholics, pregnancy), but some offer therapeutic promise. Such potentially beneficial actions include:\n\u2022\timproved \tendothelial \tfunction\n\u2022\treduced \tvascular \tinflammation\n\u2022\treduced \tplatelet \taggregability\n\u2022\tincreased \tneovascularisation \tof \tischaemic \ttissue\n\u2022\tincreased \tcirculating", "start_char_idx": 0, "end_char_idx": 3419, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a0876d5-265a-4fb5-8964-478ce5bdbb80": {"__data__": {"id_": "7a0876d5-265a-4fb5-8964-478ce5bdbb80", "embedding": null, "metadata": {"page_label": "321", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "730e17c9-c104-432f-aeb9-78e71b942c2d", "node_type": null, "metadata": {"page_label": "321", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2b3f3a4ba1e6b6864ade13872a3a0611307e42e8ed98a277fd2b328bde8d0f33"}, "2": {"node_id": "ff885003-9c67-451c-bbe8-223a505f745f", "node_type": null, "metadata": {"page_label": "321", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed2e873329ad85d6ae066a5057e0346e7a3172a8326104c5c659bbf322394ba0"}}, "hash": "8b8aae94340eb37bd5394ffd61f10b35ab2bc9fcd9ba7b52dc3aaa96de638f13", "text": "\tof \tischaemic \ttissue\n\u2022\tincreased \tcirculating \tendothelial \tprogenitor \tcells\n\u2022\tstabilisation \tof \tatherosclerotic \tplaque\n\u2022\tantithrombotic \tactions\n\u2022\tenhanced \tfibrinolysis\nThe extent to which these effects contribute to the anti-\natheromatous actions of statins is unknown.\nPharmacokinetics\nShort-acting statins are given by mouth at night to reduce peak cholesterol synthesis in the early morning. They are \nwell absorbed and extracted by the liver, their site of action, \nand are subject to extensive presystemic metabolism via cytochrome P450 and glucuronidation pathways. Simvastatin \nis an inactive lactone prodrug; it is metabolised in the liver \nto its active form, the corresponding \u03b2-hydroxy fatty acid.\nAdverse effects\nStatins are well tolerated; mild unwanted effects include muscle pain (myalgia), gastrointestinal disturbance, raised \nconcentrations of liver enzymes in plasma, insomnia and \nrash. More serious adverse effects are rare but include skeletal muscle damage (myositis, which when severe is \ndescribed as rhabdomyolysis) and angio-oedema. Myositis \nis a class effect of statins, occurring also with other lipid-lowering drugs (especially fibrates), and is dose-related.\n4\n It is more common in patients with low lean body mass or uncorrected hypothyroidism.\n4Cerivastatin, a potent statin introduced at relatively high dose, was \nwithdrawn because of rhabdomyolysis occurring particularly in patients \ntreated with gemfibrozil \u2013 discussed later in the chapter.5Standing for peroxisome proliferator-activated receptors \u2013 don\u2019t ask! \n(Peroxisomes are organelles that are not present in human cells, so something of a misnomer!) Thiazolidinedione drugs used in treating \ndiabetes act on related PPAR\u03b3 receptors; see Ch. 31.Clinical uses of HMG-CoA \nreductase inhibitors (statins, e.g. \nsimvastatin, atorvastatin) \n\u2022\tSecondary \tprevention \tof \tmyocardial \tinfarction \tand \t\nstroke in patients who have symptomatic atherosclerotic \ndisease (e.g. angina, transient ischaemic attacks, or following myocardial infarction or stroke).\n\u2022\tPrimary \tprevention \tof \tarterial \tdisease \tin \tpatients \twho \t\nare at high risk because of elevated serum cholesterol concentration, especially if there are other risk factors \nfor\tatherosclerosis \tsuch \tas \tdiabetes \t(Ch. \t32) \tor \trenal \t\nfailure\t(Ch. \t30). \tTables \t(available, \tfor \texample, \tin \tthe \t\nBritish National Formulary) are used to target treatment to those at greatest risk.\n\u2022\tAtorvastatin lowers serum cholesterol in patients with \nhomozygous familial hypercholesterolaemia.\n\u2022\tIn\tsevere \tdrug-resistant \tdyslipidaemia \t(e.g. \t\nheterozygous familial hypercholesterolaemia), \nezetimibe, which inhibits cholesterol absorption (see p. 316), is combined with statin treatment.\n\u2022\tContraindicated \tin \tpregnancy.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3372, "end_char_idx": 6630, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4af2333e-e4a0-4049-9fd4-002726170a55": {"__data__": {"id_": "4af2333e-e4a0-4049-9fd4-002726170a55", "embedding": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1b5f4d8-42d0-49f8-ba79-b40d14458f26", "node_type": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ee1cc173ef9d2e61939b8b3911f8c3f9c3766aec7a22ec40eeebf82f7a310a7e"}, "3": {"node_id": "28538dba-58a0-4933-9c1e-cc3195e882f7", "node_type": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2dd6475b9061fc43feb662d717e6bbe91e372d930b86be8e0f450daba75ef24d"}}, "hash": "a743f06834ff65f8dae38d3210f402f12e5a7e7a5f6d4d161ff3f0657692e669", "text": "24 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n316have been marketed; these are isolated from wood pulp and used to \nmake margarines or yoghurts. They reduce plasma cholesterol to a \nsmall extent and are tastier than resins. Phytosterol and phytostanol \nesters interfere with the micellar presentation of sterols to the enterocyte surface, reducing cholesterol absorption and hence the exogenous \npathway.\nEZETIMIBE\nEzetimibe is one of a group of azetidinone cholesterol \nabsorption inhibitors, and is used as an adjunct to diet and \nstatins in hypercholesterolaemia. It inhibits absorption of \ncholesterol (and of plant stanols) from the duodenum by blocking a transport protein (NPC1L1) in the brush border \nof enterocytes, without affecting the absorption of fat-soluble \nvitamins, triglycerides or bile acids. Because of its high \npotency compared with resins (a daily dose of 10 mg), it \nrepresents a useful advance as a substitute for resins as supplementary treatment to statins in patients with severe \ndyslipidaemia.\nEzetimibe is administered by mouth and is absorbed \ninto intestinal epithelial cells, where it localises to the brush border, which is its presumed site of action. It is also \nextensively (>80%) metabolised to an active metabolite. Enterohepatic recycling results in slow elimination. The \nterminal half-life is approximately 22 h. It enters milk (at \nleast in animal studies) and is contraindicated for women who are breastfeeding. It is generally well tolerated but \ncan cause diarrhoea, abdominal pain or headache; rash \nand angio-oedema have been reported.\nDRUGS THAT INHIBIT CHOLESTEROL \nABSORPTION\nHistorically, bile acid-binding resins (e.g. colestyramine, \ncolestipol) were the only agents available to reduce cho -\nlesterol absorption and were among the few means to lower \nplasma cholesterol. Taken by mouth they sequester bile acids in the intestine and prevent their reabsorption and \nenterohepatic recirculation (see Fig. 24.1). The concentration \nof HDL is unchanged, and they cause an unwanted increase in triglycerides.\n\u25bc The American Lipid Research Clinics\u2019 trial of middle-aged men \nwith primary hypercholesterolaemia showed that addition of a resin \nto dietary treatment caused a fall in plasma cholesterol and a 20%\u201325% \nfall in coronary heart disease over 7 years, but no studies have shown \nimproved survival.\nDecreased absorption of exogenous cholesterol and increased \nmetabolism of endogenous cholesterol into bile acids in the liver lead to increased expression of LDL receptors on hepatocytes, and hence \nto increased clearance of LDL from the blood and a reduced concentra-\ntion of LDL in plasma. Resins are bulky, unpalatable and often cause diarrhoea. They interfere with the absorption of fat-soluble vitamins, \nand of thiazide diuretics (Ch 30), digoxin (Ch. 22) and warfarin (Ch. \n25), which should therefore be taken at least 1 h before or 4\u20136 h after \nthe resin. With the introduction of statins, their use in treating dys -\nlipidaemia was relegated largely to additional treatment in patients with severe disease (e.g. FH) and (a separate use) treating bile salt-\nassociated symptoms of pruritus (itch) and diarrhoea \u2013 see clinical box below. Colesevelam is available in tablet form and less bulky \n(daily dose up to 4 g compared with a dose up to 36 g for colesty -\nramine) but more", "start_char_idx": 0, "end_char_idx": 3361, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "28538dba-58a0-4933-9c1e-cc3195e882f7": {"__data__": {"id_": "28538dba-58a0-4933-9c1e-cc3195e882f7", "embedding": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1b5f4d8-42d0-49f8-ba79-b40d14458f26", "node_type": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ee1cc173ef9d2e61939b8b3911f8c3f9c3766aec7a22ec40eeebf82f7a310a7e"}, "2": {"node_id": "4af2333e-e4a0-4049-9fd4-002726170a55", "node_type": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a743f06834ff65f8dae38d3210f402f12e5a7e7a5f6d4d161ff3f0657692e669"}, "3": {"node_id": "d8ef4850-8336-42be-832b-52f9abd737e2", "node_type": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50fcf4bf701966a9b1f0e4077b924d5d9831ca6045d1033cc974b4f2fb6ad9ee"}}, "hash": "2dd6475b9061fc43feb662d717e6bbe91e372d930b86be8e0f450daba75ef24d", "text": "compared with a dose up to 36 g for colesty -\nramine) but more expensive. Subsequently, plant sterols and stanols \n6For several reasons, including a tendency to lie immobile for prolonged \nperiods followed by generalised convulsions \u2013 \u2018rum fits\u2019 \u2013 and delirium \ntremens.who are predisposed to hypertriglyceridaemia but are at \nrisk of severe muscle inflammation and injury.6 Rhabdo-\nmyolysis can also be caused (rarely) by statins (see p. 315), \nand the combined use of fibrates with this class of drugs \nis therefore generally inadvisable (although it is sometimes undertaken by specialists). Gastrointestinal symptoms, \npruritus and rash are more common than with statins. \nClofibrate predisposes to gallstones, and its use is therefore limited to patients who have had a cholecystectomy (i.e. \nremoval of the gall bladder).\nNICOTINIC ACID\n\u25bc Nicotinic acid is a vitamin, and as such is essential for many \nimportant metabolic processes. Quite separately from this, it has been \nused in gram quantities as a lipid-lowering agent. It is converted to \nnicotinamide, \twhich \tinhibits \thepatic \tVLDL \tsecretion \t(see \tFig. \t24.1), \t\nwith consequent reductions in circulating triglyceride and LDL including Lp(a), and an increase in HDL. The mechanism is believed \nto be initiated by an effect on lipolysis via a G protein\u2013coupled niacin \nreceptor called HM74A and present in adipocyte membranes. Adverse effects include flushing, palpitations and gastrointestinal disturbance. \nDisappointingly, addition of nicotinic acid to a statin does not improve \ncardiovascular outcome, but does increase serious adverse effects \n(HSP2-THRIVE \ttrial), \tand \tclinical \tuse \tis \tdwindling.\nFISH OIL DERIVATIVES\n\u25bc Omega-3 marine triglycerides reduce plasma triglyceride concentra -\ntions but increase cholesterol. They are no longer generally recom -\nmended in clinical practice due to an absence of clinical benefit.Clinical uses of fibrates (e.g. \ngemfibrozil, fenofibrate) \n\u2022\tMixed\tdyslipidaemia \t(i.e. \traised \tserum \ttriglyceride \tas \t\nwell as cholesterol), provided this is not caused by \nexcessive alcohol consumption. Fenofibrate is \nuricosuric, which may be useful where hyperuricaemia \ncoexists with mixed dyslipidaemia.\n\u2022\tIn\tpatients \twith \tlow \thigh-density \tlipoprotein \tand \thigh \t\nrisk\tof\tatheromatous \tdisease \t(often \ttype \t2 \tdiabetic \t\npatients;\tsee \tCh. \t32).\n\u2022\tCombined \twith \tother \tlipid-lowering \tdrugs \tin \tpatients \t\nwith\tsevere \ttreatment-resistant \tdyslipidaemia. \tThis \t\nmay, however, increase the risk of rhabdomyolysis.\nClinical use of drugs that reduce \ncholesterol absorption: ezetimibe \nor bile acid-binding resins (e.g. colestyramine, colesevelam) \n\u2022\tAs\tan\taddition \tto \ta \tstatin \twhen \tresponse \thas \tbeen \t\ninadequate (ezetimibe).\n\u2022\tFor\thypercholesterolaemia \twhen \ta \tstatin \tis \t\ncontraindicated.\n\u2022\tUses\tunrelated \tto \tatherosclerosis, \tincluding:\n\u2013 pruritus in patients with partial biliary obstruction \n(bile acid-binding resin)\n\u2013 bile acid diarrhoea, for example, caused by diabetic \nneuropathy (bile acid-binding resin).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3312, "end_char_idx": 6423, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d8ef4850-8336-42be-832b-52f9abd737e2": {"__data__": {"id_": "d8ef4850-8336-42be-832b-52f9abd737e2", "embedding": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1b5f4d8-42d0-49f8-ba79-b40d14458f26", "node_type": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ee1cc173ef9d2e61939b8b3911f8c3f9c3766aec7a22ec40eeebf82f7a310a7e"}, "2": {"node_id": "28538dba-58a0-4933-9c1e-cc3195e882f7", "node_type": null, "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2dd6475b9061fc43feb662d717e6bbe91e372d930b86be8e0f450daba75ef24d"}}, "hash": "50fcf4bf701966a9b1f0e4077b924d5d9831ca6045d1033cc974b4f2fb6ad9ee", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6426, "end_char_idx": 6889, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7bc18bbf-a096-43ff-a9e1-59688f94bf77": {"__data__": {"id_": "7bc18bbf-a096-43ff-a9e1-59688f94bf77", "embedding": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4bf6d629-b2b7-428c-b085-2caf7b0f84e4", "node_type": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "395b986762b76a08712656dcc2b9046b013c8a1b2a5c16d08563db2e359ac3a7"}, "3": {"node_id": "f3b90126-0ad6-491b-b47e-b98be8f364e7", "node_type": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "290950e0b1a7bce1df121a4b2feb5e31e937b5612ef478d80dfa63c379948426"}}, "hash": "abecd6cb962e1f6fb1c137c9104c9fce3349a5053504b9bcff5907b665015ed8", "text": "24 AThEROSClEROSIS AND lIpOpROTEIN METAbOlISM\n317REFERENCES AND FURTHER READING\nAtherosclerosis and dyslipidaemia\nBrown, M.S., Goldstein, J.L., 1986. A receptor-mediated pathway for \ncholesterol homeostasis. Science 232, 34\u201347. ( Classic from these Nobel \nPrize winners; see also Goldstein, J.L., Brown, M.S., 1990. Regulation of the \nmevalonate pathway. Nature 343, 425\u2013430 )\nDurrington, P.N., 2007. Hyperlipidaemia: Diagnosis and Management, \nthird ed. Hodder Arnold, London. ( Extremely readable, authoritative \nbook)\nHall, S.H., 2013. Genetics: a gene of rare effect. Nature 496, 152\u2013155. \n(News feature describing the PCSK9 story as an example of a new paradigm \nfor translational research )\nRoss, R., 1999. Atherosclerosis \u2013 an inflammatory disease. N. Engl. J. \nMed. 340, 115\u2013126.\nStein, O., Stein, Y., 2005. Lipid transfer proteins (LTP) and \natherosclerosis. Atherosclerosis 178, 217\u2013230. ( Lipid transfer proteins \n\u2013 ACAT, CETP, LCAT and PLTP \u2013 and the therapeutic potential of \nmodulating them )\nStatins\nHague, W., Emberson, J., Ridker, P.M., 2001. For the Air Force/Texas \nCoronary Atherosclerosis Prevention Study Investigators. \nMeasurement of C-reactive protein for the targeting of statin therapy \nin the primary prevention of acute events. N. Engl. J. Med. 344, \n1959\u20131965. ( Statins may be effective in preventing coronary events in people \nwith unremarkable serum lipid concentrations but with elevated C-reactive \nprotein, a marker of inflammation and risk factor for coronary disease )\nLiao, J.K., Laufs, U., 2005. Pleiotropic effects of statins. Annu. Rev. \nPharmacol. Toxicol. 45, 89\u2013118. ( \u2018Many pleiotropic effects are mediated by \ninhibition of isoprenoids, which serve as lipid attachments for intracellular \nsignalling molecules. In particular, inhibition of small GTP-binding proteins, \nRho, Ras, and Rac, whose proper membrane localisation and function are dependent on isoprenylation, may play an important role in mediating the \npleiotropic effects of statins\u2019 )\nMerx, M.W., Liehn, E.A., Graf, J., et al., 2005. Statin treatment after \nonset of sepsis in a murine model improves survival. Circulation 112, \n117\u2013124. ( Statins offer the potential of effective sepsis treatment )\nVan\tDoren,\tM.,\tBroihier,\t H.T.,\tMoore,\tL.A.,\tet\tal.,\t1998.\tHMG-CoA\t\t\nreductase guides migrating primordial germ cells. Nature 396, \n466\u2013469. ( Regulated expression of HMG-CoA reductase provides spatial \nguide to migrating primordial germ cells )\nVasa,\tM.,\tFichtlscherer,\t S.,\tAdler,\tK.,\tet\tal.,\t2001.\tIncrease\t in\tcirculating\t\nendothelial progenitor cells by statin therapy in patients with stable \ncoronary artery disease. Circulation 103, 2885\u20132890. ( May participate in \nrepair after ischaemic injury )\nOther therapies\nNicotinic acid\nCanner, P.L., Furberg, C.D., Terrin, M.L., et al., 2005. Benefits of niacin \nby glycemic status in patients with healed myocardial infarction (from \nthe Coronary Drug Project). Am. J. Cardiol. 95, 254\u2013257. ( The Coronary \nDrug Project, conducted during 1966 to", "start_char_idx": 0, "end_char_idx": 3007, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f3b90126-0ad6-491b-b47e-b98be8f364e7": {"__data__": {"id_": "f3b90126-0ad6-491b-b47e-b98be8f364e7", "embedding": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4bf6d629-b2b7-428c-b085-2caf7b0f84e4", "node_type": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "395b986762b76a08712656dcc2b9046b013c8a1b2a5c16d08563db2e359ac3a7"}, "2": {"node_id": "7bc18bbf-a096-43ff-a9e1-59688f94bf77", "node_type": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "abecd6cb962e1f6fb1c137c9104c9fce3349a5053504b9bcff5907b665015ed8"}, "3": {"node_id": "a40278a1-ad22-4b65-a198-52cbe11ef39b", "node_type": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b6746f8dafaedab58d1f89c5a8546c125b1307215deb9a6a4397b28c6b917d9d"}}, "hash": "290950e0b1a7bce1df121a4b2feb5e31e937b5612ef478d80dfa63c379948426", "text": "95, 254\u2013257. ( The Coronary \nDrug Project, conducted during 1966 to 1974, was a randomised, \ndouble-blind, placebo-controlled trial in 8341 men with previous myocardial \ninfarction; nicotinic acid significantly reduced total mortality during 6.2 \nyears\u2019 treatment plus an additional 9 years of post-trial follow-up )\nHPS2-THRIVE\t Collaborative\t Group,\t2013.\tHPS2-THRIVE\t randomized\t\nplacebo-controlled trial in 25 673 high-risk patients of ER niacin/\nlaropiprant: trial design, pre-specified muscle and liver outcomes, and \nreasons for stopping study treatment. Eur. Heart J. 34, 1279\u20131291.\nFibrates\nBloomfield\t Rubins,\tH.,\tDavenport,\t J.,\tBabikian,\t V.,\tet\tal.,\t2001.\t\nReduction in stroke with gemfibrozil in men with coronary heart MIPOMERSEN\nMipomersen is approved in the United States but not, at \nthe time of writing, in Europe, for the \u2018orphan\u2019 indication \nof homozygous FH. It is an antisense oligonucleotide \ncomplementary to the coding region for apoB-100 of mRNA, \nwhich thereby inhibits synthesis of apoB-100 and LDL. \nChemical modifications (see Ch. 5) make mipomersen \nresistant to degradation by nucleases, allowing it to be \nadministered once weekly, as an adjunct to other treatment \nfor homozygous FH. It accumulates in the liver, which is \nthe site of its intended action but also of toxicity \u2013 hepato -\ntoxicity being a serious problem that limits its use and \nnecessitates careful monitoring. Other adverse effects include \nflu-like symptoms and oedema.LOMITAPIDE\nLomitapide has also recently been approved as an adjunct \nto other treatment for homozygous FH. It is a small molecule \ninhibitor of MTP. MTP plays a key role in the assembly \nand release of apoB-containing lipoproteins into the circula -\ntion and inhibition of this protein significantly lowers plasma \nlipid levels. This action contrasts with other lipid-lowering \ndrugs, which mainly work by increasing LDL uptake rather \nthan by reducing hepatic lipoprotein secretion. Lomitapide \nis administered orally once a day and the dose individu -\nalised according to how it is tolerated. Gastrointestinal \ndisturbances are common.\nDrugs in dyslipidaemia \nThe\tmain\tdrugs\tused\tin\tpatients\twith\tdyslipidaemias\t are:\n\u2022\tHMG-CoA\t reductase\t inhibitors\t (statins,\te.g.\t\nsimvastatin ): inhibit synthesis of cholesterol, increasing \nexpression of low-density lipoprotein (LDL) receptors on \nhepatocytes and hence increasing hepatic LDL \ncholesterol\t (LDL-C)\tuptake.\tThey\treduce\tcardiovascular\t\nevents and prolong life in people at risk, and clinically are \nthe most important class of drugs used in \ndyslipidaemias. Adverse effects include myalgias (rarely, \nsevere muscle damage) and raised liver enzymes.\n\u2022\tFibrates\t (e.g.\t gemfibrozil ): activate PPAR \u03b1 receptors, \nincrease activity of lipoprotein lipase, decrease hepatic \nvery-low-density lipoprotein production and enhance \nclearance\t of\tLDL\tby\tthe\tliver.\tThey\tmarkedly\t lower\tserum triglycerides, and modestly increase high-density \nlipoprotein cholesterol. Adverse effects include muscle \ndamage.\n\u2022\tAgents\t that\tinterfere\twith\tcholesterol\t absorption,\t usually\t\nas an adjunct to diet plus statin:\n\u2013 ezetimibe\n\u2013 stanol-enriched foods\n\u2013 bile acid-binding", "start_char_idx": 2951, "end_char_idx": 6135, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a40278a1-ad22-4b65-a198-52cbe11ef39b": {"__data__": {"id_": "a40278a1-ad22-4b65-a198-52cbe11ef39b", "embedding": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4bf6d629-b2b7-428c-b085-2caf7b0f84e4", "node_type": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "395b986762b76a08712656dcc2b9046b013c8a1b2a5c16d08563db2e359ac3a7"}, "2": {"node_id": "f3b90126-0ad6-491b-b47e-b98be8f364e7", "node_type": null, "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "290950e0b1a7bce1df121a4b2feb5e31e937b5612ef478d80dfa63c379948426"}}, "hash": "b6746f8dafaedab58d1f89c5a8546c125b1307215deb9a6a4397b28c6b917d9d", "text": "ezetimibe\n\u2013 stanol-enriched foods\n\u2013 bile acid-binding resins (e.g. colestyramine, \ncolesevelam).\n\u2022\tMipomersen , lomitapide , alirocumab and \nevolocumab are used as adjuncts in treating patients \nwith the rare homozygous form of familial \nhypercholesterolaemia.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6139, "end_char_idx": 6880, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b7f66bcf-28df-49b9-85f9-2032fe28ff05": {"__data__": {"id_": "b7f66bcf-28df-49b9-85f9-2032fe28ff05", "embedding": null, "metadata": {"page_label": "324", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "33fc2948-9abf-49d5-a6cf-423e0c7730fa", "node_type": null, "metadata": {"page_label": "324", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0ddbd2b526fb26b09ee87a64dbeff65e4c6ebe96afa248f4e047a824cc6de6e6"}, "3": {"node_id": "9c9b14bc-bb91-4322-9434-5ec947beda43", "node_type": null, "metadata": {"page_label": "324", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "78a015d499bccc4383c202116ce6c0fc3682fd143b851a115eec4e284e04e7c2"}}, "hash": "887e6e9181ba3b903d33b3dc596c593c0655b2de8875044a19b99535a2af9066", "text": "24 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n318patients with homozygous familial hypercholesterolaemia: a \nsingle-arm, open-label, phase 3 study. Lancet 381, 40\u201346. ( See also \naccompanying editorial: Raal, F.J., pp. 7\u20138 )\nMipomersen\nMerki, E., Graham, M.J., Mullick, A.E., 2008. Antisense oligonucleotide \ndirected to human apolipoprotein B-100 reduces lipoprotein(a) levels \nand oxidized phospholipids on human apolipoprotein B-100 particles \nin lipoprotein(a) transgenic mice. Circulation 118, 743\u2013753.\nPotential therapies\nde Medina, P., Payr\u00e1, B.L., Bernad, J., et al., 2004. Tamoxifen is a potent \ninhibitor of cholesterol esterification and prevents the formation of \nfoam cells. J. Pharmacol. Exp. Ther. 308, 1542\u20131548. ( Molecular \nmodelling revealed similarity between tamoxifen and ACAT inhibitor )\nIkenaga, M., Higaki, Y., Saku, K., 2016. High-density lipoprotein \nmimetics: a therapeutic tool for atherosclerotic diseases. J. Atheroscler. \nThromb. 23, 385\u2013394. ( HDL therapies including reconstituted HDL, \napolipoprotein (Apo) A-IMilano, ApoA-I mimetic peptides, or full-length \nApoA-I, are highly effective in animal models. The ApoA-I-mimetic peptide \nFAMP enhances the function of HDL without elevating HDL cholesterol )disease\tand\tlow\tHDL\tcholesterol.\t The\tVeterans\t Affairs\tHDL\t\nIntervention\t Trial\t(VA-HIT).\t Circulation\t 103,\t2828\u20132833.\t (Evidence that \nincreasing HDL reduces stroke )\nGervois, P., Torra, I.P., Fruchart, J.C., et al., 2000. Regulation of lipid \nand lipoprotein metabolism by PPAR activators. Clin. Chem. Lab. \nMed. 38, 3\u201311. ( Review )\nFish oil\nGISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della \nSopravivenza nell\u2019Infarto Miocardico), 1999. Dietary supplementation \nwith n-3 polyunsaturated fatty acids and vitamin E after myocardial \ninfarction: results of the GISSI-Prevenzione trial. Lancet 354, 447\u2013455. \n(11,324 patients surviving myocardial infarction were randomly assigned \nsupplements of n-3 PUFA, 1 g daily, vitamin E, both or neither for 3.5 \nyears. The primary end point was death, non-fatal myocardial infarction and \nstroke combined. Dietary supplementation with n-3 PUFA led to a clinically \nimportant and statistically significant benefit. Vitamin E had no benefit )\nEzetimibe\nKosoglou, T., Statkevich, P., Johnson-Levonas, A.O., et al., 2005. \nEzetimibe \u2013 a review of its metabolism, pharmacokinetics and drug \ninteractions. Clin. Pharmacokinet. 44, 467\u2013494.\nLomitapide\nCuchel, M., Meagher, E.A., du Toit Theron, H., et al., 2013. Efficacy and \nsafety of a microsomal triglyceride transfer protein inhibitor in mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2879, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9c9b14bc-bb91-4322-9434-5ec947beda43": {"__data__": {"id_": "9c9b14bc-bb91-4322-9434-5ec947beda43", "embedding": null, "metadata": {"page_label": "324", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "33fc2948-9abf-49d5-a6cf-423e0c7730fa", "node_type": null, "metadata": {"page_label": "324", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0ddbd2b526fb26b09ee87a64dbeff65e4c6ebe96afa248f4e047a824cc6de6e6"}, "2": {"node_id": "b7f66bcf-28df-49b9-85f9-2032fe28ff05", "node_type": null, "metadata": {"page_label": "324", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "887e6e9181ba3b903d33b3dc596c593c0655b2de8875044a19b99535a2af9066"}}, "hash": "78a015d499bccc4383c202116ce6c0fc3682fd143b851a115eec4e284e04e7c2", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2848, "end_char_idx": 3071, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "674a7eb3-bdaa-4bac-9e7a-b2197c7c737f": {"__data__": {"id_": "674a7eb3-bdaa-4bac-9e7a-b2197c7c737f", "embedding": null, "metadata": {"page_label": "325", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a989c28f-2bd2-453a-a988-e3622816055b", "node_type": null, "metadata": {"page_label": "325", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e59d4839606d7d9c1f8067312acfd805c0c036cb3ea2dde85ebded0bd5139f47"}, "3": {"node_id": "18e04564-3ed8-43b7-8417-269976978b70", "node_type": null, "metadata": {"page_label": "325", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "958f9efeada066f6caded53c53d7cf0ba31a51a7e0c65035c88ba482b5dab37a"}}, "hash": "bb7a31802937767298e6ab3d692a7e64d6f9b2ed9d404dc8cfd9e16851f84555", "text": "319\nHaemostasis and thrombosis 25 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3 \nOVERVIEW\nThis chapter summarises the main features of blood \ncoagulation, platelet function and fibrinolysis. These \nprocesses underlie haemostasis and thrombosis, and \nprovide a basis for understanding haemorrhagic disorders (e.g. haemophilia) and thrombotic diseases \nboth of arteries (e.g. thrombotic stroke, myocardial \ninfarction) and of veins (e.g. deep vein thrombosis, pulmonary embolism). Anticoagulants, antiplatelet \ndrugs and fibrinolytic drugs are especially important \nbecause of the prevalence of thrombotic disease.\nINTRODUCTION\nHaemostasis is the arrest of blood loss from damaged blood \nvessels and is essential to life. A wound causes vasoconstric -\ntion, accompanied by:\n\u2022\tadhesion \tand \tactivation \tof \tplatelets\n\u2022\tformation \tof \tfibrin\nPlatelet activation leads to the formation of a haemostatic plug, which stops the bleeding and is subsequently rein -\nforced by fibrin. The relative importance of each process depends on the type of vessel (arterial, venous or capillary) that has been injured.\nThrombosis is the pathological formation of a \u2018haemo -\nstatic\u2019 plug within the vasculature in the absence of bleeding (\u2018haemostasis in the wrong place\u2019). Over a century ago, \nRudolph Virchow defined three predisposing factors \u2013 \n\u2018Virchow triad\u2019: injury to the vessel wall \u2013 for example, when \nan atheromatous plaque ruptures or becomes eroded; altered \nblood flow \u2013 for example, in the left atrial appendage of the \nheart during atrial fibrillation, or in the veins of the legs \nwhile sitting awkwardly on a long journey; and abnormal \ncoagulability of the blood \u2013 as occurs, for example, in the \nlater stages of pregnancy or during treatment with certain \noral contraceptives (see Ch. 36). Increased coagulability of the blood can be inherited and is referred to as thrombophilia . \nA thrombus, which forms in vivo, should be distinguished \nfrom a clot, which forms in blood in vitro (for example in a glass tube). Clots are amorphous, consisting of a diffuse \nfibrin meshwork in which red and white blood cells are \ntrapped indiscriminately. By contrast, arterial and venous thrombi each have a distinct structure.\nAn arterial thrombus (Fig. 25.1) is composed of so-called \nwhite thrombus consisting mainly of platelets in a fibrin mesh. It is usually associated with atherosclerosis and can \ninterrupt blood flow, causing ischaemia or death of tissue \n(infarction) downstream. Venous thrombus is composed of \u2018red thrombus\u2019 and consists of a small white head and a large jelly-like red tail, similar in composition to a blood clot, which streams away in the flow. Thrombus can break away from its attachment and float through the circulation, \nforming an embolus; venous emboli usually lodge in a \npulmonary artery (\u2018pulmonary embolism\u2019), while a thrombus that embolises from the left heart or a carotid artery usually \nlodges in an artery in the brain or other organs, causing \ndeath, stroke or other disaster.\nDrug therapy to promote haemostasis (e.g. antifibrinolytic \nand haemostatic drugs; see p. 333) is indicated when this essential process is defective (e.g. defective or missing coagulation factors in haemophilia or following excessive anticoagulant therapy), or when it proves difficult to \nstaunch haemorrhage following surgery or for menor", "start_char_idx": 0, "end_char_idx": 3356, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "18e04564-3ed8-43b7-8417-269976978b70": {"__data__": {"id_": "18e04564-3ed8-43b7-8417-269976978b70", "embedding": null, "metadata": {"page_label": "325", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a989c28f-2bd2-453a-a988-e3622816055b", "node_type": null, "metadata": {"page_label": "325", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e59d4839606d7d9c1f8067312acfd805c0c036cb3ea2dde85ebded0bd5139f47"}, "2": {"node_id": "674a7eb3-bdaa-4bac-9e7a-b2197c7c737f", "node_type": null, "metadata": {"page_label": "325", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bb7a31802937767298e6ab3d692a7e64d6f9b2ed9d404dc8cfd9e16851f84555"}}, "hash": "958f9efeada066f6caded53c53d7cf0ba31a51a7e0c65035c88ba482b5dab37a", "text": "difficult to \nstaunch haemorrhage following surgery or for menor -\nrhagia (heavy menstrual periods). Drug therapy to treat \nor prevent thrombosis or thromboembolism is extensively \nused because such diseases are common as well as serious. \nDrugs affect haemostasis and thrombosis in three distinct ways, by influencing:\n\u2022\tblood\tcoagulation \t(fibrin \tformation)\n\u2022\tplatelet \tfunction\n\u2022\tfibrin\tremoval \t(fibrinolysis)\nBLOOD COAGULATION\nCOAGULATION CASCADE\nBlood coagulation means the conversion of liquid blood to a clot. The main event is the conversion by thrombin of \nsoluble fibrinogen to insoluble strands of fibrin , the last step \nin a complex enzyme cascade. The components (called \nfactors) are present in blood as inactive precursors (zymo -\ngens) of proteolytic enzymes and co-factors. They are activated by proteolysis, the \u2018active\u2019 forms being designated by the suffix \u2018a\u2019. Factors XIIa, XIa, Xa, IXa and thrombin \n(IIa) are all serine proteases. Activation of a small amount \nof one factor catalyses the formation of larger amounts of the next factor, which catalyses the formation of still larger amounts of the next, and so on; consequently, the cascade \nprovides a mechanism of amplification.\n1 As might be \nexpected, this accelerating enzyme cascade has to be controlled by inhibitors, because otherwise all the blood \nin the body would solidify within minutes of the initiation of haemostasis. One of the most important inhibitors is \nantithrombin III, which neutralises all the serine proteases \nin the cascade. Vascular endothelium also actively limits thrombus extension (see pp. 321\u2013322).\nTwo pathways of fibrin formation were described tradition-\nally (termed \u2018intrinsic\u2019 \u2013 because all the components are present in the blood \u2013 and \u2018extrinsic\u2019 \u2013 because some \n1Coagulation of 100 mL of blood requires 0.2 mg of factor VIII, 2 mg of \nfactor X, 15 mg of prothrombin and 250 mg of fibrinogen.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3292, "end_char_idx": 5687, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "026a0272-2484-4c95-83a5-29f11368c5c4": {"__data__": {"id_": "026a0272-2484-4c95-83a5-29f11368c5c4", "embedding": null, "metadata": {"page_label": "326", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "112ad5b0-9110-4c2d-ad3a-b8a2c3f11bd2", "node_type": null, "metadata": {"page_label": "326", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e64192db4a69877a47b6c86def847ffa54397ba6b23071fd68c2a543cdc3269"}, "3": {"node_id": "259788a4-94a0-4a9d-b0f1-fb5fdfc8f4a2", "node_type": null, "metadata": {"page_label": "326", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2a95748b02e8ba4ffbe25490a545d0c9d451d479b71fdebea364460829ceb1c"}}, "hash": "ec05c7c71c0ab7cca4de0794542a994c896d6f0ee3bc2f234149ebbc4bbc35ef", "text": "25 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n320components come from outside the blood). The intrinsic or \n\u2018contact\u2019 pathway is activated when shed blood comes into \ncontact with an artificial surface such as glass, but physiologi -\ncally the system functions as a single in vivo pathway (Fig. \n25.2). Tissue damage exposes blood to tissue factor , initiating \nthe process and leading to production of a small amount of \nthrombin. This acts through several positive feedbacks (on Va, VIIIa and on platelets) that amplify and propagate the \nprocess with production of more thrombin.\n\u25bc \u2018Tissue factor\u2019 is the cellular receptor for factor VII, which, in the \npresence of Ca2+, undergoes an active site transition. This results in \nrapid autocatalytic activation of factor VII to VIIa. The tissue factor\u2013VIIa \ncomplex activates factors IX and X. Acidic phospholipids function \nas surface catalysts . They are provided during platelet activation, which \nexposes acidic phospholipids (especially phosphatidylserine), on the \nplatelets\u2019 outwardly facing membranes, and these activate various \nclotting factors, closely juxtaposing them in functional complexes. Platelets also contribute by secreting coagulation factors, including \nfactor Va and fibrinogen. Coagulation is sustained by further generation \nof factor Xa by IXa\u2013VIIIa\u2013Ca\n2+\u2013phospholipid complex. This is needed \nbecause the tissue factor\u2013VIIa complex is rapidly inactivated in plasma \nby tissue factor pathway inhibitor and by antithrombin III. Factor BLOOD COAGULATION PLATELET REACTIONSExposure of \nacidic \nphospholipids\nSecretion of preformed \nmediators (e.g. ADP) and \nsynthesis of mediators \n(e.g.TXA2, PAF)In vivo pathway \n(tissue factor and \nfactor VIIa)Contact \npathway factors \n(XII & XI)\nFurther aggregation \nof plateletsXX a\nFibrinogen FibrinThrombin IIRupture of atherosclerotic \nplaque in artery\nAdhesion, activation and\naggregation of platelets\nThrombus\nFig. 25.1 The main events in the formation of an arterial thrombus. Exposure of acidic phospholipids during platelet activation \nprovides a surface on which factors IXa and VIIa interact with factor X; factor Xa then interacts with factor II, as illustrated in more detail in \nFig. 25.4. Activation of factor XII also initiates the fibrinolytic pathway, which is shown in Fig. 25.10. (A similar series of events occurs when there is vascular damage, leading to haemostasis.) PAF, platelet-activating factor; TXA\n2, thromboxane A 2. \n2Mr Hageman (the patient deficient in factor XII after whom it was \nnamed) died not from excessive bleeding but from a pulmonary \nembolism: factor XII deficiency does not give rise to a bleeding disorder.Xa, in the presence of Ca2+, phospholipid and factor Va, activates \nprothrombin to thrombin, the main enzyme of the cascade. The contact \n(intrinsic) pathway commences when factor XII (Hageman factor) \nadheres to a negatively charged surface and converges with the in vivo pathway at the stage of factor X activation (see Fig. 25.2). The \nproximal part of this pathway is not crucial for blood coagulation in vivo.\n2 The two pathways are not entirely separate even before they \nconverge, and various positive feedbacks promote coagulation.\nTHE\u2003ROLE \u2003OF \u2003THROMBIN\nThrombin (factor IIa) cleaves fibrinogen, producing frag -\nments that polymerise to form fibrin. It also activates", "start_char_idx": 0, "end_char_idx": 3352, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "259788a4-94a0-4a9d-b0f1-fb5fdfc8f4a2": {"__data__": {"id_": "259788a4-94a0-4a9d-b0f1-fb5fdfc8f4a2", "embedding": null, "metadata": {"page_label": "326", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "112ad5b0-9110-4c2d-ad3a-b8a2c3f11bd2", "node_type": null, "metadata": {"page_label": "326", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e64192db4a69877a47b6c86def847ffa54397ba6b23071fd68c2a543cdc3269"}, "2": {"node_id": "026a0272-2484-4c95-83a5-29f11368c5c4", "node_type": null, "metadata": {"page_label": "326", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ec05c7c71c0ab7cca4de0794542a994c896d6f0ee3bc2f234149ebbc4bbc35ef"}}, "hash": "e2a95748b02e8ba4ffbe25490a545d0c9d451d479b71fdebea364460829ceb1c", "text": "producing frag -\nments that polymerise to form fibrin. It also activates factor \nXIII, a fibrinoligase , which strengthens fibrin-to-fibrin links, \nthereby stabilising the coagulum. In addition to coagulation, \nthrombin also causes platelet aggregation, stimulates cell \nproliferation and modulates smooth muscle contraction. \nParadoxically, it can inhibit as well as promote coagulation (see pp. 321\u2013322). Effects of thrombin on platelets and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3280, "end_char_idx": 4203, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "44515883-28eb-45c9-8fe7-461e7629a000": {"__data__": {"id_": "44515883-28eb-45c9-8fe7-461e7629a000", "embedding": null, "metadata": {"page_label": "327", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4923a796-e907-4efd-b369-3ea1914d91d5", "node_type": null, "metadata": {"page_label": "327", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d890f440dfe0766b7f027e29b4ed6da4cccee58a6280ce22282bc7aa7774486a"}, "3": {"node_id": "608fa92b-01c4-4746-b294-7bdfaeedb194", "node_type": null, "metadata": {"page_label": "327", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e9b53c3fd7a5dcf7bbdd2a7f4e4841ed5901dc6c4ff6229f97d62edfcc0b3f5"}}, "hash": "187d8f4d4a08dfd41d0ce7b8805264044eea00a32db6886f8b5bcea98c41c1c7", "text": "25 HAEMOSTASIS AND THROM b OSIS\n321perhaps angiogenesis. The signal transduction mechanism \nis unusual: receptor activation requires cleavage by thrombin \nof the extracellular N-terminal domain of the receptor, \nrevealing a new N-terminal sequence that acts as a \u2018tethered agonist\u2019 (see Fig. 3.7).\nVASCULAR ENDOTHELIUM IN HAEMOSTASIS \nAND THROMBOSIS\nVascular endothelium, the container of the circulating blood, \ncan change focally from a non-thrombogenic to a throm -\nbogenic structure in response to different demands. Nor-mally, it provides a non-thrombogenic surface by virtue of membrane heparan sulfate, a glycosaminoglycan related \nto heparin, which is, like heparin, a co-factor for antithrom -\nbin III. Endothelium thus plays an essential role in prevent -\ning intravascular platelet activation and coagulation. \nHowever, it also plays an active part in haemostasis, \nsynthesising and storing several key haemostatic compo -\nnents; von Willebrand factor,\n3 tissue factor and plasminogen Fibrinogen Fibrin Stabilised fibrinXIII\nXIIIaCa2+Contact\n(e.g. with glass)\nVa\nPLCa\n2+Tissue factorVIIaPLCa\n2+\nIXXIXII\nVIIIaPLCa\n2+Heparin +\nAT III\nPlateletsExtrinsic pathway Intrinsic pathway\nII (Prothrombin)XIIa\nXIa\nIXa\nXa\nIIa (Thrombin)XTissue damage\nLMWHs +\nRivaroxaban\nHirudins +\nDabigatran etexilate\nFig. 25.2 The coagulation cascade: sites of action of anticoagulant drugs. Oral anticoagulants interfere with post-translational \n\u03b3-carboxylation of factors II, VII, IX and X (shown in blue boxes) ; see Fig. 25.4. Heparins activate antithrombin III. AT III, antithrombin III; \nLMWHs, low molecular-weight heparins; PL, negatively charged phospholipid supplied by activated platelets. \nHaemostasis and thrombosis \n\u2022\tHaemostasis \tis \tthe \tarrest \tof \tblood \tloss \tfrom \tdamaged \t\nvessels and is essential to survival. The main \nphenomena are:\n\u2013 platelet adhesion and activation\n\u2013 blood coagulation (fibrin formation)\n\u2022\tThrombosis \tis \ta \tpathological \tcondition \tresulting \tfrom \t\ninappropriate activation of haemostatic mechanisms:\n\u2013 venous thrombosis is usually associated with stasis \nof blood; a venous thrombus has a small platelet component and a large component of fibrin.\n\u2013 arterial thrombosis is usually associated with \natherosclerosis, and the thrombus has a large platelet component.\n\u2022\tA\tportion \tof \ta \tthrombus \tmay \tbreak \taway, \ttravel \tas \tan \t\nembolus and lodge downstream, causing ischaemia and/or infarction.\n3von Willebrand factor is a glycoprotein that is missing in a hereditary \nhaemorrhagic disorder called von Willebrand disease, which is the most \ncommon of the inherited bleeding disorders. It is synthesised by \nvascular endothelial cells (the presence of immunoreactive von Willebrand factor is an identifying feature of these cells in culture) and \nis also present in platelets.smooth muscle are initiated by interaction with specific \nprotease-activated receptors (PARs; see Ch. 3), which belong \nto the superfamily of G protein\u2013coupled receptors. PARs \ninitiate cellular responses that contribute not only to haemostasis and thrombosis, but also to inflammation and mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3120, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "608fa92b-01c4-4746-b294-7bdfaeedb194": {"__data__": {"id_": "608fa92b-01c4-4746-b294-7bdfaeedb194", "embedding": null, "metadata": {"page_label": "327", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4923a796-e907-4efd-b369-3ea1914d91d5", "node_type": null, "metadata": {"page_label": "327", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d890f440dfe0766b7f027e29b4ed6da4cccee58a6280ce22282bc7aa7774486a"}, "2": {"node_id": "44515883-28eb-45c9-8fe7-461e7629a000", "node_type": null, "metadata": {"page_label": "327", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "187d8f4d4a08dfd41d0ce7b8805264044eea00a32db6886f8b5bcea98c41c1c7"}}, "hash": "5e9b53c3fd7a5dcf7bbdd2a7f4e4841ed5901dc6c4ff6229f97d62edfcc0b3f5", "text": "and thrombosis, but also to inflammation and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3060, "end_char_idx": 3584, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "91294d4d-cc2f-4647-ad41-3f7c27c37991": {"__data__": {"id_": "91294d4d-cc2f-4647-ad41-3f7c27c37991", "embedding": null, "metadata": {"page_label": "328", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9b6263af-f780-4b06-b934-5ff2639a49ac", "node_type": null, "metadata": {"page_label": "328", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db48b998b85b2f9e54a071963c57fae309ceb96b3b46cd71c556f492f4a73a8a"}, "3": {"node_id": "de6b3e33-b959-4940-abc5-75af38d30094", "node_type": null, "metadata": {"page_label": "328", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c34371556cc8255c6e9d3a5574f68d8837cdcf3e869092f5347cdcd710d24bdd"}}, "hash": "aad3bebfc303e01741d4d792d8f5f1b81bc59b9cd3cca388322ed94292f0a6ba", "text": "25 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n322O\nR\nCH3\nOONa\nOCHCH 2COCH 3C6H5\nO\nVitamin K\n(natural vitamin)Warfarin\n(vitamin K antagonist)\nFig. 25.3 Vitamin K and warfarin. Warfarin, a vitamin K \nantagonist, is an oral anticoagulant. It competes with vitamin K \n(note the similarity in their structures) for the reductase enzyme (VKORC1) that activates vitamin K and is the site of its action (see Fig. 25.5). DRUGS THAT ACT ON THE \nCOAGULATION CASCADE\nDrugs are used to modify the cascade either when there \nis a defect in coagulation or when there is unwanted \ncoagulation.\nCOAGULATION DEFECTS\nGenetically determined deficiencies of clotting factors are \nnot common. Examples are classic haemophilia, caused by \nlack of factor VIII, and an even rarer form of haemophilia \n(haemophilia B or Christmas disease) caused by lack of factor IX (also called Christmas factor). Intravenous factor \nreplacement is given by specialists to prevent or to limit \nbleeding in such patients. Some patients develop factor inhibitors, and their management is particularly demanding \n(for example, by induction of immune tolerance, see Ch. \n7). Plasma-derived concentrates are giving way to pure recombinant proteins (for example, of factors VIII and IX; recombinant factor II is in development) \u2013 this is a rapidly \nevolving field. A human recombinant form of factor VIIa \nis also available for bleeding in patients with severe bleeding disorders but can cause intravascular coagulation.\nAcquired clotting defects are more common than heredi -\ntary ones. The causes include liver disease, vitamin K deficiency (universal in neonates) and excessive oral \nanticoagulant therapy, each of which may require treatment \nwith vitamin K.\nVITAMIN \u2003K\nVitamin K (for Koagulation in German) is a fat-soluble vitamin \n(Fig. 25.3) occurring naturally in plants (vitamin K 1) and \nas a series of bacterial menaquinones (vitamin K 2) formed \nin the gut (see Shearer & Newman, 2008, for a review). It \nis essential for the formation of clotting factors II, VII, IX \nand X, which are glycoproteins with \u03b3-carboxyglutamic acid \n(Gla) residues. The interaction of factors Xa and prothrombin \n(factor II) with Ca2+ and phospholipid is shown in Fig. 25.4. \n\u03b3-Carboxylation occurs after the synthesis of the amino acid \nchain, and the carboxylase enzyme requires reduced vitamin \nK as a co-factor (Fig. 25.5). Binding does not occur in the absence of \u03b3-carboxylation. Similar considerations apply to \nthe proteolytic activation of factor X by IXa and by VIIa (see Fig. 25.2).activator inhibitor (PAI)-1 are particularly important. PAI-1 is secreted in response to angiotensin IV , receptors for which \nare present on endothelial cells, providing a link between the renin\u2013angiotensin system (see Ch. 23) and thrombosis. These prothrombotic factors are involved, respectively, in \nplatelet adhesion and in coagulation and clot stabilisation. \nHowever, the endothelium is also implicated in thrombus limitation. Thus it generates prostaglandin (PG) I\n2 (pros-\ntacyclin; Ch. 18) and nitric oxide (NO; Ch. 21); converts \nADP, which causes platelet aggregation, to adenosine, which \ninhibits it (Ch. 17); synthesises tissue plasminogen activator", "start_char_idx": 0, "end_char_idx": 3214, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "de6b3e33-b959-4940-abc5-75af38d30094": {"__data__": {"id_": "de6b3e33-b959-4940-abc5-75af38d30094", "embedding": null, "metadata": {"page_label": "328", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9b6263af-f780-4b06-b934-5ff2639a49ac", "node_type": null, "metadata": {"page_label": "328", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db48b998b85b2f9e54a071963c57fae309ceb96b3b46cd71c556f492f4a73a8a"}, "2": {"node_id": "91294d4d-cc2f-4647-ad41-3f7c27c37991", "node_type": null, "metadata": {"page_label": "328", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aad3bebfc303e01741d4d792d8f5f1b81bc59b9cd3cca388322ed94292f0a6ba"}}, "hash": "c34371556cc8255c6e9d3a5574f68d8837cdcf3e869092f5347cdcd710d24bdd", "text": "it (Ch. 17); synthesises tissue plasminogen activator (tPA; see pp. 330\u2013333); and expresses thrombomodulin, a \nreceptor for thrombin. After combination with thrombo -\nmodulin, thrombin activates an anticoagulant, protein C. \nActivated protein C, helped by its co-factor protein S, \ninactivates factors Va and VIIa. This is known to be physi -\nologically important, because a naturally occurring mutation \nof the gene coding for factor V (factor V Leiden), which confers resistance to activated protein C, results in the \ncommonest recognised form of inherited thrombophilia.\nEndotoxin and some cytokines, including tumour necrosis \nfactor, tilt the balance of prothrombotic and antithrombotic endothelial functions towards thrombosis by causing loss \nof heparan (see earlier) and increased expression of tissue factor, and impair endothelial NO function. If other mecha -\nnisms limiting coagulation are also faulty or become exhausted, disseminated intravascular coagulation can result. \nThis is a serious complication of sepsis and of certain \nmalignancies, and the main treatment is to correct the \nunderlying disease.\nBlood coagulation (fibrin \nformation) \nThe clotting system consists of a cascade of proteolytic \nenzymes and co-factors.\n\u2022\tInactive \tprecursors \tare \tactivated \tsequentially, \teach \t\ngiving rise to more of the next.\n\u2022\tThe\tlast \tenzyme, \tthrombin, \tderived \tfrom \tprothrombin \t\n(II), converts soluble fibrinogen (I) to an insoluble \nmeshwork \tof \tfibrin \tin \twhich \tblood \tcells \tare \ttrapped, \t\nforming the clot.\n\u2022\tThere\tare \ttwo \tlimbs \tin \tthe \tcascade:\n\u2013 the in vivo (extrinsic) pathway\n\u2013 the contact (intrinsic) pathway\n\u2022\tBoth\tpathways \tresult \tin \tactivation \tof \tfactor \tX \tto \tXa, \t\nwhich converts prothrombin to thrombin.\n\u2022\tCalcium \tions \tand \ta \tnegatively \tcharged \tphospholipid \t\n(PL) are essential for three steps, namely the actions of:\n\u2013 factor IXa on X\n\u2013 factor VIIa on X\n\u2013 factor Xa on II\n\u2022\tPL\tis\tprovided \tby \tactivated \tplatelets \tadhering \tto \tthe \t\ndamaged vessel.\n\u2022\tSome\tfactors \tpromote \tcoagulation \tby \tbinding \tto \tPL \t\nand a serine protease factor; for example, factor Va in the activation of II by Xa, or VIIIa in the activation of X by IXa.\n\u2022\tBlood\tcoagulation \tis \tcontrolled \tby:\n\u2013 enzyme inhibitors (e.g. antithrombin III)\n\u2013 fibrinolysismebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3161, "end_char_idx": 5930, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8205c28a-ee63-45fa-9fc0-259c1b2050db": {"__data__": {"id_": "8205c28a-ee63-45fa-9fc0-259c1b2050db", "embedding": null, "metadata": {"page_label": "329", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "afe44a82-7fec-4d91-9fdd-b7ec66942809", "node_type": null, "metadata": {"page_label": "329", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a45c8b46823d17c4c06b477735fa8ffb3146307d028135815fb5f9f7e8ab25a"}, "3": {"node_id": "9f9e36c6-f5ae-40f0-b630-4a6449f088bf", "node_type": null, "metadata": {"page_label": "329", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef8b741775d1dcf5e54d060b53587fd9f70241b52320d87be865b2522f096451"}}, "hash": "8107c0656d1c1d2bed8ececac1098ea35ebc15859a2b5c0dabb7d5e27e594cb2", "text": "25 HAEMOSTASIS AND THROMbOSIS\n323\u2022\tinjectable\t anticoagulants\t (heparin and newer \nthrombin inhibitors);\n\u2022\toral\tanticoagulants\t (warfarin and related compounds; \norally active thrombin inhibitors).\nHeparins and thrombin inhibitors act immediately, whereas \nwarfarin and other vitamin K antagonists take several days \nto exert their effect. Consequently, if warfarin is used to \ntreat patients with venous thrombosis, an agent that acts \nimmediately is also administered until the effect of warfarin \nhas become established.\nHEPARIN\u2003 (INCLUDING\u2003 LOW\u2003 MOLECULAR- \u2003\nWEIGHT\u2003 HEPARINS)\nHeparin was discovered in 1916 by a second-year medical \nstudent at Johns Hopkins Hospital. He was attempting to \nextract thromboplastic (i.e. coagulant) substances from \nvarious tissues during a vacation project, but found instead There are several other vitamin K-dependent Gla proteins, \nincluding proteins C and S and osteocalcin in bone.\nAdministration and pharmacokinetic aspects\nNatural vitamin K 1 (phytomenadione ) may be given orally \nor by injection. If given by mouth, it requires bile salts for \nabsorption, and this occurs by a saturable energy-requiring \nprocess in the proximal small intestine. A synthetic prepara -\ntion, menadiol sodium phosphate , is also available. It is \nwater-soluble and does not require bile salts for its absorp -\ntion. This synthetic compound takes longer to act than \nphytomenadione. There is very little storage of vitamin K \nin the body. It is metabolised to more polar substances that \nare excreted in the urine and the bile.\nClinical uses of vitamin K are summarised in the clinical \nbox.\nTHROMBOSIS\nThrombotic and thromboembolic disease is common and \nhas severe consequences, including myocardial infarction, \nstroke, deep vein thrombosis and pulmonary embolus. The \nmain drugs used for platelet-rich \u2018white\u2019 arterial thrombi \nare the antiplatelet drugs and fibrinolytic drugs, which are \nconsidered below. The main drugs used to prevent or treat \n\u2018red\u2019 venous thrombi are:\nS S\nS SS S\nCa2+Ca2+Va\nAcidic phospholipidII Xa\nEnzymic sites \u03b3-Carboxyglutamic\nacid residues\nActivation\npeptidesSite of cleavage of\nII by Xa\nFig. 25.4 Activation of prothrombin (factor II) by factor Xa. \nThe complex of factor Va with a negatively charged phospholipid \nsurface (supplied by aggregating platelets) forms a binding site \nfor factor Xa and prothrombin (II), which have peptide chains \n(shown schematically) that are similar to one another. Platelets \nthus serve as a localising focus. Calcium ions are essential for \nbinding. Xa activates prothrombin, liberating thrombin (shown in \ngrey).\t(Modified\t from\tJackson,\t C.M.,\t1978.\tBr.\tJ.\tHaematol.\t 39,\t\n1.)Vitamin K\nreductase\n(VKORC1)Vitamin K\nreductase\n(VKORC1)\nWarfarinVitamin K\nquinoneVitamin K oxidised form\n(epoxide)Vitamin K reduced form\n(hydroquinone)\u03b3-Carboxyglutamic acid\nresidues\n(in II, VII, IX, X)O2 + CO2 + Glutamic acid\nresidues\n(in II, VII, IX, X)\nFig. 25.5 Mechanism of vitamin K and of warfarin. After \nthe peptide chains in", "start_char_idx": 0, "end_char_idx": 3014, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9f9e36c6-f5ae-40f0-b630-4a6449f088bf": {"__data__": {"id_": "9f9e36c6-f5ae-40f0-b630-4a6449f088bf", "embedding": null, "metadata": {"page_label": "329", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "afe44a82-7fec-4d91-9fdd-b7ec66942809", "node_type": null, "metadata": {"page_label": "329", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a45c8b46823d17c4c06b477735fa8ffb3146307d028135815fb5f9f7e8ab25a"}, "2": {"node_id": "8205c28a-ee63-45fa-9fc0-259c1b2050db", "node_type": null, "metadata": {"page_label": "329", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8107c0656d1c1d2bed8ececac1098ea35ebc15859a2b5c0dabb7d5e27e594cb2"}}, "hash": "ef8b741775d1dcf5e54d060b53587fd9f70241b52320d87be865b2522f096451", "text": "of vitamin K and of warfarin. After \nthe peptide chains in clotting factors II, VII, IX and X have been \nsynthesised,\t reduced\tvitamin\tK\t(the\thydroquinone)\t acts\tas\ta\t\nco-factor in the conversion of glutamic acid to \u03b3-carboxyglutamic \nacid. During this reaction, the reduced form of vitamin K is \nconverted to the epoxide, which in turn is reduced to the \nquinone\tand\tthen\tthe\thydroquinone\t by\tvitamin\tK\tepoxide\t\nreductase component 1 (VKORC1), the site of action of warfarin. \nClinical uses of vitamin K \n\u2022\tTreatment\t and/or\tprevention\t of\tbleeding:\n\u2013 from excessive oral anticoagulation (e.g. by \nwarfarin )\n\u2013 in babies: to prevent haemorrhagic disease of the \nnewborn\n\u2022\tFor\tvitamin\tK\tdeficiencies\t in\tadults:\n\u2013 sprue, coeliac disease, steatorrhoea\n\u2013\tlack\tof\tbile\t(e.g.\twith\t obstructive jaundice )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2955, "end_char_idx": 4235, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6dc726a9-71f0-43ed-b3c4-39a9acff994f": {"__data__": {"id_": "6dc726a9-71f0-43ed-b3c4-39a9acff994f", "embedding": null, "metadata": {"page_label": "330", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6168b5b7-75ce-427c-896f-b6d66a14ad5f", "node_type": null, "metadata": {"page_label": "330", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1392ac811c40c3e1b251f7de8383f034bc096d1470197931d11af3daa797e1db"}, "3": {"node_id": "e49e3e83-9577-46ff-afb5-9d911bdf8e4d", "node_type": null, "metadata": {"page_label": "330", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "513e1dc6d66aef6b2e5a0c3ada19c27a8d8496de1a61fc9c32a74ec0634f25a8"}}, "hash": "ccba42bf6f0e96585a5121d60e76f7ed41c77ae19acaa311f8aaacb9144c10bf", "text": "25 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n324LMWHs are given subcutaneously. They have a longer \nelimination half-life than unfractionated heparin, and this \nis independent of dose (first-order kinetics), so the effects \nare more predictable and dosing less frequent (once or twice a day). LMWHs do not prolong the APTT. Unlike \nunfractionated heparin, the effect of a standard dose is \nsufficiently predictable that monitoring is not required routinely. LMWHs are eliminated mainly by renal excretion, \nand unfractionated heparin is preferred in renal failure, \nbut with this exception LMWHs are at least as safe and effective as unfractionated heparin and are more convenient to use, because patients can be taught to inject themselves \nat home and there is generally no need for blood tests and \ndose adjustment.\nUnwanted effects\nHaemorrhage. The main hazard is haemorrhage, which \nis treated by stopping therapy and, if necessary, giving \nprotamine sulfate. This heparin antagonist is a strongly \nbasic protein that forms an inactive complex with heparin; it is given intravenously. The dose is estimated from the \ndose of heparin that has been administered recently, and \nit is important not to give too much, as this can itself cause bleeding. If necessary, an in vitro neutralisation test is \nperformed first on a sample of blood from the patient to \nprovide a more precise indication of the required dose.\nThrombosis. This is an uncommon but serious adverse \neffect of heparin and, as with warfarin necrosis, may be \nmisattributed to the natural history of the disease for which \nheparin is being administered.\n\u25bc Paradoxically, it is associated with heparin-induced thrombocytopenia \n(HIT). A transitory early decrease in platelet numbers is not uncommon \nafter initiating heparin treatment, and is not clinically important. \nMore serious thrombocytopenia occurring 2\u201314 days after the start a powerful anticoagulant activity.4 This was named heparin, \nbecause it was first extracted from liver.\nHeparin is not a single substance but a family of sulfated \nglycosaminoglycans (mucopolysaccharides). It is present \ntogether with histamine in the granules of mast cells. Com -\nmercial preparations are extracted from beef lung or hog intestine and, because preparations differ in potency, assayed biologically against an agreed international standard: doses \nare specified in units of activity rather than of mass.\nHeparin fragments (e.g. enoxaparin, dalteparin) or a \nsynthetic pentasaccharide (fondaparinux), referred to as \nlow molecular-weight heparins (LMWHs), are longer acting \nthan unfractionated heparin and are usually preferred, the \nunfractionated product being reserved for special situations such as patients with renal failure in whom LMWHs are \ncontraindicated.\nMechanism of action\nHeparin inhibits coagulation, both in vivo and in vitro, by \nactivating antithrombin III. Antithrombin III inhibits \nthrombin and other serine proteases by binding to the active \nsite. Heparin modifies this interaction by binding, via a unique pentasaccharide sequence, to antithrombin III, \nchanging its conformation and increasing its affinity for \nserine proteases.\nTo inhibit thrombin, it is necessary for heparin to bind \nto the enzyme as well as to antithrombin III; to inhibit factor Xa, it is necessary only for heparin to bind to antithrombin III (Fig. 25.6). Antithrombin III deficiency is very rare but can cause thrombophilia and resistance to \nheparin therapy.\nThe LMWHs increase the action", "start_char_idx": 0, "end_char_idx": 3522, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e49e3e83-9577-46ff-afb5-9d911bdf8e4d": {"__data__": {"id_": "e49e3e83-9577-46ff-afb5-9d911bdf8e4d", "embedding": null, "metadata": {"page_label": "330", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6168b5b7-75ce-427c-896f-b6d66a14ad5f", "node_type": null, "metadata": {"page_label": "330", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1392ac811c40c3e1b251f7de8383f034bc096d1470197931d11af3daa797e1db"}, "2": {"node_id": "6dc726a9-71f0-43ed-b3c4-39a9acff994f", "node_type": null, "metadata": {"page_label": "330", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ccba42bf6f0e96585a5121d60e76f7ed41c77ae19acaa311f8aaacb9144c10bf"}}, "hash": "513e1dc6d66aef6b2e5a0c3ada19c27a8d8496de1a61fc9c32a74ec0634f25a8", "text": "and resistance to \nheparin therapy.\nThe LMWHs increase the action of antithrombin III on \nfactor Xa but not its action on thrombin, because the molecules are too small to bind to both enzyme and inhibitor, \nessential for inhibition of thrombin but not for that of factor Xa (see Fig. 25.6).\nAdministration and pharmacokinetic aspects\nHeparin is not absorbed from the gut because of its charge and high molecular-weight, and it is therefore given \nintravenously or subcutaneously (intramuscular injections \nwould cause haematomas).\n\u25bc After intravenous injection of a bolus dose, there is a phase of \nrapid elimination followed by a more gradual disappearance owing \nboth to saturable processes (involving binding to sites on endothelial \ncells and macrophages) and to slower non-saturable processes including \nrenal excretion. As a result, once the dose exceeds the saturating concentration, a greater proportion is dealt with by these slower \nprocesses, and the apparent half-life increases with increasing dose \n(saturation kinetics; see Ch. 11).\nHeparin acts immediately following intravenous administra -\ntion, but the onset is delayed by up to 60 min when it is \ngiven subcutaneously. The elimination half-life is approxi -\nmately 40\u201390 m in. In urgent situations, it is therefore usual \nto start treatment with a bolus intravenous dose, followed \nby a constant-rate infusion. The activated partial thromboplastin \ntime (APTT), or some other in vitro clotting test, is measured \nand the dose of heparin adjusted to achieve a value within a target range (e.g. 1.5\u20132.5 times control).HeparinAT III IIa\nHeparinAT III Xa\nXa\nLMW HepAT III\nFig. 25.6 Action of heparins. The schematic shows \ninteractions of heparins, antithrombin III (AT III) and clotting \nfactors. To increase the inactivation of thrombin (IIa) by AT III, heparin needs to interact with both substances (top), but to \nspeed up its effect on factor Xa it need only interact with AT III (middle). Low molecular-weight heparins (LMW Hep) increase the action of AT III on factor Xa (bottom), but cannot increase \nthe action of AT III on thrombin because they cannot bind both simultaneously. \n4This kind of good fortune also favoured Vane and his colleagues in \ntheir discovery of PGI 2 (Ch. 18), where they were looking for one kind \nof biological activity and found another. More specific chemical assays \n(Ch. 8), for all their strengths, cannot throw up this kind of unexpected \ndiscovery.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3457, "end_char_idx": 6394, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b935def0-d13a-45b2-a2ae-b08cc95a68bd": {"__data__": {"id_": "b935def0-d13a-45b2-a2ae-b08cc95a68bd", "embedding": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "badb86be-a138-4e0a-a46b-cc373f58c607", "node_type": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0fb51507873b7dc0f471aeb68103e562a6993a50003e6c960ebb8519a86fab74"}, "3": {"node_id": "d8b5eb36-d3d8-402d-8431-68671ee5630f", "node_type": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f7ee155247dac4ea90f6ba25e46b8a2dba6cf64f5f1577db1b538e2102e5fd42"}}, "hash": "f780f11b08d84beeb56c458c0e24a31c15bf7cf6007804dccee226bdd9c8102e", "text": "25 HAEMOSTASIS AND THROM b OSIS\n325thrombosis. Apixiban is similar. These drugs are admin -\nistered in standard doses without laboratory monitoring \nof their anticoagulant effects. Their commonest adverse \neffects are predictable (bleeding, anaemia); rivaroxaban also commonly causes nausea. Other indications are being inves -\ntigated, and if they prove safe and effective for a range of indications, this could transform the clinical management of the large group of patients currently maintained on warfarin \n(see the clinical box on the clinical use of anticoagulants, \np. 327).\n\u25bc Various other approaches are being explored. These include several \nnaturally occurring anticoagulants (tissue factor pathway inhibitor, \nthrombomodulin and protein C) synthesised by recombinant technol -\nogy. A particularly ingenious approach is the development of thrombin agonists that are selective for the anticoagulant properties of thrombin. One such modified thrombin, differing by a single amino acid substitu -\ntion, has substrate specificity for protein C. It produces anticoagulation in monkeys without prolonging bleeding times, suggesting that it may be less likely than standard anticoagulants to cause bleeding \n(Bah et al., 2009).\nWARFARIN\n\u25bc Oral anticoagulants were discovered as an indirect result of a \nchange in agricultural policy in North America in the 1920s. Sweet clover was substituted for corn in cattle feed, and an epidemic of \ndeaths of cattle from haemorrhage ensued. This turned out to be \ncaused by bishydroxycoumarin in spoiled sweet clover, and it led to the discovery of warfarin (named for the Wisconsin Alumni Research \nFoundation). One of the first uses to which this was put was as a rat \npoison, but for more than 50 years it was the standard anticoagulant for the treatment and prevention of thromboembolic disease.\nWarfarin (see Fig. 25.3) is the most important oral antico -\nagulant; alternatives with a similar mechanism of action, \nfor example phenindione , are now used only in rare patients \nwho experience idiosyncratic adverse reactions to warfarin5 \n(see Ch. 12). Warfarin and other vitamin K antagonists require frequent blood tests to individualise dose, and are \nconsequently inconvenient as well as having a low margin of safety. Advances in the technology available for testing \ngenomic DNA mutations in every patient (from less than \n\u00a3100 for each complete genome test), means that individu -\nalised pharmacology (so-called pharmacogenomics) may \nbecome more and more viable for even the cheapest drug. \nTailoring drugs to a person\u2019s mutations to avoid such adverse reactions, is increasingly common.\nMechanism of action\nVitamin K antagonists act only in vivo and have no effect on clotting if added to blood in vitro. They interfere with \nthe post-translational \u03b3-carboxylation of glutamic acid \nresidues in clotting factors II, VII, IX and X. They do this \nby inhibiting vitamin K epoxide reductase component 1 \n(VKORC1), thus inhibiting the reduction of vitamin K epoxide to its active hydroquinone form (see Fig. 25.5). Inhibition is competitive (reflecting the structural similarity \nbetween warfarin and vitamin K; see Fig. 25.3). The VKORC1 \ngene is polymorphic (see Ch. 12), and different haplotypes of therapy is uncommon and is referred to as type II HIT. This is \ncaused by IgM or IgG antibodies against complexes of heparin and \na platelet-derived chemokine, platelet factor 4. Circulating immune \ncomplexes bind to circulating platelets, and cause thrombocytopenia. Antibody also binds to platelet factor 4 attached to the surface of \nendothelial cells,", "start_char_idx": 0, "end_char_idx": 3615, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d8b5eb36-d3d8-402d-8431-68671ee5630f": {"__data__": {"id_": "d8b5eb36-d3d8-402d-8431-68671ee5630f", "embedding": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "badb86be-a138-4e0a-a46b-cc373f58c607", "node_type": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0fb51507873b7dc0f471aeb68103e562a6993a50003e6c960ebb8519a86fab74"}, "2": {"node_id": "b935def0-d13a-45b2-a2ae-b08cc95a68bd", "node_type": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f780f11b08d84beeb56c458c0e24a31c15bf7cf6007804dccee226bdd9c8102e"}, "3": {"node_id": "7938e7af-ee10-4feb-875f-c04d050d80a6", "node_type": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b24f77ddafe27114c7b41357d5537fdeddd656697811dd7e26fe09f2123827a"}}, "hash": "f7ee155247dac4ea90f6ba25e46b8a2dba6cf64f5f1577db1b538e2102e5fd42", "text": "also binds to platelet factor 4 attached to the surface of \nendothelial cells, leading to immune injury of the vessel wall, throm -\nbosis and disseminated intravascular coagulation. LMWHs are less \nlikely than unfractionated heparin to cause thrombocytopenia and \nthrombosis by this mechanism. HIT is usually treated by substituting \ndanaparoid or a direct thrombin inhibitor such as lepirudin instead \nof the heparin preparation that caused the problem. Danaparoid is a low molecular-weight heparinoid consisting of a mixture of heparan, dermatan and chondroitin sulfates, with well-established antithrom -\nbotic activity.\nOsteoporosis with spontaneous fractures has been reported \nwith long-term (6 months or more) treatment with heparin \n(usually during pregnancy, when warfarin is contraindicated \nor problematic). Its explanation is unknown.\nHypoaldosteronism (with consequent hyperkalaemia) is \nuncommon, but increases with prolonged treatment. It is recommended to check plasma K\n+ concentration if treatment \nis to be continued for >7 days.\nHypersensitivity reactions are rare with heparin but more \ncommon with protamine. (Protamine sensitivity also occurs in patients treated with protamine zinc insulin; Ch. 32. \nProtamine is extracted from fish roe, and sensitivity to \nprotamine occurs in some people with fish allergy.)\nDIRECT \u2003THROMBIN \u2003INHIBITORS \u2003AND \u2003RELATED \u2003DRUGS\nHirudins are polypeptides that act as direct thrombin inhibi -\ntors. They are derived from the anticoagulant present in \nsaliva from the medicinal leech. Unlike the heparins, they \ndo not depend on activation of antithrombin. Lepirudin \nis a recombinant hirudin that binds irreversibly to both \nthe fibrin-binding and catalytic sites on thrombin and \nis used for thromboembolic disease in patients with type II HIT. It is administered intravenously, the dose \nbeing adjusted depending on the APTT, and can cause \nbleeding or hypersensitivity reactions (rash or fever). Bivalirudin, another hirudin analogue, is used in com-bination with aspirin and clopidogrel (see pp. 328\u2013331) \nin patients undergoing percutaneous coronary artery surgery. Treatment is initiated with an intravenous bolus \nfollowed by an infusion during and up to 4 h after the \nprocedure. It can cause bleeding and hypersensitivity \nreactions.\nOrally active direct inhibitors. This field had more than \none false dawn, but rapid progress has been made recently, \nand indications for such drugs have expanded consider -\nably. In time, orally active direct inhibitors could come to \nreplace warfarin, a venerable but troublesome drug that \nis a common cause of serious adverse effects. Dabigatran \nis a synthetic serine protease inhibitor; dabigatran etexilate, \na prodrug with a hydrophobic tail, is orally active and is licensed for prevention of venous thromboembolism \nfollowing hip or knee replacement and for the prevention of stroke and systemic embolism in atrial fibrillation (Ch. 21). It works rapidly and is administered 1\u20134 hours after \nsurgery and then once daily for up to a month (depending \non the type of surgery), or twice daily indefinitely for the prevention of stroke. The dose is reduced in patients aged \nover 75 or receiving concomitant verapamil or amiodarone. \nRivaroxaban, an orally active direct inhibitor of factor Xa rather than of thrombin, but similar to dabigatran in other \nrespects, is licensed for the same indications and in addition \nfor the treatment", "start_char_idx": 3550, "end_char_idx": 6997, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7938e7af-ee10-4feb-875f-c04d050d80a6": {"__data__": {"id_": "7938e7af-ee10-4feb-875f-c04d050d80a6", "embedding": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "badb86be-a138-4e0a-a46b-cc373f58c607", "node_type": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0fb51507873b7dc0f471aeb68103e562a6993a50003e6c960ebb8519a86fab74"}, "2": {"node_id": "d8b5eb36-d3d8-402d-8431-68671ee5630f", "node_type": null, "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f7ee155247dac4ea90f6ba25e46b8a2dba6cf64f5f1577db1b538e2102e5fd42"}}, "hash": "0b24f77ddafe27114c7b41357d5537fdeddd656697811dd7e26fe09f2123827a", "text": "other \nrespects, is licensed for the same indications and in addition \nfor the treatment (as well as prophylaxis) of deep vein 5Warfarin is a good example for \u2018personalised medicine\u2019 or \n\u2018pharmacogenomics\u2019. Prior to dosing with the anticoagulant, the patient \ncan be checked by genotyping for mutations in their VKORC1 and \nCYP2C9 genes, which are involved in the coagulation cascade and metabolism of the drug. In patients possessing common mutations of \nthese genes, standard doses of warfarin may cause potentially lethal \nbleeding or thromboembolism due to therapeutic failure.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6975, "end_char_idx": 8035, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ec3043c8-577a-4886-b6e3-8615ba38e21e": {"__data__": {"id_": "ec3043c8-577a-4886-b6e3-8615ba38e21e", "embedding": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b875acc3-b4f7-4a32-afc0-8c5c585bb5a7", "node_type": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14058296ed8a28485dee1bf91322a25df116c784cc353a798158d6437b5d4d1d"}, "3": {"node_id": "8d7af168-1420-4c69-827d-cb5e856f7cbc", "node_type": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca77c59d02b2a2804df81b5c8d86dc82d17865b84ecf61b2e2deb04b61d2225c"}}, "hash": "4252ff234d34a4f492304beece559122c9e8871e8a08eae5acf963318404e25d", "text": "25 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n326FACTORS\u2003 THAT\u2003 POTENTIATE\u2003 WARFARIN\nVarious diseases and drugs potentiate warfarin, increasing \nthe risk of haemorrhage.\nDisease\nLiver disease interferes with the synthesis of clotting factors; \nconditions in which there is a high metabolic rate, such as \nfever and thyrotoxicosis, increase the effect of anticoagulants \nby increasing degradation of clotting factors.\nDrugs (see\u2003also\u2003 Ch.\u200310)\nMany drugs potentiate warfarin.\nAgents that inhibit hepatic drug metabolism. Examples \ninclude co-trimoxazole , ciprofloxacin, metronidazole, \namiodarone and many antifungal azoles. Stereoselective \neffects (warfarin is a racemate, and its isomers are metabolised \ndifferently from one another) are described in Chapter 10.\nDrugs that inhibit platelet function. Aspirin increases \nthe risk of bleeding if given during warfarin therapy, \nalthough this combination can be used safely with careful \nmonitoring. Other non-steroidal anti-inflammatory drugs \n(NSAIDs) also increase the risk of bleeding, partly by their \neffect on platelet thromboxane synthesis (Ch. 27) and, in \nthe case of some NSAIDs, also by inhibiting warfarin \nmetabolism as above. Some antibiotics, including moxa -\nlactam and carbenicillin , inhibit platelet function.\nDrugs that displace warfarin from binding sites on plasma \nalbumin. Some of the NSAIDs and chloral hydrate cause \na transient increase in the concentration of free warfarin \nin plasma by competing with it for binding to plasma \nalbumin. This mechanism seldom causes clinically important \neffects.\nDrugs that inhibit reduction of vitamin K. Such drugs \ninclude the cephalosporins .\nDrugs that decrease the availability of vitamin K. Broad-\nspectrum antibiotics and some sulfonamides (see Ch. 51) \ndepress the intestinal flora that normally synthesise vitamin \nK2; this has little effect unless there is concurrent dietary \ndeficiency.\nFACTORS\u2003 THAT\u2003 LESSEN\u2003 THE\u2003EFFECT\u2003 OF\u2003WARFARIN\nPhysiological state/disease\nThere is a decreased response to warfarin in conditions \n(e.g. pregnancy) where there is increased coagulation factor \nsynthesis. Similarly, the effect of oral anticoagulants is \nlessened in hypothyroidism, which is associated with \nreduced degradation of coagulation factors.\nDrugs (see\u2003also\u2003 Ch.\u200310)\nSeveral drugs reduce the effectiveness of warfarin; this \nleads to increased doses being used to achieve the target \nINR. Furthermore, the dose of warfarin must be reduced \nwhen the interacting drug is discontinued, to avoid \nhaemorrhage.\nVitamin K. This vitamin is a component of some par -\nenteral feeds and vitamin preparations.\nDrugs that induce hepatic P450 enzymes. Enzyme induc -\ntion (e.g. by rifampicin, carbamazepine ) increases the rate \nof degradation of warfarin. Induction may wane only slowly \nafter the inducing drug is discontinued, making it difficult \nto adjust the warfarin dose appropriately.\nDrugs that reduce absorption. Drugs that bind warfarin \nin the gut, for example, colestyramine , reduce its \nabsorption.have different affinities for warfarin. Genotyping to deter -\nmine the haplotype, combined with genotyping CYP2C9 \n(see later), while not yet routine, can be used to optimise \nthe starting dose, reducing the variability in response to", "start_char_idx": 0, "end_char_idx": 3269, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8d7af168-1420-4c69-827d-cb5e856f7cbc": {"__data__": {"id_": "8d7af168-1420-4c69-827d-cb5e856f7cbc", "embedding": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b875acc3-b4f7-4a32-afc0-8c5c585bb5a7", "node_type": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14058296ed8a28485dee1bf91322a25df116c784cc353a798158d6437b5d4d1d"}, "2": {"node_id": "ec3043c8-577a-4886-b6e3-8615ba38e21e", "node_type": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4252ff234d34a4f492304beece559122c9e8871e8a08eae5acf963318404e25d"}, "3": {"node_id": "7080e728-63fb-4fd0-91f5-2af862b8d25d", "node_type": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e99c8086a2caf6b3ad6a5b95d720fba0b8d9deb1dff03996bf12ba923d22d3b"}}, "hash": "ca77c59d02b2a2804df81b5c8d86dc82d17865b84ecf61b2e2deb04b61d2225c", "text": "can be used to optimise \nthe starting dose, reducing the variability in response to \nwarfarin by around one-third. The effect of warfarin takes \nseveral days to develop because of the time taken for \ndegradation of preformed carboxylated clotting factors. \nOnset of action thus depends on the elimination half-lives \nof the relevant factors. Factor VII, with a half-life of 6 h, is \naffected first, then IX, X and II, with half-lives of 24, 40 and \n60 h, respectively.\nAdministration and pharmacokinetic aspects\nWarfarin is absorbed rapidly and completely from the gut \nafter oral administration. It has a small distribution volume, \nbeing strongly bound to plasma albumin (see Ch. 9). The \npeak concentration in the blood occurs within an hour of \ningestion, but because of the mechanism of action this does \nnot coincide with the peak pharmacological effect, which \noccurs about 48 h later. The effect on prothrombin time \n(PT, see later) of a single dose starts after approximately \n12\u201316 h and lasts 4\u20135 days. Warfarin is metabolised by \nCYP2C9, which is polymorphic (see Ch. 12). Partly in \nconsequence of this, its half-life is very variable, being of \nthe order of 40 h in many individuals.\nWarfarin crosses the placenta and is not given in the first \nmonths of pregnancy because it is teratogenic (see Table \n58.2, Ch. 58), nor in the later stages because it can cause \nintracranial haemorrhage in the baby during delivery. It \nappears in milk during lactation. This could theoretically \nbe important because newborn infants are naturally deficient \nin vitamin K. However, infants are routinely prescribed \nvitamin K to prevent haemorrhagic disease, so warfarin \ntreatment of the mother does not generally pose a risk to \nthe breastfed infant.\nThe therapeutic use of warfarin requires a careful balance \nbetween giving too little, leaving unwanted coagulation \nunchecked, and giving too much, thereby causing haemor -\nrhage. Therapy is complicated not only because the effect \nof each dose is maximal some 2 days after its administration, \nbut also because numerous medical and environmental \nconditions modify sensitivity to warfarin, including interac -\ntions with other drugs (see Chs 9 and 12). The effect of \nwarfarin is monitored by measuring PT, which is expressed \nas an international normalised ratio (INR).\n\u25bc The PT is the time taken for clotting of citrated plasma after the \naddition of Ca2+ and standardised reference thromboplastin; it is \nexpressed as the ratio (PT ratio) of the PT of the patient to the PT of \na pool of plasma from healthy subjects on no medication. Because of \nthe variability of thromboplastins, different results are obtained in \ndifferent laboratories. To standardise PT measurements internationally, \neach thromboplastin is assigned an international sensitivity index \n(ISI), and the patient\u2019s PT is expressed as an INR, where INR = (PT \nratio)ISI. This kind of inter-laboratory normalisation procedure shocks \npurists but provides similar results when a patient moves from, say, \nBirmingham to Baltimore. Pragmatic haematologists argue that the \nproof of the pudding is in the eating!\nThe dose of warfarin is usually adjusted to give an INR of \n2\u20134, the precise target depending on the clinical situation. \nThe duration of treatment also varies, but for several \nindications (e.g. to prevent thromboembolism in chronic \natrial fibrillation), treatment is long term, with the logistical \nchallenge of providing a worldwide network of anticoagu -\nlant clinics and demands on the patient in terms of repeat \nvisits and blood tests.mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3200, "end_char_idx": 6824, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7080e728-63fb-4fd0-91f5-2af862b8d25d": {"__data__": {"id_": "7080e728-63fb-4fd0-91f5-2af862b8d25d", "embedding": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b875acc3-b4f7-4a32-afc0-8c5c585bb5a7", "node_type": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14058296ed8a28485dee1bf91322a25df116c784cc353a798158d6437b5d4d1d"}, "2": {"node_id": "8d7af168-1420-4c69-827d-cb5e856f7cbc", "node_type": null, "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca77c59d02b2a2804df81b5c8d86dc82d17865b84ecf61b2e2deb04b61d2225c"}}, "hash": "5e99c8086a2caf6b3ad6a5b95d720fba0b8d9deb1dff03996bf12ba923d22d3b", "text": "and blood tests.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6831, "end_char_idx": 7326, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3a3167c6-df2d-4a70-b2a3-ed24afa9a93b": {"__data__": {"id_": "3a3167c6-df2d-4a70-b2a3-ed24afa9a93b", "embedding": null, "metadata": {"page_label": "333", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2a88ef1a-e938-4b33-94cb-11e29e3d261d", "node_type": null, "metadata": {"page_label": "333", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b983d5c0d4738f6006a7fb4594663a722eabfd75362aba2078ffc3968d637dcf"}, "3": {"node_id": "ed637c01-03d5-400d-8c33-7b120027f81b", "node_type": null, "metadata": {"page_label": "333", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "346d75077a2ff25bbfe0067714359cb1a34a77872489f328511c48bc2a2c1935"}}, "hash": "d26d2d7d0e92ad95f1b4aef29a5ade498793760d51bc564e52d2935fa7aa9a4a", "text": "25 HAEMOSTASIS AND THROM b OSIS\n327PLATELET ADHESION AND ACTIVATION\nPlatelets maintain the integrity of the circulation: a low \nplatelet count results in thrombocytopenic purpura .6When \nplatelets are activated, they undergo a sequence of reactions \nthat are essential for haemostasis, important for the healing \nof damaged blood vessels, and play a part in inflamma -\ntion (see Ch. 18). These reactions, several of which are \nredundant (in the sense that if one pathway of activation \nis blocked another is available) and several autocatalytic, \ninclude:\n\u2022\tadhesion following vascular damage (via von \nWillebrand factor bridging between subendothelial macromolecules and glycoprotein (GP) Ib receptors on \nthe platelet surface)\n7;\n\u2022\tshape change (from smooth discs to spiny spheres with protruding pseudopodia);\nUNWANTED \u2003EFFECTS \u2003OF \u2003WARFARIN\nHaemorrhage (especially into the bowel or the brain) is the \nmain hazard. Depending on the urgency of the situation, \ntreatment may consist of withholding warfarin (for minor \nproblems), administration of vitamin K, or fresh plasma Drugs affecting blood coagulation \nProcoagulant drugs: vitamin K\n\u2022\tReduced \tvitamin \tK \tis \ta \tco-factor \tin \tthe \tpost-\ntranslational \u03b3-carboxylation of glutamic acid (Glu) \nresidues in factors II, VII, IX and X. The \u03b3-carboxylated \nglutamic acid (Gla) residues are essential for the \ninteraction of these factors with Ca2+ and negatively \ncharged phospholipid.\nInjectable anticoagulants (e.g. heparin, low \nmolecular-weight heparins)\n\u2022\tPotentiate \tantithrombin \tIII, \ta \tnatural \tinhibitor \tthat \t\ninactivates Xa and thrombin.\n\u2022\tAct\tboth \tin \tvivo \tand \tin \tvitro.\n\u2022\tAnticoagulant \tactivity \tresults \tfrom \ta \tunique \t\npentasaccharide \tsequence \twith \thigh \taffinity \tfor \t\nantithrombin III.\n\u2022\tHeparin therapy is monitored via activated partial \nthromboplastin time (APTT), and dose individualised. \nUnfractionated heparin (UFH) is used for patients with \nimpaired renal function.\n\u2022\tLow molecular-weight heparins (LMWHs) have the \nsame effect on factor X as heparin but less effect on \nthrombin; therapeutic efficacy is similar to heparin but \nmonitoring and dose individualisation are not needed. \nPatients can administer them subcutaneously at home. They are preferred over UFH except for patients with impaired renal function.\nOral anticoagulants (e.g. warfarin, direct \nthrombin and Xa inhibitors)\n\u2022\tWarfarin is the main vitamin K antagonist.\n\u2022\tVitamin\tK \tantagonists \tact \ton \tvitamin \tK \tepoxide \t\nreductase component 1 (VKORC1) to inhibit the \nreduction of vitamin K epoxide, thus inhibiting the \u03b3-carboxylation of Glu in II, VII, IX and X.\n\u2022\tVitamin\tK \tantagonists \tact \tonly \tin \tvivo, \tand \ttheir \teffect \t\nis delayed until preformed clotting factors are depleted.\n\u2022\tMany\tfactors \tmodify \tthe \taction \tof \tvitamin \tK \t\nantagonists; genetic factors (polymorphisms of CYP2C6 and VKORC1) and drug interactions are especially important.\n\u2022\tThere\tis \twide \tvariation \tin \tresponse \tto \tvitamin \tK \t\nantagonists; their effect is monitored by measuring the international normalised ratio (INR) and the dose individualised", "start_char_idx": 0, "end_char_idx": 3106, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ed637c01-03d5-400d-8c33-7b120027f81b": {"__data__": {"id_": "ed637c01-03d5-400d-8c33-7b120027f81b", "embedding": null, "metadata": {"page_label": "333", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2a88ef1a-e938-4b33-94cb-11e29e3d261d", "node_type": null, "metadata": {"page_label": "333", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b983d5c0d4738f6006a7fb4594663a722eabfd75362aba2078ffc3968d637dcf"}, "2": {"node_id": "3a3167c6-df2d-4a70-b2a3-ed24afa9a93b", "node_type": null, "metadata": {"page_label": "333", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d26d2d7d0e92ad95f1b4aef29a5ade498793760d51bc564e52d2935fa7aa9a4a"}}, "hash": "346d75077a2ff25bbfe0067714359cb1a34a77872489f328511c48bc2a2c1935", "text": "monitored by measuring the international normalised ratio (INR) and the dose individualised accordingly.\n\u2022\tOrally\tactive \tdirect \tthrombin \tinhibitors \t(e.g. \tdabigatran \netexilate) or factor Xa inhibitors (e.g. rivaroxaban, \napixaban )\tare\tused \tincreasingly \tand \tdo \tnot \trequire \t\nlaboratory monitoring/dose titration. They are licensed \nfor\tpreventing \tstroke \tin \tpatients \twith \tatrial \tfibrillation \t\nand for preventing deep vein thrombosis after orthopaedic surgery.Clinical uses of anticoagulants \nHeparin (often as low molecular-weight heparin ) is \nused acutely. Warfarin or a direct thrombin or Xa \ninhibitor is used for more prolonged therapy. \nAnticoagulants are used to prevent:\n\u2022\tdeep\tvein \tthrombosis \t(e.g. \tperioperatively)\n\u2022\textension \tof \testablished \tdeep \tvein \tthrombosis\n\u2022\tpulmonary \tembolism\n\u2022\tthrombosis \tand \tembolisation \tin \tpatients \twith \tatrial \t\nfibrillation (Ch. 22)\n\u2022\tthrombosis \ton \tprosthetic \theart \tvalves\n\u2022\tclotting\tin \textracorporeal \tcirculations \t(e.g. \tduring \t\nhaemodialysis)\n\u2022\tprogression \tof \tmyocardial \tdamage \tin \tpatients \twith \t\nunstable\tangina \tand \tduring \ttreatment \tof \tST-elevation \t\nmyocardial infarctionor coagulation factor concentrates (for life-threatening \nbleeding).\nOral anticoagulants are teratogenic, causing disordered \nbone development which is believed to be related to binding \nto the vitamin K-dependent protein osteocalcin.\nHepatotoxicity occurs but is uncommon.\nNecrosis of soft tissues (e.g. breast or buttock) owing to \nthrombosis in venules is a rare but serious effect that occurs \nshortly after starting treatment and is attributed to inhibition \nof biosynthesis of protein C, which has a shorter elimination \nhalf-life than do the vitamin K-dependent coagulation factors; this results in a procoagulant state soon after starting treatment. Treatment with a heparin is usually started at \nthe same time as warfarin, avoiding this problem except \nin individuals experiencing HIT as an adverse effect of heparin (see p. 324).\nThe clinical use of anticoagulants is summarised in the \nbox.\n6Purpura means a purple rash caused by multiple spontaneous bleeding \npoints in the skin. When this is caused by reduced circulating platelets, \nbleeding can occur into other organs, including the gut and brain.\n7Various platelet membrane glycoproteins act as receptors or binding \nsites for adhesive proteins such as von Willebrand factor or fibrinogen.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3015, "end_char_idx": 5916, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8b04f204-f8a8-4d98-99f4-3b8a2868ad81": {"__data__": {"id_": "8b04f204-f8a8-4d98-99f4-3b8a2868ad81", "embedding": null, "metadata": {"page_label": "334", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cc87c4e8-3c67-4b89-887b-15bf2f1a3dda", "node_type": null, "metadata": {"page_label": "334", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bb7b89c81b65d705b5b35814ceb511934a7b8e83c5f2739caff109c7a5aebe97"}}, "hash": "bb7b89c81b65d705b5b35814ceb511934a7b8e83c5f2739caff109c7a5aebe97", "text": "25 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n328Ruptured atherosclerotic plaque\nTiclopidine\nClopidogrel\nEpoprostenolAdhesion of platelets to \nthrombogenic surface\nActivation of platelets\nAA generation\nProduction of cyclic \nendoperoxides\nSynthesis of TXA2\nExpression of GP \nIIb/IIIa receptors\nLinkage of adjacent platelets \nby fibrinogen binding to\nGP IIb/IIIa receptors\nAGGREGATION of \nplateletsRelease of ADP etc.\nEpoprostenol, NOAntagonists of GP \nIIb/IIIa receptors (e.g. \nabciximab, tirofiban)TXA2 \nsynthesis \ninhibitors\nTXA2-\nreceptor \nantagonistsThrombinExposure of \nacidic \nphospholipids\nCoagulation \nprocesses\nDirect thrombin \ninhibitors\n(e.g. hirudin)Aspirin\nFig. 25.7 Platelet activation. Events involved in platelet adhesion and aggregation are shown, with the sites of action of drugs and \nendogenous mediators. AA, arachidonic acid; ADP, adenosine bisphosphate; GP, glycoprotein; NO, nitric oxide; TXA 2, thromboxane A 2. 5-hydroxytryptamine and TXA 2, acting on specific \nreceptors on the platelet surface; activation by agonists \nleads to expression of GPIIb/IIIa receptors that bind \nfibrinogen, which links adjacent platelets to form aggregates;\n\u2022\texposure of acidic phospholipid on the platelet surface, promoting thrombin formation (and hence further platelet activation via thrombin receptors and fibrin \nformation via cleavage of fibrinogen; see earlier).\u2022\tsecretion of the granule contents (including platelet \nagonists, such as ADP and 5-hydroxytryptamine, and \ncoagulation factors and growth factors, such as \nplatelet-derived growth factor);\n\u2022\tbiosynthesis of labile mediators such as platelet-activating \nfactor and thromboxane (TX)A\n2 (see Ch. 18 and Fig. \n25.7);\n\u2022\taggregation, which is promoted by various agonists, \nincluding collagen, thrombin, ADP, mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2272, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "16c1f46c-0b0c-4dd8-bfee-ae81b75c1a99": {"__data__": {"id_": "16c1f46c-0b0c-4dd8-bfee-ae81b75c1a99", "embedding": null, "metadata": {"page_label": "335", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c60040ee-d3d0-4086-ba51-a42c690c633f", "node_type": null, "metadata": {"page_label": "335", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1db2d00a3203bf493c0c2bb62007a1815046023137c493c4e493d05b833995a4"}, "3": {"node_id": "d736aef1-6e1a-49d1-9226-6ed0d6054ebf", "node_type": null, "metadata": {"page_label": "335", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb5469efcb6d05fb4d2f63efdc2e057c013add42a0fc1c9db70c6e74038345e7"}}, "hash": "cd1dd237e2fc697600d06d96d03ef48e4e31477fb8120f42ef81b6b988df3106", "text": "25 HAEMOSTASIS AND THROM b OSIS\n329non-steroidal drugs that inhibit platelet TXA 2 synthesis >95% (e.g. \nsulfinpyrazone , for which there is also supportive clinical trial evidence, \nand naproxen \u2013 see Ch. 27) may have antithrombotic effects, but \nwhere inhibition of platelet TXA 2 synthesis does not reach this threshold \nthere is evidence that such drugs are proaggregatory , related to inhibition \nof COX-2, possibly due to inhibition of antiaggregatory PGI 2 in blood \nvessels.\nDIPYRIDAMOLE\nDipyridamole inhibits platelet aggregation by several \nmechanisms, including inhibition of phosphodiesterase, \nblock of adenosine uptake into red cells (see Ch. 17) and \ninhibition of TXA 2 synthesis (see Ch. 27). Clinical effective -\nness has been uncertain, but one study showed that a \nmodified-release form of dipyridamole reduced the risk \nof stroke and death in patients with transient ischaemic \nattacks by around 15% \u2013 similar to aspirin (25 mg twice \ndaily).8 The beneficial effects of aspirin and dipyridamole \nwere additive. The main side effects of dipyridamole are \ndizziness, headache and gastrointestinal disturbances; unlike \naspirin, it does not increase the risk of bleeding.\nADENOSINE \u2003(P2Y 12)\u2003RECEPTOR \u2003ANTAGONISTS\nTiclopidine was the first to be introduced, but causes neutropenia and thrombocytopenia. The main agents are \ncurrently clopidogrel, prasugrel and ticagrelor, each of \nwhich is combined with low-dose aspirin in patients with \nunstable coronary artery disease, usually for up to 1 year.These processes are essential for haemostasis but may be \ninappropriately triggered if the artery wall is diseased, most \ncommonly with atherosclerosis, resulting in thrombosis (see Fig. 25.7).\n8This dose regimen of aspirin is unconventional, being somewhat lower \nthan the 75 mg once daily commonly used in thromboprophylaxis.Platelet function \n\u2022\tHealthy \tvascular \tendothelium \tprevents \tplatelet \t\nadhesion.\n\u2022\tPlatelets \tadhere \tto \tdiseased \tor \tdamaged \tareas \tand \t\nbecome activated, changing shape and exposing \nnegatively charged phospholipids and glycoprotein (GP) IIb/IIIa receptors, and synthesise and/or release \nvarious mediators, for example, thromboxane A\n2 and \nADP, which activate other platelets, causing \naggregation.\n\u2022\tAggregation \tentails \tfibrinogen \tbinding \tto \tand \tbridging \t\nbetween GPIIb/IIIa receptors on adjacent platelets.\n\u2022\tActivated \tplatelets \tconstitute \ta \tfocus \tfor \tfibrin \t\nformation.\n\u2022\tChemotactic \tfactors \tand \tgrowth \tfactors \tnecessary \tfor \t\nrepair, but also implicated in atherogenesis, are released during platelet activation.\nANTIPLATELET DRUGS\nPlatelets play such a critical role in thromboembolic disease \nthat it is no surprise that antiplatelet drugs are of great \ntherapeutic value. Clinical trials of aspirin radically altered \nclinical practice, and more recently drugs that block ADP receptors and GPIIb/IIIa have also been found to be thera -\npeutically useful. Sites of action of antiplatelet drugs are shown in Fig. 25.7.\nASPIRIN\nLow-dose aspirin (see Ch. 27) in chronic use profoundly (>95%) inhibits platelet TXA\n2 synthesis, by irreversible \nacetylation of a serine residue in the active site of cyclo-\noxygenase I", "start_char_idx": 0, "end_char_idx": 3198, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d736aef1-6e1a-49d1-9226-6ed0d6054ebf": {"__data__": {"id_": "d736aef1-6e1a-49d1-9226-6ed0d6054ebf", "embedding": null, "metadata": {"page_label": "335", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c60040ee-d3d0-4086-ba51-a42c690c633f", "node_type": null, "metadata": {"page_label": "335", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1db2d00a3203bf493c0c2bb62007a1815046023137c493c4e493d05b833995a4"}, "2": {"node_id": "16c1f46c-0b0c-4dd8-bfee-ae81b75c1a99", "node_type": null, "metadata": {"page_label": "335", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cd1dd237e2fc697600d06d96d03ef48e4e31477fb8120f42ef81b6b988df3106"}}, "hash": "fb5469efcb6d05fb4d2f63efdc2e057c013add42a0fc1c9db70c6e74038345e7", "text": "of a serine residue in the active site of cyclo-\noxygenase I (COX-1). Oral administration is relatively \nselective for platelets partly because of presystemic drug elimination (Ch. 10). Unlike nucleated cells, platelets cannot \nsynthesise proteins, so after administration of aspirin, TXA\n2 \nsynthesis does not recover fully until the affected cohort of platelets is replaced in 7\u201310 days. Clinical trials have \ndemonstrated the efficacy of aspirin in several clinical settings (e.g. Fig. 25.8). For acute indications (progressing \nthrombotic stroke \u2013 so-called stroke-in-evolution \u2013 and acute myocardial infarction) treatment is started with a \nsingle dose of approximately 300 mg in order to achieve \nrapid substantial ( >95%) inhibition of platelet thromboxane \nsynthesis, followed by regular daily doses of 75 mg. For \nlong-term thromboprophylaxis, a low dose (often 75 mg \nonce daily) is used. At this dose, the risk of gastrointestinal \nbleeding is less than with the usual 300 mg dose given to \ncontrol inflammation, but still significant, so thrombo -\nprophylaxis is reserved for people at high cardiovascular \nrisk (e.g. survivors of myocardial infarction), in whom the \nbenefit usually outweighs the risk of gastrointestinal bleeding.\n\u25bc Treatment failure can occur despite taking aspirin, and there is \ncurrent interest in the possibility that some patients exhibit a syndrome \nof \u2018aspirin resistance\u2019, although the mechanism and possible importance \nof this remains controversial (see Goodman et al., 2008). Other 500\n400300200100\n0Cumulative number of vascular deaths\n35 28 21 14 7 0\nDays from start of trial Streptokinase infusion \nand aspirin tabletsStreptokinase infusion and placebo tabletsAspirin tablets and placebo infusionPlacebo infusion and placebo tablets\nFig. 25.8 Efficacy of aspirin and streptokinase for \nmyocardial infarction. The curves show cumulative vascular \nmortality in patients treated with placebo, aspirin alone, \nstreptokinase \talone \tor \ta \tcombined \taspirin\u2013streptokinase \t\nregimen.\t(ISIS-2 \tTrial, \t1988. \tLancet \tii, \t350\u2013360.) \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3138, "end_char_idx": 5696, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0d8f9c38-2d6d-4823-854f-a6e636005760": {"__data__": {"id_": "0d8f9c38-2d6d-4823-854f-a6e636005760", "embedding": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c9d6976a-e7f0-4756-98cb-1f142911c3c4", "node_type": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1843a3c19aceac8422abbbd81048dbeb0b7ff0e6041c16fc122217ca83dd2b28"}, "3": {"node_id": "24d8d8a1-e2e3-493b-8a13-8a47317094cc", "node_type": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d190b6f2ddf596234b84ea1130915640c5f07d1c7d15d2012449f666d79c00a8"}}, "hash": "770ed992a2b2e96dda619e6f0538a91ce2fcea0f8d12ae387f009c855c227aad", "text": "25 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n330is more effective than clopidogrel in acute coronary syn -\ndromes, but more often causes serious bleeding. Pretreat -\nment with clopidogrel and aspirin followed by longer-term \ntherapy is also effective in patients with ischaemic heart disease undergoing percutaneous coronary interventions. \nTreatment of acute coronary syndrome with ticagrelor as \ncompared with clopidogrel significantly reduces mortality for unknown reasons.\nGLYCOPROTEIN \u2003IIB/IIIA \u2003RECEPTOR \u2003ANTAGONISTS\nAntagonists of the GPIIb/IIIa receptor have the theoretical attraction that they inhibit all pathways of platelet activation \n(because these all converge on activation of GPIIb/IIIa \nreceptors). A hybrid murine\u2013human monoclonal antibody Fab fragment directed against the GPIIb/IIIa receptor, which \nrejoices in the catchy little name of abciximab,\n9 is licensed \nfor use in high-risk patients undergoing coronary angio -\nplasty, as an adjunct to heparin and aspirin. It reduces the \nrisk of restenosis at the expense of an increased risk of bleeding. Immunogenicity limits its use to a single \nadministration.\nTirofiban is a synthetic non-peptide and eptifibatide is \na cyclic peptide based on the Arg\u2013Gly\u2013Asp (\u2018RGD\u2019) sequence that is common to ligands for GPIIb/IIIa receptors. Neither \nis absorbed if administered by mouth. Given intravenously as an adjunct to aspirin and a heparin preparation, they reduce early events in acute coronary syndrome, but long-\nterm oral therapy with GPIIb/IIIa receptor antagonists is \nnot effective and may be harmful. Unsurprisingly, they increase the risk of bleeding.\nOTHER \u2003ANTIPLATELET \u2003DRUGS\nEpoprostenol (PGI 2), an agonist at prostanoid IP receptors \n(see Ch. 18), causes vasodilatation as well as inhibiting platelet \naggregation. It is added to blood entering the dialysis circuit \nin order to prevent thrombosis during haemodialysis, especially in patients in whom heparin is contraindicated. \nIt is also used in severe pulmonary hypertension (Ch. 23) \nand circulatory shock associated with meningococcal sep -\nticaemia. It is unstable under physiological conditions and \nhas a half-life of around 3 min, so it is administered as an \nintravenous infusion. Adverse effects related to its vasodilator action include flushing, headache and hypotension.\nThe clinical use of antiplatelet drugs is summarised in \nthe clinical box (p. 331).\nFIBRINOLYSIS (THROMBOLYSIS)\nWhen the coagulation system is activated, the fibrinolytic system is also set in motion via several endogenous plas-\nminogen activators, including tissue plasminogen activator (tPA), urokinase-type plasminogen activator, kallikrein and neutrophil elastase. tPA is inhibited by a structurally related \nlipoprotein, lipoprotein(a) , increased concentrations of which \nconstitute an independent risk factor for myocardial infarc -\ntion (Ch. 24). Plasminogen is deposited on the fibrin strands within a thrombus. Plasminogen activators are serine \nproteases and are unstable in circulating blood. They diffuse into thrombus and cleave plasminogen, a zymogen present Clopidogrel and prasugrel inhibit ADP-induced platelet \naggregation by irreversible inhibition of P2Y\n12 receptors \n(Ch. 17) to which they link via a disulfide bond, whereas", "start_char_idx": 0, "end_char_idx": 3277, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "24d8d8a1-e2e3-493b-8a13-8a47317094cc": {"__data__": {"id_": "24d8d8a1-e2e3-493b-8a13-8a47317094cc", "embedding": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c9d6976a-e7f0-4756-98cb-1f142911c3c4", "node_type": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1843a3c19aceac8422abbbd81048dbeb0b7ff0e6041c16fc122217ca83dd2b28"}, "2": {"node_id": "0d8f9c38-2d6d-4823-854f-a6e636005760", "node_type": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "770ed992a2b2e96dda619e6f0538a91ce2fcea0f8d12ae387f009c855c227aad"}, "3": {"node_id": "159a9cc4-1f5b-4aa2-84fd-45cf15a17b65", "node_type": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8eb06b11d968fa50735cd24176253e2bcfe0a121ae13907f2cb747347c5ed528"}}, "hash": "d190b6f2ddf596234b84ea1130915640c5f07d1c7d15d2012449f666d79c00a8", "text": "\n(Ch. 17) to which they link via a disulfide bond, whereas \nticagrelor is a reversible but non-competitive inhibitor of \nthe P2Y 12 receptor.\nPharmacokinetics and unwanted effects\nClopidogrel is well absorbed when administered by mouth, and in urgent situations is given orally as a loading dose of \n300 mg followed by maintenance dosing of 75 mg once daily. \nIt is a prodrug and is converted into its active sulfhydryl metabolite by CYP enzymes in the liver including CYP2C19. \nPatients with variant alleles of CYP2C19 (rapid or poor \nmetabolisers) are at increased risk of therapeutic failure from lack of efficacy or from bleeding. There is a potential for \ninteraction with other drugs, such as omeprazole (Ch. 31), \nthat are metabolised by CYP2C19 and current labelling \nrecommends against use with proton pump inhibitors for \nthis reason. Prasugrel and ticagrelor are also given as a \nloading dose followed by maintenance once daily dosing.\nThese drugs predictably increase the risk of haemorrhage. \nClopidogrel can cause dyspepsia, rash or diarrhoea. The \nserious blood dyscrasias caused by ticlopidine are very \nrare with clopidogrel. Prasugrel can cause rash or, rarely hypersensitivity reactions and angioedema. Ticagrelor can \ncause dyspnoea (perhaps related to the role of adenosine \nsignalling in the carotid bodies, Ch. 29) or, less commonly, gastrointestinal symptoms.\nClinical use\nClopidogrel was slightly more effective than aspirin as a single agent in reducing a composite outcome of ischaemic \nstroke, myocardial infarction or vascular death in one large \ntrial; it can be used instead of aspirin in patients with symptomatic atheromatous disease, but is usually reserved \nfor patients who are intolerant of aspirin. Clinical trials of \nadding clopidogrel to aspirin in patients with acute coronary syndromes (Fig. 25.9) and (in a megatrial of over 45,000 \npatients) in patients with acute myocardial infarction \n(COMMIT Collaborative Group, 2005) demonstrated that combined treatment reduces mortality. Treatment with clopidogrel for this indication is given for 4 weeks. Prasugrel \n0 3 69 12\nMonths of follow-upPlacebo\nClopidogrel\np < 0.00 1Cumulative hazard rate0.14\n0.12\n0.100.080.060.040.020.00\nFig. 25.9 Effect of adding clopidogrel to aspirin. The \ncurves show cumulative hazard rates for major vascular events \nin patients with acute coronary syndromes treated either with placebo + aspirin or clopidogrel + aspirin. (Modified from CURE \nInvestigators, \t2001. \tN \tEngl \tJ \tMed \t345, \t494\u2013502.)9The convention for naming monoclonals is: momab = -mouse \nmonoclonal antibody; -umab = human; -zumab = humanised; -ximab = \nchimeric \u2013 a kind of medieval mouse\u2013man nightmare.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3230, "end_char_idx": 6393, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "159a9cc4-1f5b-4aa2-84fd-45cf15a17b65": {"__data__": {"id_": "159a9cc4-1f5b-4aa2-84fd-45cf15a17b65", "embedding": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c9d6976a-e7f0-4756-98cb-1f142911c3c4", "node_type": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1843a3c19aceac8422abbbd81048dbeb0b7ff0e6041c16fc122217ca83dd2b28"}, "2": {"node_id": "24d8d8a1-e2e3-493b-8a13-8a47317094cc", "node_type": null, "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d190b6f2ddf596234b84ea1130915640c5f07d1c7d15d2012449f666d79c00a8"}}, "hash": "8eb06b11d968fa50735cd24176253e2bcfe0a121ae13907f2cb747347c5ed528", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6394, "end_char_idx": 6457, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "751a7fa1-a961-460b-be2f-7561e8df2bb5": {"__data__": {"id_": "751a7fa1-a961-460b-be2f-7561e8df2bb5", "embedding": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b0c9578d-6360-499c-8230-c338994ac720", "node_type": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fae9cd49c8bb74da361bbcc7c8bccaf7eae14a903178f79cfa761a6dd8bbb84c"}, "3": {"node_id": "2e493c11-7250-4eda-848d-ffd075936dd8", "node_type": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "639438c8a5e48b98236b95a919b629a99a9257790a0b24c032fe8689ac4ffbd0"}}, "hash": "955d2dc6c0cfabb37491b9ae412c6b6113e2385dcd13310fe18dd9b54d8c68e0", "text": "25 HAEMOSTASIS AND THROM bOSIS\n331Its action is blocked by antibodies, which appear 4 days \nor more after the initial dose: its use should not be repeated after this time has elapsed.\n12\nAlteplase and duteplase are, respectively, single- and \ndouble-chain recombinant tPA. They are more active on fibrin-bound plasminogen than on plasma plasminogen, and are therefore said to be \u2018clot selective\u2019. Recombinant tPA is not antigenic, and can be used in patients likely to have antibodies to streptokinase. Because of their short half-lives, they must be given as intravenous infusions. Reteplase is similar but has a longer elimination half-life, allowing for bolus administration and making for simplicity of administration. It is available for clinical use in myocardial infarction.\nUNWANTED \u2003EFFECTS \u2003AND \u2003CONTRAINDICATIONS\nThe main hazard of all fibrinolytic agents is bleeding, including gastrointestinal haemorrhage and haemorrhagic stroke. If serious, this can be treated with tranexamic \nacid (see p. 333), fresh plasma or coagulation factors. Streptokinase can cause allergic reactions and low-grade in plasma, to release plasmin locally (Fig. 25.10). Plasmin is a trypsin-like protease that digests fibrin as well as fibrinogen, factors II, V and VIII, and many other proteins; any that escapes into the circulation is inactivated by plasmin inhibitors, including PAI-1 (see p. 321 and Ch. 23), which protect us from digesting ourselves from within.\nDrugs affect this system by increasing or inhibiting \nfibrinolysis ( fibrinolytic and antifibrinolytic drugs, respectively).\nFIBRINOLYTIC DRUGS\nFig. 25.10 summarises the interaction of the fibrinolytic system \nwith the coagulation cascade and platelet activation, and the action of drugs that modify this. Several fibrinolytic (thrombolytic) drugs are used clinically, principally to reopen the occluded arteries in patients with acute myocardial infarction\n11 or stroke, less commonly in patients with life-\nthreatening venous thrombosis or pulmonary embolism.\nStreptokinase is a plasminogen activating protein \nextracted from cultures of streptococci. Infused intravenously, it reduces mortality in acute myocardial infarction, and this beneficial effect is additive with aspirin (see Fig. 25.8). Antiplatelet drugs \n\u2022\tAspirin inhibits cyclo-oxygenase irreversibly. In chronic \nuse, low doses very effectively ( >95%)\tinhibit\tplatelet\t\nthromboxane (TX)A 2\tsynthesis\tand\treduce\tthe\trisk\tof\t\nthrombosis. Treatment is started with a larger dose \n(300\tmg)\tin\tacute\tsettings\tin\torder\tto\tachieve\trapid\t\ninhibition of platelet thromboxane synthesis.10\n\u2022\tADP\tantagonists \tare\tcombined \twith\tlow-dose\taspirin\t\nin treating patients with unstable coronary artery disease. Clopidogrel is a prodrug. Given by mouth, it \nirreversibly inhibits P2Y\n12 receptors and thereby inhibits \nplatelet responses to ADP. Its clinical effect is additive with aspirin. Prasugrel has a similar mechanism. \nTicagrelor is reversible but non-competitive. Prasugrel and ticagrelor are more effective than \nlicensed doses of clopidogrel.\n\u2022\tAntagonists \tof\tGPIIb/IIIa\treceptors\tinclude\ta\t\nmonoclonal antibody ( abciximab) and several \nsynthetic", "start_char_idx": 0, "end_char_idx": 3174, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2e493c11-7250-4eda-848d-ffd075936dd8": {"__data__": {"id_": "2e493c11-7250-4eda-848d-ffd075936dd8", "embedding": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b0c9578d-6360-499c-8230-c338994ac720", "node_type": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fae9cd49c8bb74da361bbcc7c8bccaf7eae14a903178f79cfa761a6dd8bbb84c"}, "2": {"node_id": "751a7fa1-a961-460b-be2f-7561e8df2bb5", "node_type": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "955d2dc6c0cfabb37491b9ae412c6b6113e2385dcd13310fe18dd9b54d8c68e0"}, "3": {"node_id": "5ee96924-f2ba-451b-967e-cc8f45138261", "node_type": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e2f8d5d0da94878326fade9ba197342ed53bd8a410fc5400ca51ffb651688c4"}}, "hash": "639438c8a5e48b98236b95a919b629a99a9257790a0b24c032fe8689ac4ffbd0", "text": "antibody ( abciximab) and several \nsynthetic molecules (e.g. tirofiban). They inhibit diverse agonists, for example, ADP and TXA\n2, because \ndifferent pathways of activation converge on GPIIb/IIIa receptors. They are administered intravenously for short-term treatment.\n\u2022\tDipyridamole inhibits phosphodiesterase and \nadenosine \tuptake.\tIt\tis\tused\tin\taddition\tto\taspirin\tin\t\nsome\tpatients\twith\tstroke\tor\ttransient\tischaemic \tattack.\n\u2022\tEpoprostenol (synthetic PGI 2) is chemically unstable. \nGiven as an intravenous infusion, it acts on I prostanoid (IP) receptors on vascular smooth muscle and platelets \n(Ch.\t18),\tstimulating \tadenylyl\tcyclase\tand\tthereby\t\ncausing vasodilatation and inhibiting aggregation caused by any pathway (e.g. ADP or TXA\n2).Clinical uses of antiplatelet drugs \nThe main drug is aspirin. Other drugs with distinct \nactions (e.g. dipyridamole, clopidogrel, ticagrelor) \ncan have additive effects, or be used in patients who are intolerant of aspirin. Uses of antiplatelet drugs relate mainly to arterial thrombosis and include:\u2022\tacute myocardial infarction\n\u2022\tprevention \tof\tmyocardial \tinfarction\tin\tpatients\tat\thigh\t\nrisk,\tincluding\ta\thistory\tof\tmyocardial infarction , angina \nor intermittent claudication \t(see\tCh.\t23)\n\u2022\tfollowing \tcoronary artery bypass grafting\n\u2022\tunstable coronary syndromes (a P2Y12 antagonist such as clopidogrel, prasugrel or ticagrelor is \nadded to aspirin)\n\u2022\tfollowing \tcoronary\tartery\tangioplasty and/or stenting \n(intravenous glycoprotein IIb/IIIa antagonists, e.g. abciximab, are used in some patients in addition to aspirin)\n\u2022\ttransient cerebral ischaemic attack\n\t(\u2018ministrokes\u2019) \tor\t\nthrombotic stroke, to prevent recurrence (dipyridamole can be added to aspirin)\n\u2022\tatrial fibrillation , if oral anticoagulation is \ncontraindicated; \tor,\tby\tspecialists, \tin\thigh-risk\t\nsituations in combination with anticoagulantOther antiplatelet drugs such as epoprostenol (PGI\n2; \nsee\tCh.\t18)\thave\tspecialised \tclinical\tapplications \t(e.g.\tin\t\nhaemodialysis or haemofiltration ,\tCh.\t29,\tor\tin\tpulmonary \nhypertension ,\tCh.\t23).\n11Fibrinolytic drugs are now less widely used in acute myocardial \ninfarction since many units throughout the world provide an \nemergency angioplasty service (the blocked artery is identified angiographically, opened with a balloon catheter and, if necessary, kept open by means of a stent, Ch. 22). The important thing is to open up the thrombosed artery as swiftly as possible. If facilities are available to do this mechanically, this is at least as good as using a lytic drug. Surgical intra-arterial thrombectomy is also being introduced for acute stroke treatment.\n12A once in a lifetime drug!10Its antithrombotic actions is the main reason for the saying \u2018An aspirin \na day keeps the doctor away\u2019, although aspirin has also been found to have anti-cancer properties, particularly when it comes to colon cancer. If you\u2019re one of the unlucky individuals who is allergic to aspirin, please ignore the previous sentence.mebooksfree.net", "start_char_idx": 3136, "end_char_idx": 6144, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5ee96924-f2ba-451b-967e-cc8f45138261": {"__data__": {"id_": "5ee96924-f2ba-451b-967e-cc8f45138261", "embedding": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b0c9578d-6360-499c-8230-c338994ac720", "node_type": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fae9cd49c8bb74da361bbcc7c8bccaf7eae14a903178f79cfa761a6dd8bbb84c"}, "2": {"node_id": "2e493c11-7250-4eda-848d-ffd075936dd8", "node_type": null, "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "639438c8a5e48b98236b95a919b629a99a9257790a0b24c032fe8689ac4ffbd0"}}, "hash": "1e2f8d5d0da94878326fade9ba197342ed53bd8a410fc5400ca51ffb651688c4", "text": "allergic to aspirin, please ignore the previous sentence.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6111, "end_char_idx": 6647, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "56aaca10-6f36-4b3b-aa70-9edfbb3c096b": {"__data__": {"id_": "56aaca10-6f36-4b3b-aa70-9edfbb3c096b", "embedding": null, "metadata": {"page_label": "338", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e45c048a-a925-4a27-9be6-b9a6988b11bb", "node_type": null, "metadata": {"page_label": "338", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a002cf1075bce552f7622d837246c96ea9a54a42ec0cdf2467b788bfa67a1b9"}}, "hash": "5a002cf1075bce552f7622d837246c96ea9a54a42ec0cdf2467b788bfa67a1b9", "text": "25 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n332Fibrinolysis and drugs modifying \nfibrinolysis \n\u2022\tA\tfibrinolytic \tcascade \tis \tinitiated \tconcomitantly \twith \tthe \t\ncoagulation cascade, resulting in the formation within \nthe coagulum of plasmin, which digests fibrin.\n\u2022\tVarious \tagents \tpromote \tthe \tformation \tof \tplasmin \tfrom \t\nits precursor plasminogen, for example streptokinase, and tissue plasminogen activators (tPAs) such as alteplase, duteplase and reteplase. \nMost are infused; reteplase can be given as a bolus injection.\n\u2022\tSome\tdrugs \t(e.g. \ttranexamic acid) inhibit fibrinolysis.mechanical (mainly angioplasty) unblocking procedures. \nOther uses of fibrinolytic agents are listed in the clinical \nbox.fever. Streptokinase causes a burst of plasmin formation, generating kinins (see Ch. 18), and can cause hypotension by this mechanism.\nContraindications to the use of these agents are active \ninternal bleeding, haemorrhagic cerebrovascular disease, bleeding diatheses, pregnancy, uncontrolled hypertension, \ninvasive procedures in which haemostasis is important, \nand recent trauma \u2013 including vigorous cardiopulmonary resuscitation.\nCLINICAL \u2003USE\nSeveral large placebo-controlled studies in patients with myocardial infarction have shown convincingly that \nfibrinolytic drugs reduce mortality if given within 12 h of \nthe onset of symptoms, and that the sooner they are administered the better is the result. Similar considerations \napply to their use in thrombotic stroke. Scanning to exclude \nhaemorrhagic stroke is advisable, though not always practicable in an emergency situation. Available fibrinolytic \ndrugs, used in combination with aspirin, provide similar \nlevels of benefit, generally less than that obtained by ANTIPLATELET AGENTS \nPLASMIN PlasminogenPlaque rupture\nTHROMBUS\nVASCULAR \nENDOTHELIAL \nCELLS\nPlasminogen \nactivatorProactivators in \nplasma and \ntissuesPlatelet \nadhesion \nactivation \naggregationActivation of \nclotting factors, \ntissue factor, XIIa, \nXa, IIa, etc.\nTrapped \nblood cellsATHEROSCLEROTIC PLAQUE\nFibrin \ndegradation \nproductsFIBRIN forms the \nframework of the \nTHROMBUSANTICOAGULANTS Heparin, LMWHs, hirudin, warfarin \nFIBRINOLYTIC \nAGENTS\nAnistreplase\nAlteplase\nReteplase\nStreptokinase\nUrokinaseANTIFIBRINOLYTIC \nAGENTS\nTranexamic acid\nFig. 25.10 Fibrinolytic system. The schematic shows interactions with coagulation and platelet pathways and sites of action of drugs \nthat modify these systems. LMWHs, low molecular-weight heparins. For more details of platelet activation and the coagulation cascade, \nrefer\tto\tFigs \t25.1, \t25.2 \tand \t25.7. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3090, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "54be89f1-61a1-4538-803a-6a868930cf8e": {"__data__": {"id_": "54be89f1-61a1-4538-803a-6a868930cf8e", "embedding": null, "metadata": {"page_label": "339", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "13e5cf21-fe7e-4560-afa2-d7a7b4ff3b6f", "node_type": null, "metadata": {"page_label": "339", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8eab781191b48d7332b65c0d0b462d884ca8188288e5a9f118c24e8e4611ec92"}, "3": {"node_id": "7509cb1c-a8e8-44c2-bfa2-cf5d9c0a716a", "node_type": null, "metadata": {"page_label": "339", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "63c46084efd54623f64bc36a551cf52fca6c30be0477dc4ee71906a6307fb7f0"}}, "hash": "23026ecb09c37a5c3824d78440e6ab4595a3f061c558a051d9d4f585119f5073", "text": "25 HAEMOSTASIS AND THROMbOSIS\n333ANTIFIBRINOLYTIC\u2003 AND\u2003 HAEMOSTATIC\u2003 DRUGS\nTranexamic acid inhibits plasminogen activation and thus \nprevents fibrinolysis. It can be given orally or by intravenous \ninjection. It is used to treat various conditions in which \nthere is bleeding or risk of bleeding, such as haemorrhage \nfollowing prostatectomy or dental extraction, in menorrhagia \n(excessive menstrual blood loss) and for life-threatening \nbleeding following thrombolytic drug administration. It is \nalso used in patients with the rare disorder of hereditary \nangio-oedema.Clinical uses of fibrinolytic drugs \nThe main drugs are streptokinase and tissue \nplasminogen activators (tPAs), for example alteplase .\n\u2022\tThe\tmain\tuse\tis\tin\tacute\tmyocardial\t infarction,\t within\t\n12 h of onset (the earlier the better!).\n\u2022\tOther\tuses\tinclude:\n\u2013 acute thrombotic stroke \twithin\t3\th\tof\tonset\t(tPA),\tin\t\nselected patients\n\u2013 clearing thrombosed shunts and cannulae\n\u2013 acute arterial thromboembolism\n\u2013 life-threatening deep vein thrombosis and pulmonary \nembolism\t(streptokinase,\t given\tpromptly)\nREFERENCES AND FURTHER READING\nBlood coagulation and anticoagulants\nBah, A., Carrell, C.J., Chen, Z.W., et al., 2009. Stabilization of the E* \nform turns thrombin into an anticoagulant. J. Biol. Chem. 284, \n20034\u201320040. ( The anticoagulant profile caused by a mutation of the \nthrombin gene is due to stabilisation of the inactive E* form of thrombin that \nis selectively shifted to the active E form upon thrombomodulin and protein \nC binding )\nHirsh, J., O\u2019Donnell, M., Weitz, J.I., 2005. New anticoagulants. Blood \n105, 453\u2013463. ( Review article on limitations of existing anticoagulants, \nvitamin K antagonist and heparins that have led to the development of newer \nanticoagulant therapies )\nKoenig-Oberhuber, M.F., 2016. New antiplatelet drugs and new oral \nanticoagulants V. Br. J. Anaesth. 117 (Suppl. 2), ii74\u2013ii84.\nMartin, F.A., Murphy, R.P., Cummins, P.M., 2013. Thrombomodulin \nand the vascular endothelium: insights into functional, regulatory, \nand therapeutic aspects. Am. J. Physiol. Heart Circ. Physiol. 304 (12), \nH1585\u2013H1597.\nShearer, M.J., Newman, P., 2008. Metabolism and cell biology of \nvitamin K. Thromb. Haemost. 100, 530\u2013547. ( Review )\nEndothelium, platelets and antiplatelet agents\nChew, D.P., Bhatt, D., Sapp, S., et al., 2001. Increased mortality with \noral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of \nphase III multicenter trials. Circulation 103, 201\u2013206.\nCOMMIT Collaborative Group, 2005. Addition of clopidogrel to aspirin \nin 45 852 patients with acute myocardial infarction: randomised \nplacebo-controlled trial. Lancet 366, 1607\u20131621. ( Clopidogrel reduced the \nrisk of death, myocardial infarction or stroke combined, and of mortality \nalone; see accompanying comment by Sabatine, M.S., pp. 1587\u20131589 in the \nsame issue )\nGoodman, T., Ferro, A., Sharma,", "start_char_idx": 0, "end_char_idx": 2894, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7509cb1c-a8e8-44c2-bfa2-cf5d9c0a716a": {"__data__": {"id_": "7509cb1c-a8e8-44c2-bfa2-cf5d9c0a716a", "embedding": null, "metadata": {"page_label": "339", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "13e5cf21-fe7e-4560-afa2-d7a7b4ff3b6f", "node_type": null, "metadata": {"page_label": "339", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8eab781191b48d7332b65c0d0b462d884ca8188288e5a9f118c24e8e4611ec92"}, "2": {"node_id": "54be89f1-61a1-4538-803a-6a868930cf8e", "node_type": null, "metadata": {"page_label": "339", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23026ecb09c37a5c3824d78440e6ab4595a3f061c558a051d9d4f585119f5073"}}, "hash": "63c46084efd54623f64bc36a551cf52fca6c30be0477dc4ee71906a6307fb7f0", "text": "in the \nsame issue )\nGoodman, T., Ferro, A., Sharma, P., 2008. Pharmacogenetics of aspirin \nresistance: a comprehensive systematic review. Br. J. Clin. Pharmacol. \n66, 222\u2013232. ( Supports a genetic association between the PlA1/A2 molecular \nvariant and aspirin resistance in healthy subjects, with the effect diminishing \nin the presence of cardiovascular disease )Patrono, C., Coller, B., FitzGerald, G.A., et al., 2004. Platelet-active \ndrugs: the relationships among dose, effectiveness, and side effects. \nChest 126, 234S\u2013264S.\nWallentin, L., Becker, R.C., Budaj, A., et al., 2009. Ticagrelor versus \nclopidogrel in patients with acute coronary syndromes. N. Engl. J. \nMed. 361, 1045\u20131057.\nWiviott, S.D., Braunwald, E., McCabe, C.H., et al., 2007. For the \nTRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in \npatients with acute coronary syndromes. N. Engl. J. Med. 357, \n2001\u20132015. ( Prasugrel reduced ischaemic events, including stent thrombosis, \nbut with an increased risk of major bleeding, including fatal bleeding. \nOverall mortality did not differ significantly between treatment groups )\nClinical and general aspects\nAster, R.H., 1995. Heparin-induced thrombocytopenia and thrombosis. \nN. Engl. J. Med. 332, 1374\u20131376. ( Succinct and lucid editorial; see also \naccompanying paper, pp. 1330\u20131335 )\nDiener, H., Cunha, L., Forbes, C., et al., 1996. European Stroke \nPrevention Study 2. Dipyridamole and acetylsalicylic acid in the \nsecondary prevention of stroke. J. Neurol. Sci. 143, 1\u201314. ( Slow-release \ndipyridamole 200 mg twice daily was as effective as aspirin 25 mg twice \ndaily, and the effects of aspirin and dipyridamole were additive )\nGoldhaber, S.Z., 2004. Pulmonary embolism. Lancet 363, 1295\u20131305.\nKyrle, P.A., Eichinger, S., 2005. Deep vein thrombosis. Lancet 365, \n1163\u20131174.\nLevine, M., 1995. A comparison of low-molecular-weight heparin \nadministered primarily at home with unfractionated heparin \nadministered in the hospital for proximal deep vein thrombosis. N. \nEngl. J. Med. 334, 677\u2013681. ( Concludes that LMWH can be used safely and \neffectively at home; this has potentially very important implications for \npatient care )\nMarkus, H.S., 2005. Current treatments in neurology: stroke. J. Neurol. \n252, 260\u2013267.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2842, "end_char_idx": 5578, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "75abdf88-1c67-41ea-b955-83365e9b7e6e": {"__data__": {"id_": "75abdf88-1c67-41ea-b955-83365e9b7e6e", "embedding": null, "metadata": {"page_label": "340", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3a3de74a-d75f-417e-b629-bea2fdc88b71", "node_type": null, "metadata": {"page_label": "340", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "868e6399ce555ce7e0dc7760735d45019cdf022d559e27b7e203b9d6dd753976"}, "3": {"node_id": "6b53a586-acf1-49b8-9409-67052470c56e", "node_type": null, "metadata": {"page_label": "340", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ba17721c1643fd6c7f7023c0450b2bf0ce0b9cd95515fe717709c8b9f63e58fe"}}, "hash": "0f6c822f0850a8637ccd5ee14b6fa470dcff1d6b3772c48f988fd17ccd010d5b", "text": "334\nHaematopoietic system and \ntreatment of anaemia26 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3 \nOVERVIEW\nThis chapter summarises the different kinds of \nanaemia, caused by nutrient deficiencies, bone marrow \ndepression or increased red cell destruction, and covers \nthe main haematinic agents used to treat them. We \ndescribe haematopoietic growth factors for red and \nwhite blood cells, and conclude by mentioning two \ndrugs (hydroxycarbamide and eculizumab) used in \ntreating, respectively, sickle cell anaemia and par -\noxysmal nocturnal haemoglobinuria.\nINTRODUCTION\nIn this chapter, we briefly review the haematopoietic system \nand different types of anaemia due to blood loss, deficiency \nof nutrients, depression of the bone marrow or increased \ndestruction of red cells (haemolytic anaemias). Nutritional \ndeficiencies of iron, vitamin B 12 or folic acid are common and \nimportant, and most of the chapter is devoted to these \nhaematinic agents (i.e. nutrients needed for healthy hae -\nmatopoiesis, and related drugs). Treatment of many forms \nof bone marrow depression is mainly supportive, but \nhaematopoietic growth factors (especially epoietins \u2013 prepara -\ntions of the natural hormone erythropoietin) have a place, \nespecially in patients with chronic renal failure, and are \ncovered briefly, as are other haematopoietic factors, known \nas colony-stimulating factors (CSFs), which are used to increase \nnumbers of circulating white blood cells. Treatment of \nhaemolytic anaemias is again mainly supportive, but we \nmention two drugs ( hydroxycarbamide and eculizumab ) \nthat provide mechanistic insights as well as clinical benefit \nin two specific haemolytic disorders.\nTHE HAEMATOPOIETIC SYSTEM\nThe main components of the haematopoietic system are \nthe blood, bone marrow, lymph nodes and thymus, \nwith the spleen, liver and kidneys as important accessory \norgans. Blood consists of formed elements (red and white \nblood cells and platelets) and plasma. This chapter deals \nmainly with red cells, which have the principal function \nof carrying oxygen. Their oxygen-carrying power depends \non their haemoglobin content. The most important site of \nformation of red blood cells in adults is the bone marrow, \nwhereas the spleen acts as their slaughterhouse. The lifetime \nof a red cell is normally about 120 days, and red cell loss \nin healthy adults \u2013 about 2 x 1010 cells per day \u2013 is precisely \nbalanced by production of new cells. The liver stores vitamin \nB12 and is involved in the process of breakdown of the \nhaemoglobin liberated when red blood cells are destroyed. \nThe kidney manufactures erythropoietin , a hormone that \nstimulates red cell production and is used in the anaemia \nof chronic kidney disease (Ch. 30) as well as (notoriously) in competitive sport (Ch. 59). CSFs regulate the production \nof leukocytes and are also used therapeutically (e.g. in the \nsupportive management of patients with haematological \nmalignancies undergoing chemotherapy, Ch. 57). Throm -\nbopoietin, produced by the liver and kidneys, stimulates \nplatelet formation; attempts to develop it for therapeutic \nuse are a cautionary tale, which is mentioned briefly later. \nDrugs used to treat leukaemias, malignant disorders of \nwhite blood cell precursors, are described in Chapter 57.\nTYPES OF ANAEMIA\nAnaemia is characterised by a reduced haemoglobin content \nin the blood. It may cause fatigue but, especially if it is \nchronic, is often surprisingly asymptomatic. The commonest \ncause is blood loss", "start_char_idx": 0, "end_char_idx": 3520, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6b53a586-acf1-49b8-9409-67052470c56e": {"__data__": {"id_": "6b53a586-acf1-49b8-9409-67052470c56e", "embedding": null, "metadata": {"page_label": "340", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3a3de74a-d75f-417e-b629-bea2fdc88b71", "node_type": null, "metadata": {"page_label": "340", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "868e6399ce555ce7e0dc7760735d45019cdf022d559e27b7e203b9d6dd753976"}, "2": {"node_id": "75abdf88-1c67-41ea-b955-83365e9b7e6e", "node_type": null, "metadata": {"page_label": "340", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f6c822f0850a8637ccd5ee14b6fa470dcff1d6b3772c48f988fd17ccd010d5b"}}, "hash": "ba17721c1643fd6c7f7023c0450b2bf0ce0b9cd95515fe717709c8b9f63e58fe", "text": "\nchronic, is often surprisingly asymptomatic. The commonest \ncause is blood loss resulting from menstruation, drug \ntreatment (e.g. with aspirin or other non-steroidal anti-\ninflammatory drugs; Ch. 27) or pathological processes such \nas colonic carcinoma or (especially in developing countries) \nparasitic infestation (Ch. 56). Pregnancy and child-bearing \nare important physiological drains on iron reserves. There \nare several different types of anaemia based on indices of \nred cell size and haemoglobin content and microscopical \nexamination of a stained blood smear:\n\u2022\thypochromic , microcytic anaemia (small red cells with \nlow haemoglobin; caused by chronic blood loss giving \nrise to iron deficiency)\n\u2022\tmacrocytic anaemia (large red cells, few in number)\n\u2022\tnormochromic normocytic anaemia (fewer normal-sized \nred cells, each with a normal haemoglobin content)\n\u2022\tmixed\t pictures\nFurther evaluation may include determination of concentra -\ntions of ferritin, iron, vitamin B 12 and folic acid in serum, and \nmicroscopic examination of smears of bone marrow. This \nleads to more precise diagnostic groupings of anaemias into:\n\u2022\tDeficiency\t of\tnutrients\t necessary\t for\thaematopoiesis,\t\nmost importantly:\n\u2022\tiron\n\u2022\tfolic\tacid\tand\tvitamin\tB12\n\u2022\tpyridoxine\t and\tvitamin\tC\n\u2022\tDepression\t of\tthe\tbone\tmarrow,\t commonly\t caused\tby:\n\u2022\tdrug\ttoxicity\t(e.g.\tanticancer\t drugs,\t clozapine )\n\u2022\texposure\t to\tradiation,\t including\t radiotherapy\n\u2022\tdiseases\t of\tthe\tbone\tmarrow\t (e.g.\tidiopathic\t aplastic\t\nanaemia, leukaemias)\n\u2022\treduced\t production\t of,\tor\tresponsiveness\t to,\t\nerythropoietin (e.g. chronic renal failure, \nrheumatoid arthritis, AIDS)\n\u2022\tExcessive\t destruction\t of\tred\tblood\tcells\t(i.e.\t\nhaemolytic anaemia); this has many causes, including \nhaemoglobinopathies (such as sickle cell anaemia), \nadverse reactions to drugs and immune reactions that \nhave gone awry.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3440, "end_char_idx": 5791, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "212e0c56-885c-4896-8791-5960a4293423": {"__data__": {"id_": "212e0c56-885c-4896-8791-5960a4293423", "embedding": null, "metadata": {"page_label": "341", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ac9da951-1b83-4f48-8717-914d28570729", "node_type": null, "metadata": {"page_label": "341", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "afee0dea2b4224ddab799b4a72602f08254914927832bad50dfc2beec8f8c6e0"}, "3": {"node_id": "cd45a11a-1dfe-49f1-95f4-7dd134214af0", "node_type": null, "metadata": {"page_label": "341", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0aab8b8e523534da618dda0a6dd07ad202a0cb0410689d26f1f40923511c673c"}}, "hash": "2bc09125b2e97c60abcdbe2d3cfa080abac918353ab5502aa113618009a59be4", "text": "26 HAEMATO pOIETIC SYSTEM AND TREATMENT OF ANAEMIA\n335IRON TURNOVER AND BALANCE\nThe normal daily requirement for iron is approximately 5 mg \nfor men, and 15 m g for growing children and for menstruat -\ning women. A pregnant woman needs between 2 and 10 \ntimes this amount because of the demands of the fetus and \nincreased requirements of the mother.1 The average diet in \nWestern\tEurope \tprovides \t15\u201320 \t mg \tof \tiron \tdaily, \tmostly \tin \t\nmeat. Iron in meat is generally present as haem, and about 20%\u201340% of haem iron is available for absorption.\n\u25bc Humans are adapted to absorb haem iron. It is thought that one \nreason why modern humans have problems in maintaining iron \nbalance (there are an estimated 500 million people with iron deficiency \nin the world) is that the change from hunting to grain cultivation 10,000 years ago led to cereals, which contain little utilisable iron, \nreplacing meat in the diet. Non-haem iron in food is mainly in the \nferric state, and this needs to be converted to ferrous iron for absorption. Iron salts have low solubility at the neutral pH of the small intestine; \nhowever, in the stomach, iron dissolves and binds to a mucoprotein \ncarrier. In the presence of ascorbic acid, fructose and various amino \nacids, iron is detached from the carrier, forming soluble low molecular-\nweight complexes that enable it to remain in soluble form in the intestine. Ascorbic acid stimulates iron absorption partly by forming \nsoluble iron\u2013ascorbate chelates and partly by reducing ferric iron to \nthe more soluble ferrous form. Tetracycline forms an insoluble iron \nchelate, impairing absorption of both substances.\nThe amount of iron in the diet and the various factors affecting its \navailability are thus important determinants in absorption, but the \nregulation of iron absorption is a function of the intestinal mucosa, \ninfluenced by the body\u2019s iron stores. Because there is no mechanism whereby iron excretion is regulated, the absorptive mechanism has \na central role in iron balance as it is the sole mechanism by which \nbody iron is controlled.HAEMATINIC AGENTS\nThe use of haematinic agents is often only an adjunct to \ntreatment of the underlying cause of the anaemia \u2013 for \nexample, surgery for colon cancer (a common cause of iron \ndeficiency) or antihelminthic drugs for patients with hook -\nworm (a frequent cause of anaemia in parts of Africa and \nAsia; Ch. 56). Sometimes treatment consists of stopping an \noffending drug, for example a non-steroidal anti-inflammatory drug that is causing blood loss from the gastrointestinal \ntract (Ch. 27).\nIRON\nIron is a transition metal with two important properties \nrelevant to its biological role, namely its ability to exist in \nseveral oxidation states and to form stable coordination \ncomplexes.\nThe body of a 70-kg man contains about 4 g of iron, 65% \nof which circulates in the blood as haemoglobin. About one-half of the remainder is stored in the liver, spleen and \nbone marrow, chiefly as ferritin and haemosiderin. The iron \nin these molecules is available for haemoglobin synthesis. \nThe rest, which is not available for haemoglobin synthesis, \nis present in myoglobin, cytochromes and various enzymes.\nThe distribution and turnover of iron in an average adult \nman are shown in Table 26.1 and Fig. 26.1. The correspond -\ning values in a woman are approximately 45% less. Because \nmost of the iron in the body is either part of \u2013 or destined to be part of \u2013 haemoglobin, the most obvious clinical result of iron deficiency is anaemia, and the only indication for \ntherapy with iron is for treatment or prophylaxis of iron \ndeficiency anaemia.\nHaemoglobin", "start_char_idx": 0, "end_char_idx": 3663, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cd45a11a-1dfe-49f1-95f4-7dd134214af0": {"__data__": {"id_": "cd45a11a-1dfe-49f1-95f4-7dd134214af0", "embedding": null, "metadata": {"page_label": "341", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ac9da951-1b83-4f48-8717-914d28570729", "node_type": null, "metadata": {"page_label": "341", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "afee0dea2b4224ddab799b4a72602f08254914927832bad50dfc2beec8f8c6e0"}, "2": {"node_id": "212e0c56-885c-4896-8791-5960a4293423", "node_type": null, "metadata": {"page_label": "341", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2bc09125b2e97c60abcdbe2d3cfa080abac918353ab5502aa113618009a59be4"}}, "hash": "0aab8b8e523534da618dda0a6dd07ad202a0cb0410689d26f1f40923511c673c", "text": "is for treatment or prophylaxis of iron \ndeficiency anaemia.\nHaemoglobin is made up of four protein chain subunits \n(globins), each of which contains one haem moiety. Haem consists of a tetrapyrrole porphyrin ring containing ferrous (Fe\n2+)\tiron.\tEach\thaem\tgroup\tcan\tcarry\tone\toxygen\tmolecule, \t\nwhich is bound reversibly to Fe2+ and to a histidine residue \nin the globin chain. This reversible binding is the basis of \noxygen transport.\nTable 26.1 The distribution of iron in the body of a \nhealthy 70-kg man\nProtein Tissue Iron content (mg)\nHaemoglobin Erythrocytes 2600\nMyoglobin Muscle 400\nEnzymes \n(cytochromes, catalase, guanylyl cyclase, etc.)Liver and other tissues25\nTransferrin Plasma and extracellular fluid8\nFerritin and haemosiderinLiver 410\nSpleen 48\nBone marrow 300\n(Data from Jacobs, A., Worwood, M., 1982. Chapter 5. In: Hardisty, R.M., Weatherall, D.J. (Eds). Blood and Its Disorders. Blackwell Scientific, Oxford.)Absorption\n1\u20132 mg daily\n5 mg\n30 mg 30 mg\nBone marrow:\nin rbc precursors\n(150 mg)Loss\n1\u20132 mg daily\n24 mg6 mg\nHb in rbc\n(3000 mg)24 mgStores in mnp\n(1000 mg)Iron supplement\ne.g. ferrous sulfateDietary\niron\nPlasma\n(4 mg)\nTissues\n(150 mg)\nFig. 26.1 Distribution and turnover of iron in the body. The \nquantities by the arrows indicate the usual amounts transferred \neach day. The transfer of 6 mg from red cell precursors to \nphagocytes represents aborted cells that fail to develop into functional red blood cells. Hb, haemoglobin; mnp, mononuclear \nphagocytes (mainly in liver, spleen and bone marrow); rbc, red \nblood cells. \n1Each\tpregnancy \t\u2018costs\u2019 \tthe \tmother \t680 \tmg \tof \tiron, \tequivalent \tto \t\n1300 mL of blood, owing to the demands of the fetus, plus requirements \nof the expanded blood volume and blood loss at delivery.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3591, "end_char_idx": 5837, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3169158d-30b1-4d20-9954-d7d9354729ba": {"__data__": {"id_": "3169158d-30b1-4d20-9954-d7d9354729ba", "embedding": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c87ea696-6f92-4b46-bffc-c27dbde3386b", "node_type": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed5f488739494400223ae432db5bd04a63b21b1a4053bb425c1287e9af3d4439"}, "3": {"node_id": "710af244-aa6d-44a3-8d61-7db46d71e707", "node_type": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5c6312e28011c2549a46050c5f477282991eff5fd727e0222658d1c61977be0"}}, "hash": "7b49d990c1edef2ea46c765256b9bc8651f019549caf6381b4b2528e6afb194c", "text": "26 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n336Parenteral (outside the alimentary canal) administration \nof iron (e.g. iron-dextran, iron-sucrose) may be necessary \nin individuals who are not able to absorb oral iron because \nof malabsorption syndromes, or as a result of surgical procedures or inflammatory conditions involving the \ngastrointestinal tract. It is also used for patients who do \nnot tolerate oral preparations, and patients with chronic renal failure or with chemotherapy-induced anaemia who \nare receiving treatment with erythropoietin (see pp. 339\u2013341). \nIron-dextran can be given by deep intramuscular injection or slow intravenous infusion; iron-sucrose is given by slow intravenous infusion. A small initial dose is given because \nof the risk of anaphylactoid reaction.\nUnwanted effects\nThe unwanted effects of oral iron administration are dose-\nrelated and include nausea, abdominal cramps and diar -\nrhoea. Parenteral iron can cause anaphylactoid reactions \n(Ch.\t58).\tIron\tis\tan\timportant \tnutrient\tfor\tseveral\tpathogens \t\nand there is concern that excessive iron could worsen the clinical course of infection. Iron treatment is usually avoided \nduring infection for this reason.\nAcute iron toxicity , usually seen in young children who \nhave swallowed attractively coloured iron tablets in mistake for sweets, can result in severe necrotising gastritis with \nvomiting, haemorrhage and diarrhoea, followed by circula -\ntory collapse.Iron absorption takes place in the duodenum and upper jejunum, and is a two-stage process involving uptake across \nthe brush border into the mucosal cells, followed by transfer \ninto the plasma. The second stage, which is rate limiting, is energy dependent. Haem iron in the diet is absorbed as \nintact haem, and the iron is released in the mucosal cell by \nthe action of haem oxidase. Non-haem iron is absorbed in the ferrous state. Within the cell, ferrous iron is oxidised \nto ferric iron, which is bound to an intracellular carrier, \na transferrin-like protein; the iron is then either held in storage in the mucosal cell as ferritin (if body stores of \niron are high) or passed on to the plasma (if iron stores \nare low).\n\u25bc Iron is carried in the plasma bound to transferrin, a \u03b2-globulin \nwith two binding sites for ferric iron. The binding sites are normally \nonly approximately 30% saturated. Plasma contains 4 mg of iron at \nany one time, but the daily turnover is about 30 mg (see Fig. 26.1). \nMost of the iron that enters the plasma is derived from mononuclear \nphagocytes, following the degradation of time-expired erythrocytes. \nIntestinal absorption and mobilisation of iron from storage depots \ncontribute only small amounts. Most of the iron that leaves the plasma each day is used for haemoglobin synthesis by red cell precursors \n(erythroblasts). These have receptors that bind transferrin, releasing \nit again when its cargo of iron has been captured.\nIron is stored in two forms: soluble ferritin and insoluble haemosiderin. \nFerritin is present in all cells, the mononuclear phagocytes of liver, spleen \nand bone marrow containing especially high concentrations. It is also \npresent in plasma. The precursor of ferritin, apoferritin, is a protein of \nmolecular weight 450,000, composed of 24 identical polypeptide subunits \nthat enclose a cavity in which up to 4500 iron atoms can be stored. \nApoferritin takes up ferrous iron, oxidises it and deposits the ferric iron in its core. In this form, it constitutes", "start_char_idx": 0, "end_char_idx": 3502, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "710af244-aa6d-44a3-8d61-7db46d71e707": {"__data__": {"id_": "710af244-aa6d-44a3-8d61-7db46d71e707", "embedding": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c87ea696-6f92-4b46-bffc-c27dbde3386b", "node_type": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed5f488739494400223ae432db5bd04a63b21b1a4053bb425c1287e9af3d4439"}, "2": {"node_id": "3169158d-30b1-4d20-9954-d7d9354729ba", "node_type": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b49d990c1edef2ea46c765256b9bc8651f019549caf6381b4b2528e6afb194c"}, "3": {"node_id": "1c93590a-c955-4ed4-8ff5-19ce1e0045b2", "node_type": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a16b8aa331da5edc7476141a138447dfe7fc16d846a6052f85e0060e1c423e0"}}, "hash": "f5c6312e28011c2549a46050c5f477282991eff5fd727e0222658d1c61977be0", "text": "it and deposits the ferric iron in its core. In this form, it constitutes ferritin, the primary storage form \nof iron, from which the iron is most readily available. The lifespan of \nthis iron-laden protein is only a few days. Haemosiderin is a degraded \nform of ferritin in which the iron cores of several ferritin molecules have \naggregated, following partial disintegration of the outer protein shells.\nIron is not the most soluble of metals, hence its need to bind to transferrin (whilst transferring around the body) and ferritin for use \ninside cells (ferritin is found mostly inside cells but can exist in the \nplasma too, functioning to transport iron into cells). Ferritin in plasma contains very little iron, as two-thirds of the body\u2019s iron deposits are \nfound within red blood cells, with more ferritin in the body than free \nunbound iron. The slow turnover of iron absorbed from the diet, transferred around the body by transferrin, then held in cellular storage \nby ferritin, means that the majority of total useful iron is held in \nerythrocytes, and their rapid turnover is the main source of liberated \niron. Iron bound to plasma ferritin is, however, in equilibrium with \nthe storage ferritin in cells, and its concentration in plasma (normal \nrange 40\u2013100 ng/mL) provides a clinically useful indicator of total \nbody iron stores since values below 40 ng/mL signal mild iron \ndeficiency despite normal haemoglobin, red cell morphology, serum iron concentration and transferrin saturation, with values below 20 \nand 10 ng/mL signalling moderate and severe anaemia, respectively.\nThe body has no means of actively excreting iron. Small amounts leave the body through shedding of mucosal cells containing ferritin, \nand even smaller amounts leave in the bile, sweat and urine. A total \nof about 1 mg is lost daily. Iron balance is therefore critically dependent \non the active absorption mechanism in the intestinal mucosa. This \nabsorption is influenced by the iron stores in the body, but the precise \nmechanism of this control is uncertain. Iron balance is summarised \nin Fig. 26.1. Since red cells contain approximately 0.6 mg iron per \nmL of blood, loss of only a few millilitres of blood per day substantially \nincreases dietary iron requirement.\nADMINISTRATION OF IRON\nIron is usually given orally, e.g. as ferrous sulfate. Other \nsalts for oral administration are ferrous succinate , gluconate \nor fumarate.Clinical uses of iron salts \nTo treat iron deficiency anaemia, which can be caused \nby:\u2022\tchronic blood loss (e.g. with menorrhagia, hookworm, \ncolon cancer);\n\u2022\tincreased demand (e.g. in pregnancy and early \ninfancy);\n\u2022\tinadequate dietary intake (uncommon in developed \ncountries);\n\u2022\tinadequate absorption (e.g. following gastrectomy, or \nin diseases such as coeliac disease, where the intestinal mucosa is damaged by an immunologically based intolerance to the wheat protein gluten).\n2\u2018Bronze\tdiabetes\u2019 \t\u2013 \twhere \tchronic \tiron \toverload \tis \ttreated \tby \trepeated \t\nbleeding, one of the few modern uses of this once near-universal \n\u2018remedy\u2019; \tpolycythaemia \tvera \t(caused \tby \tmutations \tin \terythroid \t\nprogenitors that increase their proliferation) is another.Iron overload\nChronic iron toxicity or iron overload occurs in chronic \nhaemolytic anaemias requiring frequent blood transfusions, \nsuch as the thalassaemias (a large group of genetic disorders \nof globin chain synthesis) and haemochromatosis (a genetic \niron storage disease with increased iron absorption, resulting in damage to liver,", "start_char_idx": 3443, "end_char_idx": 6980, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1c93590a-c955-4ed4-8ff5-19ce1e0045b2": {"__data__": {"id_": "1c93590a-c955-4ed4-8ff5-19ce1e0045b2", "embedding": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c87ea696-6f92-4b46-bffc-c27dbde3386b", "node_type": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed5f488739494400223ae432db5bd04a63b21b1a4053bb425c1287e9af3d4439"}, "2": {"node_id": "710af244-aa6d-44a3-8d61-7db46d71e707", "node_type": null, "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5c6312e28011c2549a46050c5f477282991eff5fd727e0222658d1c61977be0"}}, "hash": "8a16b8aa331da5edc7476141a138447dfe7fc16d846a6052f85e0060e1c423e0", "text": "storage disease with increased iron absorption, resulting in damage to liver, islets of Langerhans, joints and skin).\n2\nThe treatment of acute and chronic iron toxicity involves \nthe use of iron chelators such as desferrioxamine. These \ndrugs form a complex with ferric iron which, unlike \nunbound iron, is excreted in the urine. Desferrioxamine is not absorbed from the gut. For treating chronic iron overload \n(e.g. in thalassaemia), it must be given by slow subcutaneous \ninfusion several times a week. For acute iron overdose, it mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6963, "end_char_idx": 7976, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0f6daacc-32e3-4284-861c-ac01f7ade420": {"__data__": {"id_": "0f6daacc-32e3-4284-861c-ac01f7ade420", "embedding": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1f64220e-c9fc-41bb-9fa5-522ebb51cd2f", "node_type": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "715e1196d284e8454333a98f4da7fc5fc8166ff947ad9ee4bd743dc67d1f10e6"}, "3": {"node_id": "b8b2ba2a-6444-4198-bd06-c2394f21acec", "node_type": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "450db42f6cb0b6dfc022ebebb2020cf9b8b704e250e395944d15fca89d06d577"}}, "hash": "6f68660db9006f75493feee4d48ad1503b6f8f075b71c9ab488296e729fd888f", "text": "26 HAEMATO pOIETIC SYSTEM AND TREATMENT OF ANAEMIA\n337megaloblasts \u2013 the precursors of macrocytic red cells in \npatients with B 12 or folate deficiency \u2013 are functionally \nasynchronous and feebly active, compared with the cells\u2019 \nlow haemoglobin content). Neurological disorders caused \nby deficiency of vitamin B 12 include peripheral neuropathy \nand dementia, as well as subacute combined degeneration3 of \nthe spinal cord. Folic acid deficiency is caused by dietary \ndeficiency, especially during increased demand (e.g. during \npregnancy \u2013 particularly important because of the link between folate deficiency and neural tube defects in the \nbaby\t(see \tCh. \t58) \tor \tbecause \tof \tchronic \thaemolysis \tin \t\npatients with haemoglobinopathies such as sickle cell anaemia \n\u2013 see p. 341). Vitamin B 12 deficiency, however, is usually \ndue\tto\tdecreased \tabsorption \t(see \tp. \t338).\nFOLIC ACID\nSome aspects of folate structure and metabolism are dealt with in Chapters 51 and 57, because several important antibacterial \nand anticancer drugs are antimetabolites that interfere with \nfolate synthesis in microorganisms or tumour cells. Liver and green vegetables are rich sources of folate (also known as \nvitamin B\n9). In healthy non-pregnant adults, the daily require -\nment is about 0.2 mg daily, but this is increased during \npregnancy. Healthy fetal neural development in particular \nrequires sufficient folate in the mother\u2019s diet, also leading to \nfoetal neural development defects if insufficient.\nMechanism of action\nReduction of folic acid, catalysed by dihydrofolate reductase \nin two stages yields dihydrofolate (FH 2) and tetrahydrofolate \n(FH 4), co-factors which transfer methyl groups (1-carbon \ntransfers) in several important metabolic pathways. FH 4 is \nessential for DNA synthesis because of its role as co-factor in the synthesis of purines and pyrimidines. It is also neces -\nsary for reactions involved in amino acid metabolism.\nFH\n4 is important for the conversion of deoxyuridylate \nmonophosphate (DUMP) to deoxythymidylate monophos -\nphate (DTMP). This reaction is rate limiting in mammalian \nDNA synthesis and is catalysed by thymidylate synthetase, with FH\n4 acting as methyl donor.\nPharmacokinetic aspects\nTherapeutically, folic acid is given orally and is absorbed in the ileum. Methyl-FH\n4 is the form in which folate is \nusually carried in blood and which enters cells. It is function -\nally inactive until it is demethylated in a vitamin B\n12-dependent \treaction \t(see \tp. \t338). \tFolate \tis \ttaken \tup \tinto \t\nhepatocytes and bone marrow cells by active transport. Within the cells, folic acid is reduced and formylated before \nbeing converted to the active polyglutamate form. Folinic \nacid, a synthetic FH\n4, is converted much more rapidly to \nthe polyglutamate form.\nUnwanted effects\nUnwanted effects do not occur even with large doses of \nfolic acid \u2013 except possibly in the presence of vitamin B 12 \ndeficiency, when it is possible that administration of folic \nacid may improve the anaemia while exacerbating the \nneurological lesion. It is therefore important to determine whether a megaloblastic anaemia is caused by folate or \nvitamin B\n12 deficiency and treat accordingly.FOLIC ACID AND VITAMIN B 12\nVitamin B 12 and folic acid are essential constituents of the \nhuman diet, being necessary for DNA synthesis and consequently for cell", "start_char_idx": 0, "end_char_idx": 3380, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b8b2ba2a-6444-4198-bd06-c2394f21acec": {"__data__": {"id_": "b8b2ba2a-6444-4198-bd06-c2394f21acec", "embedding": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1f64220e-c9fc-41bb-9fa5-522ebb51cd2f", "node_type": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "715e1196d284e8454333a98f4da7fc5fc8166ff947ad9ee4bd743dc67d1f10e6"}, "2": {"node_id": "0f6daacc-32e3-4284-861c-ac01f7ade420", "node_type": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f68660db9006f75493feee4d48ad1503b6f8f075b71c9ab488296e729fd888f"}, "3": {"node_id": "99551ff8-8f2a-4add-9973-322da8fc951c", "node_type": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ff51194779fc3655c0d69b547c61179c8bf0bc02dfefa19ac9f4a62fec1ecbe"}}, "hash": "450db42f6cb0b6dfc022ebebb2020cf9b8b704e250e395944d15fca89d06d577", "text": "of the \nhuman diet, being necessary for DNA synthesis and consequently for cell proliferation. Their biochemical actions \nare interdependent (see key point box, p. 339), and treatment with folic acid corrects some, but not all, of the features of \nvitamin B\n12 deficiency. Deficiency of either vitamin B 12 or \nfolic acid affects tissues with a rapid cell turnover, particu -\nlarly bone marrow, but vitamin B 12 deficiency also causes \nimportant neuronal disorders, which are not corrected (or may even be made worse) by treatment with folic acid. \nDeficiency of either vitamin causes megaloblastic haemat-\nopoiesis , in which there is disordered erythroblast differentia -\ntion and defective erythropoiesis in the bone marrow. Large abnormal erythrocyte precursors appear in the marrow, each with a high RNA:DNA ratio as a result of decreased \nDNA synthesis. The circulating abnormal erythrocytes \n(\u2018macrocytes\u2019 \t\u2013 \ti.e. \tlarge \tred \tblood \tcells) \tare \tlarge \tfragile \t\ncells, often distorted in shape. Mild leukopenia and throm -\nbocytopenia (i.e. low white blood cell and platelet counts) usually accompany the anaemia, and the nuclei of poly -\nmorphonuclear (PMN) leukocytes are structurally abnormal \n(hypersegmented \u2013 as young PMNs mature, their nuclei \nacquire\t\u2018lobes\u2019 \tin \tthe \tform \tof \tdiscrete \tbulges, \tleading \tto \t\nhypersegmentation in post-mature cells. The nuclei of Iron \n\u2022\tIron\tis\timportant \tfor \tthe \tsynthesis \tof \thaemoglobin, \t\nmyoglobin, cytochromes and other enzymes.\n\u2022\tFerric\tiron \t(Fe3+) must be converted to ferrous iron \n(Fe2+) for absorption in the gastrointestinal tract.\n\u2022\tAbsorption \tinvolves \tactive \ttransport \tinto \tmucosal \tcells \t\nin the duodenum and jejunum (the upper ileum), from \nwhere it can be transported into the plasma and/or stored intracellularly as ferritin.\n\u2022\tTotal\tbody \tiron \tis \tcontrolled \texclusively \tby \tabsorption; \t\nin iron deficiency, more is transported into plasma than is stored as ferritin in jejunal mucosa.\n\u2022\tIron\tloss \toccurs \tmainly \tby \tsloughing \tof \tferritin-\ncontaining mucosal cells.\n\u2022\tIron\tin\tplasma \tis \tbound \tto \ttransferrin, \tand \tmost \tis \t\nused for erythropoiesis. Some is stored as ferritin in \nother\ttissues. \tIron \tfrom \ttime-expired \terythrocytes \t\nenters the plasma for reuse.\n\u2022\tThe\tmain \ttherapeutic \tpreparation \tis \tferrous sulfate; \niron-sucrose can be given as an intravenous infusion.\n\u2022\tUnwanted \teffects \tinclude \tgastrointestinal \tdisturbances. \t\nSevere toxic effects occur if large doses are ingested; such acute poisoning can be treated with desferrioxamine, an iron chelator, as can chronic \niron overload in diseases such as thalassaemia.\n3\u2018Combined\u2019 \tbecause \tthe \tlateral \tas \twell \tas \tthe \tdorsal \tcolumns \tare \t\ninvolved, giving rise to motor as well as sensory symptoms.is given intramuscularly or intravenously (as well as \nintragastrically to sequester unabsorbed iron). Deferiprone \nis an orally absorbed iron chelator, used as an alternative treatment for iron overload in patients with thalassaemia major who are unable to take desferrioxamine. Agranulo -\ncytosis and other blood dyscrasias are serious potential adverse effects. Deferasirox is similar, but", "start_char_idx": 3314, "end_char_idx": 6481, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "99551ff8-8f2a-4add-9973-322da8fc951c": {"__data__": {"id_": "99551ff8-8f2a-4add-9973-322da8fc951c", "embedding": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1f64220e-c9fc-41bb-9fa5-522ebb51cd2f", "node_type": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "715e1196d284e8454333a98f4da7fc5fc8166ff947ad9ee4bd743dc67d1f10e6"}, "2": {"node_id": "b8b2ba2a-6444-4198-bd06-c2394f21acec", "node_type": null, "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "450db42f6cb0b6dfc022ebebb2020cf9b8b704e250e395944d15fca89d06d577"}}, "hash": "2ff51194779fc3655c0d69b547c61179c8bf0bc02dfefa19ac9f4a62fec1ecbe", "text": "are serious potential adverse effects. Deferasirox is similar, but can cause gastrointestinal bleeding.\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6482, "end_char_idx": 7065, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c1118dac-2851-48e3-9ecc-9f670a887767": {"__data__": {"id_": "c1118dac-2851-48e3-9ecc-9f670a887767", "embedding": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "779f268f-64e5-45b1-89f2-cd1666f58c74", "node_type": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "290f70262d7c0c1bbe1f9ef8f7cf10290ccef990fb9b473ff28541b823538ebc"}, "3": {"node_id": "ee76ea05-7417-43ed-983d-dc7e9747a0df", "node_type": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "18da60d449cbe2f75e2c667b05872a4153417721aa956704c137f9036d053c7c"}}, "hash": "b666cf9aedbac07913d214b6295eb090bd2e52ebe4dca1bd3b159c120b9b723b", "text": "26 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n338The conversion of methyl-FH 4 to FH 4. The metabolic activities of \nvitamin B 12 and folic acid are linked in the synthesis of DNA. It is \nalso through this pathway that folate/vitamin B 12 treatment can lower \nplasma homocysteine concentration. Because increased homocysteine \nconcentrations may have undesirable vascular effects (Ch. 24, Table \n24.1), this has potential therapeutic and public health implications. The reaction involves conversion of both methyl-FH\n4 to FH 4 and \nhomocysteine to methionine. The enzyme that accomplishes this \n(homocysteine\u2013methionine methyltransferase) requires vitamin B 12 as \nco-factor and methyl-FH 4 as methyl donor. The methyl group from \nmethyl-FH 4 is transferred first to B 12, and then to homocysteine to \nform methionine. Vitamin B 12 deficiency thus traps folate in the inactive \nmethyl-FH 4 form, thereby depleting the folate polyglutamate coen -\nzymes needed for DNA synthesis. Vitamin B 12-dependent methionine \nsynthesis also affects the synthesis of folate polyglutamate coenzymes by an additional mechanism. The preferred substrate for polyglutamate \nsynthesis is formyl-FH\n4, and the conversion of FH 4 to formyl-FH 4 \nrequires a formate donor such as methionine.\nIsomerisation of methylmalonyl-CoA to succinyl-CoA . This isomerisa -\ntion reaction is part of a route by which propionate is converted to \nsuccinate. Through this pathway, cholesterol, odd-chain fatty acids, \nsome amino acids and thymine can be used for gluconeogenesis or for energy production via the tricarboxylic acid (TCA) cycle. Coenzyme \nB\n12 (ado-B 12) is an essential co-factor, so methylmalonyl-CoA accu -\nmulates in vitamin B 12 deficiency. This distorts the pattern of fatty \nacid synthesis in neural tissue and may be the basis of neuropathy in vitamin B\n12 deficiency.\nAdministration of vitamin B 12\nWhen vitamin B 12 is used therapeutically (as hydroxoco-\nbalamin), it is usually given by injection4 because, as \nexplained above, vitamin B 12 deficiency commonly results \nfrom malabsorption. Patients with pernicious anaemia \nrequire life-long therapy, with maintenance injections every \n3 months following a loading dose. Hydroxocobalamin does not cause unwanted effects.\nHAEMATOPOIETIC GROWTH FACTORS\nEvery\t60\tseconds,\ta\thuman\tbeing\tmust\tgenerate \tabout\t120\t\nmillion granulocytes and 150 million erythrocytes, as well as numerous mononuclear cells and platelets.\n5 The cells \nresponsible for this remarkable productivity are derived \nfrom a relatively small number of self-renewing, pluripotent \nstem cells laid down during embryogenesis. Maintenance of haematopoiesis necessitates a balance between self-\nrenewal of the stem cells on the one hand, and differentiation \ninto the various types of blood cell on the other. The factors involved in controlling this balance are the haematopoietic \ngrowth factors , which direct the division and maturation of \nthe progeny of these cells down eight possible lines of development (Fig. 26.2). These cytokine growth factors are highly potent glycoproteins, acting at concentrations of 10\n\u221212 \nto 10\u221210 mol/L. They are present in plasma at very low \nconcentrations under basal conditions, but on stimulation their concentrations can increase within hours by 1000-fold \nor more. Erythropoietin regulates the red cell line, and the VITAMIN B 12\nVitamin B 12, also called cobalamin, corrects pernicious \nanaemia. The vitamin B 12", "start_char_idx": 0, "end_char_idx": 3464, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ee76ea05-7417-43ed-983d-dc7e9747a0df": {"__data__": {"id_": "ee76ea05-7417-43ed-983d-dc7e9747a0df", "embedding": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "779f268f-64e5-45b1-89f2-cd1666f58c74", "node_type": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "290f70262d7c0c1bbe1f9ef8f7cf10290ccef990fb9b473ff28541b823538ebc"}, "2": {"node_id": "c1118dac-2851-48e3-9ecc-9f670a887767", "node_type": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b666cf9aedbac07913d214b6295eb090bd2e52ebe4dca1bd3b159c120b9b723b"}, "3": {"node_id": "4e49e243-6364-4b25-ba41-5152a9d472c9", "node_type": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9409a29a0b4020c88b7480597a579847629e35ce3b9c0480d3555b1b3aaee8a5"}}, "hash": "18da60d449cbe2f75e2c667b05872a4153417721aa956704c137f9036d053c7c", "text": "also called cobalamin, corrects pernicious \nanaemia. The vitamin B 12 preparation used therapeutically \nis hydroxocobalamin, derived from cultured micro -\norganisms. The principal dietary sources are meat (par -\nticularly liver, where it is stored), eggs and dairy products. \nFor activity, cobalamins must be converted to methylcobalamin \n(methyl-B 12) or 5\u2032-deoxyadenosylcobalamin (ado-B 12). The \naverage\tEuropean \tdiet\tcontains\t5\u201325\t\u00b5g of vitamin B 12 per \nday, and the daily requirement is 2\u20133 \u00b5g. Absorption \nrequires intrinsic factor (a glycoprotein secreted by gastric \nparietal cells). Vitamin B 12, complexed with intrinsic factor, \nis absorbed by active transport in the terminal ileum. Healthy \nstomach secretes a large excess of intrinsic factor, but in \npatients with pernicious anaemia (an autoimmune disorder where the lining of the stomach atrophies), or following \ntotal gastrectomy, the supply of intrinsic factor is inadequate \nto maintain vitamin B\n12 absorption in the long term. Surgical \nremoval of the terminal ileum, for example, to treat Crohn\u2019s \ndisease (see Ch. 31), can also impair B 12 absorption.\nVitamin B 12 is carried in the plasma by binding proteins \ncalled transcobalamins. It is stored in the liver, the total \namount in the body being about 4 mg. This store is so large \ncompared with the daily requirement, that if vitamin B 12 \nabsorption stops suddenly \u2013 as after a total gastrectomy \u2013 it takes 2\u20134 years for evidence of deficiency to become \nmanifest.\nMechanism of action\n\u25bc Vitamin B 12 is required for two main biochemical reactions in \nhumans.Clinical uses of folic acid and \nvitamin B 12 (hydroxocobalamin) \nFolic acid (vitamin B 9)\n\u2022\tTreatment \tof \tmegaloblastic \tanaemia \tresulting \tfrom \t\nfolate deficiency, which can be caused by:\n\u2013 poor diet (common in alcoholic individuals)\n\u2013 malabsorption syndromes\n\u2013 drugs (e.g. phenytoin).\n\u2022\tTreatment \tor \tprevention \tof \ttoxicity \tfrom \t\nmethotrexate, a folate antagonist (see Chs 27 and \n57).\n\u2022\tProphylactically \tin \tindividuals \tat \thazard \tfrom \t\ndeveloping folate deficiency, for example:\n\u2013 pregnant women and before conception (especially \nif there is a risk of birth defects)\n\u2013 premature infants\n\u2013 patients with severe chronic haemolytic anaemias , \nincluding haemoglobinopathies (e.g. sickle cell anaemia).\nVitamin B 12 (hydroxocobalamin)\n\u2022\tTreatment \tof \tpernicious anaemia and other causes of \nvitamin B 12 deficiency.\n\u2022\tProphylactically \tafter \tsurgical \toperations \tthat \tremove \t\nthe site of production of intrinsic factor (the stomach) or of vitamin B\n12 absorption (the terminal ileum).\n4At least in Anglo-Saxon countries; in France, very large doses of \nvitamin B 12 are given by mouth to achieve sufficient absorption for \ntherapeutic \tefficacy \tdespite \tthe \tabsence \tof \tintrinsic \tfactor. \tEither \t\nmethod is a great improvement on eating the prodigious quantities of \nraw\tliver \trequired \tby \tMinot \tand \tMurphy\u2019s \t\u2018liver \tdiet\u2019 \tof \t1925! \t\u2013 \tno \t\nmatter how bad the taste of vitamin B 12, it\u2019s got to be better than that?\n5That\u2019s your entire genome replicated faithfully for at least 200 million \nnew blood cells every minute \u2013 our bodies are truly remarkable \nmachines.mebooksfree.net", "start_char_idx": 3405, "end_char_idx": 6608, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4e49e243-6364-4b25-ba41-5152a9d472c9": {"__data__": {"id_": "4e49e243-6364-4b25-ba41-5152a9d472c9", "embedding": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "779f268f-64e5-45b1-89f2-cd1666f58c74", "node_type": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "290f70262d7c0c1bbe1f9ef8f7cf10290ccef990fb9b473ff28541b823538ebc"}, "2": {"node_id": "ee76ea05-7417-43ed-983d-dc7e9747a0df", "node_type": null, "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "18da60d449cbe2f75e2c667b05872a4153417721aa956704c137f9036d053c7c"}}, "hash": "9409a29a0b4020c88b7480597a579847629e35ce3b9c0480d3555b1b3aaee8a5", "text": "minute \u2013 our bodies are truly remarkable \nmachines.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6602, "end_char_idx": 7132, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3e81f972-bc84-4d2b-9d89-521dc7ecc8bc": {"__data__": {"id_": "3e81f972-bc84-4d2b-9d89-521dc7ecc8bc", "embedding": null, "metadata": {"page_label": "345", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "12f7a6d7-a626-40aa-9512-f492e01ba3d7", "node_type": null, "metadata": {"page_label": "345", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e976bf79162ec2e7f64fe72f06958ffdadc0f655a4755ea1888402a6254698"}, "3": {"node_id": "0c547f5b-5455-4963-bd90-ab99ff2bfd13", "node_type": null, "metadata": {"page_label": "345", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "435f8d94f4bcd077f837f517d70da996acad1ce2089f744680b6b1b5902698c3"}}, "hash": "b249654d9dd04ae302e922c8e8bec2218e2da0c1e9e9da8c0e9bd2cd11458a82", "text": "26 HAEMATO pOIETIC SYSTEM AND TREATMENT OF ANAEMIA\n339signal for its production is blood loss and/or low tissue \noxygen tension. CSFs regulate the myeloid divisions of the \nwhite cell line, and the main stimulus for their production is infection (see also Ch. 7).\nRecombinant erythropoietin ( epoietin ),\n6 and recombinant \ngranulocyte CSF ( filgrastim, lenograstim, pegfilgrastim) \nare used clinically (see later); thrombopoietin has been \nmanufactured in recombinant form but there are concerns about effects on tumour progression (it activates a cell \nsurface protein that is an oncogene product) and it has \nbeen associated with severe immunologically mediated adverse effects. Some of the other haematopoietic growth \nfactors (e.g. interleukin-3, interleukin-5 and various other \ncytokines) are covered in Chapter 7.\nERYTHROPOIETIN\nErythropoietin \tis \ta \tglycoprotein \tproduced \tin \tjuxtatubular \t\ncells in the kidney and also in macrophages; it stimulates committed erythroid progenitor cells to proliferate and gen -\nerate erythrocytes (see Fig. 26.2). Recombinant human eryth -\nropoietins are made in cultured mammalian cells (because their pharmacokinetic properties depend critically on the \ndegree of glycosylation, a post-translational modification \nthat occurs in mammalian but not so predictably in bacterial cells) and used to treat anaemia caused by erythropoietin \ndeficiency, for example in patients with chronic kidney \ndisease,\tAIDS \tor \tcancer. \tEpoietin \t(recombinant \thuman \tErythrocytes\nPlateletsMonocytesNeutrophilsEosinophiIsBasophils\nB lymphocytes\nT lymphocytesThrombopoietin\nIL-1, IL-3,\nIL-6,\nGM-CSF,\nSCF\nMonocyte-\ngranulocyte\nprecursorMegakaryocyte\nThymusPluripotent\nstem cellCommitted\nprogenitor\ncells\nIL-3 GM-CSF Erythropoietin\nGM-CSF IL-3\nM-CSF IL-3\nIL-3GM-CSF\nGM-CSF\nG-CSF GM-CSF\nIL-5 IL-3 GM-CSF\nIL-3\nInterleukins 1,2,4,6,7\nFig. 26.2 Haematopoietic growth factors in blood cell differentiation. Various preparations of the factors shown in bold are in clinical \nuse (see text). Most T cells generated in the thymus die by apoptosis; those that emerge are either CD4 or CD8 T cells. The colours used \nfor the mature blood cells reflect how they appear in common staining preparations (and after which some are named). CSF,\tcolony-\nstimulating factor; G-CSF, \tgranulocyte \tCSF; \tGM-CSF,\tgranulocyte\u2013macrophage \tCSF; \tIL-1,\tinterleukin-1; \tIL-3,\tinterleukin-3 \tor \tmulti-CSF; \t\nM-CSF,\tmacrophage \tCSF; \tSCF, stem cell factor. (See also Ch. 7.) \n6The first therapeutic agent to be produced by recombinant technology, \nby\tAmgen \tin \t1989 \t\u2013 \ta \thuge \tcommercial \tsuccess, \theralding \tthe \t\nemergence of the biotechnology industry \u2013 albeit with some anxious \nmoments (see Fig. 26.3).Vitamin B 12 and folic acid \nBoth vitamin B 12 and folic acid are needed for DNA \nsynthesis. Deficiencies particularly affect erythropoiesis, \ncausing macrocytic megaloblastic anaemia.\nFolic acid (vitamin B 9)\n\u2022\tThere\tis \tactive", "start_char_idx": 0, "end_char_idx": 2947, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0c547f5b-5455-4963-bd90-ab99ff2bfd13": {"__data__": {"id_": "0c547f5b-5455-4963-bd90-ab99ff2bfd13", "embedding": null, "metadata": {"page_label": "345", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "12f7a6d7-a626-40aa-9512-f492e01ba3d7", "node_type": null, "metadata": {"page_label": "345", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e976bf79162ec2e7f64fe72f06958ffdadc0f655a4755ea1888402a6254698"}, "2": {"node_id": "3e81f972-bc84-4d2b-9d89-521dc7ecc8bc", "node_type": null, "metadata": {"page_label": "345", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b249654d9dd04ae302e922c8e8bec2218e2da0c1e9e9da8c0e9bd2cd11458a82"}}, "hash": "435f8d94f4bcd077f837f517d70da996acad1ce2089f744680b6b1b5902698c3", "text": "acid (vitamin B 9)\n\u2022\tThere\tis \tactive \tuptake \tof \tfolic \tacid \tinto \tcells \tand \t\nreduction\tto \ttetrahydrofolate \t(FH 4) by dihydrofolate \nreductase; extra glutamates are then added.\n\u2022\tFolate\tpolyglutamate \tis \ta \tco-factor \t(a \tcarrier \tof \t\n1-carbon\tunits) \tin \tthe \tsynthesis \tof \tpurines \tand \t\npyrimidines (especially thymidylate).\nVitamin B 12 (hydroxocobalamin)\n\u2022\tVitamin\tB12 needs intrinsic factor (a glycoprotein) \nsecreted by gastric parietal cells for absorption in the terminal ileum.\n\u2022\tIt\tis\tstored \tin \tthe \tliver.\n\u2022\tIt\tis\trequired \tfor:\n\u2013\tconversion \tof \tmethyl-FH 4\t(inactive\tform \tof \tFH4) to \nactive\tformyl-FH 4, which, after polyglutamation, is a \nco-factor\tin \tthe \tsynthesis \tof \tpurines \tand \tpyrimidines;\n\u2013\tisomerisation \tof \tmethylmalonyl-CoA \tto \tsuccinyl-CoA.\n\u2022\tDeficiency \toccurs \tmost \toften \tin \tpernicious \tanaemia, \t\nwhich results from malabsorption caused by lack of intrinsic factor from the stomach. It causes neurological disease as well as anaemia.\n\u2022\tVitamin\tB12 is given by injection every 3 months to \ntreat pernicious anaemia.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2910, "end_char_idx": 4455, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "41504459-b387-41a2-a653-2b2dff425e27": {"__data__": {"id_": "41504459-b387-41a2-a653-2b2dff425e27", "embedding": null, "metadata": {"page_label": "346", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bfda59d9-e421-4c2a-9f0a-5e3cfc44966c", "node_type": null, "metadata": {"page_label": "346", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "74dc05d2fac94bebfc0536b1ec7981e3855b601ae811d4a977838d234cf585f2"}, "3": {"node_id": "438c12b6-5c06-454f-b097-c5388ad1972f", "node_type": null, "metadata": {"page_label": "346", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "356489fcdc637cb0153886b20258ccea98d9b84a7a41f9e24902e79fefa1553b"}}, "hash": "23de97565fdaa829ad87e9ddfcde39d80afacee9eb37f745a3ad5f2189b370d7", "text": "26 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n340not only stimulate particular committed progenitor cells \nto proliferate (see Fig. 26.2) but also cause irreversible \ndifferentiation. The responding precursor cells have mem -\nbrane receptors for specific CSFs and may express receptors \nfor more than one factor, thus permitting collaborative \ninteractions between factors.\nGranulocyte CSF is produced mainly by monocytes, \nfibroblasts and endothelial cells, and controls primarily the development of neutrophils, increasing their proliferation \nand maturation, stimulating their release from bone marrow storage pools and enhancing their function. Recombinant forms (filgrastim, which is not glycosylated, and glyco -\nsylated lenograstim ) are used therapeutically. Pegfilgrastim \nis a derivative of filgrastim conjugated with polyethylene \nglycol\t(\u2018pegylated\u2019), \twhich \thas \tthe \teffect \tof \tincreasing \tits \t\nduration of action.\nThrombopoietin, made in liver and kidney, stimulates \nproliferation and maturation of megakaryocytes to form platelets. Recombinant thrombopoietin has been a tempting but horribly deceptive therapeutic target. Thrombocytopenia \nis a predictable and limiting toxicity of many chemothera -\npeutic regimens in oncology (Ch. 57), and a means to \nmitigate this would be a valuable prize. Recombinant \nthrombopoietin, seemingly the logical answer to this need, \nwas manufactured and increased platelet counts in healthy volunteers and patients with mild chemotherapy-induced thrombocytopenia. But in early trials on healthy subjects, \nrepeated dosing of a pegylated product caused the appear -\nance of neutralising antibodies and consequently prolonged \nthrombocytopenia (Li et al., 2001), driving home the message \nfrom experience with erythropoietin (see Fig. 26.3) that \nsubtle differences between biological products and natural erythropoietin) exists in several forms (alpha, beta, theta and zeta). It has a plasma half-life of about 5 hours, and \nis given by injection three times weekly. Darbepoetin, a \nhyperglycosylated form, has a longer half-life and can be \nadministered less frequently, every 1\u20134 weeks; methoxy \npolyethylene glycol-epoetin beta is another preparation \nwith\tlong \thalf-life. \tEpoietin \tand \tdarbopoetin \tare \tgiven \t\nintravenously or subcutaneously, the response being greater after subcutaneous injection and faster after intravenous \ninjection.\nEpoietins \tare \treaching \tthe \tend \tof \tpatent \tprotection \t(e.g. \t\nthe original Procrit)\tand\tthe \tfirst \t\u2018biosimilar\u2019 \tproducts \thave\t\nbeen licensed (such as Binocrit and Retacrit \tin\t2017\tand \t2018\t\nrespectively). Unlike the situation for small-molecule chemi -\ncal entities where criteria for bioequivalence are relatively uncontroversial \u2013 Chapter 9 \u2013 biologically produced macro -\nmolecules may vary markedly with seemingly minor changes \nin manufacture, and have many opportunities to form \nimmunologically distinct products during cell culture.\nUnwanted effects\nTransient influenza-like symptoms are common. Hyperten -\nsion is also common and can cause encephalopathy with headache, disorientation and sometimes convulsions. Iron \ndeficiency can be induced because more iron is required for the enhanced erythropoiesis. Blood viscosity increases \nas the haematocrit (i.e. the fraction of the blood that is \noccupied by red blood cells) rises, increasing the risk of thrombosis, especially during dialysis. There have been \nreports", "start_char_idx": 0, "end_char_idx": 3454, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "438c12b6-5c06-454f-b097-c5388ad1972f": {"__data__": {"id_": "438c12b6-5c06-454f-b097-c5388ad1972f", "embedding": null, "metadata": {"page_label": "346", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bfda59d9-e421-4c2a-9f0a-5e3cfc44966c", "node_type": null, "metadata": {"page_label": "346", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "74dc05d2fac94bebfc0536b1ec7981e3855b601ae811d4a977838d234cf585f2"}, "2": {"node_id": "41504459-b387-41a2-a653-2b2dff425e27", "node_type": null, "metadata": {"page_label": "346", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23de97565fdaa829ad87e9ddfcde39d80afacee9eb37f745a3ad5f2189b370d7"}}, "hash": "356489fcdc637cb0153886b20258ccea98d9b84a7a41f9e24902e79fefa1553b", "text": "increasing the risk of thrombosis, especially during dialysis. There have been \nreports of a devastating chronic condition known as pure \nred cell aplasia (PRCA), connected with development of neutralising antibodies directed against erythropoietin which inactivate the endogenous hormone as well as the recom -\nbinant product (Berns, 2013). This has been a huge concern with indirect implications for quality control between batches of biological products and, indirectly, for the licens -\ning of biosimilar products.\n\u25bc\tBefore\t1998, \t only \t three \t cases \t of \t PRCA \t in \t association \t with \t epoietin\t\ntreatment had been published. In that year, in response to concerns \nabout\ttransmitting \tbovine \tspongiform \tencephalopathy \t(\u2018mad \tcow \t\ndisease\u2019), the formulation of the leading brand was changed, human \nserum albumin (used to stabilise the product) being replaced by \npolysorbate \t80\tand\tglycine.\tThe\tincidence \tof\tPRCA\tincreased \tabruptly, \t\nwith approximately 250 documented cases by 2002, many of whom died or became completely dependent on blood transfusions. A large \nproportion had been treated with the new formulation. The mechanism \nwhereby the manufacturing change led to the change in immunogenic -\nity remains a matter of debate (Locatelli et a l., 2007 ), but the packaging \nand storage were changed in 2003, since when the incidence of PRCA has declined (see Fig. 26.3). The moral is that immunogenicity is \nunpredictable and can be caused by seemingly minor changes in \nmanufacture or storage (Kuhlmann & Marre, 2010).\nClinical use\nIron or folate deficiency must be corrected before starting \ntreatment. Parenteral iron preparations are often needed \n(see p. 336). Haemoglobin must be monitored and maintained \nwithin the range 10\u201312 g/dL to avoid the unwanted effects \ndescribed \tearlier. \tErythrocyte-stimulating \tagents \tcan \tbe \t\nused but there are serious cardiovascular and thrombolytic \nadverse reactions that can occur, risking mortality. The \nclinical use of epoietin is given in the box later.\nCOLONY-STIMULATING FACTORS\nCSFs are cytokines that stimulate the formation of maturing \ncolonies of leukocytes, observable in tissue culture. They 80\n6070\n503040\n1020\n0\npre-\n19981998 1999 2002 2000 2001 2004 2003 2005\nTotal cases Suspect formulationCases of PRCA\nFig. 26.3 Incidence of pure red cell aplasia (PRCA) in \nrelation to introduction in 1998 of a changed formulation of \nthe leading brand of epoietin. The incidence increased \nmarkedly and the suspect formulation (blue) accounted for \nalmost\tall\tof \tthe \tcases \tthat \twere \tpositive \tfor \tanti-erythropoietin \t\nantibody (red); the formulation and instructions for its \nadministration and storage were changed again in 2003 with an \nabrupt\tsubsequent \tdecline \tin \tPRCA. \tThe \tperiod \twhen \tthe \t\nsuspect formulation was in use is indicated by the blue \nrectangle. (Redrawn from Kuhlmann & Marre, 2010.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3367, "end_char_idx": 6742, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "46fb70cc-86b1-4c32-b60a-dcc4be1428c6": {"__data__": {"id_": "46fb70cc-86b1-4c32-b60a-dcc4be1428c6", "embedding": null, "metadata": {"page_label": "347", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a638271e-9335-46fe-9264-52c084985275", "node_type": null, "metadata": {"page_label": "347", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d2f40ea42a072917df33000d72635846b1fcb0a8c671b0c331b81b6dfb48fb02"}, "3": {"node_id": "ddd67588-9830-4bef-bed2-67deabf41a88", "node_type": null, "metadata": {"page_label": "347", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9e06d4175030aa2af6935f8db025be569fa510d94132ae726706950788b9c9c"}}, "hash": "dd5ea0926a30531336475e463066ccb0b8dd99a09e55902d1009eec8b12874a3", "text": "26 HAEMATO pOIETIC SYSTEM AND TREATMENT OF ANAEMIA\n341HAEMOLYTIC ANAEMIA\nAnaemia associated with increased red cell destruction \ncan arise from genetic causes (e.g. sickle cell disease, \nthalassaemia, paroxysmal nocturnal haemoglobinuria) \nor a variety of non-genetic causes such as autoimmunity, infections and adverse drug reactions including \nhaemolysis.\n\u25bc Sickle cell anaemia is caused by a mutation in the gene that codes \nthe \u03b2-globin chain of haemoglobin, resulting in a single amino acid \nsubstitution. The abnormal haemoglobin (haemoglobin S) can poly-\nmerise when deoxygenated, changing the physical properties of the red cells (which deform to a sickle shape, hence the name) and \ndamaging cell membranes. This can block the microcirculation, causing \npainful crises, and haemolysis can reduce the availability of nitric oxide (Ch. 21) resulting in adverse cardiovascular effects, seen when \nNO depletion by extracellular haemoglobin causes acute hypertensive \nresponses occurring generally during massive haemolysis (Schaer et \nal., 2013). Polymerisation, and the severity of the disease, are markedly \nreduced when other forms of haemoglobin (A and F) are present.\nParoxysmal nocturnal haemoglobinuria (PNH) is a rare and previously \nuntreatable form of haemolytic anaemia caused by clonal expansion \nof haematopoietic stem cells with somatic mutations that prevent formation of glycophosphatidylinositol (GPI), which anchors \nmany proteins to the cell surface, rendering the cell susceptible to \ncomplement-mediated haemolysis. In addition to anaemia, patients \nwith PNH suffer from other features, including thrombosis, attacks \nof abdominal pain and pulmonary hypertension (Ch. 23).\nDRUGS USED TO TREAT \nHAEMOLYTIC ANAEMIAS\nHydroxycarbamide (also known as hydroxyurea) is a \ncytotoxic drug that has been used for decades to lower the \nred cell and platelet counts in patients with polycythaemia \nrubra vera (a myeloproliferative disorder affecting especially the red cell lineage) or to treat chronic myeloid leukaemia. \nIt is additionally used for sickle cell disease, and reduces \nthe frequency of painful crises (Charache et al., 1995; Wang \net al., 2011; Weatherall, 2011).\nMechanism of action\nHydroxycarbamide inhibits DNA synthesis by inhibiting \nribonucleotide reductase and is S-phase specific (Ch. 6). It \nincreases circulating haemoglobin F, while reducing hae -\nmoglobin S. Hydroxycarbamide metabolism gives rise to \nnitric oxide, which may contribute to its beneficial effect \nin sickle cell disease. Some of its beneficial effect in reducing \npainful crises could relate to anti-inflammatory effects secondary to its cytotoxic action.\nAdministration and unwanted effects\nHydroxycarbamide is administered by mouth once daily at a rather lower starting dose than is used for treating \nmalignant disease; reduced doses are used in patients with \nimpaired renal function. The blood count and haemoglobin F are monitored and the dose adjusted accordingly. Once \nstabilised, treatment may be continued indefinitely.\nMyelosuppression, nausea and rashes are the commonest \nadverse effects. Animal studies demonstrated teratogenicity, and potential adverse effects on spermatogenesis. When \nused to treat malignant disease there is an increased risk of second malignancy, but this has not been observed when treating patients with sickle cell disease.\nEculizumab, licensed for the treatment of PNH, is a \nhumanised monoclonal antibody that blocks the", "start_char_idx": 0, "end_char_idx": 3480, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ddd67588-9830-4bef-bed2-67deabf41a88": {"__data__": {"id_": "ddd67588-9830-4bef-bed2-67deabf41a88", "embedding": null, "metadata": {"page_label": "347", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a638271e-9335-46fe-9264-52c084985275", "node_type": null, "metadata": {"page_label": "347", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d2f40ea42a072917df33000d72635846b1fcb0a8c671b0c331b81b6dfb48fb02"}, "2": {"node_id": "46fb70cc-86b1-4c32-b60a-dcc4be1428c6", "node_type": null, "metadata": {"page_label": "347", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd5ea0926a30531336475e463066ccb0b8dd99a09e55902d1009eec8b12874a3"}}, "hash": "d9e06d4175030aa2af6935f8db025be569fa510d94132ae726706950788b9c9c", "text": "treatment of PNH, is a \nhumanised monoclonal antibody that blocks the terminal mediators can lead to very serious immunologically medi -\nated adverse effects. Eltrombopag (a small-molecule agonist \nadministered orally) and romiplostim (a dimerised fusion \nprotein analogue that binds to and activates thrombopoietin receptors working via the JAK/STAT pathway and admin -\nistered by subcutaneous injection) are thrombopoietin \nagonists approved for treatment of patients with idiopathic \nthrombocytopaenic purpura (ITP) who have not responded to other treatments such as splenectomy; eltrombopag is \nalso used to increase platelet counts in patients with aplastic \nanaemia.\nAdministration and unwanted effects\nFilgrastim and lenograstim are given subcutaneously or by intravenous infusion. Pegfilgrastim is administered \nsubcutaneously. Gastrointestinal effects, fever, bone pain, \nmyalgia and rash are recognised adverse effects; less common effects include pulmonary infiltrates and enlarge -\nment of liver or spleen.\nHaematopoietic growth factors \nErythropoietin\n\u2022\tRegulates \tred \tcell \tproduction.\n\u2022\tIs\tgiven \tintravenously, \tsubcutaneously, \t\nintraperitoneally.\n\u2022\tCan\tcause \ttransient \tflu-like \tsymptoms, \thypertension, \t\niron deficiency and increased blood viscosity.\n\u2022\tIs\tavailable, \tas \tepoietin, \tto \ttreat \tpatients \twith \tanaemia \t\ncaused by chronic renal failure.\n\u2022\tGranulocyte \tcolony-stimulating \tfactor.\n\u2022\tStimulates \tneutrophil \tprogenitors.\n\u2022\tIs\tavailable \tas \tfilgrastim, pegfilgrastim or \nlenograstim; it is given parenterally.\nClinical uses of epoietin \n\u2022\tAnaemia \tof \tchronic \trenal failure .\n\u2022\tAnaemia \tduring \tchemotherapy for cancer.\n\u2022\tPrevention \tof \tthe \tanaemia \tthat \toccurs \tin \tpremature \ninfants (unpreserved formulations are used because \nbenzyl alcohol, used as a preservative, has been \nassociated with a fatal toxic syndrome in neonates).\n\u2022\tTo\tincrease \tthe \tyield \tof \tautologous \tblood \tbefore \tblood \ndonation.\n\u2022\tAnaemia \tof \tAIDS (exacerbated by zidovudine).\nClinical uses of the colony-stimulating factors\nColony-stimulating \tfactors \tare \tused \tin \tspecialist \tcentres:\n\u2022\tTo\treduce \tthe \tseverity/duration \tof \tneutropenia \tinduced \t\nby cytotoxic drugs during:\n\u2013 intensive chemotherapy necessitating autologous \nbone marrow rescue\n\u2013 following bone marrow transplant.\n\u2022\tTo\tharvest \tprogenitor cells.\n\u2022\tTo\texpand \tthe \tnumber \tof \tharvested \tprogenitor \tcells \tex \nvivo before reinfusing them.\n\u2022\tFor\tpersistent \tneutropenia \tin \tadvanced HIV infection.\n\u2022\tIn\taplastic \tanaemia.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3411, "end_char_idx": 6406, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "582c0e08-240d-4c8a-9462-9e46b8ce0b1e": {"__data__": {"id_": "582c0e08-240d-4c8a-9462-9e46b8ce0b1e", "embedding": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "36593695-75c2-442f-aa4d-ebe5f226aa13", "node_type": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be915860d7f3dd7d0da3d149642cd1f94a93beb895961054363d0b9fd0d4ff68"}, "3": {"node_id": "83260bee-ee46-436f-8d34-72f3bc4c1b92", "node_type": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff9b7ad638246dd93b5b8f994e93da29f5d80c6dac662a74a6feb2c2dc5ae2bf"}}, "hash": "524c59eb248e5d938e1fadb2cc9994faf20159a9f939ac10151122fbc4c03eec", "text": "26 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n342complement \tprotein \tC5 \t(Ch. \t18). \tIn \ta \tdouble-blind, \tran-\ndomised, \tcontrolled \ttrial \tof \t87 \tpatients, \ttreatment \twith \t\neculizumab dramatically reduced haemolysis and transfu -\nsion requirement during 6 months of treatment (Fig. 26.4). \nPatients must be inoculated against meningococcal infection \nbefore treatment. It is administered by intravenous infusion weekly for 4 weeks and then approximately every 2 weeks. \nSerious adverse effects include infection, notably menin -\ngococcal infection, but are uncommon. The commonest \nadverse effects are headache and back pain.\nIn most forms of haemolytic anaemia, treatment is \nsymptomatic (e.g. analgesia for painful crises in patients with sickle cell disease) and supportive (e.g. attention to fluid balance, oxygen therapy, blood transfusion when \nessential, treatment of iron overload, provision of adequate \nfolate to support increased red cell turnover and, in some cases, antibiotics and immunisation). Acute haemolytic \nanaemia associated with autoantibodies may respond to \ntreatment with glucocorticoids (Ch. 34).Placebo\nEculizumab\n01 0 20 26\n01 0 20 26LDH (U/L)\n0100020003000\nTime since randomisation (weeks)\nTime since randomisation (weeks)100\n80\n604020\n0Patients not needing blood transfusion (%)A\nB\nFig. 26.4 Effect of eculizumab in patients with paroxysmal \nnocturnal haemoglobinuria (PNH). (A) Effect on plasma lactate \ndehydrogenase (LDH) activity, a measure of haemolysis. The \nhorizontal dotted line shows the upper limit of normal. The arrow \nshows the baseline level at screening (n = 44 in placebo group, n = \n43 in eculizumab group, p < 0.001). (B) Kaplan\u2013Meier curves for \nthe time to first transfusion during treatment in the same patients shown in (A) ( p <\n 0.001). (Redrawn from Hillmen et al., 2006.)\nREFERENCES AND FURTHER READING\nGeneral\nFishbane, \tS., \t2009. \tErythropoiesis-stimulating \tagent \ttreatment \twith \tfull \t\nanemia\tcorrection: \ta \tnew \tperspective. \tKidney \tInt. \t75, \t358\u2013365.\nFishman, S.M., Christian, P., West, K.P., 2000. The role of vitamins in \nthe prevention and control of anaemia. Public Health Nutr. 3, 125\u2013150.\nKurzrock, R., 2005. Thrombopoietic factors in chronic bone marrow \nfailure states: the platelet problem revisited. Clin. Cancer Res. 11, \n1361\u20131367. ( Slow progress, see Li et al. below )\nIron and iron deficiency\nAndrews, \tN.C., \t1999. \tDisorders \tof \tiron \tmetabolism. \tN. \tEngl. \tJ. \tMed. \t\n341,\t1986\u20131995.\nProvan, D., Weatherall, D., 2000. Red cells, II: acquired anaemias and \npolycythaemia. \tLancet \t355, \t1260\u20131268.\nToh, B.H., van Driel, I.R., Gleeson, P.A., 1997. Pernicious anaemia. N. \nEngl.\tJ.\tMed. \t337, \t1441\u20131448. \t(Immunopathogenesis of pernicious anaemia; \nexcellent figures)\nEPO and pure red cell aplasia\nBerns, J.S., 2013. Pure red cell aplasia due to anti-erythropoietin \nantibodies.", "start_char_idx": 0, "end_char_idx": 2885, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "83260bee-ee46-436f-8d34-72f3bc4c1b92": {"__data__": {"id_": "83260bee-ee46-436f-8d34-72f3bc4c1b92", "embedding": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "36593695-75c2-442f-aa4d-ebe5f226aa13", "node_type": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be915860d7f3dd7d0da3d149642cd1f94a93beb895961054363d0b9fd0d4ff68"}, "2": {"node_id": "582c0e08-240d-4c8a-9462-9e46b8ce0b1e", "node_type": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "524c59eb248e5d938e1fadb2cc9994faf20159a9f939ac10151122fbc4c03eec"}, "3": {"node_id": "02c3c8da-a50a-4afb-ace7-b98972c529a7", "node_type": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01b7d882b469120bf34cc7f1bb59f3de11dc1a9414962bfd5ebf9a9e39a32340"}}, "hash": "ff9b7ad638246dd93b5b8f994e93da29f5d80c6dac662a74a6feb2c2dc5ae2bf", "text": "Pure red cell aplasia due to anti-erythropoietin \nantibodies. http://www.uptodate.com/contents/pure-red-cell-aplasi\na-due-to-anti-erythropoietin-antibodies.\nKuhlmann, M., Marre, M., 2010. Lessons learned from biosimilar \nepoietins and insulins. Br. J. Diab. Vasc. Dis. 10, 90\u201397.\nLocatelli, F., Del Vecchio, L., Pozzoni, P., 2007. Pure red-cell aplasia \u201cepidemic\u201d \n\u2013 mystery completely revealed? Perit. Dial. Int. 27 (Suppl. 2), S303\u2013S307.\nColony-stimulating factors\nLieschke, G.J., Burges, A.W., 1992. Granulocyte colony-stimulating \nfactor and granulocyte\u2013macrophage colony-stimulating factor. N.\tEngl.\tJ. \tMed. \t327, \t1\u201335, \t99\u2013106. \t(Worthwhile, comprehensive \nreviews)\nMohle, R., Kanz, L., 2007. Hematopoietic growth factors for hematopoietic \nstem cell mobilization and expansion. Semin. Hematol. 44, 193\u2013202.\nHaemolytic anaemias\nCharache, \tS., \tTerrin, \tM.L., \tMoore, \tR.D., \tet \tal., \t1995. \tEffect \tof \t\nhydroxyurea on the frequency of painful crises in sickle-cell-anemia. \nN.\tEngl.\tJ. \tMed. \t332, \t1317\u20131322. \t(Important randomised, controlled trial \nevidence of efficacy and safety over mean follow-up of 21 months)\nHillmen, P., Young, N.S., Schubert, J., et al., 2006. The complement \ninhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N. \nEngl.\tJ.\tMed. \t355, \t1233\u20131243. \t(Eculizumab is an effective therapy for PNH)\nSchaer, D.J., Buehler, P.W., Alayash, A.I., Belcher, J.D., Vercellotti, G.M., \n2013. Hemolysis and free hemoglobin revisited: exploring hemoglobin \nand hemin scavengers as a novel class of therapeutic proteins. Blood \n121,\t1276\u20131284.\nWang,\tW.C., \tWare, \tR.E., \tMiller, \tS.T., \tet \tal., \t2011. \tfor \tthe \tBABY \tHUG \t\ninvestigators. Hydroxycarbamide in very young children with sickle-cell anaemia: a multicentre, randomised, controlled trial (BABY \nHUG). Lancet 377, 1663\u20131672. (Landmark trial in infants)\nWeatherall, D.J., 2011. Hydroxycarbamide for sickle-cell anaemia in \ninfancy.\tLancet \t377, \t1628\u20131630. \t(Good article on the background and \nmechanism of hydroycarbamide)\nThrombopoietin and prolonged thrombocytopenia\nLi, J., Yang, C., Xia, Y., et al., 2001. Thrombocytopenia caused by the \ndevelopment \tof \tantibodies \tto \tthrombopoietin. \tBlood \t98, \t3241\u20133248.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 2832, "end_char_idx": 5459, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "02c3c8da-a50a-4afb-ace7-b98972c529a7": {"__data__": {"id_": "02c3c8da-a50a-4afb-ace7-b98972c529a7", "embedding": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "36593695-75c2-442f-aa4d-ebe5f226aa13", "node_type": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be915860d7f3dd7d0da3d149642cd1f94a93beb895961054363d0b9fd0d4ff68"}, "2": {"node_id": "83260bee-ee46-436f-8d34-72f3bc4c1b92", "node_type": null, "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff9b7ad638246dd93b5b8f994e93da29f5d80c6dac662a74a6feb2c2dc5ae2bf"}}, "hash": "01b7d882b469120bf34cc7f1bb59f3de11dc1a9414962bfd5ebf9a9e39a32340", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5466, "end_char_idx": 5577, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7ef6ebf5-f1af-4113-a31e-dfedd0d8b19a": {"__data__": {"id_": "7ef6ebf5-f1af-4113-a31e-dfedd0d8b19a", "embedding": null, "metadata": {"page_label": "349", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "af09c325-fd99-43cf-b4b3-c1236613f6ec", "node_type": null, "metadata": {"page_label": "349", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23d958585b2559b585e970c5210be69a699736321a412a4ed5bbad5fa2f9e954"}, "3": {"node_id": "eaad55bf-58ff-4f11-89cd-b9ddbe029a53", "node_type": null, "metadata": {"page_label": "349", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ad558b945c38e21bb465a36522face4c646731df29f74739fdc97628bd8dcf9"}}, "hash": "c49c19c7f7978d4a7542b14a7c512de7a690db9ccbae38a0619083f331101b63", "text": "343\nAnti-inflammatory and \nimmunosuppressant drugs 27 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3 \nOVERVIEW\nThis chapter deals with the main groups of anti-\ninflammatory and immunosuppressant drugs, together \nwith their therapeutic uses in a range of different \ninflammatory and immune disorders. While generally associated with conditions such as rheumatoid arthritis, \ninflammation forms a significant component of many, \nif not most, of the diseases encountered in the clinic; consequently, anti-inflammatory drugs are extensively \nemployed in virtually all branches of medicine. In \nEngland alone, 33.5 million prescriptions were written for these medicines in 2016 and since many are \navailable from pharmacy counters they are widely \nused off-prescription by the general public.\nINTRODUCTION\nAnti-inflammatory drugs may be divided conveniently into \nseven major groups:\n\u2022\tDrugs \tthat \tinhibit \tthe \tcyclo-oxygenase \t(COX) \tenzyme \t\n\u2013 the non-steroidal anti-inflammatory drugs \t(NSAIDs) \t\nand the coxibs.\n\u2022\tAntirheumatoid \tdrugs \t\u2013 \tthe \tso-called \tdisease-modifying \nantirheumatic drugs \t(DMARDs), \ttogether \twith \tsome \t\nimmunosuppressants.\n\u2022\tThe\tglucocorticoids.\n\u2022\tAnticytokines \tand \tother \tbiopharmaceutical \tagents.\n\u2022\tAntihistamines \tused \tfor \tthe \ttreatment \tof \tallergic \t\ninflammation.\n\u2022\tDrugs \tspecifically \tused \tto \tcontrol \tgout.\nIn this chapter we first describe the therapeutic effects, mechanism of action and unwanted effects common to \nNSAIDs, and then deal in a little more detail with aspirin, \nparacetamol \tand \tdrugs \tthat \tare \tselective \tfor \tCOX-2. \tThe \t\nantirheumatoid drugs comprise a rather varied group and \ninclude immunosuppressant drugs that are also used to \ntreat other autoimmune diseases, and prevent rejection of \norgan transplants. The glucocorticoids are covered in \nChapter\t34, \tbut \tare \tbriefly \tdiscussed \tin \tthis \tchapter. \tWe \t\nthen consider the biopharmaceutical \u2018revolution\u2019 which has changed the therapeutic landscape for patients with severe \ndisease. Finally, we consider drugs that are used to control \ngout and the histamine H\n1 receptor antagonists, which are \nused to treat acute allergic conditions.\nCYCLO-OXYGENASE INHIBITORS\nThis\tgroup\tincludes\tthe\t\u2018traditional\u2019 \t(in\tthe\thistorical \tsense)\t\nNSAIDs1 as well as the coxibs, which are more selective for\tCOX-2.\tNSAIDs, \tsometimes \tcalled\tthe\taspirin-like drugs \nor antipyretic analgesics, are among the most widely used \nof all medicines. There are now more than 50 different examples on the global market; common examples are listed in Table 27.1 and some significant NSAID structures are \ndepicted in Fig. 27.1.\nThese drugs provide symptomatic relief from fever, pain \nand swelling in chronic joint disease such as occurs in osteo- and rheumatoid arthritis, as well as in more acute \ninflammatory conditions such as fractures, sprains, sports and other soft tissue injuries. They are also useful in the treatment of postoperative, dental and menstrual pain, as \nwell as headaches and migraine. Several NSAIDs are \navailable over the counter and are widely used to treat minor aches and pains and other ailments. There are also \nmany different NSAID formulations available, including \ntablets, injections and gels. Virtually all these drugs, par -\nticularly the \u2018traditional\u2019 NSAIDs, can have significant \nunwanted effects, especially in the elderly. Newer agents \ngenerally provoke fewer", "start_char_idx": 0, "end_char_idx": 3406, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "eaad55bf-58ff-4f11-89cd-b9ddbe029a53": {"__data__": {"id_": "eaad55bf-58ff-4f11-89cd-b9ddbe029a53", "embedding": null, "metadata": {"page_label": "349", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "af09c325-fd99-43cf-b4b3-c1236613f6ec", "node_type": null, "metadata": {"page_label": "349", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23d958585b2559b585e970c5210be69a699736321a412a4ed5bbad5fa2f9e954"}, "2": {"node_id": "7ef6ebf5-f1af-4113-a31e-dfedd0d8b19a", "node_type": null, "metadata": {"page_label": "349", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c49c19c7f7978d4a7542b14a7c512de7a690db9ccbae38a0619083f331101b63"}}, "hash": "7ad558b945c38e21bb465a36522face4c646731df29f74739fdc97628bd8dcf9", "text": "effects, especially in the elderly. Newer agents \ngenerally provoke fewer adverse actions.\nWhile there are differences between individual NSAIDs, \ntheir primary pharmacology is related to their shared ability \nto\tinhibit \tthe \tfatty \tacid \tCOX \tenzyme, \tthereby \tinhibiting \t\nthe biosynthesis of prostaglandins and thromboxanes. As \nexplained \tin \tChapter \t18, \tthere \tare \ttwo \tcommon \tisoforms \t\nof\tthis\tenzyme,\tCOX-1\tand\tCOX-2\t(although \tthere\tmay\tbe\t\nfurther\tisoforms \tas \tyet \tuncharacterised). \tWhile \tthey \tare \t\nclosely\trelated \t(>60%\tsequence \tidentity) \tand \tcatalyse \tthe \t\nsame reaction, there are important differences between the \nexpression \tand \trole \tof \tthese \ttwo \tisoforms. \tCOX-1 \tis \ta \t\nconstitutive \tenzyme \texpressed \tin \tmost \ttissues, \tincluding \t\nblood platelets. It has a \u2018housekeeping\u2019 role in the body, being involved principally in tissue homeostasis. It is, for \nexample, responsible for the production of prostaglandins \ninvolved \tin \tgastric \tcytoprotection \t(see \tCh. \t31), \tplatelet \t\naggregation \t(Ch.\t25),\trenal\tblood\tflow\tautoregulation \t(Ch.\t\n30)\tand\tthe \tinitiation \tof \tparturition \t(Ch. \t36).\nIn\tcontrast,\tCOX-2\tis\tinduced\tin\tinflammatory \tcells\twhen\t\nthey\tare \tactivated \tby \t(for \texample) \tthe \tinflammatory \t\ncytokines \t\u2013 \tinterleukin \t(IL)-1 \tand \ttumour \tnecrosis \tfactor \t\n(TNF)-\u03b1\t(see\tCh.\t19).\tThus\tthe\tCOX-2\tisoform\tis\tconsidered \t\nto be mainly responsible for the production of the prostanoid \nmediators \tof \tinflammation \t(Vane \t& \tBotting, \t2001). \tThere \t\nare,\thowever, \tsome \tsignificant \texceptions. \tCOX-2 \tis \tcon-\nstitutively expressed in the kidney, generating prostacyclin, \nwhich\tplays \ta \tpart \tin \trenal \thomeostasis \t(see \tCh. \t30), \tand \t\nin\tthe\tcentral \tnervous \tsystem \t(CNS), \twhere \tits \tfunction \tis \t\nnot yet clear.\nThough NSAIDs differ in toxicity and degree of patient \nacceptability and tolerance, their pharmacological actions \nare broadly similar, with certain important exceptions. Aspirin has other qualitatively different pharmacological \nactions and paracetamol is an interesting exception to the \ngeneral\tNSAID \tstereotype \t(see \tlater). \tSome \tnotes \ton \tthe \t\nrelative selectivity of some NSAIDs and coxibs are provided \nin Table 27.1.1Here, we use the term NSAID to include the coxibs but this convention \nis not always followed in the literature.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3333, "end_char_idx": 6147, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a51f6ce4-b330-4ec2-a979-4f01ee1a47ec": {"__data__": {"id_": "a51f6ce4-b330-4ec2-a979-4f01ee1a47ec", "embedding": null, "metadata": {"page_label": "350", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4b0670b7-78ba-4dba-bd0f-fbf99a481289", "node_type": null, "metadata": {"page_label": "350", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef1ca5f26c01ccfe96fc46df9c194afa289d3f8cb2962eae9738f5a4381b9d9e"}, "3": {"node_id": "d3ed1dde-735c-4c47-8fe3-acabe55cf628", "node_type": null, "metadata": {"page_label": "350", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e99e23369f22c0463ada5bbfd65299a0be3d16c363875f3b91d0bdea7228fa1"}}, "hash": "27e354dcb547542cac066205a8c175d5e2cea606aef6e409c5bc5aa768918a38", "text": "27 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n344dimeric\tcomplex. \tStructurally, \tCOX-1 \tand \tCOX-2 \tare \tsimilar; \tboth \t\ncontain a hydrophobic channel into which the arachidonic or other \nsubstrate fatty acids dock so that the oxygenation reaction can proceed.\nMost\tNSAIDs \tinhibit \tonly \tthe \tinitial \tdioxygenation \treaction. \tThey \t\nare\tgenerally \trapid \t\u2018competitive \treversible\u2019 \tinhibitors \tof \tCOX-1, \tbut \t\nthere\tare \tdifferences \tin \ttheir \tkinetics. \tInhibition \tof \tCOX-2 \tis \tmore \t\ntime-dependent and the inhibition is often irreversible. To block the \nenzymes, \tN SAIDs\te nter\tt he \th ydrophobic \tc hannel,\tf orming \th ydrogen\t\nbonds with an arginine residue at position 120, thus preventing substrate fatty acids from entering the catalytic domain. However, a \nsingle\tamino \tacid \tchange \t(isoleucine \tto \tvaline \tat \tposition \t523) \tin \tthe \t\nstructure \t of \tt he\t entrance \t of \tt his \tc hannel\t in\t COX-2\t results\t in\t a\t \u2018bulge\u2019\t\nin\tthe\tchannel \tthat \tis \tnot \tfound \tin \tCOX-1. \tThis \tis \timportant \tin \t\nunderstanding why some drugs, especially those with large sulfur-\ncontaining \tside \tgroups, \tare \tmore \tselective \tfor \tthe \tCOX-2 \tisoform \tMECHANISM OF ACTION\nIn\t1971,\tVane \tand \this \tcolleagues \tdemonstrated \tthat \tthe \t\nNSAIDs inhibit prostaglandin biosynthesis by a direct action \non\tthe\tCOX \tenzyme \tand \testablished \tthe \thypothesis \tthat \t\nthis single action explained the vast majority of their \ntherapeutic actions and side effects. This has since been \nconfirmed by numerous studies.\n\u25bc\tCOX\tenzymes \tare \tbifunctional, \thaving \ttwo \tdistinct \tcatalytic \tactivities. \t\nA dioxygenase step is followed by a second, peroxidase ,\treaction \t(see \t\nCh.\t18).\tBoth \tCOX-1 \tand \tCOX-2 \tare \thaem-containing \tenzymes \tthat \t\nexist as homodimers attached to intracellular membranes. Interestingly, \nonly\tone\tmonomer \tis \tcatalytically \tactive \tat \tone \ttime. \tBinding \tof \tNSAIDs\t\nto\tone\tCOX \tmonomer \tcan \tinhibit \tthe \tcatalytic \tactivity \tof \tthe \tentire \tTable 27.1 Comparison of some common anti-inflammatory cyclo-oxygenase inhibitors\nType Drug Indication COX selectivity Comments\nPropionatesDexibruprofen OA, MS, D, H&M NT Active enantiomer of ibuprofen\nDexketoprofen PO, D, H&M NT Isomer of ketoprofen\nFenoprofen RA, OA, MS, PO Non-selective Prodrug; activated in liver\nFelbinac MS, OA NT Metabolite of fenbufen\nFlurbiprofen RA, OA, MS, PO, D, H&M Very COX-1 selective \u2014\nIbuprofen RA, OA, MS, PO, D, H&M Weakly COX-1 selective Suitable for children\nKetoprofen RA, OA, G, MS, PO, D Weakly COX-1 selective Suitable for mild disease\nNaproxen RA, OA, G, MS, PO, D", "start_char_idx": 0, "end_char_idx": 2602, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d3ed1dde-735c-4c47-8fe3-acabe55cf628": {"__data__": {"id_": "d3ed1dde-735c-4c47-8fe3-acabe55cf628", "embedding": null, "metadata": {"page_label": "350", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4b0670b7-78ba-4dba-bd0f-fbf99a481289", "node_type": null, "metadata": {"page_label": "350", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef1ca5f26c01ccfe96fc46df9c194afa289d3f8cb2962eae9738f5a4381b9d9e"}, "2": {"node_id": "a51f6ce4-b330-4ec2-a979-4f01ee1a47ec", "node_type": null, "metadata": {"page_label": "350", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e354dcb547542cac066205a8c175d5e2cea606aef6e409c5bc5aa768918a38"}}, "hash": "2e99e23369f22c0463ada5bbfd65299a0be3d16c363875f3b91d0bdea7228fa1", "text": "Weakly COX-1 selective Possibly CV safe?\nTiaprofenic acid RA, OA, MS NT \u2014\nIndoles and \nderivativesAcemetacin RD, OA, MS, PO NT Ester of indometacin\nIndometacin RA, OA, G, MS, PO, D Weakly COX-1 selective Suitable for moderate to severe disease\nSulindac RA, OA, G, MS Weakly COX-2 selective Prodrug\nOxicamsMeloxicam RA, OA, AS Moderately COX-2 selective Possibly fewer gastrointestinal effects\nPiroxicam RA, OA, AS Weakly COX-2 selective \u2014\nTenoxicam RA, OA, MS NT \u2014\nSulfonyl and sulfonamide coxibsCelecoxib RA, OA, AS Moderately COX-2 selective Fewer gastrointestinal effects\nEtoricoxib RA, OA, G, AS Very COX-2 selective \u2014\nParecoxib PO NT Prodrug activated in liver\nPhenylacetatesAceclofenac RA, OA, AS NT \u2014\nDiclofenac RA, OA, G, MS, PO, H&M Weakly COX-2 selective Moderate potency. Various salts\nFenamatesMefenamic acid RA, OA, PO, D NT Moderate activity\nTolfenamic acid H&M NT \u2014\nMiscellaneousKetorolac PO Highly COX-1 selective Mainly ocular use\nNabumetone RA, OA NT Prodrug activated in liver\nEtodolac RA, OA Moderately COX-2 selective Possibly fewer GI effects\nSalicylates Aspirin Mainly CV usage Weakly COX-1 selective Component of many OTC preparations. Unsuitable for children.\nThe chemical classes of these NSAIDs are also shown because sometimes they are referred to in this manner.AS, ankylosing spondylitis; CV, cardiovascular; D, dysmenorrhoea; G, acute gout; GI, gastrointestinal; H&M,\n headache and migraine; MS, \nmusculoskeletal injuries and pain; NT, not tested; OA, osteoarthritis; OTC, over-the-counter; PO, postoperative pain; RA, rheumatoid arthritis.\n(Data from British National Formulary 2017 and COX selectivity data, where tested, from Warner & Mitchell, 2004 and 2008.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2603, "end_char_idx": 4776, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5be5a4f0-683f-4eeb-80a3-036757513a91": {"__data__": {"id_": "5be5a4f0-683f-4eeb-80a3-036757513a91", "embedding": null, "metadata": {"page_label": "351", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "550570c8-8ba5-43c8-a412-6e8b5ff0d587", "node_type": null, "metadata": {"page_label": "351", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "010c9233bd1b2e2b98ca6692f125949b0ff1777e12eabb2bd578253aa10ba88b"}, "3": {"node_id": "6f4dda48-1c04-4e6a-849f-40333a0aba48", "node_type": null, "metadata": {"page_label": "351", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "831e4e69b028f3cdf4da3547d7fb24cf94e83c3d782a4724df520d4eade152e2"}}, "hash": "45ff0be3b5a51310ef6fd3d169b96065c8d92e2fbf319f6ffef520244b372696", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSU pp RESSANT DRUGS\n345PHARMACOLOGICAL ACTIONS\nAll the NSAIDs have actions very similar to those of aspirin, \nthe archetypal NSAID which was introduced into clinical \nmedicine \tin\tthe\t1890s.\tTheir\tpharmacological \tprofile\tis\tlisted\t\nin the key points box.(Fig.\t27.2). \tAspirin \tis, \thowever, \tan \tanomaly. \tIt \tenters \tthe \tactive \tsite \t\nand\tacetylates \ta\tserine\tat\tposition\t530,\tirreversibly \tinactivating \tCOX.\t\nThis is the basis for aspirin\u2019s long-lasting effects on platelets. Interest -\ningly,\taspirin-inactivated \tCOX-2\tcan\tstill\tgenerate\tsome\thydroxyacids, \t\nbut cannot produce the endoperoxide intermediate required for \nprostanoid synthesis.Aspirin\n(Acetylsalicylic acid)Salicylic acid\nDiclofenac IndomethacinO\nNaproxenCH3\nCH3OCHCO2H\nParacetamolNHCOCH3\nOHIbuprofenCO2H\nH3C CH3\nCH3CO2H\nOHCO2H\nCH3O\nOC\nMefenamic acidCO2HC H3\nCH3\nCelecoxibF3CSO2NH2CIC = OCO2H\nCH3H3C\nN\nCH3NN\nH\nNNH\nCI CICH2CO2H\nFig. 27.1 Significant structural features of some non-steroidal anti-inflammatory drugs (NSAIDs) and coxibs. Aspirin contains an \nacetyl group that is responsible for the inactivation of the cyclo-oxygenase (COX) enzyme. Salicylic acid is the end product when aspirin is \nde-acetylated but, oddly has anti-inflammatory activity in its own right. Paracetamol is a commonly used analgesic agent also of simple structure. Most \u2018classic\u2019 NSAIDs are carboxylic acids. Coxibs (celecoxib shown here as an example), however, often contain sulfonamide or sulfone groups. These are thought to be important in determining the selectivity of the molecule as they impede access to the hydrophobic channel in the COX-1 enzyme (see Fig. 27.2). \nTherapeutic effects of cyclo-oxygenase (COX) inhibitors \nThese drugs inhibit COX enzymes, and therefore \nprostanoid synthesis, in inflammatory cells. Inhibition of the COX-2 isoform is probably crucial for their therapeutic \nactions which include:\n\u2022\tAn anti-inflammatory action : the decrease in \nprostaglandin E\n2 and prostacyclin reduces vasodilatation \nand, indirectly, oedema. Accumulation of inflammatory cells is not directly reduced.\n\u2022\tAn analgesic effect: decreased prostaglandin generation means less sensitisation of nociceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine. Relief of headache is probably a result of decreased prostaglandin-mediated vasodilatation.\n\u2022\tAn antipyretic effect: interleukin 1 releases prostaglandins \nin the central nervous system, where they elevate the \nhypothalamic set point for temperature control, thus causing fever. Non-steroidal anti-inflammatory drugs (NSAIDs) prevent this.Important NSAIDs include aspirin, ibuprofen, \nnaproxen, indometacin, piroxicam and paracetamol. \nNewer agents with more selective inhibition of COX-2 (and thus fewer adverse effects on the gastrointestinal tract) include celecoxib and etoricoxib.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2986, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6f4dda48-1c04-4e6a-849f-40333a0aba48": {"__data__": {"id_": "6f4dda48-1c04-4e6a-849f-40333a0aba48", "embedding": null, "metadata": {"page_label": "351", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "550570c8-8ba5-43c8-a412-6e8b5ff0d587", "node_type": null, "metadata": {"page_label": "351", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "010c9233bd1b2e2b98ca6692f125949b0ff1777e12eabb2bd578253aa10ba88b"}, "2": {"node_id": "5be5a4f0-683f-4eeb-80a3-036757513a91", "node_type": null, "metadata": {"page_label": "351", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "45ff0be3b5a51310ef6fd3d169b96065c8d92e2fbf319f6ffef520244b372696"}}, "hash": "831e4e69b028f3cdf4da3547d7fb24cf94e83c3d782a4724df520d4eade152e2", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2939, "end_char_idx": 3354, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b230a9bd-60c0-4e70-a1ab-18126b94b590": {"__data__": {"id_": "b230a9bd-60c0-4e70-a1ab-18126b94b590", "embedding": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3e0838ad-1018-4dba-afcf-6e1224f3e6ff", "node_type": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24b2fc36bcccf359287cc53ad29cc5853d7d8711a69a6c0c8d9eb7ac7c6d3ab3"}, "3": {"node_id": "d24937a7-9f69-4da5-82de-df17dacceb2d", "node_type": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b70abc55cb3c81dae816e914680937f0c6027a9b870a6af83e03486a3485ab3"}}, "hash": "2087c873c31a46093e5fd03f5b9218152d0d0fd44fce60de2172315b37a6cfdd", "text": "27 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n346permeability of postcapillary venules, such as histamine; \nCh.\t18).\n\u25bc While NSAIDs suppress the signs and symptoms of inflammation, \nthey have little or no action on underlying chronic disease itself. As \na class, they are generally without direct effect on other aspects of \ninflammation, such as cytokine/chemokine release, leukocyte migra -\ntion,\tlysosomal \tenzyme\trelease\tand\ttoxic\toxygen\tradical\tproduction, \t\nwhich contribute to tissue damage in chronic inflammatory conditions \nsuch as rheumatoid arthritis, vasculitis and nephritis.\nOther\tactions \tbesides \tinhibition \tof \tCOX \tmay \tcontribute \tto \t\nthe\tanti-inflammatory \teffects \tof \tsome \tNSAIDs. \tReactive \t\noxygen radicals produced by neutrophils and macrophages \nare implicated in tissue damage in some conditions, and \nsome\tNSAIDs \t(e.g. \tsulindac)\thave\toxygen \tradical-scavenging \t\neffects\tas \twell \tas \tCOX \tinhibitory \tactivity, \tso \tmay \tdecrease \t\ntissue damage. Aspirin also inhibits expression of the transcription factor NF\u03ba\nB\t(see\tCh. \t3), \twhich \thas \ta \tkey \trole \t\nin the transcription of the genes for inflammatory mediators.\nANTIPYRETIC \u2003EFFECTS\nNeurons in the hypothalamus control the balance between heat production and heat loss, thereby regulating normal \nbody temperature. Fever occurs when there is a disturbance \nof this hypothalamic \u2018thermostat\u2019, which raises body \ntemperature. \tNSAIDs\treset\tthis\tthermostat. \tOnce\tthere\thas\t\nbeen a return to the normal \u2018set point\u2019, the temperature-\nregulating \tmechanisms \t(dilatation \tof \tsuperficial \tblood \t\nvessels,\tsweating, \tetc.)\tthen\toperate\tto\treduce\ttemperature. \t\nNormal body temperature in healthy humans is not affected by NSAIDs.\n2\n\u25bc T he NSAIDs exert their antipyretic action largely through inhibition \nof prostaglandin production in the hypothalamus. During infection, \nbacterial\tendotoxins \tcause\tthe\trelease\tfrom\tmacrophages \tof\tIL-1\t(Ch.\t\n18).\tIn\tthe \thypothalamus \tthis \tcytokine \tstimulates \tthe \tgeneration \tof \t\nE-type\tprostaglandins \tthat \televate \tthe \ttemperature \tset \tpoint. \tCOX-2 \t\nmay\thave \ta \trole \there, \tbecause \tIL-1 \tinduces \tthis \tenzyme \tin \tthe \t\nhypothalamic vascular endothelium. There is some evidence that \nprostaglandins are not the only mediators of fever, hence NSAIDs \nmay have an additional antipyretic effect by mechanisms as yet \nunknown.\nANALGESIC \u2003EFFECTS\nThe NSAIDs are effective against mild or moderate pain, \nespecially that arising from inflammation or tissue damage. \nTwo sites of action have been identified.\nPeripherally, NSAIDs decrease production of prostaglan -\ndins that sensitise nociceptors to inflammatory mediators \nsuch\ta s\tb radykinin \t( see\tC hs\t1 9\ta nd\t4 3)\ta nd\tt hey\ta re\tt herefore\t\neffective in arthritis, bursitis, pain of muscular and vascular \norigin, toothache, dysmenorrhoea, the pain of postpartum \nstates and the pain of cancer metastases in bone. All condi -\ntions are associated with increased local prostaglandin \nsynthesis \tprobably \tas \ta \tresult \tof \tCOX-2 \tinduction. \tAlone, \t\nor in combination with opioids, they decrease", "start_char_idx": 0, "end_char_idx": 3097, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d24937a7-9f69-4da5-82de-df17dacceb2d": {"__data__": {"id_": "d24937a7-9f69-4da5-82de-df17dacceb2d", "embedding": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3e0838ad-1018-4dba-afcf-6e1224f3e6ff", "node_type": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24b2fc36bcccf359287cc53ad29cc5853d7d8711a69a6c0c8d9eb7ac7c6d3ab3"}, "2": {"node_id": "b230a9bd-60c0-4e70-a1ab-18126b94b590", "node_type": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2087c873c31a46093e5fd03f5b9218152d0d0fd44fce60de2172315b37a6cfdd"}, "3": {"node_id": "3e193db3-95e9-46c3-ad84-c2c035e8a038", "node_type": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4494cb54fc42924cae5d22ee85001e852719745e2a25c69b7acd7ce59bb2506d"}}, "hash": "0b70abc55cb3c81dae816e914680937f0c6027a9b870a6af83e03486a3485ab3", "text": "\tAlone, \t\nor in combination with opioids, they decrease postoperative \npain and in some cases can reduce the requirement for \nopioids by as much as one-third. Their ability to relieve \nheadache may be related to the reduction in vasodilator prostaglandins acting on the cerebral vasculature.\nIn addition to these peripheral effects, there is a second, \nless well characterised central action in the spinal cord and \npossible\telsewhere \tin \tthe \tCNS. \tPeripheral \tinflammatory \tMost\tt raditional \tN SAIDs\ti nhibit\tb oth \tC OX-1\ta nd \tC OX-2,\t\nalthough their relative potency against the two isoforms \ndiffers.\tIt\tis\tbelieved\tthat\tthe\tanti-inflammatory \taction\t(and\t\nprobably \tmost \tanalgesic \tand \tantipyretic \tactions) \tof \tthe \t\nNSAIDs\tare \trelated \tto \tinhibition \tof \tCOX-2, \twhile \ttheir \t\nunwanted effects \u2013 particularly those affecting the \ngastrointestinal \t(GI) \ttract \t\u2013 \tare \tlargely \ta \tresult \tof \ttheir \t\ninhibition \tof\tCOX-1.\tCompounds \twith\ta\tselective\tinhibitory \t\naction\ton \tCOX-2 \tare \tnow \tin \tclinical \tuse, \tbut \twhile \tthese \t\ndrugs\tshow \tfewer \tGI \tside \teffects, \tthey \tare \tby \tno \tmeans \tas \t\nwell tolerated as was once hoped. This is partly because many patients have already been exposed to less selective \ndrugs\tand \thave \talready \tsuffered \tsome \tGI \tdamage. \tSince \t \t\nCOX-2\talso\tseems\tto\tbe\timportant \tin\thealing\tand\tresolution, \t\none can see how problems might still occur. There is also a concern about the cardiovascular effects of all NSAIDs \nwhen these are taken chronically.\nTHERAPEUTIC ACTIONS\nANTI-INFLAMMATORY \u2003EFFECTS\nAs\tdescribed \tin \tChapters \t18 \tand \t19, \tmany \tmediators \t\ncoordinate inflammatory and allergic reactions. The NSAIDs \nreduce those components in which prostaglandins, mainly \nderived\tf rom \tC OX-2,\tp lay\ta\ts ignificant \tp art.\tT hese\ti nclude\t\nnot\tonly\tthe\tcharacteristic \tvasodilatation \t(because\tof\treduced\t\nsynthesis \tof\tvasodilator \tprostaglandins) \tbut\talso\tthe\toedema\t\nof inflammation because vasodilatation facilitates and potentiates the action of mediators that increase the CH3CHCO2HFF3C\nBulky\ngroupingSO2NH2CH3\nNN\nCOX-1 inhibitorIntracellular membraneHydrophobic\n\u2018tunnel\u2019\u2018Side pocket\u2019COX-1 COX-2\nFlurbiprofenCOX-2 inhibitor\nCelecoxib\nFig. 27.2 Schematic diagram comparing the binding sites \nof cyclo-oxygenase (COX)-1 and COX-2. The illustration \nshows the differences in non-steroidal anti-inflammatory (NSAID) \nbinding sites in the two isoforms. Note that the COX-2 binding site is characterised by a \u2018side pocket\u2019 that can accommodate the realtively \u2018bulky\u2019 groups, such as the sulfonamide moiety of celecoxib, which would impede its access to the COX-1 site. Other NSAIDs, such as flurbiprofen (shown here), can enter the \nactive site of either enzyme. (After Luong et al., 1996.) \n2With possible exception of paracetamol, which has been used clinically \nto lower body temperature during surgery.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3050, "end_char_idx": 5989, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3e193db3-95e9-46c3-ad84-c2c035e8a038": {"__data__": {"id_": "3e193db3-95e9-46c3-ad84-c2c035e8a038", "embedding": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3e0838ad-1018-4dba-afcf-6e1224f3e6ff", "node_type": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24b2fc36bcccf359287cc53ad29cc5853d7d8711a69a6c0c8d9eb7ac7c6d3ab3"}, "2": {"node_id": "d24937a7-9f69-4da5-82de-df17dacceb2d", "node_type": null, "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b70abc55cb3c81dae816e914680937f0c6027a9b870a6af83e03486a3485ab3"}}, "hash": "4494cb54fc42924cae5d22ee85001e852719745e2a25c69b7acd7ce59bb2506d", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6038, "end_char_idx": 6453, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0cc1f2bf-3013-476a-afd2-664e778c2146": {"__data__": {"id_": "0cc1f2bf-3013-476a-afd2-664e778c2146", "embedding": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "46f68bf9-5d5e-43d1-bd5c-cb08da90e53c", "node_type": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b6801f622779f7467e56b2fa057de5f82adaa8c86e81a385d3db945e2089ac1"}, "3": {"node_id": "2eba9a49-5e45-451b-90c5-d50142df6e14", "node_type": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f10f94a8bd7f5481da9069d344e2b8bedde1b42909181e820538532f7ba28e3d"}}, "hash": "98f727b24c2c27b0d548df931f3230f5e054ed9c27942d5c0d33e5186b522625", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSU pp RESSANT DRUGS\n347Skin reactions\nRashes\tare \tcommon \tidiosyncratic \tunwanted \teffects \tof \t\nNSAIDs, particularly with mefenamic acid \t(10%\u201315% \t\nfrequency) \tand \tsulindac \t(5%\u201310% \tfrequency). \tThey \tvary \t\nfrom mild erythematous, urticarial and photosensitivity \nreactions to more serious and potentially fatal diseases \nincluding Stevens\u2013Johnson syndrome \t(a\tblistering \trash \tthat \t\nextends\tinto\tthe\tgut,\tsee\tCh.\t58),\tand\tits\tmore\tsevere\tform,\t\ntoxic epidermal necrolysis3\t(fortunately \tvery \trare). \tThe \t\nmechanism is unclear.\nAdverse renal effects\nTherapeutic doses of NSAIDs in healthy individuals pose \nlittle threat to kidney function, but in susceptible patients \nthey cause acute renal insufficiency, which is reversible on \ndiscontinuing \tthe\tdrug\t(see\tCh.\t58,\tTable\t58.1).\tThis\toccurs\t\nbecause of inhibition of the biosynthesis of those prostanoids \n(PGE 2\tand\tPGI 2;\tprostacyclin) \tin volved\t in \t the \t maintenance \t\nof\trenal\tblood \tflow, \tspecifically \tin \tthe \tPGE 2-mediated \ncompensatory vasodilatation that occurs in response to the \naction\tof\tnoradrenaline \t(norepinephrine) \tor\tangiotensin \tII\t\n(see\tC h.\t3 0). \tN eonates\ta nd\tt he\te lderly\ta re\te specially \ta t\tr isk,\t\nas are patients with heart, liver or kidney disease, or a reduced circulating blood volume.\nChronic\tNSAID\tconsumption, \tespecially \tNSAID\tabuse,4 \ncan cause analgesic nephropathy characterised by chronic \nnephritis \ta nd \tr enal\tp apillary\tn ecrosis\t( Ch.\t3 0).\tPhenacetin \n(now\twithdrawn) \twas \tthe \tmain \tculprit; \tparacetamol, \tone \t\nof\tits\tmajor \tmetabolites, \tis \tmuch \tless \ttoxic. \tRegular \tuse \tof \t\nprescribed \tdoses\tof\tNSAIDs\tis\tless\thazardous \tfor\tthe\tkidney\t\nthan heavy and prolonged use of over-the-counter analgesics in a social context.\nCardiovascular side effects\nThough aspirin is widely used clinically for its long-lasting \nantiplatelet \taction \t(see \tlater) \tother \tNSAIDs \tgenerally \tlack \t\nthis property and, as well as opposing the effects of some antihypertensive drugs, also raise blood pressure in patients \nnot taking antihypertensive drugs, and therefore predispose \nto adverse cardiovascular events such as stroke and myo-cardial infarction. The hypertensive effect is dose- and \ntime-dependent \t and\t rarely \t occurs \t with \tsh ort-term\t (i.e.\t days)\t\nadministration. \tIt \tis \tnow \tknown \tthat \t(with \tthe \texception \t\nof\tlow-dose \taspirin) \tthese \teffects \tare \tcommon \tto \tmost \t\nNSAIDs, especially following prolonged use. Patients with pre-existing cardiovascular risk are at particular risk. Some \ndrugs\t(e.g. \tnaproxen )\tappear\tto \tbe \tbetter \ttolerated \tin \tthis \t\nrespect\tthan \tothers \t(see \tRay \tet \tal., \t2009).\n\u25bc Astonishingly, given the fact that some of these drugs have been \nin use for half a century or more, this was only recognised as", "start_char_idx": 0, "end_char_idx": 2815, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2eba9a49-5e45-451b-90c5-d50142df6e14": {"__data__": {"id_": "2eba9a49-5e45-451b-90c5-d50142df6e14", "embedding": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "46f68bf9-5d5e-43d1-bd5c-cb08da90e53c", "node_type": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b6801f622779f7467e56b2fa057de5f82adaa8c86e81a385d3db945e2089ac1"}, "2": {"node_id": "0cc1f2bf-3013-476a-afd2-664e778c2146", "node_type": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "98f727b24c2c27b0d548df931f3230f5e054ed9c27942d5c0d33e5186b522625"}, "3": {"node_id": "b801f5c4-b2e9-4ef1-99a9-a272d5a3b998", "node_type": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14f7d268612616d587ea69137c56e985507bde906ca809b6cc5267c086986ed6"}}, "hash": "f10f94a8bd7f5481da9069d344e2b8bedde1b42909181e820538532f7ba28e3d", "text": "a serious \nissue\tduring \ttrials \tof \tthe \tCOX-2 \tinhibitor \trofecoxib \tin \t2000, \tafter \t\nwhich continuing concern about the cardiovascular risk led to the \naddition of a \u2018warning label\u2019 in 2002. The results from a later long-term \ntrial designed to assess the anticancer activity of rofecoxib confirmed \na\tsignificantly \tincreased \tthe \trisk \tof \tcardiovascular \tevents \tafter \t18 \t\nmonths of drug treatment. As a result, the drug was withdrawn in \n2004.lesions\tincrease \tCOX-2 \texpression \tand \tprostaglandin \t\nrelease within the cord, facilitating transmission from \nafferent pain fibres to relay neurons in the dorsal horn \n(see\tCh.\t43).\nUNWANTED \u2003EFFECTS\nOverall,\tthe \tburden \tof \tunwanted \tside \teffects \tamongst \t\nNSAIDs is high, probably reflecting the fact that they are used extensively, for extended periods of time, and often \nin the more vulnerable elderly population. When used for \njoint\tdiseases\t(which\tusually\tnecessitates \tfairly\tlarge\tdoses\t\nand\tsustained \ttreatment), \tthere \tis \ta \thigh \tincidence \tof \tside \t\neffects\t\u2013\tparticularly \tin \tthe \tGI \ttract \tbut \talso \tin \tthe \tliver, \t\nkidney, spleen, blood and bone marrow.\nBecause\tprostaglandins \tare\tinvolved \tin\tgastric\tcytoprotec -\ntion, platelet aggregation, renal vascular autoregulation and induction of labour, all NSAIDs share a broadly \nsimilar profile of mechanism-dependent side effects on these processes, although there may be other additional \nunwanted effects peculiar to individual members of the \ngroup.\tCOX-2-selective \tdrugs\thave\tless,\tbut\tnot\tnegligible, \t\nGI\ttoxicity.\nGastrointestinal disturbances\nAdverse\tGI \tevents \tare \tthe \tcommonest \tunwanted \teffects \t\nof the NSAIDs. They are believed to result mainly from \ninhibition \tof\tgastric\tCOX-1,\twhich\tsynthesises \tprostaglan -\ndins that normally inhibit acid secretion and protect the \nmucosa\t(see \tCh. \t31, \tFig. \t31.2).\nMild\tsymptoms \tof \tgastric \tdiscomfort \t(\u2018dyspepsia\u2019) \tand \t\nnausea result from gastric mucosal damage, which in some \ncases progresses to manifest gastric bleeding and ulceration. \nIt\thas\tbeen \testimated \tthat \t34%\u201346% \tof \tusers \tof \tNSAIDs \t\nwill\tsustain \tsome \tGI \tdamage \twhich, \twhile \tit \tmay \tbe \t\nasymptomatic, can carry a risk of serious haemorrhage \nand/or\tperforation. \tThese\tsevere\tGI\teffects\tare\tsaid\tto\tresult\t\nin the hospitalisation of over 100,000 people per year in the United States, some 15% of whom die from this iatro -\ngenic\tdisease \t(Fries, \t1998). \tDamage \tis \tseen \twhether \tthe \t\ndrugs are given orally or systemically. However, in some \ncases\t(aspirin\tbeing\ta\tgood\texample), \tlocal\tirritation \tof\tthe\t\ngastric mucosa caused directly by the drug itself may \ncompound \tt he\td amage.\tO ral\ta dministration \to f\t\u2018 replacement\u2019 \t\nprostaglandin analogues such as misoprostol \t(see\tCh. \t31) \t\ndiminishes the gastric damage produced by these agents and is occasionally co-prescribed or", "start_char_idx": 2816, "end_char_idx": 5686, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b801f5c4-b2e9-4ef1-99a9-a272d5a3b998": {"__data__": {"id_": "b801f5c4-b2e9-4ef1-99a9-a272d5a3b998", "embedding": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "46f68bf9-5d5e-43d1-bd5c-cb08da90e53c", "node_type": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b6801f622779f7467e56b2fa057de5f82adaa8c86e81a385d3db945e2089ac1"}, "2": {"node_id": "2eba9a49-5e45-451b-90c5-d50142df6e14", "node_type": null, "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f10f94a8bd7f5481da9069d344e2b8bedde1b42909181e820538532f7ba28e3d"}}, "hash": "14f7d268612616d587ea69137c56e985507bde906ca809b6cc5267c086986ed6", "text": "combined in a single \npill.\nBased\ton \textensive \texperimental \tevidence, \tit \thad \tbeen \t\npredicted \tthat\tCOX-2-selective \tagents\twould\tprovide\tgood\t\nanti-inflammatory and analgesic actions with less gastric \ndamage. \tTwo \tlarge \tprospective \tstudies \tcompared \tthe \tGI \t\nside\teffects \tof \ttwo \thighly \tselective \tCOX-2 \tinhibitors, \t\ncelecoxib and rofecoxib, with those of standard comparator \nNSAIDs in patients with arthritis. The coxibs showed some \nbenefit, although the results were not as clear-cut as had \nbeen hoped. The actual situation following therapy is \ncomplex\tbecause\tthe\tdegree\tto\twhich\tthe\ttwo\tCOX\tisoforms\t\nare inhibited depends not only upon the intrinsic activity of the drug and the inhibitory kinetics as well as the \npharmacokinetics. \tWarner \tand \tMitchell \t(2008) \thave \tsug-\ngested\tthat \tthe \tdegree \tto \twhich \tNSAIDs \tinhibit \tCOX-1 \tat \t\nthe\tconcentration \tat \twhich \tthey \tinhibit \tCOX-2 \tby \t80% \tis \t\nthe best measure of \u2018selectivity\u2019. Damage to the small intestine may also occur following NSAID treatment. It is \nnot\tclear \tif \ta \tCOX-dependent \tmechanism \tis \tinvolved.3A horrible condition where skin peels away in sheets as if scalded.\n4So\tcalled \tbecause \tthe \tavailability \tof \tNSAIDs \t(often \tin \tcombination \twith \t\nother\tsubstances, \tsuch \tas \tcaffeine) \tin \tover-the-counter \tproprietary \t\nmedicines, has tempted some people to consume them in prodigious \nquantities, for every conceivable malady. Swiss workers manufacturing \nwatches used to share analgesics in the same way as sweets or \ncigarettes!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5687, "end_char_idx": 7712, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ba28f66-92f1-4bc4-8ff0-9c60a2f323c6": {"__data__": {"id_": "8ba28f66-92f1-4bc4-8ff0-9c60a2f323c6", "embedding": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "294fe2ac-fe3e-4776-84ac-745e97c9d67d", "node_type": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3615f440002f10b50b0cbf7d7926d6e1ad4c32efc7f7fc6e0ea491c908ae210"}, "3": {"node_id": "f26bb0cb-b7fb-4de7-bdb4-5e268a6510e4", "node_type": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a52a11d2269299ea0b4aeff4c048906040a3c7e17616a3911a4d6ca8ac97250"}}, "hash": "215715bcd83560b311e31036c4e71715cb8920df558cf584e89c2e847ee821c0", "text": "27 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n348The reasons for these adverse cardiovascular effects have been the \nsubject\tof \tconsiderable \tdebate \tand \tcontroversy. \tOne \tattractive \tidea \t\nwas\tthat\tinhibition \tof \tprostacyclin \t(a \tpotent \tvasodilator) \tproduction \t\nby\tCOX-2 \tin \tvascular \ttissue \tcould \tlead \tto \ta \tnet \thypertensive \teffect \t\n(see\tGrosser\tet\tal., \t 2006). \t This \t idea \t gained \t traction \t when \t it \t was \t shown\t\nthat coxibs reduced the urinary output prostacyclin metabolites \nsuggesting \tthat \tCOX-2 \twas \tthe \tdominant \tisoform \tresponsible \tfor \t\nprostacyclin \tproduction \tin \tthe \tvasculature. \tOthers \thave \targued \tthat \t\nCOX-1\tis \tthe \tmain \tisoform \tin \tvascular \ttissue \tand \tthat \tprostacyclin \t\nmetabolites found in the urine predominately reflect intra-renal \nsynthesis \trather \tthan \toverall \tvascular \tproduction \t(see \tKirby \tet \tal., \t\n2015).\tProstaglandins \tare \timportant \tin \tthe \tregulation, \tby \tcells \tof \tthe \t\nmacula densa region, of renin release and hence blood pressure, so \ninhibition \tof \tCOX-2 \tat \tthis \tsite \tmay \tbe \tthe \tculprit. \tAn \talternative \t\nrecent\texplanation \tis \tthat \trenal \tCOX-2 \tcontrols \tthe \tmethylarginine \t\nsystem suppressing the release of cardiotoxic asymmetrical dimethyl \narginate\t(ADMA) \tby \tthe \tconstitutive \tnitric \toxide \tsynthase \t(NOS) \t\nenzyme\t(see \tKirby \tet \tal., \t2016 \tand \tCh. \t21). \tThe \tproblem \thas \tnot \tyet \t\nbeen\tsettled \tto \teveryone\u2019s \tsatisfaction \tand \ta \theated \t(and \tsometimes \t\noverheated) \tdebate \tcontinues.\nOther unwanted effects\nApproximately 5% of patients exposed to NSAIDs experi -\nence aspirin-sensitive asthma. The exact mechanism is \nunknown, \tb ut\ti nhibition \to f\tC OX\ti s\ti mplicated \t( see\tC h.\t2 9)\t\nand pre-existing viral infections may predispose. Aspirin \nis the worst offender, but there is cross-reaction with other \nNSAIDs, \texcept \tpossibly \tselective \tCOX-2 \tinhibitors \t(see \t\nCh.\t29).\tOther, \tmuch \tless \tcommon, \tunwanted \teffects \tof \t\nNSAIDs\tinclude \tCNS \teffects, \tbone \tmarrow \tdisturbances \t\nand liver disorders, the last being more likely if there is already renal impairment.\n5 Paracetamol overdose causes \nliver\tfailure.\tAll\tNSAIDs\t(except\tCOX-2\tinhibitors, \tincluding \t\nparacetamol \tin\ttherapeutic \tdoses)\tprevent\tplatelet\taggrega -\ntion to some extent and therefore may prolong bleeding. \nAgain, aspirin is the main problem in this regard.\nSOME IMPORTANT NSAIDS AND COXIBS\nTable 27.1 lists commonly used NSAIDs, and the clinical \nuses of the NSAIDs are summarised in the clinical box. \nWe now look at some of the more significant drugs in", "start_char_idx": 0, "end_char_idx": 2597, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f26bb0cb-b7fb-4de7-bdb4-5e268a6510e4": {"__data__": {"id_": "f26bb0cb-b7fb-4de7-bdb4-5e268a6510e4", "embedding": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "294fe2ac-fe3e-4776-84ac-745e97c9d67d", "node_type": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3615f440002f10b50b0cbf7d7926d6e1ad4c32efc7f7fc6e0ea491c908ae210"}, "2": {"node_id": "8ba28f66-92f1-4bc4-8ff0-9c60a2f323c6", "node_type": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "215715bcd83560b311e31036c4e71715cb8920df558cf584e89c2e847ee821c0"}, "3": {"node_id": "48f577e0-3bce-4437-80be-d6c6827109b3", "node_type": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "05fb14d51fe690a45f038b307863aa598f0d0d024bf9835cc829df02e2bddd63"}}, "hash": "4a52a11d2269299ea0b4aeff4c048906040a3c7e17616a3911a4d6ca8ac97250", "text": "a \nlittle more detail.\nASPIRIN\nAspirin\t(acetylsalicylic \tacid) \twas \tamong \tthe \tearliest \tdrugs\t\nsynthesised, and is still one of the most commonly consumed drugs worldwide.\n6 It is also a common ingredient in many \nover-the-counter \tproprietary \tmedicines \t(although \tincreasingly \t\nless\tso).\tThe \tdrug \titself \tis \trelatively \tinsoluble, \tbut \tits \tsodium\t\nand calcium salts dissolve readily in aqueous solutions.\nWhile aspirin was originally an anti-inflammatory \nworkhorse, it is seldom used for this purpose now, having \nbeen supplanted by other, better tolerated NSAIDs. Today, \nin addition to its widespread use as an over-the-counter remedy, its main clinical use is as a cardiovascular drug \nbecause of its ability to provide a prolonged suppression \nof\tplatelet \tCOX-1 \tand \thence \treduce \taggregation \t(see \t \nCh.\t25).General unwanted effects of cyclo-\noxygenase (COX) inhibitors \nUnwanted effects, many stemming from inhibition of the \nconstitutive housekeeping enzyme COX-1 isoform, are common, particularly in the elderly, and include the \nfollowing:\n\u2022\tDyspepsia, nausea, vomiting and other GI effects. \nGastric and intestinal damage may occur with chronic use, with risk of haemorrhage, ulceration and \nperforation which can be life-threatening. The cause is \nsuppression of gastroprotective prostaglandins in the gastric mucosa.\n\u2022\tAdverse cardiovascular effects . These can occur with \nmany non-steroidal anti-inflammatory drugs (NSAIDs) \nand coxibs and may be related to inhibition of COX-2 \nin the kidney or elsewhere leading to hypertension.\n\u2022\tSkin reactions . Mechanism unknown.\n\u2022\tReversible renal insufficiency. Seen mainly in individuals \nwith compromised renal function when the compensatory prostaglandin I\n2/E2-mediated \nvasodilatation is inhibited.\n\u2022\tBronchospasm. Seen in \u2018aspirin-sensitive\u2019 asthmatics. \nUncommon with coxibs.\n\u2022\t\u2018Analgesic-associated nephropathy\u2019. This can occur \nfollowing long-term high-dose regimes of NSAIDs and \nis often irreversible.\n\u2022\tLiver disorders, bone marrow depression . Relatively \nuncommon.\nClinical uses of non-steroidal \nanti-inflammatory drugs (NSAIDs) \nNSAIDs are widely used but cause serious adverse effects (especially GI, renal, pulmonary and cardiovascular effects related to their main \npharmacological actions, as well as idiosyncratic effects). \nElderly patients and those with pre-existing disorders are at particular risk. The main uses are:\u2022\tAntithrombotic: e.g. aspirin (Ch. 25) for patients at \nhigh risk of arterial thrombosis (e.g. following myocardial infarction). Other NSAIDs that cause less profound inhibition of platelet thromboxane synthesis than does aspirin, increase the risk of thrombosis and \nshould be avoided in high-risk individuals if possible.\n\u2022\tAnalgesia (e.g. for headache, dysmenorrhoea, backache, bony metastases, postoperative pain):\n\u2013 short-term use: e.g. aspirin, paracetamol, \nibuprofen;\n\u2013 chronic pain: more potent, longer-lasting drugs (e.g. \nnaproxen, piroxicam) often combined with a \nlow-potency opioid (e.g. codeine, Ch. 43);\n\u2013 to reduce the requirement for narcotic analgesics \n(the NSAID ketorolac is sometimes given \npostoperatively for this purpose).\n\u2022\tAnti-inflammatory: e.g.", "start_char_idx": 2598, "end_char_idx": 5788, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "48f577e0-3bce-4437-80be-d6c6827109b3": {"__data__": {"id_": "48f577e0-3bce-4437-80be-d6c6827109b3", "embedding": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "294fe2ac-fe3e-4776-84ac-745e97c9d67d", "node_type": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3615f440002f10b50b0cbf7d7926d6e1ad4c32efc7f7fc6e0ea491c908ae210"}, "2": {"node_id": "f26bb0cb-b7fb-4de7-bdb4-5e268a6510e4", "node_type": null, "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a52a11d2269299ea0b4aeff4c048906040a3c7e17616a3911a4d6ca8ac97250"}}, "hash": "05fb14d51fe690a45f038b307863aa598f0d0d024bf9835cc829df02e2bddd63", "text": "given \npostoperatively for this purpose).\n\u2022\tAnti-inflammatory: e.g. ibuprofen, naproxen for \nsymptomatic relief in rheumatoid arthritis, gout, soft tissue disorders.\n\u2022\tAntipyretic: paracetamol.5An odd side effect of the NSAID diclofenac came to light when a team \nof scientists investigated the curious decline in the vulture population \nof the Indian subcontinent. These birds feed on dead cattle some of \nwhich had been treated with diclofenac for veterinary reasons. Apparently, residual amounts of the drug in the carcasses proved \nuniquely toxic to this species.\n6Indeed,\tmany \tpeople \tdo \tnot \tseem \tto \tregard \tit \tas \ta \t\u2018drug\u2019 \tat \tall. \tMany \t\nstudies of human platelet aggregation have been ruined by the failure \nof volunteers to declare their consumption of aspirin.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5721, "end_char_idx": 6979, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ff58447f-cb12-48e1-8609-bff1af49f42f": {"__data__": {"id_": "ff58447f-cb12-48e1-8609-bff1af49f42f", "embedding": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0d34b8dc-6df2-4291-bf3a-8e03d0058916", "node_type": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a41cbe07952f9347919de2e33edef0b1ce2d4c5386e58b90e4da99de35a6561a"}, "3": {"node_id": "52ed733f-fe99-44da-b387-29043d10393b", "node_type": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bcb473a5db16954981aca1a50ef08525579f25f4fd07848223c61413ff6cff3b"}}, "hash": "74e3f9b44f9b162439664369480f530b2052a47a38b1fcda481dd8679f557e8e", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSU pp RESSANT DRUGS\n349\u25bc\tAcute\tsalicylate \t poisoning \t (a \t medical \t emergency \t that \t occurs \t mainly\t\nin\tchildren \tand \tattempted \tsuicides) \tcauses \tmajor \tdisturbance \tof \t\nacid\u2013base and electrolyte balance. Salicylates uncouple oxidative \nphosphorylation \t( mainly\ti n\ts keletal\tm uscle),\tl eading\tt o\th yperthermia, \t\nincreased oxygen consumption and thus increased production of \ncarbon dioxide. This stimulates respiration, which is also increased \nby a direct action of the drugs on the respiratory centre. The resulting \nhyperventilation causes a respiratory alkalosis that is normally compensated by renal mechanisms involving increased bicarbonate \nexcretion. \tLarger\tdoses\tactually\tcause\ta\tdepression \tof\tthe\trespiratory \t\ncentre,\tless\tCO 2\tis\texhaled\tand\ttherefore \tincreases \tin\tthe\tblood.\tBecause\t\nthis is superimposed on a reduction in plasma bicarbonate, an uncompensated respiratory acidosis will occur. This may be compli -\ncated by a metabolic acidosis, which results from the accumulation \nof\tmetabolites \tof \tpyruvic, \tlactic \tand \tacetoacetic \tacids \t(an \tindirect \t\nconsequence \tof\tuncoupled \toxidative \tphosphorylation). \tHyperthermia \t\nsecondary to the increased metabolic rate is also likely to be present, \nand\tdehydration \tmay \tfollow \trepeated \tvomiting. \tIn \tthe \tCNS, \tinitial \t\nstimulation with excitement is followed eventually by coma and \nrespiratory \tdepression. \tBleeding \tcan \talso \toccur, \tmainly \tas \ta \tresult \t\nof depressed platelet aggregation.\nDrug interactions\nAspirin\tmay \tcause \ta \tpotentially \thazardous \tincrease \tin \t\nthe effect of warfarin, partly by displacing it from plasma \nprotein\tbinding\tsites\t(Ch.\t11)\tthereby\tincreasing \tits\teffective\t\nconcentration and partly because its effect on platelets \nfurther\tinterferes \twith \thaemostasis \t(see \tCh. \t25). \tAspirin \t\nalso antagonises the effect of some antihypertensive and \nuricosuric agents such as probenecid and sulfinpyra-\nzone.\tBecause \tlow \tdoses \tof \taspirin \tmay, \ton \ttheir \town, \t\nreduce\turate \texcretion \t(Ch. \t30), \tit \tshould \tnot \tbe \tused \t \nin gout.\u25bc While inhibition of platelet function is a feature of most NSAIDs, \nthe effect of aspirin is longer lasting. This is because it irreversibly \nacetylates \tCOX \tenzymes, \tand \twhile \tthese \tproteins \tcan \tbe \treplaced \tin \t\nmost\tcells, \tplatelets, \tlacking \ta \tnucleus \t(and \thence \tthe \tcellular \tmachinery \t\nfor\tmaking \tnew \tproteins), \tare \tnot \table \tto \tdo \tso, \tand \tremain \tinactivated \t\nfor\ttheir\tlifetime \t(approximately \t10 \tdays). \tSince \ta \tproportion \tof \tplatelets\t\nis replaced each day from the bone marrow, this inhibition gradually \nabates\tbut \ta \tsmall \tdaily \tdose \tof \taspirin \t(e.g. \t75 \tmg/day) \tis \tall \tthat \tis \t\nrequired to suppress platelet", "start_char_idx": 0, "end_char_idx": 2774, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "52ed733f-fe99-44da-b387-29043d10393b": {"__data__": {"id_": "52ed733f-fe99-44da-b387-29043d10393b", "embedding": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0d34b8dc-6df2-4291-bf3a-8e03d0058916", "node_type": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a41cbe07952f9347919de2e33edef0b1ce2d4c5386e58b90e4da99de35a6561a"}, "2": {"node_id": "ff58447f-cb12-48e1-8609-bff1af49f42f", "node_type": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "74e3f9b44f9b162439664369480f530b2052a47a38b1fcda481dd8679f557e8e"}, "3": {"node_id": "07f36618-3186-4568-b410-8ce3492edccf", "node_type": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b948c3b6e3ade9df7bce8ba22bfb57c934dfd0ced258ffda224e8672b33b673f"}}, "hash": "bcb473a5db16954981aca1a50ef08525579f25f4fd07848223c61413ff6cff3b", "text": "function to levels which benefit patients at \nrisk\tfor\tmyocardial \tinfarction \tand \tother \tcardiovascular \tproblems \t(Ch.\t\n25).\tThe\tview \tthat \teven \tpatients \tnot \tat \trisk \twould \tbenefit \tfrom \ttaking \tthe\t\ndrug\tprophylactically \t(primary \tprevention) \twas \tchallenged \tin \ta \tmeta-\nanalysis\t(Baigent \tet \tal., \t2009) \tsuggesting \tthat \tin \tthe \tgeneral \tpopulation, \t\nthe risk from gastrointestinal bleeding just outweighs the protective \naction. In cases where there is a previous history of cardiovascular \nepisodes\tthe \tcase \tfor \tprophylactic \taspirin \t(secondary \tprevention) \tseems\t \nunassailable.\nThe use of aspirin has also been canvassed for other conditions. These \ninclude:\n\u2022\tCancer \t\u2013 \tespecially \tcolonic \tand \trectal \tcancer: \taspirin \t(and \tsome \t\nCOX-2\tinhibitors) \tmay \treduce \tthe \tincidence \tof \tseveral \ttypes \tof \t\ncancer\talthough \tone \talways \thas \tto \tbe \taware \tof \tthe \tGI \trisk \t(see \t\nPatrignani \t& \tPatrono, \t2016)\n\u2022\tAlzheimer\u2019s \tdisease \t(Ch. \t41): \tepidemiological \tevidence \tsuggested \t\nthat carefully selected doses of aspirin might be beneficial, at least \nin\tsome\tgroups \t(see \tChang \tet \tal., \t2016) \talthough \tother \tstudies \t\nhave\tbeen \tless \tencouraging \t(see \tWaldstein \tet \tal., \t2010).\n\u2022\tRadiation-induced \tdiarrhoea.\nPharmacokinetic aspects\nAspirin,\tbeing\ta\tweak\tacid,\tis\tundissociated \t(i.e.\tnot\tionised)\t\nin the acid environment of the stomach, thus facilitating \nits\tpassage \tacross \tthe \tmucosa. \tMost \tabsorption, \thowever, \t\noccurs in the ileum, because of the extensive surface area \nof the microvilli.\n\u25bc\tAspirin \tis \trapidly \t(within \t30 \tmin) \thydrolysed \tby \testerases \tin \t\nplasma and tissues, particularly the liver, yielding salicylate. This \ncompound \titself \thas \tanti-inflammatory \tactions \t(indeed, \tit \twas \t\nthe\toriginal \tanti-inflammatory \tfrom \twhich \taspirin \twas \tderived); \t\nthe mechanism is not clearly understood, although it may depend \nupon inhibition of the NF \u03baB\tsystem \t(Ch. \t3) \tand \tonly \tsecondarily \ton \t\nCOX\tinhibition. \tOral \tsalicylate \tis \tno \tlonger \tused \tfor \ttreating \tinflam -\nmation, although it is a component of some topical preparations. \nApproximately 25% of the salicylate is oxidised; some is conjugated \nto give the glucuronide or sulfate before excretion, and about 25% is excreted unchanged, the rate of excretion being higher in alkaline urine \n(see\tCh.\t9).\nThe plasma half-life of aspirin will depend on the dose, \nbut the duration of action is not directly related to the \nplasma half-life because of the irreversible nature of the \naction\tof \tthe \tacetylation \treaction \tby \twhich \tit \tinhibits \tCOX \t\nactivity.\nUnwanted effects\nSalicylates", "start_char_idx": 2775, "end_char_idx": 5420, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "07f36618-3186-4568-b410-8ce3492edccf": {"__data__": {"id_": "07f36618-3186-4568-b410-8ce3492edccf", "embedding": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0d34b8dc-6df2-4291-bf3a-8e03d0058916", "node_type": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a41cbe07952f9347919de2e33edef0b1ce2d4c5386e58b90e4da99de35a6561a"}, "2": {"node_id": "52ed733f-fe99-44da-b387-29043d10393b", "node_type": null, "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bcb473a5db16954981aca1a50ef08525579f25f4fd07848223c61413ff6cff3b"}}, "hash": "b948c3b6e3ade9df7bce8ba22bfb57c934dfd0ced258ffda224e8672b33b673f", "text": "\t(e.g.\taspirin,\tdiflunisal and sulfasalazine )\tmay\t\nproduce both local and systemic toxic effects. In addition \nto the general unwanted effects of NSAIDs outlined above., \nthere are certain specific unwanted effects that occur with \naspirin and other salicylates. Reye\u2019s syndrome , a rare disorder \nof children that is characterised by hepatic encephalopathy \nfollowing \tan\tacute\tviral\tillness,\tcarries\ta\t20%\u201340% \tmortality. \t\nSince the withdrawal of aspirin for paediatric use, the \nincidence \tof \tReye\u2019s \tsyndrome \thas \tfallen \tdramatically. \t\nSalicylism ,\tcharacterised \tby \ttinnitus \t(high \tpitched \tringing \t\nin\tthe\tears),\tvertigo,\tdecreased \thearing\tand\tsometimes \talso\t\nnausea and vomiting, occurs with over-dosage of any salicylate.Aspirin \nAspirin (acetylsalicylic acid) is the oldest non-steroidal \nanti-inflammatory drug. It acts by irreversibly inactivating cyclo-oxygenase (COX-) 1 and COX-2.\n\u2022\tIn\taddition \tto \tits \tanti-inflammatory \tactions, \taspirin \t\nstrongly inhibits platelet aggregation, and its main clinical use now is in the therapy of cardiovascular disease.\n\u2022\tIt\tis\tgiven \torally \tand \tis \trapidly \tabsorbed; \t75% \tis \t\nmetabolised in the liver.\n\u2022\tElimination \tof \tits \tmetabolite \tsalicylate \tfollows \tfirst-order \t\nkinetics with low doses (half-life 4 h), and saturation \nkinetics with high doses (half-life over 15 h).\nUnwanted effects:\n\u2022\tWith\ttherapeutic \tdoses: \tGI \tsymptoms, \toften \tincluding \t\nsome gastric bleeding (usually slight and asymptomatic).\n\u2022\tWith\tlarger \tdoses: \tdizziness, \tdeafness \tand \ttinnitus \t\n(\u2018salicylism\u2019); compensatory respiratory alkalosis may occur.\n\u2022\tWith\ttoxic \tdoses \t(e.g. \tfrom \tself-poisoning): \t\nuncompensated metabolic acidosis may occur, particularly in children.\n\u2022\tAspirin\thas \tbeen \tlinked \twith \ta \trare \tbut \tserious \t\npost-viral encephalitis (Reye\u2019s syndrome) in children and is not used for paediatric purposes.\n\u2022\tIf\tgiven\tconcomitantly \twith \twarfarin, \taspirin \tcan \tcause \t\na potentially hazardous increase in the risk of bleeding.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5421, "end_char_idx": 7910, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ced6b948-e5f3-43b5-bdd0-f78d3b22d2c9": {"__data__": {"id_": "ced6b948-e5f3-43b5-bdd0-f78d3b22d2c9", "embedding": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "779fb296-4e38-4bba-b816-02f122e4f014", "node_type": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16d023ad821d2441ecc3355eee212f4aa3cd65b86bf2fbaec7abf860859a595f"}, "3": {"node_id": "0ba36249-f72e-4be7-a783-c8c4689ccd4d", "node_type": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "56e047a7f609be6794e113f11d90b9441209996d2c7c93e2389ef187f1bb4eb8"}}, "hash": "a9dd84859b157f9d21660500d46c2110d08ac1f0c338640baaa7e83b25281bc7", "text": "27 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n350and\tothers\tmay\tbe\tavailable \telsewhere. \tCoxibs\tare\tgenerally \t\noffered to patients for whom treatment with conventional \nNSAIDs\twould \tpose \ta \thigh \tprobability \tof \tserious \tGI \tside \t\neffects. However, these can still occur with coxibs, perhaps \nbecause\tCOX-2 \thas \tbeen \timplicated \tin \tthe \thealing \tof \tpre-\nexisting ulcers, so inhibition could delay recovery from \nearlier lesions. As is the case with all NSAID treatment, \ncardiovascular risk should be assessed prior to long-term \ntreatment.\nCelecoxib and etoricoxib\nCelecoxib and etoricoxib are used for symptomatic relief \nin the treatment of osteoarthritis and rheumatoid arthritis \nand some other conditions.\n\u25bc\tBoth\tare \tadministered \torally \tand \thave \tsimilar \tpharmacokinetic \t\nprofiles, being well absorbed with peak plasma concentrations being \nachieved \twithin \t1\u20133 \th. \tThey \tare \textensively \t(>99%)\tmetabolised \tin \t\nthe\tliver, \tand \tplasma \tprotein \tbinding \tis \thigh \t(>90%).\tCommon \t\nunwanted \teffects \tmay \tinclude \theadache, \tdizziness, \trashes \tand \t\nperipheral \toedema\tcaused\tby\tfluid\tretention. \tBecause\tof\tthe\tpotential \t\nrole\tof\tCOX-2 \tin \tthe \thealing \tof \tulcers, \tpatients \twith \tpre-existing \t\ndisease should avoid the drugs.\nParecoxib\nParecoxib is a prodrug of valdecoxib. The latter drug has \nnow been withdrawn, but parecoxib is licensed for the short-term treatment of postoperative pain. It is given by \nintravenous or intramuscular injection, and is rapidly and \nvirtually \tcompletely \t(>95%)\tconverted \tinto \tthe \tactive \t\nvaldecoxib \tby \tenzymatic \thydrolysis \tin \tthe \tliver.\n\u25bc\tMaximum \tblood \tlevels \tare \tachieved \twithin \tapproximately \t\n30\u201360 m in, depending on the route of administration. Plasma protein \nbinding is high. The active metabolite, valdecoxib, is converted in \nthe liver to various inactive metabolites, and has a plasma half-life \nof\ta bout\t8\th .\tS kin\tr eactions,\ts ome\to f\tt hem\ts erious,\th ave\tb een\tr eported\t\nwith valdecoxib, and patients should be monitored carefully. The drug should also be given with caution to patients with impaired \nrenal function, and renal failure has been reported in connection with \nthis drug. Postoperative anaemia may also occur.PARACETAMOL\nParacetamol \t(called \tacetaminophen \tin \tthe \tUnited \tStates) \t\nis one of the most commonly used non-narcotic analgesic\u2013\nantipyretic agents and is a component of many over-the-\ncounter proprietary preparations. In some ways, the drug \nconstitutes an anomaly: while it is an excellent analgesic \n(see\tCh.\t43) \tand \tantipyretic, \tits \tanti-inflammatory \taction \t\nis slight and seems to be restricted to a few special cases \n(e.g.\tinflammation \tfollowing \tdental\textraction; \tsee\tSkjelbred \t\net\tal.,\t1984). \tIt \tis \talso \tsubstantially \tfree \tof \tthe \tgastric \tand \t\nplatelet side effects of the other NSAIDs. For these reasons, paracetamol is sometimes not classified as an NSAID", "start_char_idx": 0, "end_char_idx": 2929, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0ba36249-f72e-4be7-a783-c8c4689ccd4d": {"__data__": {"id_": "0ba36249-f72e-4be7-a783-c8c4689ccd4d", "embedding": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "779fb296-4e38-4bba-b816-02f122e4f014", "node_type": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16d023ad821d2441ecc3355eee212f4aa3cd65b86bf2fbaec7abf860859a595f"}, "2": {"node_id": "ced6b948-e5f3-43b5-bdd0-f78d3b22d2c9", "node_type": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a9dd84859b157f9d21660500d46c2110d08ac1f0c338640baaa7e83b25281bc7"}, "3": {"node_id": "49952cc8-c5b8-48c3-8f57-663191f17927", "node_type": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "acddcbda60a7f556222bfcb43625689eaa3e87a414e0ea49d4d9b0f4e88a1079"}}, "hash": "56e047a7f609be6794e113f11d90b9441209996d2c7c93e2389ef187f1bb4eb8", "text": " \nat all.\n\u25bc The antipyretic and analgesic activities can be traced to inhibi -\ntion\tof\tprostaglandin \tsynthesis \tin \tthe \tCNS. \tParacetamol \thas \tbeen \t\nshown to inhibit prostaglandin biosynthesis in some experimental \nsettings\t(e.g. \tin \tthe \tCNS \tduring \tfever) \tbut \tnot \tin \tothers \t(see \talso \t\nCh.\t43).\tVarious \tsolutions \tto \tthis \tpuzzle \thave \tbeen \tsuggested, \t\nincluding \tthe \tpossibility \tof \ta \tfurther \tparacetamol-sensitive \tCOX \t\nisoform\tin \tthe \tCNS. \tAn \talternative \texplanation \tis \tthat \tit \tacts \tas \ta \t\nreducing \tagent \tto \tinhibit \tCOX \tenzymes. \tInhibition \twould \tbe \tmore \t\neffective\tin \tthe \tparticular \toxidising \tmilieu \tof \tthe \tCNS \t(Ouellet \t& \t \nPercival, \t2001).\nPharmacokinetic aspects\nParacetamol is well absorbed when given orally, with peak \nplasma concentrations reached in 30\u201360 min. The plasma \nhalf-life\tof \ttherapeutic \tdoses \tis \t2\u20134 \th, \tbut \twith \ttoxic \tdoses \t\nit\tmay\tbe \textended \tto \t4\u20138 \th. \tParacetamol \tis \tinactivated \tin \t\nthe liver, being conjugated to give the glucuronide or sulfate.\nUnwanted effects\nWith therapeutic doses, side effects are few and uncommon, although allergic skin reactions sometimes occur. It is \npossible that regular intake of large doses over a long period \nmay\tcause\tkidney\tdamage.\tHowever, \ttoxic\tdoses\t(10\u201315\tg)\t\ncause potentially fatal hepatotoxicity, and nephrotoxicity. \nThis occurs when normal conjugation reactions are saturated \nand the drug is metabolised instead by mixed function \noxidases. The resulting toxic metabolite, N-acetyl-p\n-benzoquinone \timine \t(NABQI), \tis \tnormally \tinactivated \t\nby conjugation with glutathione, but when this is depleted the toxic intermediate accumulates in the liver and the \nkidney\ttubules\tand\tcauses\tnecrosis. \tChronic,\tbut\tnot\tacute,\t\nalcohol consumption can exacerbate paracetamol toxicity \nby\tinducing \tthe \tliver \tmicrosomal \tenzymes \tproducing \t \nthe\ttoxic \tmetabolite \tbut \tthe \tsituation \tis \tcomplex \t(see \t \nPrescott, \t2000).\n\u25bc The initial symptoms of acute paracetamol poisoning are nausea \nand vomiting, the hepatotoxicity being a delayed manifestation that \noccurs\t24\u201348 \th \tlater. \tFurther \tdetails \tof \tthe \ttoxic \teffects \tare \tgiven \tin \t\nChapter\t58.\tIf\tthe\tpatient\tis\tseen\tsufficiently \tsoon\tafter\tingestion, \tthe\t\nliver damage can be prevented by administering agents that increase \nglutathione \tformation \tin \tthe \tliver \t(acetylcysteine intravenously, or \nmethionine \torally).\tIf\tmore\tthan\t 12 \th \t have\t passed \t since \t the \t ingestion \t\nof a large dose, the antidotes, which themselves can cause adverse \neffects\t(nausea,\t allergic\t reactions), \tar e\t less\t likely\t to\t be\t useful. \tRe gret-\ntably, ingestion of large amounts of paracetamol is a common method \nof suicide.\nCOXIBS\nSeveral coxibs", "start_char_idx": 2930, "end_char_idx": 5679, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "49952cc8-c5b8-48c3-8f57-663191f17927": {"__data__": {"id_": "49952cc8-c5b8-48c3-8f57-663191f17927", "embedding": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "779fb296-4e38-4bba-b816-02f122e4f014", "node_type": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16d023ad821d2441ecc3355eee212f4aa3cd65b86bf2fbaec7abf860859a595f"}, "2": {"node_id": "0ba36249-f72e-4be7-a783-c8c4689ccd4d", "node_type": null, "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "56e047a7f609be6794e113f11d90b9441209996d2c7c93e2389ef187f1bb4eb8"}}, "hash": "acddcbda60a7f556222bfcb43625689eaa3e87a414e0ea49d4d9b0f4e88a1079", "text": "have been withdrawn following claims of \ncardiovascular and other toxicity, but three drugs are \ncurrently \tavailable \tfor \tclinical \tuse \tin \tthe \tUnited \tKingdom \tParacetamol \nParacetamol is a commonly used drug that is widely \navailable over the counter. It has potent analgesic and antipyretic actions but much weaker anti-inflammatory \neffects than other non-steroidal anti-inflammatory drugs \n(NSAIDs). Its cyclo-oxygenase inhibitory action seems to be mainly restricted to the central nervous system (CNS) enzyme.\n\u2022\tIt\tis\tgiven \torally \tand \tmetabolised \tin \tthe \tliver \t(half-life \t\n2\u20134 h).\n\u2022\tToxic\tdoses \tcause \tnausea \tand \tvomiting, \tthen, \tafter \t\n24\u201348 h, potentially fatal liver damage by saturating \nnormal conjugating enzymes, causing the drug to be converted by mixed function oxidases to N-acetyl-p-\nbenzoquinone imine. If not inactivated by conjugation \nwith glutathione, this compound reacts with cellular \nproteins causing tissue damage.\n\u2022\tAgents\tthat \tincrease \tglutathione \t(intravenous \t\nacetylcysteine or oral methionine) can prevent liver \ndamage if given early.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5680, "end_char_idx": 7248, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c6245616-aebd-4e15-a8bf-dcde7a3875a6": {"__data__": {"id_": "c6245616-aebd-4e15-a8bf-dcde7a3875a6", "embedding": null, "metadata": {"page_label": "357", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cef04480-afe2-46d6-b011-af9cdcaecc56", "node_type": null, "metadata": {"page_label": "357", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1fa0d82ba6a69113ec530eb13fcf815dc603ee19ae0908cad3cc36e1e1ae32ea"}, "3": {"node_id": "63cf5f09-8791-45e0-bc56-fca1bf9ff4d4", "node_type": null, "metadata": {"page_label": "357", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c00c6ee7efe331a80dbe332b94f8963d9d3714442b4ca63076f46bf459dabf2c"}}, "hash": "d54c55dd96feb84b06a827f48bc34efdf6172ec9b68d58f5b167844a8c80d079", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSU pp RESSANT DRUGS\n351inflammatory \tcytokines, \tIL-1 \tand \t(especially) \tTNF- \u03b1, have \na\tmajor\trole \tin \tthe \tdisease \t(Ch. \t19). \tA \tsimplified \tscheme \t\nshowing the development of rheumatoid arthritis and the \nsites of action of therapeutic drugs, is given in Fig. 27.3. Davis \nand\tMatteson \t(2012) \thave \treviewed \tthe \tclassification \tand \t\ntreatment of this miserable and disabling affliction.\nDISEASE-MODIFYING \u2003ANTIRHEUMATIC \u2003DRUGS\nThe drugs most frequently used in initial therapy are the \u2018disease-modifying antirheumatic drugs\u2019\n8\t(DMARDs \t\u2013 \t\nespecially methotrexate )\tand\tthe \tNSAIDs. \tUnlike \tthe \t\nNSAIDs, \twhich\tonly\treduce\tthe\tsymptoms, \tDMARDs \taim\tANTIRHEUMATOID DRUGS\nRheumatoid \tarthritis \tis \tone \tof \tthe \tcommonest \tchronic \tinflam -\nmatory conditions in developed countries, and a common \ncause of disability.7 Affected joints become swollen, painful, \ndeformed \tand \timmobile. \tOne \tin \tthree \tpatients \twith \trheu -\nmatoid arthritis is likely to become severely disabled. The disease also has cardiovascular and other systemic manifesta -\ntions and carries an increased risk of mortality. The degenera -\ntive joint changes, which are driven by an autoimmune reaction, are characterised by inflammation, proliferation of \nthe synovium and erosion of cartilage and bone. The primary Metalloproteinases\n(e.g. collagenase)T\nCD4Th0IL-2 IL-2Activated\nTh1 cellMacrophage\nOsteoclast FibroblastTNF-\u03b1 IL-1\nErosion of cartilage and bone\nJOINT DAMAGEInflux of \ninflammatory cellsRelease of other \ninflammatory \ncytokines and \nchemokines\nDMARDS:\nsulfasalazine, penicillamine, gold compounds, \nchloroquineAnti-TNF and\nIL-1 agentsAnti-IL-2 agents;\nimmunosuppressants; \nmethotrexateGlucocorticoids\nMechanism of \naction:\nnot clearly known\nFig. 27.3 A schematic diagram of the cells and mediators involved in the pathogenesis of rheumatoid joint damage, indicating \nthe sites of action of antirheumatoid drugs. DMARD, disease-modifying antirheumatic drug. For details of the anti-TNF, IL-1 and IL-2 \nreceptor agents, see Chapter 7 and Table 27.3. \n7The term \u2018arthritis\u2019 simply refers to inflammatory joint disorders. \nClinically, \tmore \tthan \t50 \tdistinguishable \ttypes \tare \trecognised. \tTo \tthe \tlay \t\nperson though, arthritis usually denotes either osteoarthritis or \nrheumatoid arthritis. These are often confused although they are entirely \nseparate entities.8Historically classified as such because, unlike NSAIDs, they lowered \nthe\terythrocyte \tsedimentation \trate \t(ESR) \t\u2013 \ta \tmarker \tof \tacute \t\ninflammation linked to increased plasma fibrinogen. Today, other acute \nphase\treactants \tsuch \tas \tC-reactive \tprotein \t(CRP) \tare \tgenerally \tpreferred \t\nby rheumatologists as biochemical markers of disease activity.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3038, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "63cf5f09-8791-45e0-bc56-fca1bf9ff4d4": {"__data__": {"id_": "63cf5f09-8791-45e0-bc56-fca1bf9ff4d4", "embedding": null, "metadata": {"page_label": "357", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cef04480-afe2-46d6-b011-af9cdcaecc56", "node_type": null, "metadata": {"page_label": "357", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1fa0d82ba6a69113ec530eb13fcf815dc603ee19ae0908cad3cc36e1e1ae32ea"}, "2": {"node_id": "c6245616-aebd-4e15-a8bf-dcde7a3875a6", "node_type": null, "metadata": {"page_label": "357", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d54c55dd96feb84b06a827f48bc34efdf6172ec9b68d58f5b167844a8c80d079"}}, "hash": "c00c6ee7efe331a80dbe332b94f8963d9d3714442b4ca63076f46bf459dabf2c", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2991, "end_char_idx": 3246, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "65e5c000-c392-4fb2-9aad-c75ca18bc91e": {"__data__": {"id_": "65e5c000-c392-4fb2-9aad-c75ca18bc91e", "embedding": null, "metadata": {"page_label": "358", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "467b566a-432d-47c4-a07d-5814b112e5c4", "node_type": null, "metadata": {"page_label": "358", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "35b0c06b7162f555d46cf97d3f38102b8a45b521833af864e1a1bc1da2591e6e"}, "3": {"node_id": "a90352d6-79b0-49d4-8f3c-2cf4f3ec14cd", "node_type": null, "metadata": {"page_label": "358", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "37612f0c348dba09df344a3d6d7029e41b1454c55535dad71fafc185b59939aa"}}, "hash": "b39885c10287fc916e51106394393d2a26be514dee0123fd97932fd705f08931", "text": "27 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n352to have a general anti-inflammatory action. Putative \nmechanisms \tof\taction\tof\tDMARDs \thave\tbeen\treviewed \tby\t\nCutolo\t(2002) \tand \tChandrashekara \t(2013).\nMethotrexate\nMethotrexate \tis \ta \tfolic \tacid \tantagonist \twith \tcytotoxic \tand \t\nimmunosuppressant \tactivity \t(Ch. \t57). \tIt \thas \ta \tuseful \tand \t\nreliable antirheumatoid action and is a common first-choice \ndrug. It has a more rapid onset of action than other \nDMARDs, \tbut\ttreatment \tmust\tbe\tclosely\tmonitored \tbecause\t\nof bone marrow depression, causing a drop in white cell \nand\tplatelet \tcounts \t(potentially \tfatal) \tand \tliver \tcirrhosis. \t\nIt\tis,\thowever, \tsuperior \tto \tmost \tother \tDMARDs \tin \tterms \t\nof efficacy and patient tolerance, and is often given in conjunction with the anticytokine drugs.\nIts mechanism of action is unrelated to its effect on folic \nacid\t(which \tis \troutinely \tco-administered \tto \tprevent \tblood \t\ndisorders) \tbut \tmay \twell \tbe \tconnected \twith \tits \tability \t \nto\tblock \tadenosine \tuptake \t(see \tCh. \t17 \tand \tChan \t& \t \nCronstein, \t2010).\nSulfasalazine\nSulfasalazine, \tanother\tcommon \tfirst-choice \tDMARD \tin\tthe\t\nUnited\tKingdom, \tproduces \tremission \tin\tactive\trheumatoid \t\narthritis and is also used for chronic inflammatory bowel \ndisease\t(see \tCh. \t31). \tIt \tprobably \tacts \tpartly \tby \tinhibit -\ning\tCOX \tand \tlipoxygenase \tpathways \tor \tby \tscavenging \t\ntoxic\tfree \tradicals \tbut \tit \talso \treduces \tthe \trelease \tof \tIL-8 \t\nfrom colonic myofibroblasts, suggesting an additional \nimmunosuppressive \tmechanism \t(Lodowska \tet \tal., \t2015). \t\nThe\tdrug \tis \ta \tcomplex \tof \ta \tsulfonamide \t(sulfapyridine) \t\nand salicylate and is split into its component parts by bacteria in the colon. It is poorly absorbed after oral \nadministration.to halt or reverse the underlying disease itself. Despite the \nfact that many of these claims err on the optimistic side, \nthese drugs are nevertheless useful in the treatment of \ndiscrete\tgroups \tof \tpatients \tand \tRau \t(2005) \thas \targued \tfor \t\ntheir continuing use despite the availability of the newer \nanticytokine \tagents \t(see \tlater). \tThe \tterm \t\u2018DMARD\u2019 \tis \ta \t\nlatex concept which has been stretched to cover a hetero -\nlogous group of agents with different chemical structures \nand mechanisms of action. Included in this category are \nmethotrexate, sulfasalazine, gold compounds, penicil-\nlamine, chloroquine \tand\tother \tantimalarials \t(Table \t27.2) \t\nand various immunosuppressant drugs.\n\u25bc T he antirheumatoid action of most of these agents was discovered \nthrough a mixture of serendipity and clinical intuition. When they \nwere introduced, nothing was known about their mechanism of \naction and decades of in vitro experiments have generally resulted \nin further bewilderment", "start_char_idx": 0, "end_char_idx": 2787, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a90352d6-79b0-49d4-8f3c-2cf4f3ec14cd": {"__data__": {"id_": "a90352d6-79b0-49d4-8f3c-2cf4f3ec14cd", "embedding": null, "metadata": {"page_label": "358", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "467b566a-432d-47c4-a07d-5814b112e5c4", "node_type": null, "metadata": {"page_label": "358", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "35b0c06b7162f555d46cf97d3f38102b8a45b521833af864e1a1bc1da2591e6e"}, "2": {"node_id": "65e5c000-c392-4fb2-9aad-c75ca18bc91e", "node_type": null, "metadata": {"page_label": "358", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b39885c10287fc916e51106394393d2a26be514dee0123fd97932fd705f08931"}}, "hash": "37612f0c348dba09df344a3d6d7029e41b1454c55535dad71fafc185b59939aa", "text": "rather than understanding. When success -\nful,\tDMARDs \tgenerally \timprove \tsymptoms \tand \treduce \tdisease \t\nactivity in rheumatoid arthritis, as measured by reduction in the number of swollen and tender joints, pain score, disability score, \nX-ray\tappearance \tand \tserum \tconcentration \tof \tacute-phase \tproteins \t\nand of rheumatoid factor \t(an\timmunoglobulin \tIgM \tantibody \tagainst \t \nhost\tIgG).\nThe\tDMARDs \tare\tsometimes \treferred\tto\tas\tsecond-line drugs , \nwith the implication that they are only resorted to when \nother\ttherapies \t(e.g.\tNSAIDs) \tfailed,\tbut\tDMARD \ttherapy\t\nmay be initiated as soon as a definite diagnosis has been \nreached.\tTheir\tclinical\teffects\tare\tusually\tslow\t(months) \tin\t\nonset, and it is usual to provide NSAID \u2018cover\u2019 during this \ninduction \tphase. \tIf \ttherapy \tis \tsuccessful \t(and \tthe \tsuccess \t\nrate\tis\tvariable), \tconcomitant \tNSAID \t(or \tglucocorticoid) \t\ntherapy\tcan\tbe\treduced.\tSome\tDMARDs \t(e.g.\tmethotrexate) \t\nhave a place in the treatment of other chronic inflammatory \ndiseases,\tw hereas \to thers\t( e.g.\tp enicillamine) \ta re\tn ot\tt hought\tTable 27.2 Comparison of some common \u2018disease-modifying\u2019 and immunosuppressive drugs used in the treatment of the \narthritides\nType Drug Indication Comments\nGold complexes Sodium aurothiomalate Progressive RA Many side effects. Long latency of action\nAntimalarialsChloroquine Moderate RA, SLE Used when other therapies fail\nHydroxychloroquine sulfate Moderate RA, SLE Also useful for some skin disorders\nImmunomodulatorsMethotrexate Moderate to severe RA, \nPS, JRAA \u2018first-choice\u2019 drug. Also used in Crohn's disease and cancer treatment. Often used in combination with other drugs\nAzathioprine RA, IBS Used when other therapies fail. Also used in transplant rejection, IBS and eczema\nCiclosporin Severe RA, AD, PA Used when other therapies fail, in some skin diseases and transplant rejection\nCyclophosphamide Severe RA Used when other therapies fail\nLeflunomide Moderate to severe RA, PA Also used in psoriatic arthritis\nNSAID Sulfasalazine RA, PA, JRA A \u2018first-choice\u2019 drug. Also used in ulcerative colitis\nPenicillin metabolite Penicillamine Severe RA Many side effects. Long latency of action\nAD, atopic dermatitis; IBS, inflammatory bowel disease; JRA, juvenile rheumatoid arthritis; NSAID, non-steroidal anti-inflammatory drug; PA, \npsoriatic arthritis; PS, psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.\n(Data from various sources, including the British National Formulary, 2017.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2788, "end_char_idx": 5765, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9f9452a6-e5b9-44ce-9fff-2853bbda5777": {"__data__": {"id_": "9f9452a6-e5b9-44ce-9fff-2853bbda5777", "embedding": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c51169bc-9770-4410-bc49-9fb873f09a55", "node_type": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d573612bbf34d112f6cfd3d22aa71411d1461ae907c1c8e519e30c7c867912c9"}, "3": {"node_id": "60a18ece-32fc-4d25-92a3-a8168011c2ac", "node_type": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c45cd09d6d69ce4d7855e531e89d813ee3364767058ac3ce8a0ac23de8468c07"}}, "hash": "12a6d02304a1ef4375504a2ce22f7211be97041b44377046f65a479f70a54335", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSUppRESSANT DRUGS\n353Chloroquine\t is\tusually\t reserved\t for\tcases\twhere\tother\t\ntreatments have failed. They are also used to treat another \nautoimmune disease, lupus erythematosus, but are \ncontraindicated in patients with psoriatic arthropathy \nbecause they exacerbate the skin lesions. The related \nantimalarial, mepacrine , is also sometimes used for discoid \n(cutaneous)\tlupus.\tThe\tantirheumatic\teffects\tdo\tnot\tappear \t\nuntil a month or more after the drug is started, and only \nabout half the patients treated respond. The administration, \npharmacokinetic aspects and unwanted effects of chloro -\nquine\tare\tdealt\twith\tin\tCh.\t55;\tscreening\tfor\tocular\ttoxicity \t\nis particularly important.\nIMMUNOSUPPRESSANT\u2003 DRUGS\nImmunosuppressants are used in the therapy of autoimmune \ndisease and also to prevent and/or treat transplant rejection. \nBecause\t they\timpair\tthe\timmune\t response,\t they\tcarry\tthe\t\nhazard\tof\ta\tdecreased\t response\t to\tinfections\t and\tmay\t\nfacilitate the emergence of malignant cell lines. However, \nthe relationship between these adverse effects and potency \nin preventing graft rejection varies with different drugs. \nThe clinical use of immunosuppressants is summarised in \nthe clinical box.\u25bc\tSulfasalazine\t is\tgenerally\t well\ttolerated\t but\tcommon\t side\teffects\t\ninclude\tGI\tdisturbances,\t malaise\tand\theadache.\t Skin\treactions\t and\t\nleukopenia can occur but are reversible on stopping the drug. The \nabsorption of folic acid is sometimes impaired; this can be countered \nby giving folic acid supplements. A reversible decrease in sperm \ncount has also been reported. As with other sulfonamides, bone marrow \ndepression and anaphylactic-type reactions may occur in a few patients. \nHaematological monitoring may be necessary.\nPenicillamine\nPenicillamine is dimethylcysteine ; it is produced by hydrolysis \nof penicillin and appears in the urine after treatment with \nthat drug. The D-isomer is used in the therapy of rheumatoid \ndisease. About 75% of patients with rheumatoid arthritis \nrespond to penicillamine. Therapeutic effects are seen within \nweeks but do not reach a plateau for several months. Penicil -\nlamine is thought to modify rheumatoid disease partly by \ndecreasing\tthe\timmune\tresponse\tand\tIL-1\tgeneration,\tand/\nor partly by preventing the maturation of newly synthesised \ncollagen. However, the precise mechanism of action is still \na matter of conjecture. The drug has a highly reactive thiol \ngroup and also has metal-chelating properties, which are put \nto good use in the treatment of Wilson\u2019s disease \t(pathological \t\ncopper deposition causing neurodegeneration and liver \ndisease)\t and\theavy\tmetal\tpoisoning.\n\u25bc Penicillamine is given orally, but only about half the dose is \nabsorbed. It reaches peak plasma concentrations in 1\u20132 h and is excreted \nin the urine. Treatment is initiated with low doses and increased only \ngradually to minimise the unwanted effects, which occur in about \n40%\tof\tpatients\tand\tmay\tnecessitate\tcessation\tof\ttherapy.\tRashes\tand \t\nstomatitis are the most common unwanted effects but may resolve \nif the dosage is lowered. Anorexia, fever, nausea and vomiting, and \ndisturbances\t of\ttaste\t(the\tlast\trelated\tto\tthe\tchelation\t", "start_char_idx": 0, "end_char_idx": 3224, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "60a18ece-32fc-4d25-92a3-a8168011c2ac": {"__data__": {"id_": "60a18ece-32fc-4d25-92a3-a8168011c2ac", "embedding": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c51169bc-9770-4410-bc49-9fb873f09a55", "node_type": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d573612bbf34d112f6cfd3d22aa71411d1461ae907c1c8e519e30c7c867912c9"}, "2": {"node_id": "9f9452a6-e5b9-44ce-9fff-2853bbda5777", "node_type": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "12a6d02304a1ef4375504a2ce22f7211be97041b44377046f65a479f70a54335"}, "3": {"node_id": "ca9a7379-7b95-4259-9a17-60476c71add2", "node_type": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "64bc67bf1fa0a9a48c69e4d7c3128acc566fa57803bb944da63ab63115c19520"}}, "hash": "c45cd09d6d69ce4d7855e531e89d813ee3364767058ac3ce8a0ac23de8468c07", "text": "of\ttaste\t(the\tlast\trelated\tto\tthe\tchelation\t of\tzinc)\tare\t\nseen, but often disappear with continued treatment. Proteinuria occurs \nin 20% of patients and should be monitored. Haematological monitor -\ning is also required when treatment is initiated. Thrombocytopenia \nmay\trequire\treduction\t in\tthe\tdose.\tLeukopenia\t or\taplastic\tanaemia\t\nare\tabsolute\t contraindications,\t as\tare\tautoimmune\t conditions\t (e.g.\t\nthyroiditis,\t myasthenia\t gravis).\t Because\t penicillamine\t is\ta\tmetal\t\nchelator,\t it\tshould\tnot\tbe\tgiven\twith\tgold\tcompounds\t (see\tlater).\nGold\nGold\tis\tadministered\t as\tan\torganic\t complex,\t sodium \naurothiomalate . The anti-inflammatory effect develops \nslowly\tover\t3\u20134\tmonths.\t Pain\tand\tjoint\tswelling\t subside,\t\nand the progression of bone and joint damage diminishes. \nThe mechanism of action is not clear. Sodium aurothiomalate \nis\tgiven\tby\tdeep\tintramuscular\t injection.\t Gold\tcomplexes\t\ngradually accumulate in synovial cells in joints as well as \nother tissues, such as liver cells, kidney tubules, the adrenal \ncortex and macrophages, and remain for some time after \ntreatment is stopped. Excretion is mostly renal, but some \nis\teliminated\tin\tthe\tGI\ttract.\tThe\thalf-life\tis\t7\tdays\tinitially \t\nbut increases with treatment, so the drug is usually given \nfirst at weekly, then at monthly intervals.\n\u25bc Unwanted effects with aurothiomalate are seen in about one-third \nof patients treated, and serious toxic effects in about 1 patient in 10. \nImportant\t unwanted\t effects\tinclude\trashes\t(which\tcan\tbe\tsevere),\t\nmouth ulcers, non-specific flu-like symptoms, proteinuria, thrombo -\ncytopenia and blood dyscrasias. Anaphylactic reactions can occur. If \ntherapy is stopped when the early symptoms appear, the incidence \nof serious toxic effects is relatively low.\nAntimalarial drugs\nHydroxychloroquine \tand\tchloroquine\t are\t4-amino-quinoline \t\ndrugs used mainly in the prevention and treatment of \nmalaria\t (Ch.\t55),\tbut\tthey\tare\talso\tused\tas\tDMARDs.\tClinical uses of \nimmunosuppressant drugs \nImmunosuppressant drugs are used by specialists, often \nin combination with glucorticoid and/or cytotoxic drugs:\n\u2022\tTo\tslow\tthe\tprogress\tof\trheumatoid\t and\tother\tarthritic\t\ndiseases including psoriatic arthritis, ankylosing \nspondylitis, juvenile arthritis: disease-modifying \nantirheumatic drugs (DMARDs), e.g. methotrexate , \nleflunomide , ciclosporin ; cytokine modulators (e.g. \nadalimumab , etanercept , infliximab ) are used when \nthe response to methotrexate or other DMARDs has \nbeen inadequate.\n\u2022\tTo\tsuppress\t rejection\tof\ttransplanted\t organs,\te.g.\t\nciclosporin , tacrolimus , sirolimus .\n\u2022\tTo\tsuppress\t graft-versus-host\t disease\tfollowing\tbone\t\nmarrow transplantation, e.g. ciclosporin .\n\u2022\tIn\tautoimmune\t disorders\t including\tidiopathic\t\nthrombocytopenic purpura, some forms of haemolytic \nanaemias and of glomerulonephritis and myasthenia \ngravis.\n\u2022\tIn\tsevere\tinflammatory\t", "start_char_idx": 3181, "end_char_idx": 6073, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ca9a7379-7b95-4259-9a17-60476c71add2": {"__data__": {"id_": "ca9a7379-7b95-4259-9a17-60476c71add2", "embedding": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c51169bc-9770-4410-bc49-9fb873f09a55", "node_type": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d573612bbf34d112f6cfd3d22aa71411d1461ae907c1c8e519e30c7c867912c9"}, "2": {"node_id": "60a18ece-32fc-4d25-92a3-a8168011c2ac", "node_type": null, "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c45cd09d6d69ce4d7855e531e89d813ee3364767058ac3ce8a0ac23de8468c07"}}, "hash": "64bc67bf1fa0a9a48c69e4d7c3128acc566fa57803bb944da63ab63115c19520", "text": "and myasthenia \ngravis.\n\u2022\tIn\tsevere\tinflammatory\t bowel\tdisease\t(e.g.\t\nciclosporin in ulcerative colitis, infliximab in Crohn\u2019s \ndisease).\n\u2022\tIn\tsevere\tskin\tdisease\t(e.g.\t pimecrolimus , \ntacrolimus topically for atopic eczema uncontrolled \nby maximal topical glucocorticoids; etanercept , \ninfliximab for very severe plaque psoriasis which has \nfailed to respond to methotrexate or ciclosporin ).\nMost\tof\tthese\tdrugs\tact\tduring\tthe\tinduction\t phase\tof\t\nthe immunological response, reducing lymphocyte prolifera -\ntion\t(see\tCh.\t7),\talthough\t others\talso\tinhibit\taspects\tof\tthe\t\neffector phase. There are three main groups:\n\u2022\tdrugs\t that\tinhibit\tIL-2\tproduction\t or\taction\t(e.g.\t\nciclosporin , tacrolimus \tand\trelated\tdrugs);mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6068, "end_char_idx": 7275, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6cd19dac-f51b-447a-a34d-178d06be3dae": {"__data__": {"id_": "6cd19dac-f51b-447a-a34d-178d06be3dae", "embedding": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "527b336c-6a65-4a5f-bd0a-2b0d4a9a0ba3", "node_type": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "834b8ac20fd94ea3543169a0886ddd0d4cd0bd0831bcdf1ff544143c53db242f"}, "3": {"node_id": "61f5ede5-58e9-4dd0-a6ef-337d9b0424e2", "node_type": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e1f952591d9510c035320bbc64297c82c35684d5e74b52f8938004544695eb9"}}, "hash": "da6189cdd402a3ffc3b6318832219db21493c8eb4855862dfc171d263ca5823e", "text": "27 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n354thereby preventing activation of Th cells and production of \nIL-2\t(Ch. \t7).\nCiclosporin \titself \tis \tpoorly \tabsorbed \tby \tmouth \tbut \tcan \t\nbe given orally in a more readily absorbed formulation, or \nby intravenous infusion. After oral administration, peak \nplasma\tconcentrations \tare \tusually \tattained \tin \tabout \t3\u20134 \t h. \t\nThe\tplasma \thalf-life \tis \tapproximately \t24 \t h. \tMetabolism \toccurs\t\nin the liver, and most of the metabolites are excreted in the \nbile.\tCiclosporin \taccumulates \tin \tmost \ttissues \tat \tconcentrations \t\nthree to four times that seen in the plasma. Some of the drug remains in lymphomyeloid tissue and remains in fat depots \nfor some time after administration has stopped.\nThe commonest and most serious unwanted effect of \nciclosporin is nephrotoxicity, which is thought to be unconnected with calcineurin inhibition. It may be a \nlimiting\tf actor \ti n\tt he\tu se\to f \tt he\td rug\ti n \ts ome\tp atients\t( see\t\nalso\tCh. \t58). \tHepatotoxicity \tand \thypertension \tcan \talso \t\noccur.\tLess \timportant \tunwanted \teffects \tinclude \tanorexia, \t\nlethargy, \thirsutism, \ttremor, \tparaesthesia \t(tingling \tsensa -\ntion),\tgum \thypertrophy \t(especially \twhen \tco-prescribed \t\nwith\tcalcium \tantagonists \tfor \thypertension; \tCh. \t23) \tand \t\nGI\tdisturbances. \tCiclosporin \thas \tno \tdepressant \teffects \ton\t\nthe bone marrow.\nTacrolimus\nTacrolimus is a macrolide antibiotic of fungal origin with \na very similar mechanism of action to ciclosporin, but higher \npotency. The main difference is that the internal receptor \nfor this drug is not cyclophilin but a different immunophilin \ntermed\tFKBP \t(FK-binding \tprotein, \tso \tcalled \tbecause \ttac-\nrolimus\twas\tinitially\ttermed\tFK506).\tThe\ttacrolimus\u2013FKBP \t\ncomplex inhibits calcineurin with the effects described previously. It is not used for arthritis but mainly in organ \ntransplantation \tand \tsevere \tatopic \teczema. \tPimecrolimus \n(used\ttopically \tto \ttreat \tatopic \teczema) \tacts \tin \ta \tsimilar \t\nway. Sirolimus \t(used\tto \tprevent \torgan \trejection \tafter \t\ntransplantation, and also in coating on cardiac stents to \nprevent\trestenosis; \tCh. \t22) \talso \tcombines \twith \tan \timmu -\nnophilin, but activates a protein kinase to produce its \nimmunosuppressant effect.\n\u25bc Tacrolimus can be given orally, by intravenous injection or as an \nointment \tfor\ttopical\tuse\tin\tinflammatory \tdisease\tof\tthe\tskin.\tIt\tis\t99%\t\nmetabolised by the liver and has a half-life of approximately 7 h. The \nunwanted effects of tacrolimus are similar to those of ciclosporin but \nare more severe. The incidence of nephrotoxicity and neurotoxicity \nis\th igher, \tb ut \tt hat\to f\th irsutism\ti s\tl", "start_char_idx": 0, "end_char_idx": 2689, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "61f5ede5-58e9-4dd0-a6ef-337d9b0424e2": {"__data__": {"id_": "61f5ede5-58e9-4dd0-a6ef-337d9b0424e2", "embedding": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "527b336c-6a65-4a5f-bd0a-2b0d4a9a0ba3", "node_type": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "834b8ac20fd94ea3543169a0886ddd0d4cd0bd0831bcdf1ff544143c53db242f"}, "2": {"node_id": "6cd19dac-f51b-447a-a34d-178d06be3dae", "node_type": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "da6189cdd402a3ffc3b6318832219db21493c8eb4855862dfc171d263ca5823e"}, "3": {"node_id": "a898b73c-7b82-4130-a8d9-a347fd806d05", "node_type": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fef9db2fb325700df3ffb4a2a350114d488c5c352c185ebf6c9177a081f3474b"}}, "hash": "1e1f952591d9510c035320bbc64297c82c35684d5e74b52f8938004544695eb9", "text": "ower.\tG I\td isturbances \ta nd\tm etabolic\t\ndisturbances \t(hyperglycaemia) \tcan \toccur. \tThrombocytopenia \tand \t\nhyperlipidaemia have been reported but decrease when the dosage is reduced.\nAzathioprine\nAzathioprine \tinterferes \twith \tpurine \tsynthesis \tand \tis \t\ncytotoxic. It is widely used for immunosuppression, par -\nticularly for control of autoimmune diseases such as \nrheumatoid arthritis and to prevent tissue rejection in \ntransplant surgery. This drug is metabolised to mercap -\ntopurine, \tan\tanalogue \tthat\tinhibits\tDNA\tsynthesis \t(see\tCh.\t\n57).\tBecause \tit \tinhibits \tclonal \tproliferation \tduring \tthe \t\ninduction \tphase\tof\tthe\timmune\tresponse \t(see\tCh.\t7)\tthrough\t\na cytotoxic action on dividing cells, both cell-mediated and antibody-mediated immune reactions are depressed by this \ndrug. As is the case with mercaptopurine itself, the main \nunwanted \teffect \tis \tdepression \tof \tthe \tbone \tmarrow. \tOther \t\ntoxic effects are nausea and vomiting, skin eruptions and \na mild hepatotoxicity.The main action is a relatively selective inhibitory \neffect\ton \tIL-2 \tgene \ttranscription, \talthough \ta \tsimilar \teffect \t\non\tinterferon \t(IFN)- \u03b3\tand\tIL-3 \thas \talso \tbeen \treported. \t\nNormally, \tinteraction \tof \tantigen \twith \ta \tT-helper \t(Th) \tcell \t\nreceptor\tresults \tin \tincreased \tintracellular \tCa2+\t(Chs\t2\tand \t\n7),\twhich \tin \tturn \tstimulates \tcalcineurin, a phosphatase. \nThis activates various transcription factors that initiate \nIL-2\texpression. \tCiclosporin \tbinds\tto\tcyclophilin , a cytosolic \nprotein\tmember \tof \tthe \timmunophilin \tfamily \t(a \tgroup \t\nof proteins that act as intracellular receptors for such \ndrugs).\tThe \tdrug\u2013immunophilin \tcomplex \tbinds \tto, \tand \t\ninhibits, calcineurin which acts in opposition to the many \nprotein\tkinases\tinvolved \tin\tsignal\ttransduction \t(see\tCh.\t3),\tImmunosuppressants \n\u2022\tClonal\tproliferation \tof \tT-helper \tcells \tcan \tbe \tdecreased \t\nthrough inhibition of transcription of interleukin (IL)-2: \nciclosporin, tacrolimus, sirolimus and \npimecrolimus and glucocorticoids act in this way.\n\u2013 Ciclosporin-like drugs bind to cytosolic proteins \n(immunophilins) which inhibit calcineurin triggering changes in gene transcription.\n\u2013 They are given orally or intravenously; a common \nadverse effect is nephrotoxicity.\n\u2022\tFor\tglucocorticoid \tactions, \tsee \tseparate \tbox.\n\u2022\tLymphocyte \tproliferation \tis \talso \tblocked \tby \tinhibitors \t\nof DNA synthesis such as:\n\u2013 azathioprine, through its active metabolite mercaptopurine;\n\u2013 mycophenolate mofetil, through inhibition of de novo purine synthesis;\n\u2013 leflunomide, through inhibition by a metabolite of pyrimidine synthesis.\u2022\tdrugs\tthat \tinhibit \tcytokine \tgene \texpression \t(e.g. \t\ncorticosteroids);\n\u2022\tdrugs\tthat \tinhibit \tpurine \tor", "start_char_idx": 2690, "end_char_idx": 5423, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a898b73c-7b82-4130-a8d9-a347fd806d05": {"__data__": {"id_": "a898b73c-7b82-4130-a8d9-a347fd806d05", "embedding": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "527b336c-6a65-4a5f-bd0a-2b0d4a9a0ba3", "node_type": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "834b8ac20fd94ea3543169a0886ddd0d4cd0bd0831bcdf1ff544143c53db242f"}, "2": {"node_id": "61f5ede5-58e9-4dd0-a6ef-337d9b0424e2", "node_type": null, "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e1f952591d9510c035320bbc64297c82c35684d5e74b52f8938004544695eb9"}}, "hash": "fef9db2fb325700df3ffb4a2a350114d488c5c352c185ebf6c9177a081f3474b", "text": "\tpyrimidine \tsynthesis \t(e.g. \t\nazathioprine, mycophenolate mofetil, leflunomide).\nCiclosporin\nCiclosporin \tis\ta\tnaturally \toccurring \tcompound \tfirst\tidenti -\nfied in a fungus. It is a cyclic peptide of 11 amino acid \nresidues\t(including \tsome\tnot\tfound\tin\tanimals)\twith\tpotent\t\nimmunosuppressive activity but no effect on the acute \ninflammatory reaction per se. Its unusual activity, which \n(unlike\tmost \tearlier \timmunosuppressants) \tdoes \tnot \tentail \t\ncytotoxicity, \twas \tdiscovered \tin \t1972 \tand \twas \tcrucial \tfor \t\nthe\tdevelopment \tof\ttransplant \tsurgery\t(for\ta\tdetailed\treview,\t\nsee\tBorel \tet \tal., \t1996). \tThe \tdrug \thas \tnumerous \tactions \tbut \t\nthose of relevance to immunosuppression are:\n\u2022\tdecreased \tclonal \tproliferation \tof \tT \tcells, \tprimarily \tby \t\ninhibiting \tIL-2 \tsynthesis \tand \tpossibly \talso \tby \t\ndecreasing \texpression \tof \tIL-2 \treceptors;\n\u2022\treduced \tinduction \tand \tclonal \tproliferation \tof \tcytotoxic \t\nT\tcells\tfrom \tCD8+ precursor T cells;\n\u2022\treduced \tfunction \tof \tthe \teffector \tT \tcells \tresponsible \tfor \t\ncell-mediated \tresponses \t(e.g. \tdecreased \tdelayed-type \t\nhypersensitivity);\n\u2022\tsome\treduction \tof \tT \tcell-dependent \tB-cell \tresponses.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5424, "end_char_idx": 7085, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "46d811c6-0d0a-4080-ab44-86e139514f9c": {"__data__": {"id_": "46d811c6-0d0a-4080-ab44-86e139514f9c", "embedding": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5bf4da5e-206d-4810-8916-aab52869ca39", "node_type": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e2b0386b354de977f06b39e1449390fa41b6defb22c3637c5b9820cade189e8"}, "3": {"node_id": "17be443e-6eb2-45f5-ac28-f13bed425d5b", "node_type": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4bb3bf9d0bd0874f546b1a1d76baffdf94ab496dc92f67ece7e9f5779e1348bd"}}, "hash": "a8793278290d6cc22f98dff5cebfec86919ca493ec2063390a7fe21c44b46a07", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSU pp RESSANT DRUGS\n355and\tother \tproteins \t(see \tCh. \t5). \tAs \tsuch, \tthey \tare \tdifficult \t\nand expensive to produce, and this limits their use. In the \nUnited\tKingdom \t(in\tthe\tNational \tHealth\tService),\tthey\tare\t\ngenerally restricted to patients who do not respond ade -\nquately\tto\tother\tDMARD \ttherapy\tand\tthey\tare\tadministered \t\nunder specialist supervision. Some are administered in \ncombination with methotrexate, which apparently provides \na synergistic anti-inflammatory action.\nThe characteristics and indications of some current biop -\nharmaceuticals are shown in Table 27.3. The effect of two of \nthese\ta gents \to n\tr heumatoid \ta rthritis\ti s\ts hown\ti n\tF ig.\t2 7.4.\tM any\t\nneutralise soluble cytokines. Adalimumab, certolizumab \npegol , golimumab , etanercept and infliximab target TNF- \u03b1; \nanakinra, secukinumab and canakinumab \ttarget\tIL-1; \ttoci-\nlizumab,\tIL-6\tand\tustekinumab ,\tILs-12\tand\t-23.\tAbatacept, \nalemtuzumab, basiliximab, belatacept, daclizumab and \nnatalizumab target T cells, either disrupting activation, pro-\nliferation or emigration. Rituximab and belimumab \ttarget\tB\t\ncells. While they are not used for treating arthritis, basiliximab, \nbelatacept \tand \tdaclizumab \tare \tincluded \tin \tthe \ttable \tas \tthey\t\nact to prevent the rejection of transplanted organs in a similar way \u2013 by suppressing T-cell proliferation.\nThere is some debate over the precise nature of the target \nof the anti-TNF agents. Some target both soluble and membrane-bound forms of TNF whereas others are more \nselective. \tAntibodies \tthat \ttarget \tmembrane-bound \tTNF \t(e.g.\t\ninfliximab \tand \tadalimumab) \tmay \tkill \tthe \thost \tcell \tby \t\ncomplement-induced lysis. This produces a different quality of effect than simple sequestration of the soluble mediator \n(by,\tfor\texample, \tetanercept). \tThis \tfact \tis \tprobably \tthe \treason\t\nwhy some of these drugs exhibit a slightly different pharm -\nacological profile despite ostensibly acting through the same \nmechanism \t(see \tArora \tet \tal., \t2009, \tfor \tfurther \tdetails).\n\u25bc As proteins, none of these drugs can be given orally. Administration \nis usually by subcutaneous injection or intravenous infusion and their \npharmacokinetic profiles vary enormously. Dosing regimes differ \nbut\t(for\texample) \tanakinra \tis \tusually \tgiven \tdaily, \tefalizumab \tand \t\netanercept \tonce\tor\ttwice\tper\tweek,\tadalimumab, \tcertolizumab \tpegol,\t\ninfliximab and rituximab every 2 weeks, and abatacept, belimumab, \ngolimumab, \tnatalizumab \tand \ttocilizumab \tevery \tmonth. \tSometimes \t\na loading dose of these drugs is given as a preliminary to regular administration.\nUsually, these biopharmaceuticals are only given to severely \naffected patients or to those in whom other therapies have \nfailed. For reasons that are not entirely clear, a proportion \nof\tthese\tpatients \t(about \t30%) \tdo \tnot \trespond \tand \ttherapy \t\nis generally discontinued if no therapeutic benefit is evident \nwithin\t2\u20134 \tweeks. \tSome \tstudies", "start_char_idx": 0, "end_char_idx": 2987, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "17be443e-6eb2-45f5-ac28-f13bed425d5b": {"__data__": {"id_": "17be443e-6eb2-45f5-ac28-f13bed425d5b", "embedding": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5bf4da5e-206d-4810-8916-aab52869ca39", "node_type": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e2b0386b354de977f06b39e1449390fa41b6defb22c3637c5b9820cade189e8"}, "2": {"node_id": "46d811c6-0d0a-4080-ab44-86e139514f9c", "node_type": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8793278290d6cc22f98dff5cebfec86919ca493ec2063390a7fe21c44b46a07"}, "3": {"node_id": "64911427-155b-4ea2-95b2-2269dc4aa688", "node_type": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a5d8570a6d0d8ac3f657b8574421e453b4c9c3852516889a338fd8f02bb0b888"}}, "hash": "4bb3bf9d0bd0874f546b1a1d76baffdf94ab496dc92f67ece7e9f5779e1348bd", "text": "benefit is evident \nwithin\t2\u20134 \tweeks. \tSome \tstudies \tsuggest \tthat \tif \ttreatment \t\nis begun using drugs such as infliximab in combination \nwith methotrexate this failure rate is reduced and a superior \nfinal\ttherapeutic \toutcome \tachieved \t(van \tder \tKooij \tet \tal., \t\n2009).\nCytokines \tare \tcrucial \tto \tthe \tregulation \tof \thost \tdefence \t\nsystems\t(see \tCh. \t19), \tand \tleukocytes \tare \tkey \tplayers \tin \tits \t\nsuccessful \tfunctioning. \tOne \tmight \tpredict, \ttherefore, \tthat \t\nanticytokine or antileukocyte therapy \u2013 like any treatment that interferes with immune function \u2013 may precipitate \nlatent\tinfections \t(e.g.\ttuberculosis \tor\thepatitis\tB)\tor\tencour -\nage\topportunistic \tinfections. \tReports \tsuggest \tthat \tthis \tis \ta \t\nproblem\twith \tsome \tof \tthese \tagents \t(e.g. \tadalimumab, \t\netanercept, \tinfliximab, \tnatalizumab \tand \trituximab). \tThe \t\narea\thas\tbeen \treviewed \tby \tBongartz \tet \tal. \t(2006). \tAnother \t\nunexpected, but fortunately rare, effect seen with these \ndrugs\tis\tthe\tonset\tof\tpsoriasis-like \tsyndrome \t(Fiorino\tet\tal.,\tCyclophosphamide\nCyclophosphamide \tis \ta \tpotent \timmunosuppressant \tthat \t\nis mainly used to treat cancer. Its mechanism of action is \nexplained \tin \tChapter \t57. \tIt \thas \tsubstantial \ttoxicity \tand \tis \t\ntherefore generally reserved for serious cases of rheumatoid arthritis in which all other therapies have failed.\nMycophenolate mofetil\nMycophenolate \tmofetil \tis \ta \tsemisynthetic \tderivative \tof \ta \t\nfungal antibiotic, and is used for preventing organ rejection. In the body, it is converted to mycophenolic acid, which \nrestrains \tproliferation \tof \tboth \tT \tand \tB \tlymphocytes \tand \t\nreduces the production of cytotoxic T cells by inhibiting \ninosine\tmonophosphate \tdehydrogenase. \tThis \tenzyme \tis \t\ncrucial\tfor \tde \tnovo \tpurine \tbiosynthesis \tin \tboth \tT \tand \tB \t\ncells\t(other \tcells \tcan \tgenerate \tpurines \tthrough \tanother \t\npathway), \tso \tthe \tdrug \thas \ta \tfairly \tselective \taction.\n\u25bc\tMycophenolate \tmofetil \tis \tgiven \torally \tand \tis \twell \tabsorbed. \t\nMagnesium \tand \taluminium \thydroxides \timpair \tabsorption, \tand \t\ncolestyramine reduces plasma concentrations. The metabolite \nmycophenolic acid undergoes enterohepatic cycling and is eliminated \nby\tthe\tkidney \tas \tthe \tinactive \tglucuronide. \tUnwanted \tGI \teffects \tare \t\ncommon.\nLeflunomide\nLeflunomide, used mainly to treat rheumatoid arthritis \nand occasionally to prevent transplant rejection, has a rela -\ntively specific inhibitory effect on activated T cells. It is transformed to a metabolite that inhibits de novo synthesis of pyrimidines by inhibiting dihydro-orotate dehydrogenase.", "start_char_idx": 2941, "end_char_idx": 5558, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "64911427-155b-4ea2-95b2-2269dc4aa688": {"__data__": {"id_": "64911427-155b-4ea2-95b2-2269dc4aa688", "embedding": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5bf4da5e-206d-4810-8916-aab52869ca39", "node_type": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e2b0386b354de977f06b39e1449390fa41b6defb22c3637c5b9820cade189e8"}, "2": {"node_id": "17be443e-6eb2-45f5-ac28-f13bed425d5b", "node_type": null, "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4bb3bf9d0bd0874f546b1a1d76baffdf94ab496dc92f67ece7e9f5779e1348bd"}}, "hash": "a5d8570a6d0d8ac3f657b8574421e453b4c9c3852516889a338fd8f02bb0b888", "text": "\nIt\tis\torally \tactive \tand \twell \tabsorbed \tfrom \tthe \tGI \ttract. \tIt \t\nhas a long plasma half-life, and the active metabolite undergoes enterohepatic circulation. Unwanted effects \ninclude\tdiarrhoea, \talopecia, \traised \tliver \tenzymes \tand \tindeed,\t\na risk of hepatic failure. The long half-life increases the risk of cumulative toxicity.\nGlucocorticoids\nThe therapeutic action of the glucocorticoids involves both their inhibitory effects on the immune response and their \nanti-inflammatory \tactions.\tThese\tare\tdescribed \tin\tChapter\t\n34,\tand\ttheir\tsites\tof\taction\ton\tcell-mediated \timmune\treac-\ntions\tare \tindicated \tin \tFig. \t27.3. \tGlucocorticoids \tare \timmu -\nnosuppressant chiefly because, like ciclosporin, they restrain \nthe clonal proliferation of Th cells, through decreasing \ntranscription \tof \tthe \tgene \tfor \tIL-2. \tHowever, \tthey \talso \t\ndecrease the transcription of many other cytokine genes \n(including \tthose \tfor \tTNF- \u03b1, IFN-\u03b3,\tIL-1\tand \tmany \tother \t\ninterleukins) \tin \tboth \tthe \tinduction \tand \teffector \tphases \tof \t\nthe immune response. The synthesis and release of anti-\ninflammatory \tproteins\t(e.g.\tannexin\t1,\tprotease\tinhibitors) \t\nis also increased. These effects are mediated through \ninhibition of the action of transcription factors, such as \nactivator protein-1 and NF \u03baB\tas\twell\tas\tthrough\tthe\taction\t\nof liganded glucocorticoid receptor in the cytosol of target \ncells\t(Ch. \t3).\nANTICYTOKINE DRUGS AND \nOTHER BIOPHARMACEUTICALS\nThe biopharmaceuticals in this section represent the greatest \ntechnological and conceptual breakthrough in the treatment \nof\tsevere \tchronic \tinflammation \tfor \tdecades \t(see \tMaini, \t\n2005).\tThese\tdrugs\tare\tengineered \trecombinant \tantibodies \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5606, "end_char_idx": 7796, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "86a1d27d-a8c8-4669-b668-d5a9ebdecf64": {"__data__": {"id_": "86a1d27d-a8c8-4669-b668-d5a9ebdecf64", "embedding": null, "metadata": {"page_label": "362", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3c8e0888-c7bb-4d17-ab88-ebfe1bbe79df", "node_type": null, "metadata": {"page_label": "362", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7b40e953aa4b3b6dba0cae46872cfda65ffb2c033042d4c88baf5d7142d544b"}, "3": {"node_id": "2b338d6c-30f2-4945-af55-bd1fd52b4280", "node_type": null, "metadata": {"page_label": "362", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "deb0293a7d5aaea0fd6a5311ca7ac076c38cbb69034d8cf53c9a2101d688a40c"}}, "hash": "e144e7e2c95aa08133fec624711c154bd249bddf1054a32376c6b2d40708339f", "text": "27 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n356systems\t(see \tChs \t19 \tand \t7, \tFig. \t7.1), \tgeneration \tof \tprosta -\nglandins, \tlipoxygenase \tproducts \tsuch\tas\tleukotriene \tB4\t(Ch.\t\n18,\tFig.\t18.1), \tand \tlocal \taccumulation \tof \tneutrophil \tgranu -\nlocytes. These engulf the crystals by phagocytosis, releasing \ntissue-damaging toxic oxygen metabolites and subsequently \ncausing\tlysis\tof\tthe\tcells\twith\trelease\tof\tproteolytic \tenzymes. \t\nUrate\tcrystals \talso \tinduce \tthe \tproduction \tof \tIL-1 \tand \tpos-\nsibly other cytokines.\nDrugs used to treat gout act in the following ways:\n\u2022\tby\tdecreasing \turic \tacid \tsynthesis \tallopurinol \t(the\t\nmain\tprophylactic \tdrug) \tor \tfebuxostat;\n\u2022\tby\tincreasing \turic \tacid \texcretion \t(uricosuric agents: \nprobenecid, sulfinpyrazone ;\tsee\tCh. \t30);\n\u2022\tby\tinhibiting \tleukocyte \tmigration \tinto \tthe \tjoint \t\n(colchicine);\n\u2022\tas\tan\t\u2018IL-1 \tdependent\u2019 \tdisease, \tbiopharmaceuticals \t\nsuch as anakinra may be useful;\n\u2022\tby\ta\tgeneral \tanti-inflammatory \tand \tanalgesic \teffect \t\n(NSAIDs \tand \toccasionally \tglucocorticoids).\nTheir\tclinical \tuses \tare \tsummarised \tin \tthe \tclinical \tbox \t(see \t\nlater).2009).\tHypersensitivity, \tinjection \tsite \treactions \tor \tmild \tGI \t\nsymptoms may be seen with any of these drugs.\nDRUGS USED IN GOUT\nGout\tis\ta \tmetabolic \tdisease \tin \twhich \turate \tcrystals \tare \t\ndeposited in tissues, usually because plasma urate concentra -\ntion is raised. Sometimes this is linked to overindulgence in alcoholic beverages, especially beer, or purine-rich foods \nsuch\tas\toffal \t(urate \tis \ta \tproduct \tof \tpurine \tmetabolism). \t\nIncreased cell turnover in haematological malignancies, \nparticularly \tafter \ttreatment \twith \tcytotoxic \tdrugs \t(see \tCh. \t\n57),\tor\timpaired \texcretion \tof \turic \tacid \tby \tdrugs \tsuch \tas \t\nordinary \ttherapeutic \tdoses\tof\taspirin\t(see\tearlier)\tare\tother\t\ncauses. It is characterised by extremely painful intermittent \nattacks of acute arthritis produced by the deposition of the \ncrystals in the synovial tissue of distal joints, such as the \nbig toe, as well as the external ear \u2013 the common theme being that these tissues are generally relatively cool, favour -\ning crystal deposition. An inflammatory response is evoked, involving activation of the kinin, complement and plasmin Table 27.3 Some biopharmaceuticals used in the treatment of inflammatory disease\nTarget Drug Type Mode of action Indication\nSoluble TNFAdalimumab Humanised mAb Immunoneutralisation RA (moderate\u2013severe), \nPA, AS, PP, CD\nCertolizumab pegol Pegylated ab fragment Immunoneutralisation RAa (moderate\u2013severe)\nGolimumab Humanised mAb Immunoneutralisation RA (moderate\u2013severe), PA, PS\nInfliximab Chimeric neutralising ab Immunoneutralisation RA\na (moderate\u2013severe), \nPA, AS, PP\nEtanercept Fusion protein", "start_char_idx": 0, "end_char_idx": 2771, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2b338d6c-30f2-4945-af55-bd1fd52b4280": {"__data__": {"id_": "2b338d6c-30f2-4945-af55-bd1fd52b4280", "embedding": null, "metadata": {"page_label": "362", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3c8e0888-c7bb-4d17-ab88-ebfe1bbe79df", "node_type": null, "metadata": {"page_label": "362", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7b40e953aa4b3b6dba0cae46872cfda65ffb2c033042d4c88baf5d7142d544b"}, "2": {"node_id": "86a1d27d-a8c8-4669-b668-d5a9ebdecf64", "node_type": null, "metadata": {"page_label": "362", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e144e7e2c95aa08133fec624711c154bd249bddf1054a32376c6b2d40708339f"}}, "hash": "deb0293a7d5aaea0fd6a5311ca7ac076c38cbb69034d8cf53c9a2101d688a40c", "text": "decoy receptorNeutralisation RA\na (moderate\u2013severe), \nPA, AS, PP\nSoluble IL-1Anakinra Recombinant version of IL-1 raNeutralisation RA\na (moderate\u2013severe)\nSecukinamab Humanised mAb Immunoneutralisation AS, PA\nCanakinumab Humanised mAb Immunoneutralisation G\nSoluble IL-6 Tocilizumab Humanised mAb Immunoneutralisation RAa (moderate\u2013severe)\nSoluble IL-12 and -23 Ustekinumab Humanised mAb Immunoneutralisation PA, PP (severe)\nT cellsAbatacept Fusion protein Prevents co-stimulation of T cells RAa (moderate\u2013severe)\nAlemtuzumab Humanised mAb Binds to CD 52 causing cell lysis MS\nBasiliximab Chimeric mAb IL-2 receptor antagonists\nImmunosuppression for \ntransplantation surgeryBelatacept Fusion protein Prevents activation of T cells\nDaclizumab Humanised mAb IL-2 receptor antagonist\nNatalizumab Humanised mAb VLA-4 on lymphocytes (neutralises) Severe multiple sclerosis\nB cellsBelimumab Humanised mAb Immunoneutralises B cell-activating factorSLE\nRituximab Chimeric mAb Causes B cells lysis RA\na (moderate\u2013severe), \nsome malignancies\naUsed in conjunction with methotrexate.\nab, antibody; AS, ankylosing spondylitis; CD, Crohn\u2019s disease; G, severe gout; IL, interleukin; mAb, monoclonal antibody; PA, psoriatic arthritis; \nPP, plaque psoriasis (e.g. skin); PS, psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TNF, tumour necrosis factor.\n(Data from various sources, including the British National Formulary, 2017.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2772, "end_char_idx": 4685, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ea7f861c-6501-4da1-bc59-edabb5bca01b": {"__data__": {"id_": "ea7f861c-6501-4da1-bc59-edabb5bca01b", "embedding": null, "metadata": {"page_label": "363", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "434450fc-2559-4ee1-9da4-d2b906367fb7", "node_type": null, "metadata": {"page_label": "363", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5586c521951b5294ac3d233f61748a762d56428e6403ac703fcb05583c8a0318"}, "3": {"node_id": "25f68f40-021e-40aa-ad15-fd9a1dbf2bc4", "node_type": null, "metadata": {"page_label": "363", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44ab430fa470c0b539455c6a5eab6b1235086b91bb5be748acc336d4c4bb6b60"}}, "hash": "3790400e8187159982f945ada9e0ddf3802518893b0e372ac87cca65d2abf72a", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSU pp RESSANT DRUGS\n357Allopurinol reduces the concentration of the relatively \ninsoluble urates and uric acid in tissues, plasma and urine, \nwhile increasing the concentration of their more soluble \nprecursors, the xanthines and hypoxanthines. The deposition \nof\turate\tcrystals\tin\ttissues\t(tophi)\tis\treversed, \tand\tthe\tforma -\ntion of renal urate stones is inhibited. Allopurinol is the \ndrug of choice in the long-term treatment of gout, but it \nactually exacerbates inflammation and pain in an acute \nattack\t(see \tlater). \tFebuxostat has a similar mechanism of \naction and pharmacology.\nAllopurinol is given orally and is well absorbed. Its \nhalf-life\tis\t2\u20133\th: \t its \t active \t metabolite \t alloxanthine \t (see \t Fig.\t\n27.5)\thas\ta\thalf-life\tof\t18\u201330\th. \t Renal \t excretion \t is \t a \t balance\t\nbetween glomerular filtration and probenecid-sensitive tubular reabsorption.\nAcute attacks of gout occur commonly during the early \nstages\tof \ttherapy \t(possibly \tas \ta \tresult \tof \tphysicochemical \t\nchanges in the surfaces of urate crystals as these start to \nre-dissolve), \tso\ttreatment \twith\tallopurinol \tis\tnever\tinitiated\t\nduring an acute attack and is usually initially combined \nwith\tan\tNSAID. \tUnwanted \teffects \tare \totherwise \tfew. \tGI \t\ndisturbances, \tallergic \treactions \t(mainly \trashes) \tand \tsome \t\nblood problems can occur but usually disappear if the drug is stopped. Potentially fatal skin diseases such as toxic \nepidermal necrolysis and Stevens\u2013Johnson syndrome are \nrare \u2013 but devastating.\n\u25bc Allopurinol increases the effect of mercaptopurine , an antimetabolite \nused in cancer chemotherapy, which is inactivated by xanthine oxidase \n(Ch.\t57), \tand \talso \tthat \tof \tazathioprine \t(see \tTable \t27.2), \twhich \tis \t\nmetabolised to mercaptopurine. Allopurinol also enhances the effect \nof\tanother \tanticancer \tdrug, \tcyclophosphamide \t(Ch. \t57). \tThe \teffect \t\nof warfarin is increased because its metabolism is inhibited.\nUricosuric agents\nUricosuric drugs increase uric acid excretion by a direct \naction\ton\tthe\trenal\ttubule\t(see\tCh.\t30).\tThey\tremain\tuseful\t\nas prophylaxis for patients with severe recurrent gout who \nhave\tsevere\tadverse\treactions \tto\tallopurinol. \tCommon \tdrugs\t\ninclude\tprobenecid \tand \tsulfinpyrazone \t(which \talso \thas \t\nNSAID\tactivity). \tBenzbromarone is also available on a Allopurinol\nAllopurinol is an analogue of hypoxanthine that reduces the synthesis of uric acid by competitive inhibition of \nxanthine \toxidase\t(Fig.\t27.5).\tThe\tdrug\tis\tfirst\tconverted \tby\t\nxanthine oxidase to alloxanthine, which persists in the tissue for a considerable time, and is an effective non-competitive \ninhibitor \tof\tthe\tenzyme.\tSome\tinhibition \tof\tde\tnovo\tpurine\t\nsynthesis also occurs.6.00\n5.005.50\n4.50\n4.00\n3.50\n3.00\n01 22 45 2\nAdalimumab EtanerceptDAS28\nWeeks\nFig. 27.4 The effect of anticytokine biopharmaceuticals on \nrheumatoid", "start_char_idx": 0, "end_char_idx": 2896, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "25f68f40-021e-40aa-ad15-fd9a1dbf2bc4": {"__data__": {"id_": "25f68f40-021e-40aa-ad15-fd9a1dbf2bc4", "embedding": null, "metadata": {"page_label": "363", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "434450fc-2559-4ee1-9da4-d2b906367fb7", "node_type": null, "metadata": {"page_label": "363", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5586c521951b5294ac3d233f61748a762d56428e6403ac703fcb05583c8a0318"}, "2": {"node_id": "ea7f861c-6501-4da1-bc59-edabb5bca01b", "node_type": null, "metadata": {"page_label": "363", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3790400e8187159982f945ada9e0ddf3802518893b0e372ac87cca65d2abf72a"}}, "hash": "44ab430fa470c0b539455c6a5eab6b1235086b91bb5be748acc336d4c4bb6b60", "text": " The effect of anticytokine biopharmaceuticals on \nrheumatoid arthritis. \tIn\tthis\tfigure, \tadalimumab \t(a \thumanised \t\nmonoclonal antibody that neutralises tumour necrosis factor \n[TNF]) and etanercept (a fusion protein decoy receptor that binds to TNF) were used to treat patients with active rheumatoid arthritis. The Y-axis measures a composite disease activity scores obtained from clinical assessment of 28 joints (DAS28: the lower the score, the less swollen and painful the joints). \n(From Jobanputra et al., 2012.)\nDrugs used in gout and \nhyperuricaemia \nTo treat acute gout:\n\u2022\tA\tnon-steroidal \tanti-inflammatory \tdrug \t(NSAID), \te.g. \t\nibuprofen, naproxen.\n\u2022\tColchicine is useful if NSAIDs are contraindicated.\n\u2022\tA\tglucocorticoid, \te.g. \thydrocortisone (oral, \nintramuscular or intra-articular) is an alternative to an \nNSAID.\n\u2022\tFor\tprophylaxis \t(must \tnot \tbe \tstarted \tuntil \tthe \tpatient \tis \t\nasymptomatic): allopurinol;\na uricosuric drug (e.g. probenecid, sulfinpyrazone), \nfor patients allergic to allopurinol\n\u2022\tRasburicase by intravenous infusion for prevention and treatment of acute hyperuricaemia in patients with haematological malignancy at risk of rapid lysis.Allopurinol\nXanthine oxidase\nXanthine oxidase\nXanthine oxidaseAlloxanthineHypoxanthine\nXanthine\nUric acid\nFig. 27.5 Inhibition of uric acid synthesis by allopurinol. \nSee text for details. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2835, "end_char_idx": 4688, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "36ff29f4-f512-4d62-8b50-2783e0bfff68": {"__data__": {"id_": "36ff29f4-f512-4d62-8b50-2783e0bfff68", "embedding": null, "metadata": {"page_label": "364", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "64c82ed1-286c-4a50-90ce-cee08768d09a", "node_type": null, "metadata": {"page_label": "364", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2eca67633c512bec11b52de9d7e1b74f0ac868b9d89de8b65e58a365cea2004b"}, "3": {"node_id": "730fe75b-fb53-46c2-8b2c-b896cb2d1813", "node_type": null, "metadata": {"page_label": "364", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a20c4c91bef05be4bc3b959c832272ab69b92bf5593c42a20da8b3367b0e460"}}, "hash": "2de76c19405003a0700548f8518d24cb62da389294d3c30746afffb5d0b0e7d3", "text": "27 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n358Table 27.4 Comparison of some commonly used systemic antihistamines (H 1 antagonists).\nType DrugCommon anti \n-allergic use Comments\n\u2018Sedating\u2019Alimemazine U Strong sedative action. Sometimes used for anaesthetic premedication\nChlorphenamine AE, H, U \u2014\nCinnarizine \u2014 Also used to treat nausea, vomiting, motion sickness\nClemastine H, U \u2014\nCyclizine \u2014 Also used to treat nausea, vomiting, motion sickness\nCyproheptadine H, U Also used for migraine\nHydroxyzine U May cause QT interval prolongation\nKetotifen H Mast cell \u2018stabilising\u2019 properties.\nPromethazine H, U, AE Strong sedative action. Also used to control nausea and vomiting\n\u2018Non-\nsedating\u2019Acrivastine H, U \u2014\nBilastine H, U \u2014\nCetirizine H, U \u2014\nDesloratadine H, U Metabolite of loratadine. Long-lasting action\nFexofenadine H, U \u2018Cardio-safe\u2019 metabolite of terfenadine\nLevocetirizine H, U Isomer of cetirizine\nLoratidine H, U \u2014\nMizolastine H, U May cause QT interval prolongation\nRupatadine H, U Also antagonises PAF (see Ch. 18)\nAE, allergic emergency (e.g. anaphylactic shock); H, hay fever; PAF, platelet activating factor; S, sedation; U, urticaria and/or pruritus.\n(Data from various sources, including the British National Formulary, 2017.)\nThe acute unwanted effects of colchicine during therapy are \nlargely\tGI \tand \tinclude \tnausea, \tvomiting \tand \tabdominal \tpain.\t\nSevere diarrhoea9 may be a problem and with large doses, or \nprolonged treatment, its antimitotic action may cause serious \nside\teffects, \tincluding \tGI \thaemorrhage, \tkidney \tdamage, \tbone\t\nmarrow depression and peripheral neuropathy.\nANTAGONISTS OF HISTAMINE\nAntihistamines \twere\tintroduced \tby\tBovet\tand\this\tcolleagues \t\nin\tthe\t1930s, \tbefore \tthe \tdiscovery \tof \tthe \tfour \thistamine \t\nreceptor\tsubtypes \tdescribed \tin \tCh. \t18. \tBy \tconvention, \tthe \t\ngeneric term \u2018antihistamine\u2019 usually refers only to the \nH1-receptor antagonists that are used for treating various \ninflammatory and allergic conditions, and it is these drugs \nthat are discussed in this section\nDetails of some typical systemic H 1-receptor antagonists \nare\tshown \tin \tTable \t27.4. \tIn \taddition \tto \tthese, \tthere \tare \t\nseveral\tothers\tthat\tare\tprimarily \tused\ttopically\t(e.g.\tin\tnasal\t\nsprays\tor \teye \tdrops) \tin \tthe \ttreatment \tof \thay \tfever \tand \t\nother allergic symptoms. These include antazoline, aze-\nlastine , epinastine , olapatadine and emedastine . In addition named patient basis for treatment of patients with renal impairment. Treatment with uricosuric drugs is initiated \ntogether with an NSAID, as in the case of allopurinol. However, aspirin and salicylates antagonise the action of \nuricosuric drugs and should not be used concurrently.\nAlthough not strictly speaking in this group, rasburicase , \na\tpreparation \tcontaining \tthe \tenzyme \turic \tacid \toxidase, \tis \t\nsometimes used for aggressive treatment of gout. It oxidises \nuric acid in the", "start_char_idx": 0, "end_char_idx": 2925, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "730fe75b-fb53-46c2-8b2c-b896cb2d1813": {"__data__": {"id_": "730fe75b-fb53-46c2-8b2c-b896cb2d1813", "embedding": null, "metadata": {"page_label": "364", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "64c82ed1-286c-4a50-90ce-cee08768d09a", "node_type": null, "metadata": {"page_label": "364", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2eca67633c512bec11b52de9d7e1b74f0ac868b9d89de8b65e58a365cea2004b"}, "2": {"node_id": "36ff29f4-f512-4d62-8b50-2783e0bfff68", "node_type": null, "metadata": {"page_label": "364", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2de76c19405003a0700548f8518d24cb62da389294d3c30746afffb5d0b0e7d3"}}, "hash": "4a20c4c91bef05be4bc3b959c832272ab69b92bf5593c42a20da8b3367b0e460", "text": "used for aggressive treatment of gout. It oxidises \nuric acid in the blood to allantoin, which is more soluble \nand thus more readily excreted.\nColchicine\nColchicine \ti s\ta n\ta lkaloid\te xtracted\tf rom\tt he \ta utumn \tc rocus.\t\nIt has a beneficial effect in gouty arthritis and can be used \nboth to prevent and to relieve acute attacks. It prevents \nmigration of neutrophils into the joint apparently by binding \nto tubulin, resulting in the depolymerisation of the micro -\ntubules\tand \treduced \tcell \tmotility. \tColchicine-treated \tneu-\ntrophils exhibit erratic locomotion often likened to a \u2018drunken \nwalk\u2019.\tColchicine \tmay \talso \tprevent \tthe \tproduction, \tby \t\nneutrophils that have phagocytosed urate crystals, of a \nputative\tinflammatory \tglycoprotein. \tOther \tmechanisms \tmay\t\nalso be important in bringing about its effects. At higher doses than are used to treat gout, colchicine inhibits mitosis, \ncarrying a risk of serious bone marrow depression.\nColchicine \tis \tgiven \torally, \tand \tis \texcreted \tpartly \tin \tthe \t\nGI\ttract\tand \tpartly \tin \tthe \turine.9Because\tthe \ttherapeutic \tmargin \tis \tso \tsmall, \tit \tused \tto \tbe \tsaid \tby \t\nrheumatologists that \u2018patients must run before they can walk\u2019!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2857, "end_char_idx": 4542, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c1a333fb-cae7-4f3a-8c07-7b8600131d54": {"__data__": {"id_": "c1a333fb-cae7-4f3a-8c07-7b8600131d54", "embedding": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7ea13995-6ba4-4224-a821-32907cf0572f", "node_type": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "970d1a1c86bd412c4c0d161bf4b15da7474a235c41cc38aad2ba779af14b5f34"}, "3": {"node_id": "a83cd0af-786c-4c12-899a-028c863b4f13", "node_type": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10d2622c60fdd6c9d4c8374b35dad7b45acd285def10e8c070a97f705afa09f2"}}, "hash": "0b21e7dc35ff98031d5dddb0510f046d6210d3698aa96d55703faf9fb10138f8", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSU pp RESSANT DRUGS\n359Pharmacokinetic aspects\nMost\torally\tactive\tH1-receptor antagonists are well absorbed \nand remain effective for 3\u20136 h, although there are some \nprominent \texceptions \t(e.g. \tloratidine, which is converted \nto\ta\tlong-acting \tmetabolite). \tMost \tappear \tto \tbe \twidely \t\ndistributed throughout the body, but some do not penetrate \nthe blood\u2013brain barrier, for example the non-sedating drugs \nmentioned \tabove\t(see\tTable\t27.4).\tThey\tare\tmainly\tmetabo -\nlised in the liver and excreted in the urine.\nMany\tantihistamines \thave \tperipheral \tanti-muscarinic \t\nside effects. The commonest of these is dryness of the mouth, but blurred vision, constipation and retention of urine can \nalso occur. Unwanted effects that are not mechanism-based \nare\talso\tseen; \tGI \tdisturbances \tare \tfairly \tcommon, \twhile \t\nallergic dermatitis can follow topical application.\nPOSSIBLE FUTURE DEVELOPMENTS IN \nANTIINFLAMMATORY THERAPY\nUndoubtedly the most exciting area of current development \nis\tin\tbiopharmaceuticals \t(see \tCh. \t5). \tThe \tsuccess \tof \tthe \t\nanti-TNF and other biological agents has been very gratify -\ning and development of antibodies that neutralise inflam -\nmogens or block key leukocyte receptors or adhesion \nmolecules is likely to continue. The main problem with this sector is their cost and lack of oral availability. This \nplaces a severe strain on health care budgets and often \nprevents them from being used as a first-line therapy. Hopefully, ways will be found to reduce the cost of produc -\ntion and development of these important medicines.\nClearly\ta \tlow-cost \talternative \tto \ta \tneutralising \tanti-TNF \t\nantibody would be a welcome development. TNF-converting \nenzyme\t(TACE;\tat \tleast \ttwo \tforms) \tcleaves \tmembrane-bound \t\nTNF thus releasing the soluble active form, and so might be an attractive target. A number of putative small-molecule \ninhibitors \tof \tthis \tenzyme \tare \teffective \tin \tanimal \tmodels \tbut\t\nhave\tnot\ttransferred \twell \tto \tthe \tclinic \t(see \tSharma \tet \tal., \t2013\t\nfor\ta\treview) \talthough \tthere \tremains \tgeneral \toptimism \tabout\t\nthis\tapproach \t(see \tfor \texample \tOuvry \tet \tal., \t2017).\nThe\tdisconcerting \trealisation \tthat \tall \tNSAIDs \t(and \tcoxibs)\t\nhave cardiovascular side effects has raised further questions about our existing therapeutic arsenal.\n10 The area was reviewed \nby\tAtkinson \tet \tal. \t(2013). \tOne \tof \tthe \tfew \treal \tinnovations \tin \tthe\t\nbeleaguered NSAID area has been the design and synthesis of \nderivatised \tNSAIDs \t\u2013 \tconventional \tNSAIDs \tthat \thave \tNO-\ndonating, or other, \u2018protective\u2019 groups attached. The ability of \nthese\tdrugs \tto \trelease \tNO \tfollowing \thydrolysis \tin \tplasma \tand\t\ntissue fluid reduces the risk of ulcerogenic events and may \nincrease\tthe \tanti-inflammatory \tactivity. \tOne \tof \tthese \tdrugs \t(e.g.\t\nnaproxcinod ,\tan\tNO-releasing \tderivative \tof \tnaproxen) \tis\t\nundergoing clinical trials. Along similar lines, a novel group", "start_char_idx": 0, "end_char_idx": 2974, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a83cd0af-786c-4c12-899a-028c863b4f13": {"__data__": {"id_": "a83cd0af-786c-4c12-899a-028c863b4f13", "embedding": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7ea13995-6ba4-4224-a821-32907cf0572f", "node_type": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "970d1a1c86bd412c4c0d161bf4b15da7474a235c41cc38aad2ba779af14b5f34"}, "2": {"node_id": "c1a333fb-cae7-4f3a-8c07-7b8600131d54", "node_type": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b21e7dc35ff98031d5dddb0510f046d6210d3698aa96d55703faf9fb10138f8"}, "3": {"node_id": "0f0cb576-2260-49b0-b634-9efadf1060aa", "node_type": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2431ab6d4a427f449a80d8c5ed4efc23813d09166648e79ea6bc0b250486283f"}}, "hash": "10d2622c60fdd6c9d4c8374b35dad7b45acd285def10e8c070a97f705afa09f2", "text": "of NSAIDs that release H\n2S \u2013 another gaseous mediator with protec -\ntive\tproperties \t\u2013 \tis \tbeing \tinvestigated \t(Wallace \tet \tal., \t2015), \twhile\t\nKirby\tet\tal. \t(2016) \thave \tproposed \tthat \tsimple \targinate \tsalts \tof\t\nNSAIDs may lack the unwanted cardiovascular side effects of their parent drugs. The quest for a \u2018safe\u2019 NSAID continues.to their H 1\tantagonist \tactivities, \tsome \tantihistamines \t(e.g. \t\nketotifen )\tmay\talso \thave \t\u2018mast \tcell \tstabilising\u2019 \tand \tother \t\nanti-inflammatory properties unrelated to histamine \nantagonism \t(see \tAssanasen \t& \tNaclerio, \t2002).\nPharmacological actions\nConventionally, \tthe \tantihistamines \tare \tdivided \tinto \t\u2018first-\ngeneration\u2019 drugs, which cross the blood\u2013brain barrier and often have sedating actions, and \u2018second-generation\u2019 drugs, \nwhich broadly speaking, do not. Some of the original \nsecond-generation \tagents\t(e.g.\tterfenadine )\texhibited \tsome\t\ncardiac\ttoxicity \t(e.g. \ttorsade de pointes ,\tsee\tCh. \t22). \tWhile \t\nthe risk was extremely low, it was increased when the drug \nwas taken with grapefruit juice or with agents that inhibit \ncytochrome \tP450 \tin \tthe \tliver \t(see \tChs \t10 \tand \t58). \tThese \t\ndrugs were therefore withdrawn and replaced by \u2018third-\ngeneration \tcardio-safe\u2019 \tdrugs \t(often \tactive \tmetabolites \tof \t\nthe original drugs, e.g. fexofenadine).\n\u25bc Pharmacologically, most of the effects of the H 1-receptor antagonists \nfollow\tfrom\tthe\tactions\tof\thistamine \toutlined\tin\tChapter\t18.\tIn\tvitro,\t\nfor example, they decrease histamine-mediated contraction of the \nsmooth muscle of the bronchi, the intestine and the uterus. They \ninhibit histamine-induced increases in vascular permeability and \nbronchospasm in the guinea pig in vivo, but are unfortunately of little value in allergic bronchospasm in humans. The clinical uses of \nH\n1-receptor antagonists are summarised in the clinical box.\nClinical uses of histamine H 1-\nreceptor antagonists \n\u2022\tAllergic\treactions \t(see \tCh. \t7):\n\u2013 non-sedating drugs (e.g. fexofenadine, cetirizine) \nare used for allergic rhinitis (hay fever) and urticaria\n\u2013 topical preparations may be used for insect bites\n\u2013 injectable formulations are useful as an adjunct to \nadrenaline (epinephrine) for severe drug \nhypersensitivity reactions and emergency treatment of anaphylaxis.\n\u2022\tAs\tantiemetics \t(see \tCh. \t31):\n\u2013 prevention of motion sickness (e.g. cyclizine, cinnarizine)\n\u2013 other causes of nausea, especially labyrinthine \ndisorders.\n\u2013 For sedation (see Ch. 45, e.g. promethazine).\n10This does not, of course, apply to low-dose aspirin.The\tCNS \t\u2018side \teffects\u2019 \tof \tsome \tolder \tH1-receptor antagonists are \nsometimes more clinically useful than the peripheral H 1-antagonist \neffects\t(e.g. \tchlorphenamine ;\tsee\tTable \t27.4). \tWhen \tused \tto \ttreat \t\nallergies, the sedative effects are generally unwanted, but there are \nother\toccasions \t(e.g. \tin \tsmall \tchildren \tapproaching \tbedtime) \twhen \t\nthey\tare\tmore\tdesirable. \tEv en \t under \tth ese \t", "start_char_idx": 2975, "end_char_idx": 5933, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0f0cb576-2260-49b0-b634-9efadf1060aa": {"__data__": {"id_": "0f0cb576-2260-49b0-b634-9efadf1060aa", "embedding": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7ea13995-6ba4-4224-a821-32907cf0572f", "node_type": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "970d1a1c86bd412c4c0d161bf4b15da7474a235c41cc38aad2ba779af14b5f34"}, "2": {"node_id": "a83cd0af-786c-4c12-899a-028c863b4f13", "node_type": null, "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10d2622c60fdd6c9d4c8374b35dad7b45acd285def10e8c070a97f705afa09f2"}}, "hash": "2431ab6d4a427f449a80d8c5ed4efc23813d09166648e79ea6bc0b250486283f", "text": "\tEv en \t under \tth ese \t circumstances, \t other \t CNS\t\neffects,\tsuch \tas \tdizziness \tand \tfatigue, \tare \tunwelcome. \tOthers \tare \t\nanti-emetic \tand\tare\tuse d \tto\tpre vent \tmot ion\tsi ckness \t(e .g. \tpromethazine ; \nsee\tCh.\t31).\nSeveral H 1-receptor antagonists show weak blockade of \u03b11 adrenocep -\ntors\t(e.g. \tpromethazine). \tCyproheptadine is a 5-HT antagonist as \nwell as an H 1-receptor antagonist and rupatadine is also a platelet \nactivating \tfactor \t(PAF) \tantagonist.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5909, "end_char_idx": 6862, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5d2014d4-5424-46e8-b831-ef32ccd10184": {"__data__": {"id_": "5d2014d4-5424-46e8-b831-ef32ccd10184", "embedding": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e18e6df7dac216e3711e04d3f10a38b78d1a85df278b9e13744ee7688c03c4"}, "3": {"node_id": "a4a3ecda-e226-4b7d-b9b6-77d8bfa4ec8e", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f4447b709dfb9ebcf53f98aa2e51605e35873d40831f10aa97ffb4770fa742e"}}, "hash": "7d6b8c8572856c502b3cc720ced552c3701ce7697ada72788bc9e67a5015663c", "text": "27 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n360REFERENCES AND FURTHER READING\nNSAIDs and coxibs\nBaigent,\t C.L.,\tBlackwell,\t L.,\tCollins,\tR.,\tet\tal.,\t2009.\tAspirin\tin\tthe\t\nprimary and secondary prevention of vascular disease: collaborative \nmeta-analysis of individual participant data from randomised trials. \nLancet\t373,\t1849\u20131860.\t (An important study of the use of aspirin in the \nprevention of cardiovascular disease )\nBaron,\tJ.A.,\tSandler,\t R.S.,\tBresalier,\t R.S.,\tet\tal.,\t2006.\tA\trandomized\t trial\t\nof rofecoxib for the chemoprevention of colorectal adenomas. \nGastroenterology\t 131,\t1674\u20131682.\t (The increased risk of cardiovascular \nevents observed during this trial indirectly led to the discovery that all \nNSAIDs and coxibs elevate blood pressure )\nChang,\tC.W.,\tHorng,\tJ.T.,\tHsu,\tC.C.,\tChen,\tJ.M.,\t2016.\tMean\tdaily\t\ndosage\tof\taspirin\tand\tthe\trisk\tof\tincident\t Alzheimer\u2019s\t dementia\t in\t\npatients with type 2 diabetes mellitus: a nationwide retrospective \ncohort\tstudy\tin\tTaiwan.\t J.\tDiabetes\t Res.\t2016,\t9027484.\nConaghan,\t P.G.,\t2012.\tA\tturbulent\t decade\tfor\tNSAIDs:\t update\ton\t\ncurrent concepts of classification, epidemiology, comparative efficacy, \nand\ttoxicity.\t Rheumatol.\t Int.\t32,\t1491\u20131502.\t (Excellent update on \nNSAIDs, coxibs and associated toxicity )\nFitzGerald,\t G.A.,\tPatrono,\t C.,\t2001.\tThe\tcoxibs,\tselective\t inhibitors\t of\t\ncyclooxygenase-2.\t N.\tEngl.\tJ.\tMed.\t345,\t433\u2013442.\t (Excellent coverage of \nthe selective COX-2 inhibitors )\nFlower,\tR.J.,\t2003.\tThe\tdevelopment\t of\tCOX-2\tinhibitors.\t Nat.\tRev.\t\nDrug\tDiscov.\t2,\t179\u2013191.\t (Reviews the work that led up to the development \nof the COX-2 inhibitors; several useful diagrams )\nFries,\tJ.F.,\t1998.\tQuality-of-life\t considerations\t with\trespect\tto\tarthritis\t\nand\tnonsteroidal\t anti-inflammatory\t drugs.\tAm.\tJ.\tMed.\t104,\t14S\u201320S,\t\ndiscussion 21S\u201322S.\nGrosser,\t T.,\tFries,\tS.,\tFitzGerald,\t G.A.,\t2006.\tBiological\t basis\tfor\tthe\t\ncardiovascular\t consequences\t of\tCOX-2\tinhibition:\t therapeutic\t\nchallenges\t and\topportunities.\t J.\tClin.\tInvest.\t116,\t4\u201315.\t(Influential \npaper showing that prostacyclin \u2013 as assessed by its urinary metabolites - is \nreduced by Cox-2 inhibitors. This was attributed to a decrease in vascular \nproduction with obvious consequences for cardiovascular health )\nHenry,\tD.,\tLim,\tL.L.,\tGarcia\tRodriguez,\t L.A.,\tet\tal.,\t1996.\tVariability\t in\t\nrisk of gastrointestinal complications with individual non-steroidal \nanti-inflammatory\t drugs:\tresults\tof\ta\tcollaborative\t meta-analysis.\t BMJ\t\n312,\t1563\u20131566.\t (Substantial analysis of the gastrointestinal effects", "start_char_idx": 0, "end_char_idx": 2564, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a4a3ecda-e226-4b7d-b9b6-77d8bfa4ec8e": {"__data__": {"id_": "a4a3ecda-e226-4b7d-b9b6-77d8bfa4ec8e", "embedding": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e18e6df7dac216e3711e04d3f10a38b78d1a85df278b9e13744ee7688c03c4"}, "2": {"node_id": "5d2014d4-5424-46e8-b831-ef32ccd10184", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7d6b8c8572856c502b3cc720ced552c3701ce7697ada72788bc9e67a5015663c"}, "3": {"node_id": "7a737159-7025-4edb-990c-4b1e5b7d11bf", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "32f77d2729256589c3dc98cc5041833a7ed8ae0936bda3d5b89350e1fdff0f8b"}}, "hash": "9f4447b709dfb9ebcf53f98aa2e51605e35873d40831f10aa97ffb4770fa742e", "text": "(Substantial analysis of the gastrointestinal effects of \nnon-selective NSAIDs )\nKirkby,\tN.S.,\tReed,\tD.M.,\tEdin,\tM.L.,\tet\tal.,\t2015.\tInherited\t human\t\ngroup IVA cytosolic phospholipase A2 deficiency abolishes platelet, \nendothelial,\t and\tleucocyte\t eicosanoid\t generation.\t FASEB\tJ.\t29,\t\n4568\u20134578.\t (The authors took advantage of an extremely rare mutation in a \nhuman subject to demonstrate that most prostacyclin metabolites found in \nthe urine arose from the kidney, not the vasculature. Read in conjunction \nwith Grosser et al. above )\nKirkby,\tN.S.,\tTesfai,\tA.,\tAhmetaj-Shala,\t B.,\tet\tal.,\t2016.\tIbuprofen\t\narginate\t retains\teNOS\tsubstrate\t activity\tand\treverses\t endothelial\t\ndysfunction:\t implications\t for\tthe\tCOX-2/ADMA\t axis.\tFASEB\tJ.\t30,\t\n4172\u20134179.\nLuong,\tC.,\tMiller,\tA.,\tBarnett,\t J.,\tet\tal.,\t1996.\tFlexibility\t of\tthe\tNSAID\t\nbinding site in the structure of human cyclooxygenase-2. Nat. Struct. \nBiol.\t3,\t927\u2013933.\t (An important research paper detailing the crystal \nstructure of COX-2 and the relevance of this to NSAID and coxib action. \nEssential reading if you are seriously interested in this topic )\nOuellet,\t M.,\tPercival,\t M.D.,\t2001.\tMechanism\t of\tacetaminophen\t\ninhibition\t of\tcyclooxygenase\t isoforms.\t Arch.\tBiochem.\t Biophys.\t 387,\t\n273\u2013280.\t (Proposes a solution to the paracetamol mystery )\nPatrignani,\t P.,\tPatrono,\t C.,\t2016.\tAspirin\tand\tcancer.\tJ.\tAm.\tColl.\t\nCardiol.\t 68,\t967\u2013976.\t (Excellent review of this interesting topic. \nRecommended )\nPrescott,\t L.F.,\t2000.\tParacetamol,\t alcohol\tand\tthe\tliver.\tBr.\tJ.\tClin.\t\nPharmacol.\t 49,\t291\u2013301.\nRay,\tW.A.,\tVaras-Lorenzo,\t C.,\tChung,\tC.P.,\tet\tal.,\t2009.\tCardiovascular\t\nrisks of non-steroidal anti-inflammatory drugs in patients after \nhospitalization\t for\tserious\tcoronary\t heart\tdisease.\t Circ.\tCardiovasc.\t\nQual.\tOutcomes\t 2,\t155\u2013163.\t (This paper, together with an editorial on \npages 146\u2013147 of the same issue, present and comment on the findings from \nobservational studies on the cardiovascular risk of a range of coxibs and \nNSAIDs)\nSkjelbred,\t P.,\tL\u00f8kken,\t P.,\tSkoglund,\t L.A.,\t1984.\tPost-operative\t\nadministration of acetaminophen to reduce swelling and other \ninflammatory\t events.\tCurr.\tTher.\tRes.\t35,\t377\u2013385.\t (A study showing \nthat paracetamol can have anti-inflammatory properties under some \ncircumstances )\nWaldstein,\t S.R.,\tWendell,\t C.R.,\tSeliger,\tS.L.,\tFerrucci,\t L.,\tMetter,\tE.J.,\t\nZonderman,\t A.B.,\t2010.\tNonsteroidal\t anti-inflammatory\t drugs,\taspirin,\tand\tcognitive\t function\t in\tthe\tBaltimore\t longitudinal\t", "start_char_idx": 2517, "end_char_idx": 5028, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a737159-7025-4edb-990c-4b1e5b7d11bf": {"__data__": {"id_": "7a737159-7025-4edb-990c-4b1e5b7d11bf", "embedding": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e18e6df7dac216e3711e04d3f10a38b78d1a85df278b9e13744ee7688c03c4"}, "2": {"node_id": "a4a3ecda-e226-4b7d-b9b6-77d8bfa4ec8e", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f4447b709dfb9ebcf53f98aa2e51605e35873d40831f10aa97ffb4770fa742e"}, "3": {"node_id": "d75fd605-3612-4ef1-89b3-bcab8dc5997f", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "89d26f57bc4f3cf5952abc028cb555210431064ea6bf9bc65fc8bd947375d867"}}, "hash": "32f77d2729256589c3dc98cc5041833a7ed8ae0936bda3d5b89350e1fdff0f8b", "text": "function\t in\tthe\tBaltimore\t longitudinal\t study\tof\t\naging.\tJ.\tAm.\tGeriatr.\tSoc.\t58,\t38\u201343.\nVane,\tJ.R.,\t1971.\tInhibition\t of\tprostaglandin\t synthesis\t as\ta\tmechanism\t\nof\taction\tfor\taspirin-like\t drugs.\tNat.\tNew\tBiol.\t231,\t232\u2013239.\t (The \ndefinitive, seminal article that proposed cyclo-oxygenase inhibition as a \nmechanism of action for the aspirin-like drugs )\nVane,\tJ.R.,\tBotting,\t R.M.\t(Eds.),\t2001.\tTherapeutic\t Roles\tof\tSelective\t\nCOX-2\tInhibitors.\t William\t Harvey\tPress,\tLondon,\t p.\t584.\t(Outstanding \nmulti-author book covering all aspects of the mechanisms of action, actions, \nadverse effects and clinical role of COX-2 inhibitors in a range of tissues; \nexcellent coverage though a bit dated now )\nWallace,\t J.L.,\t2000.\tHow\tdo\tNSAIDs\t cause\tulcer\tdisease?\t Bailli\u00e8re\u2019s\t Best\t\nPract.\tRes.\tClin.\tGastroenterol.\t 14,\t147\u2013159.\t (Proposes an interesting idea \nconcerning the role of the two COX isoforms in gastric homeostasis )\nWarner,\t T.D.,\tMitchell,\t J.A.,\t2004.\tCyclooxygenases:\t new\tforms,\tnew\t\ninhibitors,\t and\tlessons\tfrom\tthe\tclinic.\tFASEB\tJ.\t18,\t790\u2013804.\t (Excellent \nreview of COX-1/-2 inhibitors and the relative merits of coxibs and the \nphysiological role of COX-2 )\nWarner,\t T.D.,\tMitchell,\t J.A.,\t2008.\tCOX-2\tselectivity\t alone\tdoes\tnot\t\ndefine the cardiovascular risks associated with non-steroidal \nanti-inflammatory\t drugs.\tLancet\t371,\t270\u2013273.\t (Thoughtful article about \ncardiovascular risk of NSAIDs )\nAntirheumatoid drugs\nAlldred,\t A.,\tEmery,\tP.,\t2001.\tLeflunomide:\t a\tnovel\tDMARD\t for\tthe\t\ntreatment\t of\trheumatoid\t arthritis.\t Expert\tOpin.\tPharmacother.\t 2,\t\n125\u2013137.\t (Useful review and update of this DMARD )\nBondeson,\t J.,\t1997.\tThe\tmechanisms\t of\taction\tof\tdisease-modifying\t\nantirheumatic drugs: a review with emphasis on macrophage signal \ntransduction\t and\tthe\tinduction\t of\tproinflammatory\t cytokines.\t Gen.\t\nPharmacol.\t 29,\t127\u2013150.\t (Detailed review examining possible modes of \naction of these drugs )\nBorel,\tJ.F.,\tBaumann,\t G.,\tChapman,\t I.,\tet\tal.,\t1996.\t In vivo \npharmacological effects of ciclosporin and some analogues. Adv. \nPharmacol.\t 35,\t115\u2013246.\t (Borel was instrumental in the development of \nciclosporin )\nChan,\tE.S.,\tCronstein,\t B.N.,\t2010.\tMethotrexate\t \u2013\thow\tdoes\tit\treally\t\nwork?\tNat.\tRev.\tRheumatol.\t 6,\t175\u2013178.\t (An in-depth investigation of the \nactions of what is probably the most widely employed DMARD. Good \ndiagrams)\nChandrashekara,\t S.,\t2013.\tPharmacokinetic\t consideration\t of\tsynthetic\t\nDMARDs\t in\trheumatoid\t arthritis.\t", "start_char_idx": 5038, "end_char_idx": 7530, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d75fd605-3612-4ef1-89b3-bcab8dc5997f": {"__data__": {"id_": "d75fd605-3612-4ef1-89b3-bcab8dc5997f", "embedding": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e18e6df7dac216e3711e04d3f10a38b78d1a85df278b9e13744ee7688c03c4"}, "2": {"node_id": "7a737159-7025-4edb-990c-4b1e5b7d11bf", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "32f77d2729256589c3dc98cc5041833a7ed8ae0936bda3d5b89350e1fdff0f8b"}, "3": {"node_id": "7b9e86d8-1b44-4828-8d14-95c254eb9185", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0ca3f016b4f359b05ed7bbba73ee60e52e61ab1e7d77091a78177a9b781da239"}}, "hash": "89d26f57bc4f3cf5952abc028cb555210431064ea6bf9bc65fc8bd947375d867", "text": "in\trheumatoid\t arthritis.\t Expert\tOpin.\tDrug\tMetab.\tToxicol.\t\n9,\t969\u2013981.\nCutolo,\tM.,\t2002.\tEffects\tof\tDMARDs\t on\tIL-1Ra\tlevels\tin\trheumatoid\t\narthritis:\t is\tthere\tany\tevidence?\t Clin.\tExp.\tRheumatol.\t 20\t(5\tSuppl.\t27),\t\nS26\u2013S31.\t (Reviews the actions of DMARDs on the generation and release of \nthe endogenous IL-1 antagonist. An interesting slant on the mechanism of \naction of these drugs )\nDavis,\tJ.M.,\t3rd,\tMatteson,\t E.L.,\t2012.\tMy\ttreatment\t approach\t to\t\nrheumatoid\t arthritis.\t Mayo\tClin.\tProc.\t87,\t659\u2013673.\t (Written from the \nviewpoint of a practical clinician, this review explains the latest guidance on \nclassifying pathotypes of rheumatoid arthritis and adjusting the many \ndifferent types of treatment to suit the patient )\nLodowska,\t J.,\tGruchlik,\t A.,\tWolny,\tD.,\tWawszczyk,\t J.,\tDzierzewicz,\t Z.,\t\nWeglarz,\t L.,\t2015.\tThe\tEffect\tof\tsulfasalazine\t and\t5-aminosalicylic\t acid\t\non\tthe\tsecretion\t of\tinterleukin\t 8\tby\thuman\tcolon\tmyofibroblasts.\t Acta\t\nPol.\tPharm.\t72,\t917\u2013921.\nRau,\tR.,\t2005.\tHave\ttraditional\t DMARDs\t had\ttheir\tday?\tEffectiveness\t of\t\nparenteral\t gold\tcompared\t to\tbiologic\t agents.\tClin.\tRheumatol.\t 24,\t\n189\u2013202.\t (Argues for a continuing place of DMARDs in the clinic despite \nthe introduction of the new biopharmaceuticals )\nSmolen,\t J.S.,\tKalden,\tJ.R.,\tScott,\tD.L.,\tet\tal.,\t1999.\tEfficacy\t and\tsafety\tof\t\nleflunomide\t compared\t with\tplacebo\tand\tsulphasalazine\t in\tactive\t\nrheumatoid arthritis: a double-blind, randomised, multicentre trial. \nLancet\t353,\t259\u2013260.\t (Gives details of the results of a clinical trial showing \nthe efficacy of leflunomide )\nAnticytokine drugs and other biopharmaceuticals\nArora,\tT.,\tPadaki,\tR.,\tLiu,\tL.,\tet\tal.,\t2009.\tDifferences\t in\tbinding\t and\t\neffector\tfunctions\t between\t classes\tof\tTNF\tantagonists.\t Cytokine\t 45,\t\n124\u2013131.\t (A research paper detailing the significance of the membrane-bound \nversus soluble TNF neutralising actions of the drugs )\nBongartz,\t T.,\tSutton,\tA.J.,\tSweeting,\t M.J.,\tet\tal.,\t2006.\tAnti-TNF\t antibody\t\ntherapy in rheumatoid arthritis and the risk of serious infections and \nmalignancies: systematic review and meta-analysis of rare harmful \neffects\tin\trandomized\t controlled\t trials.\tJAMA\t295,\t2275\u20132285.\t (The title \nis self-explanatory )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 7545, "end_char_idx": 10117, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7b9e86d8-1b44-4828-8d14-95c254eb9185": {"__data__": {"id_": "7b9e86d8-1b44-4828-8d14-95c254eb9185", "embedding": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e18e6df7dac216e3711e04d3f10a38b78d1a85df278b9e13744ee7688c03c4"}, "2": {"node_id": "d75fd605-3612-4ef1-89b3-bcab8dc5997f", "node_type": null, "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "89d26f57bc4f3cf5952abc028cb555210431064ea6bf9bc65fc8bd947375d867"}}, "hash": "0ca3f016b4f359b05ed7bbba73ee60e52e61ab1e7d77091a78177a9b781da239", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 10095, "end_char_idx": 10286, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d8c734af-dfab-4723-90a6-764676265fff": {"__data__": {"id_": "d8c734af-dfab-4723-90a6-764676265fff", "embedding": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3747bc6e-364c-4147-8ee9-1406a61446b4", "node_type": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "206a2758dd85b042233f0fea83cb9af0425f0ce1ea952e0931c1c503f12d268a"}, "3": {"node_id": "238883a0-cd82-4a42-8431-62fe33a1e96e", "node_type": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f43eaf7dc48541451506907cba0a107c3fff999ad8f9673f28af8ba6fee3e5d1"}}, "hash": "ec52333066bfc5149716db80f6bb2f5996f8729f63c044faaadf3cb5447891ea", "text": "27 ANTI-INFlAMMATORY AND IMMUNOSUppRESSANT DRUGS\n361Antihistamines\nAssanasen,\t P.,\tNaclerio,\t R.M.,\t2002.\tAntiallergic\t anti-inflammatory\t\neffects of H 1-antihistamines\t in\thumans.\t Clin.\tAllergy\tImmunol.\t 17,\t\n101\u2013139.\t (An interesting paper that reviews several alternative mechanisms \nwhereby antihistamines may regulate inflammation )\nLeurs,\tR.,\tBlandina,\t P.,\tTedford,\t C.,\tTimmerm,\t N.H.,\t1998.\tTherapeutic\t\npotential of histamine H 3 receptor agonists and antagonists. Trends \nPharmacol.\t Sci.\t19,\t177\u2013183.\t (Describes the available H 3 receptor agonists \nand antagonists, and their effects in a variety of pharmacological models, \nwith discussion of possible therapeutic applications )\nSimons,\t F.E.R.,\tSimons,\t K.J.,\t1994.\tDrug\ttherapy:\t the\tpharmacology\t and\t\nuse of H 1-receptor-antagonist\t drugs.\tN.\tEngl.\tJ.\tMed.\t23,\t1663\u20131670.\t\n(A bit dated now but contains effective coverage of the topic from the clinical \nviewpoint )\nNew directions\nAtkinson,\t T.J.,\tFudin,\tJ.,\tJahn,\tH.L.,\tKubotera,\t N.,\tRennick,\t A.L.,\tRhorer,\t\nM.,\t2013.\tWhat\u2019s\tnew\tin\tNSAID\tpharmacotherapy:\t oral\tagents\tto\t\ninjectables.\t Pain\tMed.\t14\t(Suppl.\t1),\tS11\u2013S17.\nMoss,\tM.L.,\tSklair-Tavron,\t L.,\tNudelman,\t R.,\t2008.\tDrug\tinsight:\ttumor\t\nnecrosis\t factor-converting\t enzyme\tas\ta\tpharmaceutical\t target\tfor\t\nrheumatoid\t arthritis.\t Nat.\tClin.\tPract.\tRheumatol.\t 4,\t300\u2013309.\t (Accessible \nreview dealing with this potentially important concept. Some good diagrams )\nOuvry,\tG.,\tBerton,\tY.,\tBhurruth-Alcor,\t Y.,\tet\tal.,\t2017.\tIdentification\t of\t\nnovel\tTACE\tinhibitors\t compatible\t with\ttopical\tapplication.\t Bioorg.\t\nMed.\tChem.\tLett.\t27,\t1848\u20131853.\nSharma,\t M.,\tMohapatra,\t J.,\tAcharya,\t A.,\tet\tal.,\t2013.\tBlockade\t of\ttumor\t\nnecrosis\t factor-alpha\t converting\t enzyme\t (TACE)\tenhances\t IL-1-beta\t\nand IFN-gamma via caspase-1 activation: a probable cause for loss of \nefficacy\tof\tTACE\tinhibitors\t in\thumans?\t Eur.\tJ.\tPharmacol.\t 701,\t\n106\u2013113.\t (A discussion of the prospects and pitfalls of low molecular-weight \nTNF inhibitors )\nWallace,\t J.L.,\tde\tNucci,\tG.,\tSulaieva,\t O.,\t2015.\tToward\t more\tGI-friendly\t\nanti-inflammatory\t medications.\t Curr.\tTreat.\tOptions\t Gastroenterol.\t 13,\t\n377\u2013385.Carterton,\t N.L.,\t2000.\tCytokines\t in\trheumatoid\t arthritis:\t trials\tand\t\ntribulations.\t Mol.\tMed.\tToday\t6,\t315\u2013323.\t (Good review of agents \nmodulating the action of TNF- \u03b1 and IL-1; simple, clear diagram of cellular \naction of these cytokines, and summaries of the clinical trials of the agents", "start_char_idx": 0, "end_char_idx": 2462, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "238883a0-cd82-4a42-8431-62fe33a1e96e": {"__data__": {"id_": "238883a0-cd82-4a42-8431-62fe33a1e96e", "embedding": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3747bc6e-364c-4147-8ee9-1406a61446b4", "node_type": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "206a2758dd85b042233f0fea83cb9af0425f0ce1ea952e0931c1c503f12d268a"}, "2": {"node_id": "d8c734af-dfab-4723-90a6-764676265fff", "node_type": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ec52333066bfc5149716db80f6bb2f5996f8729f63c044faaadf3cb5447891ea"}, "3": {"node_id": "f8d419a0-e8fc-406a-99df-115fb88ac952", "node_type": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7cece93325d0f60f6eef00053f6a4b5821c643dca8d2de7d98c292df512b53e9"}}, "hash": "f43eaf7dc48541451506907cba0a107c3fff999ad8f9673f28af8ba6fee3e5d1", "text": "of these cytokines, and summaries of the clinical trials of the agents in \ntabular form )\nChoy,\tE.H.S.,\tPanayi,\tG.S.,\t2001.\tCytokine\t pathways\t and\tjoint\t\ninflammation\t in\trheumatoid\t arthritis.\t N.\tEngl.\tJ.\tMed.\t344,\t907\u2013916.\t\n(Clear description of the pathogenesis of rheumatoid arthritis, emphasising \nthe cells and mediators involved in joint damage; excellent diagrams of the \ninteraction of inflammatory cells and of the mechanism of action of \nanticytokine agents )\nFeldmann,\t M.,\t2002.\tDevelopment\t of\tanti-TNF\t therapy\tfor\trheumatoid\t\narthritis.\t Nat.\tRev.\tImmunol.\t 2,\t364\u2013371.\t (Excellent review covering the \nrole of cytokines in rheumatoid arthritis and the effects of anti-TNF therapy \nwritten by one of the pioneers of this type of therapy )\nFiorino,\t G.,\tAllez,\tM.,\tMalesci,\t A.,\tDanese,\t E.,\t2009.\tReview\tarticle:\tanti\t\nTNF-alpha induced psoriasis in patients with inflammatory bowel \ndisease.\t Aliment.\t Pharmacol.\t Ther.\t29,\t921\u2013927.\t (Deals with this rare \nand unexpected side effect of anti-TNF therapy )\nJobanputra,\t P.,\tMaggs,\tF.,\tDeeming,\t A.,\tet\tal.,\t2012.\tA\trandomised\t\nefficacy and discontinuation study of etanercept versus adalimumab \n(RED\tSEA)\tfor\trheumatoid\t arthritis:\t a\tpragmatic,\t unblinded,\t\nnon-inferiority study of first TNF inhibitor use: outcomes over 2 \nyears.\tBMJ\tOpen\t2,\t1\u20139.\nvan\tder\tKooij,\tS.M.,\tle\tCessie,\tS.,\tGoekoop-Ruiterman,\t Y.P.,\tet\tal.,\t2009.\t\nClinical\tand\tradiological\t efficacy\tof\tinitial\tvs\tdelayed\t treatment\t with\t\ninfliximab plus methotrexate in patients with early rheumatoid \narthritis.\t Ann.\tRheum.\t Dis.\t68,\t1153\u20131158.\nMaini,\tR.N.,\t2005.\tThe\t2005\tInternational\t Symposium\t on\tAdvances\t in\t\nTargeted Therapies: what have we learned in the 2000s and where are \nwe\tgoing?\tAnn.\tRheum.\t Dis.\t64\t(Suppl.\t4),\t106\u2013108.\t (An updated review \ndealing with the role of cytokines in the pathogenesis of rheumatoid arthritis \nand the results of clinical trials with anti-TNF and anti-IL-1 therapy written \nby one of the pioneers of this type of therapy )\nO\u2019Dell,\tJ.R.,\t1999.\tAnticytokine\t therapy\t\u2013\ta\tnew\tera\tin\tthe\ttreatment\t of\t\nrheumatoid\t arthritis.\t N.\tEngl.\tJ.\tMed.\t340,\t310\u2013312.\t (Editorial with \nexcellent coverage of the role of TNF- \u03b1 in rheumatoid arthritis; summarises \nthe differences between infliximab and etanercept )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2404, "end_char_idx": 5068, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f8d419a0-e8fc-406a-99df-115fb88ac952": {"__data__": {"id_": "f8d419a0-e8fc-406a-99df-115fb88ac952", "embedding": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3747bc6e-364c-4147-8ee9-1406a61446b4", "node_type": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "206a2758dd85b042233f0fea83cb9af0425f0ce1ea952e0931c1c503f12d268a"}, "2": {"node_id": "238883a0-cd82-4a42-8431-62fe33a1e96e", "node_type": null, "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f43eaf7dc48541451506907cba0a107c3fff999ad8f9673f28af8ba6fee3e5d1"}}, "hash": "7cece93325d0f60f6eef00053f6a4b5821c643dca8d2de7d98c292df512b53e9", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5080, "end_char_idx": 5223, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9ee713e5-95d9-4074-9e4f-a13d9ba71606": {"__data__": {"id_": "9ee713e5-95d9-4074-9e4f-a13d9ba71606", "embedding": null, "metadata": {"page_label": "368", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "55887517-e16d-4617-842b-bb33ab005f9b", "node_type": null, "metadata": {"page_label": "368", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a639a10047b0702d2094d8d7b581602f03bd50e7721e28e3c3c30b3be469c917"}, "3": {"node_id": "b667c4af-e649-4180-a8a5-059f32275c76", "node_type": null, "metadata": {"page_label": "368", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f70a642be562d4e1668bfbc645157dbe8a2b1d350a6efcb06a099c3d1b860a90"}}, "hash": "27e52807f8c55552c14f202bab1e814f5457ab56ab9931cf8e79ad42564dd457", "text": "362\nSkin28\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION \u20033\nOVERVIEW\nWith\u2003a\u2003surface \u2003area\u2003of\u2003about \u20031.6\u20131.8 \u2003m2\u2003and\u2003a\u2003weight \u2003\nof\u2003about \u20034.5 \u2003kg \u2003in \u2003the \u2003average \u2003adult, \u2003skin \u2003qualifies \u2003\nas\u2003the \u2003largest \u2003and \u2003heaviest \u2003organ \u2003in \u2003the \u2003body. \u2003It \u2003is\u2003\nalso\u2003an\u2003important \u2003target \u2003for\u2003drug \u2003therapy \u2003as\u2003well\u2003as\u2003\ncosmetic \u2003and \u2003other \u2003agents. \u2003Here, \u2003we \u2003look \u2003at \u2003the\u2003\nstructure \u2003of \u2003human \u2003skin \u2003and \u2003briefly \u2003review \u2003some \u2003\ncommon \u2003skin\u2003disorders. \u2003We\u2003then\u2003discuss \u2003some \u2003of\u2003the\u2003\nmany \u2003types \u2003of \u2003drugs \u2003that \u2003act \u2003upon, \u2003or \u2003through, \u2003this\u2003\norgan.\nINTRODUCTION\nSkin is a complex organ with many roles.1 Firstly, it acts \nas a barrier. Being impermeable to water, it prevents the \nloss of moisture from the body as well as the ingress of \nwater and many other substances into the body. It also cushions underlying tissues against thermal and mechanical \ndamage and shields them from ultraviolet radiation and \ninfection. Even if microorganisms survive in the slightly acidic environment of the skin\u2019s surface, they cannot easily \ncross the outer barrier of the skin. In the event that they \ndo, they encounter specialised immunological surveillance systems comprising Langerhans cells , a type of dendritic \ncell, as well as mast cells and other immunocompetent cell \ntypes.\n2\nA second function is thermoregulation. Approximately \n10% of the total blood volume is contained within the dense capillary networks of the skin. Skin arterioles, controlled \nby the sympathetic nervous system, regulate blood flow and heat loss from the skin. Sweat glands ( eccrine glands) \nin the skin secrete, under cholinergic control, an aqueous fluid which, upon evaporation, increases heat loss.\nIn the presence of sunlight, vitamin D\n3 (cholecalciferol) \nis synthesised in the stratum basale and stratum spinosum of \nskin. Absence of this vitamin caused by inadequate exposure to the ultraviolet (UV B) component of sunlight can lead to deficiency symptoms (see Ch. 37). The dark-coloured \npigment melanin , which protects skin against excessive and \npotentially damaging solar radiation and which gives skin \nits characteristic colour, is produced by melanocytes in the \nbasal dermal layer. Melanin granule formation is stimulated \nby sunlight to match the prevailing light intensity.Skin is also a profoundly sensory organ. It is densely \ninnervated with neurons, including specific nerve endings \nthat signal pain, heat and cold; specialised receptors that \ndetect touch ( Meissner corpuscles) and pressure ( Pacinian \ncorpuscles ) as well as itch \u2013 a sensation unique to skin with \nan interesting pharmacology. The cell bodies of cutaneous sensory nerves reside in the dorsal root ganglia.\nBeing highly visible, skin and its specialised appendages, \nhair and nails, play an important part in social and sexual signalling. As such, it is an important target for cosmetic preparations, camouflaging agents, suntan lotions, anti-ageing compounds and more. Because unsightly skin can \ncause problems of social adjustment or even frank psychiatric \nillness, the distinction between a therapeutic agent and a cosmetic preparation can become blurred. In fact, the market \nfor", "start_char_idx": 0, "end_char_idx": 3157, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b667c4af-e649-4180-a8a5-059f32275c76": {"__data__": {"id_": "b667c4af-e649-4180-a8a5-059f32275c76", "embedding": null, "metadata": {"page_label": "368", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "55887517-e16d-4617-842b-bb33ab005f9b", "node_type": null, "metadata": {"page_label": "368", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a639a10047b0702d2094d8d7b581602f03bd50e7721e28e3c3c30b3be469c917"}, "2": {"node_id": "9ee713e5-95d9-4074-9e4f-a13d9ba71606", "node_type": null, "metadata": {"page_label": "368", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27e52807f8c55552c14f202bab1e814f5457ab56ab9931cf8e79ad42564dd457"}}, "hash": "f70a642be562d4e1668bfbc645157dbe8a2b1d350a6efcb06a099c3d1b860a90", "text": "and a cosmetic preparation can become blurred. In fact, the market \nfor \u2018cosmeceuticals\u2019 as they are called is huge: in the United \nStates alone over US$8 billion was spent on these compounds (many of which lack any proof of efficacy) in 2012 (Nolan \net al., 2012).\nHere we look briefly at some common conditions affecting \nthe skin and at some of the drugs used to treat them (Table \n28.1). In most cases, these drugs also have other uses and their mechanisms of action are described elsewhere in the book, so the appropriate cross-references are given in Table \n28.1. Inflammation is a common feature of skin diseases, and anti-inflammatory drugs, discussed in detail in Chapter 27, are often used. In some other instances, the drugs \nthemselves, or their particular utility, are almost unique \nto skin pharmacology, so they will be explained in a little more detail. Drugs used to treat skin infections and cancers are discussed in Chapters 52, 54 and 57.\nTopical application of drugs onto the skin can be used \nas a route for systemic administration (see Ch. 9), and also to treat the underlying tissues. For example, non-steroidal \nanti-inflammatory drugs (NSAIDs) applied topically can \nreduce the inflammation of underlying joints and connective tissue with less unwanted effects than those seen after \nsystemic administration (Klinge & Sawyer, 2013). However, \nwe will not deal in depth with this topic here.\nSTRUCTURE \u2003OF \u2003SKIN\nSkin comprises three main layers: the outermost layer, the epidermis, a middle layer, the dermis, and the innermost \nlayer, the subdermis, sometimes called the hypodermis or \nsubcutis (Fig. 28.1).\nThe epidermis consists largely of keratinocytes. There \nare four layers of cells: the stratum basale is the innermost \nlayer and lies adjacent to the dermoepidermal junction. It \ncomprises mainly dividing keratinocytes interspersed with \nmelanocytes. The latter cells produce granules of melanin \nin melanosomes, which are transferred to the dividing \nkeratinocytes. As the keratinocytes divide and mature 1As the American humourist and songwriter Alan Sherman so \nsuccinctly put it, \u2018Skin\u2019s the thing that if you\u2019ve got it outside/It keeps \nyour insides in\u2019.\n2Dendritic cells were named as such by Paul Langerhans who \ndiscovered them when a medical student in 1868. Because of their shape, he mistook them for nerve cells, but they are actually phagocytic \nantigen-presenting immune cells of the monocyte/macrophage lineage.\u2003\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3086, "end_char_idx": 6029, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1478afd9-923b-4937-bf75-6eb5f4138b38": {"__data__": {"id_": "1478afd9-923b-4937-bf75-6eb5f4138b38", "embedding": null, "metadata": {"page_label": "369", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "debf93da-4e6b-4042-b6f5-f2b5a517c2aa", "node_type": null, "metadata": {"page_label": "369", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3c79b4824b10fb0e319ab2ac5455e3fbbaedde149c8da7d8acbdb8a22889551"}, "3": {"node_id": "d7f89e3b-94da-4769-b754-0f45c603a564", "node_type": null, "metadata": {"page_label": "369", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27cdfe9d00a835f04dcfbf2238b5c3ea9c730281dac6054ac71a10ac5b2d2931"}}, "hash": "85f30cb70b079313cf0336b243dc22d7bc3bb9113f56201d8422d01cceef002c", "text": "28 SkIN\n363Table 28.1 Drug treatment of some common skin disorders\nDisease Class Examples Comments Chapter\nAcneAntibacterials Erythromycin, clindamycin, various \nantiseptic agentsFor mild\u2013moderate acne. \nUsually topical but sometimes \nsystemic treatment is also used52\nRetinoids Isotretinoin, adapalene, tretinoin For more severe disease. Often \ncombined with anti-infective \nagents. Sometimes systemic \ntreatment is also used\u2014\nAndrogen antagonists Co-cyprindiol For moderate\u2013severe disease 36\nAlopecia Anti-androgen, vasodilator Finasteride, minoxidil Generally in men only 36, 23\nHirsutismInhibitor of DNA/RNA \nsynthesisEflornithine Usually in women only 57\nInfectionsAntibacterials Bacitracin, metronidazole, mupirocin, \nneomycin sulfate, polymixins, \nretapamulin, sulfadiazine, silver salts\nUsually given topically but some \ndrugs may be given orally.52\nAntivirals Aciclovir, penciclovir 53\nAntifungal Amorolfine, clotrimazole, econazole, \ngriseofulvin, ketaconazole, \nmiconazole, terbinafine, tioconazole54\nAntiparasite Topical parasiticides e.g. benzyl \nbenzoate, dimeticone, malathion, \npermethrin, tazarotene\u2014 55\nPruritusAntihistamines, topical \nanaesthetics and related \ndrugsCrotamiton, diphenhydramine, \ndoxepinAntihistamines may be given \ntopically or orally. Sometimes a \n\u2018sedating\u2019 antihistamine is useful18\nEczemaGlucocorticoids Mild\u2013potent (i.e. hydrocortisone, \nbetamethasone esters)May be combined with \nantibacterial or antifungal agent \nif infection is present27, 34\nRetinoids Alitretinoin, acitretin Given orally. Only used if \nglucocorticoid therapy has failed\u2014\nCalcineurin inhibitors Picrolimus, tacrolimus Often topical but sometimes \nsystemic. Used for more severe \ndisease27\nPsoriasisVitamin D analogues Calcipotriol, calcitriol, tacalcitol DMARDS and anticytokine \ndrugs used for severe cases5, 7, 27\nRetinoids Acitretin, alitretinoin, tazarotene Oral retinoids sometimes used \u2014\nGlucocorticoids Moderate\u2013potent (i.e. hydrocortisone \nbutyrate, clobetasol propionate)May be combined with \nantibacterial or antifungal agent \nif infection is present27, 34, 52, 54\nCalcineurin inhibitors Picrolimus, tacrolimus Maybe given topically or \nsystemically. Usually used for \nsevere cases27\nRosaceaAntibacterials or \u03b12 \nadrenergic agentsDoxycycline, erythromycin, \nmetronidazole, tetracycline or \nbrimonidineGlucocorticoids are \ncontraindicated52\nUrticariaAntihistamines Diphenhydramine, doxepin Usually given orally. Sometimes \na \u2018sedating\u2019 antihistamine is \nuseful18\nWartsKeratolytic agents and \nothersFormaldehyde, imiquimod, \npodophyllotoxin, salicylic acid, silver \nnitrateMany of these substances are \nfound in proprietary wart \ntreatments\u2014\nDMARDs, disease-modifying antirheumatic drugs.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2933, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d7f89e3b-94da-4769-b754-0f45c603a564": {"__data__": {"id_": "d7f89e3b-94da-4769-b754-0f45c603a564", "embedding": null, "metadata": {"page_label": "369", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "debf93da-4e6b-4042-b6f5-f2b5a517c2aa", "node_type": null, "metadata": {"page_label": "369", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3c79b4824b10fb0e319ab2ac5455e3fbbaedde149c8da7d8acbdb8a22889551"}, "2": {"node_id": "1478afd9-923b-4937-bf75-6eb5f4138b38", "node_type": null, "metadata": {"page_label": "369", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "85f30cb70b079313cf0336b243dc22d7bc3bb9113f56201d8422d01cceef002c"}}, "hash": "27cdfe9d00a835f04dcfbf2238b5c3ea9c730281dac6054ac71a10ac5b2d2931", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2886, "end_char_idx": 3189, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d5892d85-d382-4a66-9adb-5ef0d2d00112": {"__data__": {"id_": "d5892d85-d382-4a66-9adb-5ef0d2d00112", "embedding": null, "metadata": {"page_label": "370", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bb3d47ca-8533-4fd7-91f3-c9a8f80df3dc", "node_type": null, "metadata": {"page_label": "370", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6e563fbaa275688062d7098208bbb785738f96e5a509b92f9cd727d313123d68"}, "3": {"node_id": "beb2be14-c6a7-4e13-b71c-eb2b369866e0", "node_type": null, "metadata": {"page_label": "370", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9abba3ab79017d189bc4c05f3ba45c7ed833e69730cf791b48a4efce870924a7"}}, "hash": "c100347d2780b7c89a9b3062bde03e2d0e55079e0211bcc2f94938e8523fe583", "text": "28 SECTION \u20033\u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n364cells that produce keratin and associated melanocytes that \nproduce pigment for the growing hair shaft. Associated \nwith each hair follicle is an erector pili muscle that causes \nthe hair shaft to become erect. Cold, fear and other strong \nemotional stimuli trigger this response giving the sensation \nof \u2018goose bumps\u2019. Sebaceous glands associated with hair \nfollicles coat the hair with waxy substances. The growth of hair and the activity of these glands is controlled by \nandrogens.\nThere are two types of sweat glands: apocrine glands are \nassociated with hair, especially in the armpits and perineum. \nThey empty their proteinaceous secretion into the hair \nfollicle. Eccrine glands, on the other hand, are distributed \nover much of the skin surface.\nThe innermost layer of skin is the hypodermis or cutis. \nThis comprises connective tissue and adipose tissue, which \nmay be particularly thick at some anatomical locations (e.g. the abdomen).\nCOMMON \u2003DISEASES \u2003OF \u2003THE \u2003SKIN\n\u25bc Here we briefly review some common skin disorders, focusing \non those for which specific drug treatment is available.\nACNE\n\u25bc The most common form of the disease occurs during puberty, \nespecially in boys but also (and sometimes devastatingly) in girls. \nChanges in circulating androgens stimulate the sebaceous glands \nassociated with hair follicles, which become enlarged and blocked \nwith sebum and debris. The confined material may become infected, causing an inflammatory reaction that compounds the problem. \nNormally acne disappears after puberty but some forms may persist \nor manifest in later life and require long-term treatment. If severe, acne can cause irreversible scarring and considerable psychological \nmisery.they progress towards the skin surface. In the next layer, \nthey form the stratum spinosum (\u2018spiny\u2019 layer), so-called \nbecause desmosomes (intercellular protein links) begin to \nappear on the cells. Gradually, these cells begin to flatten adopting a squamous (scaly) morphology. They lose their \nnuclei and the cytoplasm acquires a granular appearance. Lying immediately above this is a thin translucent layer of tissue called the stratum lucidum . The outermost layer of skin \nis the stratum corneum . By now, individual keratinocytes are \nno longer viable because they have fused together (corni -\nfied). Most tissues have 10\u201330 layers of these hardened sheets of tissue. The corneocytes, as they are now called, \nare surrounded with a hydrated proteinaceous envelope. Lipid bilayers occupy the extracellular space providing a hydrophilic waterproof layer. The water and lipid content of \nskin is critical to its function. If the moisture content of the \nhydrated layer falls, the skin loses its supple properties and cracks. The keratinocytes are normally replenished about \nevery 45 days (Bergstresser & Taylor, 1977) and so healthy \nskin constantly sheds the outer layer of cornified cells. If this does not occur, patches of dry skin begin to appear.\nBelow the epidermis lies the dermis. This layer varies in \nthickness. In some tissues, it is very thick (e.g. the palms and the soles of the feet) and in others, very thin (e.g. the \neyelids). Histologically, the dermis comprises a papillary \nlayer and a deeper reticular layer. The main cell types are \nfibroblasts. These produce and secrete important structural elements of the skin such as glycoproteins, which contribute \nto the hydration of the tissue, and collagen and elastin that provide strength and elasticity. Other types of cells associ -\nated with the immune system are also present (see Ch. 7). \nThe dermis is richly", "start_char_idx": 0, "end_char_idx": 3655, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "beb2be14-c6a7-4e13-b71c-eb2b369866e0": {"__data__": {"id_": "beb2be14-c6a7-4e13-b71c-eb2b369866e0", "embedding": null, "metadata": {"page_label": "370", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bb3d47ca-8533-4fd7-91f3-c9a8f80df3dc", "node_type": null, "metadata": {"page_label": "370", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6e563fbaa275688062d7098208bbb785738f96e5a509b92f9cd727d313123d68"}, "2": {"node_id": "d5892d85-d382-4a66-9adb-5ef0d2d00112", "node_type": null, "metadata": {"page_label": "370", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c100347d2780b7c89a9b3062bde03e2d0e55079e0211bcc2f94938e8523fe583"}}, "hash": "9abba3ab79017d189bc4c05f3ba45c7ed833e69730cf791b48a4efce870924a7", "text": "with the immune system are also present (see Ch. 7). \nThe dermis is richly endowed with blood vessels and \nlymphatics and densely innervated.\nHair follicles , sebaceous glands and sweat glands are embed -\nded in the dermis. Hair follicles are lined with specialised Sensory nerveErector pili\nmuscle\nSebaceous\nglandsStratum\ncorneum\nStratum granulosumStratum lucidum\nStratum\nspinosumHair follicles\nArterioleEpidermis\nDermis\nSubdermis\nCapillariesEccrine\nglands\nFat, collagen, fibroblasts\nin subdermal layerStratum\nbasale\nFig. 28.1 A simplified diagram showing the structure of the skin. The skin comprises three main layers coloured differently in the \nright-hand drawing: epidermis (dark red/brown) ; dermis (pink); and subdermis (yellow). On the left is an enlarged diagram of the complex \nouter, epidermal, layer. Not shown are the apocrine glands within the hair follicles. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3581, "end_char_idx": 4939, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6eeb3a49-5d38-45ba-9383-787f556e3235": {"__data__": {"id_": "6eeb3a49-5d38-45ba-9383-787f556e3235", "embedding": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2a2a91fd-6f7f-4200-978b-f5cf9cf5fe17", "node_type": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e0f6395b6a5307ad7ffccd0a7460494a22714ef850069931265bd94d743c388"}, "3": {"node_id": "bb583aca-80cd-4f04-a610-e8267b714021", "node_type": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a99344c1a33e024e2f3d969c2a0725585f07f4e232ae9dd2f172b039712e5a65"}}, "hash": "ceec345e2a33520ff1082439ec802406deff3794aec71ecb51989e1050e09ced", "text": "28 SkIN\n365the growth of hair on the scalp but stimulate it elsewhere (e.g. the \nface, chest, back, etc.). Alopecia areata is a condition where hair falls \nout in patches that come and go. Eventually, these patches may \ncoalesce, leading to total baldness. The disease seems to be of auto -\nimmune origin.\nHirsutism is common in men (who seldom complain) but is less \nsocially acceptable in women. Once again, rising androgen levels are \nthe cause, stimulating the growth of hair on areas of the body where \nit does not normally occur in women (e.g. the face); this is commoner in some ethnic groups and seldom pathological but can be a symptom \nof androgenising endocrine tumours (such as Sertoli\u2013Leydig cell tumours , \nwhich are rare functioning ovarian tumours).\nECZEMA\n\u25bc This is a generic term and refers to a common condition where \nthe skin becomes dry, itchy, flaky and inflamed. The distribution is \ndistinctive, namely on flexor surfaces (e.g. wrists, elbows and behind \nthe knees, in contrast to psoriasis). There are several potential causes. \nAtopic eczema (also called atopic dermatitis ) is the most common inflam -\nmatory skin disease, affecting about a quarter of all children and \nabout 5% of adults. It is often seen in patients who also suffer from \nasthma or seasonal rhinitis (hay fever), although the long-held notion that this type of eczema is primarily an immunological disorder has \nrather little support. It tends to run in families, indicating a genetic \nsusceptibility. Contact dermatitis arises when the skin becomes \u2018sen -\nsitised\u2019 to a particular antigen. Nickel sensitivity is a classic example: contact with the metal either provokes the production of antibodies or modifies structural elements of the epidermis so that autoantibodies \nare produced. This is more often seen in women because it is a common \ncomponent of (less-expensive) jewellery.\n3 The pathophysiology is now \nbelieved to stem from disordered barrier function leading to epidermal \nwater loss, and a vicious cycle of itching and scratching with release \nof inflammatory mediators. Penetration of allergens and interaction with IgE-bearing Langerhans cells can add a Th2-mediated immu -\nnological component. Xerotic eczema refers to eczema that is produced \nwhen the skin dries out. This is more common in the winter months, especially amongst older people.\nPRURITUS\n\u25bc Pruritus \u2013 itch \u2013 is a common symptom of skin diseases, but can \nalso occur with systemic disorders, such as obstructive jaundice, or neurological disorders such as shingles (herpes zoster). Some drugs \n(e.g. opioids) also can cause itching. There is a complex relationship \nbetween the neural systems that detect and transduce pain and itch \n(see Greaves & Khalifa, 2004; Ikoma et al., 2006) and there may be a \ndedicated population of nociceptors that function as \u2018itch transducers\u2019.\nSkin diseases commonly causing itch include eczema, urticaria and \npsoriasis. These are largely caused by the release of inflammatory mediators in the skin from mast cells (e.g. histamine, leukotrienes, \nproteases and cytokines).\nURTICARIA\n\u25bc This term refers to a range of inflammatory changes in the skin \ncharacterised by the presence of raised wheals or bumps (\u2018nettle rash\u2019). \nThey are normally surrounded by a red margin and are intensely \nitchy. There are many known causes, including exposure to the sun \n(solar urticaria4), heat or cold, insect bites or stings, foodstuffs or \ninfection, as well as some drugs. Many cases are allergic in nature \nwhile", "start_char_idx": 0, "end_char_idx": 3518, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bb583aca-80cd-4f04-a610-e8267b714021": {"__data__": {"id_": "bb583aca-80cd-4f04-a610-e8267b714021", "embedding": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2a2a91fd-6f7f-4200-978b-f5cf9cf5fe17", "node_type": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e0f6395b6a5307ad7ffccd0a7460494a22714ef850069931265bd94d743c388"}, "2": {"node_id": "6eeb3a49-5d38-45ba-9383-787f556e3235", "node_type": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ceec345e2a33520ff1082439ec802406deff3794aec71ecb51989e1050e09ced"}, "3": {"node_id": "a8660e44-52bc-4ad4-9760-9edd6dd38360", "node_type": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "35c463323bfc70cc392a0c62303372b6f601877fcf3ec12836c32673c814f4a9"}}, "hash": "a99344c1a33e024e2f3d969c2a0725585f07f4e232ae9dd2f172b039712e5a65", "text": "\ninfection, as well as some drugs. Many cases are allergic in nature \nwhile others have no known cause. A bizarre manifestation of urticaria \nseen in some people is dermographia \u2013 literally \u2018skin writing\u2019. This is \nan exaggerated form of the \u2018triple response\u2019 seen after injecting \nhistamine into the skin (see Ch. 18) and in this case provoked by \nscratching or in some cases simply rubbing or stroking the skin.ROSACEA\n\u25bc The diagnostic feature of rosacea is the presence of a chronic \nhyperaemia of the facial skin. There is often a characteristic pattern with the erythema spreading across the nose, the cheeks and forehead. \nThe erythema is caused by vasodilatation and dilated blood vessels \nclose to the surface of the skin are usually visible. The affected skin may become dry and flaky; there may be a stinging or burning sensa -\ntion, and a tendency to flush in response to various stimuli, including exertion, emotional stress, heat, sunlight and spicy foods.\nThere is a genetic basis for the disorder. It is more prevalent in women \nthan men and may be exacerbated during the menopause. The disease cannot be cured and the symptoms can be very long lasting and \ndifficult to control, with both drug and other therapies playing a role. \nThere is a debate about the cause of rosacea. Infection may be a trigger but rosacea could be a disorder of the innate immune system \nin which antimicrobial peptides in the skin are indirectly responsible \nfor the symptoms (see Antal et al., 2011; Yamasaki & Gallo, 2011). \nAntibiotics or \u03b12-agonist treatment are usually the first choices where \nclinical management demands drugs.\nBALDNESS \u2003AND \u2003HIRSUTISM\n\u25bc There are two main types of baldness, male-pattern baldness \n(androgenic alopecia) and alopecia areata . Androgenic alopecia is caused \nby rising androgen levels and so particularly affects men after puberty; \nit starts with bi-temporal recession and progresses. Androgens inhibit Skin \nSkin is the largest and heaviest organ in the body. It is \ncomposed of three main components:\u2022\tThe epidermis . This is the outermost layer and is \ncomprised of four layers of keratinocytes with interspersed melanocytes. Keratinocytes divide in the basal layer and migrate upwards to the skin surface where they form cornified layers. Lipids in the \nextracellular spaces confer water-repellent properties.\n\u2022\tThe dermis . The middle layer is of variable thickness. It \nconsists of fibroblasts that produce structural \ncomponents such as collagen and elastin as well as immunocompetent cells. Hair follicles and sweat \nglands are also embedded in this layer and it is \ndensely innervated with nerves, blood vessels and lymphatics.\n\u2022\tThe subdermis (hypodermis or hypocutis). This \ncomprises connective tissue and varying amounts of adipose tissue.\nSkin has four main functions:\u2022\tA barrier . Skin prevents the egress or ingress of water, \nother chemicals and microorganisms. It also acts as a \nmechanical and thermal barrier and a shock absorber.\n\u2022\tThermoregulation. Vasodilatation of the rich capillary \nnetwork of the skin, in combination with sweating, increases the loss of heat whilst vasoconstriction has \nthe reverse effect.\n\u2022\tVitamin D synthesis. In the presence of sunlight, \nvitamin D\n3 is synthesised by cells in the epidermal \nlayer.\n\u2022\tA sensory organ. Skin contains abundant sensory \nreceptors for touch, heat, cold, pain and itch. \nInformation arising from these dermal receptors is one of the chief ways in which we interact with the outside world.\n3However, the number of men", "start_char_idx": 3456, "end_char_idx": 6988, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a8660e44-52bc-4ad4-9760-9edd6dd38360": {"__data__": {"id_": "a8660e44-52bc-4ad4-9760-9edd6dd38360", "embedding": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2a2a91fd-6f7f-4200-978b-f5cf9cf5fe17", "node_type": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e0f6395b6a5307ad7ffccd0a7460494a22714ef850069931265bd94d743c388"}, "2": {"node_id": "bb583aca-80cd-4f04-a610-e8267b714021", "node_type": null, "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a99344c1a33e024e2f3d969c2a0725585f07f4e232ae9dd2f172b039712e5a65"}}, "hash": "35c463323bfc70cc392a0c62303372b6f601877fcf3ec12836c32673c814f4a9", "text": "chief ways in which we interact with the outside world.\n3However, the number of men suffering from the condition is rising because \nof the popularity of skin piercing. If body art is your thing, insist on \nhigh-quality nickel-free jewellery.\n4Not to be confused with miliaria (prickly heat), which is caused by blocked \nsweat glands.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6968, "end_char_idx": 7781, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1493a537-b32e-4b0f-94aa-8205550e1b8c": {"__data__": {"id_": "1493a537-b32e-4b0f-94aa-8205550e1b8c", "embedding": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a0a224d3-33a8-45fc-913d-d248a20473c1", "node_type": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c2a7f7f030658656897556102151898d1f4f9cd7f3111c0f7213c1e8bc7f6d2"}, "3": {"node_id": "26a96f42-6296-4244-86d2-9bce8884a2d1", "node_type": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6aa828838a3715d139c1ba0a02b71bc1381518c07c9a3fb5f0bfcf3b5df79fb5"}}, "hash": "9b2372020811cba57b7e7d99e4a2a0140e339b6ddf71899f703ba8b1c277cb6e", "text": "28 SECTION \u20033\u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n366DRUGS \u2003ACTING \u2003ON \u2003SKIN\nFORMULATION\nTargeting drugs to the skin is both easy and difficult. Unlike \nmost therapeutic situations, drugs can be applied directly \nto the diseased tissue in ointments, solutions, creams, pastes \nor dusting powders, etc. There is an important caveat, however: since skin is a highly effective barrier, it can \nprevent the entry of many medicinal agents and this can \npose a problem. To reach its site of action (often the lower layer of the epidermis or the dermis), a drug has to pass \nthrough the epidermal layer with its highly enriched lipid \nand aqueous environment. The transdermal delivery of drugs is therefore a highly specialised topic (see Ch. 9). Generally speaking, absorption is facilitated if the molecule \nis predominately hydrophobic in nature: thus, for example, \nglucocorticoids are often derivatised with fatty acid esters to render them more easily absorbed. The use of a water -\nproof occlusion dressing to cover the skin after applying the \ndrug improves absorption by keeping the epidermis fully hydrated.\nThe vehicle in which the drug is dissolved is also impor -\ntant. Creams and ointments \u2013 essentially stable oil/water emulsions \u2013 can be tailored to individual drugs. For example, \ntacrolimus formulated as an ointment can be used topically \non the skin, whilst an oil-in-water is better for a water-\nsoluble drug such as an NSAID. The appearance and odour \nof the formulated drug are also important. Most patients \nwould rather take a tablet than apply creams that may be greasy, smelly or unsightly to large areas of skin (see Tan \net al., 2012).\nThe physical condition of the skin is important in \nmaintaining its barrier function and various agents can \nbe used to protect the skin and promote repair. These \ninclude emollients, which re-hydrate the skin and barrier \ncreams that help to prevent damage from irritants. Use \nof such agents is often indicated alongside treatment \nwith drugs.\nMany new ideas for formulating drugs for passage across \nthe skin are under investigation, including the use of \n\u2018nanocarriers\u2019 and other sophisticated chemical measures \n(see Reis et al., 2017).\nPRINCIPAL \u2003DRUGS \u2003USED \u2003IN \u2003SKIN \u2003\nDISORDERS\nMany drugs in the dermatological arsenal are also used to treat other diseases and their mechanism of action is the \nsame. The use of agents described below to treat specific \nskin disorders is shown in Table 28.1. We refer the reader to other chapters in the book where information about \nthese agents may be found. Other drugs, such as analogues \nof vitamins A and D, are rather specific to skin pharmacology.\nANTIMICROBIAL \u2003AGENTS\nChapters 51\u201356 deal in depth with the mechanism of action of this group of drugs. Antibiotics can be applied topically \nin diseases such as impetigo and acne, or given systemically \nin the case of cellulitis or rosacea. Fungal infections of the skin are generally treated with topical fungicidal drugs \nbut oral preparations of ketoconazole may be used under \nsome circumstances. Herpes simplex infections may be Urticaria is associated with inflammatory changes in the dermis, \nincluding mast cell degranulation and the accompanying release \nof mediators. It may co-exist with a related condition, angio-oedema, \nwhich primarily affects the blood vessels of the subdermal layer. \nUrticaria can resolve relatively rapidly or can persist for weeks ( chronic \nurticaria). The disorder can be difficult to manage and even gluco -\ncorticoids, which suppress most inflammatory responses, are usually ", "start_char_idx": 0, "end_char_idx": 3582, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "26a96f42-6296-4244-86d2-9bce8884a2d1": {"__data__": {"id_": "26a96f42-6296-4244-86d2-9bce8884a2d1", "embedding": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a0a224d3-33a8-45fc-913d-d248a20473c1", "node_type": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c2a7f7f030658656897556102151898d1f4f9cd7f3111c0f7213c1e8bc7f6d2"}, "2": {"node_id": "1493a537-b32e-4b0f-94aa-8205550e1b8c", "node_type": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9b2372020811cba57b7e7d99e4a2a0140e339b6ddf71899f703ba8b1c277cb6e"}, "3": {"node_id": "d559b59f-ce00-4480-b889-c5ab6bf3407a", "node_type": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0b550d945da7eb617b0428c30b341d6a0c5237fcf166363fbd9841ef9102798"}}, "hash": "6aa828838a3715d139c1ba0a02b71bc1381518c07c9a3fb5f0bfcf3b5df79fb5", "text": "-\ncorticoids, which suppress most inflammatory responses, are usually \nineffective.\nPSORIASIS\n\u25bc Aside from atopic dermatitis, psoriasis is the most common \ninflammatory skin disease affecting about 2%\u20133% of Europeans. It is an autoimmune condition and a genetic component and several \nsusceptibility loci have been identified, most of which are connected \nwith the operation of the immune system. Cytokines such as TNF, IL-17 and IL-23 are involved in the inflammatory mechanism and \nanti-cytokine biopharmaceuticals can be used to treat severe manifesta -\ntions of the disease (see Ch. 7). Histologically, it manifests as inflam -\nmation accompanied by hyper-proliferation of keratinocytes. This leads to an accumulation of scaly dead skin at the sites of the disease. \nThe most common form is plaque psoriasis. This presents as areas of \nscaly silvery-white skin surrounded by red margins. The distribution is usually quite characteristic, with plaques first appearing on the knees and elbows. The lesions may be painful and are sometimes \nitchy (in fact the word \u2018psoriasis\u2019 originates from Greek and literally \nmeans \u2018itchy skin\u2019, though in contrast to eczema, itch is by no means a predominant symptom).\nPsoriasis can also affect the fingernails, giving a \u2018pitted\u2019 appearance, \nand/or the joints (typically but not exclusively the distal inter-\nphalangeal joints) or other connective tissue ( psoriatic arthritis).\nPsoriasis is generally a life-long condition but one that can appear \nand disappear for no apparent reason. Stress is said to be a precipitating \nfactor, as is dry skin. Several drugs (e.g. \u03b2-adrenoceptor antagonists, \nNSAIDs and lithium ) are purported to precipitate bouts of the disease \n(Basavaraj et al., 2010).\nWARTS\n\u25bc Warts are caused by infection with one of the many types of human \npapilloma virus (HPV). They are characterised by small raised lesions \nwith an irregular shape. As infection of the epidermis by the virus \ncauses hyperkeratinisation, they also have a \u2018rough\u2019 feel.\nThe many varieties of HPV are usually specific for particular tissues, so different strains give rise to different types of warts at diverse \nanatomical locations. The most common type is usually found on hands and feet (e.g. as verrucas). Other types of HPV specifically \ninfect the anogenital region, giving anogenital warts.\nMost warts are benign in nature and disappear spontaneously after \na period of time (usually weeks\u2013months). However, some types of \nHPV are linked to cancers such as cervical cancer. It is hoped that, in time, immunisation against HPV will reduce the incidence of this \ndisease.\nOTHER \u2003INFECTIONS\n\u25bc In addition to acne and rosacea, there are a number of other \nimportant bacterial skin infections that can be treated with appropriate \nantibiotics, either topical or systemic. These include superficial skin \ninfections such as erysipelas and impetigo, and cellulitis, which is a \nmore deep-seated infection mainly involving the dermis and subdermis usually of the lower limbs.\nFungal infections of the skin are a common problem. Tinea, candida \nand other infections (see Ch. 54) affect skin at several sites (e.g. tinea \npedis \u2013 \u2018athlete\u2019s foot\u2019). These infections are easy to catch and can be \ndifficult to eradicate completely.\nThe most common viral infections affecting the skin are herpes simplex \n(cold sores) and herpes zoster (shingles), which can be treated with \nantiviral drugs (see Ch. 53). The most common parasite infections of \nthe skin are head lice (", "start_char_idx": 3521, "end_char_idx": 7030, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d559b59f-ce00-4480-b889-c5ab6bf3407a": {"__data__": {"id_": "d559b59f-ce00-4480-b889-c5ab6bf3407a", "embedding": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a0a224d3-33a8-45fc-913d-d248a20473c1", "node_type": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6c2a7f7f030658656897556102151898d1f4f9cd7f3111c0f7213c1e8bc7f6d2"}, "2": {"node_id": "26a96f42-6296-4244-86d2-9bce8884a2d1", "node_type": null, "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6aa828838a3715d139c1ba0a02b71bc1381518c07c9a3fb5f0bfcf3b5df79fb5"}}, "hash": "f0b550d945da7eb617b0428c30b341d6a0c5237fcf166363fbd9841ef9102798", "text": "53). The most common parasite infections of \nthe skin are head lice ( Pedicuclus humanis capitus ), crab lice ( Pthirus \npubis) and scabies (Sarcoptes scabiei).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7023, "end_char_idx": 7662, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e18e2ef9-c14c-4020-8105-58d517ff89b2": {"__data__": {"id_": "e18e2ef9-c14c-4020-8105-58d517ff89b2", "embedding": null, "metadata": {"page_label": "373", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2503914f-7267-407a-a479-c26316ddcb18", "node_type": null, "metadata": {"page_label": "373", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "996da6343d8c8324ee334b7ca01f38a05dda9f70fb6cbc5a8e4fb686fb3ba713"}, "3": {"node_id": "2225c5a7-d8fb-4597-b448-ba37729c5d13", "node_type": null, "metadata": {"page_label": "373", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6e22a3db8f4afa5422fc47408a5b64c515e89d3292aae764260b2ed8887100e3"}}, "hash": "a765d344e3c6ae61a2da8a64898e60725f428cf4784f6c76d52438f406538364", "text": "28 SkIN\n367The choice of glucocorticoid depends upon the severity of \nthe disease and, because the thickness of skin varies from one \nlocation to the other, its anatomical site. They are sometimes \nused in combination with antibacterial or fungicidal drugs if they are to be used at the site of an infection.\nThe action of glucocorticoids on the skin is similar in \nmechanism to their effect elsewhere in the body. They are potent inhibitors of the release of inflammatory mediators \nfrom mast cells, of neutrophil activation and emigration, \nand immune cell activation (see Chs 7 and 27). Their topical application produces vasoconstriction in the skin causing a characteristic \u2018blanching\u2019 reaction.\n5 The mechanism is \nunknown.\nUnwanted effects. Generally speaking, short-term treat -\nment with low potency steroid preparations is safe; some \nhydrocortisone formulations are available from pharmacies \nwithout prescription. There are potentially serious side effects associated with prolonged usage or with the more \npotent members of the class, however. These include:\n\u2022\tSteroid \u2018rebound\u2019. If topical steroid therapy is suddenly \ndiscontinued, the underlying disease often returns in a \nmore aggressive form. This is probably because the \nglucocorticoid receptor is down-regulated during topical treatment and can no longer respond to \ncirculating glucocorticoids, which maintain an \nanti-inflammatory \u2018tone\u2019, when treatment is withdrawn. Gradually tapering the drug can avoid this problem.\n\u2022\tSkin atrophy. Catabolic effects of glucocorticoids (Ch. 34) can lead to atrophy of the skin, including stretch marks (striae) and small visible vessels \n(telangiectases), that is only partially reversible upon \nstopping treatment.\n\u2022\tSystemic effects. Systemic absorption can theoretically cause depression of the hypothalamic\u2013pituitary\u2013\nadrenal axis, as described in Ch. 34, but this does not \nseem to constitute a significant risk in normal clinical \npractice (Castela et al., 2012).\n\u2022\tSpread of infection. Because glucocorticoids suppress the immune system, there is a danger that they may \nencourage or reactivate infection. For this reason they \nare contraindicated in acne, where there is a co-existent infection.\n\u2022\t\u2018Steroid rosacea\u2019 (skin reddening and pimples) is a recognised problem when treating facial skin with potent glucocorticoids.\nFor more serious cases of eczema or psoriasis or where glucocorticoids are ineffective, topical or systemic applica -\ntion of immunosuppressants such as ciclosporin, pime-\ncrolimus or tacrolimus may be successful (Ch. 27). The use \n(often \u2018off label\u2019) of biopharmaceuticals such as adalimumab \nand infliximab and other \u2018cytokine modulators\u2019 by special -\nists in severe cases is increasing and looks very promising \n(see Williams, 2012; Noda et al., 2015).\nDRUGS \u2003USED \u2003TO \u2003CONTROL \u2003HAIR \u2003GROWTH\nHair growth in both sexes is driven by androgens but so is male-pattern baldness. Because of this, androgen antago -\nnists, or compounds that modulate androgen metabolism, can be used to treat both hirsutism in women and androgenic alopecia in men.treated with topical or systemic acyclovir or penciclovir \n(see Ch. 53).\nGLUCOCORTICOIDS \u2003AND \u2003OTHER \u2003\nANTI-INFLAMMATORY \u2003AGENTS\nAs one might predict, antihistamines (Ch. 18) are useful when controlling mild pruritus, at least in some circum -\nstances, e.g. eczema, insect bites and mild inflammation. Another topical drug which is useful in treating", "start_char_idx": 0, "end_char_idx": 3442, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2225c5a7-d8fb-4597-b448-ba37729c5d13": {"__data__": {"id_": "2225c5a7-d8fb-4597-b448-ba37729c5d13", "embedding": null, "metadata": {"page_label": "373", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2503914f-7267-407a-a479-c26316ddcb18", "node_type": null, "metadata": {"page_label": "373", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "996da6343d8c8324ee334b7ca01f38a05dda9f70fb6cbc5a8e4fb686fb3ba713"}, "2": {"node_id": "e18e2ef9-c14c-4020-8105-58d517ff89b2", "node_type": null, "metadata": {"page_label": "373", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a765d344e3c6ae61a2da8a64898e60725f428cf4784f6c76d52438f406538364"}}, "hash": "6e22a3db8f4afa5422fc47408a5b64c515e89d3292aae764260b2ed8887100e3", "text": "bites and mild inflammation. Another topical drug which is useful in treating pruritus is crotamiton . This acts rapidly and has long-lasting effects. \nThe mechanism of action is not known.\nHowever, the main agents for treating inflammation of \nthe skin are the glucocorticoids. These drugs are widely \nused to treat psoriasis, eczema and to suppress pruritus. \nTheir general mechanism of action is described in Chapters 3, 27 and 34. Preparations used in dermatological practice are often formulated as fatty acid esters of the active drugs. \nThis promotes their absorption through the highly hydro-\nphobic layers of the skin but also alters their efficacy: for example, the potency of topical hydrocortisone on the skin \nis greatly enhanced by formulating it as a butyrate ester.\n\u25bc Whilst schemes around the world vary, the convention is to classify \nthese drugs by potency. For example:\n\u2022\tMild, e.g. hydrocortisone;\n\u2022\tModerate, e.g. alclometasone dipropionate, clobetasone \nbutyrate, fludroxycortide and fluocortolone;\n\u2022\tPotent, e.g. beclomethasone dipropionate, betamethasone \n(various esters) fluocinolone acetonide, fluocinonide, \nfluticasone propionate, mometasone fuorate and triamcinolone \nacetonide;\n\u2022\tVery potent, e.g. clobetasol propionate and diflucortolone \nvalerate.5This interesting observation was used by Cornell and Stoughton in \n1985 as the basis for the first quantitative assay of glucocorticoid \npotency in man.Drugs and the skin \nFormulation. Because the skin comprises a unique \ncombination of hydrophobic/hydrophilic structures, many drugs are not absorbed and special formulations may be \nnecessary to promote penetration.\nMany drugs used for skin conditions are also used to \ntreat disorders in other organs. The main groups are:\n\u2022\tGlucocorticoids. Widely used to treat psoriasis, \neczema and pruritus because of their anti-inflammatory \nproperties. They are usually specially formulated to enhance topical penetration.\n\u2022\tAntimicrobial agents. Used topically or systemically to treat skin infections (e.g. acne, impetigo, cellulitis and \nrosacea).\n\u2022\tHormone antagonists . Androgen antagonists are used \ntopically or systemically to treat male-pattern baldness \nor hirsutism in women.\n\u2022\tVitamin D derivatives. Drugs such as calcitriol, \ncalcipotriol and tacalcitol are used to treat psoriasis.Some drugs are used almost exclusively for skin \ndisorders. These include:\u2022\tRetinoids. These are derivatives of vitamin A and \ninclude tretinoin, isotretinoin, alitretinoin, \ntazarotene and adapalene. They are used to treat \nacne, eczema and psoriasis. They are usually given \ntopically, but can be given systemically.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3365, "end_char_idx": 6484, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "40b11b6c-769b-4b0b-8a10-ef756b4dbf77": {"__data__": {"id_": "40b11b6c-769b-4b0b-8a10-ef756b4dbf77", "embedding": null, "metadata": {"page_label": "374", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e56c139d-2ce7-4b49-a279-c0ca63b87e2c", "node_type": null, "metadata": {"page_label": "374", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e091ac9f87f013bb23a0e17b240d69fc66c575cb95dafd46934e42489c034525"}, "3": {"node_id": "169497ec-3c6b-4b7a-b440-e050accb0628", "node_type": null, "metadata": {"page_label": "374", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c58882285c011c6ff63b3d710525d09cec061b93d14f2faff9afe4346a9209f"}}, "hash": "820ee3b6673a1f5ac662a9c7569e136ff9ebe768feab854cf6ad84ec1b52d08d", "text": "28 SECTION \u20033\u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n368are few but some local irritation may occur. Hair loss recurs \nwhen topical application is discontinued.\nRETINOIDS\nDisturbances in vitamin A metabolism are known to result in skin pathology. The vitamin is normally acquired in \nester form from dietary sources. It is converted to retinol \nin the gut and this seems to be a storage form of the vitamin.\nVitamin A has many biological roles. As retinal, it is an \nessential component of rhodopsin and hence crucial for \nnormal vision. However, it can also undergo an irreversible oxidation to retinoic acid, which lacks any effects on the \nvisual system, but has potent effects on skin homeostasis.\nThe retinoid drugs are derivatives of retinoic acid (Fig. \n28.2). The principal examples are acitretin, adapalene, \nalitretinoin, isotretinoin, tretinoin , tazarotene. They are \nwidely used (sometimes in combination with other drugs) \nfor the treatment of acne, eczema and psoriasis. Topical application is the usual route of administration but oral \ntherapy is sometimes used for severe cases.\nMost workers believe that retinoids act by binding to \nRXR and RAR nuclear receptors (see Ch. 3 and Fig. 28.2) in their target cells, which include keratinocytes and the \ncells of sebaceous glands, although some have questioned this mechanism (Arechalde & Saurat, 2000). Retinoid binding \nproteins (RBP) on the surface of, and within, the cell aid \nin transport of the molecule to its receptor and facilitate its eventual catabolism ( Napoli, 2017). The main dermato -\nlogical actions of retinoids include modulation of epidermal cell growth and reduction in sebaceous gland activity and sebum production. They also have pleiotropic actions on \nthe adaptive and innate immune system that produce a \nnet anti-inflammatory effect (Fisher & Voorhees, 1996; \nOrfanos et al., 1997).Co-cyprindol is mixture of an anti-androgen, cyproterone \nacetate, and a female sex hormone, ethinylestrodiol. \nAntagonising androgenic actions reduces sebum production by sebaceous glands and also hair growth (which is androgen-dependent), so it can be used for treating acne \nas well as hirsutism in women. Unwanted effects include \nvenous thromboembolism and it is contraindicated in women with a family history of cardiovascular disease.\nFinasteride inhibits the enzyme (5 \u03b1-reductase) that \nconverts testosterone to the more potent androgen, dihydrotestosterone (see Ch. 36). It is used topically (usually in combination with minoxidil) for the treatment of \nandrogenic alopecia, as well as orally for prostatic hyper-trophy. The treatment takes months to produce real changes. Unwanted effects resulting from its action on androgen \nmetabolism include a reduction in libido, possibly impotence \nand tenderness of the breasts.\nEflornithine was originally developed as an antiprotozoal \ndrug (see Ch. 55). It can be used topically to treat hirsutism because it irreversibly inhibits ornithine decarboxylase in hair \nfollicles. This interrupts cell replication and the growth of \nnew hair. Unwanted effects include skin reactions and acne.\nMinoxidil is a vasodilator drug that was originally \ndeveloped for treating hypertension (see Ch. 23). Applied topically, it is converted in hair follicles to a more potent \nmetabolite, minoxidil sulfate (some preparations contain this salt). Perhaps because of its ability to increase blood \nsupply to hair follicles, it stimulates growth of new hair \nand the", "start_char_idx": 0, "end_char_idx": 3483, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "169497ec-3c6b-4b7a-b440-e050accb0628": {"__data__": {"id_": "169497ec-3c6b-4b7a-b440-e050accb0628", "embedding": null, "metadata": {"page_label": "374", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e56c139d-2ce7-4b49-a279-c0ca63b87e2c", "node_type": null, "metadata": {"page_label": "374", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e091ac9f87f013bb23a0e17b240d69fc66c575cb95dafd46934e42489c034525"}, "2": {"node_id": "40b11b6c-769b-4b0b-8a10-ef756b4dbf77", "node_type": null, "metadata": {"page_label": "374", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "820ee3b6673a1f5ac662a9c7569e136ff9ebe768feab854cf6ad84ec1b52d08d"}}, "hash": "2c58882285c011c6ff63b3d710525d09cec061b93d14f2faff9afe4346a9209f", "text": "blood \nsupply to hair follicles, it stimulates growth of new hair \nand the progression of the new follicle through successive phases of the cell cycle (Ch. 6). Existing follicles, usually stalled in their resting (telogen) phase, must first be \u2018shed\u2019 \nto make way for new, rapidly growing follicles, so initial \nhair loss following treatment is a frequent, unwelcome \u2013 and rather alarming \u2013 action of the drug. Other unwanted effects \n+ OpsinRetinol dehydrogenases\nRetinaldehyde dehydrogenases\nTretinoin\nIsotretinoin\nAlitretinoin\nTazarotene\nAdapaleneRhodopsinVitamin A and\ncarotenes in the dietRetinol\n(Vitamin A)\nRetinal\n(retinaldehyde)\nRetinoic acid\nRXRRAR\nNuclear transcription\nKeratinocyte and epithelial cell differentiationReduction in size of sebaceous glandsReduction in sebumInhibition of leukocyte activation and migrationFig. 28.2 The retinoid pathway. Vitamin \nA (retinol) is acquired largely through dietary \nsources and is reversibly converted to retinal (retinaldehyde). This may be combined with opsin to produce the visual pigment rhodopsin or irreversibly oxidised to retinoic acid. The latter species can interact with nuclear receptors (RXR and RAR; see Ch. 3) to produce changes in genes that modulate keratinocyte differentiation, reduce the size and output of sebaceous glands and exert a general anti-inflammatory action. The synthetic congeners acitretin, adapalene, alitretinoin, isotretinoin, tazarotene and tretinoin can act at the RXR and RAR, also producing potent actions in skin disorders such as acne and psoriasis. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3409, "end_char_idx": 5438, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7cf3b775-7cdc-4dd1-83d9-b8d14f6e7e22": {"__data__": {"id_": "7cf3b775-7cdc-4dd1-83d9-b8d14f6e7e22", "embedding": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c93fb2d6-62ef-47ab-8067-d60ad4126c05", "node_type": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97ec766491f46a169b3c62a7177523f15bc1348e9c4ce3cb295eb8df32353e70"}, "3": {"node_id": "1a134d3c-9374-4f7e-bceb-b8efce6586a8", "node_type": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19f00ff67d8e1111ab10b4eace9f025ed3bdf2e6bbc31698fd817dca716f64b1"}}, "hash": "2c79ac7b2bfcac46b175b7f43ab7be7bdf9f9620fa876aaca6d35ba73fbed09d", "text": "28 SkIN\n369mechanism of action is unknown, they can bring about a \nuseful therapeutic benefit in eczema, psoriasis and some \nother skin conditions, and are often the first agents to be \ntried. As one might expect, given their origin, coal tars contain carcinogenic substances but in clinical use, the risk \nappears to be slight (Roelofzen et al., 2010). Preparations \ncontaining coal tars are applied topically.\nAmongst other drugs unique to skin pharmacology are \nsalicylic acid and podophyllotoxin. Topical salicylic acid has a keratolytic effect in situations when excess skin is being \nproduced (e.g. warts), causing epidermal layers to be shed. \nIt is a common ingredient of numerous proprietary wart \nremovers. Podophyllotoxin is a toxin extracted from plants of the podophyllum family. It is usually reserved for treating \nanogenital warts. It is applied topically and prevents the \nexcess growth of skin, probably because it inhibits tubulin polymerisation and hence arrests the normal cell cycle.\nAnother agent used for anogenital warts is imiquimod. \nThis drug is an immune modifier and is also used for the topical treatment some types of skin cancer (e.g. basal cell carcinoma). Its mechanism of action is not known but it \nmay increase immune surveillance mechanisms. Unwanted \neffects include local skin reactions.\nCONCLUDING \u2003REMARKS\nDespite the plethora of preparations available to treat skin disorders, there is clearly still an unfilled therapeutic need \nin several areas (e.g. rosacea) and, as always, reducing the \nunwanted effects of existing drugs is a further worthwhile objective that would greatly enhance their clinical utility. \nSome of the most interesting ideas have arisen from \nreconsidering the design of the glucocorticoids, vitamin D analogues and especially the retinoids. All these drugs act \npredominantly through nuclear receptors and recent think -\ning suggests that differentiating the mechanisms of tran-\nsrepression and transactivation of genes by these drugs may be an achievable goal. Clearly, the prospect of separat -\ning the calcaemic from the anti-inflammatory effects of vitamin D analogues (Tremezaygues & Reichrath, 2011) \nand improving the selectivity of retinoids (Orfanos et al., \n1997) are very attractive therapeutic goals. Progress towards separating the useful from the unwanted effects of the \nglucocorticoids is already apparently yielding fruit (see \nCh. 34 for a discussion of this).\nIt is perhaps surprising that \u2018itch\u2019 is still such a problem. \nVarious new drug targets (e.g. NK\n1-receptor antagonists, \nsee Ch. 19) have been identified for treating chronic itch \n(reviewed in Benecke et al., 2013) but have not yet reached \nthe market.\nThe search for new drugs to treat psoriasis and atopic \ndermatitis has largely focused upon the actions of biop -\nharmaceuticals and the use of other immunomodulatory \ndrugs (see Gniadecki & Calverley, 2002; Pastore et al., 2008; \nNoda et al., 2015).Unwanted effects. After oral administration, retinoids \nmay cause dry or flaky skin, stinging or burning sensations \nand joint pains, possibly because they can activate the TRPV1 \nreceptor; (Yin et al., 2013). Retinoids are teratogenic (this is \nlinked to the effects of retinoids on epidermal differentiation \nthat underlie their efficacy) and can be used in women only \nin the presence of suitable contraception (see Chs 36 & 58).\nVITAMIN \u2003D \u2003ANALOGUES\nVitamin D is actually a mixture of several related substances. \nAlthough classed as a \u2018vitamin\u2019 and therefore by implication \nan essential", "start_char_idx": 0, "end_char_idx": 3555, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1a134d3c-9374-4f7e-bceb-b8efce6586a8": {"__data__": {"id_": "1a134d3c-9374-4f7e-bceb-b8efce6586a8", "embedding": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c93fb2d6-62ef-47ab-8067-d60ad4126c05", "node_type": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97ec766491f46a169b3c62a7177523f15bc1348e9c4ce3cb295eb8df32353e70"}, "2": {"node_id": "7cf3b775-7cdc-4dd1-83d9-b8d14f6e7e22", "node_type": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c79ac7b2bfcac46b175b7f43ab7be7bdf9f9620fa876aaca6d35ba73fbed09d"}, "3": {"node_id": "c9b277bd-2725-4034-9582-3c58f4ebd2c1", "node_type": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5067d8a8ca8a3b0638d5ab7299ca30b7d7125ae66b0d600fba986d42cb16cdfa"}}, "hash": "19f00ff67d8e1111ab10b4eace9f025ed3bdf2e6bbc31698fd817dca716f64b1", "text": "classed as a \u2018vitamin\u2019 and therefore by implication \nan essential dietary factor, vitamin D 3 (cholecalciferol) is \nsynthesised by the skin in the presence of sufficient sunlight (in fact, phototherapy is an important therapeutic modality \nin some skin disorders for this and other reasons). Other forms of the vitamin (e.g. D\n2) can be obtained from the \ndiet. The vitamin plays a crucial role in calcium and \nphosphate metabolism and bone formation (see Ch. 37). It \nalso has complex regulatory actions on the immune system, reducing the activity of the adaptive system but increasing \nthe activity of the innate immune system (Di Filippo et al., \n2015; Trochoutsou et al., 2015).\nThe biologically active metabolite calcitriol (see Ch. 37) \nis synthesised in the body by a multi-step process that \nrequires transformations in the liver and kidney (Fig. 37.4). \nAt the molecular level, vitamin D and its analogues act though the VDR group of nuclear receptors (Ch. 3) in \nkeratinocytes, fibroblasts, Langerhans cells and sebaceous \ngland cells, to modulate gene transcription. Amongst the effects seen after treatment are antiproliferative and pro-\ndifferentiation actions on keratinocytes, increased apoptosis \nof plaque keratinocytes (Tiberio et al., 2009) and the inhibi -\ntion of T-cell activation (Tremezaygues & Reichrath, 2011).\nThe main analogues used are calcitriol itself, calcipotriol \nand tacalcitol. Their principal clinical use is treating pso -\nriasis. Oral administration is possible but they are generally administered topically, sometimes in combination with a \nglucocorticoid.\nUnwanted effects. There is always a concern about the \npossible effects of the drugs on bone and they should be \navoided in patients who have problems related to calcium \nor bone metabolism. Topical application can lead to skin irritation.\nAGENTS \u2003ACTING \u2003BY \u2003OTHER \u2003\nMECHANISMS\nMany ancillary agents are used in dermatology, including topical antiseptics, emollients, soothing lotions and other \nsubstances. Amongst this group are \u2018 coal tars\u2019, which are \npoorly defined mixtures containing thousands of aromatic \nhydrocarbons generated during the conversion of coal to \ncoke or gas and which contain chemicals that formed the \nbasis for many early medicines. Coal tars have been used in dermatological practice for decades. Though their \nREFERENCES \u2003AND \u2003FURTHER \u2003READING\nAntal, A.S., Dombrowski, Y., Koglin, S., Ruzicka, T., Schauber, J., 2011. \nImpact of vitamin D3 on cutaneous immunity and antimicrobial \npeptide expression. Dermatoendocrinol. 3, 18\u201322. (This paper explores \nthe idea that, in addition to their protective role, antimicrobial peptides (cathelicidins) in the skin may actually cause some skin diseases such as rosacea. The paper also suggests that the inhibitory action of vitamin D analogues on cathelicidin production is a potential mechanism of action of \nthese drugs)\nArechalde, A., Saurat, J.H., 2000. Management of psoriasis: the position \nof retinoid drugs. Biodrugs 13, 327\u2013333. (Discusses the therapeutic action mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3500, "end_char_idx": 6850, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c9b277bd-2725-4034-9582-3c58f4ebd2c1": {"__data__": {"id_": "c9b277bd-2725-4034-9582-3c58f4ebd2c1", "embedding": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c93fb2d6-62ef-47ab-8067-d60ad4126c05", "node_type": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97ec766491f46a169b3c62a7177523f15bc1348e9c4ce3cb295eb8df32353e70"}, "2": {"node_id": "1a134d3c-9374-4f7e-bceb-b8efce6586a8", "node_type": null, "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19f00ff67d8e1111ab10b4eace9f025ed3bdf2e6bbc31698fd817dca716f64b1"}}, "hash": "5067d8a8ca8a3b0638d5ab7299ca30b7d7125ae66b0d600fba986d42cb16cdfa", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6859, "end_char_idx": 7082, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "38b0312b-c1ff-41b4-a9cb-7c259e93ff5b": {"__data__": {"id_": "38b0312b-c1ff-41b4-a9cb-7c259e93ff5b", "embedding": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9f846438-e0d8-4572-af11-f2f4672c1978", "node_type": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bbcd822dc7751f866918c7435b0554c68fa42604421d2ce903794e872a4090d2"}, "3": {"node_id": "55550297-5007-4947-a0ac-e4180523ac11", "node_type": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ede63c9cc9972c6d45dd2138b1f0b8ee05249464d6c03af4d578422f4d6fcb7e"}}, "hash": "aadf107741ab7383ec9b9dd8760585db99f3fd6417d91c7a24dc9e4c2de1e40f", "text": "28 SECTION\u20033 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n370Noda, S., Krueger, J.G., Guttman-Yassky, E., 2015. The translational \nrevolution and use of biologics in patients with inflammatory skin \ndiseases. J. Allergy Clin. Immunol. 135, 324\u2013336. ( Useful review of the \nuse of biologics in skin diseases focusing on psoriasis and atopic dermatitis. \nSome useful diagrams. The immunology is somewhat high powered )\nNolan, K.A., Marmur, E.S., 2012. Over-the-counter topical skincare \nproducts: a review of the literature. J. Drugs Dermatol. 11, 220\u2013224.\nOrfanos, C.E., Zouboulis, C.C., Almond-Roesler, B., Geilen, C.C., 1997. \nCurrent use and future potential role of retinoids in dermatology. \nDrugs 53, 358\u2013388.\nPastore, S., Gubinelli, E., Leoni, L., Raskovic, D., Korkina, L., 2008. \nBiological drugs targeting the immune response in the therapy of \npsoriasis. Biologics 2, 687\u2013697.\nReis, C.P., Rijo, P., Pereira, P., Antunes, A.F., 2017. Nanosystems for skin \ndelivery: from drugs to cosmetics. Curr. Drug Metab. 18, 412\u2013425.\nRitter, J.M., 2012. Drugs and the skin: psoriasis. Br. J. Clin. Pharmacol. \n74, 393\u2013395. ( Succinct and easily readable introduction to the treatment of \npsoriasis focusing on the role of cytokines in the disease mechanism and the \nutility of new biologicals. Good diagram. Highly recommended )\nRoelofzen, J.H., Aben, K.K., Oldenhof, U.T., et al., 2010. No increased \nrisk of cancer after coal tar treatment in patients with psoriasis or \neczema. J. Invest. Dermatol. 130, 953\u2013961.\nSchoepe, S., Schacke, H., May, E., Asadullah, K., 2006. Glucocorticoid \ntherapy-induced skin atrophy. Exp. Dermatol. 15, 406\u2013420. ( Good review \nof one of what is one of the main adverse effects of glucocorticoid therapy for skin \ndisorders, together with a discussion of how this can be minimised )\nTan, X., Feldman, S.R., Chang, J., Balkrishnan, R., 2012. Topical drug \ndelivery systems in dermatology: a review of patient adherence \nissues. Expert Opin. Drug Deliv. 9, 1263\u20131271.\nTiberio, R., Bozzo, C., Pertusi, G., et al., 2009. Calcipotriol induces \napoptosis in psoriatic keratinocytes. Clin. Exp. Dermatol. 34, 972\u2013974.\nTremezaygues, L., Reichrath, J., 2011. Vitamin D analogs in the \ntreatment of psoriasis: Where are we standing and where will we be \ngoing? Dermatoendocrinol. 3, 180\u2013186. ( A very useful account of the \nbiosynthesis and role of vitamin D and the action of its analogues in the \nregulation of skin inflammation. Recommended )\nTrochoutsou, A.I., Kloukina, V., Samitas, K., Xanthou, G., 2015. \nVitamin-D in the immune system: genomic and non-genomic actions. \nMini Rev. Med. Chem. 15, 953\u2013963.\nWilliams, S.C., 2012. New biologic drugs get under the skin of psoriasis. \nNat. Med. 18, 638. ( One-pager. Short account of the latest candidate \nbiologicals used in the treatment of psoriasis )\nYamasaki, K., Gallo,", "start_char_idx": 0, "end_char_idx": 2840, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "55550297-5007-4947-a0ac-e4180523ac11": {"__data__": {"id_": "55550297-5007-4947-a0ac-e4180523ac11", "embedding": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9f846438-e0d8-4572-af11-f2f4672c1978", "node_type": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bbcd822dc7751f866918c7435b0554c68fa42604421d2ce903794e872a4090d2"}, "2": {"node_id": "38b0312b-c1ff-41b4-a9cb-7c259e93ff5b", "node_type": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aadf107741ab7383ec9b9dd8760585db99f3fd6417d91c7a24dc9e4c2de1e40f"}, "3": {"node_id": "9d472aba-135d-48cd-804a-044e8eb403fb", "node_type": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f0b8866fd98acae5dbb206f77cd3048b95c599a3bb9841fea424fc0466c0b7f"}}, "hash": "ede63c9cc9972c6d45dd2138b1f0b8ee05249464d6c03af4d578422f4d6fcb7e", "text": "used in the treatment of psoriasis )\nYamasaki, K., Gallo, R.L., 2011. Rosacea as a disease of cathelicidins and \nskin innate immunity. J. Investig. Dermatol. Symp. Proc. 15, 12\u201315. \n(Could be read in conjunction with the paper by Antal et al. \u2013 above )\nYin, S., Luo, J., Qian, A., et al., 2013. Retinoids activate the irritant \nreceptor TRPV1 and produce sensory hypersensitivity. J. Clin. Invest. \n123, 3941\u20133951.of retinoids, especially tazarotene, and concludes that the mechanism of \naction is not exclusively through binding to RXR and RAR receptors )\nBasavaraj, K.H., Ashok, N.M., Rashmi, R., Praveen, T.K., 2010. The role \nof drugs in the induction and/or exacerbation of psoriasis. Int. J. \nDermatol. 49, 1351\u20131361. ( The title here is self-explanatory. Also explores \nthe mechanisms by which drugs provoke the disease )\nBenecke, H., Lotts, T., Stander, S., 2013. Investigational drugs for \npruritus. Expert Opin. Investig. Drugs 22, 1167\u20131179. ( Could be read in \nconjunction with the paper by Ikoma et al. \u2013 below )\nBergstresser, P.R., Taylor, J.R., 1977. Epidermal \u2018turnover time\u2019 \u2013 a new \nexamination. Br. J. Dermatol. 96, 503\u2013509.\nCastela, E., Archier, E., Devaux, S., et al., 2012. Topical corticosteroids in \nplaque psoriasis: a systematic review of risk of adrenal axis \nsuppression and skin atrophy. J. Eur. Acad. Dermatol. Venereol. 26 \n(Suppl. 3), 47\u201351. ( This is a systemic literature review of the area and an \nanalysis of data from many studies )\nCornell, R.C., Stoughton, R.B., 1985. Correlation of the vasoconstriction \nassay and clinical activity in psoriasis. Arch. Dermatol. 121, 63\u201367.\nDi Filippo, P., Scaparrotta, A., Rapino, D., et al., 2015. Vitamin D \nsupplementation modulates the immune system and improves atopic \ndermatitis in children. Int. Arch. Allergy Immunol. 166, 91\u201396. ( The \ntitle is self-explanatory but this paper also explains how vitamin D alters the \nimmune system. Easy to read )\nFisher, G.J., Voorhees, J.J., 1996. Molecular mechanisms of retinoid \nactions in skin. FASEB J. 10, 1002\u20131013. ( Easy-to-read very readable \nreview of retinoid action in the skin and a discussion of in vitro and in vivo \nmodels of retinoid action )\nGniadecki, R., Calverley, M.J., 2002. Emerging drugs in psoriasis. Expert \nOpin. Emerg. Drugs 7, 69\u201390. ( Deals mainly with biological and \nanticytokine drugs as potential new therapies )\nGreaves, M.W., Khalifa, N., 2004. Itch: more than skin deep. Int. Arch. \nAllergy Immunol. 135, 166\u2013172.\nIkoma, A., Steinhoff, M., Stander, S., Yosipovitch, G., Schmelz, M., 2006. \nThe neurobiology of itch. Nat. Rev. Neurosci. 7, 535\u2013547. ( A \ncomprehensive review of the neural pathways and local mediators of pruritus \nand itch. Excellent diagrams. Highly recommended )\nJames, K.A., Burkhart, C.N., Morrell, D.S., 2009. Emerging drugs for \nacne. Expert Opin. Emerg.", "start_char_idx": 2792, "end_char_idx": 5628, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9d472aba-135d-48cd-804a-044e8eb403fb": {"__data__": {"id_": "9d472aba-135d-48cd-804a-044e8eb403fb", "embedding": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9f846438-e0d8-4572-af11-f2f4672c1978", "node_type": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bbcd822dc7751f866918c7435b0554c68fa42604421d2ce903794e872a4090d2"}, "2": {"node_id": "55550297-5007-4947-a0ac-e4180523ac11", "node_type": null, "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ede63c9cc9972c6d45dd2138b1f0b8ee05249464d6c03af4d578422f4d6fcb7e"}}, "hash": "2f0b8866fd98acae5dbb206f77cd3048b95c599a3bb9841fea424fc0466c0b7f", "text": "2009. Emerging drugs for \nacne. Expert Opin. Emerg. Drugs 14, 649\u2013659.\nKlinge, S.A., Sawyer, G.A., 2013. Effectiveness and safety of topical \nversus oral nonsteroidal anti-inflammatory drugs: a comprehensive \nreview. Phys. Sportsmed. 41, 64\u201374.\nNaldi, L., Raho, G., 2009. Emerging drugs for psoriasis. Expert Opin. \nEmerg. Drugs 14, 145\u2013163.\nNapoli, J.L., 2017. Cellular retinoid binding-proteins, CRBP, CRABP, \nFABP5: Effects on retinoid metabolism, function and related diseases. \nPharmacol. Ther. 173, 19\u201333. ( Interesting review about the role of \nintracellular binding proteins in retinoid action. Worth reading if you want \nto dig deeper into the subject )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5626, "end_char_idx": 6767, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0db6b405-14c9-426a-9a74-d405c5b2c690": {"__data__": {"id_": "0db6b405-14c9-426a-9a74-d405c5b2c690", "embedding": null, "metadata": {"page_label": "377", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "815d6d58-84ca-4333-b064-eaec6d93b51f", "node_type": null, "metadata": {"page_label": "377", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "18c880e7f9014601f9c655ee5419930900147de03245565443d4a1aa22ec9958"}, "3": {"node_id": "98db308d-bff8-4c64-b516-53be4ea2e184", "node_type": null, "metadata": {"page_label": "377", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29c0ee54fd844761f72eed82a444d64cd7013f418856ff549e96176018f9ee3d"}}, "hash": "839034293c43afde81dcc7d500360bafb56857b671c1fdef9439baa3a414ca24", "text": "371\nRespiratory system 29 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3\nOVERVIEW\nBasic aspects of respiratory physiology (regulation \nof airway smooth muscle, pulmonary vasculature and \nglands) are considered as a basis for a discussion of \npulmonary disease and its treatment. We devote most of the chapter to asthma, dealing first with patho -\ngenesis and then the main drugs used in its treatment and prevention \u2013 inhaled bronchodilators and anti-inflammatory agents. We also discuss chronic obstruc -\ntive pulmonary disease (COPD), as well as idiopathic pulmonary fibrosis. There are short sections on allergic emergencies, surfactants and the treatment of cough. \nOther important pulmonary diseases, such as bacterial \ninfections (e.g. tuberculosis and acute pneumonias) and malignancies, are addressed in Chapters 52 and \n57, respectively. Antihistamines, important in treatment \nof hay fever, are covered in Chapter 27 and pulmonary \nhypertension is discussed in Chapter 23.\nTHE PHYSIOLOGY OF RESPIRATION\nCONTROL OF BREATHING\nRespiration is controlled by spontaneous rhythmic dis -\ncharges from the respiratory centre in the medulla, modu -\nlated by input from pontine and higher central nervous \nsystem (CNS) centres and vagal afferents from the lungs. Various chemical factors affect the respiratory centre, \nincluding the partial pressure of carbon dioxide in arterial \nblood (P\nACO 2) by an action on medullary chemoreceptors, \nand of oxygen (P AO2) by an action on the chemoreceptors \nin the carotid bodies.\nSome voluntary control can be superimposed on the \nautomatic regulation of breathing, implying connections between the cortex and the motor neurons innervating the \nmuscles of respiration. Bulbar poliomyelitis and certain \nlesions in the brain stem result in loss of the automatic regulation of respiration without loss of voluntary \nregulation.\n1\nREGULATION OF MUSCULATURE, BLOOD \nVESSELS AND GLANDS OF THE AIRWAYS\nIrritant receptors and non-myelinated afferent nerve fibres \nrespond to chemical irritants and cold air, and also to inflammatory mediators. Efferent pathways controlling the airways include cholinergic parasympathetic nerves and \nnon-noradrenergic non-cholinergic (NANC) inhibitory \nnerves (see Ch. 13). Inflammatory mediators (see Ch. 18) and other bronchoconstrictor mediators also have a role \nin diseased airways.\nThe tone of bronchial muscle influences airway resistance, \nwhich is also affected by the state of the mucosa and activity of the submucosal mucus-secreting glands in patients with \nasthma and bronchitis. Airway resistance can be measured indirectly by instruments that record the volume or flow \nof forced expiration. FEV\n1 is the forced expiratory volume \nin 1 second. The peak expiratory flow rate (PEFR) is the maximal flow (expressed as L/min) after a full inhalation; \nthis is simpler to measure at the bedside than FEV\n1, which \nit follows closely.\nEFFERENT PATHWAYS\nAutonomic innervation\nThe autonomic innervation of human airways is reviewed by van der Velden and Hulsmann (1999).\nParasympathetic innervation. Parasympathetic innerva -\ntion of bronchial smooth muscle predominates. Parasym -\npathetic ganglia are embedded in the walls of the bronchi and bronchioles, and the postganglionic fibres innervate airway smooth muscle, vascular smooth muscle and glands. \nFive types of muscarinic (M) receptors are present (see Ch. \n14, Table 14.2). M\n3 receptors are", "start_char_idx": 0, "end_char_idx": 3429, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "98db308d-bff8-4c64-b516-53be4ea2e184": {"__data__": {"id_": "98db308d-bff8-4c64-b516-53be4ea2e184", "embedding": null, "metadata": {"page_label": "377", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "815d6d58-84ca-4333-b064-eaec6d93b51f", "node_type": null, "metadata": {"page_label": "377", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "18c880e7f9014601f9c655ee5419930900147de03245565443d4a1aa22ec9958"}, "2": {"node_id": "0db6b405-14c9-426a-9a74-d405c5b2c690", "node_type": null, "metadata": {"page_label": "377", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "839034293c43afde81dcc7d500360bafb56857b671c1fdef9439baa3a414ca24"}}, "hash": "29c0ee54fd844761f72eed82a444d64cd7013f418856ff549e96176018f9ee3d", "text": "present (see Ch. \n14, Table 14.2). M\n3 receptors are pharmacologically the most \nimportant in airways disease. They are found on bronchial \nsmooth muscle and gland cells, and mediate bronchocon-\nstriction and mucus secretion. M 1 receptors are localised \nin ganglia and on postsynaptic cells, and facilitate nicotinic \nneurotransmission, whereas M 2 receptors are inhibitory \nautoreceptors mediating negative feedback on acetylcholine release by postganglionic cholinergic nerves. Stimulation \nof the vagus causes bronchoconstriction \u2013 mainly in the larger airways. The possible clinical relevance of the het -\nerogeneity of muscarinic receptors in the airways is discussed later.\nA distinct population of NANC nerves (see Ch. 13) also \nregulates the airways. Bronchodilators released by these nerves include vasoactive intestinal polypeptide (Table 13.2) \nand nitric oxide (NO; Ch. 21).\nSympathetic innervation. Sympathetic nerves innervate \ntracheobronchial blood vessels and glands, but not human \nairway smooth muscle. However, \u03b2 adrenoceptors are \nabundantly expressed on human airway smooth muscle \n(as well as mast cells, epithelium, glands and alveoli) and \n\u03b2 agonists relax bronchial smooth muscle, inhibit mediator \nrelease from mast cells and increase mucociliary clearance. \nIn humans, \u03b2 adrenoceptors in the airways are of the \u03b2 2 \nvariety.\nIn addition to the autonomic innervation, non-myelinated \nsensory fibres, linked to irritant receptors in the lungs, \n1Referred to as Ondine curse. Ondine was a water nymph who fell in \nlove with a mortal. When he was unfaithful to her, the king of the \nwater nymphs put a curse on him \u2013 that he must stay awake in order to \nbreathe. When exhaustion finally supervened and he fell asleep, he died. Such patients are treated with mechanical ventilation. In less \nextreme forms, patients whose respiratory centre is relatively insensitive \nhypoventilate and become hypoxic when they fall asleep, leading to multiple awakenings during the night.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3377, "end_char_idx": 5855, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1163f046-24db-49c6-865b-2d73ae9f4fd7": {"__data__": {"id_": "1163f046-24db-49c6-865b-2d73ae9f4fd7", "embedding": null, "metadata": {"page_label": "378", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "64944609-b757-4709-8db1-18b98a8841a2", "node_type": null, "metadata": {"page_label": "378", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "05f98254cd56cf7b07a1d9d9574db349e1bee6a0dbfb00526cb37744bf28f6f4"}, "3": {"node_id": "7706e9fd-ab33-4677-a28e-c995476ef7e1", "node_type": null, "metadata": {"page_label": "378", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3c1eb4657ddc01a7523c72876007669f5c514fa4eb26f49500e369c3e0f54a1b"}}, "hash": "e36554e924cef86242068c4b7e70f93ab42777b60977192aa569c4c337859f4d", "text": "29 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n372an inflammatory condition in which there is recurrent \nreversible airways obstruction in response to irritant \nstimuli that are too weak to affect non-asthmatic subjects. \nThe obstruction usually causes wheeze and merits drug treatment,\n2 although the natural history of asthma includes \nspontaneous remissions. Reversibility of airways obstruction \nin asthma contrasts with COPD, where the obstruction is \neither not reversible or at best incompletely reversible by \nbronchodilators.\nCHARACTERISTICS OF ASTHMA\nAsthmatic patients experience intermittent attacks of wheez -\ning, shortness of breath \u2013 with difficulty especially in \nbreathing out \u2013 and, sometimes, cough. As explained earlier, \nacute attacks are reversible, but the underlying pathological disorder can progress in older patients to a chronic state \nsuperficially resembling COPD.\nAcute severe asthma (also known as status asthmaticus ) \nis not easily reversed and causes hypoxaemia. Hospitalisa -\ntion is necessary, as the condition, which can be fatal, \nrequires prompt and energetic treatment.\nAsthma is characterised by:\n\u2022\tinflammation \tof \tthe \tairways\n\u2022\tbronchial \thyper-reactivity\n\u2022\treversible \tairways \tobstruction\nBronchial hyper-reactivity (or hyper-responsiveness) is abnormal sensitivity to a wide range of stimuli, such as \nirritant chemicals, cold air and stimulant drugs, all of which \ncan result in bronchoconstriction. In allergic asthma, these features may be initiated by sensitisation to allergen(s), \nbut, once established, asthma attacks can be triggered by \nvarious stimuli such as viral infection, exercise (in which the stimulus may be cold air and/or drying of the airways) \nand atmospheric pollutants such as sulfur dioxide. Immu -\nnological desensitisation to allergens such as pollen or dust \nmites is popular in some countries but is not superior to conventional inhaled drug treatment.\nPATHOGENESIS OF ASTHMA\nThe pathogenesis of asthma involves both genetic and environmental factors, and the asthmatic attack itself \nconsists, in many subjects, of two main phases: an immediate \nand a late (or delayed) phase (Fig. 29.1).\nNumerous cells and mediators play a part, and the full \ndetails of the complex events involved are still a matter of debate (Walter & Holtzman, 2005). The following simplified account is intended to provide a basis for understanding \nthe rational use of drugs in the treatment of asthma.\nAsthmatics have activated T cells, with a T-helper (Th)2 \nprofile of cytokine production (see Ch. 19 and Table 19.2) \nin their bronchial mucosa. How these cells are activated is \nnot fully understood, but allergens (Fig. 29.2) are one \nmechanism. The Th2 cytokines that are released do the following:\n\u2022\tAttract \tother \tinflammatory \tgranulocytes, \tespecially \t\neosinophils, to the mucosal surface. Interleukin (IL)-5 release tachykinins such as substance P, neurokinin A and \nneurokinin B (see Ch. 19), producing neurogenic inflammation.\nSENSORY RECEPTORS AND AFFERENT PATHWAYS\nSlowly adapting stretch receptors control respiration via the \nrespiratory centre. Unmyelinated sensory C fibres and rapidly \nadapting irritant receptors associated with myelinated vagal \nfibres are also important.\nPhysical or chemical stimuli, acting on irritant receptors \non myelinated fibres in the upper airways and/or C-fibre receptors in the lower airways, cause coughing, broncho", "start_char_idx": 0, "end_char_idx": 3435, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7706e9fd-ab33-4677-a28e-c995476ef7e1": {"__data__": {"id_": "7706e9fd-ab33-4677-a28e-c995476ef7e1", "embedding": null, "metadata": {"page_label": "378", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "64944609-b757-4709-8db1-18b98a8841a2", "node_type": null, "metadata": {"page_label": "378", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "05f98254cd56cf7b07a1d9d9574db349e1bee6a0dbfb00526cb37744bf28f6f4"}, "2": {"node_id": "1163f046-24db-49c6-865b-2d73ae9f4fd7", "node_type": null, "metadata": {"page_label": "378", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e36554e924cef86242068c4b7e70f93ab42777b60977192aa569c4c337859f4d"}}, "hash": "3c1eb4657ddc01a7523c72876007669f5c514fa4eb26f49500e369c3e0f54a1b", "text": "receptors in the lower airways, cause coughing, broncho -\nconstriction and mucus secretion. Such stimuli include cold \nair and irritants such as ammonia, sulfur dioxide, cigarette \nsmoke and the experimental tool capsaicin (Ch. 43), as well \nas endogenous inflammatory mediators.\nRegulation of airway muscle, blood \nvessels and glands \nAfferent pathways\n\u2022\tIrritant\treceptors \tand \tC \tfibres \trespond \tto \texogenous \t\nchemicals, \tinflammatory \tmediators \tand \tphysical \tstimuli \t\n(e.g.\tcold\tair).\nEfferent pathways\n\u2022\tParasympathetic \tnerves \tcause \tbronchoconstriction \t\nand\tmucus \tsecretion \tthrough \tM3\treceptors.\n\u2022\tSympathetic \tnerves \tinnervate \tblood \tvessels \tand \t\nglands,\tbut \tnot \tairway \tsmooth \tmuscle.\n\u2022\t\u03b22-Adrenoceptor \tagonists \trelax \tairway \tsmooth \tmuscle. \t\nThis\tis\tpharmacologically \timportant.\n\u2022\tInhibitory \tnon-noradrenergic \tnon-cholinergic \t(NANC) \t\nnerves\trelax \tairway \tsmooth \tmuscle \tby \treleasing \tnitric \t\noxide\tand \tvasoactive \tintestinal \tpeptide.\n\u2022\tExcitation \tof \tsensory \tnerves \tcauses \tneuroinflammation \t\nby\treleasing \ttachykinins: \tsubstance \tP \tand \tneurokinin \t\nA.\n2William Osler, 19th-century doyen of American and British clinicians, \nwrote that \u2018the asthmatic pants into old age\u2019 \u2013 this at a time when the \nmost effective drug that he could offer was to smoke stramonium \ncigarettes, a herbal remedy, the antimuscarinic effects of which were offset by direct irritation from the smoke. Its use persisted in English \nprivate schools into the 1950s, as one author can attest \u2013 much to the \nenvy of his fellows!PULMONARY DISEASE AND ITS \nTREATMENT\nCommon symptoms of pulmonary disease include shortness \nof breath, wheeze, chest pain and cough with or without \nsputum production or haemoptysis (blood in the sputum). \nIdeally, treatment is of the underlying disease, but some -\ntimes symptomatic treatment, for example of cough, is all \nthat is possible. The lung is an important target organ of \nmany diseases addressed elsewhere in this book, including infections (Chs 52\u201356), malignancy (Ch. 57) and occupational \nand rheumatological diseases; drugs (e.g. amiodarone, \nmethotrexate ) can damage lung tissue and cause pulmonary \nfibrosis. Heart failure leads to pulmonary oedema (Ch. 23). \nThromboembolic disease (Ch. 25) and pulmonary hyperten -\nsion (Ch. 23) affect the pulmonary circulation. In this present chapter, we concentrate on two important diseases of the airways: asthma and COPD.\nBRONCHIAL ASTHMA\nAsthma affects about 8% of the population; it is the commonest chronic disease in children in economically \ndeveloped countries and is also common in adults. It is mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3380, "end_char_idx": 6476, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b20c8791-4499-4226-af4a-dee6ab4c94af": {"__data__": {"id_": "b20c8791-4499-4226-af4a-dee6ab4c94af", "embedding": null, "metadata": {"page_label": "379", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce9c2d14-b060-4245-832b-b9b154d2a2fb", "node_type": null, "metadata": {"page_label": "379", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb38bf8c056897a4e7b88ff802a19ec294d503dcae277b47c6326b1c1bc7c8eb"}, "3": {"node_id": "fe7d51e0-4b89-447a-ad21-6fef162bf78d", "node_type": null, "metadata": {"page_label": "379", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7465fadd7702ce3e77070d039fc84b48e1dd8bdf19a5a02b8bc0f1201a275476"}}, "hash": "6415f30d23aa95bc888d8682099baa37d4ced57819a47ae3117714f352cdfe0e", "text": "29 RESpIRATORY SYSTEM\n373and granulocyte\u2013macrophage colony-stimulating \nfactor prime eosinophils to produce cysteinyl \nleukotrienes (see Ch. 18), and to release granule \nproteins that damage the epithelium. This damage is one cause of bronchial hyper-responsiveness.\n\u2022\tPromote \timmunoglobulin \t(Ig)E \tsynthesis \tand \t\nresponsiveness in some asthmatics (IL-4 and IL-13 \u2018switch\u2019 B cells to IgE synthesis and cause expression \nof IgE receptors on mast cells and eosinophils; they \nalso enhance adhesion of eosinophils to endothelium).\nSome asthmatics, in addition to these mechanisms, are also atopic \u2013 that is, they make allergen-specific IgE that binds to mast cells in the airways. Inhaled allergen cross-links \nIgE molecules on mast cells, triggering degranulation with \n3.0\n2.52.01.51.0\n0\nHoursInhalation\nDiluent\nGrass pollen\nEarly phase:\nbronchospasmLate phase:\ninflammation\n12 34 5678FEV1 (L)\nFig. 29.1 \tTwo phases of asthma demonstrated by the \nchanges in forced expiratory volume in 1 second (FEV 1) \nafter inhalation of grass pollen in an allergic subject. \t(From\t\nCockcroft, \tD.W., \t1983. \tLancet \tii, \t253.)\nB\nBB\nPP\nIgE\nantibodies\nIL-4\nIL-5\nIL-13APC\nT\nCD4Th1\nTh2Th0\nGlucocorticoidsAllergen\nEosinophils Mast cells\nFig. 29.2 \tThe part played by T lymphocytes in allergic asthma. \tIn\tgenetically \tsusceptible \tindividuals, \tallergen \t(green circle) \tinteracts\t\nwith\tdendritic \tcells \tand \tCD4+\tT\tcells,\tleading \tto \tthe \tdevelopment \tof \tTh0 \tlymphocytes, \twhich \tgive \trise \tto \ta \tclone \tof \tTh2 \tlymphocytes. \tThese \t\nthen\t(1)\tgenerate \ta \tcytokine \tenvironment \tthat \tswitches \tB \tcells/plasma \tcells \tto \tthe \tproduction \tand \trelease \tof \timmunoglobulin \t(Ig)E; \t(2) \t\ngenerate\tcytokines, \tsuch \tas \tinterleukin \t(IL)-5, \twhich \tpromote \tdifferentiation \tand \tactivation \tof \teosinophils; \tand \t(3) \tgenerate \tcytokines \t(e.g. \t\nIL-4\tand\tIL-13) \tthat \tinduce \texpression \tof \tIgE \treceptors. \tGlucocorticoids \tinhibit \tthe \taction \tof \tthe \tcytokines \tspecified. \tAPC,\tantigen-\npresenting \tdendritic \tcell; \tB,\tB\tcell;\tP,\tplasma\tcell; \tTh,\tT-helper\tcell. \trelease of histamine and leukotriene B 4, both of which are \npowerful bronchoconstrictors to which asthmatics are espe -\ncially sensitive because of their airway hyper-responsiveness. \nThis provides a mechanism for acute exacerbation of asthma in atopic individuals exposed to allergen. The effectiveness \nof omalizumab (an anti-IgE antibody; see p. 378) serves \nto emphasise the importance of IgE in the pathogenesis of \nasthma as well as in other allergic diseases. Noxious gases \n(e.g. sulfur dioxide, ozone) and airway dehydration can \nalso cause mast cell degranulation.\nClinicians often refer to atopic or \u2018extrinsic\u2019", "start_char_idx": 0, "end_char_idx": 2692, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fe7d51e0-4b89-447a-ad21-6fef162bf78d": {"__data__": {"id_": "fe7d51e0-4b89-447a-ad21-6fef162bf78d", "embedding": null, "metadata": {"page_label": "379", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ce9c2d14-b060-4245-832b-b9b154d2a2fb", "node_type": null, "metadata": {"page_label": "379", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb38bf8c056897a4e7b88ff802a19ec294d503dcae277b47c6326b1c1bc7c8eb"}, "2": {"node_id": "b20c8791-4499-4226-af4a-dee6ab4c94af", "node_type": null, "metadata": {"page_label": "379", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6415f30d23aa95bc888d8682099baa37d4ced57819a47ae3117714f352cdfe0e"}}, "hash": "7465fadd7702ce3e77070d039fc84b48e1dd8bdf19a5a02b8bc0f1201a275476", "text": "or \u2018extrinsic\u2019 asthma and \nnon-atopic or \u2018intrinsic\u2019 asthma; we prefer the terms allergic \nand non-allergic.\nThe immediate phase of an asthma attack\nIn allergic asthma the immediate phase (i.e. the initial \nresponse to allergen provocation) occurs abruptly and is \nmainly caused by spasm of the bronchial smooth muscle. \nAllergen interaction with mast cell-fixed IgE causes release of histamine, leukotriene B\n4 and prostaglandin (PG)D 2 (Ch. 18).\nOther mediators released include IL-4, IL-5, IL-13, \nmacrophage inflammatory protein-1 \u03b1 and tumour necrosis \nfactor (TNF)-\u03b1.\nVarious chemotaxins and chemokines (see Ch. 19) attract \nleukocytes \u2013 particularly eosinophils and mononuclear cells \u2013 setting the stage for the late phase (Fig. 29.3).\nThe late phase\nThe late phase or delayed response (see Figs 29.1 and 29.3) may be nocturnal. It is, in essence, a progressing inflam -\nmatory reaction, initiation of which occurred during the first phase, the influx of Th2 lymphocytes being of particular importance. The inflammatory cells include activated \neosinophils. These release cysteinyl leukotrienes, interleukins \nIL-3, IL-5 and IL-8, and the toxic proteins eosinophil cationic \nprotein, major basic protein and eosinophil-derived neurotoxin . mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2678, "end_char_idx": 4404, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8dff6669-4227-47c9-bad0-94d908e6a304": {"__data__": {"id_": "8dff6669-4227-47c9-bad0-94d908e6a304", "embedding": null, "metadata": {"page_label": "380", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "541ea0b3-7f17-49b1-b58e-371af9362344", "node_type": null, "metadata": {"page_label": "380", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86d63945ba6073d214ad2eeb08f3412ebbbb0d3397a4d24a1f71922bcab39194"}, "3": {"node_id": "c17c4575-b16f-4aca-9f5e-cb9bbcbd2fa2", "node_type": null, "metadata": {"page_label": "380", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed839df787abe2b10173605bad9eb1801573429f672eeb741f98c53908c880d4"}}, "hash": "a3899eb4a276f637ad1d449c59576a8d71d031638977d7daf089079caf7bd150", "text": "29 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n374Immediate phase\nSpasmogens\ncysLTs,\nH, PGD 2Chemotaxins,\nchemokines\nBronchospasm\nReversed by\n\u03b22-adrenoceptor \nagonists, \nCysLT-receptor \nantagonists and \ntheophyllineLate phase\nMediators e.g.\ncysLTs,\nneuropeptides?,\nNO?, adenosine?EMBP, ECP Mast cells,\nmononuclear cellsEliciting agent:\nallergen or\nnon-specific stimulusInfiltration of \ncytokine-releasing Th2 cells, \nand monocytes, and activation \nof inflammatory cells, \nparticularly eosinophils\nAirway\ninflammationAirway\nhyper-reactivity\nBronchospasm,\nwheezing,\ncoughingEpithelial\ndamage\nInhibited by glucocorticoids\nFig. 29.3 \tImmediate and late phases of asthma, with the actions of the main drugs. \tCysLTs,\tcysteinyl\tleukotrienes\t (leukotrienes\t C4\t\nand\tD4);\tECP,\teosinophil\t cationic\tprotein;\t EMBP,\teosinophil\t major\tbasic\tprotein;\t H,\thistamine;\t iNO,\tinduced\tnitric\toxide.\t(For\tmore\tdetail\tof\t\nthe\tTh2-derived\t cytokines\t and\tchemokines,\t see\tCh.\t17\tand\tCh.\t6,\tFig.\t6.4.)Asthma \n\u2022\tAsthma\t is\tdefined\tas\trecurrent\t reversible\t airway\t\nobstruction,\t with\tattacks\tof\twheeze,\tshortness\t of\tbreath\t\nand,\toften,\tnocturnal\t cough.\tSevere\tattacks\tcause\t\nhypoxaemia\t and\tare\tlife-threatening.\n\u2022\tEssential\t features\tinclude:\n\u2013\tairways\t inflammation,\t which\tcauses\n\u2013\tbronchial\t hyper-responsiveness,\t which\tin\tturn\tresults\t\nin\n\u2013\trecurrent\t reversible\t airway\tobstruction\n\u2022\tPathogenesis\t involves\texposure\t of\tgenetically\t disposed\t\nindividuals\t to\tallergens;\t activation\t of\tTh2\tlymphocytes\t\nand\tcytokine\tgeneration\t promote:\n\u2013\tdifferentiation\t and\tactivation\t of\teosinophils\u2013\tIgE\tproduction\t and\trelease\n\u2013\texpression\t of\tIgE\treceptors\t on\tmast\tcells\tand\t\neosinophils\n\u2022\tImportant\t mediators\t include\tleukotriene\t B4\tand\tcysteinyl\t\nleukotrienes\t (C4\tand\tD4);\tinterleukins\t (IL)-4,\tIL-5,\tIL-13;\t\nand\ttissue-damaging\t eosinophil\t proteins.\n\u2022\tAntiasthmatic\t drugs\tinclude:\n\u2013\tbronchodilators\n\u2013\tanti-inflammatory\t agents\n\u2022\tTreatment\t is\tmonitored\t by\tmeasuring\t forced\texpiratory\t\nvolume\tin\t1\tsecond\t(FEV1)\tor\tpeak\texpiratory\t flow\trate\t\nand,\tin\tacute\tsevere\tdisease,\toxygen\tsaturation\t and\t\narterial\tblood\tgases.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2572, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c17c4575-b16f-4aca-9f5e-cb9bbcbd2fa2": {"__data__": {"id_": "c17c4575-b16f-4aca-9f5e-cb9bbcbd2fa2", "embedding": null, "metadata": {"page_label": "380", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "541ea0b3-7f17-49b1-b58e-371af9362344", "node_type": null, "metadata": {"page_label": "380", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86d63945ba6073d214ad2eeb08f3412ebbbb0d3397a4d24a1f71922bcab39194"}, "2": {"node_id": "8dff6669-4227-47c9-bad0-94d908e6a304", "node_type": null, "metadata": {"page_label": "380", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a3899eb4a276f637ad1d449c59576a8d71d031638977d7daf089079caf7bd150"}}, "hash": "ed839df787abe2b10173605bad9eb1801573429f672eeb741f98c53908c880d4", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2525, "end_char_idx": 2588, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "00213433-fb3f-4cd5-8ac2-25ccc164c45c": {"__data__": {"id_": "00213433-fb3f-4cd5-8ac2-25ccc164c45c", "embedding": null, "metadata": {"page_label": "381", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "353ab20d-9cfc-46bb-a680-0773c590de7e", "node_type": null, "metadata": {"page_label": "381", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33ead84adc2e11ca4eae3e7f3cc9f979389e7534e10d20e5424394c94380a2e9"}, "3": {"node_id": "8c717a93-d2e7-401b-b913-4c8108c03143", "node_type": null, "metadata": {"page_label": "381", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48de7049835725bb4aea71bf379211bf3713624ff8f1c968ec5ad04afa2dbace"}}, "hash": "af437d55ef07ce60b957571c4d32cfa0500cf96c1b99d03a824a6ecf6ce21331", "text": "29 RESpIRATORY SYSTEM\n3752016 ) specifies a stepwise approach for adults and children \nwith chronic asthma. Very mild disease may be treated \nwith short-acting bronchodilator (usually an inhaled short-\nacting \u03b22 agonist such as salbutamol or terbutaline, used \nas required), but if patients need this more than three times \na week, a regular inhaled corticosteroid should be added. \nIf the asthma remains uncontrolled, the next step is to add a long-acting bronchodilator (salmeterol or formoterol); \nand/or consider increased doses of inhaled corticosteroid. \nTheophylline, tiotropium (a long-acting muscarinic \nantagonist) or leukotriene antagonist (such as montelukast) \nare subsequent treatment options in patients who remain symptomatic. Addition of a regular oral corticosteroid (e.g. prednisolone) is recommended only in the small group of patients who do not achieve adequate control despite \nhigh-dose therapies with the other agents. Corticosteroids \nare the mainstay of therapy because they are the only asthma drugs that potently inhibit T-cell activation, and \nthus the inflammatory response, in the asthmatic airways. \nOmalizumab is an option in those with poorly controlled asthma despite treatment with oral corticosteroids. Cro-\nmoglicate (see p. 378) has only a weak effect and is now \nseldom used.\nBRONCHODILATORS\nThe main drugs used as bronchodilators are \u03b22-adrenoceptor \nagonists; others include theophylline, cysteinyl leukotriene \nreceptor antagonists and muscarinic receptor antagonists.\n\u03b2-Adrenoceptor agonists\nThe \u03b22-adrenoceptor agonists are dealt with in Chapter 15. \nTheir primary effect in asthma is to dilate the bronchi by \na direct action on the \u03b2 2 adrenoceptors of smooth muscle. \nBeing physiological antagonists of bronchoconstrictors (see Ch. 2), they relax bronchial muscle whatever spasmogen \nis involved. They also inhibit mediator release from mast cells and TNF- \u03b1 release from monocytes, and increase mucus \nclearance by an action on cilia.\n\u03b2\n2-Adrenoceptor agonists are usually given by inhalation \nof aerosol, powder or nebulised solution (i.e. solution that \nhas been converted into a cloud or mist of fine droplets), These play an important part in the events of the late phase, \nthe toxic proteins causing damage and loss of epithelium. \nOther putative mediators of the inflammatory process in \nthe delayed phase are adenosine (acting on the A 1 receptor; \nsee Ch. 17), induced NO (see Ch. 21) and neuropeptides \n(see Ch. 19).\nGrowth factors released from inflammatory cells act on \nsmooth muscle cells, causing hypertrophy and hyperplasia, and the smooth muscle can itself release proinflammatory \nmediators and growth factors (Chs 6 and 19). Fig. 29.4 shows schematically the changes that take place in the \nbronchioles. Epithelial cell loss means that irritant receptors \nand C fibres are more accessible to irritant stimuli \u2013 an important mechanism of bronchial hyper-reactivity.\n\u2018Aspirin-sensitive\u2019 asthma\n\u25bc Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin , \ncan precipitate asthma in sensitive individuals. Such aspirin-sensitive \nasthma (Ch. 27) is relatively uncommon ( <10% of asthmatic subjects), \nand is often associated with nasal polyps. Individuals sensitive to \none NSAID are usually also sensitive to other chemically unrelated \ncyclo-oxygenase (COX) inhibitors, sometimes including paracetamol \n(Ch. 27). Abnormal leukotriene production and sensitivity are \nimplicated. Patients with", "start_char_idx": 0, "end_char_idx": 3472, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8c717a93-d2e7-401b-b913-4c8108c03143": {"__data__": {"id_": "8c717a93-d2e7-401b-b913-4c8108c03143", "embedding": null, "metadata": {"page_label": "381", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "353ab20d-9cfc-46bb-a680-0773c590de7e", "node_type": null, "metadata": {"page_label": "381", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33ead84adc2e11ca4eae3e7f3cc9f979389e7534e10d20e5424394c94380a2e9"}, "2": {"node_id": "00213433-fb3f-4cd5-8ac2-25ccc164c45c", "node_type": null, "metadata": {"page_label": "381", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "af437d55ef07ce60b957571c4d32cfa0500cf96c1b99d03a824a6ecf6ce21331"}}, "hash": "48de7049835725bb4aea71bf379211bf3713624ff8f1c968ec5ad04afa2dbace", "text": "Abnormal leukotriene production and sensitivity are \nimplicated. Patients with aspirin-sensitive asthma produce more \ncysteinyl leukotriene and have greater airway hyper-responsiveness \nto inhaled cysteinyl leukotrienes than aspirin-tolerant asthmatics. \nSuch airway hyper-responsiveness reflects elevated expression of \ncysteinyl leukotriene receptors on inflammatory cells, and this is down-regulated by aspirin desensitisation. In addition, aspirin and \nsimilar drugs directly activate eosinophils and mast cells in these \npatients through IgE-independent mechanisms.\nDRUGS USED TO TREAT AND PREVENT ASTHMA\nThere are two categories of antiasthma drugs: bronchodilators \nand anti-inflammatory agents. Bronchodilators reverse the \nbronchospasm of the immediate phase; anti-inflammatory \nagents inhibit or prevent the inflammatory components of both phases (see Fig. 29.3). These two categories are not \nmutually exclusive: some drugs classified as bronchodilators \nalso have some anti-inflammatory effect.\nHow best to use these drugs to treat asthma is complex. \nA guideline on the management of asthma (BTS/SIGN, Submucosa\nMucosa\nInfiltration of \ninflammatory cells, (mononuclear cells, eosinophils, etc.)\nHypertrophied \nsmooth muscle\nMononuclear cell\nOedemaDilated blood vessels\nEosinophil\nMucus plug with \neosinophils and desquamated epithelial cellsEpithelium\nMast cellThickened basement membrane\nFig. 29.4 \tSchematic diagram of a cross-section of a bronchiole, showing changes that occur with severe chronic asthma. \tThe\t\nindividual\telements \tdepicted \tare \tnot, \tof \tcourse, \tdrawn \tto \tscale. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3394, "end_char_idx": 5476, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ebee6b9d-43df-472e-acad-17482764456e": {"__data__": {"id_": "ebee6b9d-43df-472e-acad-17482764456e", "embedding": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a469707f-687c-424d-a3d8-3e2b1c7830ac", "node_type": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f24458b94a9a00100f11571578de3568ab108d45778ae3e2090c7988aaa2312f"}, "3": {"node_id": "d7943bd1-1797-4ea6-bdd2-11e47589bfa4", "node_type": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "18a23f03b6d432c10480ae647f87f894ecccb0e687edf0aa374f2be5a9546c0b"}}, "hash": "fc9a052b1a171ab9612380cdae931aeccd2a3e6c3c5031d4c47837963f7aa13f", "text": "29 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n376but some products may be given orally or by injection. A \nmetered-dose inhaler is used for aerosol preparations.\nTwo categories of \u03b22-adrenoceptor agonists are used in \nasthma:\n\u2022\tShort-acting \tagents: \tsalbutamol and terbutaline. \nThese are given by inhalation; they act immediately, \npeaking within 30 min and the duration of action is \n3\u20135 h; they are usually used on an \u2018as needed\u2019 basis to \ncontrol symptoms.\n\u2022\tLonger-acting \tagents: \te.g. \tsalmeterol and formoterol. \nThese are given by inhalation, and the duration of \naction is 8\u201312 h. They are not used \u2018as needed\u2019 but are \ngiven regularly, twice daily, as adjunctive therapy in patients whose asthma is inadequately controlled by \nglucocorticoids.\nAntiasthma drugs: bronchodilators \n\u2022\t\u03b22-Adrenoceptor \tagonists \t(e.g. \tsalbutamol )\tare\t\nfirst-line\tdrugs \t(for \tdetails, \tsee \tCh. \t14):\n\u2013\tThey\tact \tas \tphysiological \tantagonists \tof \tthe \t\nspasmogenic \tmediators \tbut \thave \tlittle \tor \tno \teffect \t\non\tthe\tbronchial \thyper-reactivity.\n\u2013\tSalbutamol \tis \tgiven \tby \tinhalation; \tits \teffects \tstart \t\nimmediately \tand \tlast \t3\u20135 \th, \tand \tit \tcan \talso \tbe \tgiven \t\nby\tintravenous \tinfusion \tin \tstatus \tasthmaticus.\n\u2013\tSalmeterol \tor\tformoterol \tare\tgiven \tregularly \tby \t\ninhalation; \ttheir \tduration \tof \taction \tis \t8\u201312 \th.\n\u2022\tTheophylline \t(often\tformulated \tas \taminophylline):\n\u2013\tis\ta\tmethylxanthine;\n\u2013\tinhibits\tphosphodiesterase \tand \tblocks \tadenosine \t\nreceptors;\n\u2013\thas\ta\tnarrow \ttherapeutic \twindow: \tunwanted \teffects \t\ninclude\tcardiac \tdysrhythmia, \tseizures \tand \tGI \t\ndisturbances;\n\u2013\tis\tgiven \tintravenously \t(by \tslow \tinfusion) \tfor \tstatus \t\nasthmaticus, \tor \torally \t(as \ta \tsustained-release \t\npreparation) \tas \tadd-on \ttherapy \tto \tinhaled \t\ncorticosteroids \tand \tlong-acting \t\u03b22\tagonists\t(step \t4);\n\u2013\tis\tmetabolised \tin \tthe \tliver \tby \tP450; \tliver \tdysfunction \t\nand\tviral\tinfections \tincrease \tits \tplasma \tconcentration \t\nand\thalf-life \t(normally \tapproximately \t12 \th);\n\u2013\tinteracts \timportantly \twith \tother \tdrugs; \tsome \t(e.g. \t\nspecific\tantibiotics) \tincrease \tthe \thalf-life \tof \t\ntheophylline ,\tothers\t(e.g. \tanticonvulsants) \tdecrease \t\nit.\n\u2022\tCysteinyl \tleukotriene \treceptor \tantagonists \t(e.g. \t\nmontelukast )\tare\tthird-line \tdrugs", "start_char_idx": 0, "end_char_idx": 2282, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d7943bd1-1797-4ea6-bdd2-11e47589bfa4": {"__data__": {"id_": "d7943bd1-1797-4ea6-bdd2-11e47589bfa4", "embedding": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a469707f-687c-424d-a3d8-3e2b1c7830ac", "node_type": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f24458b94a9a00100f11571578de3568ab108d45778ae3e2090c7988aaa2312f"}, "2": {"node_id": "ebee6b9d-43df-472e-acad-17482764456e", "node_type": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc9a052b1a171ab9612380cdae931aeccd2a3e6c3c5031d4c47837963f7aa13f"}, "3": {"node_id": "3f55a4ff-e379-4832-bff9-4fb66488a6db", "node_type": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aeaa85187165a41a423498284054099a77f2b59d33436ec919e6cbd0c0d37f39"}}, "hash": "18a23f03b6d432c10480ae647f87f894ecccb0e687edf0aa374f2be5a9546c0b", "text": "\tfor \tasthma. \tThey:\n\u2013\tcompete \twith \tcysteinyl \tleukotrienes \tat \tCysLT 1\t\nreceptors;\n\u2013\tare\tused \tmainly \tas \tadd-on \ttherapy \tto \tinhaled \t\ncorticosteroids \tand \tlong-acting \t\u03b22\tagonists\t(step \t4).Clinical use of \u03b22-adrenoceptor \nagonists as bronchodilators \n\u2022\tShort-acting \tdrugs \t(salbutamol \tor\tterbutaline ,\t\nusually\tby \tinhalation) \tto \tprevent \tor \ttreat \twheeze \tin \t\npatients\twith \treversible \tobstructive \tairways \tdisease.\n\u2022\tLong-acting \tdrugs \t(salmeterol ,\tformoterol )\tto\t\nprevent\tbronchospasm \t(e.g. \tat \tnight \tor \twith \texercise) \t\nin\tpatients \trequiring \tlong-term \tbronchodilator \ttherapy.\n3Over 200 years ago, William Withering recommended \u2018coffee made \nvery strong\u2019 as a remedy for asthma. Coffee contains caffeine, a related \nmethylxanthine.Unwanted effects\nThe unwanted effects of \u03b22-adrenoceptor agonists result \nfrom systemic absorption and are given in Chapter 15. In \nthe context of their use in asthma, the commonest adverse \neffect is tremor; other unwanted effects include tachycardia \nand cardiac dysrhythmia.Methylxanthines (see Chs 17 and 49)\nTheophylline (1,3-dimethylxanthine), which is also used as theophylline ethylenediamine (known as aminophyl-\nline), is the main therapeutic drug of this class, and has long been used as a bronchodilator.\n3 Here we consider \nit in the context of respiratory disease, its only current \ntherapeutic use.\nMechanism of action\nThe mechanism of theophylline is still unclear. The relaxant \neffect on smooth muscle has been attributed to inhibition of phosphodiesterase (PDE) isoenzymes, with resultant \nincrease in cAMP and/or cGMP (see Ch. 4, Fig. 4.10). \nHowever, the concentrations necessary to inhibit the isolated enzymes exceed the therapeutic range of plasma concentrations.\nCompetitive antagonism of adenosine at adenosine A\n1 \nand A 2 receptors (Ch. 17) may contribute, but the PDE \ninhibitor enprofylline, which is a potent bronchodilator, \nis not an adenosine antagonist.\nType IV PDE is implicated in inflammatory cells, and \nmethylxanthines may have some anti-inflammatory effect. \n(Roflumilast, a type IV PDE inhibitor, is mentioned later \nin the context of COPD.)\nTheophylline activates histone deacetylase (HDAC), which \ncontrols gene expression and may thereby reverse resistance to the anti-inflammatory effects of corticosteroids (Barnes, \n2006).\nMethylxanthines stimulate the CNS (Ch. 49) and respira -\ntory stimulation may be beneficial in patients with COPD who suffer from reduced respiration and retention of CO\n2. \nCaffeine has a special niche in treating hypoventilation of \nprematurity (see Ch. 49).\nUnwanted effects\nWhen theophylline is used in asthma, its other actions (CNS, \ncardiovascular, gastrointestinal [GI] and diuretic) result in \nunwanted side effects (e.g. insomnia, nervousness). The \ntherapeutic plasma concentration range is 30\u2013100 \u00b5mol/L, \nand adverse effects are common with concentrations greater \nthan 110 \u00b5mol/L; thus there is a relatively narrow therapeutic \nwindow. Serious cardiovascular and CNS effects can occur \nwhen the plasma concentration", "start_char_idx": 2283, "end_char_idx": 5353, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3f55a4ff-e379-4832-bff9-4fb66488a6db": {"__data__": {"id_": "3f55a4ff-e379-4832-bff9-4fb66488a6db", "embedding": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a469707f-687c-424d-a3d8-3e2b1c7830ac", "node_type": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f24458b94a9a00100f11571578de3568ab108d45778ae3e2090c7988aaa2312f"}, "2": {"node_id": "d7943bd1-1797-4ea6-bdd2-11e47589bfa4", "node_type": null, "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "18a23f03b6d432c10480ae647f87f894ecccb0e687edf0aa374f2be5a9546c0b"}}, "hash": "aeaa85187165a41a423498284054099a77f2b59d33436ec919e6cbd0c0d37f39", "text": "Serious cardiovascular and CNS effects can occur \nwhen the plasma concentration exceeds 200 \u00b5mol/L. The most \nserious cardiovascular effect is dysrhythmia (especially during \nintravenous administration of aminophylline), which can be \nfatal. Seizures can occur with theophylline concentrations at mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5274, "end_char_idx": 6053, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "739cb91f-159f-460a-ab41-4a6419a42efc": {"__data__": {"id_": "739cb91f-159f-460a-ab41-4a6419a42efc", "embedding": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ab2c4201-02ce-470d-a446-362837220ef6", "node_type": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "38bc24dfb97dac1ff6e129f18fa1603e604627fdfc98b68189f1776467409382"}, "3": {"node_id": "51483530-5054-405f-b6de-36aeda132c45", "node_type": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e38190600ded824335e1ff1fdeb0cbf4bf5a836d5b8873c01c8e05457ff4742"}}, "hash": "22579901968ed9b99a519d3009ff2d17089b3ad892386fbd64b14957bf0edf69", "text": "29 RESpIRATORY SYSTEM\n377Long-acting muscarinic antagonists are also quaternary \nammonium compounds, designed to have greater selectivity \ntowards the M 3 receptor, and to dissociate from the receptor \nvery slowly, producing a sustained effect with regular daily dosing. They are often used together with long-acting \u03b2\n2-\nadrenoceptor agonists in a combined inhaler for patients with COPD.or slightly above the upper limit of the therapeutic range, \nand can be fatal in patients with impaired respiration due to \nsevere asthma. Monitoring the concentration of theophylline \nin plasma is useful for optimising the dose.\nClinical use of theophylline \n\u2022\tIn\taddition \tto \tsteroids, \tin \tpatients \twhose \tasthma \tdoes \t\nnot\trespond \tadequately \tto \t\u03b22-adrenoceptor \tagonists.\n\u2022\tIn\taddition \tto \tother \tbronchodilators \tand \tsteroids \tin \t\nchronic\tobstructive \tpulmonary \tdisease \t(COPD).\n\u2022\tIntravenously \t(as \taminophylline ,\ta\tcombination \tof \t\ntheophylline \twith\tethylenediamine \tto\tincrease \tits \t\nsolubility\tin \twater) \tin \tacute \tsevere \tasthma.Clinical use of inhaled muscarinic \nreceptor antagonists \n\u2022\tFor\tasthma, \tas \tan \tadjunct \tto \t\u03b22-adrenoceptor \tagonists \t\nand\tsteroids.\n\u2022\tFor\tpatients \twith \tchronic \tobstructive \tpulmonary \t\ndisease\t(COPD), \tespecially \tlong-acting \tdrugs \t(e.g. \t\ntiotropium).\n\u2022\tFor\tbronchospasm \tprecipitated \tby \t\u03b22-adrenoceptor \t\nantagonists.\n4In 1900, Solis-Cohen reported that dried bovine adrenals had \nanti-asthma activity. He noted that the extract did not serve acutely \u2018to \ncut short the paroxysm\u2019 but was \u2018useful in averting recurrence of \nparoxysms\u2019. Mistaken for the first report on the effect of adrenaline, his astute observation was probably the first on the efficacy of steroids in \nasthma.Pharmacokinetic aspects\nTheophylline is given orally as a sustained-release prepa -\nration. Aminophylline can be given by slow intravenous \ninjection of a loading dose followed by intravenous infusion.\nTheophylline is well absorbed from the GI tract. It is \nmetabolised by P450 enzymes in the liver; the mean elimina -\ntion half-life is approximately 8 h in adults but there is \nwide inter-individual variation. The half-life is increased \nin liver disease, cardiac failure and viral infections, and is \ndecreased in heavy cigarette smokers (as a result of enzyme \ninduction leading to increased clearance). Unwanted drug interactions are clinically important: its plasma concentration \nis decreased by drugs that induce P450 enzymes (including \nrifampicin , phenytoin and carbamazepine ). The concentra -\ntion is increased by drugs that inhibit P450 enzymes, such \nas erythromycin , clarithromycin , ciprofloxacin , diltiazem \nand fluconazole. This is important in view of the narrow \ntherapeutic window; antibiotics such as clarithromycin are \noften started when asthmatics are hospitalised because of \na severe attack precipitated by a chest infection, and if the \ndose of theophylline is unaltered, severe toxicity can result.\nMuscarinic receptor antagonists\nMuscarinic receptor antagonists are dealt with in Chapter 14. Ipratropium, given by aerosol inhalation is the only \nshort-acting muscarinic antagonist that is widely used", "start_char_idx": 0, "end_char_idx": 3174, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "51483530-5054-405f-b6de-36aeda132c45": {"__data__": {"id_": "51483530-5054-405f-b6de-36aeda132c45", "embedding": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ab2c4201-02ce-470d-a446-362837220ef6", "node_type": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "38bc24dfb97dac1ff6e129f18fa1603e604627fdfc98b68189f1776467409382"}, "2": {"node_id": "739cb91f-159f-460a-ab41-4a6419a42efc", "node_type": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "22579901968ed9b99a519d3009ff2d17089b3ad892386fbd64b14957bf0edf69"}, "3": {"node_id": "13a0f414-3e4f-44c0-8064-1a948232c4bb", "node_type": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "03ac3c15dad24d4f74d66a29f5aa49b7e20fc4130b03ddd190d20b36f8545053"}}, "hash": "8e38190600ded824335e1ff1fdeb0cbf4bf5a836d5b8873c01c8e05457ff4742", "text": "inhalation is the only \nshort-acting muscarinic antagonist that is widely used clinically as a bronchodilator. Inhaled long-acting muscarinic antagonists, such as tiotropium , aclidinium , umeclidinium , \nand glycopyrrolate, are now available.\nIpratropium is a quaternary derivative of atropine. It does \nnot discriminate between muscarinic receptor subtypes (see \nCh. 14), and it is possible that its blockade of M\n2 autorecep-\ntors on the cholinergic nerves increases acetylcholine release and reduces the effectiveness of its antagonism at the M\n3 \nreceptors on smooth muscle. It is not particularly effective against allergen challenge, but it inhibits the augmentation \nof mucus secretion that occurs in asthma and may increase the mucociliary clearance of bronchial secretions. It has no \neffect on the late inflammatory phase of asthma.\nIpratropium is a quaternary nitrogen compound, and \ntherefore highly polar and not well absorbed into the circula -\ntion (Ch. 9), limiting systemic effects. The maximum effect \noccurs approximately 30 min after inhalation and persists \nfor 3\u20135 h. It has few unwanted effects and is, in general, \nsafe and well tolerated. It can be used with \u03b22-adrenoceptor \nagonists, particularly in acute settings for symptomatic relief. See the clinical box later, for clinical uses.Cysteinyl leukotriene receptor antagonists\nCysteinyl leukotrienes (LTC 4, LTD 4 and LTE 4) act on CysLT 1 \nand CysLT 2 receptors (see Ch. 18), both of which are \nexpressed in respiratory mucosa and infiltrating inflam -\nmatory cells, but the functional significance of each is \nunclear. The \u2018lukast\u2019 drugs ( montelukast and zafirlukast) \nantagonise only CysLT 1.\nLukasts inhibit exercise-induced asthma and decrease \nboth early and late responses to inhaled allergen. They dilate the airways in mild asthma but are less effective than salbutamol, with which their action is additive. They \nreduce sputum eosinophilia, but there is no clear evidence \nthat they modify the underlying inflammatory process in chronic asthma.\nThe lukasts are taken by mouth, in combination with an \ninhaled corticosteroid. They are generally well tolerated, adverse effects consisting mainly of headache and GI disturbances.\nHistamine H 1-receptor antagonists\nAlthough mast cell mediators, including histamine, play a part in the immediate phase of allergic asthma (see Fig. \n29.3) and in some types of exercise-induced asthma, his -\ntamine H\n1-receptor antagonists have no routine place in \ntherapy, although they may be modestly effective in mild atopic asthma, especially when this is precipitated by acute \nhistamine release in patients with concomitant allergy such as severe hay fever.\nANTI-INFLAMMATORY AGENTS\nGlucocorticoids\nGlucocorticoids (see Ch. 34) are the main drugs used for their anti-inflammatory action in asthma. They are not \nbronchodilators, but prevent the progression of chronic \nasthma and are effective in acute severe asthma (see clinical \nbox, p. 378).\n4mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3107, "end_char_idx": 6434, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "13a0f414-3e4f-44c0-8064-1a948232c4bb": {"__data__": {"id_": "13a0f414-3e4f-44c0-8064-1a948232c4bb", "embedding": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ab2c4201-02ce-470d-a446-362837220ef6", "node_type": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "38bc24dfb97dac1ff6e129f18fa1603e604627fdfc98b68189f1776467409382"}, "2": {"node_id": "51483530-5054-405f-b6de-36aeda132c45", "node_type": null, "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e38190600ded824335e1ff1fdeb0cbf4bf5a836d5b8873c01c8e05457ff4742"}}, "hash": "03ac3c15dad24d4f74d66a29f5aa49b7e20fc4130b03ddd190d20b36f8545053", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6455, "end_char_idx": 6630, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b396bb95-bd8c-409b-8211-327ec9a6969b": {"__data__": {"id_": "b396bb95-bd8c-409b-8211-327ec9a6969b", "embedding": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c23dd4e-ecee-4e13-a6c1-b3877d418233", "node_type": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42cd4d38d98acb8ac2f90ac4a9cd29b4500011ccdac871e7429cb6d06cbc9af3"}, "3": {"node_id": "b57448e2-6858-4d89-8c36-4e6eb7a6f969", "node_type": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ffc823cea265be29137b8be0a6e3c20a4afe08247ccda342ca81a1aceac9148"}}, "hash": "83d59421cc351178bdb1df352f66f9f94c9a1b618a97052cfcd10b62d1de3a11", "text": "29 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n378effects and short duration of action. They are given by \ninhalation as aerosols or dry powders, and can also be \nused topically for allergic conjunctivitis or rhinitis. They \nare not bronchodilators, having no direct effects on smooth muscle, nor do they inhibit the actions of any of the known \nsmooth muscle stimulants. Given prophylactically, they \nreduce both the immediate- and late-phase asthmatic responses and reduce bronchial hyper-reactivity.\nTheir mechanism of action is not fully understood. \nCromoglicate is a \u2018mast cell stabiliser\u2019, preventing histamine release from mast cells. However, this is not the basis of its action in asthma, because compounds that are more \npotent than cromoglicate at inhibiting mast cell histamine \nrelease are ineffective against asthma.\nAnti-IgE treatment\nOmalizumab is a humanised monoclonal anti-IgE antibody. \nIt is effective in patients with allergic asthma as well as in \nallergic rhinitis. It is of considerable theoretical interest \n(see review by Holgate et al., 2005), but it is expensive and \nits clinical role is principally for those patients with severe \npersistent confirmed allergic IgE-mediated asthma who \nhave required continuous or frequent treatment with oral \ncorticosteroids despite use of other standard therapies.\nInhibition of interleukin-5\nEosinophilic asthma is a recognised variant for which specific therapies (such as mepolizumab or reslizumab) targeted \nat human IL-5 are now available. IL-5 is the key cytokine involved in growth, differentiation and activation of eosinophils. Antibodies that inhibit IL-5 signalling result \nin reduced production and survival of eosinophils that \nmediate the allergic inflammatory process in patients with asthma.\nDrugs in development\nThere are several novel agents targeted at mediators of eosinophilic airway inflammation (Bel & Ten Brinke, 2017). \nExamples of these cytokine targets and associated agents \nare IL-15 (tralokinumab), IL-4 (dupilumab) and thymic stromal lymphopoietin (tezepelumab). Inhibitors of pros-\ntaglandin D2 (see Fig. 29.3) are currently in clinical trials \n(fevipiprant and timapiprant).Actions and mechanism\nThe basis of the anti-inflammatory action of glucocorticoids \nis discussed in Chapter 34. An important action, of relevance \nfor asthma, is that they restrain clonal proliferation of Th \ncells by reducing the transcription of the gene for IL-2 and decrease formation of cytokines, in particular the Th2 \ncytokines that recruit and activate eosinophils and are \nresponsible for promoting the production of IgE and the expression of IgE receptors. Glucocorticoids also inhibit \nthe generation of the vasodilators PGE\n2 and PGI 2, by inhibit -\ning induction of COX-2 (Ch. 18, Fig. 18.3). By inducing annexin 1, (see Fig. 18.3) they could inhibit production of \nleukotrienes and platelet-activating factor, although there is currently no direct evidence that annexin 1 is involved \nin the therapeutic action of glucocorticoids in human asthma.\nCorticosteroids inhibit the allergen-induced influx of \neosinophils into the lung. Glucocorticoids up-regulate \u03b2\n2 \nadrenoceptors, decrease microvascular permeability and indirectly reduce mediator release from eosinophils by \ninhibiting the production of cytokines (e.g. IL-5 and granulocyte\u2013macrophage", "start_char_idx": 0, "end_char_idx": 3351, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b57448e2-6858-4d89-8c36-4e6eb7a6f969": {"__data__": {"id_": "b57448e2-6858-4d89-8c36-4e6eb7a6f969", "embedding": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c23dd4e-ecee-4e13-a6c1-b3877d418233", "node_type": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42cd4d38d98acb8ac2f90ac4a9cd29b4500011ccdac871e7429cb6d06cbc9af3"}, "2": {"node_id": "b396bb95-bd8c-409b-8211-327ec9a6969b", "node_type": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "83d59421cc351178bdb1df352f66f9f94c9a1b618a97052cfcd10b62d1de3a11"}, "3": {"node_id": "62b6b26e-b0ab-485c-93e6-fc00bf0b5ddd", "node_type": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7c2c805952f4ed2f8859ae27284fda529a4a0c0b6d528227fc0b24f7d0335877"}}, "hash": "2ffc823cea265be29137b8be0a6e3c20a4afe08247ccda342ca81a1aceac9148", "text": "cytokines (e.g. IL-5 and granulocyte\u2013macrophage colony-stimulating factor) that \nactivate eosinophils. Reduced synthesis of IL-3 (the cytokine \nthat regulates mast cell production) may explain why long-term steroid treatment eventually reduces the number \nof mast cells in the respiratory mucosa, and hence suppresses \nthe early-phase response to allergens and exercise.\nGlucocorticoids are sometimes ineffective, even in high \ndoses, for reasons that are incompletely understood. Many \nindividual mechanisms could contribute to glucocorticoid \nresistance. The phenomenon has been linked to the number of glucocorticoid receptors, but in some situations other \nmechanisms are clearly in play \u2013 for example, reduced \nactivity of histone deacetylase (HDAC) may be important in \ncigarette smokers.\nThe main compounds used are beclometasone , budeso -\nnide , fluticasone , mometasone and ciclesonide . These are \ngiven by inhalation with a metered-dose or dry-powder \ninhaler, the full effect on bronchial hyper-responsiveness \nbeing attained only after weeks or months of therapy. There are now several inhaler formulations where inhaled \ncorticosteroids are combined together with long-acting \n\u03b2\n2-adrenoceptor agonists (Cohen et al., 2016). Oral gluco -\ncorticoids (Ch. 34) are reserved for patients with the severest \ndisease.\nUnwanted effects\nSerious unwanted effects are uncommon with inhaled \nsteroids. Oropharyngeal candidiasis (thrush; Ch. 54) can occur (T lymphocytes are important in protection against \nfungal infection), as can sore throat and croaky voice, but \nuse of \u2018spacing\u2019 devices, which decrease oropharyngeal deposition of the drug and increase airway deposition, \nreduces these problems. Regular high doses of inhaled \nglucocorticoids can produce some adrenal suppression, particularly in children, and necessitate carrying a \u2018steroid card\u2019 (Ch. 34). This is less likely with fluticasone, mometa -\nsone and ciclesonide, as these drugs are poorly absorbed from the GI tract and undergo almost complete presystemic metabolism. The unwanted effects of oral glucocorticoids \nare given in Fig. 34.7.\nCromoglicate and nedocromil\nThese two drugs, of similar chemical structure and proper -\nties, are now hardly used for the treatment of asthma. Although very safe, they have only weak anti-inflammatory Clinical use of glucocorticoids in \nasthma \n\u2022\tPatients \twho \trequire \tregular \tbronchodilators \tshould \tbe \t\nconsidered \tfor \tglucocorticoid \ttreatment \t(e.g. \twith \t\nlow-dose\tinhaled \tbeclometasone).\n\u2022\tMore\tseverely \taffected \tpatients \tare \ttreated \twith \t\nhigh-potency \tinhaled \tdrugs \t(e.g. \tfluticasone).\n\u2022\tPatients \twith \tacute \texacerbations \tof \tasthma \tmay \t\nrequire\tintravenous \thydrocortisone \tand\toral\t\nprednisolone.\n\u2022\tA\t\u2018rescue \tcourse\u2019 \tof \toral \tprednisolone \tmay \tbe \tneeded \t\nat\tany\tstage \tof \tseverity \tif \tthe \tclinical \tcondition \tis \t\ndeteriorating \trapidly.\n\u2022\tProlonged \ttreatment \twith \toral \tprednisolone, \tin \taddition \t\nto\tinhaled \tbronchodilators \tand \tsteroids, \tis \tneeded \tby \t\na\tfew\tseverely \tasthmatic \tpatients.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3309, "end_char_idx": 6434, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "62b6b26e-b0ab-485c-93e6-fc00bf0b5ddd": {"__data__": {"id_": "62b6b26e-b0ab-485c-93e6-fc00bf0b5ddd", "embedding": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c23dd4e-ecee-4e13-a6c1-b3877d418233", "node_type": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42cd4d38d98acb8ac2f90ac4a9cd29b4500011ccdac871e7429cb6d06cbc9af3"}, "2": {"node_id": "b57448e2-6858-4d89-8c36-4e6eb7a6f969", "node_type": null, "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ffc823cea265be29137b8be0a6e3c20a4afe08247ccda342ca81a1aceac9148"}}, "hash": "7c2c805952f4ed2f8859ae27284fda529a4a0c0b6d528227fc0b24f7d0335877", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6430, "end_char_idx": 6893, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "33466291-6651-4c2b-ac85-8b3b96c444ef": {"__data__": {"id_": "33466291-6651-4c2b-ac85-8b3b96c444ef", "embedding": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d033e8e3-f57d-4212-97b0-43367c042c5c", "node_type": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c2bfa1044e32505cb06c446bc0f1cabcc3b001aee41874b280250151503bbdf9"}, "3": {"node_id": "5528098d-a2e3-488d-b4d5-f6c8500133e3", "node_type": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f01a799c659551436aa1556cfc76943e6e12b0335e40a92166af51f69d2c84e"}}, "hash": "d0766344960dd96c453da2005b34a1498f44500dc9c418c7bd9646b57ac1345e", "text": "29 RESpIRATORY SYSTEM\n379Tranexamic acid (Ch. 25) or danazol (Ch. 36) may be used \nto prevent attacks in patients with hereditary angioneurotic \noedema, and administration of partially purified C1 esterase \ninhibitor or fresh plasma, with antihistamines and gluco -\ncorticoids, can terminate acute attacks. Icatibant , a peptide \nbradykinin \u03b22 receptor antagonist (Ch. 19), is effective for \nacute attacks of hereditary angio-oedema. It is administered \nsubcutaneously but can cause nausea, abdominal pain and \nnasal stuffiness.\nCHRONIC OBSTRUCTIVE PULMONARY DISEASE\nCOPD is a major global health problem \u2013 current projections suggest that it will be the third commonest cause of death \nwithin 3 years (Adeloye et al., 2015). Cigarette smoking is \nthe main cause, and is increasing in the developing world. Air pollution, also aetiologically important, is also increasing, \nand there is a huge unmet need for effective drugs. A \nresurgence of interest in new therapeutic approaches has yet to bear fruit but there are a number of promising \navenues, in particular in defining subgroups of this rather \nheterogeneous disease that are responsive to particular therapeutic measures (McDonald, 2017).\nClinical features. The clinical picture starts with attacks \nof morning cough during the winter, and progresses to \nchronic cough with intermittent exacerbations, often initiated \nby an upper respiratory infection, when the sputum becomes purulent. There is progressive breathlessness. Some patients \nhave a reversible component of airflow obstruction identifi -\nable by an improved FEV\n1 following a dose of bronchodila -\ntor. Pulmonary hypertension (Ch. 23) is a late complication, causing symptoms of heart failure ( cor pulmonale ). Exacerba -\ntions may be complicated by respiratory failure (i.e. reduced \nP\nAO2) requiring hospitalisation and intensive care. Trache -\nostomy and artificial ventilation, while prolonging survival, \nmay serve only to return the patient to a miserable life.\nPathogenesis. There is fibrosis of small airways, resulting \nin obstruction, and/or destruction of alveoli and of elastin fibres in the lung parenchyma. The latter features are \nhallmarks of emphysema,\n5 thought to be caused by pro -\nteases, including elastase, released during the inflammatory \nresponse. It is emphysema that causes respiratory failure, \nbecause it destroys the alveoli, impairing gas transfer. There is chronic inflammation (bronchitis), predominantly in small \nairways and lung parenchyma, characterised by increased \nnumbers of macrophages, neutrophils and T lymphocytes. The inflammatory mediators have not been as clearly defined \nas in asthma. Lipid mediators, inflammatory peptides, \nreactive oxygen and nitrogen species, chemokines, cytokines and growth factors are all implicated (Barnes, 2004).\nPrinciples of treatment. Stopping smoking (Ch. 49) \nslows the progress of COPD. Patients should be immunised \nagainst influenza and Pneumococcus, because superimposed \ninfections with these organisms are potentially lethal. Glucocorticoids are less effective than in asthma. This \ncontrast with asthma is puzzling, because in both diseases \nmultiple inflammatory genes are activated, which might be expected to be turned off by glucocorticoids. Inflammatory \ngene activation results from acetylation of nuclear histones \nwhich opens up the chromatin structure, allowing gene SEVERE ACUTE ASTHMA (STATUS ASTHMATICUS)\nSevere acute asthma is a medical emergency requiring hospitalisation. Treatment includes oxygen (in high con -\ncentration, usually \u226560%), inhalation of nebulised salbutamol", "start_char_idx": 0, "end_char_idx": 3609, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5528098d-a2e3-488d-b4d5-f6c8500133e3": {"__data__": {"id_": "5528098d-a2e3-488d-b4d5-f6c8500133e3", "embedding": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d033e8e3-f57d-4212-97b0-43367c042c5c", "node_type": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c2bfa1044e32505cb06c446bc0f1cabcc3b001aee41874b280250151503bbdf9"}, "2": {"node_id": "33466291-6651-4c2b-ac85-8b3b96c444ef", "node_type": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0766344960dd96c453da2005b34a1498f44500dc9c418c7bd9646b57ac1345e"}, "3": {"node_id": "44e0b660-d854-4ae8-b49b-31710c0c89de", "node_type": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "059a38e490542bc19233a8f4d6b6ebfb62b28fd844f6ce159dc7838f6b61c3d7"}}, "hash": "4f01a799c659551436aa1556cfc76943e6e12b0335e40a92166af51f69d2c84e", "text": "usually \u226560%), inhalation of nebulised salbutamol \nwith ipratropium, and intravenous hydrocortisone followed by a course of oral prednisolone. Additional measures \noccasionally used include intravenous salbutamol or \naminophylline, intravenous magnesium (considered to have bronchodilator effects), and antibiotics (if bacterial \ninfection is present). Monitoring is by PEFR or FEV\n1, and \nby measurement of arterial blood gases and oxygen saturation.\nALLERGIC EMERGENCIES\nAnaphylaxis (Ch. 7) and angio-oedema are emergencies \ninvolving acute airways obstruction; adrenaline (epineph -\nrine) is potentially life-saving. It is administered intramus -\ncularly (or occasionally intravenously, as in anaphylaxis \noccurring in association with general anaesthesia). Patients \nat risk of acute anaphylaxis, for example, from food or \ninsect sting allergy, may self-administer intramuscular adrenaline using a spring-loaded syringe. Oxygen, an \nantihistamine such as chlorphenamine and hydrocortisone \nare also indicated.\nAngio-oedema is the intermittent occurrence of focal \nswelling of the skin or intra-abdominal organs caused by plasma leakage from capillaries. Most often, it is mild and \n\u2018idiopathic\u2019, but it can occur as part of acute allergic reac -\ntions, when it is generally accompanied by urticaria \u2013 \u2018hives\u2019 \n\u2013 caused by histamine release from mast cells. If the larynx \nis involved, it is life-threatening; swelling in the peritoneal cavity can be very painful and mimic a surgical emergency. \nIt can be caused by drugs, especially angiotensin-converting \nenzyme inhibitors \u2013 perhaps because they block the inactiva -\ntion of peptides such as bradykinin (Ch. 19) \u2013 and by aspirin and related drugs in patients who are aspirin sensitive (see \nCh. 27). Hereditary angio-oedema is associated with lack of C1 esterase inhibitor \u2013 C1 esterase is an enzyme that \ndegrades the complement component C1 (see Ch. 7). Antiasthma drugs: glucocorticoids \nGlucocorticoids (for details, see Ch. 34)\n\u2022\tThese\treduce \tthe \tinflammatory \tcomponent \tin \tchronic \t\nasthma\tand \tare \tlife-saving \tin \tstatus \tasthmaticus \t(acute \t\nsevere\tasthma).\n\u2022\tThey\tdo \tnot \tprevent \tthe \timmediate \tresponse \tto \t\nallergen\tor \tother \tchallenges.\n\u2022\tThe\tmechanism \tof \taction \tinvolves \tdecreased \tformation \t\nof\tcytokines, \tparticularly \tthose \tgenerated \tby \tTh2 \t\nlymphocytes, \tdecreased \tactivation \tof \teosinophils \tand \t\nother\tinflammatory \tcells.\n\u2022\tThey\tare \tgiven \tby \tinhalation \t(e.g. \tbeclometasone );\t\nsystemic\tunwanted \teffects \tare \tuncommon \tat \t\nmoderate\tdoses, \tbut \toral \tthrush \tand \tvoice \tproblems \t\ncan\toccur. \tSystemic \teffects \tcan \toccur \twith \thigh \tdoses \t\nbut\tare\tless \tlikely \twith \tmometasone \tbecause\tof \tits \t\npresystemic \tmetabolism. \tIn \tdeteriorating \tasthma, \tan \t\noral\tglucocorticoid \t(e.g. \tprednisolone )\tor\tintravenous \t\nhydrocortisone \tis\talso\tgiven.\n5Emphysema is a pathological condition sometimes associated with \nCOPD, in which lung parenchyma is destroyed and replaced by air \nspaces that coalesce to form bullae \u2013 blister-like", "start_char_idx": 3566, "end_char_idx": 6613, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "44e0b660-d854-4ae8-b49b-31710c0c89de": {"__data__": {"id_": "44e0b660-d854-4ae8-b49b-31710c0c89de", "embedding": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d033e8e3-f57d-4212-97b0-43367c042c5c", "node_type": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c2bfa1044e32505cb06c446bc0f1cabcc3b001aee41874b280250151503bbdf9"}, "2": {"node_id": "5528098d-a2e3-488d-b4d5-f6c8500133e3", "node_type": null, "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f01a799c659551436aa1556cfc76943e6e12b0335e40a92166af51f69d2c84e"}}, "hash": "059a38e490542bc19233a8f4d6b6ebfb62b28fd844f6ce159dc7838f6b61c3d7", "text": "replaced by air \nspaces that coalesce to form bullae \u2013 blister-like air-filled spaces in the \nlung tissue.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6590, "end_char_idx": 7175, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "24fdcd30-13b2-42a5-bb51-3e21b47db5ed": {"__data__": {"id_": "24fdcd30-13b2-42a5-bb51-3e21b47db5ed", "embedding": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4eb10f2a-a899-4e74-9d73-b8727483488d", "node_type": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a18d81593ee1ca8a36f46b03448693a34a3522ffc05e2509dce86c612e67128"}, "3": {"node_id": "22336125-cac8-4f05-b868-7c51301bbd50", "node_type": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6e71b8703e1e993125354784d7dae981942ff608904539306d470a3c7269e84"}}, "hash": "777dd879bb7fe3e9a3c4694d313c368ada10b6432ea960feef24bd6a5d9fe270", "text": "29 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n380are recommended if there is evidence of infection. \nInhaled bronchodilators may provide some symptomatic \nimprovement.\nA systemically active glucocorticoid (intravenous hydro -\ncortisone or oral prednisolone) is also administered routinely, \nalthough efficacy is modest.\nIDIOPATHIC PULMONARY FIBROSIS\nIdiopathic pulmonary fibrosis is a chronic debilitating \ninflammatory disorder that results in scarring of lung tissue \nand loss of elasticity. Lung expansion and gaseous exchange \nin the alveoli are impaired due to the fibrosis and consequent increased stiffness in pulmonary tissues. In the absence of \na known aetiological agent, treatment is focused on the \nuse of anti-fibrotic agents.\nPirfenidone is an immunosuppressant that reduces \nfibroblast proliferation and production of fibrosis-related mediators. The exact mechanism of pirfenidone is not known, but it appears to reduce fibrosis-related protein and cytokines, prevent accumulation of inflammatory cells, \nand inhibit expansion of extracellular matrix that is stimu -\nlated by cytokine growth factors such as transforming \ngrowth factor-\u03b2 and platelet-derived growth factor (Borie \net al., 2016). Clinical trials have demonstrated that pirfe -\nnidone can slow the decline in lung function and exercise \ncapacity caused by pulmonary fibrosis.\nNintedanib is a small-molecule tyrosine kinase inhibitor \nthat is thought to reduce inflammatory and fibrotic change in the lung. The drug acts through inhibition of signalling \ncascades from platelet-derived and fibroblast-derived growth factor receptors that are involved in the proliferation and \ndifferentiation of pulmonary fibroblasts and myoblasts \n(Borie et al., 2016). Clinical trials have demonstrated the \nefficacy of nintedanib in slowing the progressive loss of \nlung function that is seen in pulmonary fibrosis.\nSURFACTANTS\nPulmonary surfactants act, not by binding to specific targets, but by lowering the surface tension of fluid lining the alveoli, \nallowing air to enter. They are effective in the prophylaxis \nand management of respiratory distress syndrome in newborn \nbabies, especially premature babies in whom endogenous \nsurfactant production is deficient. Examples include beract -\nant and poractant alpha, which are derivatives of the \nphysiological pulmonary surfactant protein. They are administered directly into the tracheobronchial tree via an \nendotracheal tube. (The mothers of premature infants are sometimes treated with glucocorticoids before birth in an attempt to accelerate maturation of the fetal lung and \nminimise incidence of this disorder.)\nCOUGH\nCough is a protective reflex that removes foreign material \nand secretions from the bronchi and bronchioles. It is a \nvery common adverse effect of angiotensin-converting \nenzyme inhibitors, in which case the treatment is usually to substitute an alternative drug, often an angiotensin-\nreceptor antagonist, less likely to cause this adverse effect \n(Ch. 23). It can be triggered by inflammation in the respira -\ntory tract, for example, by undiagnosed asthma or chronic \nreflux with aspiration, or by neoplasia. In these cases, cough \nsuppressant (antitussive) drugs are sometimes useful, for example for the dry painful cough associated with bronchial carcinoma, but are to be avoided in cases of chronic pul -\nmonary infection, as they can cause undesirable thickening transcription and synthesis of inflammatory proteins to proceed. HDAC de-acetylates", "start_char_idx": 0, "end_char_idx": 3515, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "22336125-cac8-4f05-b868-7c51301bbd50": {"__data__": {"id_": "22336125-cac8-4f05-b868-7c51301bbd50", "embedding": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4eb10f2a-a899-4e74-9d73-b8727483488d", "node_type": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a18d81593ee1ca8a36f46b03448693a34a3522ffc05e2509dce86c612e67128"}, "2": {"node_id": "24fdcd30-13b2-42a5-bb51-3e21b47db5ed", "node_type": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "777dd879bb7fe3e9a3c4694d313c368ada10b6432ea960feef24bd6a5d9fe270"}, "3": {"node_id": "c3d76d51-7596-424a-9ba9-18a87c2401de", "node_type": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "780bb47e4a5b0d03ec4770df3516acd0ee1c378f5afb78d08ac20317617b44e3"}}, "hash": "d6e71b8703e1e993125354784d7dae981942ff608904539306d470a3c7269e84", "text": "and synthesis of inflammatory proteins to proceed. HDAC de-acetylates histones, and suppresses production of proinflammatory cytokines. Corticosteroids \nrecruit HDAC to activated genes, switching off inflam -\nmatory gene transcription (Barnes et al., 2004). There is \na link between the severity of COPD (but not of asthma) \nand reduced HDAC activity in lung tissue (Ito et al., 2005); \nfurthermore, HDAC activity is inhibited by smoking-related \noxidative stress, which may explain the relative lack of \neffectiveness of glucocorticoids in patients with COPD, as \ncompared to those with asthma. Inhaled steroids do not influence the progressive decline in lung function in patients \nwith COPD, but do improve the quality of life, probably as \na result of a modest reduction in hospital admissions. This is counter-balanced by the increased risk of pneumonia \nassociated with use of inhaled corticosteroids in patients \nwith COPD.\nLong-acting bronchodilators give modest benefit, but do \nnot deal with the underlying inflammation. No currently licensed treatments reduce the progression of COPD or \nsuppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflam -\nmatory process are in clinical development (Barnes, 2013). Some, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung \nparenchyma, whereas others target inflammatory cytokines \nsuch as TNF- \u03b1. The PDE IV inhibitor roflumilast is licensed \nas an adjunct to bronchodilators for patients with severe \nCOPD and frequent exacerbations. Other drugs that inhibit \ncell signalling (see Chs 3 and 6) include inhibitors of p38 mitogen-activated protein kinase, nuclear factor \u03ba\u03b2 and \nphosphoinositide-3 kinase-\u03b3. More specific approaches \ninclude antioxidants, inhibitors of inducible NO synthase, and leukotriene \u03b2\n4 antagonists. Other treatments have the \npotential to combat mucus hypersecretion, and there is a \nsearch for serine protease and matrix metalloprotease \ninhibitors to prevent lung destruction and the development of emphysema.\nSpecific aspects of treatment. Short- and long-acting \ninhaled bronchodilators can provide useful palliation in \npatients with a reversible component. The main short-acting \ndrugs are ipratropium and salbutamol; long-acting drugs include muscarinic antagonists (e.g. tiotropium ) which are \noften given together with \u03b2\n2 agonists (such as salmeterol or \nformoterol) (Chs 14 and 15; Cohen et al, 2016). Theophylline \n(Ch. 17) can be given by mouth but is of uncertain benefit. Its respiratory stimulant effect may be useful for patients \nwho tend to retain CO\n2. Other respiratory stimulants (e.g. \ndoxapram) are sometimes used briefly in acute respiratory failure (e.g. postoperatively) but have largely been replaced \nby non-invasive ventilation as well as mechanical ventilatory support (intermittent positive-pressure ventilation).\nLong-term oxygen therapy administered at home prolongs \nlife in patients with severe disease and hypoxaemia (at least if they refrain from smoking \u2013 an oxygen fire is not \na pleasant way to go).\nAcute exacerbations. Acute exacerbations of COPD are \ntreated with inhaled O 2 in a concentration (initially, at \nleast) of 24\u201328% O 2, that is, only just above atmospheric \nO2 concentration (approximately 20%). The need for caution \nis because of the risk of precipitating CO 2 retention as a \nconsequence of terminating the hypoxic drive to respiration. Blood gases and tissue", "start_char_idx": 3455, "end_char_idx": 6976, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c3d76d51-7596-424a-9ba9-18a87c2401de": {"__data__": {"id_": "c3d76d51-7596-424a-9ba9-18a87c2401de", "embedding": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4eb10f2a-a899-4e74-9d73-b8727483488d", "node_type": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a18d81593ee1ca8a36f46b03448693a34a3522ffc05e2509dce86c612e67128"}, "2": {"node_id": "22336125-cac8-4f05-b868-7c51301bbd50", "node_type": null, "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6e71b8703e1e993125354784d7dae981942ff608904539306d470a3c7269e84"}}, "hash": "780bb47e4a5b0d03ec4770df3516acd0ee1c378f5afb78d08ac20317617b44e3", "text": "\nconsequence of terminating the hypoxic drive to respiration. Blood gases and tissue oxygen saturation are monitored, and \ninspired O\n2 subsequently adjusted accordingly. Antibiot -\nics such as aminopenicillins, macrolides or tetracyclines mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6953, "end_char_idx": 7672, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "98e062e6-5172-405c-9449-ed6b10239451": {"__data__": {"id_": "98e062e6-5172-405c-9449-ed6b10239451", "embedding": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8ab2bab2-794f-445c-8f1c-71c5c84e29e4", "node_type": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "872643a7a8da9d139e2fedcc0da3de712fd1ce3d784f4082d7cdf79b5c320c85"}, "3": {"node_id": "2c16a1bb-6d1a-4ff8-9629-7455fb909680", "node_type": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0ae2e6da598abf4f4bd5452e99f67726366b322551fdcd2b7b19930e642abced"}}, "hash": "483e5af3dbc926a842345aebf6a1b1eca05d61f2bb613db5f06488894762b3c4", "text": "29 RESpIRATORY SYSTEM\n381REFERENCES AND FURTHER READING\nGeneral\nBarnes, P.J., 2011. Pathophysiology of allergic inflammation. Immunol. \nRev. 242, SI31\u2013SI50.\nBezemer, G.F.G., Sagar, S., van Bergenhenegouwen, J., et al., 2012. Dual \nrole of toll-like receptors in asthma and chronic obstructive \npulmonary disease. Pharmacol. Rev. 64, 337\u2013358. (Update on the role of \nTLRs in asthma and in COPD which discusses targeting these for airway \ndiseases. TLR agonist, adjuvant and antagonist therapies could all be argued to be effective. Because of a possible dual role of TLRs in airway diseases \nwith shared symptoms and risk factors but different immunological \nmechanisms, caution should be taken while designing pulmonary TLR-based therapies)\nBorie, R., Justet, A., Beltramo, G., et al., 2016. Pharmacological \nmanagement of IPF. Respirology 21, 615\u2013625.\nKorkmaz, B., Horwitz, M.S., Jenne, D.E., Gauthier, F., 2010. Neutrophil \nelastase, proteinase 3, and cathepsin G as therapeutic targets in human diseases. Pharmacol. Rev. 62, 726\u2013759. (Describes the functions of these proteases, their role in human diseases and discusses identifying new \ntherapeutics; also describes how non-human primate experimental models \ncould assist)\nMelo, R.C.N., Liu, L., Xenakis, J.J., 2013. Eosinophil-derived cytokines in \nhealth and disease: unraveling novel mechanisms of selective secretion. Allergy 68, 274\u2013284.\nvan der Velden, V.H.J., Hulsmann, A.R., 1999. Autonomic innervation \nof human airways: structure, function, and pathophysiology in asthma. Neuroimmunomodulation 6, 145\u2013159. (Review)\nVelasquez, R., Teran, L.M., 2011. Chemokines and their receptors in the \nallergic airway inflammatory process. Clin. Rev. Allergy Immunol. 41, 76\u201388.\nAsthma\nBerry, M., Hargadon, B., Morgan, A., et al., 2005. Alveolar nitric oxide \nin adults with asthma: evidence of distal lung inflammation in refractory asthma. Eur. Respir. J. 25, 986\u2013991. (Alveolar NO as a measure \nof distal airway inflammation)\nBTS/SIGN (British Thoracic Society/Scottish Intercollegiate Guideline \nNetwork), 2016. British Guideline on Management of Asthma. www.brit-thoracic.org.uk. (Accessed August 2017).\nPelaia, G., Cuda, G., Vatrella, A., et al., 2005. Mitogen-activated protein \nkinases and asthma. J. Cell. Physiol. 202, 642\u2013653. (Reviews involvement \nof mitogen-activated protein kinases in asthma pathogenesis, and discusses \ntheir possible role as molecular targets for antiasthma drugs)\nWadsworth, S.J., Sandford, A.J., 2013. Personalised medicine and \nasthma diagnostics/management. Curr. Allergy Asthma Rep. 13, 118\u2013129.\nWalter, M.J., Holtzman, M.J., 2005. A centennial history of research on \nasthma pathogenesis. Am. J. Respir. Cell Mol. Biol. 32, 483\u2013489.\nChronic obstructive pulmonary disease\nAdeloye, D., Chua, S., Lee, C., et al., 2015. Global and regional estimates \nof COPD prevalence: Systematic review and meta-analysis. J. Glob.", "start_char_idx": 0, "end_char_idx": 2910, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2c16a1bb-6d1a-4ff8-9629-7455fb909680": {"__data__": {"id_": "2c16a1bb-6d1a-4ff8-9629-7455fb909680", "embedding": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8ab2bab2-794f-445c-8f1c-71c5c84e29e4", "node_type": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "872643a7a8da9d139e2fedcc0da3de712fd1ce3d784f4082d7cdf79b5c320c85"}, "2": {"node_id": "98e062e6-5172-405c-9449-ed6b10239451", "node_type": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "483e5af3dbc926a842345aebf6a1b1eca05d61f2bb613db5f06488894762b3c4"}, "3": {"node_id": "1df41d06-85b8-4333-97ce-a3b749c1eb23", "node_type": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e185390e19c873ea8e5e6ce60fa7343ee377bbe5c299aaf37169e1ff7b294ab"}}, "hash": "0ae2e6da598abf4f4bd5452e99f67726366b322551fdcd2b7b19930e642abced", "text": "COPD prevalence: Systematic review and meta-analysis. J. Glob. \nHealth 5, 020415.\nBarnes, P.J., 2004. Mediators of chronic obstructive pulmonary disease. \nPharmacol. Rev. 56, 515\u2013548. (\u2018The identification of inflammatory mediators and understanding their interactions is important for the \ndevelopment of anti-inflammatory treatments for this important disease\u2019)Barnes, P.J., 2013. New anti-inflammatory targets for chronic obstructive \npulmonary disease. Nat. Rev. Drug Discov. 12, 543\u2013559.\nBarnes, P.J., Ito, K., Adcock, I.M., 2004. Corticosteroid resistance in \nchronic obstructive pulmonary disease: inactivation of histone \ndeacetylase. Lancet 363, 731\u2013733. (Hypothesis that in patients with \nCOPD, HDAC is impaired by cigarette smoking and oxidative stress, \nleading to reduced responsiveness to corticosteroids; see also Ito et al., 2005, \nbelow)\nCohen, J.S., Miles, M.C., Donohue, J.F., Ohar, J.A., 2016. Dual therapy \nstrategies for COPD: the scientific rationale for LAMA + LABA. Int. J. \nChron. Obstruct. Pulmon. Dis. 11, 785\u2013797. (Good review of combination \nbronchodilator therapy in COPD)\nIto, K., Ito, M., Elliott, W.M., et al., 2005. Decreased histone deacetylase \nactivity in chronic obstructive pulmonary disease. N. Engl. J. Med. 352, 1967\u20131976. (There is a link between the severity of COPD and the \nreduction in HDAC activity in the peripheral lung tissue; HDAC is a key \nmolecule in the repression of production of proinflammatory cytokines in alveolar macrophages)\nMcDonald, C.F., 2017. Eosinophil biology in COPD. N. Engl. J. Med. \n377, 1680\u20131682.\nCough\nMorice, A.H., Kastelik, J.A., Thompson, R., 2001. Cough challenge in the \nassessment of cough reflex. Br. J. Clin. Pharmacol. 52, 365\u2013375.\nReynolds, S.M., Mackenzie, A.J., Spina, D., Page, C.P., 2004. The \npharmacology of cough. Trends Pharmacol. Sci. 25, 569\u2013576. (Discusses the pathophysiological mechanisms of cough and implications for developing \nnew antitussive drugs)\nDrugs and therapeutic aspects\nBarnes, P.J., 2006. How corticosteroids control inflammation. Br. J. \nPharmacol. 148, 245\u2013254.\nBel, E.H., Ten Brinke, A., 2017. New anti-eosinophil drugs for asthma \nand COPD: targeting the trait! Chest 152 (6), 1276\u20131282.\nBen-Noun, L., 2000. Drug-induced respiratory disorders: incidence, \nprevention and management. Drug Saf. 23, 143\u2013164. (Diverse \npulmonary adverse drug effects)\nCazzola, M., Page, C.P., Calzetta, L., Matera, M.G., 2012. Pharmacology \nand therapeutics of bronchodilators. Pharmacol. Rev. 64, 450\u2013504.\nConti, M., Beavo, J., 2007. Biochemistry and physiology of cyclic \nnucleotide phosphodiesterases: essential components in cyclic \nnucleotide signaling. Annu. Rev. Biochem. 76, 481\u2013511.\nGiri, S.N., 2003. Novel pharmacological approaches to manage \ninterstitial lung fibrosis in the twenty first century. Annu. Rev. Pharmacol. Toxicol. 43, 73\u201395. (Reviews", "start_char_idx": 2856, "end_char_idx": 5716, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1df41d06-85b8-4333-97ce-a3b749c1eb23": {"__data__": {"id_": "1df41d06-85b8-4333-97ce-a3b749c1eb23", "embedding": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8ab2bab2-794f-445c-8f1c-71c5c84e29e4", "node_type": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "872643a7a8da9d139e2fedcc0da3de712fd1ce3d784f4082d7cdf79b5c320c85"}, "2": {"node_id": "2c16a1bb-6d1a-4ff8-9629-7455fb909680", "node_type": null, "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0ae2e6da598abf4f4bd5452e99f67726366b322551fdcd2b7b19930e642abced"}}, "hash": "9e185390e19c873ea8e5e6ce60fa7343ee377bbe5c299aaf37169e1ff7b294ab", "text": "Rev. Pharmacol. Toxicol. 43, 73\u201395. (Reviews approaches including maintaining \nintracellular nicotinamide adenine dinucleotide [NAD\n+] and ATP, blocking \ntransforming growth factor-\u03b2 and integrins, platelet-activating factor \nreceptor antagonists and NO synthase inhibitors)\nHolgate, S.T., Djukanovic, R., Casale, T., Bousquet, J., 2005. \nAnti-immunoglobulin E treatment with omalizumab in allergic diseases: an update on anti-inflammatory activity and clinical efficacy. \nClin. Exp. Allergy 35, 408\u2013416. (Reviews mechanism and clinical studies)\nLewis, J.F., Veldhuizen, R., 2003. The role of exogenous surfactant in the \ntreatment of acute lung injury. Annu. Rev. Physiol. 65, 613\u2013642.and retention of sputum, and in asthma because of the risk \nof respiratory depression.\nDRUGS USED FOR COUGH\nOpioid analgesics are the most effective antitussive drugs in clinical use (Ch. 43). They act by inhibiting an ill-defined \n\u2018cough centre\u2019 in the brain stem, and suppress cough in \ndoses below those required for pain relief. Those used as cough suppressants have minimal analgesic actions and \naddictive properties. New opioid analogues that suppress \ncough by inhibiting release of excitatory neuropeptides through an action on \u00b5 receptors (see Table 43.2) on sensory \nnerves in the bronchi are being assessed.Codeine (methylmorphine) is a weak opioid (see Ch. \n43) with considerably less addiction liability than a strong opioid, and is a mild cough suppressant. It decreases \nsecretions in the bronchioles, which thickens sputum, and \ninhibits ciliary activity. Constipation is common. Dex-\ntromethorphan (a drug with many actions, including \n\u00b5-receptor and sigma-1-receptor agonist, non-selective \nserotonin-uptake inhibitor) and pholcodine (\u00b5-receptor \nagonist with weak analgesic effects) have less adverse effects \nthan codeine. Respiratory depression is a risk with all \ncentrally acting cough suppressants. Morphine is used for \npalliative care in cases of lung cancer associated with \ndistressing cough.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5727, "end_char_idx": 8214, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d80b283-99c2-43d5-9da3-0047109f8bfc": {"__data__": {"id_": "6d80b283-99c2-43d5-9da3-0047109f8bfc", "embedding": null, "metadata": {"page_label": "388", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e763a431-4c45-4243-a631-ed84595d35d4", "node_type": null, "metadata": {"page_label": "388", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3cf9f87c2d2d5b9b6ace15f05b70d8192be6d8fd11694a422ecd44b48d6785f2"}, "3": {"node_id": "9236b2b4-db6a-418d-a035-2e047a71caad", "node_type": null, "metadata": {"page_label": "388", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "891d370f7a0cd8c0fe89efcba127b69f5a8abe13f9067076c358b3462acaf2a9"}}, "hash": "3c176af2ef3569731932a486f3f6f575edfcb2a3d3299091fb220a6e596caf5b", "text": "382\nThe kidney and urinary system30 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3\nOVERVIEW\nWe set the scene with a brief outline of renal physiol -\nogy based on the functional unit of the kidney \u2013 the \nnephron \u2013 before describing drugs that affect renal \nfunction. Emphasis is on diuretics \u2013 drugs that increase the excretion of Na\n+ ions and water, and reduce \narterial blood pressure. We also mention drugs used \nto treat patients with renal failure and urinary tract \ndisorders, several of which are also covered in other chapters.\nINTRODUCTION\nThe main function of the kidneys is to maintain the con -\nstancy of the \u2018interior environment\u2019 by eliminating waste \nproducts and by regulating the volume, electrolyte content \nand pH of the extracellular fluid in the face of varying dietary intake and other environmental (e.g. climatic) \ndemands. The kidneys receive approximately 20% of the \ncardiac output from which, in a young adult human, their glomeruli filter approximately 180 L of fluid per day, of \nwhich 99% is reabsorbed by the tubules. This results in a \ndaily urine output of approximately 1.8 L (Table 30.1). The kidneys have important related endocrine functions includ -\ning synthesis of erythropoietin (Ch. 25), renin (Ch. 23) and \nof the active form of vitamin D (Ch. 37), and are sites of \naction of mediators including vasopressin (Ch. 34) and angiotensin II (Ch. 23).\nThe kidneys are targets of the familiar range of pathologi -\ncal processes \u2013 infectious, structural, immunological, toxic (including drug toxicities) and so on \u2013 but the diverse \ndiseases that result all converge via impairment of renal \nfunction (reduced glomerular filtration rate) to a common end stage of renal failure which (if the pathological process \nis reversible) may be acute and recoverable or (if not) chronic \nand irreversible other than by transplantation.\nThe main drugs that work by altering renal function \u2013 the \ndiuretics \u2013 are crucial in treating cardiovascular disease, especially hypertension and heart failure (Ch 23), as well as management of patients with renal disease with an impaired \nability to excrete salt and water. Immunosuppressant \ndrugs (effective in several of the diseases that can cause renal failure, and crucial following renal transplantation) are covered in Chapter 27 and antibacterial drugs (used \nto treat renal and urinary tract infections) in Chapter 52. \nSeveral drugs that act on the autonomic nervous system influence the muscle of the bladder (the detrusor muscle) \nand its sphincter, and some of these are used therapeu -\ntically in attempts to improve symptoms of detrusor \ninstability or urinary obstruction (\u2018prostatism\u2019) (Chs 14, \n15 and 36).The kidneys are the main organ by which drugs and \ntheir metabolites are eliminated from the body (Ch. 10), so the dosing regimens of many drugs must be modified \nin patients with impaired renal function. A further challenge \nfor clinical nephrologists is drug treatment of patients with renal failure who are being supported by an artificial form \nof dialysis that clears drugs differently from the kidneys. \nThese are outside the scope of this book and interested readers are directed to the chapters by Golper, Udy and \nLipman, and by Olyaei, Foster and Lermer in the Oxford \nTextbook of Clinical Nephrology (2015). Here we provide an introduction to renal physiology followed by coverage of drugs acting on the kidney, and short sections on drugs \nused in renal failure and drugs used in urinary tract \ndisorders.\nOUTLINE OF RENAL FUNCTION\nThe glomerular filtrate is similar in composition", "start_char_idx": 0, "end_char_idx": 3583, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9236b2b4-db6a-418d-a035-2e047a71caad": {"__data__": {"id_": "9236b2b4-db6a-418d-a035-2e047a71caad", "embedding": null, "metadata": {"page_label": "388", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e763a431-4c45-4243-a631-ed84595d35d4", "node_type": null, "metadata": {"page_label": "388", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3cf9f87c2d2d5b9b6ace15f05b70d8192be6d8fd11694a422ecd44b48d6785f2"}, "2": {"node_id": "6d80b283-99c2-43d5-9da3-0047109f8bfc", "node_type": null, "metadata": {"page_label": "388", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3c176af2ef3569731932a486f3f6f575edfcb2a3d3299091fb220a6e596caf5b"}}, "hash": "891d370f7a0cd8c0fe89efcba127b69f5a8abe13f9067076c358b3462acaf2a9", "text": "OF RENAL FUNCTION\nThe glomerular filtrate is similar in composition to plasma, apart from the absence of protein. As it passes through the \nrenal tubule, about 99% of the filtered water, and much of \nthe filtered Na\n+, is reabsorbed, and some substances are \nsecreted into it from the blood.\nEach kidney consists of an outer cortex, an inner medulla \nand the renal pelvis, which empties into the ureter. The functional unit is the nephron, of which there are approxi -\nmately 1.4 \u00d7 10\n6 in each kidney (approximately half this \nnumber in people with hypertension), with considerable \nvariation between individuals. Nephron number declines \nwith age, even in healthy people, accompanied by a predict -\nable decline in renal function.\nTHE STRUCTURE AND FUNCTION OF \nTHE NEPHRON\nEach nephron consists of a glomerulus , proximal tubule , loop \nof Henle , distal convoluted tubule and collecting duct (Fig. 30.1). \nThe glomerulus comprises a tuft of capillaries projecting into Bowman\u2019s capsule, a cup-like sack draining into the proximal tubule. Most nephrons lie largely or entirely in \nthe cortex. The remaining 12%, called the juxtamedullary \nnephrons , have their glomeruli and convoluted tubules next \nto the junction of the medulla and cortex, and their loops of Henle pass deep into the medulla.\nTHE BLOOD SUPPLY TO THE NEPHRON\nNephrons possess the special characteristic of having two \ncapillary beds in series with each other (see Fig. 30.1). \nThe afferent arteriole of each cortical nephron branches \nto form the glomerulus; glomerular capillaries coalesce into the efferent arteriole which supplies a second capil -\nlary network in the cortex, around the convoluted tubules mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3516, "end_char_idx": 5679, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7fa3bb7a-19a5-4cc3-a20c-84851cea07dd": {"__data__": {"id_": "7fa3bb7a-19a5-4cc3-a20c-84851cea07dd", "embedding": null, "metadata": {"page_label": "389", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c961578-7459-42d9-8442-b99bf2746719", "node_type": null, "metadata": {"page_label": "389", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b5ad3fe8879d08886c6ae29cae3ab4d97657f85fd5b26d833093ed30d29723e"}, "3": {"node_id": "875b4881-10e3-447b-9781-462665b17a91", "node_type": null, "metadata": {"page_label": "389", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e57da79cea93d3519ad03113efe86684b44fe7d4dadf00e6a617efd0086eb25"}}, "hash": "b78407e19deccd2e5686fd3fc5b9b70350841249211fe7c433a07dbf52ac08d3", "text": "30 ThE kIDNEY AND URINARY SYSTEM\n383Table 30.1 Reabsorption of fluid and solute in the \nkidneya\nFiltered/\ndayExcreted/day\nbPercentage reabsorbed\nNa+ (mmol) 25,000 150 99+%\nK+ (mmol) 600 90 93+%\nCl\u2212 (mmol) 18,000 150 99+%\nHCO 3\u2212 (mmol) 4900 0 100%\nTotal solute (mosmol) 54,000 700 87%\nH2O (L) 180 ~1.5 99+%\naTypical values for a healthy young adult: renal blood flow, \n1200 mL/min (20%\u201325% of cardiac output); renal plasma flow, \n660 mL/min; glomerular filtration rate, 125 mL/min.\nbThese are typical figures for an individual eating a Western diet. \nThe kidney excretes more or less of each of these substances \nto maintain the constancy of the internal milieu, so on a low-sodium diet (for instance in the Yanomami Indians of the upper Amazon basin), NaCl excretion may be reduced to below \n10 mmol/day! At the other extreme, individuals living in some \nfishing communities in Japan eat (and therefore excrete) several hundred mmol/day.\nBowman's capsule Glomerulus\nProximal tubuleDistal tubule\nCollecting\ntubule\nArcuate\nartery\nArcuate\nvein\nCollecting duct Loop of Henle Vasa rectaVenulePeritubular capillariesEfferent arterioleAfferent arterioleCORTEX MEDULLA\nFig. 30.1 Simplified diagram of a juxtamedullary nephron and its blood supply. The tubules and the blood vessels are shown \nseparately for clarity. In the kidney, the peritubular capillary network surrounds the convoluted tubules, and the distal convoluted tubule passes close to the glomerulus, between the afferent and efferent arterioles. (This last is shown in more detail in Fig. 30.2.) and loops of Henle, before converging to form venules \nand then renal veins. By contrast, efferent arterioles of \njuxtamedullary nephrons lead to vessel loops ( vasa recta) \nthat pass deep into the medulla with the thin loops of Henle \n(see Fig. 30.1).\nTHE JUXTAGLOMERULAR APPARATUS\nA conjunction of afferent arteriole, efferent arteriole and \ndistal convoluted tubule near the glomerulus forms the \njuxtaglomerular apparatus (Fig. 30.2). At this site, there \nare specialised cells in both the afferent arteriole and the tubule. The latter, termed macula densa cells, respond to \nchanges in the rate of flow and the composition of tubule fluid, and they control, probably by purinergic signalling (see Ch. 17), renin release from specialised granular renin-\ncontaining cells in the afferent arteriole (Ch. 23). These cells \nalso release renin in response to decreased pressure in the afferent arteriole. Various chemical mediators also influence renin secretion, including \u03b2\n2-adrenoceptor agonists, vasodila -\ntor prostaglandins and feedback inhibition from angiotensin \nII acting on AT 1 receptors (see Fig. 23.4). The role of the \njuxtaglomerular apparatus in the control of Na+ balance is \ndealt with below.\nGLOMERULAR FILTRATION\nFluid is driven from the capillaries into Bowman\u2019s capsule \nby hydrodynamic force opposed by the oncotic pressure \nof the plasma proteins, to which the glomerular capillaries \nare impermeable. All the low molecular-weight constituents mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 0, "end_char_idx": 3206, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "875b4881-10e3-447b-9781-462665b17a91": {"__data__": {"id_": "875b4881-10e3-447b-9781-462665b17a91", "embedding": null, "metadata": {"page_label": "389", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c961578-7459-42d9-8442-b99bf2746719", "node_type": null, "metadata": {"page_label": "389", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b5ad3fe8879d08886c6ae29cae3ab4d97657f85fd5b26d833093ed30d29723e"}, "2": {"node_id": "7fa3bb7a-19a5-4cc3-a20c-84851cea07dd", "node_type": null, "metadata": {"page_label": "389", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b78407e19deccd2e5686fd3fc5b9b70350841249211fe7c433a07dbf52ac08d3"}}, "hash": "1e57da79cea93d3519ad03113efe86684b44fe7d4dadf00e6a617efd0086eb25", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3159, "end_char_idx": 3510, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b2fe2401-8202-4007-aec1-fffce6e9d217": {"__data__": {"id_": "b2fe2401-8202-4007-aec1-fffce6e9d217", "embedding": null, "metadata": {"page_label": "390", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7740e11c-ca6e-424e-8d9c-460596e4d962", "node_type": null, "metadata": {"page_label": "390", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9539754edfc0fe35e779fa59eb6132da6ee1a70d721755b6807153bce2536198"}, "3": {"node_id": "fc489a2a-8fc0-44bb-aad7-582f37a29dfa", "node_type": null, "metadata": {"page_label": "390", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6fb1609e22263415e84fb377654ebc6b211a4da4b52bfc9fc10618fd48abc052"}}, "hash": "988017bd46466c3c7a8d816fcd509c43f2bcc3b6b48341683ad6ebb653bc07fc", "text": "30 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n384\u25bc Bicarbonate is normally completely reabsorbed in the proximal \ntubule. This is achieved by combination with protons, yielding carbonic \nacid, which dissociates to form carbon dioxide and water \u2013 a reaction \ncatalysed by carbonic anhydrase present in the lumenal brush border \nof the proximal tubule cells (see Fig. 30.5A) \u2013 followed by passive reabsorption of the dissolved carbon dioxide.\n1 The selective removal \nof sodium bicarbonate, with accompanying water, in the early proximal \ntubule causes a secondary rise in the concentration of chloride ions. \nDiffusion of chloride down its concentration gradient via the paracel -\nlular shunt (see Fig. 30.5A) leads, in turn, to a lumen-positive potential \ndifference that favours reabsorption of sodium. The other mechanism \ninvolved in movement via the paracellular route is that sodium ions are secreted by Na\n+-K+-ATPase into the lateral intercellular space, \nsomewhat raising its osmolality because of the 3 Na+:2 K+ stoichiometry \nof the transporter. This leads to osmotic movement of water across \nthe tight junction (see Fig. 30.5A), in turn causing sodium and chloride \nion reabsorption by convection (so-called solvent drag).of plasma appear in the filtrate, while albumin and larger \nproteins are retained in the blood.\nTUBULAR FUNCTION\nThe apex (lumenal surface) of each tubular cell is surrounded by a tight junction, as in all epithelia. This is a specialised \nregion of membrane that separates the intercellular space \nfrom the lumen. The movement of ions and water across the epithelium can occur through cells (the transcellular \npathway) and between cells through the tight junctions (the \nparacellular pathway). A common theme is that energy is expended to pump Na\n+ out of the cell by Na+-K+-ATPase \nsituated in the basolateral cell membrane and the resulting \ngradient of Na+ concentration drives the entry of Na+ from \nthe lumen via various transporters that facilitate Na+ entry \ncoupled with movement of other ions, either in the same direction as Na\n+, in which case they are called symporters \nor co-transporters, or in the opposite direction, in which \ncase they are called antiporters. These transporters vary in \ndifferent parts of the nephron, as described later.\nTHE PROXIMAL CONVOLUTED TUBULE\nThe epithelium of the proximal convoluted tubule is \u2018leaky\u2019, \ni.e. the tight junctions in the proximal tubule are not so \n\u2018tight\u2019 after all, being permeable to ions and water, and \npermitting passive flow in either direction. This prevents the build-up of large concentration gradients; thus, although \napproximately 60%\u201370% of Na\n+ reabsorption occurs in the \nproximal tubule, this transfer is accompanied by passive absorption of water so that fluid leaving the proximal tubule \nremains approximately isotonic to the glomerular filtrate.\nSome of the transport processes in the proximal tubule \nare shown in Figs 30.3\u201330.5. The most important mechanism for Na\n+ entry into proximal tubular cells from the filtrate \noccurs by Na+/H+ exchange (see Fig. 30.5). Intracellular \ncarbonic anhydrase is essential for production of H+ for \nsecretion into the lumen. Na+ is reabsorbed from tubular \nfluid into the cytoplasm of proximal tubular cells in exchange \nfor cytoplasmic H+. It is then transported out of the cells \ninto the interstitium by a Na+-K+-ATPase (sodium", "start_char_idx": 0, "end_char_idx": 3398, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fc489a2a-8fc0-44bb-aad7-582f37a29dfa": {"__data__": {"id_": "fc489a2a-8fc0-44bb-aad7-582f37a29dfa", "embedding": null, "metadata": {"page_label": "390", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7740e11c-ca6e-424e-8d9c-460596e4d962", "node_type": null, "metadata": {"page_label": "390", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9539754edfc0fe35e779fa59eb6132da6ee1a70d721755b6807153bce2536198"}, "2": {"node_id": "b2fe2401-8202-4007-aec1-fffce6e9d217", "node_type": null, "metadata": {"page_label": "390", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "988017bd46466c3c7a8d816fcd509c43f2bcc3b6b48341683ad6ebb653bc07fc"}}, "hash": "6fb1609e22263415e84fb377654ebc6b211a4da4b52bfc9fc10618fd48abc052", "text": "the interstitium by a Na+-K+-ATPase (sodium pump) \nin the basolateral membrane. This is the main active transport mechanism of the nephron in terms of energy \nconsumption. Reabsorbed Na\n+ then diffuses into blood \nvessels.G\nDTAfferent\narteriole\nEfferent\narteriole\nGranular\ncellsMacula densa cellsDistal tubule\nGlomerulus\nFig. 30.2 The juxtaglomerular apparatus. The cutaway \nsections show the granular renin-containing cells around the \nafferent arteriole, and the macula densa cells in the distal convoluted tubule. The inset shows the general relationships between the structures. DT, distal tubule; G, glomerulus. Organic acids \nand bases\n(see Table 9.7)\nNa+, Cl\u2212, \nglucose, HCO3\u2212, \namino acids, \nwater (isosmotic)\nAmmoniaLUMEN\nFig. 30.3 Transport processes in the proximal convoluted \ntubule. The main driving force for the absorption of solutes and water from the lumen is the Na\n+-K+-ATPase in the basolateral \nmembrane of the tubule cells. Many drugs are secreted into the proximal tubule (see Ch. 10). (Redrawn from Burg, 1985. Brenner, B.M., Rector, F.C. (eds). In: The Kidney, third ed., Philadelphia: WB Saunders, pp 145\u2013175.)\n1The reaction is reversible, and the enzyme (as any catalyst) does not alter \nthe equilibrium, just speeds up the rate with which it is attained. The \nconcentrations inside the cell are such that carbon dioxide combines with \nwater to produce carbonic acid: the same enzyme (carbonic anhydrase) catalyses this as well (see Fig. 30.5A).Many organic acids and bases are actively secreted into \nthe tubule from the blood by specific transporters (see later, \nFig. 30.3 and Ch. 10).\nAfter passage through the proximal tubule, tubular fluid \n(now 30%\u201340% of the original volume of the filtrate) passes on to the loop of Henle.\nTHE LOOP OF HENLE, MEDULLARY COUNTER-CURRENT \nMULTIPLIER AND EXCHANGER\nThe loop of Henle consists of a descending and an ascending \nportion (see Figs 30.1 and 30.4 ), the ascending portion having \nboth thick and thin segments. This part of the nephron mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3355, "end_char_idx": 5850, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e2ee6ed0-b26c-4b62-a94d-6bcd3d0cfc61": {"__data__": {"id_": "e2ee6ed0-b26c-4b62-a94d-6bcd3d0cfc61", "embedding": null, "metadata": {"page_label": "391", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "028bd9ba-0f31-4648-ab15-95667ca88369", "node_type": null, "metadata": {"page_label": "391", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "394c2e51c58a5f674ea377571225afa5aadd925d1e42f61be31c1e3791fc5d64"}, "3": {"node_id": "d8ba0ebd-42aa-46a7-bb7d-fab0a734ccc6", "node_type": null, "metadata": {"page_label": "391", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a5dfbeb40d7e59a65401140ef07ad3c4df3c177b707ce5f068306a53bbdeb439"}}, "hash": "388f424756f8fa8223fd19b2a84bf7922064d0aadd89a904ec022cd070fe7c6c", "text": "30 ThE kIDNEY AND URINARY SYSTEM\n385water, reducing the osmolality of the tubular fluid and making the \ninterstitial fluid of the medulla hypertonic. The osmotic gradient in the \nmedullary interstitium is the key consequence of the counter-current \nmultiplier system, the main principle being that small horizontal osmotic gradients stack up to produce a large vertical gradient. Urea contributes \nto the gradient because it is more slowly reabsorbed than water and \nmay be added to fluid in the descending limb, so its concentration rises along the nephron until it reaches the collecting tubules, where it diffuses \nout into the interstitium. It is thus trapped in the inner medulla.\nIons move into cells of the thick ascending limb of the loop \nof Henle across the apical membrane by a Na+/K+/2Cl\u2212 co-\ntransporter, driven by the Na+ gradient produced by Na+-\nK+-ATPase in the basolateral membrane (see Fig. 30.5B). Most \nof the K+ taken into the cell by the Na+/K+/2Cl\u2212 co-transporter \nreturns to the lumen through apical potassium channels, but \nsome K+ is reabsorbed, along with Mg2+ and Ca2+.\nReabsorption of salt from the thick ascending limb is \nnot balanced by reabsorption of water, so tubular fluid \nis hypotonic with respect to plasma as it enters the distal convoluted tubule (see Fig. 30.4). The thick ascending limb \nis therefore sometimes referred to as the \u2018diluting segment\u2019.\nTHE DISTAL TUBULE\nIn the early distal tubule, NaCl reabsorption, coupled \nwith impermeability of the zonula occludens to water, \nfurther dilutes the tubular fluid. Transport is driven by Na\n+-K+-ATPase in the basolateral membrane. This lowers enables the kidney to excrete urine that is either more or less concentrated than plasma, and hence to regulate the osmotic balance of the body as a whole. The loops of Henle \nof the juxtamedullary nephrons function as counter-current \nmultipliers, and the vasa recta as counter-current exchangers. NaCl is actively reabsorbed in the thick ascending limb, \ncausing hypertonicity of the interstitium. The descending \nlimb is permeable to water, and this interstitial hypertonicity causes water to move out, so that the tubular fluid becomes \nprogressively more concentrated as it approaches the bend.\n\u25bc In juxtamedullary nephrons with long loops, there is extensive \nmovement of water out of the tubule so that the fluid eventually \nreaching the tip of the loop has a high osmolality \u2013 normally approxi -\nmately 1200 mosmol/kg, but up to 1500 mosmol/kg under conditions \nof dehydration \u2013 compared with plasma and extracellular fluid, which \nis approximately 300 mosmol/kg.2 The hypertonic milieu of medulla, \nthrough which the collecting ducts of all nephrons pass on the way \nto the renal pelvis, is important in providing a mechanism by which \nthe osmolarity of the urine is controlled.\nThe ascending limb has very low permeability to water, i.e. the tight \njunctions really are tight, enabling the build-up of a substantial con -\ncentration gradient across the wall of the tubule. It is here, in the thick \nascending limb of the loop of Henle, that 20%\u201330% of filtered Na+ is \nreabsorbed. There is active reabsorption of NaCl, unaccompanied by", "start_char_idx": 0, "end_char_idx": 3189, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d8ba0ebd-42aa-46a7-bb7d-fab0a734ccc6": {"__data__": {"id_": "d8ba0ebd-42aa-46a7-bb7d-fab0a734ccc6", "embedding": null, "metadata": {"page_label": "391", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "028bd9ba-0f31-4648-ab15-95667ca88369", "node_type": null, "metadata": {"page_label": "391", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "394c2e51c58a5f674ea377571225afa5aadd925d1e42f61be31c1e3791fc5d64"}, "2": {"node_id": "e2ee6ed0-b26c-4b62-a94d-6bcd3d0cfc61", "node_type": null, "metadata": {"page_label": "391", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "388f424756f8fa8223fd19b2a84bf7922064d0aadd89a904ec022cd070fe7c6c"}}, "hash": "a5dfbeb40d7e59a65401140ef07ad3c4df3c177b707ce5f068306a53bbdeb439", "text": "is \nreabsorbed. There is active reabsorption of NaCl, unaccompanied by Loop\ndiuretics\nSpironolactoneINTERSTITIUMINTERSTITIUMINTERSTITIUMNa+Cl\u2212Na+H+\nNa+K+\n2Cl\u2212\nAldosteroneTALDT\nCT\nPCT1\n23\nNa+Cl\u2212\nNa+ 0.1%\u20132%\nCl\u2212 0.1%\u20132%Na+ 145, 100%\nCl\u2212 115, 100%Na+ 30, 10%\nCl\u2212 30, 10%Na+ 3%\nCl\u2212 3%\nOsmotic diuretics\nmodify filtrate\ncontentThiazides\n4Na+ 145, 35%\nCl\u2212 115, 40%Amiloride\nFig. 30.4 Schematic showing the absorption of sodium and chloride in the nephron and the main sites of action of drugs. Cells \nare depicted as a pink border round the yellow tubular lumen. Mechanisms of ion absorption at the apical margin of the tubule cell: (1) Na+/\nH+ exchange; (2) Na+/K+/2Cl\u2212 co-transport; (3) Na+/Cl\u2212 co-transport; (4) Na+ entry through sodium channels. Sodium is pumped out of the \ncells into the interstitium by the Na+-K+-ATPase in the basolateral margin of the tubular cells (not shown). The numbers in the boxes give \nthe concentration of ions as millimoles per litre of filtrate, and the percentage of filtered ions still remaining in the tubular fluid at the sites \nspecified. CT, collecting tubule; DT, distal tubule; PCT, proximal convoluted tubule; TAL, thick ascending loop. (Data from Greger, 2000.)\n2These figures are for humans; some other species, notably the desert rat, \ncan do much better, with urine osmolalities up to 5000 mosmol/kg.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3119, "end_char_idx": 4944, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3b36e16d-2823-4163-857e-be9c11b6d61d": {"__data__": {"id_": "3b36e16d-2823-4163-857e-be9c11b6d61d", "embedding": null, "metadata": {"page_label": "392", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d283bc2a-2aae-46af-9947-d79f37917033", "node_type": null, "metadata": {"page_label": "392", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44373e7f36d4158435ab49515c1ab5593e040ed4c5a34458d822de8d0597d89c"}, "3": {"node_id": "d39c77d6-d716-4b2b-ba16-b26761842279", "node_type": null, "metadata": {"page_label": "392", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c70db81d43de421114065eeb2ffe8b839e592080974ac7e309ba9581ebf1003"}}, "hash": "eef73eaa3d864d7cd3eccd225562204a4cb90efcbdc3e170bb2cb62a64f1e199", "text": "30 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n386in this part of the nephron, by parathormone (PTH) and \ncalcitriol, both of which increase Ca2+ reabsorption and \nphosphate excretion by increasing the synthesis of several \nof these transporters (see Ch. 37).\nTHE COLLECTING TUBULE AND COLLECTING DUCT\nDistal convoluted tubules empty into collecting tubules, \nwhich coalesce to form collecting ducts (see Fig. 30.1). \nCollecting tubules include principal cells, which reabsorb \nNa+ and secrete K+ (see Fig. 30.5D), and two populations cytoplasmic Na+ concentration, and consequently Na+ enters \nthe cell from the lumen down its concentration gradient, \naccompanied by Cl\u2212, by means of a Na+/Cl\u2212 co-transporter \n(see Fig. 30.5C).\nThe apical surfaces (lumen side) of distal tubular cells \nare permeable to Ca2+ via the TRPV5 channel. On the \nbasolateral surface there is an active Na+/Ca2+ transporter, \nand the basolateral ATP-dependent Na+/K+ pump produces \nthe gradient for Ca2+ to be reabsorbed via a separate Na+/\nCa2+ basolateral antiporter. The excretion of Ca2+ is regulated ZONA OCCLUDENSBASOLATERAL\nMEMBRANE\nLUMENBLOODHCO3\u2013 HCO3\u2013Na+\nH+ H+Na+ Na+\nK+ K+P\nH2CO3\nH2O + CO2HCO3\u2212\nH2CO3\nMetabolismH2O + CO2\nH2O,CL\u2212\nH2O,CL\u2212CO2NaHCO3\nCarbonic\nanhydrase\ninhibitor\nAscending limb of Henle loop\nLUMEN BLOOD\nZONA OCCLUDENSNa+\nNa+Na+\nK+\nK+K+ K+\nCl\u2013 Cl\u2013\nCl\u2013Cl\u20132Cl\u2013\n+ve\n\u2212ve4\u201310 mVBASOLATERAL\nMEMBRANE\nC1\nC2PFiltrate\nhypo-osmoticBASOLATERAL\nMEMBRANE\nLUMEN BLOOD\nZONA OCCLUDENSNa+\nNa+Na+\nK+\nK+K+ K+\nCl\u2013\nCl\u2013\nCl\u2013Cl\u2013C3\nC3P\nCollecting tubule\nLUMEN BLOODNa+Na+ Na+\nK+K+K+\nCl\u2013\nCl\u2013PH2OH2O\nLoop diuretics \ne.g. furosemideAmiloride\nTriamterene\nAldosteroneCarbonic\nanhydrase Carbonic\nanhydrase\nBASOLATERAL\nMEMBRANE\nAldosterone\nstimulates\nsynthesisADH\n(vasopressin)\nincreases\nthe numberProximal tubule Distal tubule\nThiazides and\nrelated drugs\n(e.g. chlortalidone,\nindapamide,\nmetolazone)A\nBC\nD\nFig. 30.5 Drug effects on renal tubular ion transport. The primary active transport mechanism is the Na+/K+ pump (P) in the \nbasolateral membrane of cells in each location; the diagrams are simplified in that the pump exchanges three Na+ for two K+ ions. \n(A) Bicarbonate ion reabsorption in the proximal convoluted tubule, showing the action of carbonic anhydrase inhibitors. (B) Ion transport in \nthe thick ascending limb of Henle loop, showing the site of action of loop diuretics, namely the Na+/K+/2Cl\u2013 co-transporter (C1). Chloride \nions leave the cell both through basolateral chloride channels and by an electroneutral K+/Cl\u2013 co-transporter (C2) which are also present in \nthe distal tubule.", "start_char_idx": 0, "end_char_idx": 2584, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d39c77d6-d716-4b2b-ba16-b26761842279": {"__data__": {"id_": "d39c77d6-d716-4b2b-ba16-b26761842279", "embedding": null, "metadata": {"page_label": "392", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d283bc2a-2aae-46af-9947-d79f37917033", "node_type": null, "metadata": {"page_label": "392", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44373e7f36d4158435ab49515c1ab5593e040ed4c5a34458d822de8d0597d89c"}, "2": {"node_id": "3b36e16d-2823-4163-857e-be9c11b6d61d", "node_type": null, "metadata": {"page_label": "392", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eef73eaa3d864d7cd3eccd225562204a4cb90efcbdc3e170bb2cb62a64f1e199"}}, "hash": "4c70db81d43de421114065eeb2ffe8b839e592080974ac7e309ba9581ebf1003", "text": "co-transporter (C2) which are also present in \nthe distal tubule. (C) Salt transport in the distal convoluted tubule, showing the site of action of thiazide diuretics, namely the Na+/Cl\u2013 \nco-transporter (C3). (D) Actions of hormones and drugs on the collecting tubule. The cells are impermeable to water in the absence of \nantidiuretic hormone (ADH), and to Na+ in the absence of aldosterone. Aldosterone acts on a nuclear receptor within the tubule cell and on \nmembrane receptors. (Adapted from Greger, 2000.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2519, "end_char_idx": 3509, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1f07b549-1915-415b-8aab-3fccfb9ae59e": {"__data__": {"id_": "1f07b549-1915-415b-8aab-3fccfb9ae59e", "embedding": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "23964bd6-98c3-4daa-a759-58a6af6cd0ce", "node_type": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2b7534d3a0f9fc47aebc81795cfb33b3a516bdf06d474303bc9ea35ec6c5785"}, "3": {"node_id": "022cc04c-08dd-40c7-aa1c-4514c5cca6e8", "node_type": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d3cb239a743400868e9195f6f0db0dacabb17569195eca3fd005e715e6ab2ef"}}, "hash": "9bfa66046edfebc0a713575f8dac0c5382f05d9eaef989c56acc04d5b9a7656a", "text": "30 ThE kIDNEY AND URINARY SYSTEM\n387ACID\u2013BASE BALANCE\nThe kidneys (together with the lungs; Ch. 29) regulate the \nH+ concentration of body fluids. Acid or alkaline urine can \nbe excreted according to need, the usual requirement being \nto form acid urine to eliminate phosphoric and sulfuric \nacids generated during the metabolism of nucleic acids and of sulfur-containing amino acids consumed in the diet. \nConsequently, metabolic acidosis is a common accompani -\nment of renal failure. Altering urine pH to alter drug \nexcretion is mentioned later.of intercalated cells, \u03b1 and \u03b2, which secrete acid and base, respectively.\nThe tight junctions in this portion of the nephron are \nimpermeable to water and cations. The movement of ions and water in this segment is under independent hormonal \ncontrol: absorption of NaCl by aldosterone (Ch. 23), and \nabsorption of water by antidiuretic hormone (ADH), also \ntermed vasopressin (Ch. 34).\nAldosterone enhances Na\n+ reabsorption and promotes \nK+ excretion (see Fig. 30.5D). It promotes Na+ reabsorption \nby:\n\u2022\ta\trapid \teffect, \tup-regulating \tepithelial \tsodium \t \nchannels in the collecting duct, increasing apical membrane permeability and hence reabsorption of \nsodium ions by an action on membrane aldosterone receptors.\n3\n\u2022\tdelayed \teffects, \tvia \tnuclear \treceptors \t(see \tCh. \t3), \t\ndirecting the synthesis of a specific protein mediator up-regulating and activating the basolateral Na\n+/K+ \npump, which pumps three sodium ions out of the cell, \ninto the interstitial fluid and two potassium ions into \nthe cell from the interstitial fluid and stimulates synthesis of the epithelial sodium ion channel in \naddition to its rapid effect via the membrane receptor \nmentioned above.\nADH and nephrogenic diabetes insipidus. ADH is secreted \nby the posterior pituitary (Ch. 34) and acts on V 2 receptors \nin the basolateral membranes of cells in the collecting tubules \nand ducts, increasing expression of aquaporin (water chan -\nnels; see Ch. 9) in the apical membranes (see Fig. 30.5D). \nThis renders this part of the nephron permeable to water, \nallowing passive reabsorption of water as the collecting \nduct traverses the hyperosmotic region of the medulla, and hence the excretion of concentrated urine. Conversely, in \nthe absence of ADH, collecting duct epithelium is imperme -\nable to water, so hypotonic fluid that leaves the distal tubule \nremains hypotonic as it passes down the collecting ducts, leading to the excretion of dilute urine. Defective ADH \nsecretion (Ch. 34) or action on the kidney results in diabetes \ninsipidus , an uncommon disorder in which patients excrete \nlarge volumes of dilute urine.\nEthanol (Ch. 50) inhibits the secretion of ADH, causing \na water diuresis (possibly familiar to some of our readers) \nas a kind of transient diabetes insipidus. Nicotine enhances \nADH secretion (perhaps contributing to the appeal of an after-dinner cigar?).\nSeveral drugs inhibit the action of ADH: lithium (used \nin psychiatric disorders; see Ch. 48, demeclocycline (a \ntetracycline used not as an antibiotic, but rather to treat inappropriate secretion of ADH from tumours or in other \nconditions), colchicine (Ch. 27) and vinca alkaloids (Ch. \n57). Recently, more specific antagonists of ADH (e.g. \nconivaptan ,", "start_char_idx": 0, "end_char_idx": 3287, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "022cc04c-08dd-40c7-aa1c-4514c5cca6e8": {"__data__": {"id_": "022cc04c-08dd-40c7-aa1c-4514c5cca6e8", "embedding": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "23964bd6-98c3-4daa-a759-58a6af6cd0ce", "node_type": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2b7534d3a0f9fc47aebc81795cfb33b3a516bdf06d474303bc9ea35ec6c5785"}, "2": {"node_id": "1f07b549-1915-415b-8aab-3fccfb9ae59e", "node_type": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9bfa66046edfebc0a713575f8dac0c5382f05d9eaef989c56acc04d5b9a7656a"}, "3": {"node_id": "bf2c45db-bb35-422d-827a-f92b35566317", "node_type": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e144003ced7d56624e493fe158ae6309d7bfb2f300d656e187130f268689741a"}}, "hash": "8d3cb239a743400868e9195f6f0db0dacabb17569195eca3fd005e715e6ab2ef", "text": "Recently, more specific antagonists of ADH (e.g. \nconivaptan , tolvaptan ) have been introduced for treatment \nof hyponatraemia. Any of these drugs, given in excess, can cause acquired forms of nephrogenic diabetes insipi-\ndus, caused by a failure of the renal collecting ducts to respond to ADH. Nephrogenic diabetes insipidus can also \nbe caused by genetic disorders affecting the V\n2 receptor or \naquaporin.Renal tubular function \n\u2022\tProtein-free \tglomerular \tfiltrate \tenters \tvia \tBowman\u2019s \t\ncapsule.\n\u2022\tNa+-K+-ATPase in the basolateral membrane is the \nmain active transporter. It provides the Na+-gradients \n(low cytoplasmic Na+ concentrations) for passive \ntransporters in the apical membranes which facilitate \nNa+ entry (reabsorption) from the tubular fluid down a \nconcentration gradient and in exchange for hydrogen ions (H\n+).\n\u2022\t60%\u201370% \tof \tthe \tfiltered \tNa+ and >90% of HCO 3\u2212 is \nabsorbed in the proximal tubule.\n\u2022\tCarbonic \tanhydrase \tis \tkey \tfor \tNaHCO 3 reabsorption in \nthe proximal tubule and also for distal tubular urine acidification.\n\u2022\tThe\tthick \tascending \tlimb \tof \tHenle \tloop \tis \timpermeable \t\nto water; 20%\u201330% of the filtered NaCl is actively reabsorbed in this segment.\n\u2022\tIons\tare \treabsorbed \tfrom \ttubular \tfluid \tby \ta \tNa+/\nK+/2Cl\u2212 co-transporter in the apical membranes of the \nthick ascending limb.\n\u2022\tNa+/K+/2Cl\u2212 co-transport is inhibited by loop diuretics.\n\u2022\tFiltrate\tis \tdiluted \tas \tit \ttraverses \tthe \tthick \tascending \t\nlimb as ions are reabsorbed, so that it is hypotonic when it leaves.\n\u2022\tThe\ttubular \tcounter-current \tmultiplier \tactively \t\ngenerates a concentration gradient \u2013 small horizontal differences in solute concentration between tubular fluid and interstitium are multiplied vertically. The \ndeeper in the medulla, the more concentrated is the \ninterstitial fluid.\n\u2022\tMedullary \thypertonicity \tis \tpreserved \tpassively \tby \t\ncounter-current exchange in the vasa recta.\n\u2022\tNa+/Cl\u2212 co-transport (inhibited by thiazide diuretics) \nreabsorbs 5%\u201310% of filtered Na+ in the distal tubule.\n\u2022\tK+ is secreted into tubular fluid in the distal tubule and \nthe collecting tubules and collecting ducts.\n\u2022\tIn\tthe\tabsence \tof \tantidiuretic \thormone \t(ADH), \tthe \t\ncollecting tubule and collecting duct have low permeability to salt and water. ADH increases water permeability.\n\u2022\tNa\n+ is reabsorbed from the collecting duct through \nepithelial sodium channels.\n\u2022\tThese\tepithelial \tNa+ channels are activated by \naldosterone and inhibited by amiloride and by \ntriamterene. K+ or H+ is secreted into the tubule in \nexchange for Na+ in this distal region.\n3A mechanism distinct from regulation of gene transcription, which is \nthe usual transduction mechanism for steroid hormones (Ch. 3).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3234, "end_char_idx": 6247, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bf2c45db-bb35-422d-827a-f92b35566317": {"__data__": {"id_": "bf2c45db-bb35-422d-827a-f92b35566317", "embedding": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "23964bd6-98c3-4daa-a759-58a6af6cd0ce", "node_type": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2b7534d3a0f9fc47aebc81795cfb33b3a516bdf06d474303bc9ea35ec6c5785"}, "2": {"node_id": "022cc04c-08dd-40c7-aa1c-4514c5cca6e8", "node_type": null, "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d3cb239a743400868e9195f6f0db0dacabb17569195eca3fd005e715e6ab2ef"}}, "hash": "e144003ced7d56624e493fe158ae6309d7bfb2f300d656e187130f268689741a", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6270, "end_char_idx": 6493, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0c23416e-ae30-4688-afa3-fda6ddb23e09": {"__data__": {"id_": "0c23416e-ae30-4688-afa3-fda6ddb23e09", "embedding": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9793ce56-41fc-4689-8dca-fce50ad70ab5", "node_type": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "00dac5ab42dba231f9bdf586521105925ab711ef30c2794141e7f17c298e5a58"}, "3": {"node_id": "f75857ee-22e6-4b22-a79d-8f80a0ba490d", "node_type": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91fed0c105060326815d1779a22da4b7c53d10ff0dab4fe7cc7a2c50f9e01089"}}, "hash": "39bc37f02bd7ce2a7fb13c04fc0684a875a871bc9aa8f324602dfe7defe3fe50", "text": "30 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n388actions. The tubular actions include the inhibition of \nangiotensin II-stimulated Na+ and water reabsorption in \nthe proximal convoluted tubule, and of the action of ADH \nin promoting water reabsorption in the collecting tubule.\nWithin the kidney, the post-translational processing of \nANP prohormone differs from that in other tissues, resulting in an additional four amino acids being added to the amino \nterminus of ANP to yield a related peptide, urodilatin , that \npromotes Na\n+ excretion by acting on natriuretic peptide A \nreceptors.\nPROSTAGLANDINS AND RENAL FUNCTION\nProstaglandins (PGs; see Ch. 18) generated in the kidney influence its haemodynamic and excretory functions. The \nmain renal prostaglandins in humans are vasodilator and \nnatriuretic, namely PGE\n2 in the medulla and PGI 2 (prosta-\ncyclin) in glomeruli. Factors that stimulate their synthesis \ninclude ischaemia, angiotensin II, ADH and bradykinin.\nProstaglandin biosynthesis is low under basal conditions. \nHowever, when vasoconstrictors (e.g. angiotensin II, noradrenaline) are released, local release of PGE\n2 and PGI 2 \ncompensates, preserving renal blood flow by their vasodila -\ntor action.\nThe influence of renal prostaglandins on salt balance \nand haemodynamics can be inferred from the effects of non-steroidal anti-inflammatory drugs (NSAIDs, which \ninhibit prostaglandin production by inhibiting cyclo-oxygenase; see Ch. 27). NSAIDs have little or no effect on \nrenal function in healthy people, but predictably cause acute \nrenal failure in clinical conditions in which renal blood flow depends on vasodilator prostaglandin biosynthesis. These include cirrhosis of the liver, heart failure, nephrotic \nsyndrome, glomerulonephritis and extracellular volume \ncontraction (see Ch. 58, Table 58.1). NSAIDs increase blood pressure in patients treated for hypertension by \nimpairing PG-mediated vasodilatation and salt excre-\ntion. They exacerbate salt and water retention in patients with heart failure (see Ch. 23), partly by this same direct \nmechanism.\n4\nDRUGS ACTING ON THE KIDNEY\nDIURETICS\nDiuretics increase the excretion of Na+ and water. They \ndecrease the reabsorption of Na+ and an accompanying \nanion (usually Cl\u2212) from the filtrate, increased water loss \nbeing secondary to the increased excretion of NaCl (natriu -\nresis). This can be achieved:\n\u2022\tby\ta\tdirect \taction \ton \tthe \tcells \tof \tthe \tnephron\n\u2022\tindirectly, \tby \tmodifying \tthe \tcontent \tof \tthe \tfiltrate\nBecause a very large proportion of salt (NaCl) and water that passes into the tubule via the glomerulus is reabsorbed \n(see Table 30.1), even a small decrease in reabsorption can \ncause a marked increase in Na\n+ excretion. A summary \ndiagram of the mechanisms and sites of action of various POTASSIUM BALANCE\nExtracellular K+ concentration \u2013 critically important for \nexcitable tissue function (see Ch. 4) \u2013 is tightly controlled \nthrough regulation of K+ excretion by the kidney. Urinary \nK+ excretion matches dietary intake, usually approximately \n50\u2013100 mmol in 24 h in Western countries. Many diuretics \ncause K+ loss (see later).\nPotassium ions are transported into collecting duct and \ncollecting tubule cells from interstitial fluid by an Na+-K+-\nATPase in the basolateral membrane which is under the control", "start_char_idx": 0, "end_char_idx": 3334, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f75857ee-22e6-4b22-a79d-8f80a0ba490d": {"__data__": {"id_": "f75857ee-22e6-4b22-a79d-8f80a0ba490d", "embedding": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9793ce56-41fc-4689-8dca-fce50ad70ab5", "node_type": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "00dac5ab42dba231f9bdf586521105925ab711ef30c2794141e7f17c298e5a58"}, "2": {"node_id": "0c23416e-ae30-4688-afa3-fda6ddb23e09", "node_type": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39bc37f02bd7ce2a7fb13c04fc0684a875a871bc9aa8f324602dfe7defe3fe50"}, "3": {"node_id": "442a3b37-55fd-47a6-bc9e-e75918124e9f", "node_type": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2313c44cb023f0e6cb285c0fab355acc37e9ab164a17507ab4cf3a2afaaf424"}}, "hash": "91fed0c105060326815d1779a22da4b7c53d10ff0dab4fe7cc7a2c50f9e01089", "text": "in the basolateral membrane which is under the control of aldosterone (see earlier, p. 387), and leak into \nthe lumen through a K\n+-selective ion channel. Na+ passes \nfrom tubular fluid through sodium channels in the apical \nmembrane down the electrochemical gradient created by \nthe Na+-K+-ATPase; a lumen-negative potential difference \nacross the cell results, increasing the driving force for K+ \nsecretion into the lumen. Thus K+ secretion is coupled to \nNa+ reabsorption.\nConsequently, K+ is lost when:\n\u2022\tmore\tNa+ reaches the collecting duct, as occurs with \nany diuretic acting proximal to the collecting duct;\n\u2022\tNa+ reabsorption in the collecting duct is increased \ndirectly (e.g. in hyperaldosteronism).\nConversely, K+ is retained when:\n\u2022\tNa+ reabsorption in the collecting duct is decreased, \nfor example by amiloride or triamterene, which block \nthe sodium channel in this part of the nephron, or \nspironolactone or eplerenone, which antagonise aldosterone (see later).\nEXCRETION OF ORGANIC MOLECULES\nThere are distinct mechanisms (see Ch. 10, Table 10.7) for secreting organic anions and cations into the proximal \ntubular lumen. Secreted anions include several important \ndrugs, for example, thiazides, furosemide, salicylate (Ch. \n27), and most penicillins and cephalosporins (Ch. 52). Similarly, \nseveral secreted organic cations are important drugs, for example, triamterene, amiloride, atropine (Ch. 14), mor-\nphine (Ch. 43) and quinine (Ch. 55). Both anion and cation \ntransport mechanisms are, like other renal ion transport processes, indirectly powered by active transport of Na\n+ \nand K+, the energy being derived from Na+-K+-ATPase in \nthe basolateral membrane.\nOrganic anions in the interstitial fluid are exchanged \nwith cytoplasmic \u03b1-ketoglutarate by an antiport (i.e. an \nexchanger that couples uptake and release of \u03b1 -ketoglutarate \nwith, in the opposite direction, uptake and release of a different organic anion) in the basolateral membrane, and diffuse passively into the tubular lumen (see Fig. 30.3).\nOrganic cations diffuse into the cell from the interstitium \nand are then actively transported into the tubular lumen in exchange for H\n+.\nNATRIURETIC PEPTIDES\nEndogenous A, B and C natriuretic peptides (ANP, BNP and CNP; see Chs 22 and 23) are involved in the regulation \nof Na\n+ excretion. They are released from the heart in \nresponse to stretch (A and B), from endothelium (C) and from brain (B). They activate guanylyl cyclase (Ch. 3), and \ncause natriuresis both by renal haemodynamic effects (increasing glomerular capillary pressure by dilating afferent \nand constricting efferent arterioles) and by direct tubular 4Additionally, NSAIDs make many of the diuretics used to treat heart \nfailure less effective by competing with them for the organic anion \ntransport (OAT) mechanism mentioned above; loop diuretics and \nthiazides act from within the lumen by inhibiting exchange mechanisms \u2013 see later in this chapter \u2013 so blocking their secretion into the lumen \nreduces their effectiveness by reducing their concentrations at their sites \nof action.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3289, "end_char_idx": 6638, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "442a3b37-55fd-47a6-bc9e-e75918124e9f": {"__data__": {"id_": "442a3b37-55fd-47a6-bc9e-e75918124e9f", "embedding": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9793ce56-41fc-4689-8dca-fce50ad70ab5", "node_type": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "00dac5ab42dba231f9bdf586521105925ab711ef30c2794141e7f17c298e5a58"}, "2": {"node_id": "f75857ee-22e6-4b22-a79d-8f80a0ba490d", "node_type": null, "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91fed0c105060326815d1779a22da4b7c53d10ff0dab4fe7cc7a2c50f9e01089"}}, "hash": "b2313c44cb023f0e6cb285c0fab355acc37e9ab164a17507ab4cf3a2afaaf424", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6637, "end_char_idx": 6908, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "10446981-7715-4581-9c58-9d5f10656c32": {"__data__": {"id_": "10446981-7715-4581-9c58-9d5f10656c32", "embedding": null, "metadata": {"page_label": "395", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "21ffe82c-df0d-4aaa-a237-03ed78ebb398", "node_type": null, "metadata": {"page_label": "395", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "316fa0f1ba3bb130f2c49b343ae8a9961fbc6b03aca85fffc258b2b2ea9a8a64"}, "3": {"node_id": "42d6406f-08ff-4bc3-8916-3c38dd2fc136", "node_type": null, "metadata": {"page_label": "395", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a36879f8a873e2a4f7d5cf4e2487a961b5b0fc576f65bbc002359d75e646b84e"}}, "hash": "f42fb5e8a64f935160a94e5b6a4d67ea69007755b5824ab0accfe11f6d72ed84", "text": "30 ThE kIDNEY AND URINARY SYSTEM\n389mechanisms that have been invoked include decreased \nvascular responsiveness to vasoconstrictors such as angio -\ntensin II and noradrenaline; increased formation of vasodilat -\ning prostaglandins (see earlier); decreased production of the endogenous ouabain-like natriuretic hormone (Na\n+-K+-\nATPase inhibitor; see Ch. 22); and potassium-channel \nopening effects in resistance arteries (see Ellison & Sub -\nramanya, 2015).\nLoop diuretics increase the delivery of Na+ to the distal \nnephron, causing loss of H+ and K+. Because Cl\u2212 but not \nHCO 3\u2212 is lost in the urine, the plasma concentration of \nHCO 3\u2212 increases as plasma volume is reduced \u2013 a form of \nmetabolic alkalosis therefore referred to as \u2018contraction alkalosis\u2019.\nLoop diuretics increase excretion of Ca\n2+ and Mg2+ and \ndecrease excretion of uric acid.\nPharmacokinetic aspects\nLoop diuretics are absorbed from the gastrointestinal tract, \nand are usually given by mouth. They may also be given \nintravenously in urgent situations (e.g. acute pulmonary oedema) or when intestinal absorption is impaired, for \nexample, as a result of reduced intestinal perfusion in \npatients with severe chronic congestive heart failure, who can become resistant to the action of orally administered \ndiuretics. Given orally, they act within 1 h; given intra -\nvenously, they produce a peak effect within 30 min. Loop \ndiuretics are strongly bound to plasma protein, and so do not pass directly into the glomerular filtrate. They reach \ntheir site of action \u2013 the lumenal membrane of the cells of \nthe thick ascending limb \u2013 by being secreted in the proximal convoluted tubule by the organic acid transport mechanism; \nthe fraction thus secreted is excreted in the urine.\nIn nephrotic syndrome,\n5 loop diuretics become bound \nto albumin in the tubular fluid, and consequently are not available to act on the Na\n+/K+/2Cl\u2212 carrier \u2013 another cause \nof diuretic resistance.\nThe fraction of the diuretic not excreted in the urine is \nmetabolised, mainly in liver \u2013 bumetanide by cytochrome \nP450 pathways and furosemide by glucuronide formation. The plasma half-life of both these drugs is approximately \n90 min (longer in renal failure), and the duration of action \n3\u20136 h. The clinical use of loop diuretics is given in the box.\nUnwanted effects\nUnwanted effects directly related to the renal action of \nloop diuretics are common.6 Excessive Na+ and water loss, \nespecially in elderly patients, can cause hypovolaemia and hypotension. Potassium loss, resulting in low plasma K\n+ \n(hypokalaemia), and metabolic alkalosis are common. Hypokalaemia increases the effects and toxicity of several \ndrugs (e.g. digoxin and type III antidysrhythmic drugs, \nCh. 22), so this is potentially a clinically important source \nof drug interaction. If necessary, hypokalaemia can be diuretics is given in Fig. 30.4 and more detailed information \non different classes of drugs in Fig. 30.5.\nMost diuretics with a direct action on the nephron act \nfrom within the tubular lumen and reach their sites of action by being secreted into the proximal tubule ( spirono -\nlactone is an exception).\nDIURETICS ACTING DIRECTLY ON CELLS OF \nTHE NEPHRON\nThe main therapeutically useful diuretics act on the:\n\u2022\tthick\tascending \tloop \tof \tHenle\n\u2022\tearly\tdistal \ttubule\n\u2022\tcollecting \ttubules \tand", "start_char_idx": 0, "end_char_idx": 3344, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "42d6406f-08ff-4bc3-8916-3c38dd2fc136": {"__data__": {"id_": "42d6406f-08ff-4bc3-8916-3c38dd2fc136", "embedding": null, "metadata": {"page_label": "395", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "21ffe82c-df0d-4aaa-a237-03ed78ebb398", "node_type": null, "metadata": {"page_label": "395", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "316fa0f1ba3bb130f2c49b343ae8a9961fbc6b03aca85fffc258b2b2ea9a8a64"}, "2": {"node_id": "10446981-7715-4581-9c58-9d5f10656c32", "node_type": null, "metadata": {"page_label": "395", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f42fb5e8a64f935160a94e5b6a4d67ea69007755b5824ab0accfe11f6d72ed84"}}, "hash": "a36879f8a873e2a4f7d5cf4e2487a961b5b0fc576f65bbc002359d75e646b84e", "text": "\ttubule\n\u2022\tcollecting \ttubules \tand \tducts\nFor a more detailed review of the actions and clinical uses of the diuretics, see Ellison and Subramanya (2015).\nLoop diuretics\nLoop diuretics (see Fig. 30.5B) are the most powerful diuret -\nics (see Fig. 30.6 for a comparison with thiazides), capable \nof causing the excretion of 15%\u201325% of filtered Na+. Their \naction is often described \u2013 in a phrase that conjures up a rather uncomfortable picture \u2013 as causing \u2018torrential urine \nflow\u2019. The main example is furosemide; bumetanide and \ntorasemide are alternative agents. These drugs act on the \nthick ascending limb, inhibiting the Na\n+/K+/2Cl\u2212 carrier \nin the lumenal membrane by combining with its Cl\u2212 \nbinding site.\nLoop diuretics also have incompletely understood vas -\ncular actions. Intravenous administration of furosemide to \npatients with pulmonary oedema caused by acute heart \nfailure (see Ch. 23) causes a therapeutically useful vasodila -\ntor effect independent of the onset of diuresis. Possible \n02468101214\n100 10 1.0 0.1 0.01\nDose (mg/kg)ControlHydrochlorothiazideFurosemideSodium in urine (mEq/kg over 5 h)\nFig. 30.6 Dose\u2013response curves for furosemide and \nhydrochlorothiazide, showing differences in potency and \nmaximum effect \u2018ceiling\u2019. Note that these doses are not used \nclinically. (Adapted from Timmerman, R.J. et al., 1964. Curr. \nTher. Res 6, 88.)5Several diseases that damage renal glomeruli impair their ability to \nretain plasma albumin, causing massive loss of albumin in the urine \nand a reduced concentration of albumin in the plasma, which can in \nturn cause peripheral oedema. This is referred to as nephrotic syndrome.\n6Such unwanted effects are re-enacted in extreme form in Bartter \nsyndrome type 1, a rare loss-of-function genetic disorder of the Na+/\nK+/2Cl\u2212 transporter, the features of which include polyhydramnios \n\u2013 caused by fetal polyuria \u2013 and, postnatally, renal salt loss, low blood \npressure, hypokalaemic metabolic alkalosis and hypercalciuria.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3310, "end_char_idx": 5782, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e2300ea6-c926-4dad-b42c-d43221cfbe76": {"__data__": {"id_": "e2300ea6-c926-4dad-b42c-d43221cfbe76", "embedding": null, "metadata": {"page_label": "396", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "459d999d-7177-4ebf-802b-4cc4ccc2ce49", "node_type": null, "metadata": {"page_label": "396", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c20b7c45a1ebccb4b20cf69310d2ced2f46fde77fd1e4a5402036658b7c711a6"}, "3": {"node_id": "a166e3c1-9ebc-494a-93d5-cdb67fad0f92", "node_type": null, "metadata": {"page_label": "396", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "851527a4a50a12c0187052f44a29d7ade636dd3b5aa8332bde1dc3c0f3ccf012"}}, "hash": "1a10b9cba02435616f73abc091bdc1d51cec320979d847a28fa009aacb7b2ea1", "text": "30 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n390in magnitude. In contrast to loop diuretics, however, thi -\nazides reduce Ca2+ excretion, possibly advantageous in older \npatients at risk of osteoporosis and favouring thiazides \nover loop diuretics in this setting (Aung & Htay, 2011).\nAlthough thiazides are milder than loop diuretics when \nused alone, co-administration with loop diuretics has a synergistic effect, because the loop diuretic delivers a greater \nfraction of the filtered load of Na\n+ to the site of action of \nthe thiazide in the distal tubule.\nThiazide diuretics have a vasodilator action. When used \nin the treatment of hypertension (Ch. 23), the initial fall in blood pressure results from the decreased blood volume \ncaused by diuresis, but vasodilatation contributes to the \nlater phase.\nThiazide diuretics have a paradoxical effect in diabetes \ninsipidus, where they reduce the volume of urine by interfer -\ning with the production of hypotonic fluid in the distal tubule, and hence reduce the ability of the kidney to excrete hypotonic urine (i.e. they reduce free water clearance).\nPharmacokinetic aspects\nThiazides and thiazide-related drugs are effective orally. \nAll are excreted in the urine, mainly by tubular secretion, \nand they compete with uric acid for the organic anion transporter (OAT; see Ch. 9). Bendroflumethiazide has its \nmaximum effect at about 4\u20136 h and duration is 8\u201312 h. \nChlortalidone has a longer duration of action.\nThe clinical use of thiazide diuretics is given in the clinical \nbox.averted or treated by concomitant use of K+-sparing diuretics \n(see later), or supplementary potassium replacement. \nHypomagnesaemia is less often recognised but can also be \nclinically important. Hyperuricaemia is common and can precipitate acute gout (see Ch. 27). Excessive diuresis leads \nto reduced renal perfusion and consequent impairment of \nrenal function (an early warning of this is a rise in serum urea concentration).\nUnwanted effects unrelated to the renal actions of the drugs \nare infrequent. Dose-related hearing loss (compounded by concomitant use of other ototoxic drugs such as aminogly -\ncoside antibiotics) can result from impaired ion transport \nby the basolateral membrane of the stria vascularis in the \ninner ear. It occurs only at much higher doses than usually needed to produce diuresis. Adverse reactions unrelated \nto the main pharmacological effect (e.g. rashes, bone marrow \ndepression) can occur.\nDiuretics acting on the distal tubule\nDiuretics acting on the distal tubule include thiazides (e.g. bendroflumethiazide, hydrochlorothiazide) and related \ndrugs (e.g. chlortalidone, indapamide and metolazone; \nsee Fig. 30.5C).\nThiazides are less powerful than loop diuretics, at least \nin terms of peak increase in rate of urine formation, and are preferred in treating uncomplicated hypertension (Ch. 23). They are better tolerated than loop diuretics, and in \nclinical trials have been shown to reduce risks of stroke \nand heart attack associated with hypertension. In the largest trial (ALLHAT, 2002), chlortalidone performed as well as newer antihypertensive drugs (an angiotensin-converting \nenzyme [ACE] inhibitor and a calcium antagonist, see Ch. \n23). Thiazides bind the Cl\n\u2212 site of the distal tubular Na+/\nCl\u2212 co-transport system, inhibiting its action and causing \nnatriuresis with loss of", "start_char_idx": 0, "end_char_idx": 3381, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a166e3c1-9ebc-494a-93d5-cdb67fad0f92": {"__data__": {"id_": "a166e3c1-9ebc-494a-93d5-cdb67fad0f92", "embedding": null, "metadata": {"page_label": "396", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "459d999d-7177-4ebf-802b-4cc4ccc2ce49", "node_type": null, "metadata": {"page_label": "396", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c20b7c45a1ebccb4b20cf69310d2ced2f46fde77fd1e4a5402036658b7c711a6"}, "2": {"node_id": "e2300ea6-c926-4dad-b42c-d43221cfbe76", "node_type": null, "metadata": {"page_label": "396", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1a10b9cba02435616f73abc091bdc1d51cec320979d847a28fa009aacb7b2ea1"}}, "hash": "851527a4a50a12c0187052f44a29d7ade636dd3b5aa8332bde1dc3c0f3ccf012", "text": "system, inhibiting its action and causing \nnatriuresis with loss of sodium and chloride ions in the \nurine. The resulting contraction in blood volume stimulates \nrenin secretion, leading to angiotensin formation and aldosterone secretion (Ch. 23, see Figs 23.4 and 23.9). This \nhomeostatic mechanism limits the effect of the diuretic on \nblood pressure, resulting in an in vivo dose\u2013hypotensive response relationship with only a gentle gradient during \nchronic dosing.\nEffects of thiazides on Na\n+, K+, H+ and Mg2+ balance are \nqualitatively similar to those of loop diuretics, but smaller Clinical uses of loop diuretics \n(e.g. furosemide) \n\u2022\tLoop\tdiuretics \tare \tused \t(cautiously!), \tin \tconjunction \t\nwith dietary salt restriction and often with other classes \nof diuretic, in the treatment of salt and water overload associated with:\n\u2013 acute pulmonary oedema\n\u2013 chronic heart failure\n\u2013 cirrhosis of the liver complicated by ascites\n\u2013 nephrotic syndrome\n\u2013 renal failure\n\u2022\tTreatment \tof \thypertension complicated by renal \nimpairment (thiazides are preferred if renal function is preserved).\n\u2022\tTreatment \tof \thypercalcaemia after replacement of \nplasma volume with intravenous NaCl solution.\n7The chemically related sulfonylurea group of drugs used to treat \ndiabetes mellitus (Ch. 32) act in the opposite way, by closing K ATP \nchannels and enhancing insulin secretion.Clinical uses of thiazide diuretics \n(e.g. bendroflumethiazide) \n\u2022\tHypertension.\n\u2022\tMild\theart failure (loop diuretics are usually preferred).\n\u2022\tSevere\tresistant \toedema (metolazone, especially, is \nused, together with loop diuretics).\n\u2022\tTo\tprevent \trecurrent \tstone \tformation \tin \tidiopathic \nhypercalciuria.\n\u2022\tNephrogenic diabetes insipidus .\nUnwanted effects\nApart from an increase in urinary frequency , the commonest \nunwanted effect of thiazides not obviously related to their \nmain renal action is erectile dysfunction . This emerged in an \nanalysis of reasons given by patients for withdrawing from \nblinded treatment in the Medical Research Council mild \nhypertension trial, where (to the surprise of the investigators) \nerectile dysfunction was substantially more common than in men allocated to a \u03b2-adrenoceptor antagonist or to \nplacebo. Thiazide-associated erectile dysfunction is revers -\nible; it is less common with the low doses used in current practice but remains a problem. Potassium loss can be \nimportant, as can loss of Mg\n2+. Excretion of uric acid is \ndecreased, and hypochloraemic alkalosis can occur.\nImpaired glucose tolerance (see Ch. 32), due to inhibition \nof insulin secretion, is thought to result from activation of K\nATP channels in pancreatic islet cells.7 Diazoxide, a mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3314, "end_char_idx": 6474, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5dd6ccf6-bab8-4700-b78e-505e5eb656b0": {"__data__": {"id_": "5dd6ccf6-bab8-4700-b78e-505e5eb656b0", "embedding": null, "metadata": {"page_label": "397", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc16a687-6c9e-4f66-9194-286eeefa4fcc", "node_type": null, "metadata": {"page_label": "397", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59b17a160cdbb3244daac599b65f388ea7736a01e32751097d73cff1534d9f80"}, "3": {"node_id": "f329a71c-ca45-4ec2-91db-63079e33ec5e", "node_type": null, "metadata": {"page_label": "397", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c4fba03a085b590afbb2dbd751ceb1fedc2c0f08cffb009c24e592c18630ac22"}}, "hash": "a39c2d77dd0a0f4c05383b29c5dd5364f0755631b989461575fde92b55ac2df7", "text": "30 ThE kIDNEY AND URINARY SYSTEM\n391lumenal sodium channels (see Ch. 4), thereby indirectly \ndecreasing K+ excretion (see Fig. 30.5D).\nThey can be given with loop diuretics or thiazides in \norder to maintain potassium balance.\nPharmacokinetic aspects\nTriamterene is well absorbed in the gastrointestinal tract. \nIts onset of action is within 2 h, and its duration of action \n12\u201316 h. It is partly metabolised in the liver and partly \nexcreted unchanged in the urine. Amiloride is less well \nabsorbed and has a slower onset, with a peak action at 6 h \nand duration of about 24 h. Most of the drug is excreted \nunchanged in the urine.\nUnwanted effects\nThe main unwanted effect, hyperkalaemia, is related to the pharmacological action of these drugs and can be dangerous, \nespecially in patients with renal impairment or receiving \nother drugs that can increase plasma K\n+ (see above). \nGastrointestinal disturbances have been reported but are \ninfrequent. Idiosyncratic reactions, for example, rashes, are \nuncommon.\nCarbonic anhydrase inhibitors\nCarbonic anhydrase inhibitors (see Fig. 30.5A ) \u2013 for example, \nacetazolamide \u2013 increase excretion of bicarbonate with \naccompanying Na+, K+ and water, resulting in an increased \nflow of an alkaline urine and metabolic acidosis. These agents, although not now used as diuretics, are still used \nin the treatment of glaucoma to reduce the formation of aqueous humour (Ch. 14), in some types of infantile \nepilepsy (Ch. 46), and to accelerate acclimatisation to high \naltitude.\nUrinary loss of bicarbonate depletes extracellular bicar -\nbonate, and the diuretic effect of carbonic anhydrase \ninhibitors is consequently self-limiting. Acetazolamide is a sulfonamide and unwanted effects such as rashes, blood dyscrasias and interstitial nephritis can occur as with other \nsulfonamides (Ch. 52).\nDIURETICS THAT ACT INDIRECTLY BY MODIFYING THE \nCONTENT OF THE FILTRATE\nOsmotic diuretics\nOsmotic diuretics are pharmacologically inert substances \n(e.g. mannitol) that are filtered in the glomerulus but not non-diuretic thiazide, also activates K ATP channels, causing \nvasodilatation and impaired insulin secretion. Indapamide \nis said to lower blood pressure with less metabolic distur -\nbance than related drugs, possibly because it is marketed at a lower equivalent dose.\nHyponatraemia is potentially serious, especially in the \nelderly. Hypokalaemia can be a cause of adverse drug interaction (see previously under Loop diuretics) and can \nprecipitate encephalopathy in patients with severe liver \ndisease.\nAdverse reactions unrelated to the main pharmacology \n(e.g. rashes, blood dyscrasias) are not common but can be \nserious.\nAldosterone antagonists\nSpironolactone and eplerenone (Weinberger, 2004) have \nlimited diuretic action when used singly, because distal \nNa+/K+ exchange \u2013 the site on which they act \u2013 accounts \nfor reabsorption of only 2% of filtered Na+. They do, \nhowever, have marked antihypertensive effects (Ch. 23), prolong survival in selected patients with heart failure (Ch. \n23) and can prevent hypokalaemia when combined with loop diuretics or with thiazides. They compete with aldos -\nterone for its intracellular receptor (see Ch. 34), thereby inhibiting distal Na\n+ retention and K+ secretion (see Fig. \n30.5D).\nPharmacokinetic aspects\nSpironolactone is", "start_char_idx": 0, "end_char_idx": 3333, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f329a71c-ca45-4ec2-91db-63079e33ec5e": {"__data__": {"id_": "f329a71c-ca45-4ec2-91db-63079e33ec5e", "embedding": null, "metadata": {"page_label": "397", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bc16a687-6c9e-4f66-9194-286eeefa4fcc", "node_type": null, "metadata": {"page_label": "397", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59b17a160cdbb3244daac599b65f388ea7736a01e32751097d73cff1534d9f80"}, "2": {"node_id": "5dd6ccf6-bab8-4700-b78e-505e5eb656b0", "node_type": null, "metadata": {"page_label": "397", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a39c2d77dd0a0f4c05383b29c5dd5364f0755631b989461575fde92b55ac2df7"}}, "hash": "c4fba03a085b590afbb2dbd751ceb1fedc2c0f08cffb009c24e592c18630ac22", "text": "\n30.5D).\nPharmacokinetic aspects\nSpironolactone is well absorbed from the gut. Its plasma \nhalf-life is only 10 min, but its active metabolite, canrenone , \nhas a plasma half-life of 16 h. The action of spironolactone \nis largely attributable to canrenone. This, in addition to the slow turnover of membrane transporters, results in a slow \nonset of action, occurring over several days. Eplerenone \nhas a shorter elimination half-life than canrenone and has no active metabolites. It is administered by mouth \nonce daily.\nUnwanted effects\nAldosterone antagonists predispose to hyperkalaemia, \nwhich is potentially fatal. Potassium supplements should not be co-prescribed other than in exceptional circumstances and then with close monitoring of plasma \ncreatinine and electrolytes. Such monitoring is also \nneeded if these drugs are used for patients with impaired renal function, especially if other drugs that can increase \nplasma potassium, such as ACE inhibitors, angiotensin \nreceptor antagonists (sartans) (Ch. 23) or \u03b2-adrenoceptor \nantagonists (Ch. 15) are also prescribed \u2013 as they often are \nfor patients with heart failure. Gastrointestinal upset is quite common. Actions of spironolactone/canrenone on progesterone and androgen receptors in tissues other than \nthe kidney can cause gynaecomastia, menstrual disorders \nand testicular atrophy. Eplerenone has lower affinity for these receptors, and such oestrogen-like side effects are less \ncommon.\nThe clinical use of potassium-sparing diuretics is given \nin the clinical box.\nTriamterene and amiloride\nLike aldosterone antagonists, triamterene and amiloride \nhave only limited diuretic efficacy, because they also act \nin the distal nephron, where only a small fraction of Na+ \nreabsorption occurs. They act on the collecting tubules and collecting ducts, inhibiting Na\n+ reabsorption by blocking Clinical uses of potassium-sparing \ndiuretics (e.g. spironolactone, \namiloride) \n\u2022\tWith\tK+-losing (i.e. loop or thiazide) diuretics to prevent \nK+ loss, where hypokalaemia is especially hazardous \n(e.g. patients requiring digoxin or amiodarone; see \nCh. 22).\n\u2022\tSpironolactone or eplerenone is used in:\n\u2013 heart failure , to improve survival (see Ch. 22)\n\u2013 primary hyperaldosteronism \t(Conn\u2019s\tsyndrome)\n\u2013 resistant essential hypertension (especially low-renin \nhypertension)\n\u2013 secondary hyperaldosteronism caused by hepatic \ncirrhosis complicated by ascitesmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3283, "end_char_idx": 6184, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "93396b37-9a2f-4a6d-bb09-c8dbaa22042a": {"__data__": {"id_": "93396b37-9a2f-4a6d-bb09-c8dbaa22042a", "embedding": null, "metadata": {"page_label": "398", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3056a80d-c271-43fb-804d-8d5552bd4c21", "node_type": null, "metadata": {"page_label": "398", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd89c50caaf256de5de6faca5a368a5424fb01802ed1da1d02a1ff3f6c698f74"}, "3": {"node_id": "aa25fe5d-5214-46eb-86f8-180bab29671c", "node_type": null, "metadata": {"page_label": "398", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4cf7f9cfe8175d909c4c09fa778ff76aea939d3e8b81c3fec4352e6956ab8d7a"}}, "hash": "d0886ae921394611398dd75216ccf06bb9b432515cbf00999888c1c973ba8cdf", "text": "30 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n392Urinary pH can be decreased with ammonium chloride , \nbut this is now rarely, if ever, used clinically.\nDRUGS THAT ALTER THE EXCRETION OF \nORGANIC MOLECULES\nUric acid metabolism and excretion are relevant in the \ntreatment and prevention of gout (Ch. 27), and a few points \nabout its excretion are made here. Normal plasma urate \nconcentration is approximately 0.24 mmol/L, higher \nconcentrations predisposing to gout (see Ch. 27)\nUric acid is derived from the catabolism of purines, and \nis present in plasma mainly as ionised urate. In humans, \nit passes freely into the glomerular filtrate, and most is then reabsorbed in the proximal tubule while a small \namount is secreted into the tubule by the anion-secreting \nmechanism. The net result is excretion of approximately 8%\u201312% of filtered urate. The secretory mechanism is \ngenerally inhibited by low doses of drugs that affect uric \nacid transport (see later), whereas higher doses are needed to block reabsorption. Such drugs therefore tend to cause retention of uric acid at low doses, while promoting its \nexcretion at higher doses. Drugs that increase the elimination \nof urate ( uricosuric agents , e.g. probenecid and sulfinpyra -\nzone) may be useful in such patients, although these have \nlargely been supplanted by allopurinol , which inhibits urate \nsynthesis (Ch. 27).reabsorbed (see Fig. 30.4).8 Their main effect is exerted in \nthose parts of the nephron that are freely permeable to water: the proximal tubule, descending limb of the loop \nand (in the presence of ADH; see earlier) the collecting tubules. Passive water reabsorption is reduced by the \npresence of non-reabsorbable solute within the tubule; \nconsequently a larger volume of fluid remains within the proximal tubule. This has the secondary effect of reducing \nNa\n+ reabsorption.\nTherefore the main effect of osmotic diuretics is to increase \nthe amount of water excreted, with a smaller increase in \nNa+ excretion. They are sometimes used in acute renal \nfailure, which can occur as a result of haemorrhage, injury \nor systemic infections. In acute renal failure, glomerular \nfiltration rate is reduced, and absorption of NaCl and water in the proximal tubule becomes almost complete, so that \nmore distal parts of the nephron virtually \u2018dry up\u2019, and \nurine flow ceases. Protein is deposited in the tubules and may impede the flow of fluid. Osmotic diuretics (e.g. man-\nnitol\n given intravenously in a dose of 12\u201315 g) can limit \nthese effects, at least if given in the earliest stages, albeit while increasing intravascular volume and risking left \nventricular failure.\nOsmotic diuretics are also used for the emergency treat-\nment of acutely raised intracranial or intraocular pressure. Such treatment has nothing to do with the kidney, but \nrelies on the increase in plasma osmolarity by solutes that do not enter the brain or eye, which results in efflux of \nwater from these compartments.\nUnwanted effects include transient expansion of the \nextracellular fluid volume (with a risk of precipitating left \nventricular failure) and hyponatraemia. Headache, nausea \nand vomiting can occur.\nDRUGS THAT ALTER THE pH OF \nTHE URINE\nIt is possible, using pharmacological agents, to produce \nurinary pH values ranging from approximately 5 to 8.5.\nCarbonic anhydrase inhibitors increase urinary pH by \nblocking", "start_char_idx": 0, "end_char_idx": 3402, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aa25fe5d-5214-46eb-86f8-180bab29671c": {"__data__": {"id_": "aa25fe5d-5214-46eb-86f8-180bab29671c", "embedding": null, "metadata": {"page_label": "398", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3056a80d-c271-43fb-804d-8d5552bd4c21", "node_type": null, "metadata": {"page_label": "398", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd89c50caaf256de5de6faca5a368a5424fb01802ed1da1d02a1ff3f6c698f74"}, "2": {"node_id": "93396b37-9a2f-4a6d-bb09-c8dbaa22042a", "node_type": null, "metadata": {"page_label": "398", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0886ae921394611398dd75216ccf06bb9b432515cbf00999888c1c973ba8cdf"}}, "hash": "4cf7f9cfe8175d909c4c09fa778ff76aea939d3e8b81c3fec4352e6956ab8d7a", "text": "anhydrase inhibitors increase urinary pH by \nblocking bicarbonate reabsorption (see earlier). Citrate (given by mouth as a mixture of sodium and potassium \nsalts) is metabolised via the Krebs cycle with generation \nof bicarbonate, which is excreted, alkalinising the urine. This may have some antibacterial effects, as well as improv -\ning dysuria (a common symptom of bladder infection, consisting of a burning sensation while passing urine). Additionally, some citrate is excreted in the urine as such and inhibits urinary stone formation. Alkalinisation is \nimportant in preventing certain weak acid drugs with \nlimited aqueous solubility, such as sulfonamides (see Ch. 52), from crystallising in the urine; it also decreases the \nformation of uric acid and cystine stones by favouring the \ncharged anionic form that is more water-soluble (Ch. 9).\nAlkalinising the urine increases the excretion of drugs \nthat are weak acids (e.g. salicylates and some barbiturates). Sodium bicarbonate is sometimes used to treat salicylate overdose (Ch. 10).Diuretics \n\u2022\tNormally \t<1% of filtered Na+ is excreted.\n\u2022\tDiuretics \tincrease \tthe \texcretion \tof \tsalt \t(NaCl \tor \t\nNaHCO 3) and water.\n\u2022\tLoop\tdiuretics, \tthiazides \tand \tK+-sparing diuretics are \nthe main therapeutic drugs.\n\u2022\tLoop\tdiuretics \t(e.g. \tfurosemide) cause copious urine \nproduction. They inhibit the Na+/K+/2Cl\u2212 co-transporter \nin the thick ascending loop of Henle. They are used to \ntreat heart failure and other diseases complicated by \nsalt and water retention. Hypovolaemia and \nhypokalaemia are important unwanted effects.\n\u2022\tThiazides \t(e.g. \tbendroflumethiazide) have a smaller \ndiuretic effect than loop diuretics. They inhibit the Na+/\nCl\u2212 co-transporter in the distal convoluted tubule. They \nare used to treat hypertension, working partly through an indirect vasodilator action. Erectile dysfunction is an \nimportant adverse effect. Hypokalaemia and other \nmetabolic effects (e.g. hyperuricaemia, hyperglycaemia) can occur, especially with high doses.\n\u2022\tPotassium-sparing \tdiuretics:\n\u2013 act in the distal nephron and collecting tubules; they \nare weak diuretics but effective in some forms of hypertension and heart failure, and they can prevent hypokalaemia caused by loop diuretics or thiazides.\n\u2013 canrenone, the active metabolite of spironolactone \nand eplerenone compete with aldosterone for its \nreceptor.\n\u2013 amiloride and triamterene act by blocking the sodium \nchannels\tcontrolled \tby \taldosterone\u2019s \tprotein \tmediator.\n8In hyperglycaemia, glucose acts as an osmotic diuretic once plasma \nglucose exceeds the renal reabsorptive capacity (usually approximately \n12 mmol/L), accounting for the cardinal symptom of polyuria in \ndiabetes mellitus; see Chapter 32.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3349, "end_char_idx": 6560, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a3c8c6f8-ad37-4671-b6ff-e768df124503": {"__data__": {"id_": "a3c8c6f8-ad37-4671-b6ff-e768df124503", "embedding": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "99654b0e-1227-4397-b5f6-0115d42111d6", "node_type": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d989682b6d91b30bc095fce67b1979e979d0b42f4811626cee8e3d90f85258c7"}, "3": {"node_id": "36957aa3-39da-46a2-ada9-495e1c9e200d", "node_type": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "41a2537f406573429d27489d7250a301f740b0993bd5b58a0cf7cbe746906313"}}, "hash": "d4e432afcfd385a8e758bef28d44d18de3eab3becc1b233576f7f7aeea1a6e4e", "text": "30 ThE kIDNEY AND URINARY SYSTEM\n393is not absorbed from the gut and has an additional effect \nin lowering low-density lipoprotein cholesterol. It is given \nin gram doses by mouth three times a day with meals. Its \nadverse effects are gastrointestinal disturbance, and it is contraindicated in bowel obstruction.\nHYPERKALAEMIA\nSevere hyperkalaemia is life-threatening. Cardiac toxicity is counteracted directly by administering calcium gluconate \nintravenously (Table 22.1), and by measures that shift K\n+ \ninto the intracellular compartment, for example glucose plus insulin (Ch. 32). Salbutamol, administered intra-\nvenously or by inhalation, also causes cellular K\n+ uptake \nand is used for this indication (e.g. Murdoch et al., 1991); \nit acts synergistically with insulin. Intravenous sodium \nbicarbonate is also often recommended, and moves potas -\nsium ions into cells in exchange for intracellular protons that emerge to buffer the extracellular fluid. Removal of excessive potassium from the body can be achieved by \ncation exchange resins such as sodium or calcium poly -\nstyrene sulfonate administered by mouth (in combination \nwith sorbitol to prevent constipation) or as an enema. \nDialysis is often needed.\nDRUGS USED IN URINARY TRACT \nDISORDERS\nBed wetting (enuresis) is normal in very young children \nand persists in around 5% of children aged 10 years. \nNocturnal enuresis in children aged 10 years or more may \nwarrant treatment with desmopressin (an analogue of \nantidiuretic hormone, given by mouth or by nasal spray \nfor the treatment of diabetes insipidus caused by ADH \ndeficiency due to disease of the posterior pituitary gland Ch. 34), combined with restricting fluid intake in the evening.\nDisordered micturition is also common in adults. Symp -\ntoms from benign prostatic hyperplasia may be improved by \u03b1\n1-adrenoceptor antagonists, for example doxazosin or \ntamsulosin (Ch. 15), or by an inhibitor of androgen synthesis \nsuch as finasteride (Ch. 36).\nMuscarinic receptor antagonists (Ch. 14) such as oxybu-\ntinin are used for neurogenic detrusor muscle instability \n(\u2018overactive bladder\u2019), but the dose is limited by their adverse \neffects. A selective \u03b23 agonist ( mirabegron ) is also licensed \nfor this indication (Ch. 15), but can cause tachycardia and \natrial fibrillation.Probenecid inhibits the anion transporter responsible for \nthe reabsorption of urate in the proximal tubule, increasing its excretion. It has the opposite effect on penicillin, inhibit -\ning its secretion into the tubules and raising its plasma \nconcentration. Given orally, probenecid is well absorbed \nin the gastrointestinal tract, maximal concentrations in the \nplasma occurring in about 3 h. Approximately 90% is bound \nto plasma albumin. Free drug passes into the glomerular \nfiltrate but more is actively secreted into the proximal tubule, \nwhence it may diffuse back because of its high lipid solubil -\nity (see also Ch. 10). Sulfinpyrazone acts similarly.\nThe main effect of uricosuric drugs is to block urate \nreabsorption and lower plasma urate concentration. Both \nprobenecid and sulfinpyrazone inhibit the secretion as well as the reabsorption of urate and, if given in subtherapeutic \ndoses, can actually increase plasma urate concentrations.\nDRUGS USED IN RENAL FAILURE\nMany drugs used in chronic renal failure (e.g. antihyper-\ntensives, vitamin D preparations and", "start_char_idx": 0, "end_char_idx": 3394, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "36957aa3-39da-46a2-ada9-495e1c9e200d": {"__data__": {"id_": "36957aa3-39da-46a2-ada9-495e1c9e200d", "embedding": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "99654b0e-1227-4397-b5f6-0115d42111d6", "node_type": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d989682b6d91b30bc095fce67b1979e979d0b42f4811626cee8e3d90f85258c7"}, "2": {"node_id": "a3c8c6f8-ad37-4671-b6ff-e768df124503", "node_type": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4e432afcfd385a8e758bef28d44d18de3eab3becc1b233576f7f7aeea1a6e4e"}, "3": {"node_id": "581e61cb-ce6d-45e7-b18e-2c91986aa04f", "node_type": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ef262367b8b39049d87cd61951afc03557b62434e59055bdb4850aa11fcc903"}}, "hash": "41a2537f406573429d27489d7250a301f740b0993bd5b58a0cf7cbe746906313", "text": "antihyper-\ntensives, vitamin D preparations and epoetin ) are covered \nin other chapters. Electrolyte disorders are particularly important in renal failure, notably hyperphosphataemia and \nhyperkalaemia, and may require drug treatment.\nHYPERPHOSPHATAEMIA\nPhosphate metabolism is closely linked with that of calcium and is discussed in Chapter 37.\nThe antacid aluminium hydroxide (Ch. 31) binds phos -\nphate in the gastrointestinal tract, reducing its absorption, but may increase plasma aluminium in dialysis patients.\n9 \nCalcium-based phosphate-binding agents (e.g. calcium \ncarbonate) are widely used to treat hyperphosphatemia. \nThey are contraindicated in hypercalcaemia or hypercalciuria but until recently have been believed to be otherwise safe. \nHowever, calcium salts may predispose to tissue calcification \n(including of artery walls), and calcium-containing phos -\nphate binders may actually contribute to the very high \ndeath rates from cardiovascular disease in dialysis patients.\nAn anion exchange resin, sevelamer, lowers plasma \nphosphate, and is less likely than calcium carbonate to \ncause arterial calcification (Tonelli et al., 2010). Sevelamer \n9Before Kerr identified the cause in Newcastle, the use of alum to purify \nmunicipal water supplies led to a horrible and untreatable \nneurodegenerative condition known as \u2018dialysis dementia\u2019, and also to \na particularly painful and refractory form of bone disease.\nREFERENCES AND FURTHER READING\nPhysiological aspects\nAgre, P., 2004. Aquaporin water channels (Nobel lecture). Angew. \nChem. Int. Ed. Engl. 43, 4278\u20134290.\nGamba, G., 2015. Molecular physiology and pathophysiology of \nelectroneutral cation-chloride cotransporters. Physiol. Rev. 85, 423\u2013493. (Comprehensive review of this family: some of these cotransporters \nare targets for loop diuretics and thiazide-type diuretics, and inactivating \nmutations of three members of the family cause Bartter\u2019s, Gitelman\u2019s, and Anderman\u2019s diseases)\nGreger, R., 2000. Physiology of sodium transport. Am. J. Med. Sci. \n319, 51\u201362. (Outstanding article. Covers not only Na\n+ transport \nbut also, briefly, that of K+, H+, Cl\u2212, HCO 3\u2212, Ca2+, Mg2+ and some \norganic substances in each of the main parts of the nephron. Discusses \nregulatory factors, pathophysiological aspects and pharmacological \nprinciples)Nigam, S.K., Bush, K.T., Martovetsky, G., 2016. The organic anion \ntransporter (oat) family: a systems biology perspective. Physiol. Rev. \n95, 83\u2013123. (The organic anion transporter (OAT) subfamily has received a \ngreat deal of attention because of its role in handling of common drugs including antibiotics, antivirals, diuretics, and nonsteroidal \nanti-inflammatory drugs in addition to toxins and nutrient vitamins and \nflavonoids)\nDrugs and therapeutic aspects\nDiuretics\nAung, K., Htay, T., 2011. Thiazide diuretics and the risk of hip fracture. \nCochrane Database Syst. Rev. (10), CD005185, doi:10.1002/14651858.\nCD005185.pub2.\nEllison, D.H., Subramanya, A.R., 2015. Clinical use of diuretics. In: \nTurner, N.N., Lameire, N., Goldsmith, D.J., Winearls, C.G., mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3352, "end_char_idx": 6503, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "581e61cb-ce6d-45e7-b18e-2c91986aa04f": {"__data__": {"id_": "581e61cb-ce6d-45e7-b18e-2c91986aa04f", "embedding": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "99654b0e-1227-4397-b5f6-0115d42111d6", "node_type": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d989682b6d91b30bc095fce67b1979e979d0b42f4811626cee8e3d90f85258c7"}, "2": {"node_id": "36957aa3-39da-46a2-ada9-495e1c9e200d", "node_type": null, "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "41a2537f406573429d27489d7250a301f740b0993bd5b58a0cf7cbe746906313"}}, "hash": "2ef262367b8b39049d87cd61951afc03557b62434e59055bdb4850aa11fcc903", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6483, "end_char_idx": 6962, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1e766be0-80d5-496d-bf71-cde443af6211": {"__data__": {"id_": "1e766be0-80d5-496d-bf71-cde443af6211", "embedding": null, "metadata": {"page_label": "400", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e275ccf1-1505-4c57-811f-366b460d12df", "node_type": null, "metadata": {"page_label": "400", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a49e672af1436412f5b536ad227eb1fcd6ca382ea10958e4398c05dffa4aec78"}, "3": {"node_id": "a90a5b27-a4d8-4607-ad33-7797848116cf", "node_type": null, "metadata": {"page_label": "400", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "849c0a3fca7d6987d488cb0233c40a2437bc38d57172bc8a4ee2118eef1248c5"}}, "hash": "5094d86dcc33731170f17d163e9d82f3385b351e4476fc2453d93bc3e77e808b", "text": "30 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n394Nijenhuis, T., Vallon, V., van der Kemp, A.W., et al., 2005. Enhanced \npassive Ca2+ reabsorption and reduced Mg2+ channel abundance \nexplains thiazide-induced hypocalciuria and hypomagnesemia. J. Clin. \nInvest. 115, 1651\u20131658. (Micropuncture studies in mouse knock-outs \nshowing that enhanced passive Ca2+ transport in the proximal tubule rather \nthan active Ca2+ transport in distal convolution explains thiazide-induced \nhypocalciuria)\nSodium and potassium ion disorders\nCoca, S.G., Perazella, M.A., Buller, G.K., 2005. The cardiovascular \nimplications of hypokalemia. Am. J. Kidney Dis. 45, 233\u2013247. (This \nreview addresses the relative benefits of modulating potassium balance versus \nnon-renal effects of aldosterone blockade)\nMurdoch, I.A., Dos Anjos, R., Haycock, G.B., 1991. Treatment of \nhyperkalaemia with intravenous salbutamol. Arch. Dis. Child. 66, 527\u2013528. (First description of this approach in children)\nDrug utilisation in kidney disease\nGolper, T.A., Udy, A.A., Lipman, J., 2015. Drug dosing in acute kidney \ninjury. In: Turner, N.N., Lameire, N., Goldsmith, D.J., Winearls, C.G., \nHimmelfarb, J.Remuzzi, G. (Eds.), Oxford Textbook of Clinical \nNephrology, fourth ed. Oxford University Press, Oxford.\nOlyaei, A.J., Foster, T.A., Lermer, E.V., 2015. Drug dosing in chronic \nkidney disease. In: Turner, N.N., Lameire, N., Goldsmith, D.J., Winearls, C.G., Himmelfarb, J.Remuzzi, G. (Eds.), Oxford Textbook of Clinical Nephrology, fourth ed. Oxford University Press, Oxford.Himmelfarb, J.Remuzzi, G. (Eds.), Oxford Textbook of Clinical Nephrology, fourth ed. Oxford University Press, Oxford.\nShankar, S.S., Brater, D.C., 2003. Loop diuretics: from the Na\u2013K\u20132Cl \ntransporter to clinical use. Am. J. Physiol. Renal Physiol. 284, F11\u2013F21. (Reviews pharmacokinetics and pharmacodynamics of loop diuretics in health \nand in oedematous disorders)\nWeinberger, M.H., 2004. Eplerenone \u2013 a new selective aldosterone \nreceptor antagonist. Drugs Today 40, 481\u2013485. (Review)\nCa2+/PO 4\u2212 (see also Diuretics section, above)\nTonelli, M., Pannu, N., Manns, B., 2010. Drug therapy: oral phosphate \nbinders in patients with kidney failure. N. Engl. J. Med. 362, 1312\u20131324.\nVervloet, M., Cozzolino, M., 2017. Vascular calcification in chronic \nkidney disease: different bricks in the wall? Kidney Int. 91, 808\u2013817. (Complexity due to different kinds of vascular calcification in chronic kidney \ndiosease patients, with different implications regarding vascular risk)\nAntihypertensives and renal protection\nALLHAT Officers and Coordinators for the ALLHAT Collaborative \nResearch Group, 2002. Major outcomes in high-risk hypertensive \npatients randomized to angiotensin-converting enzyme inhibitor or \ncalcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). \nJAMA 288,", "start_char_idx": 0, "end_char_idx": 2890, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a90a5b27-a4d8-4607-ad33-7797848116cf": {"__data__": {"id_": "a90a5b27-a4d8-4607-ad33-7797848116cf", "embedding": null, "metadata": {"page_label": "400", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e275ccf1-1505-4c57-811f-366b460d12df", "node_type": null, "metadata": {"page_label": "400", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a49e672af1436412f5b536ad227eb1fcd6ca382ea10958e4398c05dffa4aec78"}, "2": {"node_id": "1e766be0-80d5-496d-bf71-cde443af6211", "node_type": null, "metadata": {"page_label": "400", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5094d86dcc33731170f17d163e9d82f3385b351e4476fc2453d93bc3e77e808b"}}, "hash": "849c0a3fca7d6987d488cb0233c40a2437bc38d57172bc8a4ee2118eef1248c5", "text": "Treatment to Prevent Heart Attack Trial (ALLHAT). \nJAMA 288, 2981\u20132997. (Massive trial; see also Appel, L.J. for editorial \ncomment: \u2018The verdict from ALLHAT \u2013 thiazide diuretics are the preferred initial therapy for hypertension\u2019. JAMA 288, 3039\u20133042)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2830, "end_char_idx": 3561, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6849990d-27d9-45d5-996f-645854487eb0": {"__data__": {"id_": "6849990d-27d9-45d5-996f-645854487eb0", "embedding": null, "metadata": {"page_label": "401", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "34ba7415-d15f-442f-a6b0-4dab14e18ba6", "node_type": null, "metadata": {"page_label": "401", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69dd597644737822a37a670e4105189c8564263f088567e6d3f7268389fca4b1"}, "3": {"node_id": "e7533d64-c5a3-4d86-b883-908fa045d964", "node_type": null, "metadata": {"page_label": "401", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "81fa9086c41fbcaead90a7199ec7e8c355b39939bca12a03ea5d701770d83879"}}, "hash": "bfd537d266cc8c3923e11bdc8ad82f53411fa64f72bc9f4aa2624982a48ca9b0", "text": "395\nThe gastrointestinal tract 31 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3\nOVERVIEW\nIn addition to its main function of digestion and \nabsorption of food, the gastrointestinal (GI) tract is \none of the major endocrine systems in the body. It \nalso has its own integrative neuronal network, the enteric nervous system (see Ch. 13), which contains \nalmost the same number of neurons as the spinal cord. It is the site of many common pathologies, ranging from simple dyspepsia to complex autoimmune \nconditions such as Crohn\u2019s disease, and medicines \nfor treating GI disorders comprise some 8% of all prescriptions. In this chapter, we briefly review the \nphysiological control of GI function and then discuss \nthe pharmacological characteristics of drugs affecting gastric secretion and motility, and those used to treat \nintestinal inflammatory disease.\nTHE INNERVATION AND HORMONES OF \nTHE GASTROINTESTINAL TRACT\nThe blood vessels and the glands (exocrine, endocrine and \nparacrine) of the GI tract are under both neuronal and \nhormonal control.\nNEURONAL CONTROL\nThere are two principal intramural plexuses in the tract: \nthe myenteric plexus (Auerbach\u2019s plexus) lies between the \nouter, longitudinal and the middle, circular muscle layers, and the submucous plexus (Meissner\u2019s plexus) lies on the lumenal side of the circular muscle layer. These plexuses \nare interconnected and their ganglion cells receive pregan -\nglionic parasympathetic fibres from the vagus. These are \nmostly cholinergic and excitatory, although a few are \ninhibitory. Incoming sympathetic fibres are largely post -\nganglionic. In addition to innervating blood vessels, smooth \nmuscle and some glandular cells directly, some sympathetic fibres terminate in these plexuses, where they inhibit \nacetylcholine secretion (see Ch. 13).\nThe neurons within the plexuses constitute the \nenteric nervous system and secrete not only acetylcho -\nline and noradrenaline (norepinephrine), but also 5- \nhydroxytryptamine (5-HT), purines, nitric oxide and a \nvariety of pharmacologically active peptides (see Chs 13\u201321). \nThe enteric plexus also contains sensory neurons, which respond to mechanical and chemical stimuli.\nHORMONAL CONTROL\nThe hormones of the GI tract include both endocrine and paracrine secretions. The endocrine secretions (i.e. substances \nreleased into the bloodstream) are mainly peptides syn -\nthesised by endocrine cells in the mucosa. Important examples include gastrin and cholecystokinin. The paracrine \nsecretions include many regulatory peptides released from \nspecial cells found throughout the wall of the tract. These \nhormones act on nearby cells, and in the stomach the most important of these is histamine. Some of these paracrine \nfactors also function as neurotransmitters.\nOrally administered drugs are, of course, absorbed during \ntheir passage through the GI tract (Ch. 9). Other functions \nof the GI tract that are important from the viewpoint of \npharmacological intervention are:\n\u2022\tgastric \tsecretion\n\u2022\tvomiting \t(emesis) \tand \tnausea\n\u2022\tgut\tmotility \tand \tdefecation\n\u2022\tthe\tformation \tand \texcretion \tof \tbile\nGASTRIC SECRETION\nThe stomach secretes about 2.5 L of gastric juice daily. The \nprincipal exocrine components are proenzymes such as prorennin and pepsinogen elaborated by the chief or peptic \ncells, and hydrochloric acid (HCl) and intrinsic factor (see Ch. \n26) secreted by the parietal", "start_char_idx": 0, "end_char_idx": 3411, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e7533d64-c5a3-4d86-b883-908fa045d964": {"__data__": {"id_": "e7533d64-c5a3-4d86-b883-908fa045d964", "embedding": null, "metadata": {"page_label": "401", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "34ba7415-d15f-442f-a6b0-4dab14e18ba6", "node_type": null, "metadata": {"page_label": "401", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69dd597644737822a37a670e4105189c8564263f088567e6d3f7268389fca4b1"}, "2": {"node_id": "6849990d-27d9-45d5-996f-645854487eb0", "node_type": null, "metadata": {"page_label": "401", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bfd537d266cc8c3923e11bdc8ad82f53411fa64f72bc9f4aa2624982a48ca9b0"}}, "hash": "81fa9086c41fbcaead90a7199ec7e8c355b39939bca12a03ea5d701770d83879", "text": "and intrinsic factor (see Ch. \n26) secreted by the parietal or oxyntic cells. The production \nof acid is important for promoting proteolytic digestion of foodstuffs, iron absorption and killing pathogens. Mucus-\nsecreting cells also abound in the gastric mucosa. Bicarbonate ions are secreted and trapped in the mucus, creating a \ngel-like protective barrier that maintains the mucosal surface \nat a pH of 6\u20137 in the face of a much more acidic environment (pH 1\u20132) in the lumen. Alcohol and bile can disrupt this protective layer. Locally produced \u2018cytoprotective\u2019 prosta -\nglandins stimulate the secretion of both mucus and bicarbonate.\nDisturbances in these secretory and protective mechanisms \nare thought to be involved in the pathogenesis of peptic \nulcer, and indeed in other types of gastric damage such as gastro-oesophageal reflux disease (GORD\n1) and injury caused \nby non-steroidal anti-inflammatory drugs (NSAIDs).\nTHE REGULATION OF ACID SECERETION BY \nPARIETAL CELLS\nDisturbances of acid secretion are important in the \npathogenesis of peptic ulcer and constitute a particular \ntarget for drug action. The secretion of the parietal cells is \nan isotonic solution of HCl (150 mmol/L) with a pH less \nthan 1, the concentration of hydrogen ions being more than \na million times higher than that in the plasma. To produce \nthis, Cl\u2212 is actively transported into canaliculi in the cells \n1Or GERD in the United States, to reflect the different spelling of \nesophageal.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3351, "end_char_idx": 5309, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d51cd763-d745-493c-9af3-05fb4ab6c1e1": {"__data__": {"id_": "d51cd763-d745-493c-9af3-05fb4ab6c1e1", "embedding": null, "metadata": {"page_label": "402", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d38b635f-a2d7-4015-aa8c-3557648c55ab", "node_type": null, "metadata": {"page_label": "402", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c58fefeddc2c4136eb5e8f6494f652c156978f92ce9a42f8b062560de4d7dbae"}, "3": {"node_id": "ae4b4816-65bc-4759-be2b-f9a4738694a5", "node_type": null, "metadata": {"page_label": "402", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5afd8f20db19cb7678b92a7612132ec5bbd28e8294dabb90664bee24174a83e0"}}, "hash": "17c7c926cac851314e63ee38f7e6b8c86fbf1ae2d8091c5826995d68ed8a32c6", "text": "31 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n396GASTRIN\nGastrin is a polypeptide of 34 residues but also exists in \nshorter forms. It is synthesised by G cells in the gastric \nantrum and secreted into the portal blood, acting as a circulating hormone. Its main action is stimulation of acid secretion by ECL cells through its action at gastrin/\ncholecystokinin (CCK)\n2 receptors,2 which elevate intracellular \nCa2+. Gastrin receptors also occur on the parietal cells but \ntheir significance in the control of physiological secretion is controversial. CCK\n2 receptors are blocked by the experi -\nmental drugs such as netazepide and proglumide (Fig. \n31.2), but none of these agents have progressed into licensed \nclinical use.\nGastrin also stimulates histamine synthesis by ECL cells \nand indirectly increases pepsinogen secretion, stimulates blood flow and increases gastric motility. Release of gastrin is controlled by both neuronal transmitters and blood-borne \nmediators, as well as by the chemistry of the stomach \ncontents. Amino acids and small peptides directly stimulate the gastrin-secreting cells, as do milk and solutions of calcium salts, explaining why it is inappropriate to use \ncalcium-containing salts as antacids.\nACETYLCHOLINE\nAcetylcholine, released (together with a battery of other \nneurotransmitters and peptides), from postganglionic \ncholinergic neurons, stimulates specific muscarinic M 3 \nreceptors on the surface of the parietal cells (see Ch. 14), thereby elevating intracellular Ca\n2+ and stimulating acid \nsecretion. It also has complex effects on other cell types; by inhibiting somatostatin release from D cells , it potentiates \nits action on parietal cell acid secretion.\nPROSTAGLANDINS\nMost cells of the GI tract produce prostaglandins (PGs; see \nCh. 18), the most important being PGE 2 and I 2. Prostaglan -\ndins exert \u2018cytoprotective\u2019 effects on many aspects of gastric \nfunction including increasing bicarbonate secretion (EP 1/2 \nreceptors), increasing the release of protective mucin (EP 4 \nreceptor), reducing gastric acid output, probably by acting on EP\n2/3 receptors on ECL cells and preventing the vaso -\nconstriction (and thus damage to the mucosa) that follows injury or insult. The latter is probably an action mediated \nthrough EP\n2/4 receptors. Misoprostol (see later) is a synthetic \nprostaglandin that probably exploits many of these effects \nto bring about its therapeutic action.\nSOMATOSTATIN\nThis peptide hormone is released from D cells at several \nlocations within the stomach. By acting at its somatostatin (SST)\n2 receptor, it exerts paracrine inhibitory actions on \ngastrin release from G cells, histamine release from ECL cells, as well as directly on parietal cell acid output.\nTHE COORDINATION OF FACTORS REGULATING \nACID SECRETION\nThe regulation of the parietal cell is complex and many \nlocal hormones probably play a role in the fine-tuning of \nthe secretory response. The generally accepted model today \nis that the gastrin\u2013ECL\u2013parietal cell axis is the dominant that communicate with the lumen of the gastric glands and thus with the stomach itself. This is accompanied by K\n+ \nsecretion, which is then exchanged for H+ from within the \ncell by a K+-H+-ATPase (the \u2018proton pump\u2019, Fig. 31.1 ). Within \nthe cell, carbonic anhydrase catalyses the combination of \ncarbon dioxide and water to give carbonic acid, which", "start_char_idx": 0, "end_char_idx": 3395, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ae4b4816-65bc-4759-be2b-f9a4738694a5": {"__data__": {"id_": "ae4b4816-65bc-4759-be2b-f9a4738694a5", "embedding": null, "metadata": {"page_label": "402", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d38b635f-a2d7-4015-aa8c-3557648c55ab", "node_type": null, "metadata": {"page_label": "402", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c58fefeddc2c4136eb5e8f6494f652c156978f92ce9a42f8b062560de4d7dbae"}, "2": {"node_id": "d51cd763-d745-493c-9af3-05fb4ab6c1e1", "node_type": null, "metadata": {"page_label": "402", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "17c7c926cac851314e63ee38f7e6b8c86fbf1ae2d8091c5826995d68ed8a32c6"}}, "hash": "5afd8f20db19cb7678b92a7612132ec5bbd28e8294dabb90664bee24174a83e0", "text": "catalyses the combination of \ncarbon dioxide and water to give carbonic acid, which \ndissociates into H+ and bicarbonate ions. The latter exchanges \nacross the basal membrane of the parietal cell for Cl\u2212. The \nprincipal mediators that directly \u2013 or indirectly \u2013 control \nparietal cell acid output are:\n\u2022\thistamine \t(a \tstimulatory \tlocal \thormone)\n\u2022\tgastrin \t(a \tstimulatory \tpeptide \thormone)\n\u2022\tacetylcholine \t(a \tstimulatory \tneurotransmitter)\n\u2022\tprostaglandins \tE2 and I 2 (local hormones that inhibit \nacid secretion)\n\u2022\tsomatostatin \t(an \tinhibitory \tpeptide \thormone)\nHISTAMINE\nHistamine is discussed in Chapter 18, and only those aspects \nof its pharmacology relevant to gastric secretion will be \ndealt with here. Neuroendocrine cells abound in the stomach \nand the dominant type are the ECL cells (enterochromaffin-\nlike cells). These are histamine-containing cells similar to \nmast cells, which lie close to the parietal cells. They sustain \na steady basal release of histamine, which is further increased by gastrin and acetylcholine. Histamine acts in a paracrine \nfashion on parietal cell H\n2 receptors, increasing intracellular \ncAMP. These cells are responsive to histamine concentrations that are below the threshold required for vascular H\n2 \nreceptor activation.PARIETAL\nCELLPLASMA LUMENA\nK+ K+Cl\u2212Cl\u2212\nPCl\u2212Cl\u2212\nHCO3\u2212HCO3\u2212\nH+\nCarbonic\nanhydrase\nH2O CO2H2CO3 H+C\nFig. 31.1 A schematic illustration of the secretion of \nhydrochloric acid by the gastric parietal cell. Secretion \ninvolves a proton pump (P), which is an H+-K+-ATPase, a \nsymport carrier (C) for K+ and Cl\u2212, and an antiport (A), which \nexchanges Cl\u2212 and HCO 3\u2212. An additional Na+/H+ antiport situated \nat the interface with the plasma may also have a role (not \nshown). \n2These two peptides share the same, biologically active, C-terminal \npentapeptide sequence.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3312, "end_char_idx": 5631, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c970f7e2-74ae-44b2-841a-1c9923b8b20b": {"__data__": {"id_": "c970f7e2-74ae-44b2-841a-1c9923b8b20b", "embedding": null, "metadata": {"page_label": "403", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3051b853-f6b0-4484-8001-ad7309298951", "node_type": null, "metadata": {"page_label": "403", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aac257b0fa00f78a75eb50643ed03b107482c690615dc252c44c6efeda467ba5"}, "3": {"node_id": "e2bfe371-8cad-4c88-a11a-a7944fbe4eaa", "node_type": null, "metadata": {"page_label": "403", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59a6cb649e49a5a4fb623c546d2a6f7459351e3a99ffe92b8ab5b194e67e4c34"}}, "hash": "432726e7236491f3b99c1405949ab45369907d447fa6f3d08f262fc66902d497", "text": "31 ThE GASTROINTESTINA l TRACT\n397cells to elevate cAMP and to activate the secretion of protons \nas described.\nDirect vagal stimulation can also provoke acid secretion \n(the basis for \u2018stress ulcers\u2019) through a release of acetyl -\ncholine, which directly stimulates M 3 receptors on parietal \ncells. Somatostatin probably exerts a tonic inhibitory \ninfluence on G cells, ECL and parietal cells, and local (or \ntherapeutically administered) prostaglandins, acting through EP\n2/3 receptors, exert inhibitory effects predominantly on \nECL cell function.\nThis control system is clearly complex, but prolonged \nexposure of tissues to excess acid secretion is dangerous and must be tightly regulated (see Schubert & Peura, 2008).\nmechanism for controlling acid secretion. According to this \nidea (see Fig. 31.2), which is supported by the majority of \ntransgenic \u2018knock-out\u2019 mouse studies, the initial step in controlling physiological secretion is the release of gastrin \nfrom G cells. This acts through its CCK\n2 receptor on ECL \ncells to release histamine and may also have a secondary direct effect on parietal cells themselves, although this has \nbeen disputed. Histamine acts on H\n2 receptors on parietal G cell SST2R\nSST2R\nSST2RH2R\nM3RCCK2R?EP2/3RCCK2R\nECL cell\nAchSomatostatinProglumide\nNSAIDs\nH2 blockersAA\nPGE2\nHistamineGastrin\nH+K+Cl\u2212H+K+Cl\u2212\nC PAtropineMisoprostol \nPARIETAL CELL\nProton\npump\ninhibitors\nFig. 31.2 Schematic diagram showing the regulation of \nthe acid-secreting gastric parietal cell, illustrating the site of \naction of drugs influencing acid secretion. The initial step in \ncontrolling physiological secretion is the release of gastrin from G cells. This acts through its gastrin/cholecystokinin (CCK\n2) \nreceptor on mast cell-like histamine-secreting enterochromaffin \n(ECL) cells to release histamine and may also have a secondary direct effect on parietal cells themselves, although this is not entirely clear. Histamine acts on parietal cell H\n2 receptors to \nelevate cAMP that activates the secretion of acid by the proton pump. Direct vagal stimulation also provokes acid secretion and released acetylcholine directly stimulates M\n3 receptors on \nparietal cells. The influence of somatostatin on G cells, ECL cells and parietal cells is inhibitory. Local (or therapeutically administered) prostaglandins exert inhibitory effects predominately on ECL cell function. Receptors depicted in red \nhave inhibitory effects on cell secretion, whilst those in blue \nstimulate cell secretion. AA, arachidonic acid; ACh, \nacetylcholine; C, symport carrier for K\n+ and Cl\u2212; CCK 2, gastrin/\ncholecystokinin receptor; NSAIDs, non-steroidal anti-inflammatory drugs; P, proton pump (H\n+-K+-ATPase); PGE 2, \nprostaglandin E 2. Secretion of gastric acid, mucus \nand bicarbonate \nThe control of the gastrointestinal tract is through \nnervous and humoral mechanisms.\n\u2022\tAcid\tis\tsecreted \tfrom \tgastric \tparietal \tcells \tby \ta \tproton \t\npump (K+-H+-ATPase).\n\u2022\tThe\tthree \tendogenous \tsecretagogues \tfor \tacid \tare \t\nhistamine, acetylcholine and gastrin.\n\u2022\tProstaglandins \tE2 and I 2 inhibit acid, stimulate mucus \nand bicarbonate secretion, and dilate mucosal blood", "start_char_idx": 0, "end_char_idx": 3173, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e2bfe371-8cad-4c88-a11a-a7944fbe4eaa": {"__data__": {"id_": "e2bfe371-8cad-4c88-a11a-a7944fbe4eaa", "embedding": null, "metadata": {"page_label": "403", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3051b853-f6b0-4484-8001-ad7309298951", "node_type": null, "metadata": {"page_label": "403", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aac257b0fa00f78a75eb50643ed03b107482c690615dc252c44c6efeda467ba5"}, "2": {"node_id": "c970f7e2-74ae-44b2-841a-1c9923b8b20b", "node_type": null, "metadata": {"page_label": "403", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "432726e7236491f3b99c1405949ab45369907d447fa6f3d08f262fc66902d497"}}, "hash": "59a6cb649e49a5a4fb623c546d2a6f7459351e3a99ffe92b8ab5b194e67e4c34", "text": "mucus \nand bicarbonate secretion, and dilate mucosal blood vessels.\n\u2022\tSomatostatin \tinhibits \tall \tphases \tof \tparietal \tcell \t\nactivation.\nThe genesis of peptic ulcers involves:\n\u2022\tinfection \tof \tthe \tgastric \tmucosa \twith \tHelicobacter \npylori;\n\u2022\tan\timbalance \tbetween \tthe \tmucosal-damaging, \t(acid, \t\npepsin) and the mucosal-protecting, agents (mucus, bicarbonate, prostaglandins E\n2 and I 2, and nitric oxide).\n3H. pylori infection in the stomach has also been classified as a class 1 \n(definite) carcinogen for gastric cancer.DRUGS USED TO INHIBIT OR NEUTRALISE \nGASTRIC ACID SECRETION\nThe principal clinical indications for reducing acid secretion \nare peptic ulceration (both duodenal and gastric), GORD (in \nwhich gastric secretion causes damage to the oesophagus) and the Zollinger\u2013Ellison syndrome (a rare hypersecretory \ncondition caused by a gastrin-producing tumour). If \nuntreated, GORD can cause a dysplasia of the oesophageal \nepithelium which may progress to a potentially dangerous pre-cancerous condition called Barrett oesophagus.\nThe reasons why peptic ulcers develop are not fully \nunderstood, although infection of the stomach mucosa with Helicobacter pylori\n3 \u2013 a Gram-negative bacillus that \ncauses chronic gastritis \u2013 is now generally considered to \nbe a major cause (especially of duodenal ulcer) and forms \nthe usual basis for therapy. Treatment of H. pylori infection \nis discussed later.\nMany non-specific NSAIDs (see Ch. 27) cause gastric \nbleeding and erosions by inhibiting cyclo-oxygenase I, the enzyme responsible for synthesis of protective prostaglan -\ndins. More selective cyclo-oxygenase II inhibitors such as celecoxib appear to cause less stomach damage (but see Ch. 27 for a discussion of this issue).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3115, "end_char_idx": 5340, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c1685c77-0791-476d-8f4f-99ae01b8a3f8": {"__data__": {"id_": "c1685c77-0791-476d-8f4f-99ae01b8a3f8", "embedding": null, "metadata": {"page_label": "404", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "040a53fd-ccb9-4b81-9599-fb4d43c1f1ad", "node_type": null, "metadata": {"page_label": "404", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e21029f6549a4ef6be980c9aa9429718a68a3ca7b746d52cabe7363b323cf815"}, "3": {"node_id": "bbff54d8-d23b-41b7-9044-375049a593f5", "node_type": null, "metadata": {"page_label": "404", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4fb8947aaa7ef9a788c61c755feaf3b8e4a13f80df15723c1a890251d79bfde"}}, "hash": "f23946687042395e5fd81d577a571193d5ba1e8d134d2345bb63da9714276c12", "text": "31 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n39860\n60150\n150180\n180210\n2104\n321\n4\n3\n2\n130\n30120\n120\nCimetidine\nor placebo\nCimetidine\nor placeboBetazole\nBetazole\nTime (min)Acid secretion (mEq/15 min)Pepsin secretion (units 10-4/15 min)\nFig. 31.3 The effect of cimetidine on betazole-stimulated \ngastric acid and pepsin secretion in humans. Either \ncimetidine or a placebo was given orally 60 min prior to a \nsubcutaneous injection (1.5 mg/kg) of betazole, a relatively \nspecific histamine H 2-receptor agonist that stimulates gastric \nacid secretion. (Modified from Binder & Donaldson, 1978.)Clinical use of agents affecting \ngastric acidity \n\u2022\tHistamine \tH2 receptor antagonists (e.g. ranitidine):\n\u2013 peptic ulcer\n\u2013 reflux oesophagitis\n\u2022\tProton\tpump \tinhibitors \t(e.g. \tomeprazole, \nlansoprazole):\n\u2013 peptic ulcer\n\u2013 reflux oesophagitis\n\u2013 as one component of therapy for Helicobacter pylori \ninfection\n\u2013 Zollinger\u2013Ellison syndrome (a rare condition caused \nby gastrin-secreting tumours)\n\u2022\tAntacids \t(e.g. \tmagnesium \ttrisilicate, \taluminium \t\nhydroxide, alginates):\n\u2013 dyspepsia\n\u2013 symptomatic relief in peptic ulcer or (alginate) \noesophageal reflux\n\u2022\tBismuth chelate:\n\u2013 as one component of therapy for H. pylori infection\n4This era has been referred to as the \u2018BC\u2019 \u2013 before cimetidine \u2013 era of \ngastroenterology (Schubert & Peura, 2008)! It is an indication of the \nclinical importance of the development of this drug.Therapy of peptic ulcer and reflux oesophagitis aims to \ndecrease the secretion of gastric acid with H 2 receptor \nantagonists or proton pump inhibitors, and/or to neutralise \nsecreted acid with antacids (see Huang & Hunt, 2001). These \ntreatments are often coupled with measures to eradicate H. pylori (see Blaser, 1998; Horn, 2000).\nHISTAMINE \u2003H2\u2003RECEPTOR \u2003ANTAGONISTS\nThe discovery and development of histamine H 2-blocking \ndrugs by Black and his colleagues in 1972 was a major \nbreakthrough in the treatment of gastric ulcers \u2013 a condition \nthat could hitherto only be treated by (sometimes rather heroic) surgery.\n4 Indeed, the ability to distinguish between \nhistamine receptor subtypes using pharmacological agents \nwas, in itself, a major intellectual achievement. H 2 receptor \nantagonists competitively inhibit histamine actions at all H\n2 receptors, but their main clinical use is as inhibitors of \ngastric acid secretion. They can inhibit histamine- and gastrin-stimulated acid secretion; pepsin secretion also falls \nwith the reduction in volume of gastric juice. These agents not only decrease both basal and food-stimulated acid \nsecretion by 90% or more, but numerous clinical trials \nindicate that they also promote healing of gastric and duodenal ulcers. However, relapses are likely to follow \ncessation of treatment.\nThe main drugs used are cimetidine, ranitidine (some-\ntimes in combination with bismuth), nizatidine and \nfamotidine. There is little difference between them. The effect of cimetidine on gastric secretion in human subjects \nis shown in Fig. 31.3. The clinical use of H\n2 receptor \nantagonists is explained in the clinical box.\nPharmacokinetic aspects and unwanted", "start_char_idx": 0, "end_char_idx": 3131, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bbff54d8-d23b-41b7-9044-375049a593f5": {"__data__": {"id_": "bbff54d8-d23b-41b7-9044-375049a593f5", "embedding": null, "metadata": {"page_label": "404", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "040a53fd-ccb9-4b81-9599-fb4d43c1f1ad", "node_type": null, "metadata": {"page_label": "404", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e21029f6549a4ef6be980c9aa9429718a68a3ca7b746d52cabe7363b323cf815"}, "2": {"node_id": "c1685c77-0791-476d-8f4f-99ae01b8a3f8", "node_type": null, "metadata": {"page_label": "404", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f23946687042395e5fd81d577a571193d5ba1e8d134d2345bb63da9714276c12"}}, "hash": "f4fb8947aaa7ef9a788c61c755feaf3b8e4a13f80df15723c1a890251d79bfde", "text": "is explained in the clinical box.\nPharmacokinetic aspects and unwanted effects\nThe drugs are generally given orally and are well absorbed, although preparations for intramuscular and intravenous \nuse are also available (except famotidine). Dosage regimens vary depending on the condition under treatment. Low-\ndosage over-the-counter formulations of cimetidine, ran -\nitidine and famotidine are available from pharmacies for short-term use, without prescription.\nUnwanted effects are rare. Diarrhoea, dizziness, muscle \npains, alopecia, transient rashes, confusion in the elderly and hypergastrinaemia have been reported. Cimetidine sometimes causes gynaecomastia in men and, rarely, a \ndecrease in sexual function. This is probably caused by a \nmodest affinity for androgen receptors. Cimetidine (but not other H\n2 receptor antagonists) also inhibits cytochrome \nP450, and can retard the metabolism (and thus potentiate \nthe action) of a range of drugs including oral anticoagulants \nand tricyclic antidepressants.\nPROTON \u2003PUMP \u2003INHIBITORS\nThe first proton pump inhibitor was omeprazole, which \nirreversibly inhibits the H+-K+-ATPase (the proton pump), \nthe terminal step in the acid secretory pathway (see Figs \n31.1 and 31.2). Both basal and stimulated gastric acid secre -\ntion (Fig. 31.4) is reduced. The drug comprises a racemic \nmixture of two enantiomers. As a weak base, it accumulates \nin the acid environment of the canaliculi of the stimulated \nparietal cell where it is converted into an achiral form and is then able to react with, and inactivate, the ATPase. This \npreferential accumulation means that it has a specific effect mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3061, "end_char_idx": 5182, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a135e1ef-2ceb-4179-a4b4-fa98fba6e104": {"__data__": {"id_": "a135e1ef-2ceb-4179-a4b4-fa98fba6e104", "embedding": null, "metadata": {"page_label": "405", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "544e3366-4ef5-4ab6-8de9-5b98ea46d522", "node_type": null, "metadata": {"page_label": "405", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3832e796a846ff6a641127fc6f434848850ee83e3e55253d8311421f82e7923"}, "3": {"node_id": "32e6c6aa-80de-4d95-a871-da0b37a21d1e", "node_type": null, "metadata": {"page_label": "405", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe5721070bf533a3eac81a77c10c762b18cb0a5120a9db744cac905f2e0f6824"}}, "hash": "4e17dba4f5e192d669c7ea3af0752be3ef7bd4dc7b2517b7ff3ef929e9da29c8", "text": "31 ThE GASTROINTESTINA l TRACT\n399acid and this also has the effect of inhibiting the activity \nof peptic enzymes, which practically ceases at pH 5. Given \nin sufficient quantity for long enough, they can produce \nhealing of duodenal ulcers, but are less effective for gastric ulcers.\nMost antacids in common use are salts of magnesium \nand aluminium. Magnesium salts cause diarrhoea and aluminium salts, constipation \u2013 so mixtures of these two \ncan, happily, be used to preserve normal bowel function. \nPreparations of these substances (e.g. magnesium trisilicate \nmixtures and some proprietary aluminium preparations) containing high concentrations of sodium should not be \ngiven to patients on a sodium-restricted diet. Numerous \nantacid preparations are available; a few of the more sig-nificant are given later.\nMagnesium hydroxide is an insoluble powder that forms \nmagnesium chloride in the stomach. It does not produce systemic alkalosis, because Mg\n2+ is poorly absorbed from \nthe gut. Another salt, magnesium trisilicate, is an insoluble \npowder that reacts slowly with the gastric juice, forming \nmagnesium chloride and colloidal silica. This agent has a prolonged antacid effect, and it also adsorbs pepsin. \nMagnesium carbonate is also used.\nAluminium hydroxide gel forms aluminium chloride \nin the stomach; when this reaches the intestine, the chloride is released and is reabsorbed. Aluminium hydroxide raises \nthe pH of the gastric juice to about 4, and also adsorbs pepsin. Its action is gradual, and its effect continues for several hours.\n5 Colloidal aluminium hydroxide combines \nwith phosphates in the GI tract and the increased excretion \nof phosphate in the faeces that occurs results in decreased \nexcretion of phosphate via the kidney. This effect has been used in treating patients with chronic renal failure (see Ch. \n30). Other preparations such as hydrotalcite contain \nmixtures of both aluminium and magnesium salts.\nAlginates or simeticone are sometimes combined with \nantacids. Alginates are believed to increase the viscosity and adherence of mucus to the oesophageal mucosa, forming a protective barrier, whereas simeticone is an anti-foaming agent, intended to relieve bloating and flatulence.\nTREATMENT OF HELICOBACTER PYLORI \nINFECTION\nH. pylori infection has been implicated as a causative factor \nin the production of gastric and, more particularly, duodenal \nulcers, as well as a risk factor for gastric cancer. Indeed, \nsome would argue that infectious gastroduodenitis is actually the chief clinical entity associated with ulcers, and \ngastric cancer its prominent sequela. Certainly, eradication \nof H. pylori infection promotes rapid and long-term healing \nof ulcers, and it is routine practice to test for the organism \nin patients presenting with suggestive symptoms. If the \ntest is positive, then the organism can generally be eradicated with a 1- or 2-week regimen of \u2018triple therapy\u2019, comprising a proton pump inhibitor in combination with the antibacteri -\nals amoxicillin and metronidazole or clarithromycin (see \nCh. 52); other combinations are also used. Bismuth-containing preparations (see later) are sometimes added. on these cells. Other proton pump inhibitors (all of which have a similar mode of activation and pharmacology) include esomeprazole (the [S] isomer of omeprazole), lansoprazole , \npantoprazole and rabeprazole. The clinical indication for \nthese drugs is given in the clinical box (see earlier).\nPharmacokinetic aspects and unwanted", "start_char_idx": 0, "end_char_idx": 3512, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "32e6c6aa-80de-4d95-a871-da0b37a21d1e": {"__data__": {"id_": "32e6c6aa-80de-4d95-a871-da0b37a21d1e", "embedding": null, "metadata": {"page_label": "405", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "544e3366-4ef5-4ab6-8de9-5b98ea46d522", "node_type": null, "metadata": {"page_label": "405", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3832e796a846ff6a641127fc6f434848850ee83e3e55253d8311421f82e7923"}, "2": {"node_id": "a135e1ef-2ceb-4179-a4b4-fa98fba6e104", "node_type": null, "metadata": {"page_label": "405", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e17dba4f5e192d669c7ea3af0752be3ef7bd4dc7b2517b7ff3ef929e9da29c8"}}, "hash": "fe5721070bf533a3eac81a77c10c762b18cb0a5120a9db744cac905f2e0f6824", "text": "in the clinical box (see earlier).\nPharmacokinetic aspects and unwanted effects\nOral administration is the most common route of administra -\ntion, although some injectable preparations are available. \nOmeprazole is given orally, but as it degrades rapidly at \nlow pH, it is administered as capsules containing enteric-coated granules. Following absorption in the small intestine, \nit passes from the blood into the parietal cells and then \ninto the canaliculi where it exerts its effects. Increased doses give disproportionately higher increases in plasma con -\ncentration (possibly because its inhibitory effect on acid secretion improves its own bioavailability). Although its \nhalf-life is about 1 h, a single daily dose affects acid secretion \nfor 2\u20133 days, partly because of the accumulation in the canaliculi and partly because it inhibits the H\n+-K+-ATPase \nirreversibly. With daily dosage, there is an increasing \nantisecretory effect for up to 5 days, after which a plateau \nis reached.\nUnwanted effects of this class of drugs are uncommon. \nThey may include headache, diarrhoea (both sometimes severe) and rashes. Acid-suppression with proton pump inhibitors is associated with increased risk of Clostridium \ndifficile diarrhoea, particularly in patients who are immu-nosuppressed or have been receiving antibiotics. Dizziness, somnolence, mental confusion, impotence, gynaecomastia, and pain in muscles and joints have been reported. Proton \npump inhibitors should be used with caution in patients \nwith liver disease, or in women who are pregnant or breastfeeding. The use of these drugs may \u2018mask\u2019 the \nsymptoms of gastric cancer.\nANTACIDS\nAntacids are the simplest way to treat the symptoms of \nexcessive gastric acid secretion. They directly neutralise \nAP accumulation\n(% of maximum response)100\n50\n0\nOmeprazole concentration (mol/L)IC50 ~50 nmol/L\n10\u2212910\u2212810\u2212710\u2212610\u22125\nFig. 31.4 The inhibitory action of omeprazole on acid \nsecretion from isolated human gastric glands stimulated by \n50 \u00b5mol/L histamine. Acid secretion was measured by the \naccumulation of a radiolabelled weak base, aminopyrine (AP), in \nthe secretory channels. The data represent the mean and standard error of measurements from eight patients. (Adapted \nfrom Lindberg, P. et al., 1987. Trends Pharmacol. Sci. 8, \n399\u2013402.)\n5There was a suggestion \u2013 no longer widely believed \u2013 that aluminium \ncould trigger Alzheimer\u2019s disease. In fact, aluminium is not absorbed to \nany significant extent following oral administration of aluminium \nhydroxide, although when introduced by other routes (e.g. during renal dialysis with aluminium-contaminated solutions) it is extremely toxic.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3441, "end_char_idx": 6587, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a2964688-c523-497d-abf6-7686e14d4eeb": {"__data__": {"id_": "a2964688-c523-497d-abf6-7686e14d4eeb", "embedding": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d514026-f152-4b70-a49f-66cda4af0f27", "node_type": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e3a03f38d1472789340abac7de5d50d766b41f9a2d6bc4c8b81c094abb26344f"}, "3": {"node_id": "1ca39d2b-1856-4fbd-9ce0-4f5fb6733e69", "node_type": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "604fcc78ff8f2de6cbe127f68cc2bfdef233fc7a9264f7148414214bb88a6540"}}, "hash": "024b3a63ed03c103a72d962d59008d1a0895d595eed36b8244170dd7aca33282", "text": "31 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n400secretion of gastric acid as well as the stimulation of produc -\ntion seen in response to food, pentagastrin and caffeine. It \nalso increases mucosal blood flow and augments the \nsecretion of mucus and bicarbonate.\nUnwanted effects include diarrhoea and abdominal \ncramps; uterine contractions can also occur, so the drug should not be given during pregnancy (unless deliberately to induce a therapeutic abortion; see Ch. 36). Prostaglan -\ndins and NSAIDs are discussed more fully in Chapters 7 \nand 27.\nVOMITING\nNausea and vomiting are unwanted side effects of many clinically used drugs, notably those used for cancer chemo -\ntherapy but also opioids, general anaesthetics and digoxin. They also occur in motion sickness,\n7 during early pregnancy \nand in numerous disease states (e.g. migraine) as well as \nbacterial and viral infections.\nTHE REFLEX MECHANISM OF VOMITING\nVomiting is a defensive response intended to rid the organ -\nism of toxic or irritating material. Poisonous compounds, bacterial toxins, many cytotoxic drugs (as well as mechanical \ndistension) trigger the release, from enterochromaffin cells in the lining of the GI tract, of mediators such as 5-HT. \nThese transmitters trigger signals in vagal afferent fibres. \nThe physical act of vomiting is co-ordinated centrally by the vomiting (or emetic) centre in the medulla; Fig. 31.5. \nActually, this is not a discrete anatomical location but a network of neural pathways that integrate signals arriving from other locations. One of these, in the area postrema is \nknown as the chemoreceptor trigger zone (CTZ). The CTZ \nreceives inputs from the labyrinth in the inner ear through \nthe vestibular nuclei (which explains the mechanism of motion \nsickness) and vagal afferents arising from the GI tract. Toxic \nchemicals in the bloodstream can also be detected directly \nby the CTZ because the blood\u2013brain barrier is relatively permeable in this area. The CTZ is therefore a primary site \nof action of many emetic and antiemetic drugs (Table 31.1).\nThe vomiting centre also receives signals directly from \nvagal afferents, as well as those relayed through the CTZ. In addition, it receives input from higher cortical centres, \nexplaining why unpleasant or repulsive sights or smells, or strong emotional stimuli, can sometimes induce nausea \nand vomiting.\nThe main neurotransmitters involved in this neurocir -\ncuitry are acetylcholine, histamine, 5-HT, dopamine and substance P and receptors for these transmitters have been \ndemonstrated in the relevant areas (see Chs 13\u201317). It has been hypothesised that enkephalins (see Ch. 43) are also implicated in the mediation of vomiting, acting possibly \nat \u03b4 (CTZ) or \u00b5 (vomiting centre) opioid receptors. Substance \nP (see Ch. 19) acting at neurokinin-1 receptors in the CTZ, \nand endocannabinoids (Ch. 20), may also be involved.\nThe neurobiology of nausea is much less well understood. \nNausea and vomiting may occur together or separately and may subserve different physiological functions (see While elimination of the bacillus can produce long-term remission of ulcers, reinfection with the organism can occur.\nDRUGS THAT PROTECT THE MUCOSA\nSome agents, termed cytoprotective, are said to enhance endogenous mucosal protection mechanisms and/or to \nprovide a physical barrier over the surface of the", "start_char_idx": 0, "end_char_idx": 3379, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1ca39d2b-1856-4fbd-9ce0-4f5fb6733e69": {"__data__": {"id_": "1ca39d2b-1856-4fbd-9ce0-4f5fb6733e69", "embedding": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d514026-f152-4b70-a49f-66cda4af0f27", "node_type": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e3a03f38d1472789340abac7de5d50d766b41f9a2d6bc4c8b81c094abb26344f"}, "2": {"node_id": "a2964688-c523-497d-abf6-7686e14d4eeb", "node_type": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "024b3a63ed03c103a72d962d59008d1a0895d595eed36b8244170dd7aca33282"}, "3": {"node_id": "551b99f4-0926-4476-a331-20d0a3014f96", "node_type": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0211424d80f2b5acc4450588c5411647b2caa2241b04b3c57c3f2f3b1f4f48a7"}}, "hash": "604fcc78ff8f2de6cbe127f68cc2bfdef233fc7a9264f7148414214bb88a6540", "text": "protection mechanisms and/or to \nprovide a physical barrier over the surface of the ulcer.\nBismuth chelate\nBismuth chelate (tripotassium dicitratobismuthate) is \nsometimes used in combination regimens to treat H. pylori. \nIt has toxic effects on the bacillus, and may also prevent \nits adherence to the mucosa or inhibit its bacterial proteolytic enzymes. It is also believed to have other mucosa-protecting \nactions, by mechanisms that are unclear, and is widely \nused as an over-the-counter remedy for mild GI symptoms. Very little is absorbed, but if renal excretion is impaired, \nthe raised plasma concentrations of bismuth can result in \nencephalopathy.\nUnwanted effects include nausea and vomiting, and \nblackening of the tongue and faeces.\nSucralfate\nSucralfate is a complex of aluminium hydroxide and sulfated sucrose, which releases aluminium in the presence \nof acid. The residual complex carries a strong negative \ncharge and binds to cationic groups in proteins, glycopro -\nteins, etc. It can form complex gels with mucus, an action \nthat is thought to decrease the degradation of mucus by \npepsin and to limit the diffusion of H\n+ ions. Sucralfate can \nalso inhibit the action of pepsin and stimulate secretion of \nmucus, bicarbonate and prostaglandins from the gastric \nmucosa. All these actions contribute to its mucosa-protecting action.\nSucralfate is given orally and about 30% is still present \nin the stomach 3 h after administration. In the acid environ -\nment, the polymerised product forms a tenacious paste, \nwhich can sometimes produce an obstructive lump (known \nas a bezoar6) that gets stuck in the stomach. It reduces the \nabsorption of a number of other drugs, including fluoro -\nquinolone antibiotics, theophylline, tetracycline, digoxin \nand amitriptyline . Because it requires an acid environment \nfor activation, antacids given concurrently or prior to its \nadministration will reduce its efficacy.\nUnwanted effects are few, the most common being \nconstipation. Less common effects apart from bezoar forma -\ntion, include dry mouth, nausea, vomiting, headache and \nrashes.\nMisoprostol\nProstaglandins of the E and I series have a generally homeostatic protective action in the GI tract, and a deficiency \nin endogenous production (after ingestion of an NSAID, \nfor example) may contribute to ulcer formation. Misoprostol \nis a stable analogue of prostaglandin E\n1. It is given orally \nand is used to promote the healing of ulcers or to prevent \nthe gastric damage that can occur with chronic use of \nNSAIDs. It exerts a direct action on the ECL cell (and possibly parietal cell also; see Fig. 31.2), inhibiting the basal \n6From the Persian word meaning \u2018a cure for poisoning\u2019. It refers to the \nbelief that a concoction made from lumps of impacted rubbish retrieved \nfrom the stomach of goats would protect against poisoning by one\u2019s \nenemies.7In fact, the word nausea is derived from the Greek word meaning \n\u2018boat\u2019, with the obvious implication of associated motion sickness. \nVomiting is derived from a Latin word and a vomitorium was the \u2018fast \nexit\u2019 passageway in ancient theatres. It has a certain resonance, as we think you will agree!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3309, "end_char_idx": 6691, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "551b99f4-0926-4476-a331-20d0a3014f96": {"__data__": {"id_": "551b99f4-0926-4476-a331-20d0a3014f96", "embedding": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d514026-f152-4b70-a49f-66cda4af0f27", "node_type": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e3a03f38d1472789340abac7de5d50d766b41f9a2d6bc4c8b81c094abb26344f"}, "2": {"node_id": "1ca39d2b-1856-4fbd-9ce0-4f5fb6733e69", "node_type": null, "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "604fcc78ff8f2de6cbe127f68cc2bfdef233fc7a9264f7148414214bb88a6540"}}, "hash": "0211424d80f2b5acc4450588c5411647b2caa2241b04b3c57c3f2f3b1f4f48a7", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6731, "end_char_idx": 7034, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e3b27242-39bc-4869-bf8a-9b557a241abc": {"__data__": {"id_": "e3b27242-39bc-4869-bf8a-9b557a241abc", "embedding": null, "metadata": {"page_label": "407", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e650d844-414d-4f8f-aa1e-70cf34d6d048", "node_type": null, "metadata": {"page_label": "407", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c88d42f356b784938343685e9b7e28f4da86bcea3d83c9bad527a8227df61187"}, "3": {"node_id": "769a2906-02a7-4d8b-b0a0-ef191e0d83f9", "node_type": null, "metadata": {"page_label": "407", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "171fc8ad59571952e6915df07bcc2a0ea5f3dd67dc5162e064feb9fa8090220e"}}, "hash": "d0a373e029fc081f5accd9ec2887f1b5f7011390c3f3493c877b90460686c976", "text": "31 ThE GASTROINTESTINA l TRACT\n401months of pregnancy, if possible. Details of the main cat -\negories of antiemetics are given later, and their main clinical \nuses are summarised in the box. The clinical box and Table \n31.1 give an overview of their likely sites of action and \ntheir clinical utility.\nRECEPTOR \u2003ANTAGONISTS\nMany H 1 (see Ch. 27), muscarinic (see Ch. 14), 5-HT 3 (see \nCh. 16), dopamine (see Ch. 47) and neurokinin NK 1 receptor \nantagonists exhibit clinically useful antiemetic activity.\nH1 receptor antagonists\nCinnarizine, cyclizine and promethazine are the most \ncommonly employed; they are effective against nausea and \nvomiting arising from many causes, including motion \nsickness and the presence of irritants in the stomach. None is very effective against substances that act directly on the \nCTZ. Promethazine is used for morning sickness of preg -\nnancy (on the rare occasions when this is so severe that \ndrug treatment is justified), and has been used by NASA \nto treat space motion sickness. Drowsiness and sedation, Andrews & Horn, 2006). From the pharmacologist\u2019s view -\npoint, it is easier to control vomiting than nausea, and \nmany effective antiemetics (e.g. 5-HT\n3 antagonists) are much \nless successful in this regard.\nANTIEMETIC DRUGS\nSeveral antiemetic agents are available, and these are generally used for specific conditions, although there may \nbe some overlap. Such drugs are of particular importance \nas an adjunct to cancer chemotherapy, where the nausea and vomiting produced by many cytotoxic drugs (see Ch. \n57) can be almost unendurable.\n8 In using drugs to treat the \nmorning sickness of pregnancy, the problem of potential damage to the fetus has always to be borne in mind. In \ngeneral, all drugs should be avoided during the first 3 Vomiting centre\nIntegrate incoming signals:\ncoordinates emesisHyoscine (M1 receptors)Antihistamines (H1 receptors)\nPhenothiazines (D2 receptors)\nDomperidone (D2 receptors)\nMetoclopramide (D2 receptors)\nDroperidol, haloperidol \n(D2 receptors)\nGranisetron, ondansetron, \npalonosetron (5-HT3 receptors)Higher cortical centres\nPain, repulsive sights\nand smells and\nemotional factors\nCTZ\nMain site for sensing\nemetic stimuliVestibular nuclei\nInput from the\nlabyrinth\nVagal afferents\nConvey signals from\ngut to brainstem\nEnterochromaffin cells\nSense toxic chemicals\nor toxins in gutNabilone (CB1 receptors)\nMetoclopramide (D2 receptors)\nGranisetron, ondansetron ,\n palonosetron (5-HT3 receptors)\nAprepitant, fosaprepitant\n (NK1 receptors)\nFig. 31.5 Schematic diagram of the factors involved in the control of vomiting, with the probable sites of action of antiemetic \ndrugs. There are three important centres located in the medulla. The chemoreceptor trigger zone (CTZ), the vomiting centre and the \nvestibular nuclei. The vomiting centre receives inputs from the CTZ, the gastrointestinal (GI) tract (through vagal afferent connections) and higher cortical centres and coordinates the physical act of emesis. Vagal afferents arising from the GI tract also feed into the CTZ directly as does input from the vestibular nuclei, which in turn, receive inputs from the labyrinth. (Based partly on a diagram from", "start_char_idx": 0, "end_char_idx": 3206, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "769a2906-02a7-4d8b-b0a0-ef191e0d83f9": {"__data__": {"id_": "769a2906-02a7-4d8b-b0a0-ef191e0d83f9", "embedding": null, "metadata": {"page_label": "407", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e650d844-414d-4f8f-aa1e-70cf34d6d048", "node_type": null, "metadata": {"page_label": "407", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c88d42f356b784938343685e9b7e28f4da86bcea3d83c9bad527a8227df61187"}, "2": {"node_id": "e3b27242-39bc-4869-bf8a-9b557a241abc", "node_type": null, "metadata": {"page_label": "407", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0a373e029fc081f5accd9ec2887f1b5f7011390c3f3493c877b90460686c976"}}, "hash": "171fc8ad59571952e6915df07bcc2a0ea5f3dd67dc5162e064feb9fa8090220e", "text": "turn, receive inputs from the labyrinth. (Based partly on a diagram from Rojas & Slusher, 2012.)\n8It was reported that a young, medically qualified patient being treated \nby combination chemotherapy for sarcoma stated that \u2018the severity of \nvomiting at times made the thought of death seem like a welcome \nrelief\u2019.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3134, "end_char_idx": 3927, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "43f1bcef-ac11-472a-ad3e-b5d1e15c7951": {"__data__": {"id_": "43f1bcef-ac11-472a-ad3e-b5d1e15c7951", "embedding": null, "metadata": {"page_label": "408", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "77594511-d23f-440b-89b4-0ae1da545e05", "node_type": null, "metadata": {"page_label": "408", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7554ce4a60091306654f6d31c35242cb7e7b6a9c2ff0acb82e9f554516b8f1d7"}, "3": {"node_id": "5cf46334-19dc-4cf6-81d6-9991ca244fa0", "node_type": null, "metadata": {"page_label": "408", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "32655d7c48796d6445d7de3a785afcbd3472a14c7cdd6f783cee7ff0f3177b5e"}}, "hash": "67f1b26d137807b5e183d3613d8bb5adc2a1993cf9703c7bc406fb34d3f420cc", "text": "31 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n402Table 31.1 Sites of action of common antiemetic drugs\nClass Drugs Site of action Comments\nAntihistamines Cinnarizine, cyclizine, promethazineH1 receptors in the CNS (causing \nsedation) and possibly anticholinergic \nactions in the vestibular apparatusWidely effective regardless of \ncause of emesis\nAntimuscarinics Hyoscine Anticholinergic actions in the vestibular \napparatus and possibly elsewhereMainly motion sickness\nCannabinoids Nabilone Probably CB 1 receptors in the GI tract CINV in patients where other \ndrugs have been ineffective\nDopamine \nantagonistsPhenothiazines: prochlorphenazine, \nperphenazine, trifluorphenazine, \nchlorpromazineD2 receptors in CTZ CINV, PONV, RS\nRelated drugs: droperidol, \nhaloperidolD2 receptors in GI tract CINV, PONV, RS\nMetoclopramide D2 receptors in the CTZ and GI tract PONV, CINV\nGlucocorticoids Dexamethasone Probably multiple sites of action, \nincluding the GI tractPONV, CINV; typically used in \ncombination with other drugs\n5-HT 3 antagonists Granisteron, ondansetron, \npalonosetron5-HT 3 receptors in CTZ and GI tract PONV, CINV\nNeurokinin-1 \nantagonistsAprepitant, fosaprepitant NK 1 receptors in CTZ, vomiting centre \nand possibly the GI tractCINV; given in combination \nwith another drug\n5-HT, 5-hydroxytryptamine; CINV, cytotoxic drug-induced vomiting; CNS, central nervous system; CTZ, chemoreceptor trigger zone; GI, \ngastrointestinal; PONV, postoperative nausea and vomiting; RS, radiation sickness.\nThe reflex mechanism of vomiting \nEmetic stimuli include:\n\u2022\tchemicals\t or\tdrugs\tin\tthe\tblood\tor\tintestine;\n\u2022\tneuronal\t input\tfrom\tthe\tgastrointestinal\t (GI)\ttract,\t\nlabyrinth and central nervous system (CNS).\nPathways and mediators include:\n\u2022\timpulses\t from\tthe\tchemoreceptor\t trigger\tzone\tand\t\nvarious other CNS centres relayed to the vomiting \ncentre;\n\u2022\tchemical\t transmitters\t such\tas\thistamine,\t acetylcholine,\t\ndopamine, 5-hydroxytryptamine (5-HT) and substance \nP, acting on H 1, muscarinic, D 2, 5-HT 3 and NK 1 \nreceptors, respectively.\nAntiemetic drugs include:\n\u2022\tH 1 receptor antagonists (e.g. cinnarizine );\n\u2022\tmuscarinic\t antagonists\t (e.g.\t hyoscine );\n\u2022\t5-HT 3 receptor antagonists (e.g. ondansetron );\n\u2022\tD 2 receptor antagonists (e.g. metoclopramide );\n\u2022\tcannabinoids\t (e.g.\t nabilone );\n\u2022\tneurokinin-1\t antagonists\t (e.g.\t aprepitant , \nfosaprepitant ).\nMain side effects of principal antiemetics include:\n\u2022\tdrowsiness\t and\tantiparasympathetic\t effects\t\n(hyoscine , nabilone > cinnarizine );\n\u2022\tdystonic\t reactions\t (metoclopramide );\n\u2022\tgeneral\t CNS\tdisturbances\t (nabilone );\n\u2022\theadache,\t GI\ttract\tupsets\t(ondansetron ).Clinical use of antiemetic drugs \n\u2022\tHistamine\t H1 receptor antagonists (see also clinical \nbox in Ch. 27):\n\u2013 Cyclizine : motion sickness,", "start_char_idx": 0, "end_char_idx": 2788, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5cf46334-19dc-4cf6-81d6-9991ca244fa0": {"__data__": {"id_": "5cf46334-19dc-4cf6-81d6-9991ca244fa0", "embedding": null, "metadata": {"page_label": "408", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "77594511-d23f-440b-89b4-0ae1da545e05", "node_type": null, "metadata": {"page_label": "408", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7554ce4a60091306654f6d31c35242cb7e7b6a9c2ff0acb82e9f554516b8f1d7"}, "2": {"node_id": "43f1bcef-ac11-472a-ad3e-b5d1e15c7951", "node_type": null, "metadata": {"page_label": "408", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67f1b26d137807b5e183d3613d8bb5adc2a1993cf9703c7bc406fb34d3f420cc"}}, "hash": "32655d7c48796d6445d7de3a785afcbd3472a14c7cdd6f783cee7ff0f3177b5e", "text": "clinical \nbox in Ch. 27):\n\u2013 Cyclizine : motion sickness, vestibular disorders, \nnausea and vomiting associated with surgery and \npostoperative narcotic analgesic use.\n\u2013 Cinnarizine : motion sickness, vestibular disorders \n(e.g. Meni\u00e8re\u2019s disease).\n\u2013 Promethazine : severe morning sickness of \npregnancy, motion sickness, vestibular disorders.\n\u2022\tMuscarinic\t receptor\tantagonists:\n\u2013 Hyoscine : motion sickness.\n\u2022\tDopamine\t D2 receptor antagonists:\n\u2013 Phenothiazines (e.g. prochlorperazine ): vomiting \ncaused by migraine, vestibular disorders, radiation, \nviral gastroenteritis, severe morning sickness of \npregnancy.\n\u2013 Metoclopramide : vomiting caused by migraine, \nradiation, gastrointestinal disorders, cytotoxic drugs, \nprevention of nausea and vomiting in the \npostoperative period.\n\u2013 Domperidone is less liable to cause central \nnervous system side effects in patients with \nParkinson\u2019s disease as it penetrates the blood\u2013brain \nbarrier poorly.\n\u2022\t5-Hydroxytryptamine\t (5-HT) 3 receptor antagonists (e.g. \nondansetron ): cytotoxic drugs or radiation, \npostoperative vomiting.\n\u2022\tCannabinoids\t (e.g.\t nabilone ): cytotoxic drugs (see \nCh. 20).\n\u2022\tNK 1 receptor antagonists (e.g. fosaprepitant): cytotoxic \ndrugs.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2732, "end_char_idx": 4424, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d428b0ce-8ebd-48b3-9581-8666291316aa": {"__data__": {"id_": "d428b0ce-8ebd-48b3-9581-8666291316aa", "embedding": null, "metadata": {"page_label": "409", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "81cf952d-df94-4a31-b40a-5d6168dd268d", "node_type": null, "metadata": {"page_label": "409", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "15de7735e552b40b7715dd20cad4de6f534f298206e715928fd39406385aacb0"}, "3": {"node_id": "d0403fc9-d183-4966-97c8-c0970c1a5e4b", "node_type": null, "metadata": {"page_label": "409", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24e69aeaad2689497585c8ff833b040a4d30605cf1f3550fb6b7ae1f70f7962d"}}, "hash": "252baf1b50919336ff41bece1b5c8591b6e3a36ef3fe84570b3d187f01a17469", "text": "31 ThE GASTROINTESTINA l TRACT\n403torticollis (involuntary twisting of the neck) and oculogyric \ncrises (involuntary upward eye movements). It stimulates \nprolactin release (see Chs 34 and 36) causing galactorrhoea \nand disorders of menstruation.\nDomperidone is a similar drug used to treat vomiting \ndue to cytotoxic therapy as well as GI symptoms. Unlike metoclopramide, it does not readily penetrate the blood\u2013brain barrier and is consequently less prone to producing \ncentral side effects. However, domperidone is associated \nwith a small increased risk of serious cardiac adverse effects (particularly at higher doses and in older patients), and its use is now restricted.\nBoth drugs are given orally, have plasma half-lives of \n4\u20135 h and are excreted in the urine.\nNK 1 receptor antagonists\nSubstance P causes vomiting when injected intravenously and is released by GI vagal afferent nerves as well as in \nthe vomiting centre itself. Aprepitant blocks substance \nP (NK\n1) receptors (see Ch. 19) in the CTZ and vomiting \ncentre. Aprepitant is given orally, and is effective in controlling the late phase of emesis caused by cytotoxic \ndrugs, with few significant unwanted effects. Fosap-\nrepitant is a prodrug of aprepitant, which is administered \nintravenously.\nOTHER \u2003ANTIEMETIC \u2003DRUGS\nAnecdotal evidence originally suggested the possibility of using cannabinoids (see Ch. 20) as antiemetics (see Pertwee, \n2001). The synthetic cannabinol nabilone has been found \nto decrease vomiting caused by agents that stimulate the CTZ, and is sometimes effective where other drugs have \nfailed. The antiemetic effect is antagonised by naloxone, \nwhich implies that opioid receptors may be important \nin the mechanism of action. Nabilone is given orally; it \nis well absorbed from the GI tract and is metabolised \nin many tissues. Its plasma half-life is approximately \n120 min, and its metabolites are excreted in the urine \nand faeces.\nUnwanted effects are common, especially drowsiness, \ndizziness and dry mouth. Mood changes and postural hypotension are also fairly frequent. Some patients experi -\nence hallucinations and psychotic reactions, resembling the effect of other cannabinoids (see Ch. 20).\nHigh-dose glucocorticoids (particularly dexamethasone ; \nsee Chs 27 and 34) can also control emesis, especially when this is caused by cytotoxic drugs. The mechanism of action is not clear. Dexamethasone is typically deployed in combination with metoclopramide or ondansetron in \npatients receiving cytotoxics, or in postoperative nausea \nand vomiting.\nTHE MOTILITY OF THE GI TRACT\nDrugs that alter the motility of the GI tract include:\n\u2022\tpurgatives, \twhich \taccelerate \tthe \tpassage \tof \tfood \t\nthrough the intestine;\n\u2022\tagents \tthat \tincrease \tthe \tmotility \tof \tthe \tGI \tsmooth \t\nmuscle without causing purgation;\n\u2022\tantidiarrhoeal \tdrugs, \twhich \tdecrease \tmotility;\n\u2022\tantispasmodic \tdrugs, \twhich \tdecrease \tsmooth \tmuscle \t\ntone.while possibly contributing to their clinical efficacy, are the chief unwanted effects.\nBetahistine has complicated effects on histamine action, \nantagonising H\n3 receptors but having a weak agonist activity \non H 1 receptors. It is used to control the nausea and vertigo \nassociated with Meni\u00e8re\u2019s disease.9\nMuscarinic receptor antagonists\nHyoscine (scopolamine) is employed principally for", "start_char_idx": 0, "end_char_idx": 3330, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d0403fc9-d183-4966-97c8-c0970c1a5e4b": {"__data__": {"id_": "d0403fc9-d183-4966-97c8-c0970c1a5e4b", "embedding": null, "metadata": {"page_label": "409", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "81cf952d-df94-4a31-b40a-5d6168dd268d", "node_type": null, "metadata": {"page_label": "409", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "15de7735e552b40b7715dd20cad4de6f534f298206e715928fd39406385aacb0"}, "2": {"node_id": "d428b0ce-8ebd-48b3-9581-8666291316aa", "node_type": null, "metadata": {"page_label": "409", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "252baf1b50919336ff41bece1b5c8591b6e3a36ef3fe84570b3d187f01a17469"}}, "hash": "24e69aeaad2689497585c8ff833b040a4d30605cf1f3550fb6b7ae1f70f7962d", "text": "receptor antagonists\nHyoscine (scopolamine) is employed principally for prophylaxis and treatment of motion sickness, and may \nbe administered orally or as a transdermal patch. Dry mouth \nand blurred vision are the most common unwanted effects. Drowsiness also occurs, but the drug has less sedative action \nthan the antihistamines because of poor central nervous \nsystem penetration.\n5-HT 3 receptor antagonists\nGranisetron, ondansetron and palonosetron (see Ch. \n16) are of particular value in preventing and treating the \nvomiting and, to a lesser extent the nausea, commonly \nencountered postoperatively as well as that caused by radiation therapy or administration of cytotoxic drugs \nsuch as cisplatin. The primary site of action of these \ndrugs is the CTZ. They may be given orally or by injection (sometimes helpful if nausea is already present). Unwanted \neffects such as headache and GI upsets are relatively \nuncommon.\nDopamine antagonists\nAntipsychotic phenothiazines (see Ch. 47), such as chlor-\npromazine, perphenazine, prochlorperazine and triflu-\noperazine, are effective antiemetics commonly used for \ntreating the more severe nausea and vomiting associated with cancer, radiation therapy, cytotoxic drugs, opioids, \nanaesthetics and other drugs. They can be administered \norally, intravenously or by suppository. They act mainly as antagonists of the dopamine D\n2 receptors in the CTZ \n(see Fig. 31.5) but they also block histamine and muscarinic \nreceptors.\nUnwanted effects are common and include sedation \n(especially chlorpromazine), hypotension and extrapyrami -\ndal symptoms including dystonias and tardive dyskinesia \n(Ch. 47).\nOther antipsychotic drugs, such as haloperidol, the related \ncompound droperidol and levomepromazine (Ch. 47), also \nact as D 2 antagonists in the CTZ and can be used for acute \nchemotherapy-induced emesis.\nMetoclopramide and domperidone\nMetoclopramide is a D 2 receptor antagonist (see Fig. 31.5), \nclosely related to the phenothiazine group, that acts centrally \non the CTZ and also has a peripheral action on the GI tract \nitself, increasing the motility of the oesophagus, stomach and intestine. This not only adds to the antiemetic effect, \nbut explains its use in the treatment of gastro-oesophageal \nreflux and hepatic and biliary disorders. As metoclopramide also blocks dopamine receptors elsewhere in the central \nnervous system, it produces a number of unwanted effects \nincluding disorders of movement (more common in children and young adults), fatigue, motor restlessness, spasmodic \n9A disabling condition named after the eponymous French physician \nwho discovered that the nausea and vertigo that characterise this \ncondition were associated with a disorder of the inner ear.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3259, "end_char_idx": 6486, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "13d70202-9dc9-4f42-827d-dd1d9b7e54c3": {"__data__": {"id_": "13d70202-9dc9-4f42-827d-dd1d9b7e54c3", "embedding": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5f14dca-ec26-4fbf-a6ca-dc57c95ddf14", "node_type": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "af7a40c529671e8a3a552f08f90dd9ad313cdcf7af55829ad22b266cd8f3c7c5"}, "3": {"node_id": "6c170b46-2299-4e7d-b615-274e2bba5b00", "node_type": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "375b4d0d4d40ec2af366ba944e57b141cf3521179d1966f5074debcdacbeb4d6"}}, "hash": "9f237f8992361e0da86f0e79daabdc47688afa1a655b251822eb8a72350328cd", "text": "31 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n404FAECAL\u2003 SOFTENERS\nDocusate sodium is a surface-active compound that acts \nin the GI tract in a manner similar to a detergent and \nproduces softer faeces. It is also a weak stimulant laxative. \nOther agents that achieve the same effect include arachis \noil, which is given as an enema, and liquid paraffin , \nalthough this is now seldom used.\nSTIMULANT\u2003 LAXATIVES\nThe stimulant laxative drugs act mainly by increasing \nelectrolyte and hence water secretion by the mucosa, and \nby increasing peristalsis \u2013 possibly by stimulating enteric \nnerves. Abdominal cramping may be experienced as a side \neffect with almost any of these drugs.\nBisacodyl may be given by mouth but is often given by \nsuppository. In the latter case, it stimulates the rectal mucosa, \ninducing defecation in 15\u201330 min. Glycerol suppositories \nact in the same manner. Sodium picosulfate and docusate \nsodium have similar actions. The former is given orally \nand is often used in preparation for intestinal surgery or \ncolonoscopy.\nSenna and dantron are anthraquinone laxatives. The \nactive principle (after hydrolysis of glycosidic linkages in \nthe case of the plant extract, senna) directly stimulates the \nmyenteric plexus, resulting in increased peristalsis and thus \ndefecation. Dantron is similar. As this drug is a skin irritant \nand may be carcinogenic, it is generally used only in the \nterminally ill.\nLaxatives of any type should not be used when there is \nobstruction of the bowel. Overuse can lead to an atonic \ncolon where the natural propulsive activity is diminished. \nIn these circumstances, the only way to achieve defecation \nis to take further amounts of laxatives, so a sort of depend -\nency arises.\nDRUGS THAT INCREASE \nGASTROINTESTINAL MOTILITY\nDomperidone is primarily used as an antiemetic (as \ndescribed previously), but it also increases GI motility \n(although the mechanism is unknown).\nMetoclopramide (also an antiemetic) stimulates gastric \nmotility, causing a marked acceleration of gastric emptying. \nIt is useful in gastro-oesophageal reflux and in disorders \nof gastric emptying, but is ineffective in paralytic ileus.\nPrucalopride is a selective 5-HT 4 receptor agonist that has \nmarked prokinetic properties on the gut. It is generally only \nused when other types of laxative treatment have failed.\nLubiprostone is a chloride channel-2 activator that acts \non cells in the apical membrane of the small intestine to \npromote chloride and fluid secretion into the lumen, with \nassociated improvements in gut motility and softer stool. \nIt has regulatory approval for treatment of constipation \ndue to opioids, in irritable bowel syndrome, and in patients \nwho have failed to respond to non-drug treatment of \nconstipation.\nNaloxegol is a \u00b5 opioid-receptor antagonist that is \nsimilar to naloxone, but with the addition of a pegylated \nportion to prevent penetration into the central nervous \nsystem. Naloxegol counteracts the reduced GI motility and \nhypertonicity that is seen in opioid-induced constipation, \nbut without exerting any adverse effect on the analgesic \nproperties of opioid agonists centrally. Methylnaltrexone \nis a peripheral opioid-receptor antagonist that is licensed \nfor opioid-induced constipation, and there are a number Clinical uses of drugs that affect the motility of the GI tract \nare summarised in the", "start_char_idx": 0, "end_char_idx": 3398, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6c170b46-2299-4e7d-b615-274e2bba5b00": {"__data__": {"id_": "6c170b46-2299-4e7d-b615-274e2bba5b00", "embedding": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5f14dca-ec26-4fbf-a6ca-dc57c95ddf14", "node_type": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "af7a40c529671e8a3a552f08f90dd9ad313cdcf7af55829ad22b266cd8f3c7c5"}, "2": {"node_id": "13d70202-9dc9-4f42-827d-dd1d9b7e54c3", "node_type": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f237f8992361e0da86f0e79daabdc47688afa1a655b251822eb8a72350328cd"}, "3": {"node_id": "8bb3eacb-95f4-4234-879a-1ea058fbaed3", "node_type": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57d776aa0b6b2434a0db31d068d72cc5bf4e794a60aba955f9b66c7cf02b1721"}}, "hash": "375b4d0d4d40ec2af366ba944e57b141cf3521179d1966f5074debcdacbeb4d6", "text": "drugs that affect the motility of the GI tract \nare summarised in the clinical box below.\nDrugs and GI tract motility \n\u2022\tPurgatives\t include:\n\u2013 bulk laxatives (e.g. ispaghula husk , first choice for \nslow action);\n\u2013 osmotic laxatives (e.g. lactulose );\n\u2013 faecal softeners (e.g. docusate );\n\u2013 stimulant purgatives (e.g. senna ).\n\u2022\tDrugs\tused\tto\ttreat\tdiarrhoea:\n\u2013 oral rehydration with isotonic solutions of NaCl plus \nglucose and starch-based cereal (important in \ninfants);\n\u2013 antimotility agents, e.g. loperamide (unwanted \neffects: drowsiness and nausea).\nPURGATIVES\nThe transit of food through the intestine may be hastened \nby several different types of drugs, including laxatives, \nfaecal softeners and stimulant purgatives. The latter agents \nmay be used to relieve constipation or to clear the bowel \nprior to surgery or examination.\nBULK\u2003 AND\u2003 OSMOTIC\u2003 LAXATIVES\nThe bulk laxatives include methylcellulose and certain plant \nextracts such as sterculia , agar , bran and ispaghula husk . \nThese agents are polysaccharide polymers that are not \ndigested in the upper part of the GI tract. They form a \nbulky hydrated mass in the gut lumen promoting peristalsis \nand improving faecal consistency. They may take several \ndays to work but have no serious unwanted effects.\nThe osmotic laxatives consist of poorly absorbed solutes \n\u2013 the saline purgatives \u2013 and lactulose . The main salts in \nuse are magnesium sulfate and magnesium hydroxide. By \nproducing an osmotic load, these agents trap increased \nvolumes of fluid in the lumen of the bowel, accelerating \nthe transfer of the gut contents through the small intestine. \nThis results in an abnormally large volume entering the \ncolon, causing distension and purgation within about an \nhour. Abdominal cramps can occur. The amount of mag -\nnesium absorbed after an oral dose is usually too small to \nhave adverse systemic effects, but these salts should be \navoided in small children and in patients with poor renal \nfunction, in whom they can cause heart block, neuromuscular \nblock or central nervous system depression. While isotonic \nor hypotonic solutions of saline purgatives cause purgation, \nhypertonic solutions can cause vomiting. Sometimes, other \nsodium salts of phosphate and citrate are given rectally, \nby suppository, to relieve constipation.\nLactulose is a semisynthetic disaccharide of fructose and \ngalactose. It is poorly absorbed and produces an effect \nsimilar to that of the other osmotic laxatives. It takes 2\u20133 \ndays to act. Unwanted effects, seen with high doses, include \nflatulence, cramps, diarrhoea and electrolyte disturbance. \nTolerance can develop. Another agent, macrogol , which \nconsists of inert ethylene glycol polymers, acts in the \nsame way, and is sometimes formulated together with \nelectrolyte ions to ensure that the laxative effect does not \ncause marked changes in sodium, potassium and water \nbalance.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3342, "end_char_idx": 6666, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8bb3eacb-95f4-4234-879a-1ea058fbaed3": {"__data__": {"id_": "8bb3eacb-95f4-4234-879a-1ea058fbaed3", "embedding": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5f14dca-ec26-4fbf-a6ca-dc57c95ddf14", "node_type": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "af7a40c529671e8a3a552f08f90dd9ad313cdcf7af55829ad22b266cd8f3c7c5"}, "2": {"node_id": "6c170b46-2299-4e7d-b615-274e2bba5b00", "node_type": null, "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "375b4d0d4d40ec2af366ba944e57b141cf3521179d1966f5074debcdacbeb4d6"}}, "hash": "57d776aa0b6b2434a0db31d068d72cc5bf4e794a60aba955f9b66c7cf02b1721", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6676, "end_char_idx": 6787, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fd88ea8f-70e9-4371-9b41-c4063edf4ac5": {"__data__": {"id_": "fd88ea8f-70e9-4371-9b41-c4063edf4ac5", "embedding": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0f37a124-1cd5-474c-a1b7-aa2fb1c84bfd", "node_type": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "822f2623ca4f974afdc67d839d3317c9571706e1e78e52471754cace7715d935"}, "3": {"node_id": "fd2053ae-96fa-46b0-896b-42224cb46063", "node_type": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91e6042c5d4c91648eff3acd5643829af14dff5f75bac32a8cdbda5aec1841c1"}}, "hash": "268d95b0e8580291f84923a192b4962faa5296d86cf6d136a62c1128b014a3a4", "text": "31 ThE GASTROINTESTINA l TRACT\n405information on the condition, including the prevalence of \ninfectious organisms around the globe as well as recom -\nmended treatment guidelines, is issued in the United Kingdom by the National Travel Health Network and Centre (see web links in the reference list).\nANTIMOTILITY \u2003AND \u2003SPASMOLYTIC \u2003AGENTS\nThe main pharmacological agents that decrease motility are opioids (Ch. 43) and muscarinic receptor antagonists \n(Ch. 14). Agents in this latter group are seldom employed \nas primary therapy for diarrhoea because of their actions on other systems, but small doses of atropine are sometimes \nused, combined with diphenoxylate. The action of mor-phine, the archetypal opiate, on the alimentary tract is complex; it increases the tone and rhythmic contractions \nof the intestine but diminishes propulsive activity. The \npyloric, ileocolic and anal sphincters are contracted, and the tone of the large intestine is markedly increased. Its overall effect is constipating.\nThe main opioids used for the symptomatic relief of \ndiarrhoea are codeine (a morphine congener), diphenoxylate \nand loperamide (both pethidine congeners that do not \nreadily penetrate the blood\u2013brain barrier and are used only for their actions in the gut). All may have unwanted effects, including constipation, abdominal cramps, drowsiness and \ndizziness. Complete loss of intestinal motility (paralytic \nileus) can also occur. They should not be used in young (<4 years of age) children.\nLoperamide is the drug of first choice for pharmaco -\ntherapy of travellers\u2019 diarrhoea and is a component of several proprietary antidiarrhoeal medicines. It has a rela -\ntively selective action on the GI tract and undergoes sig -\nnificant enterohepatic cycling. It reduces the frequency of abdominal cramps, decreases the passage of faeces and \nshortens the duration of the illness.\nDiphenoxylate also lacks morphine-like activity in the \ncentral nervous system, although large doses (25-fold higher) \nproduce typical opioid effects. Preparations of diphenoxylate \nusually contain atropine as well. Codeine and loperamide \nhave antisecretory actions in addition to their effects on intestinal motility.\n\u2018Endogenous opioids\u2019, enkephalins (Ch. 43), also play a role \nin regulation of intestinal secretion. Racecadotril is a prodrug \nof thiorphan , an inhibitor of enkephalinase. By preventing the \nbreakdown of enkephalins, this drug reduces the excessive intestinal secretion seen during episodes of diarrhoea. It is used in combination with rehydration therapy.\nCannabinoid receptor agonists also reduce gut motility \nin animals, most probably by decreasing acetylcholine release from enteric nerves. There have been anecdotal \nreports of a beneficial effect of cannabis against dysentery \nand cholera.\nDrugs that reduce GI motility are also useful in irritable \nbowel syndrome and diverticular disease. Muscarinic receptor antagonists (Ch. 14) used for this purpose include atropine, hyoscine, propantheline and dicycloverine. The last named \nis thought to have some additional direct relaxant action on \nsmooth muscle. All produce antimuscarinic side effects such \nas dry mouth, blurred vision and urinary retention. Mebev -\nerine, a derivative of reserpine, has a direct relaxant action \non GI smooth muscle. Unwanted effects are few.\nADSORBENTS\nAdsorbent agents are used in the symptomatic treatment \nof some types of diarrhoea, although properly controlled of related compounds (examples include naldemedine and", "start_char_idx": 0, "end_char_idx": 3516, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fd2053ae-96fa-46b0-896b-42224cb46063": {"__data__": {"id_": "fd2053ae-96fa-46b0-896b-42224cb46063", "embedding": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0f37a124-1cd5-474c-a1b7-aa2fb1c84bfd", "node_type": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "822f2623ca4f974afdc67d839d3317c9571706e1e78e52471754cace7715d935"}, "2": {"node_id": "fd88ea8f-70e9-4371-9b41-c4063edf4ac5", "node_type": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "268d95b0e8580291f84923a192b4962faa5296d86cf6d136a62c1128b014a3a4"}, "3": {"node_id": "e80cabce-fa55-42cf-8b2b-f432c2088172", "node_type": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "986057d783a517f82288e2ffcf032e9a746f6efa37a46e7dad1cafb4382486b7"}}, "hash": "91e6042c5d4c91648eff3acd5643829af14dff5f75bac32a8cdbda5aec1841c1", "text": "although properly controlled of related compounds (examples include naldemedine and \naxelopran) in development (Nelson & Camilleri, 2016).\nANTIDIARRHOEAL AGENTS\nThere are numerous causes of diarrhoea, including underlying disease, infection, toxins and even anxiety. It may \nalso arise as a side effect of drug or radiation therapy. The \nconsequences range from mild discomfort and inconvenience to a medical emergency requiring hospitalisation, parenteral \nfluid and electrolyte replacement therapy. Globally, acute \ndiarrhoeal disease is one of the principal causes of death in malnourished infants, especially in developing countries \nwhere medical care is less accessible and 1\u20132 million children \ndie each year for want of simple counter-measures.\nDuring an episode of diarrhoea, there is an increase in \nthe motility of the GI tract, accompanied by an increased \nsecretion, coupled with a decreased absorption, of fluid. This \nleads to a loss of electrolytes (particularly Na\n+) and water. \nCholera toxins and some other bacterial toxins produce \na profound increase in electrolyte and fluid secretion by \nirreversibly activating the G proteins that couple the surface receptors of the mucosal cells to adenylyl cyclase (see Ch. 3).\nThere are three approaches to the treatment of severe \nacute diarrhoea:\n\u2022\tmaintenance \tof \tfluid \tand \telectrolyte \tbalance;\n\u2022\tuse\tof\tanti-infective \tagents;\n\u2022\tuse\tof\tspasmolytic \tor \tother \tantidiarrhoeal \tagents.\nThe maintenance of fluid and electrolyte balance by means of oral rehydration is the first priority. Wider application \nof this cheap and simple remedy could save the lives of \nmany infants in the developing world. Indeed, many patients require no other treatment.\nIn the ileum, as in the nephron, there is co-transport of \nNa\n+ and glucose across the epithelial cell. The presence of \nglucose (and some amino acids) therefore enhances Na+ \nabsorption and thus water uptake. Preparations of sodium \nchloride and glucose for oral rehydration are available in \npowder form, ready to be dissolved in water before use.\nMany GI infections are viral in origin. Those that are \nbacterial generally resolve fairly rapidly, so the use of anti-infective agents is usually neither necessary nor useful. Other cases may require more aggressive therapy, \nhowever. Campylobacter spp. is the commonest cause of \nbacterial gastroenteritis in the United Kingdom, and severe \ninfections may require ciprofloxacin. The most common \nbacterial organisms encountered by travellers include \nEscherichia coli, Salmonella and Shigella, as well as protozoa \nsuch as Giardia and Cryptosporidium spp. Drug treatment \n(Chs 52 and 55) may be necessary in these and other more \nserious infections.\nTRAVELLERS\u2019 \u2003DIARRHOEA\nMillions of people cross international borders each year. \nMany travel hopefully, but many return with GI symptoms \nsuch as diarrhoea, having encountered enterotoxin-\nproducing E. coli (the most common cause) or other organ -\nisms. Most infections are mild and self-limiting, requiring \nonly oral replacement of fluid and salt, as detailed previ -\nously. General principles for the drug treatment of travellers\u2019 \ndiarrhoea are detailed by Gorbach (1987).10 Up-to-date \n10Who flippantly (although accurately) observed that \u2018travel broadens \nthe mind and loosens the bowels\u2019.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3443, "end_char_idx": 6905, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e80cabce-fa55-42cf-8b2b-f432c2088172": {"__data__": {"id_": "e80cabce-fa55-42cf-8b2b-f432c2088172", "embedding": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0f37a124-1cd5-474c-a1b7-aa2fb1c84bfd", "node_type": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "822f2623ca4f974afdc67d839d3317c9571706e1e78e52471754cace7715d935"}, "2": {"node_id": "fd2053ae-96fa-46b0-896b-42224cb46063", "node_type": null, "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91e6042c5d4c91648eff3acd5643829af14dff5f75bac32a8cdbda5aec1841c1"}}, "hash": "986057d783a517f82288e2ffcf032e9a746f6efa37a46e7dad1cafb4382486b7", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6932, "end_char_idx": 7315, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "02c9c37a-a7de-49e4-8fdd-3991662ce8ff": {"__data__": {"id_": "02c9c37a-a7de-49e4-8fdd-3991662ce8ff", "embedding": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e3a78cca-7e3b-46e9-8bc4-d1e549e98389", "node_type": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1609c54e34682bd200ebb29bad582d307e3879ffe906968ef0af859748ce3a9e"}, "3": {"node_id": "136cec3d-5ef7-48ae-b550-128f4f7e26f8", "node_type": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "28b3eb9ee4c11a98d698e52f249dc22b9cac224347d7d9f3f26e34edd53a390b"}}, "hash": "263600ef11083495471933dc033a55d0e5fb5e5f24b197d0b280d4b4f49e85cd", "text": "31 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n406the active moiety when it is released in the colon. Its \nmechanism of action is obscure. It may reduce inflammation \nby scavenging free radicals, by inhibiting prostaglandin \nand leukotriene production, and/or by decreasing neutro -\nphil chemotaxis and superoxide generation. Its unwanted \neffects include diarrhoea, salicylate sensitivity and interstitial \nnephritis. 5-ASA is not absorbed, but the sulfapyridine moiety, which seems to be therapeutically inert in this \ninstance, is absorbed, and its unwanted effects are those \nassociated with the sulfonamides (see Ch. 52).\nNewer compounds in this class, which presumably share \na similar mechanism of action, include mesalazine (5-ASA \nitself), olsalazine (a 5-ASA dimer linked by a bond that is \nhydrolysed by colonic bacteria) and balsalazide (a prodrug \nfrom which 5-ASA is also released following hydrolysis of \na diazo linkage).\nOTHER \u2003DRUGS\nMethotrexate and the immunosuppressants ciclosporin, \ntacrolimus, azathioprine and 6-mercaptopurine (see Ch. \n27) are also sometimes used in patients with severe IBD. \nThe biopharmaceuticals infliximab, adalimumab and \ngolimumab , monoclonal antibodies directed against tumour \nnecrosis factor (TNF)-\u03b1 (see Ch. 27), have also been used with success. These drugs are expensive, and their principal indication is for moderate and severe Crohn\u2019s disease that \nis unresponsive to glucocorticoids or immunomodulators.\nNewer biopharmaceuticals agents have been developed \ntowards alternative targets in the inflammatory pathway. \nVedolizumab is a humanised monoclonal antibody with \nspecific binding properties for \u03b14\u03b27 integrin on T-helper \nlymphocytes that migrate to the gut. The inhibition of \u03b14\u03b27 \nintegrin stops the interaction of these lymphocytes with mucosal addressin cell adhesion molecule-1 on gut epithelial \ncells, thus reducing the inflammatory effects in the bowel tissue that arise from trans-migration of T lymphocytes. \nIn contrast, ustekinumab is targeted at the p40 protein \nsubunit of interleukin (IL)-12 and IL-23, and prevents these cytokines from binding to IL-12R \u03b21 receptors on immune \ncells. Vedolizumab and ustekinumab are indicated in those with moderately to severely active Crohn\u2019s disease, who have not responded to or cannot tolerate conventional \ntreatment and other biopharmaceuticals.\nThe antiallergy drug sodium cromoglicate (see Ch. 29) \nis sometimes used for treating GI symptoms associated with food allergies.\nDRUGS AFFECTING THE BILIARY SYSTEM\nThe commonest pathological condition of the biliary tract \nis cholesterol cholelithiasis \u2013 the formation of gallstones with \nhigh cholesterol content. Surgery is generally the preferred option, but there are orally active drugs that dissolve non-calcified \u2018radiolucent\u2019 cholesterol gallstones. The principal \nagent is ursodeoxycholic acid , a minor constituent of human \nbile (but the main bile acid in the bear, hence urso-). Diar-\nrhoea is the main unwanted effect.\nBiliary colic, the pain produced by the passage of gall -\nstones through the bile duct, can be very intense, and \nimmediate relief may be required. Morphine relieves the pain effectively, but it may have an undesirable local effect \nbecause it constricts the sphincter of Oddi and raises the \npressure in the bile", "start_char_idx": 0, "end_char_idx": 3325, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "136cec3d-5ef7-48ae-b550-128f4f7e26f8": {"__data__": {"id_": "136cec3d-5ef7-48ae-b550-128f4f7e26f8", "embedding": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e3a78cca-7e3b-46e9-8bc4-d1e549e98389", "node_type": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1609c54e34682bd200ebb29bad582d307e3879ffe906968ef0af859748ce3a9e"}, "2": {"node_id": "02c9c37a-a7de-49e4-8fdd-3991662ce8ff", "node_type": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "263600ef11083495471933dc033a55d0e5fb5e5f24b197d0b280d4b4f49e85cd"}, "3": {"node_id": "f0ce8a9d-0847-41bc-b857-4498dbc0a601", "node_type": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39c72ae4b769d3f537d0781fb9cbfd7cc74671f05953ca9f0ce5c633eb5bf1ca"}}, "hash": "28b3eb9ee4c11a98d698e52f249dc22b9cac224347d7d9f3f26e34edd53a390b", "text": "the sphincter of Oddi and raises the \npressure in the bile duct. Buprenorphine may be preferable. \nPethidine has similar actions, although it relaxes other trials proving efficacy have not been carried out. The main preparations used contain kaolin, pectin, chalk, charcoal, \nmethylcellulose and activated attapulgite (magnesium \naluminium silicate). It has been suggested that these agents may act by adsorbing microorganisms or toxins, by altering \nthe intestinal flora or by coating and protecting the intestinal \nmucosa, but there is no hard evidence for this. Kaolin is sometimes given as a mixture with morphine (e.g. kaolin \nand morphine mixture BP).\nDRUGS FOR CHRONIC BOWEL DISEASE\nThis category comprises irritable bowel syndrome (IBS) and \ninflammatory bowel disease (IBD). IBS is characterised by bouts \nof diarrhoea, constipation or abdominal pain. The aetiology of the disease is uncertain, but psychological factors may play a part. Treatment is symptomatic, with a high-residue \ndiet plus loperamide or a laxative if needed.\nEluxadoline is a mixed \u00b5 and \u03ba opioid-receptor agonist \nand \u03b4-receptor antagonist that has recently been licensed \nfor treatment of IBS with diarrhoea. The drug acts on \nopioids receptors in enteric neurons that regulate motility and visceral sensation in the GI tract, resulting in slowing of intestinal transit and improved stool consistency. \nEluxadoline has low oral bioavailability and is considered \nto have limited potential for adverse effects on opioid receptors in the central nervous system (see Corsetti & \nWhorwell, 2016).\nLinaclotide has recently received regulatory approval \nfor symptomatic treatment of moderate to severe IBS with \nconstipation in adults. It is a synthetic peptide that is \nstructurally related to endogenous guanylin peptides. Linaclotide is an agonist at the guanylate cyclase-C receptor \non the luminal surface of intestinal epithelium, and increases \nthe concentration of cyclic guanosine monophosphate in the intestinal cells. This results in greater secretion of \nchloride and bicarbonate ions and intestinal fluid, as well \nas more rapid intestinal transit. Clinical trials have dem -\nonstrated improvements in bowel movements and reduction \nin abdominal discomfort, although diarrhoea is a recognised \nadverse effect (see Corsetti & Whorwell, 2016).\nUlcerative colitis and Crohn\u2019s disease are forms of IBD, \naffecting the colon or ileum. They are autoimmune inflam -\nmatory disorders, which can be severe and progressive, requiring long-term drug treatment with anti-inflammatory and immunosuppressant drugs (see Ch. 27), and occasionally \nsurgical resection. The following agents are commonly used.\nGLUCOCORTICOIDS\nGlucocorticoids are potent anti-inflammatory agents and \nare dealt with in Chapters 27 and 34. The drugs of choice \nare generally prednisolone or budesonide (although others \ncan be used). They are administered orally or locally into \nthe bowel by suppository or enema.\nAMINOSALICYLATES\nWhile glucocorticoids are useful for the acute attacks of IBDs, they are not the ideal for the long-term treatment \nbecause of their side effects. Maintenance of remission in \nboth ulcerative colitis and Crohn\u2019s disease is generally achieved with aminosalicylates, although they are less useful \nin the latter condition.\nSulfasalazine consists of the sulfonamide sulfapyridine \nlinked to 5-aminosalicylic acid (5-ASA). The latter forms mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3278, "end_char_idx": 6768, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f0ce8a9d-0847-41bc-b857-4498dbc0a601": {"__data__": {"id_": "f0ce8a9d-0847-41bc-b857-4498dbc0a601", "embedding": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e3a78cca-7e3b-46e9-8bc4-d1e549e98389", "node_type": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1609c54e34682bd200ebb29bad582d307e3879ffe906968ef0af859748ce3a9e"}, "2": {"node_id": "136cec3d-5ef7-48ae-b550-128f4f7e26f8", "node_type": null, "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "28b3eb9ee4c11a98d698e52f249dc22b9cac224347d7d9f3f26e34edd53a390b"}}, "hash": "39c72ae4b769d3f537d0781fb9cbfd7cc74671f05953ca9f0ce5c633eb5bf1ca", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6753, "end_char_idx": 7232, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "07c9f9ad-bc8e-47c0-8e80-4e152d7ef48f": {"__data__": {"id_": "07c9f9ad-bc8e-47c0-8e80-4e152d7ef48f", "embedding": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ee455c59-34dc-472c-88a3-efdfd8de10c7", "node_type": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "763ec9e1e17c69a720539be00b396b12abfa176d06b0d6c1ef2ddd4d9d3f2e5c"}, "3": {"node_id": "3865516f-794c-4679-b4a3-6ee814305867", "node_type": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d12dd3f32207476b0901b71cd9086b113bc060c61ffa9e7d3b06394631b8fe6f"}}, "hash": "cca726dad1da1ee5765ef7755f06f4bcb8dc042160a85fd7c7c9ef109ec34463", "text": "31 ThE GASTROINTESTINA l TRACT\n407are gastrin/cholecystokinin-2 receptor antagonists (with \nlittle success) and potassium competitive acid-blocking \ndrugs (Inatomi et al., 2016). The latter agents work because \npotassium ions are exchanged for protons by the proton pump (see Fig. 31.1) and so potassium antagonists with \nrapid onset of action and sustained effect would represent \na promising modality for inhibiting the secretion of acid. Unfortunately, the agents produced so far have not been \nconclusively proven to be superior to proton pump inhibi -\ntors, and currently, the two available agents ( revaprazan, \nvonoprazan) are licensed only in a few Asian countries \n(Inatomi et al., 2016).smooth muscle, for example, that of the ureter. Atropine \nis commonly employed to relieve biliary spasm because it \nhas antispasmodic action and may be used in conjunction \nwith morphine. Glyceryl trinitrate (see Ch. 22) can produce \na marked fall of intrabiliary pressure and may be used to \nrelieve biliary spasm.\nFUTURE DIRECTIONS\nThe quest for novel antisecretory drugs is an ongoing task. \nAmongst the newer agents that have undergone evaluation \nREFERENCES AND FURTHER READING\nInnervation and hormones of the gastrointestinal tract\nHansen, M.B., 2003. The enteric nervous system II: gastrointestinal \nfunctions. Pharmacol. Toxicol. 92, 249\u2013257. (Small review on the role of \nthe enteric nervous system in the control of gastrointestinal motility, \nsecretory activity, blood flow and immune status; easy to read)\nSanger, G.J., 2004. Neurokinin NK 1 and NK 3 receptors as targets for \ndrugs to treat gastrointestinal motility disorders and pain. Br. J. \nPharmacol. 141, 1303\u20131312. (Useful review that deals with the present and \npotential future uses of neurokinin antagonists in gastrointestinal physiology and pathology)\nSpiller, R., 2002. Serotonergic modulating drugs for functional \ngastrointestinal diseases. Br. J. Clin. Pharmacol. 54, 11\u201320. (An excellent and \u2018easily digestible\u2019 article describing the latest thinking on the use of \n5-hydroxytryptamine agonists and antagonists in gastrointestinal function; \nuseful diagrams)\nGastric secretion\nBinder, H.J., Donaldson, R.M., Jr., 1978. Effect of cimetidine on \nintrinsic factor and pepsin secretion in man. Gastroenterology 74, \n371\u2013375.\nChen, D., Friis-Hansen, L., H\u00e5kanson, R., Zhao, C.M., 2005. Genetic \ndissection of the signaling pathways that control gastric acid secretion. Inflammopharmacology 13, 201\u2013207. (Describes experiments using \nreceptor \u2018knock-outs\u2019 to analyse the mechanisms that control gastric acid production)\nCui, G., Waldum, H.L., 2007. Physiological and clinical significance of \nenterochromaffin-like cell activation in the regulation of gastric acid secretion. World J. Gastroenterol. 13, 493\u2013496. (Short review on the \ncentral role of ECL cells in the regulation of gastric acid secretion. Easy to \nread)\nHorn, J., 2000. The proton-pump inhibitors: similarities and differences. \nClin. Ther. 22, 266\u2013280, discussion 265. (Excellent overview)\nHuang, J.Q., Hunt, R.H., 2001. Pharmacological and pharmacodynamic \nessentials of H(2)-receptor antagonists and proton pump inhibitors for \nthe practising physician. Best Pract. Res. Clin. Gastroenterol. 15, \n355\u2013370.\nInatomi, N., Matsukawa, J.,", "start_char_idx": 0, "end_char_idx": 3279, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3865516f-794c-4679-b4a3-6ee814305867": {"__data__": {"id_": "3865516f-794c-4679-b4a3-6ee814305867", "embedding": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ee455c59-34dc-472c-88a3-efdfd8de10c7", "node_type": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "763ec9e1e17c69a720539be00b396b12abfa176d06b0d6c1ef2ddd4d9d3f2e5c"}, "2": {"node_id": "07c9f9ad-bc8e-47c0-8e80-4e152d7ef48f", "node_type": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cca726dad1da1ee5765ef7755f06f4bcb8dc042160a85fd7c7c9ef109ec34463"}, "3": {"node_id": "48343d4b-9113-4132-9559-eaea883d4e14", "node_type": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3d5614e17ed6cb76894ddd4dafcc5d622a442bef214ab92f6655778920cdc78"}}, "hash": "d12dd3f32207476b0901b71cd9086b113bc060c61ffa9e7d3b06394631b8fe6f", "text": "\n355\u2013370.\nInatomi, N., Matsukawa, J., Sakurai, Y., Otake, K., 2016. \nPotassium-competitive acid blockers: advanced therapeutic option for acid-related diseases. Pharmacol. Ther. 168, 12\u201322. (A good account of the shortcomings of current anti-secretory drugs and developments in the \nfield)\nLinberg, P., Brandstrom, A., Wallmark, B., 1987. Structure-activity \nrelationships of omeprazole analogues and their mechanism of action. Trends Pharmacol. Sci. 8, 399\u2013402.\nSchubert, M.L., Peura, D.A., 2008. Control of gastric acid secretion in \nhealth and disease. Gastroenterology 134, 1842\u20131860. (Excellent review of the physiology and pharmacology of gastric acid secretion. Authoritative \nand well illustrated)\nDrugs in GI disorders\nBlack, J.W., Duncan, W.A.M., Durant, C.J., et al., 1972. Definition and \nantagonism of histamine H 2-receptors. Nature 236, 385\u2013390. (Seminal \npaper outlining the pharmacological approach to inhibition of acid secretion \nthrough antagonism at an alternative histamine receptor)Blaser, M.J., 1998. Helicobacter pylori and gastric diseases. BMJ 316, \n1507\u20131510. (Succinct review, emphasis on future developments)\nKlotz, U., 2000. The role of aminosalicylates at the beginning of the new \nmillennium in the treatment of chronic inflammatory bowel disease. \nEur. J. Clin. Pharmacol. 56, 353\u2013362.\nMossner, J., Caca, K., 2005. Developments in the inhibition of gastric \nacid secretion. Eur. J. Clin. Invest. 35, 469\u2013475. (Useful overview of several new directions in gastrointestinal drug development)\nPertwee, R.G., 2001. Cannabinoids and the gastrointestinal tract. Gut 48, \n859\u2013867.\nNausea and vomiting\nAndrews, P.L., Horn, C.C., 2006. Signals for nausea and emesis: \nimplications for models of upper gastrointestinal diseases. Auton. \nNeurosci. 125, 100\u2013115.\nHesketh, P.J., 2001. Potential role of the NK 1 receptor antagonists in \nchemotherapy-induced nausea and vomiting. Support. Care Cancer 9, 350\u2013354.\nHornby, P.J., 2001. Central neurocircuitry associated with emesis. Am. J. \nMed. 111, 106S\u2013112S. (Comprehensive review of central control of vomiting)\nRojas, C., Slusher, B.S., 2012. Pharmacological mechanisms of 5-HT(3) \nand tachykinin NK(1) receptor antagonism to prevent chemotherapy-induced nausea and vomiting. Eur. J. Pharmacol. 684, \n1\u20137.\nTram\u00e8r, M.R., Moore, R., Reynolds, D.J., McQuay, H.J., 1997. A \nquantitative systematic review of ondansetron in treatment of established postoperative nausea and vomiting. Br. Med. J. 314, 1088\u20131092.\nYates, B.J., Miller, A.D., Lucot, J.B., 1998. Physiological basis and \npharmacology of motion sickness: an update. Brain Res. Bull. 5, 395\u2013406. (Good account of the mechanisms underlying motion sickness and \nits treatment)\nMotility of the gastrointestinal tract\nCorsetti, M., Whorwell, P., 2016. Novel pharmacological therapies for \nirritable bowel syndrome. Expert Rev. Gastroenterol. Hepatol. 10, 807\u2013815. (Good review article covering current treatments)\nDe Las Casas, C., Adachi, J.,", "start_char_idx": 3246, "end_char_idx": 6213, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "48343d4b-9113-4132-9559-eaea883d4e14": {"__data__": {"id_": "48343d4b-9113-4132-9559-eaea883d4e14", "embedding": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ee455c59-34dc-472c-88a3-efdfd8de10c7", "node_type": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "763ec9e1e17c69a720539be00b396b12abfa176d06b0d6c1ef2ddd4d9d3f2e5c"}, "2": {"node_id": "3865516f-794c-4679-b4a3-6ee814305867", "node_type": null, "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d12dd3f32207476b0901b71cd9086b113bc060c61ffa9e7d3b06394631b8fe6f"}}, "hash": "b3d5614e17ed6cb76894ddd4dafcc5d622a442bef214ab92f6655778920cdc78", "text": "covering current treatments)\nDe Las Casas, C., Adachi, J., Dupont, H., 1999. Travellers\u2019 diarrhoea. \nAliment. Pharmacol. Ther. 13, 1373\u20131378. (Review article)\nGorbach, S.L., 1987. Bacterial diarrhoea and its treatment. Lancet \n1378\u20131382.\nNelson, A.D., Camilleri, M., 2016. Opioid-induced constipation: \nadvances and clinical guidance. Ther. Adv. Chronic Dis. 7, 121\u2013134.\nThe biliary system\nBateson, M.C., 1997. Bile acid research and applications. Lancet 349, 5\u20136.\nUseful Web resources\nwww.nathnac.org. (This is the site for the UK Health Protection Agency\u2019s \nNational Travel Health Network and Centre. There are two components to the site, one for lay people and one for health professionals. Click on the latter \nand enter \u2018Travellers\u2019 diarrhoea\u2019 as a search term to retrieve current information and advice)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6189, "end_char_idx": 7477, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4226a34f-efbd-435e-a006-486a26c4b6bc": {"__data__": {"id_": "4226a34f-efbd-435e-a006-486a26c4b6bc", "embedding": null, "metadata": {"page_label": "414", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "18bb695d-d5b3-4dd6-8e2c-808da289330f", "node_type": null, "metadata": {"page_label": "414", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0d0cedb409b139bb03c4fa0d9bb93a893a14dc4b7bb27a21f7d2a920f6af634"}, "3": {"node_id": "675b56e7-c395-4a6a-b690-2a98c6883a14", "node_type": null, "metadata": {"page_label": "414", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0696d261ebf04a95be35a6d61593b68f80cd73149eef984c8c104b8f02689ee7"}}, "hash": "c5fce7597aac4b022c48fc9473f1c750451af01589975de717f4c57d93bffb0b", "text": "408\nThe control of blood glucose and \ndrug treatment of diabetes mellitus32 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3\nOVERVIEW\nIn this chapter we describe the endocrine control of \nblood glucose by pancreatic hormones, especially \ninsulin but also glucagon and somatostatin, and the \ngut hormones (incretins) glucagon-like peptide-1 \n(GLP-1) and gastric inhibitory peptide (GIP, which is \nalso known as glucose-dependent insulinotropic \npeptide). This underpins coverage of diabetes mellitus and its treatment with insulin preparations (including \ninsulin analogues), and other hypoglycaemic agents \n\u2013 metformin, sulfonylureas, \u03b1-glucosidase inhibitors, \nlong-acting incretin mimetics such as exenatide, \ngliptins, which potentiate incretins by blocking their \ndegradation, and renal tubular sodium\u2013glucose co-transport inhibitors.\nINTRODUCTION\nInsulin is the main hormone controlling intermediary \nmetabolism. Its most striking acute effect is to lower blood \nglucose. Reduced (or absent) secretion of insulin causes \ndiabetes mellitus. It is often coupled with reduced sensitivity \nto its action, \u2018insulin resistance\u2019, which is closely related \nto obesity. Diabetes mellitus, recognised since ancient times, \nis named for the production of sugary urine in copious volumes (due to the osmotic diuretic action of the high \nurine glucose concentration). Diabetes is rapidly increasing \nto epidemic proportions (in step with obesity, Ch. 33), and its consequences are dire \u2013 especially accelerated athero -\nsclerosis (myocardial and cerebral infarction, gangrene \nor limb amputation), kidney failure, neuropathy and blindness.\nIn this chapter, we first describe the control of blood \nsugar. The second part of the chapter is devoted to the different kinds of diabetes mellitus and the role of drugs in their treatment. Diabetes, along with obesity (Ch. 33), \nhypertension (Ch. 23), dyslipidaemia (Ch. 24), and fatty \ninfiltration of the liver, comprise a \u2018metabolic syndrome\u2019, a common pathological cluster and a rapidly growing \nproblem that is associated with many life-threatening \nconditions. Drugs that act on some of the many mechanisms that become deranged in metabolic syndrome, including \nseveral directed at controlling blood sugar, have been \ndeveloped, but clinical success has so far been modest.\nCONTROL OF BLOOD GLUCOSE\nGlucose is the obligatory source of energy for the adult brain, and physiological control of blood glucose reflects \nthe need to maintain adequate fuel supplies in the face of intermittent food intake and variable metabolic demands. \nMore fuel is made available by feeding than is required \nimmediately, and excess calories are stored as glycogen or \nfat. During fasting, these energy stores need to be mobilised in a regulated manner. The most important regulatory hormone is insulin , the actions of which are described below. \nIncreased blood glucose stimulates insulin secretion (Fig. 32.1), whereas reduced blood glucose reduces insulin secretion. The effect of glucose on insulin secretion depends \non whether the glucose load is administered intravenously \nor by mouth. Glucose administered by mouth is more effective in stimulating insulin secretion because it stimulates \nrelease from the gut of incretin hormones which promote \ninsulin secretion (see Fig. 32.1). Glucose is less effective in \nstimulating insulin secretion in patients with diabetes (Fig. \n32.2). Hypoglycaemia, caused by excessive exogenous insulin, \nnot only reduces endogenous insulin secretion but also elicits secretion of an array of", "start_char_idx": 0, "end_char_idx": 3556, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "675b56e7-c395-4a6a-b690-2a98c6883a14": {"__data__": {"id_": "675b56e7-c395-4a6a-b690-2a98c6883a14", "embedding": null, "metadata": {"page_label": "414", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "18bb695d-d5b3-4dd6-8e2c-808da289330f", "node_type": null, "metadata": {"page_label": "414", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0d0cedb409b139bb03c4fa0d9bb93a893a14dc4b7bb27a21f7d2a920f6af634"}, "2": {"node_id": "4226a34f-efbd-435e-a006-486a26c4b6bc", "node_type": null, "metadata": {"page_label": "414", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c5fce7597aac4b022c48fc9473f1c750451af01589975de717f4c57d93bffb0b"}}, "hash": "0696d261ebf04a95be35a6d61593b68f80cd73149eef984c8c104b8f02689ee7", "text": "only reduces endogenous insulin secretion but also elicits secretion of an array of \u2018counter-regulatory\u2019 hormones, \nincluding glucagon, adrenaline (Ch. 15), glucocorticoids (Ch. \n34) and growth hormone (Ch. 34), all of which increase blood \nglucose. Their main effects on glucose uptake and carbo-hydrate metabolism are summarised and contrasted with \nthose of insulin in Table 32.1.\nThe kidneys also have an important role in glucose \nregulation. Substantial amounts of glucose (approximately \n900 mmol or 160 g) are filtered each day from the plasma \ninto the renal tubules (Abdul-Ghani et al., 2015). However, \nin those with normal glucose homeostasis, very little or no glucose is excreted in the urine because renal tubular \nsodium\u2013glucose co-transporters (SGLT) reclaim all the \nfiltered glucose. The co-transporters are large transmem-brane proteins (670 amino acids) that actively transport \nglucose against the concentration gradient through a \nmechanism that involves coupling with sodium transport \n(Abdul-Ghani et al., 2011). There are two SGLT variants \nin the kidney \u2013 SGLT2 (located in the early convoluted segment of the proximal tubule) has low affinity but high \ncapacity, and is responsible for reclaiming about 90% of \nthe filtered renal glucose, whilst the remaining 10% is reclaimed by high affinity, low capacity SGLT1 (located \nfurther on in the distal straight segment of the proximal \ntubule; DeFronzo et al., 2012). SGLT1 is also found in the \nheart, lungs and gastrointestinal (GI) tract, whereas SGLT2 \nis principally located in the kidney so selective inhibitors \nof SGLT2 can promote glucose excretion without influencing \nglucose transport in other organs.\nThe evolutionary role of SGLT in the kidney has been \nattributed to the benefits of retaining glucose in times when starvation or food shortages were commonplace. However, when the renal capacity for glucose re-absorption is exceeded \nin diabetes, glucose spills over into the urine (glycosuria) \nand causes an osmotic diuresis (polyuria) which, in turn, results in dehydration, thirst and increased drinking (polydipsia). The chronically elevated glucose concentrations mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3473, "end_char_idx": 6118, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bcdad38a-6280-44d5-9bc5-f281f59774e7": {"__data__": {"id_": "bcdad38a-6280-44d5-9bc5-f281f59774e7", "embedding": null, "metadata": {"page_label": "415", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dbabfb56-d12d-4403-b909-458c4da9bc1d", "node_type": null, "metadata": {"page_label": "415", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4c8d379ce8f403b9442322462e2686b56a2445bd8762d5b3450cde6a99fe3e0"}, "3": {"node_id": "69503932-2784-471b-90f2-6a0eb8d89f66", "node_type": null, "metadata": {"page_label": "415", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e55ae24f23e8f3d679fe92fcb5e331219edfb857a1a4b53bd9cf0ad113d8f6d"}}, "hash": "72ae7a3e7272bf4e13b20de117458ab70f9d8348b35b7b90ef349c9b9719470c", "text": "32 ThE CONTRO l OF bl OOD G l UCOSE AND DRUG TREATMENT OF DIA b ETES ME ll ITUS\n409B cell\nA cellD cellGlucose Amino acidsF atty acidsBLOOD\nSomatostatin\nGlucagon\nInsulinSulfonylureas\nAmylinPANCREATIC\nISLETDigested foodINTESTINE\nGIT horm ones:\nincretins\n(GIP , GLP-1)\nSympathetic\nnerves and\nadrenaline\n(on \u03b12\nadrenoceptors)Parasympathetic\nnerves\n(on muscarinic\nreceptors)Incretin mimetics:\n-exenatide (GLP-1 mimetic)-gliptins (block incretin breakdow n)\nFig. 32.1 Factors regulating insulin secretion. Blood glucose \nis the most important factor. Drugs used to stimulate insulin \nsecretion are shown in red-bordered boxes . Glucagon potentiates \ninsulin release but opposes some of its peripheral actions and increases blood glucose. GIP, gastric inhibitory peptide; GIT, \ngastrointestinal tract; GLP-1, glucagon-like peptide-1. 20406080\nTime (minutes)75 60 45 30 15 0\nGlucoseInsulin (\u00b5U/mL)Type 2 diabetesNormal\nType 1 diabetes2nd phase 1st phase\nBasal\nlevel\nFig. 32.2 Schematic diagram of the two-phase release of \ninsulin in response to a constant glucose infusion. The first \nphase is missing in type 2 (non insulin-dependent) diabetes \nmellitus, and both are missing in type 1 (insulin-dependent) diabetes mellitus. The first phase is also produced by amino acids, sulfonylureas, glucagon and gastrointestinal tract hormones. (Data from Pfeifer, M.A., Halter, J.B., Porte, D. Jr., 1981. Am. J. Med. 70, 579\u2013588.)Table 32.1 The effect of hormones on blood glucose\nHormone Main actions Main stimuli for secretion Main effect\nMain regulatory hormone\nInsulin\u2191 Glucose uptake\nAcute rise in blood glucose\nIncretins (GIP and GLP-1)\u2193 Blood glucose\u2191 Glycogen synthesis\u2193 Glycogenolysis\u2193 Gluconeogenesis\nMain counter-regulatory hormones\nGlucagon \u2191 Glycogenolysis\nHypoglycaemia (i.e. blood glucose \n<\n3 mmol/L), (e.g. with exercise, stress, \nhigh-protein meals), etc.\u2191 Blood glucose\u2191 Glyconeogenesis\nAdrenaline (epinephrine) \u2191 Glycogenolysis\nGlucocorticoids \u2193 Glucose uptake\u2191 Gluconeogenesis\u2193 Glucose uptake and utilisation\nGrowth hormone \u2193 Glucose uptake\nGIP, gastric inhibitory peptide; GLP-1, glucagon-like peptide-1.\nin patients with diabetes leads to up-regulation of SGLT2 \nexpression and greater re-absorption of glucose, thus \nreducing glycosuria at the expense of worsening hyper -\nglycaemia (DeFronzo et al., 2012). Because SGLT2 is a \nco-transporter that reabsorbs sodium ions with glucose, its increased expression also causes salt retention and \nhypertension.\nPANCREATIC ISLET HORMONES\nThe islets of Langerhans, the endocrine part of the pancreas, contain four main types of peptide-secreting cells: \u03b2 (or B) \ncells secrete insulin , \u03b1 (or A) cells secrete glucagon , \u03b4 (or D) \ncells secrete somatostatin, PP cells secrete pancreatic polypeptide \n(PP) plus one minor player, \u03b5", "start_char_idx": 0, "end_char_idx": 2800, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "69503932-2784-471b-90f2-6a0eb8d89f66": {"__data__": {"id_": "69503932-2784-471b-90f2-6a0eb8d89f66", "embedding": null, "metadata": {"page_label": "415", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dbabfb56-d12d-4403-b909-458c4da9bc1d", "node_type": null, "metadata": {"page_label": "415", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4c8d379ce8f403b9442322462e2686b56a2445bd8762d5b3450cde6a99fe3e0"}, "2": {"node_id": "bcdad38a-6280-44d5-9bc5-f281f59774e7", "node_type": null, "metadata": {"page_label": "415", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "72ae7a3e7272bf4e13b20de117458ab70f9d8348b35b7b90ef349c9b9719470c"}}, "hash": "4e55ae24f23e8f3d679fe92fcb5e331219edfb857a1a4b53bd9cf0ad113d8f6d", "text": "pancreatic polypeptide \n(PP) plus one minor player, \u03b5 (or E) cells. These are present \nin the developing pancreas and secrete ghrelin, a peptide \nhormone that releases growth hormone and is implicated in appetite control (Ch. 32).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2746, "end_char_idx": 3456, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a0ba89dd-dd77-4988-a722-ddf1ae55b762": {"__data__": {"id_": "a0ba89dd-dd77-4988-a722-ddf1ae55b762", "embedding": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d1595cf5-5fd4-4b2b-b5a2-e7dedadf0bb3", "node_type": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3a4d9bf2fc5069e0690273978b9c51e0e066adf0220cfa1c9f820c44fb90d4a5"}, "3": {"node_id": "887cfd2a-06d0-4a8a-a1e5-75e4daf663c0", "node_type": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d134f04d632b1b3228ca3ba2d4e8ada258b437098f7ad5fc6f6c2700e4db7447"}}, "hash": "2526d67b4637264fa5fd492dee50e151250377a36c346dc70118db9d98772924", "text": "32 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n410facilitates further Ca2+ entry) and 12-lipoxygenase products \nof arachidonic acid (mainly 12-S-hydroxyeicosatetraenoic acid \nor 12-S-HETE; see Ch. 18). Phospholipases are commonly \nactivated by Ca2+, but free arachidonic acid is liberated in \n\u03b2 cells by an ATP-sensitive Ca2+-insensitive (ASCI) phos -\npholipase A 2. Consequently, in \u03b2 cells, Ca2+ entry and \narachidonic acid production are both driven by ATP, linking \ncellular energy status to insulin secretion.\nInsulin release is inhibited by the sympathetic nervous \nsystem (see Fig. 32.1). Adrenaline (epinephrine) increases blood glucose by inhibiting insulin release (via \u03b1\n2 adrenocep -\ntors) and by promoting glycogenolysis via \u03b22 adrenoceptors \nin striated muscle and liver. Several peptides, including somatostatin, galanin (an endogenous K\nATP activator) and \namylin, also inhibit insulin release.\nAbout one-fifth of the insulin stored in the pancreas of \nthe human adult is secreted daily. The plasma insulin \nconcentration after an overnight fast is 20\u201350 pmol/L. \nPlasma insulin concentration is reduced in patients with \ntype 1 (insulin-dependent) diabetes mellitus (see p. 413), \nand markedly increased in patients with insulinomas (uncom -\nmon functioning tumours of \u03b2 cells), as is C-peptide, with \nwhich it is co-released.2 It is also raised in obesity and other \nnormoglycaemic insulin-resistant states.\nACTIONS\nInsulin is the main hormone controlling intermediary \nmetabolism, with actions on liver, fat and muscle (Table \n32.2). It is an anabolic hormone : its overall effect is to conserve \nfuel by facilitating the uptake and storage of glucose, amino \nacids and fats after a meal. Acutely, it reduces blood glucose. \nConsequently, a fall in plasma insulin increases blood \nglucose. The biochemical pathways through which insulin exerts its effects are summarised in Fig. 32.3, and molecular \naspects of its mechanism are discussed below.\nInsulin influences glucose metabolism in most tissues, \nespecially the liver, where it inhibits glycogenolysis (gly -\ncogen breakdown) and gluconeogenesis (synthesis of glucose from non-carbohydrate sources) while stimulating glycogen \nsynthesis. It also increases glucose utilisation by glycolysis, but the overall effect is to increase hepatic glycogen stores.\nIn muscle, unlike liver, uptake of glucose is slow and is \nthe rate-limiting step in carbohydrate metabolism. Insulin causes a glucose transporter called Glut-4, which is seques -\ntered in vesicles, to be expressed within minutes on the surface membrane. This facilitates glucose uptake, and stimulates glycogen synthesis and glycolysis.\nInsulin increases glucose uptake by Glut-4 in adipose \ntissue as well as in muscle. One of the main products of glucose metabolism in adipose tissue is glycerol, which is \nesterified with fatty acids to form triglycerides, thereby \naffecting fat metabolism (see Table 32.2).\nInsulin increases synthesis of fatty acid and triglyceride \nin adipose tissue and in liver. It inhibits lipolysis, partly via dephosphorylation \u2013 and hence inactivation \u2013 of lipases (see Table 32.2). It also inhibits the lipolytic actions of \u25bc PP is a", "start_char_idx": 0, "end_char_idx": 3203, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "887cfd2a-06d0-4a8a-a1e5-75e4daf663c0": {"__data__": {"id_": "887cfd2a-06d0-4a8a-a1e5-75e4daf663c0", "embedding": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d1595cf5-5fd4-4b2b-b5a2-e7dedadf0bb3", "node_type": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3a4d9bf2fc5069e0690273978b9c51e0e066adf0220cfa1c9f820c44fb90d4a5"}, "2": {"node_id": "a0ba89dd-dd77-4988-a722-ddf1ae55b762", "node_type": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2526d67b4637264fa5fd492dee50e151250377a36c346dc70118db9d98772924"}, "3": {"node_id": "de856f56-1525-4475-a70a-38243bb2a706", "node_type": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "762a338dbab7b4ad15ee11ab03a37249c380a38df53785ba3f5fed2dc108ea48"}}, "hash": "d134f04d632b1b3228ca3ba2d4e8ada258b437098f7ad5fc6f6c2700e4db7447", "text": "32.2). It also inhibits the lipolytic actions of \u25bc PP is a 36-amino acid peptide closely related to neuropeptide Y \n(Ch. 13) and peptide YY (Ch. 33). It is released by eating a meal and \nis implicated in control of food intake (Ch. 33): PP acts on G protein\u2013\ncoupled receptors and also inhibits secretion of exocrine pancreatic secretions and contraction of intestinal and biliary smooth muscle.\nThe core of each islet contains mainly the predominant \u03b2 \ncells surrounded by a mantle of \u03b1 cells interspersed with \n\u03b4 cells or PP cells (see Fig. 32.1). In addition to insulin, \u03b2 \ncells secrete a peptide known as islet amyloid polypeptide or \namylin , which delays gastric emptying and opposes insulin \nby stimulating glycogen breakdown in striated muscle, and \nC-peptide (see p. 412). Glucagon opposes insulin, increasing blood glucose and stimulating protein breakdown in muscle. \nSomatostatin inhibits secretion of insulin and of glucagon. \nIt is widely distributed outside the pancreas and is also released from the hypothalamus, inhibiting the release of growth hormone from the pituitary gland (Ch. 34).\nINSULIN\nInsulin was the first protein for which the amino acid sequence was determined (by Sanger\u2019s group in Cambridge \nin 1955). It consists of two peptide chains (of 21 and 30 \namino acid residues) linked by two disulfide bonds.\nSYNTHESIS \u2003AND \u2003SECRETION\nLike other peptide hormones (see Ch. 19), insulin is syn -\nthesised as a precursor (preproinsulin) in the rough \nendoplasmic reticulum. Preproinsulin is transported to the \nGolgi apparatus, where it undergoes proteolytic cleavage to proinsulin and then to insulin plus a fragment of uncertain \nfunction called C-peptide.\n1 Insulin and C-peptide are stored \nin granules in \u03b2 cells, and are normally co-secreted by exocytosis in equimolar amounts together with smaller and \nvariable amounts of proinsulin.\nThe main factor controlling the synthesis and secretion \nof insulin is the blood glucose concentration (see Fig. 32.1). \u03b2 cells respond both to the absolute glucose concentration and to the rate of change of blood glucose. Other physio -\nlogical stimuli to insulin release include amino acids (particularly arginine and leucine), fatty acids, the para -\nsympathetic nervous system and incretins (especially GLP-1 \nand GIP, see p. 413). Pharmacologically, sulfonylurea drugs \n(see p. 416) act by releasing insulin.\nThere is a steady basal release of insulin and an increase \nin blood glucose stimulates an additional response. This \nresponse has two phases: an initial rapid phase reflecting \nrelease of stored hormone, and a slower, delayed phase reflecting continued release of stored hormone and new \nsynthesis (see Fig. 32.2). The response is abnormal in diabetes \nmellitus, as discussed later.\nATP-sensitive potassium channels (K\nATP; Ch. 4) determine \nthe resting membrane potential in \u03b2 cells. Glucose enters \n\u03b2 cells via a surface membrane transporter called Glut-2, \nand its subsequent metabolism via glucokinase (which is the rate-limiting glycolytic enzyme in \u03b2 cells) links insulin \nsecretion to extracellular glucose. The consequent rise in ATP within \u03b2 cells blocks K\nATP channels, causing membrane \ndepolarisation. Depolarisation opens voltage-dependent \ncalcium channels, leading to Ca2+ influx. This triggers insulin \nsecretion in the presence of amplifying", "start_char_idx": 3157, "end_char_idx": 6501, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "de856f56-1525-4475-a70a-38243bb2a706": {"__data__": {"id_": "de856f56-1525-4475-a70a-38243bb2a706", "embedding": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d1595cf5-5fd4-4b2b-b5a2-e7dedadf0bb3", "node_type": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3a4d9bf2fc5069e0690273978b9c51e0e066adf0220cfa1c9f820c44fb90d4a5"}, "2": {"node_id": "887cfd2a-06d0-4a8a-a1e5-75e4daf663c0", "node_type": null, "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d134f04d632b1b3228ca3ba2d4e8ada258b437098f7ad5fc6f6c2700e4db7447"}}, "hash": "762a338dbab7b4ad15ee11ab03a37249c380a38df53785ba3f5fed2dc108ea48", "text": "influx. This triggers insulin \nsecretion in the presence of amplifying messengers, includ -\ning diacylglycerol, non-esterified arachidonic acid (which \n1Not to be confused with C-reactive peptide, which is an acute-phase \nreactant used clinically as a marker of inflammation (Ch. 7).2Insulin for injection does not contain C-peptide, which therefore \nprovides a means of distinguishing endogenous from exogenous \ninsulin. This is used to differentiate insulinoma (an insulin-secreting \ntumour causing high circulating insulin with high C-peptide) from surreptitious injection of insulin (high insulin with low C-peptide). \nDeliberate induction of hypoglycaemia by self-injection with insulin is a \nwell-recognised, if unusual, manifestation of psychiatric disorder, especially in health professionals \u2013 it has also been used in murder.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6478, "end_char_idx": 7792, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9ecec95d-7020-4297-9347-787ca53687f2": {"__data__": {"id_": "9ecec95d-7020-4297-9347-787ca53687f2", "embedding": null, "metadata": {"page_label": "417", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3a68ba85-c614-462b-9571-13368b753e80", "node_type": null, "metadata": {"page_label": "417", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff36f851ade55636b1d10088bd157bd17740d1314530759a7749a1526e3a5dcf"}}, "hash": "ff36f851ade55636b1d10088bd157bd17740d1314530759a7749a1526e3a5dcf", "text": "32 ThE CONTROl OF blOOD GlUCOSE AND DRUG TREATMENT OF DIAbETES MEllITUS\n411Table 32.2 Effects of insulin on carbohydrate, fat and protein metabolism\nType of metabolism Liver cells Fat cells Muscle\nCarbohydrate metabolism\u2191 Glucose uptake\n\u2191 Glycerol synthesis\u2191 Glucose uptake\n\u2191 Glycolysis\n\u2191 Glycogenesis\u2193 Gluconeogenesis\n\u2193 Glycogenolysis\n\u2191 Glycolysis\n\u2191 Glycogenesis\nFat metabolism\u2191 Lipogenesis\n\u2193 Lipolysis\u2191 Synthesis of triglycerides\n\u2191 Fatty acid synthesis\n\u2193 Lipolysis\nProtein metabolism \u2193 Protein breakdown \u2013\u2191 Amino acid uptake\n\u2191 Protein synthesis\nSS SSS\n\u03b2\u03b1\u03b1\nP\nPPPS\n\u03b2\nRecruitment of \nglucose \ntransportersCELL MEMBRANEINSULIN RECEPTOR\nGlucose\nGlut-4\nSH2 domain proteins\nAlteration in the pattern of phosphorylation \nof key enzymes (e.g. MAP kinase and \nprotein phosphatase 1)Effects on kinases and phosphatases and thus:Ras \ncomplexActions on DNA \nand RNA\nEffects on \nsynthesis of \nkey enzymes\nDecreased formation of \nglucose from glycogen, \nfat and proteinGrowth and \ngene \nexpression\nDecreased blood glucoseIncreased \nutilisation of \nglucoseIncreased \nuptake of \nglucoseIncreased formation \nof glycogen, protein \nand fatEndocytosis of \ninsulin\u2013receptor \ncomplex\nIRS\u03b2 subunit\ntyrosine kinase\nactivationII\nFig. 32.3 Insulin signalling pathways. I, insulin; Glut-4, an insulin-sensitive glucose transporter present in muscle and fat cells; \nIRS, insulin receptor substrate (several forms: 1\u20134). mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1876, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d54efd7-4848-42f4-b435-0988359afcec": {"__data__": {"id_": "6d54efd7-4848-42f4-b435-0988359afcec", "embedding": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e64e9b6-14bf-4927-9bd5-388f8567ec4a", "node_type": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6cadf67a868ab1e1cbf1369d1b499f66d51f8b42beaadb7cdaff9477485d0e2b"}, "3": {"node_id": "b137ff51-1eaf-4859-a20b-6b425c584d75", "node_type": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c93ea31b7fc3ce8fb733111b79474a8d1e95e406033a7ad8b32a30ce1497e060"}}, "hash": "5f2f1d4083ad955b81db500fecea46eca92397d354af83344f7203fa09c8e539", "text": "32 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n412phosphorylation cascade that results in activation of mitogen-activated \nprotein kinase (MAP-kinase), which in turn activates several nuclear \ntranscription factors, leading to the expression of genes that are \ninvolved with cell growth and with intermediary metabolism.\nInsulin for treatment of diabetes mellitus is considered \nbelow.\nGLUCAGON\nSYNTHESIS \u2003AND \u2003SECRETION\nGlucagon is a single-chain polypeptide of 21 amino acid residues synthesised mainly in the \u03b1 cell of the islets, but \nalso in the upper GI tract. It has considerable structural homology with other GI tract hormones, including secretin, vasoactive intestinal peptide and GIP (see Ch. 31).\nAmino acids (especially L-arginine) stimulate glucagon \nsecretion, as does ingestion of a high-protein meal, but diurnal variation in plasma glucagon concentrations is less \nthan for insulin. Glucagon secretion is stimulated by low \nand inhibited by high concentrations of glucose and fatty acids in the plasma. Sympathetic nerve activity and circulat -\ning adrenaline stimulate glucagon release via \u03b2 adrenocep -\ntors. Parasympathetic nerve activity also increases secretion, whereas somatostatin, released from \u03b4 cells adjacent to the \nglucagon-secreting \u03b1 cells in the periphery of the islets, \ninhibits glucagon release.adrenaline, growth hormone and glucagon by opposing their actions on adenylyl cyclase.\nInsulin stimulates uptake of amino acids into muscle \nand increases protein synthesis. It also decreases protein catabolism and inhibits oxidation of amino acids in the \nliver.\nOther metabolic effects of insulin include transport into \ncells of K\n+, Ca2+, nucleosides and inorganic phosphate.3\nLong-term effects of insulin\nIn addition to rapid effects on metabolism, exerted via \naltered activity of enzymes and transport proteins, insulin \nhas long-term actions via altered enzyme synthesis. It is \nan important anabolic hormone during fetal development. It stimulates cell proliferation (mitogenic action) and is \nimplicated in somatic and visceral growth and development.\nMitogenic actions of insulin are of great concern in the \ndevelopment of insulin analogues; insulin glargine (one \nwidely used analogue; see p. 415) is six- to eight-fold more \nmitogenic than human insulin, and cultured breast cancer cells proliferate in response to near-therapeutic concentra -\ntions of this analogue in vitro, but it is not known if there \nis any clinically significant parallel in vivo. Mammary \ntumours developed in rats given one long-acting insulin analogue.\nMechanism of action\nInsulin binds to a specific receptor on the surface of its target cells. The receptor is a large transmembrane glyco-\nprotein complex belonging to the tyrosine kinase-linked \ntype 3 receptor superfamily (Ch. 3) and consisting of two \u03b1 and two \u03b2 subunits (see Fig. 32.3).\nOccupied receptors aggregate into clusters, which are \nsubsequently internalised in vesicles, resulting in down-regulation. Internalised insulin is degraded in lysosomes, \nbut the receptors are recycled to the plasma membrane.\n\u25bc The signal transduction mechanisms that link receptor binding to \nthe biological effects of insulin are complex. Receptor autophosphoryla -\ntion \u2013 the first step in signal transduction \u2013 is a consequence of dimerisation, allowing each receptor to phosphorylate the other, as explained in Chapter 3.\nInsulin receptor substrate (IRS) proteins undergo rapid tyrosine phos -\nphorylation specifically in response to insulin and", "start_char_idx": 0, "end_char_idx": 3528, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b137ff51-1eaf-4859-a20b-6b425c584d75": {"__data__": {"id_": "b137ff51-1eaf-4859-a20b-6b425c584d75", "embedding": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e64e9b6-14bf-4927-9bd5-388f8567ec4a", "node_type": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6cadf67a868ab1e1cbf1369d1b499f66d51f8b42beaadb7cdaff9477485d0e2b"}, "2": {"node_id": "6d54efd7-4848-42f4-b435-0988359afcec", "node_type": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5f2f1d4083ad955b81db500fecea46eca92397d354af83344f7203fa09c8e539"}, "3": {"node_id": "15958383-3ff9-49aa-aeb0-8d715c07117b", "node_type": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fea17030ae2530074ff75341e8919ff067311f72a25c01d8feb6d116cc5ff4c7"}}, "hash": "c93ea31b7fc3ce8fb733111b79474a8d1e95e406033a7ad8b32a30ce1497e060", "text": "rapid tyrosine phos -\nphorylation specifically in response to insulin and insulin-like growth \nfactor-1 but not to other growth factors. The best-characterised substrate \nis IRS-1, which contains 22 tyrosine residues that are potential phosphorylation sites. It interacts with proteins that contain a so-called \nSH2 domain (see Ch. 3, Fig. 3.15), thereby passing on the insulin \nsignal. Knock-out mice lacking IRS-1 are hyporesponsive to insulin (insulin-resistant) but do not become diabetic, because of robust \u03b2-cell \ncompensation with increased insulin secretion. By contrast, mice lacking IRS-2 fail to compensate and develop overt diabetes, implicating the IRS-2 gene as a candidate for human type 2 diabetes (IRS proteins \nare reviewed by Lavin et al., 2016). Activation of phosphatidylinositol \n3-kinase by interaction of its SH2 domain with phosphorylated IRS has several important effects, including recruitment of insulin-sensitive \nglucose transporters (Glut-4) from the Golgi apparatus to the plasma \nmembrane in muscle and fat cells.\nThe longer-term actions of insulin entail effects on DNA and RNA, \nmediated partly at least by the Ras signalling complex. Ras is a protein that regulates cell growth and cycles between an active GTP-bound \nform and an inactive GDP-bound form (see Chs 3 and 57). Insulin \nshifts the equilibrium in favour of the active form, and initiates a Endocrine pancreas and \nblood glucose \n\u2022\tIslets\tof \tLangerhans \tsecrete \tinsulin \tfrom \t\u03b2 (or B) cells, \nglucagon from \u03b1 cells and somatostatin from \u03b4 cells.\n\u2022\tMany\tfactors \tstimulate \tinsulin \tsecretion, \tbut \tthe \tmain \t\none\tis\tblood \tglucose. \tIncretins, \tespecially \tgastric \t\ninhibitory\tpeptide \t(GIP) \tand \tglucagon-like \tpeptide-1 \t\n(GLP-1)\tsecreted, \trespectively, \tby \tK \tand \tL \tcells \tin \tthe \t\ngut are also important.\n\u2022\tInsulin\thas \tessential \tmetabolic \tactions \tas \ta \tfuel-\nstorage hormone and also affects cell growth and \ndifferentiation. \tIt \tdecreases \tblood \tglucose \tby:\n\u2013 increasing glucose uptake into muscle and fat via \nGlut-4\n\u2013 increasing glycogen synthesis\n\u2013 decreasing gluconeogenesis\n\u2013 decreasing glycogen breakdown.\n\u2022\tGlucagon \tis \ta \tfuel-mobilising \thormone, \tstimulating \t\ngluconeogenesis and glycogenolysis, also lipolysis and \nproteolysis. \tIt \tincreases \tblood \tsugar \tand \talso \t\nincreases the force of contraction of the heart.\n\u2022\tDiabetes \tmellitus \tis \ta \tchronic \tmetabolic \tdisorder \tin \t\nwhich there is hyperglycaemia. There are two main \ntypes:\n\u2013 type 1 (insulin-dependent) diabetes, with an absolute \ndeficiency of insulin;\n\u2013 type 2 (non insulin-dependent) diabetes, with a \nrelative deficiency of insulin associated with reduced sensitivity to its action (insulin resistance).\n3The action on K+ is exploited in the emergency treatment of \nhyperkalaemia by intravenous glucose with insulin (see Ch. 30).ACTIONS\nGlucagon increases blood glucose and causes breakdown \nof fat and protein. It acts on specific G protein\u2013coupled \nreceptors to stimulate adenylyl cyclase, and its actions are mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3465, "end_char_idx": 6629, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "15958383-3ff9-49aa-aeb0-8d715c07117b": {"__data__": {"id_": "15958383-3ff9-49aa-aeb0-8d715c07117b", "embedding": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e64e9b6-14bf-4927-9bd5-388f8567ec4a", "node_type": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6cadf67a868ab1e1cbf1369d1b499f66d51f8b42beaadb7cdaff9477485d0e2b"}, "2": {"node_id": "b137ff51-1eaf-4859-a20b-6b425c584d75", "node_type": null, "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c93ea31b7fc3ce8fb733111b79474a8d1e95e406033a7ad8b32a30ce1497e060"}}, "hash": "fea17030ae2530074ff75341e8919ff067311f72a25c01d8feb6d116cc5ff4c7", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6646, "end_char_idx": 7029, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6bca0e1e-a140-4b2a-9515-66f6157cb895": {"__data__": {"id_": "6bca0e1e-a140-4b2a-9515-66f6157cb895", "embedding": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "10d93c43-49d6-4722-bdad-b82c3ed8f929", "node_type": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ddc9d35568dee2c8cb4aec6fdc19dbe33a7a9a34c308e54e4008f14343af9ed6"}, "3": {"node_id": "6f83af4c-b1d9-4de2-860f-e7c656925840", "node_type": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9bb3823b3d2a1f8f0a806893df4c560806cd83c6b8a30d4408bd9009e199a0d6"}}, "hash": "9cf76f3b360c26ce67571f59410cedb5f42bf7633ed363a675160f742dd05f73", "text": "32 ThE CONTRO l OF bl OOD G l UCOSE AND DRUG TREATMENT OF DIA b ETES ME ll ITUS\n413Clinical uses of glucagon \n\u2022\tGlucagon can be given intramuscularly or \nsubcutaneously as well as intravenously.\n\u2022\tTreatment \tof \thypoglycaemia in unconscious patients \n(who cannot drink); unlike intravenous glucose, it can be administered by non-medical personnel (e.g. \nspouses\tor \tambulance \tcrew). \tIt \tis \tuseful \tif \tobtaining \t\nintravenous access is difficult.\n\u2022\tTreatment \tof \tacute cardiac failure precipitated by \n\u03b2-adrenoceptor antagonists.\n4Octreotide is used either short term before surgery on the pituitary \ntumour, or while waiting for radiotherapy of the tumour to take effect, \nor if other treatments have been ineffective.mealtime insulin but have not achieved satisfactory glucose \ncontrol. It is injected subcutaneously before each major \nmeal as an adjunct to insulin, and reduces insulin require -\nments. Pramlintide reduces the speed of gastric emptying \nand decreases the postprandial rise in glucagon. Unwanted \neffects include hypoglycaemia and nausea \u2013 it is contra-\nindicated in patients with loss of gastric motility (gastro -\nparesis), a complication of diabetic autonomic neuropathy \n(Younk et al., 2011).\nINCRETINS\nLa Barre suggested in the 1930s that crude secretin contained two active principles: \u2018excretin\u2019, which stimulates the \nexocrine pancreas, and \u2018incretin\u2019, which stimulates insulin \nrelease. He proposed that incretin presented possibilities for the treatment of diabetes. \u2018Excretin\u2019 did not catch on \n(perhaps not helped by an unfortunate association with \nother bodily functions \u2013 at least to an Anglo-Saxon ear), but \u2018incretin\u2019 has gone from strength to strength, and some \n80 years later several incretin-based drugs are now licensed \nfor clinical use (see later). Incretin action proved to be due to peptide hormones released from the gut, mainly GIP and GLP-1. These are both members of the glucagon peptide \nsuperfamily (Ch. 19). GIP is a 42-amino acid peptide stored in and secreted by enteroendocrine K cells in the duodenum and proximal jejunum. GLP-1 is secreted by L cells which \nare more widely distributed in the gut, including in the \nileum and colon as well as more proximally. Two forms of GLP-1 are secreted after a meal: GLP-1(7-37) and \nGLP-1(7-36) amide; these are similarly potent. Most of the \ncirculating activity is due to GLP-1(7-36) amide. Release of GIP and GLP-1 by ingested food provides an early \nstimulus to insulin secretion before absorbed glucose or \nother products of digestion reach the islet cells in the portal blood (see Fig. 32.1 ). As well as stimulating insulin secretion, \nboth these hormones inhibit pancreatic glucagon secretion and slow the rate of absorption of digested food by reducing gastric emptying. They are also implicated in control of \nfood intake via appetite and satiety (see Ch. 33). The actions \nof GIP and GLP-1 are terminated rapidly by dipeptidyl peptidase-4 (DPP-4). This enzyme is a membrane glyco -\nprotein with rather wide substrate specificity \u2013 it has been \nimplicated in suppression of malignancy and in athero-\ngenesis (e.g. Waumans et al., 2015), but inhibitors are \nlicensed to treat diabetes (see later, p.", "start_char_idx": 0, "end_char_idx": 3219, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6f83af4c-b1d9-4de2-860f-e7c656925840": {"__data__": {"id_": "6f83af4c-b1d9-4de2-860f-e7c656925840", "embedding": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "10d93c43-49d6-4722-bdad-b82c3ed8f929", "node_type": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ddc9d35568dee2c8cb4aec6fdc19dbe33a7a9a34c308e54e4008f14343af9ed6"}, "2": {"node_id": "6bca0e1e-a140-4b2a-9515-66f6157cb895", "node_type": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9cf76f3b360c26ce67571f59410cedb5f42bf7633ed363a675160f742dd05f73"}, "3": {"node_id": "6b23c76a-e936-4db4-b769-09f2ff121d1c", "node_type": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b28185bf9b123e8b4e483d7d236dcdd618c62fb5c5dd4cdbba33e9eb3144c233"}}, "hash": "9bb3823b3d2a1f8f0a806893df4c560806cd83c6b8a30d4408bd9009e199a0d6", "text": "2015), but inhibitors are \nlicensed to treat diabetes (see later, p. 418).\nDIABETES MELLITUS\nDiabetes mellitus is a chronic metabolic disorder charac -\nterised by a high blood glucose concentration \u2013 hyper -\nglycaemia (fasting plasma glucose >7.0 mmol/L, or plasma \nglucose >11.1 mmol/L, 2 h after a meal) \u2013 caused by insulin \ndeficiency, often combined with insulin resistance. There \nare two main types of diabetes mellitus:\n1. Type 1 diabetes (previously known as insulin-dependent diabetes mellitus \u2013 IDDM \u2013 or \njuvenile-onset diabetes), in which there is an absolute \ndeficiency of insulin.\n2. Type 2 diabetes (previously known as non insulin-dependent diabetes mellitus \u2013 NIDDM \u2013 or \nmaturity-onset diabetes), in which there is a relative \ndeficiency of insulin associated with reduced sensitivity to its action (insulin resistance).somewhat similar to \u03b2-adrenoceptor\u2013mediated actions of adrenaline. Unlike adrenaline, however, its metabolic effects \nare more pronounced than its cardiovascular actions. \nGlucagon is proportionately more active on liver, while the metabolic actions of adrenaline are more pronounced \non muscle and fat. Glucagon stimulates glycogen breakdown \nand gluconeogenesis, and inhibits glycogen synthesis and glucose oxidation. Its metabolic actions on target tissues \nare thus the opposite of those of insulin. Glucagon increases \nthe rate and force of contraction of the heart, although less markedly than adrenaline.\nClinical uses of glucagon are summarised in the clinical \nbox.\nSOMATOSTATIN\nSomatostatin is secreted by the \u03b4 cells of the islets. It is also \ngenerated in the hypothalamus, where it inhibits the release \nof growth hormone (see Ch. 33). In the islet, it inhibits \nrelease of insulin and of glucagon. Octreotide is a long-acting \nanalogue of somatostatin. It inhibits release of a number \nof hormones, and is used clinically to relieve symptoms \nfrom several uncommon gastroenteropancreatic endocrine tumours, and for treatment of acromegaly\n4 (the endocrine \ndisorder caused by a functioning tumour of cells that secrete \ngrowth hormone from the anterior pituitary; see Ch. 34).\nAMYLIN (ISLET AMYLOID POLYPEPTIDE)\n\u25bc The term amyloid refers to amorphous protein deposits in different \ntissues that occur in a variety of diseases, including several neuro -\ndegenerative conditions (see Ch. 41). Amyloid deposits occur in the \npancreas of patients with diabetes mellitus, although it is not known if this is functionally important. The major component of pancreatic \namyloid is a 37-amino acid residue peptide known as islet amyloid \npolypeptide or amylin. This is stored with insulin in secretory granules in \u03b2 cells and is co-secreted with insulin. Amylin delays gastric \nemptying. Supraphysiological concentrations stimulate the breakdown of glycogen to lactate in striated muscle. Amylin also inhibits insulin \nsecretion (see Fig. 32.1). It is structurally related to calcitonin (see Ch. \n37) and has weak calcitonin-like actions on calcium metabolism and osteoclast activity. It is also about 50% identical with calcitonin gene-\nrelated peptide (CGRP; see Ch. 19), and large intravenous doses cause \nvasodilatation, presumably by an action on CGRP receptors.\nPramlintide , an amylin analogue with three proline substitu -\ntions that reduce its tendency to aggregate into insoluble \nfibrils, is approved in the", "start_char_idx": 3162, "end_char_idx": 6529, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6b23c76a-e936-4db4-b769-09f2ff121d1c": {"__data__": {"id_": "6b23c76a-e936-4db4-b769-09f2ff121d1c", "embedding": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "10d93c43-49d6-4722-bdad-b82c3ed8f929", "node_type": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ddc9d35568dee2c8cb4aec6fdc19dbe33a7a9a34c308e54e4008f14343af9ed6"}, "2": {"node_id": "6f83af4c-b1d9-4de2-860f-e7c656925840", "node_type": null, "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9bb3823b3d2a1f8f0a806893df4c560806cd83c6b8a30d4408bd9009e199a0d6"}}, "hash": "b28185bf9b123e8b4e483d7d236dcdd618c62fb5c5dd4cdbba33e9eb3144c233", "text": "its tendency to aggregate into insoluble \nfibrils, is approved in the United States to treat patients \nwith type 1 diabetes and for type 2 diabetics who use mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6518, "end_char_idx": 7154, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "617b1410-4657-4ad8-a9c1-bfb94c259f01": {"__data__": {"id_": "617b1410-4657-4ad8-a9c1-bfb94c259f01", "embedding": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3bb5c1b9-69f0-400d-96d9-ed370ec80a0c", "node_type": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a86e5db92f0cc30c5a7ceba8a6a740655c31b27187f2625bc6b006e86a1422b8"}, "3": {"node_id": "b5cfe58e-6c13-412a-8f41-62087256a43c", "node_type": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eabaca7c0319e20e061398bc8e273a38b447624435b08e3c2b44b0d5d8c86995"}}, "hash": "1eb4ed4467911a015d75c612dba51744742165e52d1ed0ed84b7625c42707bf8", "text": "32 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n414including immunosuppression, early insulin therapy, \nantioxidants, nicotinamide and many others; so far these \nhave disappointed, but this remains a very active field.\nType 2 diabetes is accompanied both by insulin resistance \n(which precedes overt disease) and by impaired insulin secretion, each of which are important in its pathogenesis. \nSuch patients are often obese and usually present in adult life, the incidence rising progressively with age as \u03b2-cell \nfunction declines. Treatment is initially dietary, although oral hypoglycaemic drugs usually become necessary, and most patients ultimately benefit from exogenous insulin. Prospective studies have demonstrated a relentless deteriora -\ntion in diabetic control\n6 with increasing age and duration \nof disease.\nInsulin secretion (basal, and in response to a meal) in a \ntype 1 and a type 2 diabetic patient is contrasted schemati -\ncally with that in a healthy control in Fig. 32.2.\nThere are many other less common forms of diabetes \nmellitus in addition to the two main ones described earlier (for example, syndromes associated with autoantibodies \ndirected against insulin receptors which cause severe insulin \nresistance, functional \u03b1-cell tumours, \u2018glucagonomas\u2019, and \nmany other rarities), and hyperglycaemia can also be a clinically important adverse effect of several drugs, including \nglucocorticoids (Ch. 34), high doses of thiazide diuretics \n(Ch. 30) and several of the protease inhibitors used to treat HIV infection (Ch. 53).\nDRUGS USED IN THE TREATMENT OF DIABETES\nThe main groups of drugs used are:\nAgents given by injection\n\u2022\tInsulin, \tin \tvarious \tforms \tand \tformulations \t(used \tin \t\ntype 1 and type 2 diabetes)\n\u2022\tIncretin \tmimetics \t(e.g. \texenatide, liraglutide)\nOral agents (used in type 2 diabetes)\n\u2022\tBiguanides \t(e.g. \tmetformin)\n\u2022\tSulfonylureas \t(e.g. \ttolbutamide, glibenclamide, \nglipizide) and related drugs (e.g. repaglinide, \nnateglinide)\n\u2022\tThiazolidinediones \t(e.g. \tpioglitazone)\n\u2022\tGliptins \t(e.g. \tsitagliptin)\n\u2022\tGlucose \ttransport \tinhibitors \t(e.g. \tempagliflozin)\nINSULIN \u2003TREATMENT\nThe effects of insulin and its mechanism of action are \ndescribed earlier. Here we describe pharmacokinetic aspects \nand adverse effects, both of which are central to its thera -\npeutic use. Insulin for clinical use was once either porcine \nor bovine but is now almost entirely human (made in \nexpression systems by recombinant DNA technology, Ch. \n5). Animal insulins are liable to elicit an immune response; this is less of an issue with recombinant human insulins. \nAlthough recombinant insulin is more consistent in quality \nthan insulins extracted from pancreases of freshly slaugh -\ntered animals, doses are still quantified in terms of units of activity (Ch. 8), with which doctors and patients are \nfamiliar, rather than of mass.Hyperglycaemia occurs because of uncontrolled hepatic \nglucose output and reduced uptake of glucose by skeletal muscle with reduced glycogen synthesis. Insulin deficiency \ncauses muscle wasting through increased breakdown and \nreduced synthesis of proteins. Diabetic ketoacidosis is an acute emergency that is predominantly seen in patients \nwith type 1 diabetes. It develops in the absence of insulin \nbecause of", "start_char_idx": 0, "end_char_idx": 3288, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b5cfe58e-6c13-412a-8f41-62087256a43c": {"__data__": {"id_": "b5cfe58e-6c13-412a-8f41-62087256a43c", "embedding": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3bb5c1b9-69f0-400d-96d9-ed370ec80a0c", "node_type": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a86e5db92f0cc30c5a7ceba8a6a740655c31b27187f2625bc6b006e86a1422b8"}, "2": {"node_id": "617b1410-4657-4ad8-a9c1-bfb94c259f01", "node_type": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1eb4ed4467911a015d75c612dba51744742165e52d1ed0ed84b7625c42707bf8"}, "3": {"node_id": "5f84b6da-6208-4650-b7f5-bb7dfeef5a01", "node_type": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fd0e70947315c59e21a3b19b52124ed189d853d70417b72a272abc1f232be171"}}, "hash": "eabaca7c0319e20e061398bc8e273a38b447624435b08e3c2b44b0d5d8c86995", "text": "\nwith type 1 diabetes. It develops in the absence of insulin \nbecause of accelerated breakdown of fat to acetyl-CoA, which, in the absence of aerobic carbohydrate metabolism, \nis converted to acetoacetate and \u03b2-hydroxybutyrate (which \ncause acidosis) and acetone (a ketone).\nVarious complications develop as a consequence of the \nmetabolic derangements in diabetes, often over several \nyears. Many of these are the result of disease of blood vessels, either large (macrovascular disease) or small \n(microangiopathy). Dysfunction of vascular endothelium \n(see Ch. 23) is an early and critical event in the development of vascular complications. Oxygen-derived free radicals, protein kinase C and non-enzymic products of glucose and \nalbumin called advanced glycation end products (AGE) have \nbeen implicated. Macrovascular disease consists of acceler -\nated atheroma (Ch. 24) and its thrombotic complications (Ch. 25), which are commoner and more severe in diabetic \npatients. Microangiopathy is a distinctive feature of diabetes mellitus and particularly affects the retina, kidney and \nperipheral nerves. Diabetes mellitus is the commonest cause \nof chronic renal failure, a huge and rapidly increasing problem, and a major burden to society as well as to \nindividual patients. Co-existent hypertension promotes \nprogressive renal damage, and treatment of hypertension slows the progression of diabetic nephropathy and reduces \nthe risk of myocardial infarction. Angiotensin-converting \nenzyme inhibitors or angiotensin receptor antagonists (Ch. 23) are more effective in preventing diabetic nephropathy \nthan other antihypertensive drugs, perhaps because they \nprevent fibroproliferative actions of angiotensin II and aldosterone.\nDiabetic neuropathy\n5 is associated with accumulation of \nosmotically active metabolites of glucose, produced by the \naction of aldose reductase, but aldose reductase inhibitors \nhave been disappointing as therapeutic drugs (see Farmer \net al., 2012, for a review).\nType 1 diabetes can occur at any age, but patients are \nusually young (children or adolescents) and not obese when they first develop symptoms. There is an inherited predis -\nposition, with a 10- to 15-fold increased incidence in \nfirst-degree relatives of an index case, and strong associations \nwith particular histocompatibility antigens (HLA types). \nIdentical twins are less than fully concordant, so environ -\nmental factors such as viral infection (e.g. with coxsackie \nvirus or echovirus) are believed to be necessary for geneti -\ncally predisposed individuals to express the disease. Viral \ninfection may damage pancreatic \u03b2 cells and expose antigens \nthat initiate a self-perpetuating autoimmune process. The \npatient becomes overtly diabetic only when more than 90% \nof the \u03b2 cells have been destroyed. This natural history \nprovides a tantalising prospect of intervening in the pre -\ndiabetic stage, and a variety of strategies have been mooted, \n6Diabetic control is not easily estimated by determination of blood \nglucose, because this is so variable. Instead, glycated haemoglobin \n(haemoglobin A 1C) is measured. This provides an integrated measure of \ncontrol over the lifespan of the red cell: approximately 120 days. In \nhealthy individuals, 4%\u20136% (20\u201342 mmol/mol) of haemoglobin is \nglycated; levels above 6.5% (48 mmol/mol) are indicative of diabetes.5Neuropathy (\u2018disease of the nerves\u2019) causes dysfunction of peripheral \nnerve fibres, which can be motor, sensory or autonomic. Diabetic neuropathy often causes", "start_char_idx": 3229, "end_char_idx": 6764, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5f84b6da-6208-4650-b7f5-bb7dfeef5a01": {"__data__": {"id_": "5f84b6da-6208-4650-b7f5-bb7dfeef5a01", "embedding": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3bb5c1b9-69f0-400d-96d9-ed370ec80a0c", "node_type": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a86e5db92f0cc30c5a7ceba8a6a740655c31b27187f2625bc6b006e86a1422b8"}, "2": {"node_id": "b5cfe58e-6c13-412a-8f41-62087256a43c", "node_type": null, "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eabaca7c0319e20e061398bc8e273a38b447624435b08e3c2b44b0d5d8c86995"}}, "hash": "fd0e70947315c59e21a3b19b52124ed189d853d70417b72a272abc1f232be171", "text": "can be motor, sensory or autonomic. Diabetic neuropathy often causes numbness in a \u2018stocking\u2019 distribution caused \nby damage to sensory fibres, and postural hypotension and erectile dysfunction due to autonomic neuropathy.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6756, "end_char_idx": 7457, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e243cb8-c9c7-4081-bc81-3b196ea0c344": {"__data__": {"id_": "8e243cb8-c9c7-4081-bc81-3b196ea0c344", "embedding": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8a7dba6b-db6f-469a-873d-664d4db22805", "node_type": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d1e296a0afc4da78865e6e71ed9808f55942a350c50e333d7f438a9d2b12936f"}, "3": {"node_id": "5a5d641d-b3ca-4b7f-bcaa-b6b88e212115", "node_type": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "badca1a1044ba3789f3ccee320a86cca8dc19a8ad01ca34a0b069303e79e1333"}}, "hash": "1248f23c433550844a63a0fd3094c522066f74758786470fe245700494d1fe0b", "text": "32 ThE CONTRO l OF bl OOD G l UCOSE AND DRUG TREATMENT OF DIA b ETES ME ll ITUS\n4157This could, in theory, provide variable release of insulin controlled by \nthe prevailing glucose concentration, because glucose and glycated \ninsulin compete for binding sites on the lectin.insulins twice daily, before breakfast and before the evening \nmeal. Improved control of blood glucose can be achieved \nwith multiple daily injections of rapid-acting insulin \nanalogues given with meals, and a basal insulin analogue injected once daily (often at night). Insulin pumps are used \nin hospital to control blood glucose acutely and are also \navailable in a portable form that delivers continuous subcutaneous infusion for outpatients. The most sophisti -\ncated forms of pump regulate the dose by means of a sensor that continuously measures blood glucose, but these are not yet used routinely \u2013 this seemingly logical approach is limited by the complexity of insulin\u2019s effects on intermedi -\nary metabolism (see Table 32.2, Fig. 32.3) which are imperfectly captured by existing continuous glucose monitoring technology, and by risks of infection.\nUnwanted effects\nThe main undesirable effect of insulin is hypoglycaemia. This is common and, if very severe, can cause brain damage \nor sudden cardiac death. In the Diabetes Control and \nComplications Trial mentioned before, intensive insulin therapy resulted in a three-fold increase in severe hypo -\nglycaemic episodes compared with usual care. The treatment of hypoglycaemia is to take a sweet drink or snack or, if the patient is unconscious, to give intravenous glucose or \nintramuscular glucagon (see clinical box, p. 413). Rebound \nhyperglycaemia (\u2018Somogyi effect\u2019) can follow insulin-induced hypoglycaemia, because of the release of counter-regulatory hormones (e.g. adrenaline, glucagon and \nglucocorticoids). This can cause hyperglycaemia before \nbreakfast following an unrecognised hypoglycaemic attack during sleep in the early hours of the morning. It is essential \nto appreciate this possibility to avoid the mistake of increas -\ning (rather than reducing) the evening dose of insulin in \nthis situation.\nAllergy to human insulin is unusual but can occur. It \nmay take the form of local or systemic reactions. Insulin resistance as a consequence of antibody formation is rare. \nTheoretical concerns regarding mitogenic effects of insulin \nanalogues are mentioned earlier (p. 412).\nBiguanides\nMetformin (present in French lilac, Galega officinalis , which \nwas used to treat diabetes in traditional medicine for \ncenturies) is the only biguanide used clinically to treat type \n2 diabetes, for which it is now a drug of first choice.8\nActions and mechanismThe molecular target or targets through which biguanides \nact remain unclear, but their biochemical actions are well \nunderstood, and include:\n\u2022\treduced \thepatic \tglucose \tproduction \t(gluconeogenesis) \t\nwhich is markedly increased in type 2 diabetes;\n\u2022\tincreased \tglucose \tuptake \tand \tutilisation \tin \tskeletal \t\nmuscle (i.e. reduced insulin resistance);\n\u2022\treduced \tcarbohydrate \tabsorption \tfrom \tthe \tintestine;\n\u2022\tincreased \tfatty \tacid \toxidation;\n\u2022\treduced \tcirculating \tlow-density \tand \tvery \tlow-density \t\nlipoprotein (LDL and VLDL, respectively, see Ch. 24).Pharmacokinetic aspects and insulin preparations\nInsulin is destroyed in the GI tract, and is ordinarily given by injection \u2013 usually subcutaneously, but intravenously or \noccasionally intramuscularly in emergencies. Intraperito", "start_char_idx": 0, "end_char_idx": 3507, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5a5d641d-b3ca-4b7f-bcaa-b6b88e212115": {"__data__": {"id_": "5a5d641d-b3ca-4b7f-bcaa-b6b88e212115", "embedding": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8a7dba6b-db6f-469a-873d-664d4db22805", "node_type": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d1e296a0afc4da78865e6e71ed9808f55942a350c50e333d7f438a9d2b12936f"}, "2": {"node_id": "8e243cb8-c9c7-4081-bc81-3b196ea0c344", "node_type": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1248f23c433550844a63a0fd3094c522066f74758786470fe245700494d1fe0b"}, "3": {"node_id": "1609c0d6-6496-4a84-a9e4-e435886c0f26", "node_type": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "399df38734d9255c3b0e8d9aa6ad42d8bc321856e0587f101b5cbc9c3b067faa"}}, "hash": "badca1a1044ba3789f3ccee320a86cca8dc19a8ad01ca34a0b069303e79e1333", "text": "or \noccasionally intramuscularly in emergencies. Intraperito -\nneal insulin can be used in rare instances in patients with \ndiabetes, through a continuous infusion pump, or through \nambulatory peritoneal dialysis for those with end stage renal \nfailure. Other potential approaches include incorporation of insulin into biodegradable polymer microspheres as a \nslow-release formulation, and its encapsulation with a lectin \nin a glucose-permeable membrane.\n7 Once absorbed, insulin \nhas an elimination half-life of approximately 10 min. It is \ninactivated enzymically in the liver and kidney, and 10% is excreted in the urine. Renal impairment reduces insulin \nrequirement.\nOne of the main problems in using insulin is to avoid \nwide fluctuations in plasma concentration and thus in blood glucose. Different formulations vary in the timing of their \npeak effect and duration of action. Soluble insulin produces \na rapid and short-lived effect. Longer-acting preparations \nare made by precipitating insulin with protamine or zinc, \nthus forming finely divided amorphous solid or relatively insoluble crystals, which are injected as a suspension from which insulin is slowly absorbed. These preparations include \nisophane insulin and amorphous or crystalline insulin zinc \nsuspensions . Mixtures of different forms in fixed proportions \nare available.\nMore recently, modifications of insulin molecules have \nfocused on two different areas \u2013 one being the production \nof molecules with a more rapid onset of action to cover \nmealtimes, and the other being even longer-acting formula -\ntions. Development of rapid-acting analogues is based on \namino acid substitutions that promote formation of insulin \nmonomers for faster absorption, whilst reducing the \naggregation of insulin dimers and hexamers (Atkin et al., \n2015). Example of these analogues include insulin aspart, \ninsulin lispro and insulin glulisine, which involve different \namino acid switches at positions such as B28 or B29 in the \ninsulin molecule. These analogues act more rapidly (onset of action <15 min and typically reaching peak concentrations \nwithin 40\u201370 min after injection) but for a shorter time than \nnatural insulin, enabling patients to inject themselves \nimmediately before the start of a meal rather than 30 min \nbefore eating with human insulin.\nBasal or longer-acting insulin analogues are designed \nwith the opposite intention, namely to provide a constant basal insulin supply and mimic physiological postabsorptive basal insulin secretion. Insulin glargine, which is a clear \nsolution, forms a microprecipitate at the physiological pH of subcutaneous tissue, and absorption from the subcutane -\nous site of injection is prolonged. In contrast, subcutaneous \ninjection of insulin detemir causes the molecules to bind \ntogether more avidly, thus slowing the absorption into the \ncirculation (Atkin et al., 2015). Insulin degludec is formed \nby the addition of a fatty-diacid side chain to human insulin, and the resulting molecules join up to form a depot of long \nmultihexamers after subcutaneous injection. Monomers of insulin degludec slowly dissociate from this depot, thus \ngiving a protracted duration of action >\n40 h.\nVarious dosage regimens are used. Some type 1 patients \ninject a combination of short- and intermediate-acting \n8Metformin had a very slow start. It was first synthesised in 1922, one \nof a large series of biguanides with many different pharmacological \nactions, which proved largely unsuitable for clinical use. Its glucose-\nlowering effect was noted early on, but was eclipsed by the discovery of insulin. It did not receive FDA approval until 1995.mebooksfree.net", "start_char_idx": 3453, "end_char_idx": 7136, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1609c0d6-6496-4a84-a9e4-e435886c0f26": {"__data__": {"id_": "1609c0d6-6496-4a84-a9e4-e435886c0f26", "embedding": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8a7dba6b-db6f-469a-873d-664d4db22805", "node_type": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d1e296a0afc4da78865e6e71ed9808f55942a350c50e333d7f438a9d2b12936f"}, "2": {"node_id": "5a5d641d-b3ca-4b7f-bcaa-b6b88e212115", "node_type": null, "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "badca1a1044ba3789f3ccee320a86cca8dc19a8ad01ca34a0b069303e79e1333"}}, "hash": "399df38734d9255c3b0e8d9aa6ad42d8bc321856e0587f101b5cbc9c3b067faa", "text": "insulin. It did not receive FDA approval until 1995.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7124, "end_char_idx": 7655, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "81852fad-7813-45c0-894e-d5c64e01aa5d": {"__data__": {"id_": "81852fad-7813-45c0-894e-d5c64e01aa5d", "embedding": null, "metadata": {"page_label": "422", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9b640bb3-9609-4196-926b-75c54e7d9973", "node_type": null, "metadata": {"page_label": "422", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3717d11cfde36f38cc17050034a2b173f406d7362801f9d8901ff91e3ec2792"}, "3": {"node_id": "5c245962-bd49-4809-81e9-2ead60fe7d17", "node_type": null, "metadata": {"page_label": "422", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4153f33a2668f9d0ff39b4e6883e0990a837d7cea6889c08b110f5c58fed8f76"}}, "hash": "2f05a96d497dee5a0855cf7022736d689861f7eda2526cd1b8ad3bd7243dec0f", "text": "32 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n416Clinical use\nMetformin is used to treat patients with type 2 diabetes. It \ndoes not stimulate appetite (rather the reverse; see earlier!) \nand is the drug of first choice in the majority of type 2 patients who are obese, provided they have unimpaired \nrenal and hepatic function. It can be combined with other \nglucose-lowering agents if blood glucose is inadequately controlled. Potential uses outside type 2 diabetes include \nother syndromes with accompanying insulin resistance \nincluding polycystic ovary syndrome, non-alcoholic fatty liver disease, gestational diabetes and some forms of \npremature puberty.\nSulfonylureas\nThe sulfonylureas were developed following the chance \nobservation that a sulfonamide derivative (which was \nbeing used to treat typhoid) caused hypoglycaemia. \nNumerous sulfonylureas are available. The first used therapeutically were tolbutamide and chlorpropamide . \nChlorpropamide has a long duration of action and a substantial fraction is excreted in the urine. Conse -\nquently, it can cause severe hypoglycaemia, especially \nin elderly patients in whom renal function declines \ninevitably but insidiously (Ch. 30). It causes flushing after alcohol because of a disulfiram-like effect (Ch. 50), and has an action like that of antidiuretic hormone on \nthe distal nephron, giving rise to hyponatraemia and \nwater intoxication. Williams (1994) comments that \u2018time honoured but idiosyncratic chlorpropamide should now \nbe laid to rest\u2019 \u2013 a sentiment with which we concur. \nTolbutamide, however, remains useful. So-called second-generation sulfonylureas (e.g. glibenclamide , glipizide ; \nTable 32.3) are more potent, but their maximum hypo -\nglycaemic effect is no greater and control of blood glucose no better than with tolbutamide. These drugs \nall contain the sulfonylurea moiety and act in the same \nway, but different substitutions result in differences in pharmacokinetics and hence in duration of action (see \nTable 32.3).\nMechanism of action\nThe principal action of sulfonylureas is on \u03b2 cells (see Fig. \n32.1), stimulating insulin secretion and thus reducing plasma \nglucose. High-affinity binding sites for sulfonylureas are present on the K\nATP channels (Ch. 4) in the surface mem -\nbranes of \u03b2 cells, and the binding of various sulfonylureas \nparallels their potency in stimulating insulin release. Block by sulfonylurea drugs of K\nATP channel activation causes \ndepolarisation of \u03b2 cells, Ca2+ entry and insulin secretion. \n(Compare this with the physiological control of insulin \nsecretion, see Fig. 32.1.)\nPharmacokinetic aspects\nSulfonylureas are well absorbed after oral administration, \nand most reach peak plasma concentrations within 2\u20134 h. \nThe duration of action varies (see Table 32.3). All bind \nstrongly to plasma albumin and are implicated in interac -\ntions with other drugs (e.g. salicylates and sulfonamides) that compete for these binding sites (see Ch. 9). Most sulfonylureas (or their active metabolites) are excreted in \nthe urine, so their action is increased and prolonged in the \nelderly and in patients with renal disease.\nMost sulfonylureas cross the placenta and enter breast \nmilk and their use is contraindicated in pregnancy and in breastfeeding.Reduced hepatic gluconeogenesis is especially important. Metformin decreases hepatic glucose production directly \nor indirectly by inhibiting the mitochondrial", "start_char_idx": 0, "end_char_idx": 3437, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5c245962-bd49-4809-81e9-2ead60fe7d17": {"__data__": {"id_": "5c245962-bd49-4809-81e9-2ead60fe7d17", "embedding": null, "metadata": {"page_label": "422", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9b640bb3-9609-4196-926b-75c54e7d9973", "node_type": null, "metadata": {"page_label": "422", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3717d11cfde36f38cc17050034a2b173f406d7362801f9d8901ff91e3ec2792"}, "2": {"node_id": "81852fad-7813-45c0-894e-d5c64e01aa5d", "node_type": null, "metadata": {"page_label": "422", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f05a96d497dee5a0855cf7022736d689861f7eda2526cd1b8ad3bd7243dec0f"}}, "hash": "4153f33a2668f9d0ff39b4e6883e0990a837d7cea6889c08b110f5c58fed8f76", "text": "glucose production directly \nor indirectly by inhibiting the mitochondrial respiratory \nchain complex I (reviewed by Viollet et al., 2012). The \nresulting increase in AMP activates AMP-activated protein \nkinase (AMPK) which is a master regulator of energy \nhomeostasis in eukaryotes (Myers et al., 2017). Activation \nof AMPK in the duodenum triggers release of GLP-1 which stimulates a gut\u2013brain\u2013liver vagal network that regulates \nhepatic glucose production (Duca et al., 2015). Chronic \nadministration of metformin alters recirculation of bile acids \nand composition of the gut microbiome in type 2 leading \nto increased GLP-1 secretion in diabetes patients (Napolitano \net al., 2014).\nMetformin has a half-life of about 3 h and is excreted \nunchanged in the urine.\nUnwanted effects\nMetformin, while preventing hyperglycaemia, does not \ncause hypoglycaemia, and the commonest unwanted effects \nare dose-related GI disturbances (e.g. anorexia, diarrhoea, \nnausea), which are usually, but not always, transient. Lactic acidosis is a rare but potentially fatal toxic effect, and \nmetformin should not be given routinely to patients with \nrenal or hepatic disease, hypoxic pulmonary disease or shock. Such patients are predisposed to lactic acidosis \nbecause of reduced drug elimination or reduced tissue \noxygenation. It should be avoided in other situations that predispose to lactic acidosis including alcohol intoxication, and some forms of mitochondrial myopathy that are associ -\nated with diabetes. Long-term use may interfere with absorption of vitamin B\n12.Clinical uses of insulin and other \nhypoglycaemic drugs for injection \n\u2022\tPatients \twith \ttype 1 diabetes require long-term \ninsulin:\n\u2013 an intermediate-acting preparation (e.g. isophane \ninsulin) or a long-acting analogue (e.g. glargine) is \noften combined with soluble insulin or a short-acting \nanalogue (e.g. lispro) taken before meals.\n\u2022\tSoluble insulin is used (intravenously) in treatment of \nhyperglycaemic emergencies (e.g. diabetic \nketoacidosis).\n\u2022\tApproximately \tone-third \tof \tpatients \twith \ttype 2 \ndiabetes ultimately require insulin.\n\u2022\tShort-term \ttreatment \tof \tpatients \twith \ttype \t2 \tdiabetes \t\nor impaired glucose tolerance during intercurrent events (e.g. operations, infections, myocardial \ninfarction).\n\u2022\tDuring\tpregnancy, \tfor \tgestational diabetes not \ncontrolled by diet alone.\n\u2022\tEmergency \ttreatment \tof \thyperkalaemia: insulin is \ngiven\twith \tglucose \tto \tlower \textracellular \tK+ via \nredistribution into cells.\n\u2022\tGlucagon-like \tpeptide-1 \t(GLP-1) agonist for type 2 \ndiabetes in addition to oral agents to improve control and lose weight.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3363, "end_char_idx": 6480, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0f1bab4d-9416-440a-9ac3-c29f02aefb41": {"__data__": {"id_": "0f1bab4d-9416-440a-9ac3-c29f02aefb41", "embedding": null, "metadata": {"page_label": "423", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5bd0fbc9-b3ac-43bb-9669-150414168aaa", "node_type": null, "metadata": {"page_label": "423", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53ef2d87245f66fbbff035b1635739d1b6ae20426e7a106865a35ddc3baa972a"}, "3": {"node_id": "331c640d-7aa1-4e31-bf87-d54380542dc2", "node_type": null, "metadata": {"page_label": "423", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d4d96827b89d796759021d1a29d46326206a9bcb3c001d6f36991c83211ec40"}}, "hash": "cfdae7797c840ac3e9a0b9a3180873dc100d0e82ab8888a391415a6ec1bdd708", "text": "32 ThE CONTRO l OF bl OOD G l UCOSE AND DRUG TREATMENT OF DIA b ETES ME ll ITUS\n417Table 32.3 Oral hypoglycaemic sulfonylurea drugs\nDrugRelative \npotencyaDuration of action and (half-life) (hours) Pharmacokinetic aspects\nbGeneral comments\nTolbutamide 1 6\u201312 (4)Some converted in liver to weakly \nactive hydroxytolbutamide; some carboxylated to inactive compoundRenal excretionA safe drug; least likely to cause hypoglycaemiaMay decrease iodide uptake by thyroidContraindicated in liver failure\nGlibenclamide\nc150 18\u201324 (10)Some is oxidised in the liver to moderately active products and is excreted in urine; 50% is excreted unchanged in the faecesMay cause hypoglycaemiaThe active metabolite accumulates in renal failure\nGlipizide 100 16\u201324 (7)\nPeak plasma levels in 1 h\nMost is metabolised in the liver to inactive products, which are excreted in urine; 12% is excreted in faecesMay cause hypoglycaemiaHas diuretic actionOnly inactive products accumulate in renal failure\naRelative to tolbutamide.\nbAll are highly protein bound (90%\u201395%).\ncTermed\tglyburide \tin \tthe \tUnited \tStates.\nwith a sulfonylurea. The probable basis of most of these \ninteractions is competition for metabolising enzymes, but \ninterference with plasma protein binding or with transport \nmechanisms facilitating excretion may play some part.\nAgents that decrease the action of sulfonylureas on blood \nglucose include high doses of thiazide diuretics (Chs 22 and 30) and glucocorticoids (pharmacodynamic interactions).\nClinical use\nSulfonylureas are used to treat type 2 diabetes in its early stages, but because they require functional \u03b2 cells, they are \nnot useful in type 1 or late-stage type 2 diabetes. They can \nbe combined with metformin.\nOTHER \u2003DRUGS \u2003THAT \u2003STIMULATE \u2003INSULIN \u2003SECRETION\nSeveral drugs that act, like the sulfonylureas, by blocking \nthe sulfonylurea receptor on K ATP channels in pancreatic \u03b2 \ncells but lack the sulfonylurea moiety have been developed. \nThese include repaglinide and nateglinide which, though \nmuch less potent than most sulfonylureas, have rapid onset \nand offset kinetics leading to short duration of action and \na low risk of hypoglycaemia.9 These drugs are administered \nshortly before a meal to reduce the postprandial rise in blood glucose in type 2 diabetic patients inadequately \ncontrolled with diet and exercise. They may cause less weight gain than conventional sulfonylureas. Later in the \ncourse of the disease, they can be combined with metformin \nor other oral hypoglycaemic agents. Unlike glibenclamide, these drugs are relatively selective for K\nATP channels on \u03b2 \ncells versus K ATP channels in vascular smooth muscle.\nThiazolidinediones (glitazones): pioglitazone\nThe thiazolidinediones (or glitazones) were developed fol-lowing the chance observation that a clofibrate analogue, Unwanted effects\nThe sulfonylureas are usually well tolerated. Unwanted \neffects are specified in Table 32.3. The commonest adverse \neffect is hypoglycaemia, which can be severe and pro -\nlonged, the highest incidence occurring with long-acting chlorpropamide and glibenclamide and the lowest with \ntolbutamide. Long-acting sulfonylureas are best avoided \nin the elderly and in patients with even mild renal impair -\nment because of the risk of hypoglycaemia.", "start_char_idx": 0, "end_char_idx": 3285, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "331c640d-7aa1-4e31-bf87-d54380542dc2": {"__data__": {"id_": "331c640d-7aa1-4e31-bf87-d54380542dc2", "embedding": null, "metadata": {"page_label": "423", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5bd0fbc9-b3ac-43bb-9669-150414168aaa", "node_type": null, "metadata": {"page_label": "423", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53ef2d87245f66fbbff035b1635739d1b6ae20426e7a106865a35ddc3baa972a"}, "2": {"node_id": "0f1bab4d-9416-440a-9ac3-c29f02aefb41", "node_type": null, "metadata": {"page_label": "423", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cfdae7797c840ac3e9a0b9a3180873dc100d0e82ab8888a391415a6ec1bdd708"}}, "hash": "5d4d96827b89d796759021d1a29d46326206a9bcb3c001d6f36991c83211ec40", "text": "even mild renal impair -\nment because of the risk of hypoglycaemia. Sulfonylureas \nstimulate appetite and often cause weight gain. This is \na major concern in obese diabetic patients. About 3% of patients experience GI upsets. Allergic rashes can occur, \nand bone marrow toxicity (Ch. 58), although rare, can be \nsevere.\nDuring and for a few days after acute myocardial infarc -\ntion in diabetic patients, insulin must be substituted for \nsulfonylurea treatment. Such substitution is associated with a substantial reduction in short-term mortality, although \nit remains unclear if this is due to a beneficial effect specific \nto insulin or to avoiding a detrimental effect of sulfonylurea drugs in this setting, or both. Another vexing question is \nwhether prolonged therapy with oral hypoglycaemic drugs \nhas adverse cardiovascular effects. Blockade of K\nATP in heart \nand vascular tissue could theoretically have adverse effects, \nand an observational study recorded an increased risk of \ndeath and cardiovascular disease during follow-up for up to 8 years in newly diagnosed type 2 diabetic patients treated \nwith sulfonylureas compared with those treated with \nmetformin (Evans et al., 2006).\nDrug interactions\nSeveral drugs augment the hypoglycaemic effect of sulfo -\nnylureas. Non-steroidal anti-inflammatory drugs, warfarin, some uricosuric drugs (e.g. sulfinpyrazone), alcohol, \nmonoamine oxidase inhibitors, some antibacterial drugs \n(including sulfonamides, trimethoprim and chlorampheni \u00ad\ncol) and some imidazole antifungal drugs have all been \nreported to produce severe hypoglycaemia when given 9It is ironic that these aggressively marketed drugs share many of the \nproperties of tolbutamide, the oldest, least expensive and least \nfashionable of the sulfonylureas.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3218, "end_char_idx": 5479, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f0fde337-cd5e-4257-abce-64cb2b460067": {"__data__": {"id_": "f0fde337-cd5e-4257-abce-64cb2b460067", "embedding": null, "metadata": {"page_label": "424", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7d0dd8eb-6503-43bb-a5c3-6c5f9e718220", "node_type": null, "metadata": {"page_label": "424", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "efb085f420d4ecd89324413ab18988c821be6eb3825e6ad90f0a1d1c201ae024"}, "3": {"node_id": "d5268398-a667-455d-9943-d5d44b918b18", "node_type": null, "metadata": {"page_label": "424", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5582549dbb8cb335a2caba986ee7322af8d48c9ddfcccc367b40be882b2f3b5c"}}, "hash": "fb04262a457f223b74f45809772165c42b4a96497010d58efbd5d73b786796e1", "text": "32 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n418without other agents. It delays carbohydrate absorption, \nreducing the postprandial increase in blood glucose. The \ncommonest adverse effects are related to its main action \nand consist of flatulence, loose stools or diarrhoea, and abdominal pain and bloating. Like metformin, it may be \nparticularly helpful in obese type 2 patients, and it can be \nco-administered with metformin.\nIncretin mimetics and related drugs\nExenatide is a synthetic version of exendin-4, a peptide \nfound in the saliva of the Gila monster (a lizard that presum -\nably evolved this as means to disable its prey by rendering them hypoglycaemic).\nGLP-1 agonists lower blood glucose after a meal by \nincreasing insulin secretion, suppressing glucagon secretion and slowing gastric emptying (see earlier). They reduce food intake (by an effect on satiety, see Ch. 33) and are \nassociated with modest weight loss. They reduce hepatic \nfat accumulation.\nGLP-1 agonists are administered by subcutaneous \ninjection, either once daily (exenatide, liraglutide, lixi\u00ad\nsenatide) or once weekly (extended release exenatide, albiglutide , dulaglutide ). Pancreatitis is rare but potentially \nsevere.\nGLP-1 agonists are used in patients with type 2 diabetes \nin combination with other drugs (metformin with or without a sulfonylurea, pioglitazone, insulin).\nGliptins\nGliptins (e.g. sitagliptin, vildagliptin, saxagliptin, lina\u00ad\ngliptin) are synthetic drugs that competitively inhibit \ndipeptidyl peptidase-4 (DPP-4), thereby lowering blood \nglucose by potentiating endogenous incretins (GLP-1 and GIP, see p. 413) which stimulate insulin secretion. They do \nnot cause weight loss or weight gain.\nThey are absorbed from the gut and administered once \n(or, in the case of vildagliptin, twice) daily by mouth. They are eliminated partly by renal excretion and are also \nmetabolised by hepatic CYP enzymes. They are usually well tolerated with a range of mild GI adverse effects; liver disease, heart failure (particularly with saxagliptin or \nalogliptin) and pancreatitis (incidence approximately \n0.1%\u20131%) are less common but potentially serious. There is also concern that they may act as tumour promoters (see \nCh. 58). Gliptins are used for type 2 diabetes in addition \nto other oral hypoglycaemic drugs (see clinical box on uses of oral hypoglycaemic drugs, p. 420).\nEvidence of cardiovascular efficacy or effect on mortality \nis inconsistent, with liraglutide the only agent to produce \na demonstrable reduction in major adverse cardiac events (Paneni & Luscher, 2017), whereas neither sitagliptin nor \nexenatide have shown such benefits in large-scale clinical trials.\nGlucose transport inhibitors\nSeveral SGLT2 inhibitors are licensed for use in type 2 diabetes. Examples include canagliflozin, dapagliflozin, \nand empagliflozin.\nMechanism of action\nThe SGLT2 inhibitors act by promoting glucose excretion \ninto the urine, thereby reducing the concentration of circulat -\ning glucose. The resulting glycosuria is associated with an \nosmotic diuresis and salt excretionciglitazone , which was being screened for effects on lipids, \nunexpectedly lowered blood glucose. Ciglitazone caused \nliver toxicity, and this class of drugs (despite consider-\nable commercial success) has been", "start_char_idx": 0, "end_char_idx": 3304, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d5268398-a667-455d-9943-d5d44b918b18": {"__data__": {"id_": "d5268398-a667-455d-9943-d5d44b918b18", "embedding": null, "metadata": {"page_label": "424", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7d0dd8eb-6503-43bb-a5c3-6c5f9e718220", "node_type": null, "metadata": {"page_label": "424", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "efb085f420d4ecd89324413ab18988c821be6eb3825e6ad90f0a1d1c201ae024"}, "2": {"node_id": "f0fde337-cd5e-4257-abce-64cb2b460067", "node_type": null, "metadata": {"page_label": "424", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb04262a457f223b74f45809772165c42b4a96497010d58efbd5d73b786796e1"}}, "hash": "5582549dbb8cb335a2caba986ee7322af8d48c9ddfcccc367b40be882b2f3b5c", "text": "toxicity, and this class of drugs (despite consider-\nable commercial success) has been dogged by adverse \neffects (especially cardiovascular), regulatory withdraw -\nals and controversy. No clinical trials of these agents have demonstrated a beneficial effect on mortality, and \nthey were licensed on the basis of statistically significant \neffects on haemoglobin A1c (a surrogate marker of longer-term diabetes status) of uncertain clinical significance. \nPioglitazone is the only drug of this class that remains in \nclinical use, its predecessors, rosiglitazone and troglitazone, having faced regulatory action because of increased risk \nof heart attacks and liver damage, respectively \u2013 at the \ntime, a cause c\u00e9l\u00e8bre , and very expensive for the companies \ninvolved.\nEffects\nThe effect of thiazolidinediones on blood glucose is slow \nin onset, the maximum effect being achieved only after 1\u20132 \nmonths of treatment. They act by enhancing the effectiveness of endogenous insulin, thereby reducing hepatic glucose \noutput, and increasing glucose uptake into muscle.\nThey reduce the amount of exogenous insulin needed \nto maintain a given level of blood glucose by approximately \n30%. Reduced blood glucose concentration is accompanied \nby reduced insulin and free fatty acid concentrations. Weight \ngain of 1\u20134 kg is common, usually stabilising in 6\u201312 months. \nSome of this is attributable to fluid retention: there is an \nincrease in plasma volume of up to 500 mL, with a con -\ncomitant reduction in haemoglobin concentration caused by haemodilution; there is also an increase in extravascular \nfluid, and increased deposition of subcutaneous (as opposed to visceral) fat.\nMechanism of action\nThiazolidinediones bind to a nuclear receptor called the \nperoxisome proliferator-activated receptor- \u03b3 (PPAR \u03b3), which is \ncomplexed with retinoid X receptor (RXR; see Ch. 3).\n10 It \nremains something of a mystery that glucose homeostasis should be so responsive to drugs that bind to receptors \nfound mainly in fat cells; it has been suggested that the explanation may lie in resetting of the glucose\u2013fatty acid \n(Randle) cycle by the reduction in circulating free fatty \nacids.\nUnwanted effects\nClinical trial data have demonstrated significantly increased risk of a range of adverse events with pioglitazone, including heart failure, bone fracture, oedema, and weight gain. (Liao \net al., 2017), and glitazones are now far less frequently used.\nClinical usePioglitazone is additive with other oral hypoglycaemic \ndrugs in terms of effect on blood glucose, and a combination \ntablet with metformin is marketed.\n\u03b1-Glucosidase inhibitors\nAcarbose, an inhibitor of intestinal \u03b1-glucosidase, is used \nin type 2 diabetes inadequately controlled by diet with or \n10Compare with fibrates (to which thiazolidinediones are structurally \nrelated), which bind to PPAR\u03b1 (see Ch. 24).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3218, "end_char_idx": 6570, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "95df82f6-f7bf-42d7-a7b5-b54a68cfdfec": {"__data__": {"id_": "95df82f6-f7bf-42d7-a7b5-b54a68cfdfec", "embedding": null, "metadata": {"page_label": "425", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0b6426d3-a63f-4105-9992-493ee8871ee7", "node_type": null, "metadata": {"page_label": "425", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b50a74b28ef50b10e730c8ebf70a658abac5a96845eaf761d1f4918657c85842"}, "3": {"node_id": "9d491806-a9b1-4e3b-b19f-8940c2b5d820", "node_type": null, "metadata": {"page_label": "425", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "996e3d9c72fce0299b8d430d49e9cbe148becb16f9a5fd0bf3c7eb89970aa262"}}, "hash": "fe0ed6559505092506fa4a14aa53a671f3dace8d09123093e0d897c6d10fabdb", "text": "32 ThE CONTRO l OF bl OOD G l UCOSE AND DRUG TREATMENT OF DIA b ETES ME ll ITUS\n419recommended option in patients who are susceptible to \nhypoglycaemia.\nTREATMENT OF DIABETES MELLITUS\nInsulin is essential for the treatment of type 1 diabetes, and a valuable component of the treatment of many patients \nwith type 2 disease.\n\u25bc For many years it was assumed, as an act of faith, that normalis-\ning plasma glucose would reduce the risk of diabetic complications. \nThe Diabetes Control and Complications Trial (American Diabetes \nAssociation, 1993) showed that this faith was well placed: type 1 diabetic patients were randomly allocated to intensive or conven -\ntional management. Mean fasting blood glucose concentration was \n2.8 mmol/L lower in the intensively treated group, who had a \nsubstantial reduction in the occurrence and progression of retinopathy, nephropathy and neuropathy over a period of 4\u20139 years. Benefits, \nincluding reduced atheromatous as well as microvascular disease, \nwere long-lasting and outweighed adverse effects, which included a three-fold increase in severe hypoglycaemic attacks and modest excess \nweight gain.\nThe UK Prospective Diabetes Study showed that lowering blood pressure \nmarkedly improves outcome in type 2 diabetes. Normalisation of \nblood glucose was not achieved even in intensively treated patients. Better metabolic control did improve outcome, but (in contrast to \nlowering blood pressure) the magnitude of the benefit was disap -\npointing and statistically significant only for microvascular complica -\ntions. In long-term follow-up, patients from this study who had been allocated to intensive treatment continued to have better outcomes \nthan patients treated with diet alone (despite diabetic control becoming similar in the two groups after the blinded treatment period had \nfinished), suggesting that early diabetic control (within the first 12 \nyears from diagnosis) is important (Holman et al., 2008). By contrast, \nstudies of intensive control later in the course of the disease have \nbeen disappointing with harm from hypoglycaemia outweighing any \nbenefit.\nRealistic goals in type 2 diabetic patients are usually less ambitious \nthan in younger type 1 patients. Dietary restriction leading to weight \nloss in overweight and obese patients is the cornerstone (albeit one with a tendency to crumble), combined with increased exercise. Oral \nagents are used to control symptoms from hyperglycaemia, as well \nas to limit microvascular complications, and are introduced early. Dietary measures and statins to prevent atheromatous disease (Ch. \n24) are crucial. Details of dietary management and treatment for \nspecific diabetic complications are beyond the scope of this book. Glitazones and drugs that mimic or potentiate incretins reduce \nglycated haemoglobin (typically by 0.5\u20131 percentage points) but their \neffects (if any) on clinical outcomes such as diabetic complications have not been consistently demonstrated. There is some evidence \nthat pioglitazone, liraglutide and empagliflozin can improve \ncardiovascular outcomes in type 2 diabetic patients (Paneni & L\u00fcscher, \n2017) \u2013 possibly due to cardiovascular actions distinct from their \nmetabolic effects.Effects\nClinical studies have found elevated amounts of glucose \nin the urine over sustained periods, and an associated \nincrease in urinary volume. As the efficacy of SGLT2 inhibi -\ntors rely on adequate renal function and urine output, these \nagents have limited or no effect in patients with chronic \nkidney disease. Clinical trials have confirmed improvements in fasting and post-prandial glucose concentrations, and significant reduction in glycosylated haemoglobin (Storgaard \net al., 2016). The osmotic diuretic effect and the caloric", "start_char_idx": 0, "end_char_idx": 3775, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9d491806-a9b1-4e3b-b19f-8940c2b5d820": {"__data__": {"id_": "9d491806-a9b1-4e3b-b19f-8940c2b5d820", "embedding": null, "metadata": {"page_label": "425", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0b6426d3-a63f-4105-9992-493ee8871ee7", "node_type": null, "metadata": {"page_label": "425", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b50a74b28ef50b10e730c8ebf70a658abac5a96845eaf761d1f4918657c85842"}, "2": {"node_id": "95df82f6-f7bf-42d7-a7b5-b54a68cfdfec", "node_type": null, "metadata": {"page_label": "425", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe0ed6559505092506fa4a14aa53a671f3dace8d09123093e0d897c6d10fabdb"}}, "hash": "996e3d9c72fce0299b8d430d49e9cbe148becb16f9a5fd0bf3c7eb89970aa262", "text": " \net al., 2016). The osmotic diuretic effect and the caloric loss \n(from glucose in the urine) also leads to reduction in systolic \nblood pressure and body weight (Abdul-Ghani et al., 2015). \nA clinical trial of empaglifozen (EMPA-REG OUTCOME) reported substantial reductions in cardiovascular endpoints, \nto which these haemodynamic effects probably contributed \nsubstantially (Paneni & Luscher, 2017).\nPharmacokinetic aspects\nSGLT2 inhibitors are rapidly absorbed, with time to peak \nplasma concentrations of less than 2 h. They are highly \nbound to plasma proteins (>80%).\nUnwanted effects\nA significant increase in the risk of urinary tract and fungal infections such as candidal vaginitis or balanitis has been \nreported with SGLT2 inhibition, presumably due to the \nglycosuria ( Storgaard et a l., 2016 ). Natriuresis with diuresis \ncan lead to increased urinary volume, hypotension and \ndehydration, and is accentuated with concomitant use of \nthiazide diuretics.\nSafety signals that are currently under regulatory evalu -\nation include potential serious adverse events such as increased susceptibility to diabetic ketoacidosis, and lower \nlimb amputations.\nClinical use\nSGLT2 inhibitors are licensed for use in type 2 diabetes, either alone (when metformin is inappropriate) or in combination with insulin or other oral glucose lowering \ntherapies. Typically, this would involve SGLT2 use in dual \nor triple therapy where sulfonylureas are not tolerated or have not been sufficiently efficacious. A potential advantage \nof SGLT2 inhibition in those with inadequate diabetes \ncontrol is that the amount of glucose excreted in the urine will be proportionately greater in patients whose plasma \nglucose concentrations are high.\nThe SGLT2 inhibitors are also considered to have a rela -\ntively low risk of hypoglycaemia, and are therefore a mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3715, "end_char_idx": 6045, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6564894f-de5c-49d2-97aa-697429b775bd": {"__data__": {"id_": "6564894f-de5c-49d2-97aa-697429b775bd", "embedding": null, "metadata": {"page_label": "426", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a4f0c629-c4a3-4f39-93c8-bb69973fae60", "node_type": null, "metadata": {"page_label": "426", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6770f6adf0921e53209b56cd0a19119cc2292f1ba3aba6b1474d80085dce6161"}, "3": {"node_id": "e6848ed3-eab3-40bd-915b-f26ada7b52cc", "node_type": null, "metadata": {"page_label": "426", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4093bfe849c6796f0af1c9d483e90d60c72f50a9af296e2dfaebb63fe3af6f5a"}}, "hash": "6f342b32a446346b1b0b6405c307cb419c446ac8a556867195251b36be6f0f09", "text": "32 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n420Clinical uses of oral hypoglycaemic drugs \n\u2022\tType 2 diabetes mellitus , to reduce symptoms from \nhyperglycaemia\t (e.g.\tthirst,\texcessive\t urination).\t (\u2018Tight\u2019\t\ncontrol of blood glucose has only a small effect on \nvascular complications in this setting.)\n\u2022\tMetformin is preferred, especially for obese patients \nunless contraindicated by factors that predispose to \nlactic acidosis (renal or liver failure, poorly compensated \nheart\tfailure,\thypoxaemia).\n\u2022\tAcarbose (\u03b1-glucosidase inhibitor) reduces carbohydrate \nabsorption; it causes flatulence and diarrhoea.\n\u2022\tDrugs\tthat\tact\ton\tthe\tsulfonylurea\t receptor\t(e.g.\t\ntolbutamide , glibenclamide ) are well tolerated but \noften promote weight gain. They are associated with \nincreased cardiovascular risk compared with metformin .\n\u2022\tPioglitazone improves control (reduces haemoglobin \nA1C) but increases weight, causes heart failure, fluid retention and increases risk of fractures. Glucagon-like \npeptide\t(GLP)-1\tagonists\t(e.g.\t exenatide, lixisenatide, \nor liraglutide ) are injected once daily or ( extended \nrelease exenatide ) once weekly in obese patients \ninadequately controlled on two hypoglycaemic drugs. \nThese agents are associated with the potential for weight \nloss or prevention of weight gain in overweight or obese \npatients.\n\u2022\tDipeptidyl\t peptidase-4\t (DPP-4)\tinhibitors\t (gliptins,\te.g.\t\nsitagliptin ) improve control, are well tolerated and \nweight-neutral, but outcome evidence is inconsistent. \nPancreatitis and heart failure are possible adverse effects \nof concern.\n\u2022\tSodium\u2013glucose\t co-transporter\t (SGLT)2\tinhibitors\t\nimprove control, but long-term outcomes and safety data \nare still emerging.Drugs used in diabetes mellitus \nInsulin and other injectable drugs\n\u2022\tHuman\t insulin is made by recombinant DNA \ntechnology. For routine use, it is given subcutaneously \n(by intravenous infusion in emergencies).\n\u2022\tDifferent\t formulations\t of\tinsulin differ in their duration of \naction:\n\u2013 fast- and short-acting soluble insulin : peak action \nafter subcutaneous dose 2\u20134 h and duration 6\u20138 h; \nit is the only formulation that can be given \nintravenously\n\u2013 intermediate-acting insulin (e.g. isophane insulin )\n\u2013 long-acting forms (e.g. insulin zinc suspension )\n\u2022\tThe\tmain\tunwanted\t effect\tis\thypoglycaemia.\n\u2022\tAltering\t the\tamino\tacid\tsequence\t (insulin\tanalogues,\t e.g.\t\nlispro and glargine ) can usefully alter insulin kinetics.\n\u2022\tInsulins are used for all type 1 diabetic patients and \napproximately\t one-third\t of\tpatients\twith\ttype\t2\tdiabetes.\n\u2022\tExenatide and liraglutide are injectable glucagon-like \npeptide-1\t (GLP-1)\tagonists\tused\tas\tadd-on\ttreatment\t in\t\ncertain inadequately controlled type 2 diabetic patients. \nUnlike insulin they cause weight loss.\nOral hypoglycaemic drugs\n\u2022\tThese\tare\tused\tin\ttype\t2\tdiabetes.\n\u2022\tBiguanides\t (e.g.\t metformin ):\n\u2013\thave\tcomplex\tperipheral\t actions\tin\tthe\tpresence\t of\t\nresidual", "start_char_idx": 0, "end_char_idx": 2957, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e6848ed3-eab3-40bd-915b-f26ada7b52cc": {"__data__": {"id_": "e6848ed3-eab3-40bd-915b-f26ada7b52cc", "embedding": null, "metadata": {"page_label": "426", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a4f0c629-c4a3-4f39-93c8-bb69973fae60", "node_type": null, "metadata": {"page_label": "426", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6770f6adf0921e53209b56cd0a19119cc2292f1ba3aba6b1474d80085dce6161"}, "2": {"node_id": "6564894f-de5c-49d2-97aa-697429b775bd", "node_type": null, "metadata": {"page_label": "426", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f342b32a446346b1b0b6405c307cb419c446ac8a556867195251b36be6f0f09"}}, "hash": "4093bfe849c6796f0af1c9d483e90d60c72f50a9af296e2dfaebb63fe3af6f5a", "text": "actions\tin\tthe\tpresence\t of\t\nresidual insulin, increasing glucose uptake in striated \nmuscle and inhibiting hepatic glucose output and \nintestinal glucose absorption\n\u2013\tcause\tanorexia\tand\tencourage\t weight\tloss\n\u2013 can be combined with sulfonylureas\n\u2022\tSulfonylureas\t and\tother\tdrugs\tthat\tstimulate\t insulin\t\nsecretion (e.g. tolbutamide , glibenclamide , \nnateglinide ):\u2013 can cause hypoglycaemia (which stimulates appetite \nand leads to weight gain)\n\u2013 are effective only if \u03b2 cells are functional\n\u2013 block ATP-sensitive potassium channels in \u03b2 cells\n\u2013 are well tolerated but promote weight gain and are \nassociated with more cardiovascular disease than is \nmetformin\n\u2022\tThiazolidinediones\t have\tbeen\tassociated\t with\tserious\t\ncardiac\ttoxicity.\nPioglitazone is the only one still widely marketed; it:\n\u2013 increases insulin sensitivity and lowers blood glucose \nin type 2 diabetes\n\u2013 can cause weight gain and oedema\n\u2013 increases osteoporotic fractures\n\u2013\tis\ta\tperoxisome\t proliferator-activated\t receptor- \u03b3 (a \nnuclear receptor) agonist\n\u2022\tGliptins\t (e.g.\t sitagliptin ):\n\u2013 potentiate endogenous incretins by blocking dipeptidyl \npeptidase-4 (DPP-4)\n\u2013 are added to other orally active drugs to improve \ncontrol in patients with type 2 diabetes\n\u2013 are weight-neutral; they are usually well tolerated but \npancreatitis is a concern\n\u2022\tSodium\u2013glucose\t co-transporter\t (SGLT)2\tinhibitors\t (e.g.\t\nempagliflozin)\n\u2013\tPromote\t urinary\texcretion\t of\tglucose\n\u2013 Have potentially beneficial effects on weight, blood \npressure and cardiovascular outcome\n\u2013\tIncrease\t the\trisk\tof\tdehydration\t and\turinary\ttract\t\ninfections\n\u2022\t\u03b1-Glucosidase inhibitor, acarbose :\n\u2013 reduces carbohydrate absorption\n\u2013 causes flatulence and diarrhoeamebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2920, "end_char_idx": 5098, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "22e3b19b-05a9-4daf-9c76-55625727846e": {"__data__": {"id_": "22e3b19b-05a9-4daf-9c76-55625727846e", "embedding": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3d39e92f-9ad8-48e2-a334-f19a5608ef50", "node_type": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9baaa44dbf6f291f2dd3fcec32d8ce23e1ac600234211ba0290a1a431c9573fd"}, "3": {"node_id": "963b3814-45b7-4bdc-903d-1032614872a4", "node_type": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "148d41ae86cd643fb13a783acb000ac269b508793f7173d1459e1fa0547ca025"}}, "hash": "9199b86b0c44dd7dc7287d25be66583942c67292da4d8909cfeaf2d10f49fc0d", "text": "32 ThE CONTROl OF blOOD GlUCOSE AND DRUG TREATMENT OF DIAbETES MEllITUS\n421REFERENCES AND FURTHER READING\nReferences\nAbdul-Ghani, M.A., Norton, L., DeFronzo, R.A., 2011. Role of \nsodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of \ntype 2 diabetes. Endocr. Rev. 32 (4), 515\u2013531.\nAbdul-Ghani, M.A., Norton, L., DeFronzo, R.A., 2015. Renal \nsodium-glucose cotransporter inhibition in the management of \ntype 2 diabetes mellitus. Am. J. Physiol. Renal Physiol. 309 (11), \nF889\u2013F900.\nAmerican Diabetes Association, 1993. Implications of the diabetes \ncontrol and complications trial. Diabetes 42, 1555\u20131558. ( Landmark \nclinical trial )\nAtkin, S., Javed, Z., Fulcher, G., 2015. Insulin degludec and insulin \naspart: novel insulins for the management of diabetes mellitus. Ther. \nAdv. Chronic. Dis. 6 (6), 375\u2013388. ( Excellent summary of development and \npharmacokinetics of insulin analogues )\nDeFronzo, R.A., Davidson, J.A., Del Prato, S., 2012. The role of the \nkidneys in glucose homeostasis: a new path towards normalizing \nglycaemia. Diabetes Obes. Metab. 14 (1), 5\u201314. ( Good review article \ndiscussing glucose homeostasis and the kidney )\nDuca, F.A., Cote, C.D., Rasmussen, B.A., et al., 2015. Metformin \nactivates a duodenal Ampk-dependent pathway to lower hepatic \nglucose production in rats. Nat. Med. 21, 506\u2013511.\nEvans, J.M.M., Ogston, S.A., Emslie-Smith, A., Morris, A.D., 2006. Risk \nof mortality and adverse cardiovascular outcomes in type 2 diabetes: \na comparison of patients treated with sulfonylureas and metformin. \nDiabetologia 49, 930\u2013936. ( Observational cohort study in 5700 newly \ntreated type 2 patients, 1000 deaths in up to 8 years follow-up. Sulfonylurea \nuse was associated with increased risk of death and of cardiovascular disease. \nNot proof but pretty suggestive! )\nHolman, R.R., Sanjoy, K.P., Bethel, M.A., et al., 2008. 10-year follow-up \nof intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, \n1577\u20131589.\nLiao, H.W., Saver, J.L., Wu, Y.L., Chen, T.H., Lee, M., Ovbiagele, B., \n2017. Pioglitazone and cardiovascular outcomes in patients with \ninsulin resistance, pre-diabetes and type 2 diabetes: a systematic \nreview and meta-analysis. BMJ open. 7 (1), e013927.\nMyers, R.W., Guan, H.P., Ehrhart, J., et al., 2017. Systemic pan-AMPK \nactivator MK-8722 improves glucose homeostasis but induces cardiac \nhypertrophy. Science 357, 507\u2013511.\nNapolitano, A., Miller, S., Nicholls, A.W., et al., 2014. Novel gut-based \npharmacology of metformin in patients with type 2 diabetes mellitus. \nPLoS ONE 9, e100778.\nPaneni, F., Luscher, T.F., 2017. Cardiovascular protection in the \ntreatment of type 2 diabetes: a review of clinical trial results across \ndrug classes. Science 120, S17\u2013S27. ( Good summary of cardiovascular \noutcomes in trials of different classes of hypoglycaemic agents )\nStorgaard,", "start_char_idx": 0, "end_char_idx": 2857, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "963b3814-45b7-4bdc-903d-1032614872a4": {"__data__": {"id_": "963b3814-45b7-4bdc-903d-1032614872a4", "embedding": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3d39e92f-9ad8-48e2-a334-f19a5608ef50", "node_type": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9baaa44dbf6f291f2dd3fcec32d8ce23e1ac600234211ba0290a1a431c9573fd"}, "2": {"node_id": "22e3b19b-05a9-4daf-9c76-55625727846e", "node_type": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9199b86b0c44dd7dc7287d25be66583942c67292da4d8909cfeaf2d10f49fc0d"}, "3": {"node_id": "ce1b6e13-d127-4b8e-a6ee-5f24c54efe3f", "node_type": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ac63dfc57fa367252a21563efb863881507bd78b95d9ba54b59901c7897eee7f"}}, "hash": "148d41ae86cd643fb13a783acb000ac269b508793f7173d1459e1fa0547ca025", "text": "in trials of different classes of hypoglycaemic agents )\nStorgaard, H., Gluud, L.L., Bennett, C., et al., 2016. Benefits and harms \nof sodium-glucose co-transporter 2 inhibitors in patients with type 2 \ndiabetes: a systematic review and meta-analysis. PLoS ONE 11 (11).\nViollet, B., Guigas, B., Garcia, N.S., Leclerc, J., Foretz, M., Andreelli, F., \n2012. Cellular and molecular mechanisms of metformin: an overview. \nClin. Sci. 122, 253\u2013270. ( Reviews mechanisms as a setting for novel \ntherapeutic uses, for example in non-alcoholic fatty liver disease )\nWaumans, Y., Baerts, L., Kehoe, K., Lambeir, A.M., De Meester, I., 2015. \nThe dipeptidyl peptidase family, prolyl oligopeptidase, and prolyl \ncarboxypeptidase in the immune system and inflammatory disease, \nincluding atherosclerosis. Front. Immunol. 6, 387.\nWilliams, G., 1994. Management of non-insulin dependent diabetes \nmellitus. Lancet 343, 95\u2013100.\nYu, D.M.T., Yao, T.W., Chowdhary, S., 2010. The dipeptidyl peptidase \nIV family in cancer and cell biology. FEBS J. 277, 1126\u20131144. ( Discusses \ncurrent understanding of this unique family of enzymes )Further reading\nPhysiological and pathophysiological aspects\nLavin, D.P., White, M.F., Brazil, D.P., 2016. IRS proteins and diabetic \ncomplications. Diabetologia 59, 2280\u20132291. ( Reviews the role of IRS \nproteins in linking cell surface receptors to intracellular signalling cascades \nand potential mechanisms that lead to development and progression of \ndiabetic complications\u2019 )\nWithers, D.J., Gutierrez, J.S., Towery, H., et al., 1998. Disruption of IRS-2 \ncauses type 2 diabetes in mice. Nature 391, 900\u2013904. ( Dysfunction of \nIRS-2 may \u2018contribute to the pathophysiology of human type 2 diabetes\u2019; see \nalso accompanying commentary by Avruch, J., A signal for \u03b2-cell failure, pp. \n846\u2013847 )\nZimmet, P., Alberti, K.G.M.M., Shaw, J., 2001. Global and societal \nimplications of the diabetes epidemic. Nature 414, 782\u2013787. ( Changes \nin human behaviour have resulted in a dramatic increase in type 2 diabetes \nworldwide )\nInsulins\nOwens, D.R., Zinman, B., Bolli, G.B., 2001. Insulins today and beyond. \nLancet 358, 739\u2013746. ( Reviews the physiology of glucose homeostasis, \ngenetically engineered \u2018designer\u2019 insulins and developments in insulin \ndelivery and glucose sensing )\nOral hypoglycaemic drugs\nGale, E.A.M., 2001. Lessons from the glitazones: a story of drug \ndevelopment. Lancet 357, 1870\u20131875. ( Fighting stuff: \u2018Troglitazone was \nvoluntarily withdrawn in Europe, but went on to generate sales of over $2 \nbillion in the USA and caused 90 cases of liver failure before being \nwithdrawn. Rosiglitazone and pioglitazone reached the USA for use alone or \nin combination with other drugs whereas in Europe the same dossiers were \nused to apply for a limited licence as second-line agents. How should we use \nthem? How did they achieve blockbuster status without any clear evidence of \nadvantage over existing therapy?\u2019 )\nGuan, Y., Hao, C., Cha, D.R., et al., 2005.", "start_char_idx": 2799, "end_char_idx": 5782, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ce1b6e13-d127-4b8e-a6ee-5f24c54efe3f": {"__data__": {"id_": "ce1b6e13-d127-4b8e-a6ee-5f24c54efe3f", "embedding": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3d39e92f-9ad8-48e2-a334-f19a5608ef50", "node_type": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9baaa44dbf6f291f2dd3fcec32d8ce23e1ac600234211ba0290a1a431c9573fd"}, "2": {"node_id": "963b3814-45b7-4bdc-903d-1032614872a4", "node_type": null, "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "148d41ae86cd643fb13a783acb000ac269b508793f7173d1459e1fa0547ca025"}}, "hash": "ac63dfc57fa367252a21563efb863881507bd78b95d9ba54b59901c7897eee7f", "text": "Y., Hao, C., Cha, D.R., et al., 2005. Thiazolidinediones expand \nbody fluid volume through PPAR \u03b3 stimulation of ENaC-mediated \nrenal salt absorption. Nat. Med. 11, 861\u2013865. ( Mechanism of fluid \nretention caused by thiazolidinediones and suggestion that amiloride may \nprovide a specific therapy for this )\nOther drugs for diabetes, and therapeutic aspects\nBrenner, B.M., Cooper, M.E., de Zeeuw, D., et al., 2001. Effects of \nlosartan on renal and cardiovascular outcomes in patients with type 2 \ndiabetes and nephropathy. N. Engl. J. Med. 345, 861\u2013869. ( Significant \nrenal benefits from the AT 1 antagonist; see also two adjacent articles: Lewis, \nE.J., et al., pp. 851\u2013860, and Parving, H.-H., et al., pp. 870\u2013878, and an \neditorial on prevention of renal disease caused by type 2 diabetes by \nHostetter, T.H., pp. 910\u2013911 )\nFarmer, K.L., Li, C.Y., Dobrowsky, R.T., 2012. Diabetic neuropathy: \nshould a chaperone accompany our therapeutic approach? Pharmacol. \nRev. 64, 880\u2013900. ( Currently no satisfactory therapy )\nYounk, L.M., Mikeladze, M., Davis, S.N., 2011. Pramlintide and the \ntreatment of diabetes: a review of the data since its introduction. \nExpert Opin. Pharmacother. 12, 1439\u20131451. ( \u2018Pramlintide significantly \nreduces hemoglobin A(1c) and body weight in patients with type 1 and type \n2 diabetes mellitus. Newer research is focusing on weight loss effects of \npramlintide and pramlintide plus metreleptin in nondiabetic obese \nindividuals\u2019 )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5804, "end_char_idx": 7744, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "30bc525e-55b3-445d-8f81-0f91eb0c3408": {"__data__": {"id_": "30bc525e-55b3-445d-8f81-0f91eb0c3408", "embedding": null, "metadata": {"page_label": "428", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8d4373a2-f564-435b-88f9-e88d1b9f68bf", "node_type": null, "metadata": {"page_label": "428", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1dd37f466db8db1c92b9d53d33ecab04036e41c673c59e1b40495a50f8af7301"}, "3": {"node_id": "1cae5436-6306-48bc-819f-17e946256121", "node_type": null, "metadata": {"page_label": "428", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2e819c49e3dcb07c60d550bf5bb118b80cfc7b6b3dcda5b36b5bb7fe8e56c77"}}, "hash": "fe13db833b3a3b817d78232e3164d7fcfc949cf53c3b7fded996257312cbcb3c", "text": "422\nObesity33\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION \u20033\nOVERVIEW\nObesity \u2003is \u2003a \u2003growing \u2003health \u2003issue \u2003around \u2003the \u2003world \u2003\nand\u2003is\u2003reaching \u2003epidemic \u2003proportions \u2003in\u2003some \u2003nations. \u2003\nThe\u2003problem \u2003is\u2003not\u2003restricted \u2003to\u2003the\u2003inhabitants \u2003of\u2003the\u2003\naffluent \u2003countries, \u2003to \u2003the \u2003adult \u2003population \u2003or \u2003to \u2003any\u2003\none\u2003socioeconomic \u2003class. \u2003Body \u2003fat \u2003represents \u2003stored \u2003\nenergy \u2003and \u2003obesity \u2003occurs \u2003when \u2003the \u2003homeostatic \u2003\nmechanisms \u2003controlling \u2003energy \u2003balance \u2003become \u2003\ndisordered \u2003or \u2003overwhelmed. \u2003In \u2003this \u2003chapter \u2003we \u2003first\u2003\noutline \u2003the \u2003endogenous \u2003regulation \u2003of \u2003appetite \u2003and\u2003\nbody \u2003mass, \u2003and\u2003then\u2003consider \u2003the\u2003main \u2003health \u2003implica -\ntions\u2003of\u2003obesity \u2003and\u2003its\u2003pathophysiology. \u2003We\u2003conclude \u2003\nwith\u2003a \u2003discussion \u2003of \u2003the \u2003drugs \u2003currently \u2003licensed \u2003for\u2003\nthe\u2003treatment \u2003of\u2003obesity \u2003and\u2003glance \u2003at\u2003possible \u2003future \u2003\npharmacological \u2003treatments \u2003for \u2003this \u2003condition.\nINTRODUCTION\nSurvival requires a continuous provision of energy to \nmaintain homeostasis, even when the supply of food is \nintermittent. Evolution has furnished a mechanism for \nstoring excess energy latent in foodstuffs in adipose tissue as energy-dense triglycerides, such that these can be easily \nmobilised when food is scarce. This mechanism, controlled \nby the so-called thrifty genes, was an obvious asset to our \nhunter\u2013gatherer ancestors, but in many societies a combina -\ntion of sedentary lifestyle, genetic susceptibility, cultural influences and unrestricted access to an ample supply of calorie-dense foods has led to a global epidemic of obesity, or \u2018globesity\u2019 as it is sometimes called. Obesity is one \ncomponent of a cluster of disorders described in other \nchapters, which often coexist in the same individual, comprising what is now described as \u2018metabolic syndrome\u2019 \n(formerly \u2018metabolic X syndrome\u2019), and which constitutes \na rapidly growing public health problem.\nDEFINITION \u2003OF \u2003OBESITY\n\u2018Obesity\u2019 may be defined as an illness where health (and hence life expectancy) is adversely affected by excess body \nfat.\n1 But at what point does an individual become \u2018obese\u2019? \nThe generally accepted (WHO) benchmark is the body mass index (BMI). The BMI is expressed as W/h\n2, where W = \nbody weight (in kg), h = height (in metres). Although it is not a perfect index (e.g. it does not distinguish between \nfat and lean mass), the BMI is generally well correlated with other measurements of body fat, and it is widely \nutilised as a convenient index. While there are problems \nin defining a \u2018healthy\u2019 weight for a particular population, the WHO classifies adults with a BMI of \u226525 as being \noverweight and those with a BMI of \u226530 as obese. Childhood \nobesity is more difficult to assess.\nSince the BMI obviously depends on the overall energy \nbalance, another operational definition of obesity would \nbe that it is a multifactorial disorder of energy balance in \nwhich calorie intake over the long term exceeds energy", "start_char_idx": 0, "end_char_idx": 2918, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1cae5436-6306-48bc-819f-17e946256121": {"__data__": {"id_": "1cae5436-6306-48bc-819f-17e946256121", "embedding": null, "metadata": {"page_label": "428", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8d4373a2-f564-435b-88f9-e88d1b9f68bf", "node_type": null, "metadata": {"page_label": "428", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1dd37f466db8db1c92b9d53d33ecab04036e41c673c59e1b40495a50f8af7301"}, "2": {"node_id": "30bc525e-55b3-445d-8f81-0f91eb0c3408", "node_type": null, "metadata": {"page_label": "428", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe13db833b3a3b817d78232e3164d7fcfc949cf53c3b7fded996257312cbcb3c"}}, "hash": "e2e819c49e3dcb07c60d550bf5bb118b80cfc7b6b3dcda5b36b5bb7fe8e56c77", "text": "disorder of energy balance in \nwhich calorie intake over the long term exceeds energy output.\nOBESITY \u2003AS \u2003A \u2003HEALTH \u2003PROBLEM\nObesity is a growing and costly global health problem. The WHO in 2016 estimated that worldwide obesity has doubled \nsince 1980 and there were more than 1.9 billion overweight \nadults, approximately one-third of whom \u2013 amounting to more than 13% of the world\u2019s population \u2013 were obese \naccording to the criteria outlined earlier. National obesity \nlevels vary enormously, being less than 4% in Japan and parts of Africa, but a staggering 40% or more in parts of \nPolynesia. Adult obesity levels in the United States, Europe \nand the United Kingdom (among others) have increased three-fold since 1980, with figures of 34% being quoted for the United States by WHO (2016) and about 25% for many \nother industrialised nations including the United Kingdom. \nThe disease is not confined to adults: some 42 million children or infants under 5 years old are estimated to be \noverweight. In the United States, the number of overweight \nchildren has doubled and the number of overweight adolescents has trebled since 1980, although there are now \nsigns of it stabilising at around 17% (data from the US \nCenter for Disease Control and Prevention, 2015). Ironically, obesity often coexists with malnutrition in many developing \ncountries. All socioeconomic classes are affected. In the \npoorest countries, it is the top socioeconomic classes in whom obesity is prevalent, but in the affluent West it is \nusually the reverse.\nOverall, more people die in the world from being \noverweight and obese than being underweight, and the financial burden on the healthcare system is huge. An \ninfluential report (McKinsey Global Institute, 2014) esti -\nmated the global economic burden was estimated at US$2.1 trillion in 2014, 2.9% of the global GDP \u2013 more than the \ncost incurred by armed violence, war and terrorism taken \naltogether.\n\u25bc While obesity itself is rarely fatal, it often coexists with metabolic \nand other disorders (particularly hypertension, hypercholesterolaemia \nand type 2 diabetes), together comprising the metabolic syndrome . This \ncarries a high risk of cardiovascular conditions, strokes, cancers (particularly hormone-dependent), respiratory disorders (particularly sleep apnoea) and digestive problems, as well as osteoarthritis. One \ncommentator (Kopelman, 2000) has remarked that obesity \u2018is beginning \nto replace under-nutrition and infectious diseases as the most significant contributor to ill health\u2019. Increasingly, social stigma is suffered by \nobese individuals, leading to a sense of psychological isolation.\n1\u2018Persons who are naturally very fat are apt to die earlier than those \nwho are slender\u2019 observed Hippocrates.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2833, "end_char_idx": 6075, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "91dd174e-7c11-438b-86b4-ea666cedc7bb": {"__data__": {"id_": "91dd174e-7c11-438b-86b4-ea666cedc7bb", "embedding": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "80ab4d67-a0bf-49e3-9574-67e6bf5921df", "node_type": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e927cd90fed6dfbb83b34c2851b072fb9cd1b3ca035a0d0179a86cedb0bd04d1"}, "3": {"node_id": "a403ee8d-2a0a-44ea-ad33-c4ae270ba46b", "node_type": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c815c70e48558d0dd4756619d8d02761794aa28cc0a1a2359b351f0723c1366b"}}, "hash": "9328512aa2fae2d1d5e00e2ef3f79f298d9bd810779bffbcbed8e068ff5bb592", "text": "33 ObESITY\n423An important conceptual breakthrough came in 1994, \nwhen Friedman and his colleagues (see Zhang et al., 1994) \ncloned the Ob gene and identified its protein product as \nthe polypeptide leptin.2 When recombinant leptin was \nadministered systemically to Ob/Ob mice, it strikingly \nreduced food intake and body weight. It had a similar \neffect when injected directly into the lateral or the third ventricle, implying that it acted on the regions of the brain \nthat control food intake and energy balance. Recombinant \nleptin has similar effects in humans (Fig. 33.1).\nLeptin mRNA is expressed in adipocytes; its synthesis \nis increased by glucocorticoids, insulin and oestrogens, and is reduced by \u03b2-adrenoceptor agonists. In normal human \nsubjects, the release of leptin is pulsatile and varies according to the state of the fat stores and the BMI. Insulin (see Ch. \n32) may also stimulate leptin release although the relation -\nship between these two hormones is complex.\nIn addition to leptin and insulin, several other mediators \noriginating mainly from the gastrointestinal (GI) tract as \nwell as in the hypothalamus, play a crucial role in determin -\ning food intake, meal size and the feeling of satisfaction \nproduced (\u2018satiety\u2019).\n3 Peptide hormones secreted by cells \nin the wall of the small intestine in response to the arrival of food (see Ch. 31) are important in this connection. Table \n33.1 and Fig. 33.2 summarise the chief characteristics of \nthese mediators.\nThe majority of these peptides are released either during, \nor in anticipation of, eating and most are inhibitory in nature, producing either satiety or satiation. Two exceptions are \nthe gastric hormone, ghrelin, which promotes hunger, and \nleptin itself, which is controlled by the amount of adipose tissue and is thus more involved with the longer-term energy status of the individual. The main targets for these hormones \nare receptors on vagal afferent fibres or within the hypo -\nthalamus (or elsewhere in the central nervous system [CNS]). \nHere, they modulate the release of other neurotransmitters \nthat exert a fine regulation over eating behaviour, energy \nexpenditure and body weight. Other actions of these peptide hormones include the release of insulin by the incretins \n(see Ch. 32), which include glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP).\nAnother factor, nesfatin 1 , has recently attracted attention \nas a potentially important regulator of feeding behaviour \nand energy homeostasis (see Ramesh et al., 2017). This is \nan 82-amino acid peptide produced from a precursor molecule nucleobindin 2. Unlike many of the hormones \nalready discussed, nesfatin 1 may be produced by many peripheral and central tissues. It acts centrally to produce an anorexigenic effect by modulating the neuropeptides \nin the hypothalamic circuits described later. It may also \nhave additional actions on the pancreas as well as GI func -\ntion and even the cardiovascular system.\nNEUROLOGICAL \u2003CIRCUITS \u2003THAT \u2003CONTROL \u2003\nBODY \u2003WEIGHT \u2003AND \u2003EATING \u2003BEHAVIOUR\nCONTROL OF FOOD INTAKE\nThe manner in which all these hormonal signals are processed and integrated with other viscerosensory, gustatory or The risk of developing type 2 diabetes (which represents 85% of all \ncases of the disease) rises sharply with increasing BMI. The WHO \nreports that some 90% of those diagnosed with the disease are obese. \nIn a study of the disease in women, the risk of developing diabetes \nwas closely correlated with BMI, increasing five-fold when", "start_char_idx": 0, "end_char_idx": 3542, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a403ee8d-2a0a-44ea-ad33-c4ae270ba46b": {"__data__": {"id_": "a403ee8d-2a0a-44ea-ad33-c4ae270ba46b", "embedding": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "80ab4d67-a0bf-49e3-9574-67e6bf5921df", "node_type": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e927cd90fed6dfbb83b34c2851b072fb9cd1b3ca035a0d0179a86cedb0bd04d1"}, "2": {"node_id": "91dd174e-7c11-438b-86b4-ea666cedc7bb", "node_type": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9328512aa2fae2d1d5e00e2ef3f79f298d9bd810779bffbcbed8e068ff5bb592"}, "3": {"node_id": "81fc9d5f-eb9e-4436-9741-d1428a71e4eb", "node_type": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42036680d52b90ce2eaca45b767e4b9b0f051623c05e8e0a6e32ac822edda2fd"}}, "hash": "c815c70e48558d0dd4756619d8d02761794aa28cc0a1a2359b351f0723c1366b", "text": "of developing diabetes \nwas closely correlated with BMI, increasing five-fold when the BMI \nwas 25 kg/m2, to 93-fold when the BMI was 35 kg/m2 or above (Colditz \net al., 1995). Cardiovascular disease is also increased in the obese \nindividual, and the increased thoracic and abdominal adipose tissue reduces lung volume and makes respiration difficult. Obese subjects \nalso have an increased risk of colon, breast, prostate, gall bladder, \novarian and uterine cancer. Numerous other disorders are associated with excess body weight, including osteoarthritis, hyperuricaemia \nand male hypogonadism. \u2018Gross\u2019 obesity (BMI \u2265\n40 k g/m2) is associated \nwith a 12-fold increase in mortality in the group aged 25\u201335 years \ncompared with those in this age group with a BMI of 20\u201325 kg/m2.\nHOMEOSTATIC \u2003MECHANISMS \u2003\nCONTROLLING \u2003ENERGY \u2003BALANCE\nA common view, and one that is implicitly encouraged by \nauthors of numerous self-help books as well as the enor -\nmously lucrative dieting industry, is that obesity is simply the result of bad diet or willful overeating (hyperphagia). In truth, however, the situation is more complex. On its \nown, dieting seldom provides a lasting solution: the failure \nrate is high (probably 90%), and most dieters eventually return to their original starting weight. This suggests the \noperation of some intrinsic homeostatic system to maintain \na particular set weight. This mechanism is normally exceptionally precise, and is capable of regulating energy balance to within 0.17% per decade (Weigle, 1994), a truly \nastonishing feat, considering the day-to-day variations in \nfood intake.\nWhen exposed to the same dietary choices, some individu -\nals will become obese whereas others will not. Studies of obesity in monozygotic and dizygotic twins have established a strong genetic influence on the susceptibility to the condi -\ntion, and studies of rare mutations in mice (and more recently in humans) have led to the discovery and elucida -\ntion of the neuroendocrine pathways that match food intake \nwith energy expenditure. These, in turn, have led to the \nconcept that disorders of these control systems are largely responsible for the onset and maintenance of obesity.\nTHE\u2003ROLE \u2003OF \u2003GUT \u2003AND \u2003OTHER \u2003HORMONES \u2003IN\u2003\nBODY \u2003WEIGHT \u2003REGULATION\nAt the beginning of the 20th century it was observed that patients with damage to the hypothalamus tended to gain \nweight. In the 1940s it was also shown that discrete lesions in \nthe hypothalamus of rodents caused them to become obese or exhibit unusual feeding behaviour. On the basis of early \n(1953) observations in rats, Kennedy proposed that a hormone \nreleased from adipose tissue acted on the hypothalamus to regulate body fat and food intake. These seminal findings \nset the stage for future discoveries in this area.\nIt was also observed that mice became obese as a result \nof mutations in certain genes. At least five of these have \nnow been characterised, including the Ob (obesity), Tub \n(tubby), Fat and Db (diabetes) genes. Mice that are homozy -\ngous for mutant forms of these genes \u2013 Ob/Ob mice and \nDb/Db mice \u2013 eat excessively, have low energy expenditure, \nbecome grossly fat and have numerous metabolic and other abnormalities. Weight gain in an Ob/Ob mouse is suppressed \nif its circulation is linked to that of a normal mouse, implying \nthat the obesity is caused by lack of a blood-borne factor. 2The word is derived", "start_char_idx": 3471, "end_char_idx": 6886, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "81fc9d5f-eb9e-4436-9741-d1428a71e4eb": {"__data__": {"id_": "81fc9d5f-eb9e-4436-9741-d1428a71e4eb", "embedding": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "80ab4d67-a0bf-49e3-9574-67e6bf5921df", "node_type": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e927cd90fed6dfbb83b34c2851b072fb9cd1b3ca035a0d0179a86cedb0bd04d1"}, "2": {"node_id": "a403ee8d-2a0a-44ea-ad33-c4ae270ba46b", "node_type": null, "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c815c70e48558d0dd4756619d8d02761794aa28cc0a1a2359b351f0723c1366b"}}, "hash": "42036680d52b90ce2eaca45b767e4b9b0f051623c05e8e0a6e32ac822edda2fd", "text": "obesity is caused by lack of a blood-borne factor. 2The word is derived from the Greek leptos, meaning thin.\n3The terminology can be confusing. \u2018Hunger\u2019 obviously refers to the \ndesire to eat; \u2018satiation\u2019 is the feeling that you have eaten enough in the \ncourse of a meal. \u2018Satiety\u2019 refers to the feeling after a meal that you \ndon\u2019t yet need another.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6887, "end_char_idx": 7717, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3d0932a0-96f3-492c-809e-f708f224120f": {"__data__": {"id_": "3d0932a0-96f3-492c-809e-f708f224120f", "embedding": null, "metadata": {"page_label": "430", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fde39d50-f267-459e-9439-1deed63cd890", "node_type": null, "metadata": {"page_label": "430", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "74e10f82af181a66d29eb2f16c12e99420795d25a9575f00e26089ad338f9e51"}}, "hash": "74e10f82af181a66d29eb2f16c12e99420795d25a9575f00e26089ad338f9e51", "text": "33 SECTION \u20033 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n424\nChange in body mass (kg)\nMonths of treatment-182\n-20\n-6\n-10\n-14\n02468 10 12Weight (kg)\nAge (years)Start of leptin\ntherapy\n0100\n90\n8070\n60\n50403020\n10\n012345678 91 02nd percentile50th percentile98th percentile\nTotal\nweightFat\nmassLean\nmassWeight (kg)\nMonths of treatment60100\n95\n90\n85\n80757065\n0123456789 10 11\n12A B\nC\nFig. 33.1 The effect of recombinant leptin on body weight in a 9-year-old severely obese child with endogenous leptin \ndeficiency because of a frame shift mutation in the leptin gene. Although of normal birth weight, the child began gaining weight at 4 \nmonths and was constantly demanding food. Prior to treatment, the child weighed 94.4 kg. Weight loss began after 2 weeks\u2019 treatment, \nand her eating pattern returned to normal. She had lost 15.6 kg of body fat after 1 year of treatment. (Data and figure adapted from \nFarooqi et al., 1999.)\nTable 33.1 Some peripheral hormones that regulate eating behaviour\nHormone Source Stimulus to release Target Effect\nCCK GI tract During feeding or just before Vagal afferents Limits size of meal\nAmylin, insulin, \nglucagonPancreas During feeding or just before Vagal afferents Limits size of meal\nPYY3\u201336 Ileum, colon After feeding Brain stem, hypothalamus Postpones need for next meal\nGLP-1 Stomach After feeding Brain stem, hypothalamus Postpones need for next meal\nOxyntomodulin Stomach After feeding Brain stem, hypothalamus Postpones need for next meal\nLeptin Adipose tissue Adiposity \u2018status\u2019 Brain stem, arcuate nucleus Longer-term regulation of food intake\nGhrelin Stomach Hunger, feeding Vagus, hypothalamusIncreases food intake by increasing size and number of meals\nNesfatin 1Hypothalamus, pancreas, adipose tissue and GI tractFood intake Orexigenic NPY neurones. Decreases appetite\nCCK, cholecystokinin; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; NPY, neuropeptide Y; PYY3\u201336, peptide YY.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2417, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d4c9dc79-f587-4af8-a4b4-b5651652be89": {"__data__": {"id_": "d4c9dc79-f587-4af8-a4b4-b5651652be89", "embedding": null, "metadata": {"page_label": "431", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c721cb69-d1e4-48d5-ae01-1d121671dd89", "node_type": null, "metadata": {"page_label": "431", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f10ac3e10aece985efbf1be94e2703d4aab9b9140ab70a5275d93eb1f58b5204"}, "3": {"node_id": "50e21c4d-6bd0-47ed-b307-bf7455a14863", "node_type": null, "metadata": {"page_label": "431", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cfccc409afe5dae635e6b51358a31b238965ec4a8a009c5aa2e6935026178c10"}}, "hash": "e4976b21dde4814d562985201f97680ecb17531d3cdd74efd096125715c4ca47", "text": "33 ObESITY\n425MSH\nPYY3\u201336\nLeptin\nGLP-1\nInsulin\n5-HTGhrelin\nOrexin\nCCK\nAmylin\nLeptin\nGLP-1\nInsulin\n5-HTOpioids\nNPY\nOrexinBrain stem\nMotor nuclei\nand other output\nIncrease feeding\nDecrease energy\nexpenditure\nDecrease feeding\nIncrease energy\nexpenditureGI tract\nm e t s n i a r B y r e h p i r e PVagal afferents\nAdipose\ntissueLeptinNPY/AgRP\nPOMC/CARTOxyntomodulin\nGLP-1PYY\n3\u201336\nCCKAmylinInsulinGlucagonGhrelin\nArcuate nucleus\nFig. 33.2 A simplified representation of the role of peripheral hormones and other mediators in the regulation of energy balance \nand fat stores. The primary level of hypothalamic control is vested in two groups of neurons, with opposing actions, in the arcuate nucleus \n(ARC). In one group, the peptides neuropeptide Y (NPY) and agouti-related peptide (AgRP) are co-localised; the other contains the \npolypeptides prepro-opiomelanocortin (POMC) and cocaine- and amphetamine-related transcript (CART), which release \u03b1 melanocyte-\nstimulating hormone (MSH). Blood-borne hormones arising from the GI tract or adipose tissue are sensed by receptors on vagal and other afferents and are relayed through the nucleus tractus solitarius to modify the activity of these neuronal circuits. The influence of hormones on each neuronal group is indicated. Some (e.g. leptin) arise from the peripheral blood and influence the ARC neurons directly or indirectly through neuronal signals; while others (e.g. 5-hydroxytryptamine [5-HT], orexin) originate within the central nervous system itself. Activation of the NPY/AgRP group by, for example, a fall in leptin or an increase in ghrelin levels results in increased food intake and decreased energy expenditure. In the POMC/CART group of neurons, increased leptin or other hormone levels triggered by overfeeding produces a predominately inhibitory effect on feeding behaviour. Several other hormones such as cholecystokinin (CCK) and amylin also alter the properties of the ARC neurons although the mechanism is not clear. The recently discovered factor, nesfatin 1, is not shown. GLP-1, \nglucagon-like peptide-1; PYY\n3-36, peptide YY. (Modified from Adan et al., 2008.)\n4So called because the administration of cocaine or amphetamine \nstimulates the transcription of this gene. Its expression in the \nhypothalamus is related to nutritional status implicating it in the \ncontrol of appetite. Its receptor is unknown but it probably modulates the action of NPY and leptin.olfactory information within the CNS is complex. Many \nsites are involved in different aspects of the process and \nsome 50 hormones and neurotransmitters are implicated. \nThe account we present here is therefore necessarily an oversimplification: the Further Reading list should be \nconsulted for a more complete picture.\nAs early lesioning studies predicted, the hypothalamus \nis the main brain centre that regulates appetite, feeding behaviour and energy status, although other sites in the \nbrain such as the nucleus accumbens (NAc), the amygdala and, especially, the nucleus tractus solitarius (NTS) in the medulla, are also crucial. Within the hypothalamus, the \narcuate nucleus (ARC), situated in the floor of the third \nventricle, is a key site. It receives afferent signals originating from the GI tract and contains receptors for leptin and \nother significant hormones. It also has", "start_char_idx": 0, "end_char_idx": 3325, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "50e21c4d-6bd0-47ed-b307-bf7455a14863": {"__data__": {"id_": "50e21c4d-6bd0-47ed-b307-bf7455a14863", "embedding": null, "metadata": {"page_label": "431", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c721cb69-d1e4-48d5-ae01-1d121671dd89", "node_type": null, "metadata": {"page_label": "431", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f10ac3e10aece985efbf1be94e2703d4aab9b9140ab70a5275d93eb1f58b5204"}, "2": {"node_id": "d4c9dc79-f587-4af8-a4b4-b5651652be89", "node_type": null, "metadata": {"page_label": "431", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4976b21dde4814d562985201f97680ecb17531d3cdd74efd096125715c4ca47"}}, "hash": "cfccc409afe5dae635e6b51358a31b238965ec4a8a009c5aa2e6935026178c10", "text": "and contains receptors for leptin and \nother significant hormones. It also has extensive reciprocal \nconnections with other parts of the hypothalamus involved in monitoring energy status, in particular the paraventricular nuclei and the ventromedial hypothalamus. Fig. 33.2 sum -\nmarises in a simplified fashion some of the interactions that occur in the ARC.\nWithin the ARC are two groups of functionally distinct \nneurons that exert opposite effects on appetite. One group, termed anorexigenic (appetite-suppressing), secrete pro-opiomelanocortin (POMC)-derived peptides (such as \n\u03b1 melanocyte-stimulating hormone; \u03b1-MSH) or cocaine- and \namphetamine-regulated transcript (CART\n4)-derived peptides. \nThe other group, termed orexigenic (appetite-promoting) mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3247, "end_char_idx": 4484, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6e061338-7bba-40bb-b9eb-56e63dadbad1": {"__data__": {"id_": "6e061338-7bba-40bb-b9eb-56e63dadbad1", "embedding": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b08c4506-d2c5-4f4c-957a-55d28660b9f5", "node_type": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "198eeada6a07bcd0c108eb789f18430d8dd026be647deee43c4863440ce01cc0"}, "3": {"node_id": "614157a1-f7f1-4575-9470-f30c43733680", "node_type": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "940a5744bacc05f4a857debc4b61d9407de34d5827e4153e9aaa3f994e2dabe2"}}, "hash": "6ad3fea5f9a66504b8a16bf2b9c645430f527b3ff08d710263ad8dc0a11de627", "text": "33 SECTION \u20033 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n426CONTROL OF ENERGY EXPENDITURE\nBalancing food intake is the energy expenditure required \nto maintain metabolism, physical activity and thermogenesis \n(heat production). The metabolic aspects include, among \nother things, cardiorespiratory work and the energy required by a multitude of enzymes. Physical activity increases all \nthese, as well as increasing energy consumption by skeletal \nmuscles. Exposure to cold also stimulates thermogenesis, and the reverse is also true. The, often dramatic (20%\u201340% \nincrease), thermogenic effect of feeding itself may provide \na partial protection against developing obesity.\nThe sympathetic nervous system (sometimes in concert \nwith thyroid hormone) plays a significant part in energy \nregulation in cardiovascular and skeletal muscle function \nduring physical activity, as well as the thermogenic response of adipose tissue and the response to cold. Both \u2018white\u2019 \nand (especially) \u2018brown\u2019 fat cells (the colour is caused by \nthe high density of mitochondria) play a major role in thermogenesis. Brown fat, which is densely innervated by \nthe sympathetic nervous system, is abundant in rodents \nand human infants, although in human adults these cells are generally to be found more interspersed amongst white \nfat cells. Because of their abundant mitochondria, they are \nremarkable heat generators. The basis for this, as determined in mice, is the presence of mitochondrial uncoupling proteins \n(UCP). Three isoforms, UCP-1, -2 and -3, are known and have different distributions, although all are found in brown fat. These proteins \u2018uncouple\u2019 oxidative phosphorylation, \nso that mitochondria dissipate most energy as heat rather \nthan producing ATP. As one might anticipate, exposure to cold or leptin administration increases both the activity and (after prolonged stimulation) the amount of UCP-1 in \nbrown fat. Noradrenaline, acting on \u03b2 adrenoceptors (mainly \n\u03b2\n3) in brown fat, increases the activity of the peroxisome \nproliferator-activated receptor- \u03b3 (PPAR \u03b3) transcription factor, \nwhich, in turn, activates the gene for UCP-1. The expression \nof \u03b23 adrenoceptors is decreased in genetically obese mice.\nTHE\u2003PATHOPHYSIOLOGY \u2003OF \u2003HUMAN \u2003\nOBESITY\nIn most adults, body fat and body weight remain more or less constant over many years, even decades, in the face \nof very large variations in food intake and energy expendi -\nture amounting to about a million calories per year. The \nsteady-state body weight and BMI of an individual, as \nexplained, depends upon the integration of multiple interact -\ning regulatory pathways. How, then, does obesity occur? \nWhy is it so difficult for the obese to lose weight and \nmaintain the lower weight?\nThe main determinant is manifestly a disturbance of the \nhomeostatic mechanisms that control energy balance, and \ngenetic factors that underlie this disturbance. Other factors, \nsuch as food availability and lack of physical activity, also \ncontribute. Additionally, of course, there are overlaying social, cultural and psychological aspects. We discuss here \nthe physiological and genetic mechanisms; the role of social, \ncultural and psychological aspects we will leave (with a profound sigh of relief) to the psychosociologists!\nFOOD \u2003INTAKE \u2003AND \u2003OBESITY\nAs Spiegelman and Flier (1996) point out, \u2018one need not be a rocket scientist to notice that increased food intake neurons, secrete neuropeptide Y (NPY) or agouti-related peptide (AgRP). As these groups of neurons have opposing \nactions, energy homeostasis depends, in the first instance, \non the", "start_char_idx": 0, "end_char_idx": 3603, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "614157a1-f7f1-4575-9470-f30c43733680": {"__data__": {"id_": "614157a1-f7f1-4575-9470-f30c43733680", "embedding": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b08c4506-d2c5-4f4c-957a-55d28660b9f5", "node_type": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "198eeada6a07bcd0c108eb789f18430d8dd026be647deee43c4863440ce01cc0"}, "2": {"node_id": "6e061338-7bba-40bb-b9eb-56e63dadbad1", "node_type": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6ad3fea5f9a66504b8a16bf2b9c645430f527b3ff08d710263ad8dc0a11de627"}, "3": {"node_id": "32b3de1f-95ad-47c7-8973-fd4b8ffaf6d3", "node_type": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2702557972a65377aa025c4931af1a1f794bd6491178ba125c62e5cc83aca4da"}}, "hash": "940a5744bacc05f4a857debc4b61d9407de34d5827e4153e9aaa3f994e2dabe2", "text": "opposing \nactions, energy homeostasis depends, in the first instance, \non the balance between these actions, the final effects of which are transduced by the brain stem motor system and \nchange feeding behaviour.\nNeurotransmitters such as GABA, noradrenaline, \n5-hydroxytryptamine (5-HT) and dopamine also play a role in the modulation of satiety signals alongside the peptide \ntransmitters. Noradrenaline is co-localised with NPY in some neurons and greatly potentiates its hyperphagic action. \nDeficit of dopamine impairs feeding behaviour, as do \nagonists at the 5-HT\n2C receptor; antagonists at this receptor \nhave the reverse effect. GABA is released from AgRP \nneurons and is modulated by nutritional status as well as \nby hormones such as leptin.\nMany neural signals arising from the GI tract are inte -\ngrated, and relayed on to the hypothalamus, by the NTS in the medulla. Some of these signals, including those of gustatory, olfactory, mechanical and viscerosensory signals, \narise from vagal and other spinal afferents originating in \nthe GI tract or liver. Endocrine signals have more complex signalling pathways. For example, cholecystokinin (CCK) is secreted by the duodenum in response to the process of \neating and digestion of (especially fatty) foodstuffs. CCK \nacts locally on CCK\nA receptors in the GI tract to stimulate \nvagal afferents and also acts on CCK B receptors in the brain \nto function as a satiety factor.\nGhrelin, the only hormone known to increase appetite, \nstimulates growth hormone release (Ch. 34) and has a direct action on neurons in the ARC to modify feeding behaviour. \nBlood ghrelin levels normally fall after eating but not in \nobese individuals (English et al., 2002). Interestingly, poly -\nmorphisms in the ghrelin gene may be important in the pathogenesis of the Prader\u2013Willi syndrome, a rare genetic \nchildhood disorder that predisposes to life-threatening obesity.\nLeptin also targets these neurons in the ARC. Falling \nleptin levels activate the orexigenic neurons, resulting in increased food intake and synthesis and storage of fat \n(anabolism), as well as decreased energy expenditure. \nConversely, rising leptin levels activate the second group of neurons, producing the opposite anorexigenic and cata -\nbolic effect.\nInputs from other parts of the CNS also influence feeding \nbehaviour. Of importance to us is the input from the NAc. This centre seems to regulate those aspects of eating that \nare driven by pleasure or reward \u2013 the so-called \u2018hedonic\u2019 \naspects of eating (see also Ch. 50). The endocannabinoid system (Ch. 20) is important in this response. The hypo -\nthalamus contains large amounts of 2-arachidonyl glycerol and anandamide as well as the CB\n1 receptor. Administration \nof endogenous or exogenous (e.g. \u03949-THC) cannabinoids \nprovokes a powerful feeding response.5 This system in turn \nmay be modulated by \u2018stress\u2019 and other factors in the environment.\nMany other hormones such as prolactin, androgens and \noestrogens can modulate the activity of the hypothalamic control centres, and the situation is complex. The reader \nis referred to Cornejo et al. (2016) for a summary of recent \nthinking in this area.\n5This effect is responsible for the \u2018munchies\u2019, a common side effect of \nsmoking cannabis.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3537, "end_char_idx": 7032, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "32b3de1f-95ad-47c7-8973-fd4b8ffaf6d3": {"__data__": {"id_": "32b3de1f-95ad-47c7-8973-fd4b8ffaf6d3", "embedding": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b08c4506-d2c5-4f4c-957a-55d28660b9f5", "node_type": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "198eeada6a07bcd0c108eb789f18430d8dd026be647deee43c4863440ce01cc0"}, "2": {"node_id": "614157a1-f7f1-4575-9470-f30c43733680", "node_type": null, "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "940a5744bacc05f4a857debc4b61d9407de34d5827e4153e9aaa3f994e2dabe2"}}, "hash": "2702557972a65377aa025c4931af1a1f794bd6491178ba125c62e5cc83aca4da", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7052, "end_char_idx": 7355, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ac10f0df-8b89-4598-818c-99f758f6683d": {"__data__": {"id_": "ac10f0df-8b89-4598-818c-99f758f6683d", "embedding": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "94eb0f05-74ce-4633-bc7d-555b62a25fdd", "node_type": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "28f00552652b6f2cccc80d9495f7e385a4ad5cb97aa0db5f8b07844435c53db6"}, "3": {"node_id": "f231a0b9-00bf-4a16-bb3a-3d43f09778dd", "node_type": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "225a73cc9909c31fe20fd854b56107819a69f43fddeeab7499bfce437bce4d0b"}}, "hash": "e1a6c59893025d57a3b1f76bc06f4b049c979419c836c25b19454866f00cf7e8", "text": "33 ObESITY\n427fat storage and adjusting energy balance in the obese, \nparticularly if associated with modification of the diet. A \nserendipitous natural population study provides an example. \nMany years ago, a tribe of Pima Indians split into two groups. One group in Mexico continued to live simply at \nsubsistence level, eating frugally and spending most of the \nweek in hard physical labour. They are generally lean and have a low incidence of type 2 diabetes. The other group \nsettled in the United States \u2013 an environment with easy \naccess to calorie-rich food and less need for hard physical \nwork. They are, on average, 57 lb (26 kg) heavier than the \nMexican group and have a high incidence of early-onset type 2 diabetes.\nOBESITY \u2003AS \u2003A \u2003DISORDER \u2003OF \u2003THE \u2003HOMEOSTATIC \u2003\nCONTROL \u2003OF \u2003ENERGY \u2003BALANCE\nBecause the homeostatic control of energy balance is complex, it is not easy to determine exactly what goes wrong \nin obesity.\n6 When the leptin story unfolded, it was thought \nthat alterations in leptin kinetics might provide a simple explanation. There is a considerable inter-individual vari -\nation in sensitivity to leptin, and some individuals seem \nto produce insufficient amounts of this hormone. Paradoxi -\ncally, however, plasma leptin is often higher in obese than non-obese subjects, not lower as might be expected. The reason for this is that resistance to leptin, rather than insuf -\nficient hormone, is more prevalent in obesity. Such resistance could be caused by defects in leptin carriage in the circula -\ntion, transport into the CNS, in leptin receptors in the hypothalamus (as occurs in obese Db/Db mice) or in post-\nreceptor signalling.\nMediators other than leptin are also implicated. For \nexample, tumour necrosis factor (TNF)-\u03b1, a cytokine that can relay information from fat tissue to brain, is increased \nin the adipose tissue of insulin-resistant obese individuals. Reduced insulin sensitivity of muscle and fat also occurs, \nas well as decreased \u03b2\n3-adrenoceptor function in brown \nadipose tissue; alternatively, the uncoupling protein UCP-2 in adipocytes, may be dysfunctional.\nA further suggestion is that alterations in the function \nof specific nuclear receptors, such as PPAR \u03b1, \u03b2 and \u03b3, may \nplay a role in obesity. These receptors regulate gene expres -\nsion of enzymes associated with lipid and glucose \nhomeostasis, and they also promote the formation of adipose \ntissue. PPAR\u03b3 is expressed preferentially in fat cells and \nsynergises with another transcription factor, C/EBP \u03b1, to \nconvert precursor cells to fat cells (see Spiegelman & Flier, \n1996). The gene for UCP in white fat cells also has regulatory \nsites that respond to PPAR \u03b1 and C/EBP \u03b1. Pioglitazone, \nused to treat type 2 diabetes (see Ch. 32), activates PPAR\u03b3 \nand causes weight gain. The pathophysiology of obesity could involve disturbance(s) in any of the multitude of \nother factors involved in energy balance.\nGENETIC \u2003FACTORS \u2003AND \u2003OBESITY\nAnalyses of large-scale studies of over 100,000 human monozygotic and dizygotic twin pairs indicated that \n50%\u201390% of the variance of BMI can be attributed to genetic tends to be associated with obesity\u2019. A typical obese subject \nwill usually gain 20 kg over a decade or so. This means \nthat there has been a daily excess of energy input over \nenergy requirement of 30\u201340 kcal initially (i.e. 1.5%\u20132%), \nincreasing gradually to maintain the increased body weight.\nThe type of food eaten,", "start_char_idx": 0, "end_char_idx": 3452, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f231a0b9-00bf-4a16-bb3a-3d43f09778dd": {"__data__": {"id_": "f231a0b9-00bf-4a16-bb3a-3d43f09778dd", "embedding": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "94eb0f05-74ce-4633-bc7d-555b62a25fdd", "node_type": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "28f00552652b6f2cccc80d9495f7e385a4ad5cb97aa0db5f8b07844435c53db6"}, "2": {"node_id": "ac10f0df-8b89-4598-818c-99f758f6683d", "node_type": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e1a6c59893025d57a3b1f76bc06f4b049c979419c836c25b19454866f00cf7e8"}, "3": {"node_id": "fc403662-c0a8-4843-b2c1-ed251cb99157", "node_type": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ade94f6d2f334452d3266e3cae982c804ea4060b0263209b23847e87abfe1f1c"}}, "hash": "225a73cc9909c31fe20fd854b56107819a69f43fddeeab7499bfce437bce4d0b", "text": "gradually to maintain the increased body weight.\nThe type of food eaten, as well as the quantity, can disturb \nenergy homeostasis. Fat is an energy-dense foodstuff, and \nit may be that the satiety mechanisms regulating appetite, which react rapidly to carbohydrate and protein, react too \nslowly to stop an individual consuming excess fat.\nHowever, when obese individuals reduce their calorie \nintake as part of a diet regime, they shift into negative energy balance. When they lose weight, the resting metabolic rate \ndecreases, and there is a concomitant reduction in energy expenditure. Thus an individual who was previously obese and is now of normal weight generally needs fewer calories \nto maintain that weight than an individual who has never \nbeen obese. The decrease in energy expenditure appears to be largely caused by an alteration in the conversion \nefficiency of chemical energy to mechanical work in the \nskeletal muscles. This adaptation to the caloric reduction contributes to the difficulty of maintaining weight loss \nby diet.\nPHYSICAL \u2003EXERCISE \u2003AND \u2003OBESITY\nIt used to be said that the only exercise effective in combating obesity was pushing one\u2019s chair back from the table. It is \nnow recognised that physical activity \u2013 i.e. increased energy \nexpenditure \u2013 has a much more positive role in reducing Energy balance \nEnergy balance depends on food intake, energy storage \nin fat and energy expenditure. In most individuals the process is tightly regulated by a homeostatic system that \nintegrates inputs from a number of internal sensors and \nexternal factors. Important components of the system include the following:\n\u2022\tHormones \tthat \tsignal \tthe \tstatus \tof \tfat \tstores \t(e.g. \t\nleptin). Increasing fat storage promotes leptin release from adipocytes.\n\u2022\tHormones \treleased \tfrom \tthe \tgut \tduring \tfeeding \tthat \t\nconvey sensations of hunger (e.g. ghrelin), satiety (e.g. cholecystokinin [CCK]) or satiation (e.g. peptide YY [PYY\n3\u201336]).\n\u2022\tThis\thormonal \tinformation \ttogether \twith \tneural, \t\ngustatory, olfactory and viscerosensory input is integrated in the hypothalamus. The arcuate nucleus is a key site.\n\u2022\tTwo\tgroups \tof \topposing \tneurons \tin \tthe \tarcuate \t\nnucleus sense hormonal and other signals. Those secreting pro-opiomelanocortin (POMC)/ cocaine- and amphetamine-regulated transcript (CART) products \npromote feeding while those secreting neuropeptide Y \n(NPY)/ agouti-related peptide (AgRP) inhibit feeding. Many other central nervous system neurotransmitters (e.g. endocannabinoids) are involved.\nThe net output from this process is relayed to other \nsites in the brain stem motor nuclei that control feeding \nbehaviour.\n6Even the type of gut flora has come under scrutiny as a potential \ndetermining factor in obesity (see review by Duranti et al., 2017). The \nnotion that this could be supplemented with \u2018probiotics\u2019 to modify the \nrisk is attracting attention. \u2018Holy shit!\u2019 was the title of one magazine \narticle on the subject (The Economist, 12 November 2009).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3391, "end_char_idx": 6849, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fc403662-c0a8-4843-b2c1-ed251cb99157": {"__data__": {"id_": "fc403662-c0a8-4843-b2c1-ed251cb99157", "embedding": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "94eb0f05-74ce-4633-bc7d-555b62a25fdd", "node_type": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "28f00552652b6f2cccc80d9495f7e385a4ad5cb97aa0db5f8b07844435c53db6"}, "2": {"node_id": "f231a0b9-00bf-4a16-bb3a-3d43f09778dd", "node_type": null, "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "225a73cc9909c31fe20fd854b56107819a69f43fddeeab7499bfce437bce4d0b"}}, "hash": "ade94f6d2f334452d3266e3cae982c804ea4060b0263209b23847e87abfe1f1c", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6880, "end_char_idx": 6943, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "55a067c0-f5da-4144-8ebe-53f5416917d4": {"__data__": {"id_": "55a067c0-f5da-4144-8ebe-53f5416917d4", "embedding": null, "metadata": {"page_label": "434", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "70d91e22-2a1d-4d6b-8b9b-89bd66b57320", "node_type": null, "metadata": {"page_label": "434", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3d626c74b2713543709404978d2dcb17e77fc6d8de4e591fcba8f1d3274af33c"}, "3": {"node_id": "913a253c-ecd3-408d-8e36-be3ee8b6d7db", "node_type": null, "metadata": {"page_label": "434", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e48ca8fc949233e333d385e68fc34f3b97891ad2d0e82a0807a9a6b6cab5ea74"}}, "hash": "a93f9589b80138efc18747541da20dafc1e958d77afd923bdd5a9e9684e9d4fe", "text": "33 SECTION \u20033 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n428short-term efficacy, leaving surgical techniques (such as \ngastric stapling or bypass) or drug therapy as a viable \nalternative. Bariatric (weight loss) surgery is much more \neffective than currently licensed drugs, and is believed to \nwork chiefly, not by mechanically limiting gastric capacity, \nbut by its effects on gut hormone responses to feeding, \nacting, for example, to produce earlier satiety. This may be construed as indirect evidence for the utility of \npharmacological measures designed to interrupt these \nmessengers.\nThe attempt to control body weight with drugs has had \na long and regrettably, a largely undistinguished\n8 history. \nMany types of \u2018anorectic\u2019 (appetite suppressant) agents \nhave been tested in the past, including the uncoupling agent \ndinitrophenol (DNP), amphetamine and derivatives such \nas dexfenfluramine and fenfluramine. All have been \nwithdrawn from clinical use because of serious adverse effects. DNP, an industrial chemical, is advertised online for slimmers and body-builders as a weight loss and \u2018fat-\nburning agent\u2019, and has caused deaths among those who \nuse it for this purpose. It blocks mitochondrial ATP produc -\ntion, diverting energy metabolism to generate heat instead factors, and suggested a relatively minor role for environ -\nmental influences ( Barsh et al ., 2000). The updated Human \nObesity Gene Map (Rankinen et al., 2006) identified >250 \nquantitative trait loci7 that contribute to obesity in humans. \nThe prevailing view is that susceptibility to obesity is largely \ndetermined genetically, while environmental factors regulate the expression of the disease.\nObesity is conventionally classified as being monogenic, \nsyndromic or common (polygenic), depending upon the \ngenetic background to the disease. As the name implies, monogenic obesity arises through the action of a single gene. \nThe discovery that spontaneous mutations arising in single \ngenes (e.g. the Ob/Ob genotype) produced obese phenotypes \nin mice led to a search for equivalent genes in humans. \nA review (P\u00e9russe et al., 2005) identified over 170 human \nobesity cases that could be traced to single gene mutations in 10 different genes. Mutations in the POMC gene, the gene \nfor FTO gene (fat mass- and obesity-associated gene), the \nleptin gene itself or the gene for its receptor are sometimes the culprits. Melanocortin MC\n4 receptor mutations are the \nmost common (1%\u20136%) in obese patients but there are many \nother potential candidates (e.g. see Barsh et al., 2000).\nPolygenic (common) obesity comprises most of the \ncases of the disease. Here, obesity is usually the result of \ncontributions of many genes, each of which has a small effect \non the overall phenotype. Other genes that may influence obesity include the neurotransmitter receptors involved \nin the central processing of appetite/energy expenditure \n(e.g. the CB\n1, D 2, 5-HT 2C receptors), the \u03b23 adrenoceptor and \nthe glucocorticoid receptor. Decreased function of the \u03b23 \nadrenoceptor gene could be associated with impairment of \nlipolysis in white fat or with thermogenesis in brown fat. \nA mutation of this gene has been found to be associated with abdominal obesity, insulin resistance and early-onset \ntype 2 diabetes in some subjects and a markedly increased \npropensity to gain weight in a separate group of morbidly obese subjects. Alterations in the function of the glucocor-\nticoid receptor could be associated with obesity through \nthe permissive effect of glucocorticoids on several aspects of fat", "start_char_idx": 0, "end_char_idx": 3583, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "913a253c-ecd3-408d-8e36-be3ee8b6d7db": {"__data__": {"id_": "913a253c-ecd3-408d-8e36-be3ee8b6d7db", "embedding": null, "metadata": {"page_label": "434", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "70d91e22-2a1d-4d6b-8b9b-89bd66b57320", "node_type": null, "metadata": {"page_label": "434", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3d626c74b2713543709404978d2dcb17e77fc6d8de4e591fcba8f1d3274af33c"}, "2": {"node_id": "55a067c0-f5da-4144-8ebe-53f5416917d4", "node_type": null, "metadata": {"page_label": "434", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a93f9589b80138efc18747541da20dafc1e958d77afd923bdd5a9e9684e9d4fe"}}, "hash": "e48ca8fc949233e333d385e68fc34f3b97891ad2d0e82a0807a9a6b6cab5ea74", "text": "through \nthe permissive effect of glucocorticoids on several aspects of fat metabolism and energy balance. The significance of polymorphisms in the ghrelin gene has already been \nmentioned.\nIn syndromic obesity, the obesity is associated with a \ndistinctive clinical picture. Prader\u2013Willi syndrome is the most common (at 1 in 15,000\u201325,000 live births) and is \nassociated with defects in gene expression on chromosome 15q. The clinical picture is multifaceted and obesity is only \none component.\nRecently, the interpretation of genetic data in obesity \nhas become even more complicated with the recognition of the importance of epigenetic modification of the genome. \nThe subject cannot be discussed here but is well reviewed \nby Lopomo et al. (2016). Clearly it will be a while before \nwe have a clear appreciation of all these issues.\nPHARMACOLOGICAL \u2003APPROACHES \u2003TO \u2003\nTHE\u2003PROBLEM \u2003OF \u2003OBESITY\nThe first weapons in the fight against obesity are diet and exercise. Unfortunately, these often fail or show only Obesity \n\u2022\tObesity \tis \ta \tmultifactorial \tdisorder \tof \tenergy \tbalance, \t\nin which long-term calorie intake exceeds energy \noutput.\n\u2022\tA\tsubject \twith \ta \tbody \tmass \tindex \t(BMI) \t(W/h2) of \n20\u201325 kg/m2 is considered as having a healthy body \nweight, one with a BMI of 25\u201330 kg/m2 as overweight, \nand one with a BMI >30 kg/m2 as obese.\n\u2022\tObesity \tis \ta \tgrowing \tproblem \tin \tmost \trich \tnations; \tthe \t\nincidence \u2013 at present approximately >30% in the \nUnited States and >20% in Europe \u2013 is increasing.\n\u2022\tA\tBMI\t>30 kg/m2 significantly increases the risk of \ntype 2 diabetes, hypercholesterolaemia, hypertension, ischaemic heart disease, gallstones and some \ncancers.\n\u2022\tThe\tcauses \tof \tobesity \tinclude:\n\u2013 dietary, exercise, social, financial and cultural \nfactors;\n\u2013 genetic susceptibility;\n\u2013 deficiencies in the synthesis or action of leptin or \nother gut hormone signals;\n\u2013 defects in the hypothalamic neuronal systems \nresponding to any of these signals;\n\u2013 defects in the systems controlling energy \nexpenditure (e.g. reduced sympathetic activity), \ndecreased metabolic expenditure of energy or decreased thermogenesis caused by a reduction in \n\u03b2\n3 adrenoceptor-mediated tone and/or dysfunction \nof the proteins that uncouple oxidative \nphosphorylation.\n7In other words, a stretch of DNA which correlates with the \ndevelopment of obesity and which is likely therefore to contain \u2013 or be \nlinked to \u2013 a relevant gene.8As the showman Bynum said: \u2018There\u2019s a sucker born every minute \u2026 \nand one born to take him\u2019 \u2026 thyroxine (to increase metabolic rate, Ch. 35), swallowing parasites (intestinal worms compete for ingested food), \namphetamines (Ch. 59), drugs that cause malabsorption, hence leaking fat per rectum (see later in this chapter) \u2026 really!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3508, "end_char_idx": 6755, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f92a79d5-3013-4d64-906d-327f87223ea6": {"__data__": {"id_": "f92a79d5-3013-4d64-906d-327f87223ea6", "embedding": null, "metadata": {"page_label": "435", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4cca624c-4b7f-4dd6-a411-aa6c86e724a7", "node_type": null, "metadata": {"page_label": "435", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33b7df119b354ef7aa087bf138ffb21cb94917c716c5055204041cfc244c6437"}, "3": {"node_id": "dc9094a5-53f0-4925-8d93-13388b06df39", "node_type": null, "metadata": {"page_label": "435", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d323c0428de00e017d07bfdf6761d78ba341792adce1ec7a41bb376dc630fc9d"}}, "hash": "afd0cc14282e6e97e920601748d99c5039f381814485e9e778d2fce83588a95a", "text": "33 ObESITY\n429POMC levels in the hypothalamus. In clinical trials it \nenhanced weight loss through dieting, but patients regained \nweight after stopping the drug. Qsymia, a mixture of an \nold appetite suppressant drug, phentermine and an \nanticonvulsant, topiramate was approved in the United \nStates in 2012 despite some reservations about cardiovascular \nand other side effects. The drug stimulates the synaptic release of serotonin as well as noradrenaline and dopamine \n(and increases GABA action).\nOther centrally acting drugs that are used in some \ncountries for treating obesity include Contrave, a mixture \nof the opioid-receptor antagonist naltrexone and the \nnoradrenaline\u2013dopamine uptake\u2013reuptake inhibitor, \nbupropion. The cannabinoid pathway was the target of the CB\n1 receptor antagonist rimonabant which was originally \ndeveloped to promote smoking cessation (see Ch. 20). This \ndrug was introduced as an appetite suppressant following \nsome encouraging clinical trials but was eventually with -\ndrawn in the United States in 2008 because of adverse effects \non mood seen in some patients. A similar fate overtook \nanother promising CB 1 antagonist, taranabant.\nORLISTAT\nThe only drug currently (2017) licensed in the United Kingdom for the treatment of obesity is the lipase inhibitor \norlistat, used with concomitant dietary and other therapy \n(e.g. exercise).\nIn the intestine, orlistat reacts with serine residues at the \nactive sites of gastric and pancreatic lipases, irreversibly inhibiting these enzymes and thereby preventing the break -\ndown of dietary fat to fatty acids and glycerol. It therefore \ndecreases absorption (and correspondingly causes faecal \nexcretion) of some 30% of dietary fat. Given in conjunction with a low-calorie diet in obese individuals, it produces a modest but consistent loss of weight compared with \nplacebo-treated control subjects. In a meta-analysis of 11 \nlong-term placebo-controlled trials encompassing more than 6000 patients, orlistat was found to produce a 2.9% greater \nreduction in body weight than in the control group, and \n12% more patients lost 10% or more of their body weight \ncompared with the controls (Padwal et al., 2003).\nOrlistat is also reported to be effective in patients suffering \nfrom type 2 diabetes and other complications of obesity. \nIt reduces leptin levels and blood pressure, protects against \nweight loss-induced changes in biliary secretion, delays gastric emptying and gastric secretion and improves several \nimportant metabolic parameters without interfering with \nthe release or action of thyroid or other important hormones (Curran & Scott, 2004). It does not induce changes in energy \nexpenditure.\nPHARMACOKINETIC ASPECTS AND \nUNWANTED EFFECTS\nVirtually all (97%) of orlistat is excreted in the faeces (83% \nunchanged), with only negligible amounts of the drug or \nits metabolites being absorbed.\nAbdominal cramps, flatus with discharge and faecal \nincontinence can occur, as can intestinal borborygmi (rumbling) and oily spotting. Surprisingly, in view of the \npossibility of these antisocial effects occurring, the drug is well tolerated. Supplementary therapy with fat-soluble \nvitamins may be needed. The absorption of contraceptive \npills and ciclosporin (see Ch. 27) may be decreased. The \nformer is not usually clinically significant but the latter is potentially more serious. Given its good safety record, of ATP and increasing the overall metabolic rate, which \ncan cause life-threatening hyperthermia.\n9\nCENTRALLY \u2003ACTING \u2003APPETITE \u2003SUPPRESSANTS\nThere have been many attempts to use centrally acting", "start_char_idx": 0, "end_char_idx": 3610, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dc9094a5-53f0-4925-8d93-13388b06df39": {"__data__": {"id_": "dc9094a5-53f0-4925-8d93-13388b06df39", "embedding": null, "metadata": {"page_label": "435", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4cca624c-4b7f-4dd6-a411-aa6c86e724a7", "node_type": null, "metadata": {"page_label": "435", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33b7df119b354ef7aa087bf138ffb21cb94917c716c5055204041cfc244c6437"}, "2": {"node_id": "f92a79d5-3013-4d64-906d-327f87223ea6", "node_type": null, "metadata": {"page_label": "435", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "afd0cc14282e6e97e920601748d99c5039f381814485e9e778d2fce83588a95a"}}, "hash": "d323c0428de00e017d07bfdf6761d78ba341792adce1ec7a41bb376dc630fc9d", "text": "\u2003SUPPRESSANTS\nThere have been many attempts to use centrally acting \ndrugs to control appetite and this is an area which is still \nbeing actively exploited by drug hunters. Sibutramine (now \nwithdrawn in most countries because of clinical trial evi -\ndence demonstrating increased cardiovascular risk) inhibits the reuptake of 5-HT and noradrenaline at the hypothalamic \nsites that regulate food intake.\n10 Its main effects are to reduce \nfood intake and cause dose-dependent weight loss (Fig. \n33.3). It enhanced satiety and was reported to produce a \nreduction in waist circumference, a decrease in plasma triglycerides and very-low-density lipoproteins, but an \nincrease in high-density lipoproteins. Like many similar \ndrug regimes, sibutramine was much more effective when \ncombined with lifestyle modification (Wadden et al., 2005).\nHowever, other serotoninergic drugs have shown promise. \nLorcaserin, a 5-HT 2C receptor agonist (see Chs 16 and 38), \nwas approved in the United States in 2012 for uses as an \nappetite suppressant in certain patients. It acts by increasing Weeks0\n2\n468\n10121416Weight loss (kg)\n0361 01 84 05 2\nCombined therapy Lifestyle modification\naloneSibutramine+ brief therapySibutramine alone\nFig. 33.3 The effect of treatment with the centrally acting \nappetite suppressant, sibutramine, alone or in combination \nwith lifestyle modification. In this study, 224 obese patients were given sibutramine alone, lifestyle modification counselling alone or sibutramine together with a \u2018brief\u2019 or more extensive programme of lifestyle counselling. The Y axis shows the weight loss in kg ( \u00b1 standard error) over time (X axis). It is evident that \nsibutramine is far more effective as a weight-loss therapy when combined with lifestyle changes. This is a common experience when treating obesity. Note: Sibutramine has been withdrawn because of adverse cardiovascular side effects. (Redrawn from \nWadden et al., 2005.)\n9DNP is reported to have been given to Russian soldiers in the Second \nWorld War, to keep them warm.\n10Many antidepressant drugs act by the same mechanism (see Ch. 48), \nand also cause weight loss by reducing appetite. However, sibutramine \ndoes not have antidepressant properties. Furthermore, depressed \npatients are often obese, and antidepressant drugs are used to treat both \nconditions (see Appolinario et al., 2004).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3543, "end_char_idx": 6389, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "eac69758-e61c-4ac2-aff6-a63239bd31a4": {"__data__": {"id_": "eac69758-e61c-4ac2-aff6-a63239bd31a4", "embedding": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ce50f95-9cc9-43a9-a00a-a8608ae5b687", "node_type": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33ee8a7d6e316047d0d42a07f1f90b2bdbcc816d05d42d0543a1ed1e7a1aae43"}, "3": {"node_id": "62ee83b0-a634-4eb8-a607-2e3671abad21", "node_type": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3242827da49dcd051928905cbed13259c1004587868f180baaa01b8a8d2ec449"}}, "hash": "133227267ae5caa21439491436468f49844c4163f330610f38c1e07f0f026216", "text": "33 SECTION \u20033 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n430(Ch. 32), also has anorexic actions (Astrup et al., 2009) and \nis approved in the United States for obesity treatment (by \ninjection only). Other peptides trialled include amylin, \noxyntomodulin and leptin analogues and NPY antagonists. \nEven vaccination against ghrelin or somatostatin has been \nmooted as a therapeutic strategy (Bhat et al., 2017).\nOther strategies aim to alter the CNS levels of neuro -\ntransmitters such as NPY or melanocortins, which transduce \nhormonal signals regulating appetite (Halford, 2006). The \ntractability of the MC 4 receptor itself as a drug target, \ncoupled with the observation that defects in MC 4 signalling \nare prevalent in obesity, has attracted much interest from \nthe pharmaceutical industry.\nGiven the importance of the sympathetic nervous system \nin the control of energy regulation, one might predict that \u03b2\n3-adrenoceptor agonists might be useful therapeutics. \nDisappointingly, whilst having been extensively researched (see Arch, 2008), they have so far failed to yield an acceptable \ntherapeutic lead. In contrast, the serotonergic system remains squarely in the frame for the development of further anti-\nobesity agents (Oh et al., 2016).\nKang and Park (2012) highlight the value of combination \ntherapies targeting complex pathways involved in appetite \nregulation. Most drug therapies are much more effective \nwhen used in conjunction with lifestyle and other behav -\nioural modification. The importance of this joint approach \nis reviewed by Vetter et al. (2010).\nIn summary, at the time of writing, it is disappointing \nto report that the number of drugs licensed for use in obesity, \nat least in the United Kingdom, seems to be inversely \nproportional to the growing magnitude of the associated health problem. In some other countries, such as the United \nStates, the situation is slightly better (Daneschvar et al., \n2016) although there has been some debate about how useful this latest group of drugs will really prove to be (Kim, \n2016). All in all, it is depressing that despite all the ground-\nbreaking work on the neuroendocrine control of feeding and body weight, so few really novel drugs have found \ntheir way on to the market. The lack of sustained success \nwith pharmacological therapies has led to the emergence of bariatric surgery as a more promising long-term option \nfor reducing complications such as hypertension and \ndiabetes mellitus in patients with severe obesity.orlistat has recently been licensed for inclusion in some over-the-counter medicines for weight loss.\nClinical uses of anti-obesity drugs \n\u2022\tThe\tmain \ttreatment \tof \tobesity \tis \ta \tsuitable \tdiet \tand \t\nincreased exercise.\n\u2022\tOrlistat, which causes fat malabsorption, is used \ntogether with dietary restriction in obese individuals, \nand also in overweight patients who have additional \ncardiovascular risk factors (e.g. diabetes mellitus, hypertension).\n\u2013 Orlistat therapy should be stopped after 12 weeks if \nthe patient has not been able to lose at least 5% of their body weight from the time of drug initiation.\n\u2022\tMany\tcentrally \tacting \tappetite \tsuppressants \t(e.g. \t\nfenfluramine, sibutramine) have been withdrawn because of addiction, pulmonary hypertension or other serious adverse effects.\n\u2022\tGastrointestinal \t(\u2018bariatric\u2019) \tsurgery \tfor \tobesity \t\ninfluences incretin secretion, and is effective in severe obesity.\nNEW \u2003APPROACHES \u2003TO \u2003\u2003\nOBESITY \u2003THERAPY\nAs might be imagined,", "start_char_idx": 0, "end_char_idx": 3495, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "62ee83b0-a634-4eb8-a607-2e3671abad21": {"__data__": {"id_": "62ee83b0-a634-4eb8-a607-2e3671abad21", "embedding": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ce50f95-9cc9-43a9-a00a-a8608ae5b687", "node_type": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33ee8a7d6e316047d0d42a07f1f90b2bdbcc816d05d42d0543a1ed1e7a1aae43"}, "2": {"node_id": "eac69758-e61c-4ac2-aff6-a63239bd31a4", "node_type": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "133227267ae5caa21439491436468f49844c4163f330610f38c1e07f0f026216"}, "3": {"node_id": "56fb8b77-5304-4f54-bf73-554e8ca81b9e", "node_type": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2b2756abc87c28c5b35e690007207d63736ead95d64a640f5ab0d36597ce41b8"}}, "hash": "3242827da49dcd051928905cbed13259c1004587868f180baaa01b8a8d2ec449", "text": "\u2003\u2003\nOBESITY \u2003THERAPY\nAs might be imagined, the quest for further effective anti-\nobesity agents is the subject of prodigious efforts by the \npharmaceutical industry.\nRare cases of leptin deficiency in patients have been \nsuccessfully treated by long-term treatment with the hormone, but this is unlikely to be of more than limited \nuse in the future. Many other approaches are being piloted (see Kang & Park, 2012). Some aim to exploit the action or \nproduction of neuroendocrine satiety signals such as CCK to produce appetite suppression. Many of these GI satiety hormones produce such effects when given systemically to humans or rodents, although these are not always useful; \nfor example, CCK reduces meal size but increases meal \nfrequency (West et al., 1984). Glucagon-like peptides such \nas liraglutide, which is used for treating type 2 diabetes \nREFERENCES \u2003AND \u2003FURTHER \u2003READING\nBody weight regulation and obesity\nAdan, R.A., Vanderschuren, L.J., la Fleur, S.E., 2008. Anti-obesity drugs \nand neural circuits of feeding. Trends Pharmacol. Sci. 29, 208\u2013217. \n(Very accessible overview of the area. Recommended)\nAhima, R.S., Osei, S., 2001. Molecular regulation of eating behaviour: \nnew insights and prospects for future strategies. Trends Mol. \nMed. 7, 205\u2013213. (Praiseworthy short review; excellent figures and useful \ntables of the mediators involved in stimulation and inhibition of feeding behaviour)\nBarsh, G.S., Farooqi, I.S., O\u2019Rahilly, S., 2000. Genetics of body-weight \nregulation. Nature 404, 644\u2013651.\nColditz, G.A., Willett, W.C., Rotnitzky, A., Manson, J.E., 1995. Weight \ngain as a risk factor for clinical diabetes mellitus in women. Ann. Intern. Med. 122, 481\u2013486.\nCornejo, M.P., Hentges, S.T., Maliqueo, M., Coirini, H., Becu-Villalobos, \nD., Elias, C.F., 2016. Neuroendocrine regulation of metabolism. J. Neuroendocrinol. 28, 1\u201312. (A readable account of the latest developments in the field of neuroendocrine control of apetite and feeding. Covers some \nmaterial not included here. Recommended)\nDuranti, S., Ferrario, C., van Sinderen, D., Ventura, M., Turroni, F., \n2017. Obesity and microbiota: an example of an intricate relationship. Genes Nutr. 12 (18). (Review role of gut bacteria in obesity)English, P.J., Ghatei, M.A., Malik, I.A., et al., 2002. Food fails to \nsuppress ghrelin levels in obese humans. J. Clin. Endocrinol. Metab. \n87, 2984\u20132987.\nFarooqi, I.S., Jebb, S.A., Langmack, G., et al., 1999. Effects of \nrecombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879\u2013884. (A classic clinical paper on the \nrole of leptin in the control of feeding behaviour and weight control)\nKennedy, G.C., 1953. The role of depot fat in the hypothalamic control \nof food intake in the rat. Proc. R. Soc. Lond. B. Biol Sci 140, 578\u2013592. (The paper that put forward the proposal, based on experiments on rats, that \nthere was a hypothalamus-based homeostatic mechanism for controlling \nbody fat)\nKopelman, P.G., 2000. Obesity as a medical problem. Nature 404, \n635\u2013643.\nP\u00e9russe, C., Rankinen, T., Zuberi, A., et ", "start_char_idx": 3459, "end_char_idx": 6544, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "56fb8b77-5304-4f54-bf73-554e8ca81b9e": {"__data__": {"id_": "56fb8b77-5304-4f54-bf73-554e8ca81b9e", "embedding": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ce50f95-9cc9-43a9-a00a-a8608ae5b687", "node_type": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33ee8a7d6e316047d0d42a07f1f90b2bdbcc816d05d42d0543a1ed1e7a1aae43"}, "2": {"node_id": "62ee83b0-a634-4eb8-a607-2e3671abad21", "node_type": null, "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3242827da49dcd051928905cbed13259c1004587868f180baaa01b8a8d2ec449"}}, "hash": "2b2756abc87c28c5b35e690007207d63736ead95d64a640f5ab0d36597ce41b8", "text": "C., Rankinen, T., Zuberi, A., et al., 2005. The human obesity \ngene map: the 2004 update. Obes. Res. 13, 381\u2013490. (Detailed review of \nthe genes, markers and chromosomal regions that have been shown to be \nassociated with human obesity)\nLopomo, A., Burgio, E., Migliore, L., 2016. Epigenetics of obesity. Prog. \nMol. Biol. Transl. Sci. 140, 151\u2013184.\nMcKinsey Global Institute, 2014. Overcoming obesity: an initial \neconomic analysis, p. 120.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6548, "end_char_idx": 7469, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ec4215cf-706c-452d-b9d7-6daa4f4ca5c2": {"__data__": {"id_": "ec4215cf-706c-452d-b9d7-6daa4f4ca5c2", "embedding": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "442fa97b-11ef-445c-9fe7-9abf8218cbd3", "node_type": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f6c37bcfc4053398c62a7e83bdca981ef3399152467fdb2b7cf80676b2032e8c"}, "3": {"node_id": "a2b98e81-c227-4d70-a51d-13be4ddd8cb5", "node_type": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b78af79c80dca67f7077f21a88ea0a60369b2cbbfdbd2296d5971df952f0e46f"}}, "hash": "5b227ba0b2c8068d6a364f63eebd60b8f0bcb8f263a2bbef90084fc7daa8f65d", "text": "33 ObESITY\n431Daneschvar, H.L., Aronson, M.D., Smetana, G.W., 2016. FDA-approved \nanti-obesity drugs in the United States. Am. J. Med. 129 (879), \ne871\u2013e876. (A brief review of five drugs recently approved by the FDA for \nthe treatment of obesity. Covers most of the pharmacology of these drugs. Useful)\nDi Marzo, V., Matias, I., 2005. Endocannabinoid control of food intake \nand energy balance. Nat. Neurosci. 8, 585\u2013589. (A discussion of the putative role of endocannabinoids in this complex physiological mechanism; \nalso considers therapeutic applications arising from this area)\nHalford, J.C., 2006. Obesity drugs in clinical development. Curr. Opin. \nInvest. Drugs 7, 312\u2013318.\nKang, J.G., Park, C.Y., 2012. Anti-obesity drugs: a review about their \neffects and safety. Diabetes Metab. J. 36, 13\u201325. (A brief and easy-to-read \nreview dealing with prospective new drug therapies for obesity)\nKaplan, L.M., 2005. Pharmacological therapies for obesity. \nGastroenterol. Clin. North Am. 34, 91\u2013104.\nKim, S., 2016. Drugs to treat obesity: do they work? Postgrad. Med. J. \n92, 401\u2013406. (A rather critical look at some recent drug candidates which point out that the average weight loss is only some 3%-10% of the starting weight)\nOh, C.M., Park, S., Kim, H., 2016. Serotonin as a new therapeutic target \nfor diabetes mellitus and obesity. Diabetes Metab. J. 40, 89\u201398. (Mainly deals with the potential regulatory role of 5-HT in the peripheral regulation \nof tissue metabolism and its potential for exploitation for future anti-obesity \nagents)\nPadwal, R., Li, S.K., Lau, D.C., 2003. Long-term pharmacotherapy for \noverweight and obesity: a systematic review and meta-analysis of randomized controlled trials. Int. J. Obes. Relat. Metab. Disord. 27, 1437\u20131446.\nWadden, T.A., Berkowitz, R.I., Womble, G., et al., 2005. Randomized \ntrial of lifestyle modification and pharmacotherapy for obesity. N. Engl. J. Med. 353, 2111\u20132120.\nVetter, M.L., Faulconbridge, L.F., Webb, V.L., Wadden, T.A., 2010. \nBehavioral and pharmacologic therapies for obesity. Nat. Rev. Endocrinol. 6, 578\u2013588. (This review stresses the importance of lifestyle \nchanges in combination with drug therapy to combat obesity)\nWest, D.B., Fey, D., Woods, S.C., 1984. Cholecystokinin persistently \nsuppresses meal size but not food intake in free-feeding rats. Am. J. Physiol. 246, R776\u2013R787.\nWilding, J.P.H. (Ed.). 2008. Pharmacotherapy of obesity. In: Parnham, \nM.J., Bruinvels, J. (Eds.), Milestones in Drug Therapy. Birkh\u00e4user, Basle. (This book covers a wide variety of topics connected with obesity and \nits therapy. The contributors are experts in the field)\nUseful web resource\nwww.who.int. (This is the World Health Organization Web page that carries \ndata about the prevalence of \u2018globesity\u2019 and its distribution around the world; \nclick on the \u2018Health Topics\u2019 link and navigate to \u2018Obesity\u2019 in the alphabetical \nlist of topics for further information)\nwww.cdc.gov. (This is the web page for the US Center for Disease Control \nand Prevention. There is a link here to a list of health", "start_char_idx": 0, "end_char_idx": 3057, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a2b98e81-c227-4d70-a51d-13be4ddd8cb5": {"__data__": {"id_": "a2b98e81-c227-4d70-a51d-13be4ddd8cb5", "embedding": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "442fa97b-11ef-445c-9fe7-9abf8218cbd3", "node_type": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f6c37bcfc4053398c62a7e83bdca981ef3399152467fdb2b7cf80676b2032e8c"}, "2": {"node_id": "ec4215cf-706c-452d-b9d7-6daa4f4ca5c2", "node_type": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5b227ba0b2c8068d6a364f63eebd60b8f0bcb8f263a2bbef90084fc7daa8f65d"}, "3": {"node_id": "350a4ddb-72ea-480e-8178-f4a57e8f1293", "node_type": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27336674fddea0ef001ce352f7fd7c0a402f0bc4a0c0741230b7aad6f619f477"}}, "hash": "b78af79c80dca67f7077f21a88ea0a60369b2cbbfdbd2296d5971df952f0e46f", "text": "for Disease Control \nand Prevention. There is a link here to a list of health topics from which you can select \u2018Obesity\u2019)Ramesh, N., Gawli, K., Pasupulleti, V., Unniappan, S., 2017. Metabolic \nand cardiovascular actions of nesfatin-1: implications in health and \ndisease. Curr. Pharm. Des. 23, 1453\u20131464.\nRankinen, T., Zuberi, A., Chagnon, Y.C., et al., 2006. The human obesity \ngene map: the 2005 update. Obesity (Silver Spring) 14, 529\u2013644.\nSchwartz, M.W., Woods, S.C., Porte, D.J., et al., 2000. Central nervous \ncontrol of food intake. Nature 404, 661\u2013671. (Outlines a model that \ndelineates the roles of hormones and neuropeptides in the control of food \nintake. Outstanding diagrams. Note that there are several other excellent \narticles in this Nature Insight supplement on obesity)\nSpiegelman, B.M., Flier, J.S., 1996. Adipogenesis and obesity: rounding \nout the big picture. Cell 87, 377\u2013389.\nSpiegelman, B.M., Flier, J.S., 2001. Obesity regulation and energy \nbalance. Cell 104, 531\u2013543. (Excellent review of the CNS control of energy \nintake/body weight, monogenic obesities, leptin physiology, central neural \ncircuits, the melanocortin pathway, the role of insulin and adaptive thermogenesis)\nWeigle, D.S., 1994. Appetite and the regulation of body composition. \nFASEB J. 8, 302\u2013310.\nZhang, Y., Proenca, R., Maffei, M., et al., 1994. Positional cloning of the \nmouse obese gene and its human homologue. Nature 372, 425\u2013432.\nDrugs in obesity\nAppolinario, J.C., Bueno, J.R., Coutinho, W., 2004. Psychotropic drugs in \nthe treatment of obesity: what promise? CNS Drugs 18, 629\u2013651.\nArch, J.R., 2008. The discovery of drugs for obesity, the metabolic effects \nof leptin and variable receptor pharmacology: perspectives from beta\n3-adrenoceptor agonists. Naunyn Schmiedebergs Arch. Pharmacol. \n378, 225\u2013240. (A comprehensive review that focuses on the quest for \nanti-obesity drugs that act through the \u03b2 3 adrenoceptor. Useful comments \nand insights into the field as a whole)\nAstrup, A., Rossner, S., Van Gaal, L., et al.; NN8022-1807 Study Group, \n2009. Effects of liraglutide in the treatment of obesity: a randomised, \ndouble-blind, placebo-controlled study. Lancet 374, 1606\u20131616.\nBhat, S.P., Sharma, A., 2017. Current drug targets in obesity \npharmacotherapy - A review. Curr. Drug Targets 18, 983\u2013993. (Useful review of diverse agents being trialed as potential anti-obesity agents. \nIncludes hormone and other agents)\nChiesi, M., Huppertz, C., Hofbauer, K.G., 2001. Pharmacotherapy of \nobesity: targets and perspectives. Trends Pharmacol. Sci. 22, 247\u2013254. (Commendable, succinct review; table of the potential targets, and useful, \nsimple figures of the central and peripheral pathways of energy regulation and of the regulation of thermogenesis)\nCollins, P., Williams, G., 2001. Drug treatment of obesity: from past \nfailures to future successes? Br. J. Clin. Pharmacol. 51, 13\u201325. (Overview \u2013 from a clinical perspective \u2013 of currently available anti-obesity \ndrugs and potential future drugs; well written)\nCrowley, V.E.F., Yeo,", "start_char_idx": 2995, "end_char_idx": 6048, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "350a4ddb-72ea-480e-8178-f4a57e8f1293": {"__data__": {"id_": "350a4ddb-72ea-480e-8178-f4a57e8f1293", "embedding": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "442fa97b-11ef-445c-9fe7-9abf8218cbd3", "node_type": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f6c37bcfc4053398c62a7e83bdca981ef3399152467fdb2b7cf80676b2032e8c"}, "2": {"node_id": "a2b98e81-c227-4d70-a51d-13be4ddd8cb5", "node_type": null, "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b78af79c80dca67f7077f21a88ea0a60369b2cbbfdbd2296d5971df952f0e46f"}}, "hash": "27336674fddea0ef001ce352f7fd7c0a402f0bc4a0c0741230b7aad6f619f477", "text": "drugs; well written)\nCrowley, V.E.F., Yeo, G.S.H., O\u2019Rahilly, S., 2002. Obesity therapy: \naltering the energy intake-and-expenditure balance sheet. Nat. Rev. Drug Discov. 1, 276\u2013286. (Review stressing that pharmacological \napproaches to obesity therapy necessitate altering the balance between energy intake and expenditure and/or altering the partitioning of nutrients between \nlean tissue and fat)\nCurran, M.P., Scott, L.J., 2004. Orlistat: a review of its use in the \nmanagement of patients with obesity. Drugs 64, 2845\u20132864.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6069, "end_char_idx": 7076, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a3e3666-65fd-4cb3-a369-06299f527e81": {"__data__": {"id_": "7a3e3666-65fd-4cb3-a369-06299f527e81", "embedding": null, "metadata": {"page_label": "438", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "604a33e6-286b-4d31-99b4-65feefa34286", "node_type": null, "metadata": {"page_label": "438", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f326425a6afefa1fe3702b559d21607c32c4ffb4b7541b6a17fdd6e484c4554"}, "3": {"node_id": "3b45257c-29ab-43d4-ab55-39176d02d2ab", "node_type": null, "metadata": {"page_label": "438", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed185f65922ee7db0189e392073e853d0795d2002b4a455b8904b62a83e8010f"}}, "hash": "e7cae7b28c9e22d2e11de61934459c175f3a3d39cefef4c74e247b27fda71a98", "text": "432\nThe pituitary and the \nadrenal cortex34 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3\nOVERVIEW\nThe pituitary gland and the adrenal cortex release \nhormones that regulate salt and water balance, energy \nexpenditure, growth, sexual behaviour, immune \nfunction and many other vital mechanisms. The commander-in-chief of this impressive hormonal \ncampaign is the hypothalamus and the functioning \nunit is known as the hypothalamo\u2013pituitary\u2013adrenal \n(HPA) axis . In the first part of this chapter we review \nthe control of pituitary function by hypothalamic hormones, and the physiological roles and clinical utilities of both anterior and posterior pituitary hor -\nmones. The second part of the chapter focuses on adrenal hormones and, in particular, the anti-inflammatory effect of glucocorticoids. This should be \nread in conjunction with the relevant sections of \nChapters 3 and 27.\nTHE PITUITARY GLAND\nThe pituitary gland comprises three histologically distinct \nstructures which arise from two separate embryological \nprecursors (Fig. 34.1). The anterior pituitary and the intermedi -\nate lobe are derived from the endoderm of the buccal cavity, \nwhile the posterior pituitary is derived from neural ectoderm. \nThe anterior and posterior lobes receive independent \nneuronal input from the hypothalamus, with which they have an intimate functional relationship.\nTHE ANTERIOR PITUITARY GLAND\nThe anterior pituitary gland ( adenohypophysis) secretes a \nnumber of hormones crucial for normal physiological \nfunction. Within this tissue are specialised cells such as \ncorticotrophs , lactotrophs (mammotrophs ), somatotrophs , thyro -\ntrophs and gonadotrophs , which secrete hormones that regulate \ndifferent endocrine organs of the body (Table 34.1). Inter -\nspersed among these are other cell types, including follicu -\nlostellate cells, which exert a nurturing and regulatory \ninfluence on the hormone-secreting endocrine cells.\nSecretion from the anterior pituitary is largely regulated \nby the release from the hypothalamus of, what are generally \nknown as, \u2018releasing factors\u2019 \u2013 in effect, local hormones \u2013 that \nreach the pituitary through the bloodstream.1 The blood \nsupply to the hypothalamus divides to form a meshwork of capillaries, the primary plexus, which drains into the \nhypophyseal portal vessels. These pass through the pituitary stalk to feed a secondary plexus of capillaries in the anterior \npituitary. Peptidergic neurons in the hypothalamus secrete \na variety of releasing or inhibitory hormones directly into \nthe capillaries of the primary capillary plexus (see Table \n34.1 and Fig. 34.1). Most of these regulate the secretion of hormones from the anterior lobe, although the melanocyte-\nstimulating hormones (MSHs) are secreted mainly from the intermediate lobe.\nThe release of stimulatory hormones is regulated by \nnegative feedback pathways between the hormones of the hypothalamus, the anterior pituitary and the peripheral endocrine glands. Hormones secreted from the peripheral \nglands exert regulatory actions on both the hypothalamus \nand the anterior pituitary, constituting the long negative \nfeedback pathways. Anterior pituitary hormones acting \ndirectly on the hypothalamus comprise the short negative \nfeedback pathway.\nThe peptidergic neurons in the hypothalamus are them -\nselves influenced by other centres within the central nervous system (CNS) and mediated through neural pathways that \nrelease dopamine, noradrenaline, 5-hydroxytryptamine and the opioid peptides (which are particularly", "start_char_idx": 0, "end_char_idx": 3541, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3b45257c-29ab-43d4-ab55-39176d02d2ab": {"__data__": {"id_": "3b45257c-29ab-43d4-ab55-39176d02d2ab", "embedding": null, "metadata": {"page_label": "438", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "604a33e6-286b-4d31-99b4-65feefa34286", "node_type": null, "metadata": {"page_label": "438", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f326425a6afefa1fe3702b559d21607c32c4ffb4b7541b6a17fdd6e484c4554"}, "2": {"node_id": "7a3e3666-65fd-4cb3-a369-06299f527e81", "node_type": null, "metadata": {"page_label": "438", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e7cae7b28c9e22d2e11de61934459c175f3a3d39cefef4c74e247b27fda71a98"}}, "hash": "ed185f65922ee7db0189e392073e853d0795d2002b4a455b8904b62a83e8010f", "text": "5-hydroxytryptamine and the opioid peptides (which are particularly abundant in \nthe hypothalamus). Hypothalamic control of the anterior \npituitary is also exerted through the tuberohypophyseal \ndopaminergic pathway (see Ch. 40), the neurons of which lie \nin close apposition to the primary capillary plexus. Dopa -\nmine secreted directly into the hypophyseal portal circula -\ntion reaches the anterior pituitary via the bloodstream, \ninhibiting the secretion of prolactin (see Ch. 36).\nHYPOTHALAMIC HORMONES\nThe secretion of anterior pituitary hormones, then, is primar -\nily regulated by the peptide \u2018releasing factors\u2019 that originate from the hypothalamus. The most significant are described \nin more detail later. Somatostatin and gonadotrophin-releasing hormone are used therapeutically, the others have \nmainly diagnostic utilities or are useful research tools. Some \nof these peptides also function as neurotransmitters or neuromodulators elsewhere in the CNS (Ch. 40).\nSOMATOSTATIN\nSomatostatin is a peptide of 14 amino acid residues. It inhibits the release of growth hormone and thyroid-\nstimulating hormone (TSH, thyrotrophin) from the anterior \npituitary (Fig. 34.2), and insulin and glucagon from the pancreas. It also decreases the release of most gastrointestinal \n(GI) hormones, and reduces gastric acid and pancreatic \nsecretion.\nOctreotide is a long-acting analogue of somatostatin. It \nis used for the treatment of carcinoid and other hormone-\nsecreting tumours (Ch. 16). It also has a place in the therapy of acromegaly (a condition in which there is oversecretion \nof growth hormone in an adult). It also constricts splanchnic \nblood vessels, and is used to treat bleeding oesophageal 1The term \u2018factor\u2019 was originally coined at a time when their structure \nand function were not known. These are blood-borne messengers, and \nas such are clearly hormones but the nomenclature, though irrational, \nlingers on.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3474, "end_char_idx": 5883, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8921c41e-9f51-46db-b8c0-19bb64d113bd": {"__data__": {"id_": "8921c41e-9f51-46db-b8c0-19bb64d113bd", "embedding": null, "metadata": {"page_label": "439", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eaf61b3e-9b8e-499a-a3cf-2b6d8a187ccb", "node_type": null, "metadata": {"page_label": "439", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0fb278cbd0d790646ebefbe528b3f466a08666d612082be956453f42958188e"}, "3": {"node_id": "18263f17-13ca-4dcd-b2fd-c9a1dc7c0b0d", "node_type": null, "metadata": {"page_label": "439", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "73e54b1ec8bd6d7bc20ae5e8f40b79a624a2a1a994b7cb7eb7cafcdf2b6a55b7"}}, "hash": "c03666e7797b19500dad9429e3afed8ec4e8c9cd9b44e819941a3355247b3962", "text": "34 ThE pITUITARY AND T h E ADRENA l CORTE x\n433have also been reported and acute hepatitis or pancreatitis \nhas occurred in a few cases.\nLanreotide and pasireotide have similar effects. Lanreo -\ntide is also used in the treatment of thyroid tumours, while pasireotide, which is a particularly potent analogue, is used \nin the treatment of Cushing\u2019s syndrome when surgery is \ninappropriate or has been ineffective.\nGONADOTROPHIN-RELEASING HORMONE\nGonadotrophin- (or luteinising hormone [LH]-) releasing \nhormone (GnRH, previously known as LHRH) is a deca -\npeptide that releases both follicle-stimulating hormone and luteinising hormone from gonadotrophs. Gonadorelin\n2 and \nits analogues ( buserelin , goserelin , leuprorelin , nafarelin \nand triptorelin ) are used mainly in the treatment of infertility \nand some hormone-dependent tumours (see Ch. 36).\nGROWTH HORMONE-RELEASING FACTOR \n(SOMATORELIN)\nGrowth hormone-releasing factor (GHRF) is a peptide with \n44 amino acid residues. The main action of GHRF is sum-\nmarised in Fig. 34.2.\n\u25bc An analogue, sermorelin (discontinued in some countries), has \nbeen used as a diagnostic test for growth hormone secretion. Given \nintravenously, subcutaneously or intranasally, it causes secretion of \ngrowth hormone within minutes and peak concentrations in 1 h. The \naction is selective for the somatotrophs in the anterior pituitary, and \nno other pituitary hormones are affected. Unwanted effects are rare.\nTHYROTROPHIN-RELEASING HORMONE\nThyrotrophin-releasing hormone (TRH) from the hypo-\nthalamus releases TSH from the thyrotrophs.\n\u25bc Protirelin (now discontinued in the United Kingdom) is a synthetic \nTRH that has been used for the diagnosis of thyroid disorders (see \nCh. 35). Given intravenously in normal subjects, it causes an increase \nin plasma TSH concentration, whereas in patients with hyperthyroidism there is a blunted response because the raised blood thyroxine \nconcentration has a negative feedback effect on the anterior pituitary. \nThe opposite occurs with hypothyroidism, where there is an intrinsic defect in the thyroid itself.\nCORTICOTROPHIN-RELEASING FACTOR\nCorticotrophin-releasing factor (CRF) is a peptide that \nreleases adrenocorticotrophic hormone (ACTH, cortico-\ntrophin) and \u03b2 -endorphin from corticotrophs in the anterior \npituitary gland. CRF acts synergistically with antidiuretic \nhormone (ADH; arginine-vasopressin, see Ch. 30), and both \nits action and release are inhibited by glucocorticoids (see \nFig. 34.4). Synthetic preparations have been used to test the ability of the pituitary to secrete ACTH, and to assess \nwhether ACTH deficiency is caused by a pituitary or a \nhypothalamic defect. It has also been used to evaluate hypothalamic pituitary function after therapy for Cushing\u2019s syndrome (see Fig. 34.7).\nANTERIOR PITUITARY HORMONES\nThe main hormones of the anterior pituitary are listed in Table 34.1. The gonadotrophins are dealt with in Chapter \n36 and TSH in Chapter 35. The actions of the remainder \nare summarised", "start_char_idx": 0, "end_char_idx": 3019, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "18263f17-13ca-4dcd-b2fd-c9a1dc7c0b0d": {"__data__": {"id_": "18263f17-13ca-4dcd-b2fd-c9a1dc7c0b0d", "embedding": null, "metadata": {"page_label": "439", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "eaf61b3e-9b8e-499a-a3cf-2b6d8a187ccb", "node_type": null, "metadata": {"page_label": "439", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0fb278cbd0d790646ebefbe528b3f466a08666d612082be956453f42958188e"}, "2": {"node_id": "8921c41e-9f51-46db-b8c0-19bb64d113bd", "node_type": null, "metadata": {"page_label": "439", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c03666e7797b19500dad9429e3afed8ec4e8c9cd9b44e819941a3355247b3962"}}, "hash": "73e54b1ec8bd6d7bc20ae5e8f40b79a624a2a1a994b7cb7eb7cafcdf2b6a55b7", "text": "and TSH in Chapter 35. The actions of the remainder \nare summarised below.Hypothalamic\u2013\nhypophyseal\ntract\nPOSTERIOR\nPITUITAR Y\n(neurohypophysis)\nVenous \noutflowArtery\nANTERIOR\nPITUITARY\nVenous outflowSecondary\ncapillary plexusLong portal vessels\nArteryIntermediate\nlobePeptidergic and \ndopaminergic neuronsHYPOTHALAMUS\nPrimary capillary plexus\nFig. 34.1 Schematic diagram of vascular and neuronal \nrelationships between the hypothalamus, the posterior \npituitary and the anterior pituitary. The main portal vessels to \nthe anterior pituitary lie in the pituitary stalk and arise from the primary plexus in the hypothalamus, but some (the short portal vessels) arise from the vascular bed in the posterior pituitary (not shown). \n2In this context, the suffix \u2018-relin\u2019 denotes peptides that stimulate \nhormone release.Hypothalamu s\nGHRF Somatostatin\nGrowth of peripheral tissueIGF-1LiverGrowth\nhormoneSomatropinAnterior pituitarySermorelin\nMecasermin\nrecombinant IGF-1Octreotide\nLanreotide\nPasireotide\nFig. 34.2 Control of growth hormone secretion and its \nactions. Drugs are shown in red-bordered boxes. GHRF, \ngrowth hormone-releasing factor; IGF-1, insulin-like growth \nfactor-1. \nvarices. Octreotide is generally given subcutaneously. The \npeak action is at 2 h, and the suppressant effect lasts for \nup to 8 h.\nUnwanted effects include pain at the injection site and \nGI disturbances. Gallstones and postprandial hyperglycaemia mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2952, "end_char_idx": 4867, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2f6aa599-1480-4568-8b07-467fc7887b2d": {"__data__": {"id_": "2f6aa599-1480-4568-8b07-467fc7887b2d", "embedding": null, "metadata": {"page_label": "440", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d49edcd6-ca1c-4342-84b3-94a78c2e1297", "node_type": null, "metadata": {"page_label": "440", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd0eaf811f030cf5079d7796bc9bdc552e8a5df1a2b50180ba8496ce12256d53"}, "3": {"node_id": "501917eb-3284-4ed2-906d-c542c38b38bc", "node_type": null, "metadata": {"page_label": "440", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ca8d7194e4e40b42f15fde4ce00d64cc8af8e4e7c8b552a4fb7cb79dd17434f"}}, "hash": "69a9faf9fed19e6b54a7a4245a5b4fe6a40dfcb00a56b104898b4f1676462b23", "text": "34 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n434which is released from the liver, has an inhibitory effect \non growth hormone secretion by stimulating somatostatin \nrelease from the hypothalamus.\nAs with other anterior pituitary secretions, growth \nhormone release is pulsatile, and its plasma concentration may fluctuate 10- to 100-fold. These surges occur repeatedly \nduring the day and night, and reflect the dynamics of hypothalamic control. Deep sleep is a potent stimulus to \ngrowth hormone secretion, particularly in children.\nActions\nThe main effect of growth hormone (and its analogues) is \nto stimulate normal growth. To do so, it acts in conjunction \nwith other hormones secreted from the thyroid, the gonads \nand the adrenal cortex. It stimulates hepatic production of the IGFs \u2013 also termed somatomedins \u2013 which mediate most \nof its anabolic actions. IGF-1 (the principal mediator) medi -\nates many of these anabolic effects, stimulating the uptake GROWTH HORMONE (SOMATOTROPHIN)\nGrowth hormone is secreted by the somatotroph cells and \nis the most abundant pituitary hormone. Secretion is high \nin the newborn, decreasing at 4 years to an intermediate \nlevel, which is then maintained until after puberty, after which there is a further decline. Recombinant human growth \nhormone, somatropin, is available for treating growth \ndefects and other developmental problems.\nRegulation of secretion\nSecretion of growth hormone is regulated by the action of \nhypothalamic GHRF and modulated by somatostatin, as \ndescribed above and outlined in Fig. 34.2. A different peptide \nreleaser of growth hormone (\u2018ghrelin\u2019) is released from the stomach and pancreas and is implicated in the control of \nappetite and of body weight (Ch. 33). One of the mediators \nof growth hormone action, insulin-like growth factor (IGF)-1, Table 34.1 Hormones secreted by the hypothalamus and the anterior pituitary and some related drugs\nHypothalamic factor/hormoneaEffect on anterior \npituitary Main effects of anterior pituitary hormone\nCRFReleases ACTH \n(corticotrophin)Analogue: tetracosactideStimulates secretion of adrenal cortical hormones (mainly glucocorticoids); maintains integrity of adrenal cortex.\nTRHAnalogue: protirelinReleases TSH (thyrotrophin)Stimulates synthesis and secretion of thyroid hormones; maintains integrity of thyroid gland.\nGHRF (somatorelin)Analogue: sermorelinReleases GH (somatotrophin)Analogue: somatropinRegulates growth, partly directly, but also by releasing somatomedins from the liver and elsewhere; increases protein synthesis, increases blood glucose, stimulates lipolysis.\nGrowth hormone release-inhibiting factor (somatostatin)Analogues: octreotide, lanreotide, paseriotideInhibits the release of GH Prevents effects of GHRF. Blocks TSH release.\nGnRHAnalogues: \u2018gonadorelin analogues\u2019 \u2013 buserelin, goserelin, leuprorelin, naferelin, triptorelinReleases FSH (see Ch. 36)Stimulates the growth of the ovum and the Graafian follicle (female) and gametogenesis (male); with LH, stimulates the secretion of oestrogen throughout the menstrual cycle and progesterone in the second half.\nRelease of LH or interstitial cell-stimulating hormone (see Ch. 36)Stimulation of ovulation and the development of the corpus luteum; with FSH, stimulation of", "start_char_idx": 0, "end_char_idx": 3277, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "501917eb-3284-4ed2-906d-c542c38b38bc": {"__data__": {"id_": "501917eb-3284-4ed2-906d-c542c38b38bc", "embedding": null, "metadata": {"page_label": "440", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d49edcd6-ca1c-4342-84b3-94a78c2e1297", "node_type": null, "metadata": {"page_label": "440", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd0eaf811f030cf5079d7796bc9bdc552e8a5df1a2b50180ba8496ce12256d53"}, "2": {"node_id": "2f6aa599-1480-4568-8b07-467fc7887b2d", "node_type": null, "metadata": {"page_label": "440", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69a9faf9fed19e6b54a7a4245a5b4fe6a40dfcb00a56b104898b4f1676462b23"}}, "hash": "2ca8d7194e4e40b42f15fde4ce00d64cc8af8e4e7c8b552a4fb7cb79dd17434f", "text": "and the development of the corpus luteum; with FSH, stimulation of secretion of oestrogen and progesterone in the menstrual cycle; in male, regulation of testosterone secretion.\nPRF Releases prolactinTogether with other hormones, prolactin promotes development of mammary tissue during pregnancy and stimulates milk production in the postpartum period.\nProlactin release-inhibiting factor (probably dopamine)Inhibits the release of prolactinPrevents effects of PRF.\nMSH-releasing factor Releases \u03b1-, \u03b2- and \u03b3-MSHPromotes formation of melanin, which causes darkening of skin; MSH has anti-inflammatory actions and also regulates appetite/feeding.\nMSH release-inhibiting factorInhibits the release of \u03b1-, \n\u03b2- and \u03b3-MSHPrevents effects of MSH.\naThese hormones are often spelled without the \u2018h\u2019 (e.g. corticotropin, thyrotropin, etc.) in contemporary texts. We have retained the original \nnomenclature in this edition.ACTH, adrenocorticotrophic hormone; CRF, corticotrophin-releasing factor; FSH, follicle stimulating hormone; GH, growth hormone; GHRF, \ngrowth hormone-releasing factor; GnRH, gonadotrophin (or luteinising hormone)-releasing hormone; LH, luteinising hormone; MSH, \nmelanocyte-stimulating hormone; PRF, prolactin-releasing factor; TRH, thyrotrophin-releasing hormone; TSH, thyroid-stimulating hormone.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3211, "end_char_idx": 5003, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c29ece5c-f913-4967-9239-56fa29febe2c": {"__data__": {"id_": "c29ece5c-f913-4967-9239-56fa29febe2c", "embedding": null, "metadata": {"page_label": "441", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a3200552-b3b7-4610-87c5-0179aca80007", "node_type": null, "metadata": {"page_label": "441", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0dfd154d6d3477654ea0a8579392ca2d7c84f9a80d7d62345f0e6311ba29ce58"}, "3": {"node_id": "1d6670dc-a646-47ae-a604-a93d9f62a716", "node_type": null, "metadata": {"page_label": "441", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1bdfc318d0d0ae928250d90af9767462ab1046df0004ab0a4e5de84b5e951993"}}, "hash": "541fbfb96f74fff082bc55edb13bd7cf77d03aa16c420346624dfafd684b1f56", "text": "34 ThE pITUITARY AND T h E ADRENA l CORTE x\n435drugs; see Ch. 47) are potent stimulants of prolactin release, \nwhereas agonists such as bromocriptine (Chs 40 and 47) \nsuppress prolactin release. Bromocriptine is also used in \nParkinson\u2019s disease (Ch. 41).\nActions\nThe prolactin receptor is a single transmembrane domain receptor of the kinase-linked type (Ch. 3) related to the \ncytokine receptors. Several different isoforms and splice \nvariants are known. These are found not only in the mammary gland but are widely distributed throughout \nthe body, including the brain, ovary, heart, lungs and \nimmune system. The main function of prolactin in women is the control of milk production. At parturition the prolactin \nconcentration rises and lactation is initiated. Maintenance \nof lactation depends on suckling (see earlier), which causes a 10- to 100-fold increase in blood prolactin levels within \n30 min.\nTogether with other hormones, prolactin is responsible \nfor the proliferation and differentiation of mammary tissue \nduring pregnancy. It also inhibits gonadotrophin release \nand/or the response of the ovaries to these trophic hor -\nmones. This is one of the reasons why ovulation does not \nusually occur during breastfeeding.\n\u25bc According to one rather appealing hypothesis, the high postpartum \nconcentration of prolactin reflects its biological function as a \u2018parental\u2019 \nhormone. Certainly, broodiness and nest-building activity can be \ninduced in birds, mice and rabbits by prolactin injections. Prolactin \nalso exerts other, apparently unrelated, actions, including stimulating mitogenesis in lymphocytes. There is some evidence that it may play \na part in regulating immune responses.of amino acids and increasing protein synthesis by skeletal \nmuscle (and therefore muscle bulk) as well as by the cartilage \nat the epiphyses of long bones (thus influencing bone \ngrowth). Receptors for IGF-1 exist on many other cell types, including liver cells and fat cells.\nDisorders of production and clinical use\nDeficiency of growth hormone (or failure of its action) results in pituitary dwarfism. In this condition, which may \nresult from lack of GHRF or a lack of IGF generation or action, the normal proportions of the body are maintained even though overall stature is reduced. Growth hormone \nis used therapeutically in these patients (often children) as \nwell as those suffering from the short stature caused by chronic renal insufficiency or associated with the chromo -\nsomal disorder known as Turner\u2019s syndrome.\nHumans are insensitive to growth hormone of other \nspecies, so human growth hormone (hGH) must be used clinically. Human cadavers were the original source, but \nthis led to the spread of Creutzfeldt\u2013Jakob disease , a prion-\nmediated neurodegenerative disorder (Ch. 41). hGH is now \nprepared by recombinant DNA technology (somatropin), \nwhich avoids this risk. Satisfactory linear growth can be \nachieved by giving somatropin subcutaneously, six to seven times per week, and therapy is most successful when started \nearly.\nhGH is also used illicitly by athletes (see Ch. 59) to \nincrease muscle mass. The large doses used have serious side effects, causing abnormal bone growth and cardio -\nmegaly. It has also been tested as a means of combating \nthe bodily changes in senescence; clinical trials have shown \nincreases in body mass, but no functional improvement. \nHuman recombinant IGF-1 ( mecasermin) is also available \nfor the treatment of growth failure in children who lack \nadequate amounts of this", "start_char_idx": 0, "end_char_idx": 3536, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1d6670dc-a646-47ae-a604-a93d9f62a716": {"__data__": {"id_": "1d6670dc-a646-47ae-a604-a93d9f62a716", "embedding": null, "metadata": {"page_label": "441", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a3200552-b3b7-4610-87c5-0179aca80007", "node_type": null, "metadata": {"page_label": "441", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0dfd154d6d3477654ea0a8579392ca2d7c84f9a80d7d62345f0e6311ba29ce58"}, "2": {"node_id": "c29ece5c-f913-4967-9239-56fa29febe2c", "node_type": null, "metadata": {"page_label": "441", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "541fbfb96f74fff082bc55edb13bd7cf77d03aa16c420346624dfafd684b1f56"}}, "hash": "1bdfc318d0d0ae928250d90af9767462ab1046df0004ab0a4e5de84b5e951993", "text": "\nfor the treatment of growth failure in children who lack \nadequate amounts of this hormone.\nAn excessive production of growth hormone in children \nresults in gigantism. An excessive production in adults, \nwhich is usually the result of a benign pituitary tumour, results in acromegaly , in which there is enlargement mainly \nof the jaw and of the hands and feet. The dopamine agonist \nbromocriptine and octreotide may mitigate the condition. \nAnother useful agent is pegvisomant , a modified analogue \nof growth hormone prepared by recombinant technology that is a highly selective antagonist of growth hormone \nactions.\nPROLACTIN\nProlactin is secreted from the anterior pituitary gland by \nlactotroph (mammotroph) cells. These are abundant in the \ngland and increase in number during pregnancy, probably \nunder the influence of oestrogen.\nREGULATION OF SECRETION\nProlactin secretion is under tonic inhibitory control by dopamine (acting on D\n2 receptors on the lactotrophs) \nreleased from the hypothalamus (Fig. 34.3 and see Table \n34.1). The main stimulus for release is suckling; in rats, \nboth the smell and the sounds of hungry pups are also effective triggers. Neural reflexes from the breast may \nstimulate the secretion from the hypothalamus of prolactin-\nreleasing factor(s), possible candidates for which include TRH and oxytocin. Oestrogens increase both prolactin \nsecretion and the proliferation of lactotrophs through the \nrelease, from a subset of lactotrophs, of the neuropeptide galanin. Dopamine antagonists (used mainly as antipsychotic Suckling\nreflex\nMammary glandsProlactinAnterior pituitaryDopamine\nantagonistsCabergoline\nBromocriptine\nQuinagolidePRIF\n(dopamine)Oxytocin\n?PRF\n?TRHHypothalamus\nFig. 34.3 Control of prolactin secretion. Drugs are shown in \nred-bordered boxes. PRF, prolactin-releasing factor(s); PRIF, \nprolactin release-inhibiting factor(s); TRH, thyrotrophin-releasing \nhormone. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3453, "end_char_idx": 5855, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "12334442-18e6-432d-b1b2-9022f0ba0dfa": {"__data__": {"id_": "12334442-18e6-432d-b1b2-9022f0ba0dfa", "embedding": null, "metadata": {"page_label": "442", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6570956f-6008-4b2c-9836-9db29840a48d", "node_type": null, "metadata": {"page_label": "442", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10a224f8f9084a731034b273742bc15910ab0055e8cf7dc820ccc00b54705e56"}, "3": {"node_id": "d74f85bf-b60b-446f-b2ef-ca1cb6b1a30a", "node_type": null, "metadata": {"page_label": "442", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a5fc2fe101a3dc28b65a3fd97141bce72478d08eaca4dc1d0758a66e65b98b8f"}}, "hash": "ed3a37bd00db8ae9401beea6dede67363b2fa11ae895567aed0ffde3682fff86", "text": "34 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n436MELANOCYTE-STIMULATING HORMONE (MSH)\n\u03b1-, \u03b2- and \u03b3-MSH are peptide hormones with structural \nsimilarity to ACTH and are derived from the same precursor. \nTogether, these peptides are referred to as melanocortins, \nbecause their first recognised action was to stimulate the production of melanin by specialised skin cells called mel-\nanocytes . As such, they play an important part in determining \nhair colouration, skin colour and reaction to ultraviolet light.\nMSH acts on melanocortin receptors, of which five (MC\n1\u20135) \nhave been cloned. These are G protein\u2013coupled receptors \n(GPCRs) that activate cAMP synthesis. Melanin formation \nis controlled by the MC 1 receptor. Excessive \u03b1-MSH produc -\ntion can provoke abnormal proliferation of melanocytes \nand may predispose to melanoma.\n\u25bc Melanocortins exhibit numerous other biological effects. For \nexample, \u03b1-MSH inhibits the release of interleukin (IL)-1 \u03b2 and tumour Long negative\nfeedback loop\nShort negative\nfeedback loop\nAdrenal\ncortex\nPeripheral actions\non salt and water\nmetabolismPeripheral actions\n(metabolic, anti-\ninflammatory,\nimmunosuppressive)Exogenous\nmineralocorticoids\n(e.g. fludrocortisone)Exogenous\nglucocorticoids\n(e.g. prednisolone)Exogenous\nACTH\nRenin\u2013angiotensin\nsystemHypothalamus\nCRF\nADH\nACTH\nGlucocorticoids MineralocorticoidsMetyrapone\nMitotane\nTrilostaneAnterior pituitary\nFig. 34.4 Regulation of synthesis and secretion of adrenal \ncorticosteroids. The long negative feedback loop is more \nphysiologically significant than the short loop (dashed lines). \nAdrenocorticotrophic hormone (ACTH, corticotrophin) has only a minimal effect on mineralocorticoid production. Drugs are shown in red-bordered boxes . ADH, antidiuretic hormone (vasopressin); \nCRF, corticotrophin-releasing factor. Clinical uses of bromocriptine \n\u2022\tTo\tprevent \tlactation.\n\u2022\tTo\ttreat \tgalactorrhoea \t(i.e. \tnon-puerperal \tlactation \tin \t\neither sex), owing to excessive prolactin secretion.\n\u2022\tTo\ttreat \tprolactin-secreting \tpituitary \ttumours \t\n(prolactinomas).\n\u2022\tIn\tthe\ttreatment \tof \tParkinson\u2019s \tdisease \t(Ch. \t41) \tand \tof \t\nacromegaly.Modification of prolactin secretion\nProlactin itself is not used clinically. Bromocriptine, a \ndopamine receptor agonist, is used to decrease excessive \nprolactin secretion ( hyperprolactinaemia ). It is well absorbed \norally, and peak concentrations occur after 2 h . Unwanted \nreactions include nausea and vomiting. Dizziness, constipa -\ntion and postural hypotension may also occur. Cabergoline \nand quinagolide are similar.\nADRENOCORTICOTROPHIC HORMONE\nAdrenocorticotrophic hormone (ACTH, corticotrophin) is \nthe anterior pituitary secretion that controls the synthesis \nand release of the glucocorticoids of the adrenal cortex (see \nTable 34.1). It is a 39-residue peptide derived from the precursor pro-opiomelanocortin (POMC) by sequential \nproteolytic processing. It acts on the MC\n2 member of the", "start_char_idx": 0, "end_char_idx": 2955, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d74f85bf-b60b-446f-b2ef-ca1cb6b1a30a": {"__data__": {"id_": "d74f85bf-b60b-446f-b2ef-ca1cb6b1a30a", "embedding": null, "metadata": {"page_label": "442", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6570956f-6008-4b2c-9836-9db29840a48d", "node_type": null, "metadata": {"page_label": "442", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10a224f8f9084a731034b273742bc15910ab0055e8cf7dc820ccc00b54705e56"}, "2": {"node_id": "12334442-18e6-432d-b1b2-9022f0ba0dfa", "node_type": null, "metadata": {"page_label": "442", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed3a37bd00db8ae9401beea6dede67363b2fa11ae895567aed0ffde3682fff86"}}, "hash": "a5fc2fe101a3dc28b65a3fd97141bce72478d08eaca4dc1d0758a66e65b98b8f", "text": "by sequential \nproteolytic processing. It acts on the MC\n2 member of the \nfamily of melanocortin receptors (see later). Failure of ACTH action because of defects in its receptor or intracellular \nsignalling pathways can lead to severe glucocorticoid \ndeficiency (Chan et al., 2008). Details of the regulation of \nACTH secretion are shown in Fig. 34.4.\n\u25bc This hormone occupies (together with cortisone) an important \nplace in the history of inflammation therapy because of the work of \nHench and his colleagues in the 1940s, who first observed that both \nsubstances had anti-inflammatory effects in patients with rheumatoid \ndisease. The effect of ACTH was thought to be secondary to stimulation of the adrenal cortex but, interestingly, the hormone also has anti-\ninflammatory actions in its own right, through activation of macrophage \n(melanocortin) MC\n3 receptors (Getting et al., 2002).\nACTH itself is not often used in therapy today, because \nits action is less predictable than that of the corticosteroids \nand it may provoke antibody formation. Tetracosactide \n(tetracosactrin), a synthetic polypeptide that consists of \nthe first 24 N-terminal residues of human ACTH, suffers \nfrom some of the same drawbacks but is now widely used \nfor assessing the competency of the adrenal cortex. The drug is given intramuscularly or intravenously, and the \nconcentration of hydrocortisone in the plasma is measured \nby radioimmunoassay.\nActions\nActing through MC 2 receptors, tetracosactide and ACTH \nhave two actions on the adrenal cortex:\n\u2022\tStimulation \tof \tthe \tsynthesis \tand \trelease \tof \t\nglucocorticoids. This action occurs within minutes of injection, and the ensuing biological actions are \npredominately those of the released steroids.\n\u2022\tA\ttrophic \taction \ton \tadrenal \tcortical \tcells, \tand \tregulation \t\nof the levels of key mitochondrial steroidogenic \nenzymes. The loss of this effect accounts for the adrenal \natrophy that results from chronic glucocorticoid \nadministration, which suppresses ACTH secretion.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2883, "end_char_idx": 5384, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "82e1819e-3ada-4883-8853-022aabfaa75f": {"__data__": {"id_": "82e1819e-3ada-4883-8853-022aabfaa75f", "embedding": null, "metadata": {"page_label": "443", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7478c90f-6ce5-456c-ab05-cd2ba27596af", "node_type": null, "metadata": {"page_label": "443", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "34e789e5081fa7332c00c72504d81e6944a736b8998364819d5597c1a00156e5"}, "3": {"node_id": "ff80669c-5298-4860-97b2-82303f9f4487", "node_type": null, "metadata": {"page_label": "443", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce1874e73c8d04dccfc209e25f41a15c1d59064141e218065d0d5f0482b1ebdc"}}, "hash": "40e1990a69b631e9e8f6f54fb6fefc85addf76ceaeea13043c19f2b9709ca132", "text": "34 ThE pITUITARY AND T h E ADRENA l CORTE x\n437necrosis factor (TNF)-\u03b1, reduces neutrophil infiltration, and exhibits \nanti-inflammatory and antipyretic activity. Levels of \u03b1-MSH are \nincreased in synovial fluid of patients with rheumatoid arthritis. These immunomodulatory effects are transduced by MC\n1 and MC 3 receptors. \nAgonists at these receptors with potential anti-inflammatory activity \nare being sought. Central injection of \u03b1-MSH also causes changes in \nanimal behaviour, such as increased grooming and sexual activity \nas well as reduced feeding through actions on MC 4 receptors, and \nagonists of MC 4 are under investigation as potential treatments for \nobesity and for erectile impotence.\nIntracerebroventricular or intravenous injection of \u03b3-MSH \nincreases blood pressure, heart rate and cerebral blood flow. \nThese effects are also likely to be mediated by the MC 4 \nreceptor.\nTwo naturally occurring ligands for melanocortin recep -\ntors (agouti-signalling protein and agouti-related peptide, \ntogether called the agouti ) have been discovered in human \ntissues. These are proteins that competitively antagonise the effect of MSH at melanocortin receptors.\nThe anterior pituitary gland and \nhypothalamus \n\u2022\tThe\tanterior \tpituitary \tgland \tsecretes \thormones \tthat \t\nregulate:\n\u2013 the release of glucocorticoids from the adrenal cortex\n\u2013 the release of thyroid hormones\n\u2013 the release of sex hormones: ovulation in the female \nand spermatogenesis in the male\n\u2013 growth\n\u2013 mammary gland structure and function\n\u2022\tEach\tanterior \tpituitary \thormone \tis \titself \tregulated \tby \ta \t\nspecific hypothalamic releasing factor. Feedback \nmechanisms govern the release of these factors. Clinically useful drugs of this type include:\n\u2013 growth hormone-releasing factor (sermorelin) and \nanalogues of growth hormone ( somatrophin)\n\u2013 thyrotrophin-releasing factor (protirelin) and thyroid-stimulating hormone (thyrotrophin; used to test thyroid function)\n\u2013 octreotide and lanreotide, analogues of \nsomatostatin, which inhibit growth hormone release\n\u2013 corticotrophin-releasing factor, used in diagnosis\n\u2013 gonadotrophin-releasing factor, gonadorelin and \nanalogues. Used to treat infertility and some carcinomasAdrenocorticotrophic hormone and \nthe adrenal steroids \n\u2022\tAdrenocorticotrophic \thormone \t(ACTH; \ttetracosactrin, \ntetracosactide) stimulates synthesis and release of glucocorticoids (e.g. hydrocortisone), as well as \nsome androgens, from the adrenal cortex.\n\u2022\tCorticotrophin-releasing \tfactor \t(CRF) \tfrom \tthe \t\nhypothalamus regulates ACTH release, and is \nregulated in turn by neural factors and negative feedback effects of plasma glucocorticoids.\n\u2022\tMineralocorticoid \t(e.g. \taldosterone) \trelease \tfrom \tthe \t\nadrenal cortex is controlled by the renin\u2013angiotensin system.\n3Oxytocin is released during childbirth, lactation and orgasm and has \nbeen shown to promote trust and other prosocial behaviour. This has \nearned it the nickname of the \u2018love hormone\u2019 (or even more \nnauseatingly, the \u2018cuddle hormone\u2019) in the popular press and internet discussion groups.POSTERIOR PITUITARY GLAND\nThe posterior pituitary gland (neurohypophysis) consists \nlargely of the terminals of nerve cells originating from the \nsupraoptic and", "start_char_idx": 0, "end_char_idx": 3235, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ff80669c-5298-4860-97b2-82303f9f4487": {"__data__": {"id_": "ff80669c-5298-4860-97b2-82303f9f4487", "embedding": null, "metadata": {"page_label": "443", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7478c90f-6ce5-456c-ab05-cd2ba27596af", "node_type": null, "metadata": {"page_label": "443", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "34e789e5081fa7332c00c72504d81e6944a736b8998364819d5597c1a00156e5"}, "2": {"node_id": "82e1819e-3ada-4883-8853-022aabfaa75f", "node_type": null, "metadata": {"page_label": "443", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "40e1990a69b631e9e8f6f54fb6fefc85addf76ceaeea13043c19f2b9709ca132"}}, "hash": "ce1874e73c8d04dccfc209e25f41a15c1d59064141e218065d0d5f0482b1ebdc", "text": "of the terminals of nerve cells originating from the \nsupraoptic and paraventricular nuclei of the hypothalamus. \nTheir axons form the hypothalamic\u2013hypophyseal tract, and \nthe fibres terminate in dilated nerve endings in close association with capillaries in the posterior pituitary gland \n(see Fig. 34.1). Peptides, synthesised in the hypothalamic nuclei, pass down these axons into the posterior pituitary, \nwhere they are stored and eventually secreted into the \nbloodstream.\nThe two main hormones of the posterior pituitary are \noxytocin (which contracts the smooth muscle of the uterus; for details see Ch. 36) and vasopressin (ADH; see Chs 23 \nand 30). They are highly homologous cyclic nonapeptides. \nSeveral analogues have been synthesised that vary in their \nantidiuretic, vasopressor and oxytocic (uterine stimulant) properties.\nVASOPRESSIN\nRegulation of secretion and physiological role\nVasopressin released from the posterior pituitary has a crucial role in the control of the water content of the body \nthrough its action on the cells of the distal part of the \nnephron and the collecting tubules in the kidney (see Ch. 30). The hypothalamic nuclei that control fluid balance lie \nclose to the nuclei that synthesise and secrete vasopressin.\nOne of the main stimuli for vasopressin release is an \nincrease in plasma osmolarity (which produces a sensation of thirst). A decrease in circulating blood volume ( hypovol -\naemia) is another, and here the stimuli arise from stretch \nreceptors in the cardiovascular system or from angiotensin release. Diabetes insipidus is a condition in which large \nvolumes of dilute urine are produced because vasopressin secretion is reduced or absent, or because of a reduced sensitivity of the kidney to the hormone.\nVasopressin receptors\nThere are three classes of receptor: V 1A, V 1B and V 2. All are \nGPCRs. V 2 receptors stimulate adenylyl cyclase, which \nmediates the main physiological actions of vasopressin in \nthe kidney, whereas the V 1A and V 1B receptors are coupled \nto the phospholipase C/inositol trisphosphate system.\nThe receptor for oxytocin (OT receptor) is also a GPCR, \nwhich primarily signals through phospholipase C stimula -\ntion but has a secondary action on adenylyl cyclase. Vaso -\npressin is a partial agonist at OT, but its effects are limited \nby the distribution of the receptor, which, as might be inferred from its classic action on the pregnant uterus, is \nhigh in the myometrium, endometrium, mammary gland \nand ovary. The central actions of oxytocin (and vasopressin) have also attracted the attention of sociobiologists as they are important in \u2018pair bonding\u2019 and the other psychosocial \ninteractions.\n3mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3167, "end_char_idx": 6334, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "992e714f-e521-4509-8a00-dacf00a91c33": {"__data__": {"id_": "992e714f-e521-4509-8a00-dacf00a91c33", "embedding": null, "metadata": {"page_label": "444", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2233b4f0-bbd0-463f-a462-1560b270a0b9", "node_type": null, "metadata": {"page_label": "444", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57f051e2fc14a3f86a54b8dd10171ef49ed02369f281e8cd5425fe90d21cc3e0"}, "3": {"node_id": "9f07bd86-791c-4d0b-99f6-1c7d2ea23b4a", "node_type": null, "metadata": {"page_label": "444", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "062feb5b744944bfd9264d17e9f4ae8ddeddf8c862deda1ff0afb2911922177b"}}, "hash": "f95eb06d93e404239b8c90365d7396d7a2c3c037679afe6469acf6b475039931", "text": "34 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n438removed by the kidney. Desmopressin is less subject to \ndegradation by peptidases, and its plasma half-life is 75 min.\nUnwanted effects\nThere are few unwanted effects and these are mainly \ncardiovascular in nature: intravenous vasopressin may \ncause spasm of the coronary arteries with resultant angina, \nbut this risk can be minimised if the antidiuretic peptides are administered intranasally.Actions\nRenal actions\nVasopressin binds to V 2 receptors in the basolateral mem-\nbrane of the cells of the distal tubule and collecting ducts \nof the nephron. Its main effect in the collecting duct is to \nincrease the rate of insertion of water channels ( aquaporins ) \ninto the lumenal membrane, thus increasing the permeability \nof the membrane to water (see Ch. 30). It also activates \nurea transporters and transiently increases Na+ absorption, \nparticularly in the distal tubule.\nSeveral drugs affect the action of vasopressin. Non-\nsteroidal anti-inflammatory drugs and carbamazepine increase, and lithium, colchicine and vinca alkaloids \ndecrease, vasopressin effects. The effects of the last two agents are secondary to their action on the microtubules required for translocation of water channels. The V\n2 receptor \nantagonists tolvaptan and demeclocycline (actually a \ntetracycline antibiotic) counteract the action of vasopressin in renal tubules and can be used to treat patients with water retention combined with urinary salt loss (and thus \nhyponatraemia ) caused by excessive secretion of the hormone. \nThis syndrome of inappropriate ADH secretion (\u2018SIADH\u2019) is \nassociated with lung or other malignancies or head injury. Specific V\n2 receptor antagonists are also being investigated \nin the treatment of heart failure (Ch. 23).\nOther non-renal actions\nVasopressin causes contraction of smooth muscle, particu -\nlarly in the cardiovascular system, by acting on V 1A receptors \n(see Ch. 23). The affinity of vasopressin for these receptors \nis lower than that for V 2 receptors, and smooth muscle \neffects are seen only with doses larger than those affecting the kidney. Vasopressin also stimulates blood platelet \naggregation and mobilisation of coagulation factors. When released into the pituitary portal circulation it promotes \nthe release of ACTH from the anterior pituitary by an action \non V\n1B receptors (see Fig. 34.4). In the CNS, vasopressin, \nlike oxytocin, is believed to have a role in modulating \nemotional and social behaviour.\nPharmacokinetic aspects\nVasopressin, and various peptide analogues, are used \nclinically either for the treatment of diabetes insipidus or \nas vasoconstrictors. Several analogues have been developed \nto (a) increase their duration of action and (b) shift the relative potency between the V\n1 and V 2 receptors.\nThe main substances used are:\n\u2022\tvasopressin itself: short duration of action, weak selectivity for V\n2 receptors, given by subcutaneous or \nintramuscular injection, or by intravenous infusion;\n\u2022\tdesmopressin: increased duration of action, V 2-selective \nand therefore fewer pressor effects, can be given by \nseveral routes including nasal spray;\n\u2022\tterlipressin: increased duration of action, low but \nprotracted vasopressor action (and minimal \nantidiuretic properties), used to reduce bleeding (e.g. \nfrom oesophageal varices) and maintain blood pressure;\n\u2022\tfelypressin: a short-acting", "start_char_idx": 0, "end_char_idx": 3410, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9f07bd86-791c-4d0b-99f6-1c7d2ea23b4a": {"__data__": {"id_": "9f07bd86-791c-4d0b-99f6-1c7d2ea23b4a", "embedding": null, "metadata": {"page_label": "444", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2233b4f0-bbd0-463f-a462-1560b270a0b9", "node_type": null, "metadata": {"page_label": "444", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57f051e2fc14a3f86a54b8dd10171ef49ed02369f281e8cd5425fe90d21cc3e0"}, "2": {"node_id": "992e714f-e521-4509-8a00-dacf00a91c33", "node_type": null, "metadata": {"page_label": "444", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f95eb06d93e404239b8c90365d7396d7a2c3c037679afe6469acf6b475039931"}}, "hash": "062feb5b744944bfd9264d17e9f4ae8ddeddf8c862deda1ff0afb2911922177b", "text": "and maintain blood pressure;\n\u2022\tfelypressin: a short-acting vasoconstrictor that is injected with local anaesthetics such as prilocaine to prolong their action (see Ch. 44).\nVasopressin itself is rapidly eliminated, with a plasma \nhalf-life less than 10 min and a short duration of action. \nTissue peptidases metabolise the hormone and 33% is The posterior pituitary gland \n\u2022\tThe\tposterior \tpituitary \tgland \tsecretes:\n\u2013 oxytocin (see Ch. 36)\n\u2013 antidiuretic hormone ( vasopressin), which acts on \nV2 receptors in the distal kidney tubule to increase \nwater reabsorption and, in higher concentrations, on \nV1A\treceptors \tto \tcause \tvasoconstriction. \tIt \talso \t\nstimulates adrenocorticotrophic hormone secretion.\n\u2022\tSubstances \tavailable \tfor \tclinical \tuse \tare \tvasopressin \nand the analogues desmopressin, felypressin and \nterlipressin.\nClinical uses of antidiuretic \nhormone (vasopressin) \nand analogues \n\u2022\tDiabetes \tinsipidus: \tfelypressin, desmopressin.\n\u2022\tInitial\ttreatment \tof \tbleeding \toesophageal \tvarices: \t\nvasopressin, terlipressin, felypressin. (Octreotide \n\u2013 a somatostatin analogue \u2013 is also used, but direct injection of sclerosant via an endoscope is the main \ntreatment.)\n\u2022\tProphylaxis \tagainst \tbleeding \tin \thaemophilia \t(e.g. \t\nbefore tooth extraction): vasopressin, desmopressin \n(by\tincreasing \tthe \tconcentration \tof \tfactor \tVIII).\n\u2022\tFelypressin is used as a vasoconstrictor with local \nanaesthetics \t(see \tCh. \t44).\n\u2022\tDesmopressin is used for persistent nocturnal \nenuresis in older children and adults.\n4So named because early experimenters noticed that separate fractions \nof adrenal gland extracts caused changes in either blood glucose or salt \nand water retention.THE ADRENAL CORTEX\nThe adrenal glands consist of two parts: the inner medulla, \nwhich secretes catecholamines (see Ch. 15), and the outer \ncortex , which secretes adrenal steroids. The cortex comprises \nthree concentric zones: the zona glomerulosa (the outermost \nlayer), which elaborates mineralocorticoids, the zona fas-\nciculata, which elaborates glucocorticoids, and the innermost \nzona reticularis, which produces androgen precursors. The principal adrenal steroids are those with glucocorticoid \nand mineralocorticoid activities.\n4 Androgen secretion (see \nCh. 36) by the cortex is not considered further in this chapter.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3352, "end_char_idx": 6154, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "87da8920-04a8-4ba1-aaf8-9b33e3d5f494": {"__data__": {"id_": "87da8920-04a8-4ba1-aaf8-9b33e3d5f494", "embedding": null, "metadata": {"page_label": "445", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "260b477b-054b-434e-990c-fa1046bfe017", "node_type": null, "metadata": {"page_label": "445", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f4adf97caa8aa2024be1ad386bba0f5cfb4d9fef0589ec9668f06228105477c"}, "3": {"node_id": "ddee49c9-73ff-47bd-b923-47cd8b169032", "node_type": null, "metadata": {"page_label": "445", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b9748d95794f6ccef8f465bbeedf8c1ea3f544ac51118c4a61d3dae1d19acc6"}}, "hash": "2134edcdf61679eb9752df85469d0688223748cb6e76b5633b822117b6d4b10b", "text": "34 ThE pITUITARY AND T h E ADRENA l CORTE x\n439sites such as thymus and skin (see Talaber et al., 2015; \nHannen et al., 2017) providing a fresh perspective on the \nlocal control of inflammatory processes.\nWith the exception of replacement therapy , glucocorticoids \nare most commonly employed for their anti-inflammatory \nand immunosuppressive properties (see Ch. 27). In this therapeutic context, their metabolic and other actions are \nseen as unwanted side effects. Synthetic steroids have \nbeen developed in which exhibit a partial separation of the glucocorticoid from the mineralocorticoid actions \n(Table 34.2), but it has not yet been possible completely \nto separate the anti-inflammatory from the other actions of the glucocorticoids.\n\u25bc The adrenal gland is essential to life, and animals deprived of \nthese glands are able to survive only under rigorously controlled \nconditions. In humans, a deficiency in corticosteroid production, \ntermed Addison\u2019s disease , is characterised by muscular weakness, low \nblood pressure, depression, anorexia, loss of weight and hypogly -\ncaemia. Addison\u2019s disease may have an autoimmune aetiology, or it may be secondary to destruction of the gland by chronic inflammatory \nconditions such as tuberculosis.\nWhen corticosteroids are produced in excess, the clinical picture \ndepends on which molecular species predominates. Excessive gluco-\ncorticoid activity results in Cushing\u2019s syndrome, the manifestations of \nwhich are outlined in Fig. 34.7. This can be caused by hypersecretion from the adrenal glands or by prolonged therapeutic use of The mineralocorticoids regulate water and electrolyte \nbalance, and the main endogenous hormone is aldosterone . \nThe glucocorticoids have widespread actions on carbohy -\ndrate and protein metabolism, as well as potent regulatory \neffects on host defence mechanisms (Chs 7 and 27). The \nadrenal gland secretes a mixture of glucocorticoids; in \nhumans the main hormone is hydrocortisone (also, confus -\ningly, known as cortisol), and in rodents it is corticosterone. \nThe mineralocorticoid and glucocorticoid actions are not completely separated in naturally occurring steroids and some glucocorticoids have quite substantial effects on water and electrolyte balance. In fact, both hydrocortisone and \naldosterone are equiactive on mineralocorticoid receptors \nbut, in mineralocorticoid-sensitive tissues such as the kidney, the action of 11\u03b2-hydroxysteroid dehydrogenase Type 2 converts \nhydrocortisone to the inactive metabolite cortisone,\n5 thereby \npreventing the tissue from responding to hydrocortisone. \nInterestingly, there is increasing evidence that some glu -\ncocorticoid synthesis can take place locally at extra-adrenal Table 34.2 Comparison of the main corticosteroid agents used for systemic therapy (using hydrocortisone as a standard)\nCompoundRelative \naffinity for GRApproximate relative \npotency in clinical useDuration of action after oral dose\naCommentsAnti-inflammatorySodium retaining\nHydrocortisone \n(cortisol)1 1 1 Short Drug of choice for replacement therapy.\nCortisone 0 (Prodrug) 0.8 0.8 ShortInactive until converted to hydrocortisone; not used as anti-inflammatory because of mineralocorticoid effects.\nDeflazacort 0 (Prodrug) 3 Minimal Short Converted by plasma esterases into active metabolite. Similar utility to prednisolone.\nPrednisolone 2.2 4 0.8 Intermediate Drug of choice for systemic anti-inflammatory and immunosuppressive effects.\nPrednisone 0 (Prodrug) 4 0.8 Intermediate Inactive until", "start_char_idx": 0, "end_char_idx": 3523, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ddee49c9-73ff-47bd-b923-47cd8b169032": {"__data__": {"id_": "ddee49c9-73ff-47bd-b923-47cd8b169032", "embedding": null, "metadata": {"page_label": "445", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "260b477b-054b-434e-990c-fa1046bfe017", "node_type": null, "metadata": {"page_label": "445", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f4adf97caa8aa2024be1ad386bba0f5cfb4d9fef0589ec9668f06228105477c"}, "2": {"node_id": "87da8920-04a8-4ba1-aaf8-9b33e3d5f494", "node_type": null, "metadata": {"page_label": "445", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2134edcdf61679eb9752df85469d0688223748cb6e76b5633b822117b6d4b10b"}}, "hash": "3b9748d95794f6ccef8f465bbeedf8c1ea3f544ac51118c4a61d3dae1d19acc6", "text": "effects.\nPrednisone 0 (Prodrug) 4 0.8 Intermediate Inactive until converted to prednisolone.\nMethylprednisolone 11.9 5 Minimal Intermediate Anti-inflammatory and immunosuppressive.\nTriamcinolone 1.9 5 None Intermediate Relatively more toxic than others.\nDexamethasone 7.1 27 Minimal LongAnti-inflammatory and immunosuppressive, used especially where water retention is undesirable (e.g. cerebral oedema); drug of choice for suppression of ACTH production.\nBetamethasone 5.4 27 Negligible Long Anti-inflammatory and immunosuppressive, used especially when water retention is undesirable.\nFludrocortisone 3.5 15 150 Short Drug of choice for mineralocorticoid effects.\nAldosterone 0.38 None 500 N/A Endogenous mineralocorticoid.\naDuration\tof \taction \t(half-lives \tin \thours): \tshort, \t8\u201312; \tintermediate, \t12\u201336; \tlong, \t36\u201372. \tSome \tdrugs \tare \tinactive \tuntil \tconverted \tto \tactive \t\ncompounds in vivo and therefore have negligible affinity for the glucocorticoid receptor.GR, glucocorticoid receptor.\n(Data\tfor\trelative \taffinity \tobtained \tfrom \tBaxter \t& \tRousseau, \t1979.)\n5Oddly, it was cortisone that Hench originally demonstrated to have \npotent anti-inflammatory activity in his classic studies of 1949. The \nreason for this apparent anomaly is the presence in some tissues of the \nenzyme 11\u03b2-hydroxysteroid dehydrogenase Type 1 which can reduce \ncortisone to cortisol (i.e. hydrocortisone), thus restoring its biological \nactivity.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3458, "end_char_idx": 5379, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "400939b7-957f-4407-9ffb-2677e117a11e": {"__data__": {"id_": "400939b7-957f-4407-9ffb-2677e117a11e", "embedding": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fff825a5-980f-4a33-9ec5-45034f496869", "node_type": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48958b4d2f7b1573fee0c5d47dfc4bf235f51eb8feaa90dfd2d3b6410d369ff2"}, "3": {"node_id": "cc302f03-5698-4418-9f8b-d4c4f36f6d9f", "node_type": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5ee5cfcd4dc5f7b57fac61030d67a50354c95335f84f639119de5d6bf8bd48b6"}}, "hash": "f02f40ed7948ddcdaf34f831a5b6b6e301d4610c4b1ac55548975b22c4131b74", "text": "34 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n440superfamily (although there may be other binding proteins \nor sites; see Norman et al., 2004). This superfamily also \nincludes the receptors for mineralocorticoids, the sex \nsteroids, thyroid hormones, vitamin D 3 and retinoic acid \n(see Ch. 3). The actual mechanism of transcriptional control \nis complex, with at least four mechanisms operating within \nthe nucleus. These are summarised diagrammatically in Fig. 34.6.\nWhen the nuclear actions of glucocorticoid receptors were \nfirst discovered it was thought that this mechanism could account for all the actions of the hormones, but a surprising \ndiscovery overturned this idea. Reichardt et al. (1998), using \ntransgenic mice in which the glucocorticoid receptor was unable to dimerise (and therefore unable to function in the \nnucleus), found that glucocorticoids were still able to exert \na great many biological actions. This suggested that in addition to controlling gene expression within the nucleus, \nthe liganded receptor itself could initiate important signal \ntransduction events while still in the cytosolic compartment (there may even be a subpopulation of receptors that reside \nthere permanently). One such effect seems to be interaction \nof the receptor with the regulatory complex, NF-\u03baB (see Fig. 34.6 and Ch. 3) and other important interactions may involve protein kinases/phosphatase signalling systems. \nSome of these cytosolic actions are very rapid. For example, \nthe liganded glucocorticoid receptor-induced phosphoryla -\ntion by PKC and subsequent release of the protein annexin \nA1, which has potent inhibitory effects on leukocyte traf -\nficking and other anti-inflammatory actions, occurs in minutes and cannot be accounted for by changes in protein \nsynthesis and there are many other examples (see Buttgereit \n& Scheffold, 2002).\nIn recent years, our understanding of the glucocorticoid \nfield has been further enriched by the discovery of numerous \nisoforms and splice variants of glucocorticoid receptor (GR), some of which are expressed in a tissue-specific manner \n(see Oakley & Cidlowsky, 2013). This opens up a real \npossibility of highly selective glucocorticoid drugs in the \nfuture.glucocorticoids. An excessive production of mineralocorticoids results \nin retention of Na+ and loss of K+. This may be caused by hyperactivity \nor tumours of the adrenals ( primary hyperaldosteronism, or Conn\u2019s \nsyndrome, an uncommon but important cause of hypertension; see \nCh. 23), or by excessive activation of the renin\u2013angiotensin system such as occurs in some forms of kidney disease, cirrhosis of the liver \nor congestive cardiac failure (secondary hyperaldosteronism).\nGLUCOCORTICOIDS\nSynthesis and release\nGlucocorticoids are not stored in the adrenal gland but are \nsynthesised under the influence of circulating ACTH \nsecreted from the anterior pituitary gland (see Fig. 34.4) \nand released in a pulsatile fashion into the blood. While glucocorticoids are continuously released, there is a well-\ndefined circadian rhythm in the secretion in healthy humans, \nwith the net blood concentration being highest early in the morning, gradually diminishing throughout the day and \nreaching a low point in the evening or night. ACTH secretion \nitself (also pulsatile in nature) is regulated by CRF released from the hypothalamus, and by vasopressin released from the posterior pituitary gland. The release of both ACTH \nand CRF, in turn, is reflexly inhibited by the ensuing rising \nconcentrations of", "start_char_idx": 0, "end_char_idx": 3542, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cc302f03-5698-4418-9f8b-d4c4f36f6d9f": {"__data__": {"id_": "cc302f03-5698-4418-9f8b-d4c4f36f6d9f", "embedding": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fff825a5-980f-4a33-9ec5-45034f496869", "node_type": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48958b4d2f7b1573fee0c5d47dfc4bf235f51eb8feaa90dfd2d3b6410d369ff2"}, "2": {"node_id": "400939b7-957f-4407-9ffb-2677e117a11e", "node_type": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f02f40ed7948ddcdaf34f831a5b6b6e301d4610c4b1ac55548975b22c4131b74"}, "3": {"node_id": "6d57d4b0-be94-4983-92f2-c426018027fc", "node_type": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "867b4d67e9450409400a53c77144c45c28c1675d430d5e9de55fe5822d255d71"}}, "hash": "5ee5cfcd4dc5f7b57fac61030d67a50354c95335f84f639119de5d6bf8bd48b6", "text": "in turn, is reflexly inhibited by the ensuing rising \nconcentrations of glucocorticoids in the blood.\nOpioid peptides also exercise a tonic inhibitory control \non the secretion of CRF, and psychological factors, excessive heat or cold, injury or infections can also affect the release of both vasopressin and CRF. This is the principal mecha -\nnism whereby the HPA axis is activated in response to perceived threats in the external environment.\nThe biosynthetic precursor of glucocorticoids is cho -\nlesterol (Fig. 34.5). The initial conversion of cholesterol to pregnenolone is the rate-limiting step and is regulated \nby ACTH. Some biosynthetic reactions can be inhibited \nby drugs and these have a utility in treating Cushing\u2019s \ndisease or adrenocortical carcinoma. Metyrapone prevents \nthe \u03b2-hydroxylation at C11, and thus the formation of \nhydrocortisone and corticosterone. Synthesis is blocked at the 11-deoxycorticosteroid stage, leaving intermediates that have no effects on the hypothalamus and pituitary, so there is a marked increase in ACTH in the blood. Metyrapone \ncan therefore be used to test ACTH production, and may \nalso be used to treat patients with Cushing\u2019s syndrome. Trilostane (previously used to treat Cushing\u2019s syndrome \nand primary hyperaldosteronism but now largely restricted \nto veterinary indications) blocks an earlier enzyme in the pathway \u2013 the 3\u03b2-dehydrogenase. Aminoglutethimide inhibits \nthe initial step in the biosynthetic pathway and has the same overall effect as metyrapone.\nTrilostane and aminoglutethimide are not currently used \nin the United Kingdom but ketoconazole, an antifungal \nagent (Ch. 54), also inhibits steroidogenesis and may be of value in the specialised treatment of Cushing\u2019s syndrome. \nMitotane suppresses glucocorticoid synthesis by a direct \n(and unknown) mechanism on the adrenal gland. It is chiefly used to treat adrenocortical carcinomas.\nMechanism of glucocorticoid action\nThe glucocorticoid effects relevant to this discussion are initiated by interaction of the drugs with specific intracellular \nglucocorticoid receptors\n6 belonging to the nuclear receptor \n6Reader beware! The glucocorticoid receptor is also referred to as the \nType II corticosteroid receptor. The Type I corticosteroid receptor being \nwhat we more usually call the mineralocorticoid receptor (MR).Mechanism of action of the \nglucocorticoids \n\u2022\tGlucocorticoids \tbind \tintracellular \treceptors \tthat \tthen \t\ndimerise, migrate to the nucleus and interact with DNA \nto modify gene transcription, inducing synthesis of some proteins and inhibiting synthesis of others.\n\u2022\tMany\tacute \tglucocorticoid \tactions \tare \tmediated \tby \t\nsignalling systems triggered by the liganded receptor \nin\tthe\tcytosol. \tSome \tare \tvery \trapid.\n\u2022\tThere\tmay \tbe \tdifferent \tpopulations \tof \treceptors \t\nincluding membrane bound receptors which may also transduce rapid actions.\n\u2022\tTissue\tand \tspice \tvariants \tof \tthe \tglucocorticoid \t\nreceptor are found to be distributed in a tissue-specific fashion.\nActions\nGeneral metabolic and systemic effects\nThe main metabolic effects are on carbohydrate and protein \nmetabolism. The glucocorticoids cause both a decrease in \nthe uptake and utilisation of glucose and an increase in gluconeogenesis, resulting in a tendency to hyperglycaemia mebooksfree.net", "start_char_idx": 3482, "end_char_idx": 6800, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d57d4b0-be94-4983-92f2-c426018027fc": {"__data__": {"id_": "6d57d4b0-be94-4983-92f2-c426018027fc", "embedding": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fff825a5-980f-4a33-9ec5-45034f496869", "node_type": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48958b4d2f7b1573fee0c5d47dfc4bf235f51eb8feaa90dfd2d3b6410d369ff2"}, "2": {"node_id": "cc302f03-5698-4418-9f8b-d4c4f36f6d9f", "node_type": null, "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5ee5cfcd4dc5f7b57fac61030d67a50354c95335f84f639119de5d6bf8bd48b6"}}, "hash": "867b4d67e9450409400a53c77144c45c28c1675d430d5e9de55fe5822d255d71", "text": "resulting in a tendency to hyperglycaemia mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6804, "end_char_idx": 7325, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dfed8f9d-c594-4b62-91ec-c00b65a13f11": {"__data__": {"id_": "dfed8f9d-c594-4b62-91ec-c00b65a13f11", "embedding": null, "metadata": {"page_label": "447", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "30581b13-5955-4c1c-9b76-227c358212a8", "node_type": null, "metadata": {"page_label": "447", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "126590074ff44754754c85f8605a1fae695883d648f9dcf90aeaf242ef932dd6"}, "3": {"node_id": "68f95947-7920-4bdd-8a8b-70dd97c46727", "node_type": null, "metadata": {"page_label": "447", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3408e8605dbb50aeeddf31e9d7b450f18a84cb17718dd15501a0dc298f379186"}}, "hash": "8d1d324474ae35cf8d5584adf9d63af4286f8a2be087652939a281a09eb4a3c9", "text": "34 ThE pITUITARY AND T h E ADRENA l CORTE x\n441redistribution of body fat characteristic of Cushing\u2019s \nsyndrome (Fig. 34.7).\nGlucocorticoids tend to produce a negative calcium \nbalance by decreasing Ca2+ absorption in the GI tract and \nincreasing its excretion by the kidney. Together with \nincreased breakdown of bone matrix protein this may cause \nosteoporosis. In higher, non-physiological concentrations, the glucocorticoids have some mineralocorticoid actions, \ncausing Na\n+ retention and K+ loss \u2013 possibly by swamping \nthe protective 11 \u03b2-hydroxysteroid dehydrogenase and acting \nat mineralocorticoid receptors.(see Ch. 32). There is a concomitant increase in glycogen storage, which may be a result of insulin secretion in \nresponse to the increase in blood sugar. Overall, there is decreased protein synthesis and increased protein break -\ndown, particularly in muscle, and this can lead to tissue wasting. Catecholamines and some other hormones cause lipase activation through a cAMP-dependent kinase, the \nsynthesis of which requires the \u2018permissive\u2019 presence of \nglucocorticoids and are several other examples of this type of hormone action have been observed. Large doses of \nglucocorticoids given over a long period result in the Cholesterol\nACTH\nAngio II\nTrilostane\nMetapyrone\nCarbenoxolone\nAngio IIAmino-\nglutethimideOH1\n43529\n68\n7101213\n141617\n2720 23 2521 22 24 26\n1511\n19\nCholesterol\nAldosteronePregnenolone\nProgesterone\nCorticosterone Hydrocortisone\nCortisoneDehydroepi-\nandrosterone17\u03b1-OH-\npregnenolone17-\u03b1-OH\n21-\u03b2-OH\n11-\u03b2-OH\n11-\u03b2-dehyd21-\u03b2-OH11-\u03b2-OH17-\u03b1-OH\n17-\u03b1-OH3-\u03b2-dehyd 3-\u03b2-dehyd 3-\u03b2-dehyd\n17\u03b1-OH-\nprogesteroneAndrostenedione\nTestosterone\nMineralocorticoids Glucocorticoids Sex hormonesOestradiol\nOestriol\nOestrone\nFig. 34.5 Biosynthesis of corticosteroids, mineralocorticoids and sex hormones. All steroid hormones are synthesised from \ncholesterol. The biosynthetic pathway involves successive steps of hydroxylation and dehydrogenation and these are targets for drugs. \nIntermediates \tare \tshown \tin \tgreen boxes ; interconversions occur between the pathways. Blue boxes indicate circulating hormones. Drugs \nare shown in red-bordered boxes \tadjacent\tto \ttheir \tsites \tof \taction. \tGlucocorticoids \tare \tproduced \tby \tcells \tof \tthe \tzona \tfasciculata, \tand \ttheir \t\nsynthesis\tis \tstimulated \tby \tadrenocorticotrophic \thormone \t(ACTH); \taldosterone \tis \tproduced \tby \tcells \tof \tthe \tzona \tglomerulosa, \tand \tits \t\nsynthesis\tis \tstimulated \tby \tangiotensin \tII \t(angio \tII). \tMetyrapone \tinhibits \tglucocorticoid \tsynthesis, \taminoglutethimide \tand \ttrilostane \tblock \t\nsynthesis of all three types of adrenal steroid (see text for details). Carbenoxolone inhibits the interconversion of hydrocortisone and \ncortisone\tin \tthe \tkidney. \tNot \tshown \tis \tmitotane, \twhich \tsuppresses \tadrenal \thormone \tsynthesis \tthrough \tan \tunknown \tmechanism. \tEnzymes: \t\n17-\u03b1-OH, 17-\u03b1-hydroxylase; 3-\u03b2-dehyd,", "start_char_idx": 0, "end_char_idx": 2927, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "68f95947-7920-4bdd-8a8b-70dd97c46727": {"__data__": {"id_": "68f95947-7920-4bdd-8a8b-70dd97c46727", "embedding": null, "metadata": {"page_label": "447", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "30581b13-5955-4c1c-9b76-227c358212a8", "node_type": null, "metadata": {"page_label": "447", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "126590074ff44754754c85f8605a1fae695883d648f9dcf90aeaf242ef932dd6"}, "2": {"node_id": "dfed8f9d-c594-4b62-91ec-c00b65a13f11", "node_type": null, "metadata": {"page_label": "447", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d1d324474ae35cf8d5584adf9d63af4286f8a2be087652939a281a09eb4a3c9"}}, "hash": "3408e8605dbb50aeeddf31e9d7b450f18a84cb17718dd15501a0dc298f379186", "text": "17-\u03b1-hydroxylase; 3-\u03b2-dehyd, 3- \u03b2-dehydrogenase; 21-\u03b2-OH, 21-\u03b2-hydroxylase; 11-\u03b2-OH, 11-\u03b2-hydroxylase; 11-\u03b2-dehyd, \n11-\u03b2-hydroxysteroid dehydrogenase. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2899, "end_char_idx": 3529, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "eac2feb1-0ddf-4e04-998c-9a381846734c": {"__data__": {"id_": "eac2feb1-0ddf-4e04-998c-9a381846734c", "embedding": null, "metadata": {"page_label": "448", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "64009123-9510-48c2-8b17-fc140eccdcb1", "node_type": null, "metadata": {"page_label": "448", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23a844d6bc070cc205cc2c2e18245f53b07c9e9607bfa984ca9a197d388f4bdc"}, "3": {"node_id": "f38c5afb-61d2-47eb-9ddb-d022b4beee0c", "node_type": null, "metadata": {"page_label": "448", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "99aafee7020aa340154b13b90454ec86100f684a10352e43eed7e138dd8f6734"}}, "hash": "2854793363931d065eff70fd79839b465170cb4cd79ca2430ff162c2262f1097", "text": "34 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n442and injuries. On this basis, it has been suggested that a \nfailure of appropriate glucocorticoid secretion in response \nto injury or infection may underlie certain chronic inflam -\nmatory human pathologies.\nExogenous glucocorticoids are the anti-inflammatory drugs \npar excellence , and when given therapeutically, suppress the \noperation of both the innate and adaptive immune system. \nThey reverse virtually all types of inflammatory reaction, \nwhether caused by invading pathogens, by chemical or \nphysical stimuli, or by inappropriately deployed immune responses such as are seen in hypersensitivity or autoimmune disease. When used prophylactically to suppress graft rejec -\ntion, glucocorticoids are more efficient in suppressing the initiation and generation of the immune response than they are in preventing the operation of an established response \nwhere clonal proliferation has already occurred.Negative feedback effects on the anterior pituitary \nand hypothalamus\nBoth endogenous and exogenous glucocorticoids have a \nnegative feedback effect on the secretion of CRF and ACTH (see Fig. 34.4), thus inhibiting the secretion of endogenous \nglucocorticoids and potentially causing atrophy of the \nadrenal cortex. If therapy is prolonged, it may take many months to return to normal function once the drugs are \nstopped.\nAnti-inflammatory and immunosuppressive effects\nEndogenous glucocorticoids maintain a low-level anti-\ninflammatory tone, and are secreted in increased amounts \nin response to inflammatory stimuli. Consequently, adrenalectomised animals and humans with adrenal insuf -\nficiency show a heightened response to even mild insults +\n+\n+\n+A\nB\nC\nDGRETM\nGRETM\nnGRETM TFTF\nnGRETM\nAP-1TM\nAP-1TM\nTM TM\nNFBN FBFos Jun\nP\n65P\n50GR\u03b1GR\u03b1\nGR\u03b1GR\u03b1\nFos JunGR\u03b1GR\u03b1\nGR\u03b1GR\u03b1P\n65P\n50\nFig. 34.6 Molecular mechanism of action of glucocorticoids. The schematic figure shows four possible ways by which the liganded \nglucocorticoid receptor can control gene expression following translocation into the nucleus. (A) Basic transactivation mechanism. Here, the \ntranscriptional \tmachinery \t(TM) \tis \tpresumed \tto \tbe \toperating \tat \ta \tlow \tlevel. \tThe \tliganded \tglucocorticoid \treceptor \t(GR) \tdimer \tbinds \tto \tone \tor \t\nmore\t\u2018positive\u2019 \tglucocorticoid \tresponse \telements \t(GREs) \twithin \tthe \tpromoter \tsequence \t(shaded zone) and upregulates transcription. (B) \nBasic\ttransrepression \tmechanism. \tThe \tTM \tis \tconstitutively \tdriven \tby \ttranscription \tfactors \t(TF). \tIn \tbinding \tto \tthe \t\u2018negative\u2019 \tGRE \t(nGRE), \tthe \t\nreceptor complex displaces these factors and expression falls. (C) Fos/Jun mechanism. Transcription is driven at a high level by Fos/Jun \ntranscription \tfactors \tbinding \tto \ttheir \tAP-1 \tregulatory \tsite. \tThis \teffect \tis \treduced \tin \tthe \tpresence \tof \tthe \tGR. \t(D) \tNuclear \tfactor \t(NF)- \u03ba\u03b2 \nmechanism. \tThe \tTFs \tP65 \tand \tP50 \tbind \tto \tthe \tNF-\u03ba\u03b2\tsite,\tpromoting \tgene \texpression. \tThis \tis \tprevented \tby \tthe \tpresence \tof \tthe \tGR, \twhich \t\nbinds the TFs, preventing their action (this may occur in the cytoplasm also). (For further details of the structure of the glucocorticoid", "start_char_idx": 0, "end_char_idx": 3178, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f38c5afb-61d2-47eb-9ddb-d022b4beee0c": {"__data__": {"id_": "f38c5afb-61d2-47eb-9ddb-d022b4beee0c", "embedding": null, "metadata": {"page_label": "448", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "64009123-9510-48c2-8b17-fc140eccdcb1", "node_type": null, "metadata": {"page_label": "448", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23a844d6bc070cc205cc2c2e18245f53b07c9e9607bfa984ca9a197d388f4bdc"}, "2": {"node_id": "eac2feb1-0ddf-4e04-998c-9a381846734c", "node_type": null, "metadata": {"page_label": "448", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2854793363931d065eff70fd79839b465170cb4cd79ca2430ff162c2262f1097"}}, "hash": "99aafee7020aa340154b13b90454ec86100f684a10352e43eed7e138dd8f6734", "text": "also). (For further details of the structure of the glucocorticoid \nreceptor,\tsee \tCh. \t3.) \t(Redrawn \tfrom \tOakley \t& \tCidlowski, \t2001.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3112, "end_char_idx": 3729, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7921d4ee-9614-4b40-a6c9-a5216c534ade": {"__data__": {"id_": "7921d4ee-9614-4b40-a6c9-a5216c534ade", "embedding": null, "metadata": {"page_label": "449", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8d9a0294-31f5-49c5-a0dd-c28c6bf3decc", "node_type": null, "metadata": {"page_label": "449", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b7e4a59e2ba6fb350569bbb344286b4602742d3b5be1a691859f9b96dbe46346"}, "3": {"node_id": "8c00e6bd-4b8b-4c24-9f58-b333eab0c412", "node_type": null, "metadata": {"page_label": "449", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e13795b865f305186975b651c7843facf16c917afad89bb6cf2e486619dbf00"}}, "hash": "2735404e1608ee7552aebec2ce24633fed4b4d94168ca1e30d246362e36fae86", "text": "34 ThE pITUITARY AND T h E ADRENA l CORTE x\n443colony-stimulating factor. These are largely secondary \nto inhibition of gene transcription;\n\u2022\treduction \tin \tthe \tconcentration \tof \tcomplement \t\ncomponents in the plasma;\n\u2022\tdecreased \tgeneration \tof \tnitric \toxide \tby \tthe \tinducible \t\nnitric oxide synthase 2 (NOS2) isoform;\n\u2022\tdecreased \trelease \tof \thistamine \tand \tother \tmediators \t\nfrom basophils and mast cells;\n\u2022\tdecreased \timmunoglobulin \tG \t(IgG) \tproduction;\n\u2022\tincreased \tsynthesis \tof \tanti-inflammatory \tfactors \tsuch \t\nas IL-10, IL-1-soluble receptor and annexin 1.\nEndogenous anti-inflammatory glucocorticoids circulate constantly in the blood and are increased during inflam-\nmatory episodes \u2013 or even by the anticipation of a stressful \nevent. It is suggested (see Munck et al., 1984), that the \nanti-inflammatory and immunosuppressive actions of \nendogenous glucocorticoids play a crucial counter-regulatory \nrole, in that they prevent excessive activation of inflamma-\ntion and other powerful defence reactions that might, if unchecked, threaten homeostasis. Certainly, this view is \nborne out by experimental work. While these drugs are of \ngreat value in treating conditions characterised by hyper -\nsensitivity and unwanted inflammation, they carry the \nhazard that they are able to suppress the same defence \nreactions that protect us from infection and other insults.\nUnwanted effects\nLow-dose glucocorticoid replacement therapy is usually without problems but serious unwanted effects occur with \nlarge doses or prolonged administration of glucocorticoids. \nThe major effects are as follows:\n\u2022\tSuppression of the response to infection or injury: \nopportunistic infection can be potentially very serious \nunless quickly treated with antimicrobial agents along with an increase in the dose of steroid. Oral thrush \n(candidiasis, a fungal infection; see Ch. 54) frequently \noccurs when glucocorticoids are taken by inhalation, because of suppression of local anti-infective \nmechanisms. Wound healing is impaired, and peptic \nulceration may also occur.\n\u2022\tCushing\u2019s syndrome (see Fig. 34.7).\n\u2022\tOsteoporosis, with the attendant hazard of fractures, is one of the main limitations to long-term glucocorticoid therapy. These drugs influence bone density both by \nregulation of calcium and phosphate metabolism and \nthrough effects on collagen turnover. They reduce osteoblast function (which deposits bone matrix) and increase the activity of osteoclasts (which digest bone \nmatrix). An effect on the blood supply to bone can \nresult in avascular necrosis of the head of the femur (see Ch. 37).\n\u2022\tHyperglycaemia produced by exogenous glucocorticoids may develop into frank diabetes.\n\u2022\tMuscle wasting and proximal muscle weakness.\n\u2022\tIn\tchildren, \tinhibition of growth7 if treatment is \ncontinued for more than 6 months.\n\u2022\tCNS effects: euphoria and psychosis with short-term administration, depression with chronic treatment.Given that glucocorticoids modify the expression of so \nmany genes (approximately 1% of the total genome is affected), and that the extent and direction of regulation varies between tissues and even at different times during \ndisease, you will not be surprised to learn that their anti-\ninflammatory effects are complex.\nActions on inflammatory cells include:\n\u2022\tdecreased \tegress \tof \tneutrophils \tfrom \tblood \tvessels \t\nand reduced activation of neutrophils, macrophages and mast cells secondary to decreased transcription of \nthe genes for cell adhesion factors and", "start_char_idx": 0, "end_char_idx": 3510, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8c00e6bd-4b8b-4c24-9f58-b333eab0c412": {"__data__": {"id_": "8c00e6bd-4b8b-4c24-9f58-b333eab0c412", "embedding": null, "metadata": {"page_label": "449", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8d9a0294-31f5-49c5-a0dd-c28c6bf3decc", "node_type": null, "metadata": {"page_label": "449", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b7e4a59e2ba6fb350569bbb344286b4602742d3b5be1a691859f9b96dbe46346"}, "2": {"node_id": "7921d4ee-9614-4b40-a6c9-a5216c534ade", "node_type": null, "metadata": {"page_label": "449", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2735404e1608ee7552aebec2ce24633fed4b4d94168ca1e30d246362e36fae86"}}, "hash": "1e13795b865f305186975b651c7843facf16c917afad89bb6cf2e486619dbf00", "text": "cells secondary to decreased transcription of \nthe genes for cell adhesion factors and cytokines;\n\u2022\tdecreased \toverall \tactivation \tof \tT-helper \t(Th) \tcells, \t\nreduced clonal proliferation of T cells, and a \u2018switch\u2019 \nfrom the Th1 to the Th2 immune response (see Ch. 7);\n\u2022\tdecreased \tfibroblast \tfunction, \tless \tproduction \tof \t\ncollagen and glycosaminoglycans, and, under some circumstances, reduced healing and repair.\nActions on the mediators of inflammatory and immune responses (Chs 18 and 19) include:\n\u2022\tdecreased \tproduction \tof \tprostanoids \tthrough \treduced \t\nexpression of cyclo-oxygenase II and suppression of substrate arachidonic acid release;\n\u2022\tdecreased \tgeneration \tof \tmany \tcytokines, \tincluding \t\nIL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-\u03b1, cell adhesion factors and granulocyte\u2013macrophage Also:\nOsteoporosisTendency to hyperglycaemiaNegative nitrogen balanceIncreased appetiteIncreased susceptibility to infectionObesity(Benign intracranial\nhypertension)\n(Cataracts)\nMoon face, with red\n(plethoric) cheeks\nIncreased \nabdominal fat\n(Avascular necrosis\nof femoral head)\nEasy bruising\nPoor wound\nhealingBuffalo hump\n(Hypertension)\nThinning\nof skinEuphoria\n(though sometimes depression or psychoticsymptoms, and emotional lability)\nThin arms\nand legs:muscle wasting\nFig. 34.7 Cushing\u2019s syndrome. This is caused by excessive \nexposure to endogenous glucocorticoids, by disease (e.g. an \nadrenocorticotrophic hormone-secreting tumour) or by prolonged administration of glucocorticoid drugs ( iatrogenic \nCushing\u2019s syndrome). Italicised effects are particularly common. \nLess\tfrequent \teffects, \trelated \tto \tdose \tand \tduration \tof \ttherapy, \t\nare shown in parentheses .\t(Redrawn \tfrom \tBaxter \t& \tRousseau, \t\n1979)\n7However, some of the diseases for which glucocorticoids are indicated \nthemselves retard growth. In a classical trial, glucocorticoid treatment \nincreased growth in adolescents with inflammatory bowel disease as the \ndisease resolved (Whittington et al., 1977).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3424, "end_char_idx": 5903, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d899a16b-0fc6-4d30-988d-7d9cc3d9c5b9": {"__data__": {"id_": "d899a16b-0fc6-4d30-988d-7d9cc3d9c5b9", "embedding": null, "metadata": {"page_label": "450", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2926298c-ec4f-453b-9824-e36cb8bd97c9", "node_type": null, "metadata": {"page_label": "450", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7254ea083f3f584996f9005dc8803203b4268c5f1f1ecdd2fc1134947efccca"}, "3": {"node_id": "33ed7693-2f69-4c8d-a5b0-97027e9a1123", "node_type": null, "metadata": {"page_label": "450", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27b0b47ae9babb38c30db049cbf8622132dc9dfb9bb669594ab49634fff614b9"}}, "hash": "91558ecbb18278851e629b4fcd2850df890976f41eec1334b1783ffc0c94493d", "text": "34 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n444\u2022\tOther effects: glaucoma (in genetically predisposed \npersons), raised intracranial pressure and an increased \nincidence of cataracts.\nSudden withdrawal of the drugs after prolonged therapy \nmay result in acute adrenal insufficiency because of sup -\npression of the patient\u2019s capacity to synthesise cortico -\nsteroids.8 Careful procedures for phased withdrawal should \nbe followed. Recovery of full adrenal function usually takes \nabout 8 weeks, although it can take 18 months or more \nafter prolonged high-dose treatment.\nPharmacokinetic aspects\nThere are many glucocorticoid drugs in therapeutic use. Although cortisol (hydrocortisone), the endogenous \nhormone, is often used, synthetic derivatives are even more common. These have different physicochemical properties as well as varying potencies and have been optimised for \nadministration by oral, systemic or intra-articular routes \nor for topical application such as by aerosol directly into the respiratory tract or nose or as eye drops. They may be \nformulated as creams or ointments for application to the \nskin (see Ch. 28); or as foam enemas for the GI tract (Ch. 31). Topical administration diminishes the likelihood of systemic toxic effects unless large quantities are used. When \nprolonged use of systemic glucocorticoids is necessary, \ntherapy on alternate days may decrease suppression of the HPA axis and other unwanted effects.\nEndogenous glucocorticoids are transported in the plasma \nbound to corticosteroid-binding globulin (CBG) and to albumin. \nAbout 77% of plasma hydrocortisone is bound to CBG, but \nmany synthetic glucocorticoids are not bound at all. Albumin \nhas a lower affinity for hydrocortisone but binds both natural and synthetic steroids. Both CBG-bound and albumin-bound \nsteroids are biologically inactive. Hydrocortisone has a \nplasma half-life of 90 min, although many of its biological \neffects have a latency of 2\u20138 h.\nAs small lipophilic molecules, glucocorticoids probably \nenter their target cells by simple diffusion. Biological inactivation, which occurs in liver cells and elsewhere, is \ninitiated by reduction of the C4\u2013C5 double bond. Cortisone and prednisone are inactive until converted in vivo by the \n11\u03b2 dehydrogenase type 1 to hydrocortisone and predni-\nsolone, respectively.\nThe clinical uses of systemic glucocorticoids are sum -\nmarised in the clinical box. Dexamethasone has a special use: it is used to test HPA axis function. In the dexametha -\nsone suppression test a relatively low dose of dexamethasone is given, usually at night. This would be expected to suppress \nthe hypothalamus and pituitary, resulting in a reduced \nACTH secretion and hydrocortisone output in the plasma \nabout 9 h later. Failure of suppression implies hypersecretion \nof ACTH or of glucocorticoids (Cushing\u2019s syndrome).\nMINERALOCORTICOIDS\nThe main endogenous mineralocorticoid is aldosterone. Its chief action is to increase Na\n+ reabsorption by the distal \ntubules in the kidney, with a concomitant increase in \nexcretion of K+ and H+ (see Ch. 30). An excessive secretion \nof mineralocorticoids, as in Conn\u2019s syndrome , causes marked \nNa+ and water retention, with increased extracellular fluid Actions of glucocorticoids \nCommon drugs used systemically include \nhydrocortisone, prednisolone and dexamethasone.\nMetabolic actions\n\u2022\tCarbohydrates: decreased", "start_char_idx": 0, "end_char_idx": 3412, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "33ed7693-2f69-4c8d-a5b0-97027e9a1123": {"__data__": {"id_": "33ed7693-2f69-4c8d-a5b0-97027e9a1123", "embedding": null, "metadata": {"page_label": "450", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2926298c-ec4f-453b-9824-e36cb8bd97c9", "node_type": null, "metadata": {"page_label": "450", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7254ea083f3f584996f9005dc8803203b4268c5f1f1ecdd2fc1134947efccca"}, "2": {"node_id": "d899a16b-0fc6-4d30-988d-7d9cc3d9c5b9", "node_type": null, "metadata": {"page_label": "450", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91558ecbb18278851e629b4fcd2850df890976f41eec1334b1783ffc0c94493d"}}, "hash": "27b0b47ae9babb38c30db049cbf8622132dc9dfb9bb669594ab49634fff614b9", "text": "actions\n\u2022\tCarbohydrates: decreased uptake and utilisation of glucose accompanied by increased gluconeogenesis; this causes a tendency to hyperglycaemia.\n\u2022\tProteins: increased catabolism, reduced anabolism.\n\u2022\tLipids: a permissive effect on lipolytic hormones and a redistribution of fat, as observed in Cushing\u2019s syndrome.\nRegulatory actions\n\u2022\tHypothalamus and anterior pituitary gland : a negative \nfeedback action resulting in reduced release of ACTH and therefore endogenous glucocorticoids.\n\u2022\tCardiovascular system: reduced vasodilatation, decreased fluid exudation.\n\u2022\tMusculoskeletal: decreased osteoblast and increased osteoclast activity.\n\u2022\tInflammation and immunity:\n\u2013 in acute inflammation: decreased influx and activity \nof leukocytes;\n\u2013 in chronic inflammation: decreased activity of \nmononuclear cells, decreased angiogenesis, less fibrosis;\n\u2013 in lymphoid tissues: decreased clonal expansion of \nT and B cells, and decreased action of cytokine-\nsecreting\tT \tcells. \tSwitch \tfrom \tTh1 \tto \tTh2 \tresponse;\n\u2013 decreased production and action of many pro-\ninflammatory cytokines, including interleukins, tumour necrosis factor- \u03b1 and granulocyte\u2013\nmacrophage colony-stimulating factor;\n\u2013 reduced generation of eicosanoids;\n\u2013\tdecreased \tgeneration \tof \tIgG;\n\u2013 decrease in complement components in the blood;\n\u2013 increased release of anti-inflammatory factors such \nas\tinterleukin \t(IL)-10, \tIL-1ra \tand \tannexin \t1.\n\u2022\tOverall\teffects: \treduction \tin \tthe \tactivity \tof \tthe \tinnate \t\nand\tacquired \timmune \tsystems, \tbut \talso \tdiminution \tin \t\nthe protective aspects of the inflammatory response and sometimes decreased healing.\n8Patients on long-term glucocorticoid therapy are advised to carry a \ncard stating, \u2018I am a patient on STEROID TREATMENT which must not \nbe stopped abruptly\u2019.volume and sometimes hypokalaemia, alkalosis and \nhypertension. Decreased secretion, as in some patients with \nAddison\u2019s disease, causes Na+ loss and a marked decrease \nin extracellular fluid volume. There is a concomitant decrease in the excretion of K\n+, resulting in hyperkalaemia.\nRegulation of aldosterone synthesis and release\nThe regulation of the synthesis and release of aldosterone \ndepends mainly on the electrolyte composition of the \nplasma and on the activity of the angiotensin II system \n(see Fig. 34.4; Chs 23 and 30). Low plasma Na+ or high \nplasma K+ concentrations directly stimulate aldosterone \nrelease from the zona glomerulosa cells of the adrenal. \nDepletion of Na+ also activates the renin\u2013angiotensin system \n(see Ch. 23, Fig. 23.4). One of the effects of angiotensin II is to increase the synthesis and release of aldosterone (see \nCh. 30, Fig. 30.5).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3378, "end_char_idx": 6526, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a381370e-26fc-4243-a959-a2564dabbf6d": {"__data__": {"id_": "a381370e-26fc-4243-a959-a2564dabbf6d", "embedding": null, "metadata": {"page_label": "451", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73c223ef-4a3b-48ce-a7a8-1d74ddb38fe2", "node_type": null, "metadata": {"page_label": "451", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19bcafefe98eda0966fc7abc97cd77465d0ef1f75423b9d36a3774f06e21886b"}, "3": {"node_id": "37a81382-4c25-49bc-a08e-ac445af7e11b", "node_type": null, "metadata": {"page_label": "451", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b862964de9413839cae3925013d661070e5cd648fb1f8ae7ab22161c1146b6aa"}}, "hash": "6b5b796e360d3d7c358ac8783db1229807271d4dc4c84bb47fd73d19d98db460", "text": "34 ThE pITUITARY AND T h E ADRENA l CORTE x\n445enzyme is inhibited by carbenoxolone, a compound derived \nfrom liquorice (and previously used to treat gastric ulcers; \nsee Ch. 31). If this inhibition is marked, cortisol accumulates \nand acts on the mineralocorticoid receptor, producing an effect similar to Conn\u2019s syndrome ( primary hyperaldosteron -\nism) except that the circulating aldosterone concentration is not raised.\nAs with the glucocorticoids, the interaction of aldosterone \nwith its receptor initiates transcription and translation of specific proteins, resulting in an increase in the number of sodium channels in the apical membrane of the renal tubular cell, and subsequently an increase in the number of Na\n+-\nK+-ATPase molecules in the basolateral membrane (see Fig. \n30.5), causing increased K+ excretion (see Ch. 30). In addition \nto the genomic effects, there is evidence for a rapid non-\ngenomic effect of aldosterone on Na+ influx, through an \naction on the Na+-H+ exchanger in the apical membrane.\nClinical use of mineralocorticoids and antagonists\nThe main clinical use of mineralocorticoids is replacement therapy of patients with Addison\u2019s disease. The most \ncommonly used drug is fludrocortisone (see Table 34.2 \nand Fig. 34.4), which can be taken orally to supplement \nthe necessary glucocorticoid replacement. Spironolactone \nis a competitive antagonist of aldosterone, and it also prevents the mineralocorticoid effects of other adrenal steroids on the renal tubule (Ch. 30). Side effects include \ngynaecomastia and impotence, because spironolactone also \nhas some blocking action on androgen and progesterone receptors. It is used to treat primary or secondary hyper -\naldosteronism and, in conjunction with other drugs, for \nthe treatment of resistant hypertension and of heart failure \n(Ch. 23) and oedema (Ch. 30). Eplerenone has a similar \nindication and mechanism of action, although fewer side \neffects as it has lower affinity for sex hormone receptors \n(Ch. 23).\nMechanism of action\nLike other steroid hormones, aldosterone acts through specific intracellular receptors of the nuclear receptor family. \nUnlike the glucocorticoid receptor, which is present in most \ncells, the mineralocorticoid receptor (also called the corticosteroid \nreceptor Type I) is restricted to a few tissues, such as the \nkidney and the transporting epithelia of the colon and \nbladder. Cells containing mineralocorticoid receptors also contain the 11 \u03b2-hydroxysteroid dehydrogenase type 2 \nenzyme, which converts hydrocortisone (cortisol) into inactive cortisone, but does not inactivate aldosterone. This ensures that the cells are appropriately affected only by the mineralocorticoid hormone itself. Interestingly, this Clinical uses of glucocorticoids \n\u2022\tReplacement \ttherapy \tfor \tpatients \twith \tadrenal \tfailure \t\n(Addison\u2019s disease).\n\u2022\tAnti-inflammatory/immunosuppressive \ttherapy \t(see \t\nalso Ch. 27):\n\u2013 in asthma\t(Ch.\t29)\n\u2013 topically in various inflammatory conditions of skin, \neye, ear or nose (e.g. eczema, allergic conjunctivitis \nor rhinitis; see Ch. 28)\n\u2013 hypersensitivity states (e.g. severe allergic reactions)\n\u2013 in miscellaneous diseases with autoimmune and \ninflammatory components (e.g. rheumatoid arthritis \nand other \u2018connective tissue\u2019 diseases, inflammatory \nbowel diseases , some forms of haemolytic anaemia , \nidiopathic", "start_char_idx": 0, "end_char_idx": 3369, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "37a81382-4c25-49bc-a08e-ac445af7e11b": {"__data__": {"id_": "37a81382-4c25-49bc-a08e-ac445af7e11b", "embedding": null, "metadata": {"page_label": "451", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73c223ef-4a3b-48ce-a7a8-1d74ddb38fe2", "node_type": null, "metadata": {"page_label": "451", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19bcafefe98eda0966fc7abc97cd77465d0ef1f75423b9d36a3774f06e21886b"}, "2": {"node_id": "a381370e-26fc-4243-a959-a2564dabbf6d", "node_type": null, "metadata": {"page_label": "451", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b5b796e360d3d7c358ac8783db1229807271d4dc4c84bb47fd73d19d98db460"}}, "hash": "b862964de9413839cae3925013d661070e5cd648fb1f8ae7ab22161c1146b6aa", "text": "diseases , some forms of haemolytic anaemia , \nidiopathic thrombocytopenic purpura)\n\u2013 to prevent graft-versus-host disease following organ \nor bone marrow transplantation\n\u2022\tIn\tneoplastic \tdisease \t(Ch. \t57):\n\u2013 in combination with cytotoxic drugs in treatment of \nspecific malignancies (e.g. Hodgkin\u2019s disease , acute \nlymphocytic leukaemia)\n\u2013 to reduce cerebral oedema in patients with \nmetastatic or primary brain tumours \n(dexamethasone).Mineralocorticoids \nFludrocortisone is given orally to produce a mineralocorticoid effect. This drug:\n\u2022\tincreases \tNa+ reabsorption in distal tubules and \nincreases K+ and H+ efflux into the tubules;\n\u2022\tacts\ton \tintracellular \treceptors \tthat \tmodulate \tDNA \t\ntranscription, causing synthesis of Na+ channel and \nother proteins that mediate the effect of the drug;\n\u2022\tmay\tbe \tused \ttogether \twith \ta \tglucocorticoid \tin \t\nreplacement therapy regimes.Pharmacokinetics and unwanted \nactions of the glucocorticoids \n\u2022\tAdministration \tcan \tbe \toral, \ttopical \tor \tparenteral. \tMost \t\nnaturally occurring glucocorticoids are transported in the blood by corticosteroid-binding globulin or albumen and enter cells by diffusion. They are \nmetabolised in the liver.\n\u2022\tUnwanted \teffects \tare \tseen \tmainly \tafter \tprolonged \t\nsystemic use as anti-inflammatory or \nimmunosuppressive agents but not usually following replacement therapy. The most important of these are:\n\u2013 suppression of response to infection\n\u2013 suppression of endogenous glucocorticoid synthesis\n\u2013 metabolic actions (see earlier)\n\u2013 osteoporosis\n\u2013\tiatrogenic \tCushing\u2019s \tsyndrome \t(see \tFig. \t34.7)\nNEW DIRECTIONS IN GLUCOCORTICOID \nTHERAPY\nGlucocorticoids are highly effective in controlling inflam -\nmation, but their utility is constrained by their potentially \nharmful side effects. The ideal solution would be a gluco -\ncorticoid possessing the anti-inflammatory but not the \nunwanted metabolic or other effects.\nFollowing the discovery of cortisol, the pharmaceutical \nindustry pursued this ambitious goal by testing straight -\nforward structural analogues of cortisol. While this yielded mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3312, "end_char_idx": 5879, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "be2204da-aa24-47c6-a1bf-981bc81dbeac": {"__data__": {"id_": "be2204da-aa24-47c6-a1bf-981bc81dbeac", "embedding": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e130cb5f-021e-4944-bde3-bdb43f2b5c97", "node_type": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cc92b524d9d43506ee9ac939de727914f497b0c72d2f78ed874c01135b7f452d"}, "3": {"node_id": "005f1136-a4d1-4f71-90bf-76e37b68fbd4", "node_type": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3086c67c8b2f4e8e4981d560f46b72c60c6905725dd4fa996eb7db1e6c7b659"}}, "hash": "3f6b0ede3d8757f75b90860db325a038608cd0691f2d4d3dde1357d72c85ef92", "text": "34 SECTION 3 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n446Because transactivation and transrepression utilise dif-\nferent molecular pathways (see Fig. 34.6) which depend \nupon different conformational states of the GR, researchers \nhave sought Selective Glucocorticoid Receptor Agonists \n(SEGRAs) that promote one set of actions without the \nother. The application of this idea has been reviewed by \nSchacke et al. (2007) and the development of compounds \nfor treating skin and ocular conditions has been reported \n(Schacke et al., 2009; Spinelli et al., 2014). However, some \nanti-inflammatory effects of glucocorticoids do not fit neatly \ninto this scheme (Vandevyver et al., 2013); its shortcomings \nhave been reviewed by Clark and Belvisi (2012).\nAnother approach focuses upon the histone deacetylase \nenzymes that facilitate the transcriptional regulation of \ngenes following nuclear receptor binding to hormone \nresponse elements (Hayashi et al., 2004). There may be a \nspecific isoform of this enzyme that deals with gene up-regulation, and if this could be inhibited, it would lessen \nthe possibility of those unwanted effects. Barnes (2011) has \nreviewed this approach, particularly as it relates to the \ntherapy of asthma. A more general review of the whole \narea, with particular relevance to the treatment of rheumatic \ndiseases, has been provided by Strehl et al. (2011). Other \nmolecular tactics that show promise include the use of \nGILZ (Glucocorticoid-Induced Leucine Zipper protein) as \na therapeutic agent (Beaulieu & Morand, 2011) or exploita -\ntion of the cytosolic, non-genomic actions of these drugs \n(Jiang et al., 2014)\nThe quest for the glucocorticoid magic bullet continues.many new active and interesting compounds (several of which are in clinical use today), none achieved a true \n\u2018separation\u2019 of the glucocorticoid actions. There have been \nrecently been fresh attempts to accomplish this. The develop -\nment of structural analogues at novel sites on the steroid \ntemplate (e.g. Uings et al ., 2013 ) has met with more success, \nand structural details of the receptor revealed by X-ray crystallography has enabled the design of non-steroidal \nreceptor ligands (see, for example, Biggadike et al., 2009; \nHe et al., 2014). Another approach has been to add other \nfunctional groups on to the steroid molecule, which alters \nthe conformation of the liganded receptor. Fiorucci et al. \n(2002) attached a nitric oxide donating group to predniso -\nlone, finding augmented efficacy and reduced unwanted \neffects. The compound is reported to be useful in the \ntreatment of inflammatory bowel disease (see Schacke et al., \n2007). The design of \u2018soft\u2019 glucocorticoids which are rapidly \nmetabolised to inactive species thereby limiting their capac -\nity for producing side effects is also being investigated (see \nDobricic et al., 2017).\nMany investigators in this area have been influenced by \nthe \u2018dissociated steroids\u2019 or \u2018transrepression hypothesis\u2019: this \nis the notion, based upon some experimental observations, \nthat the anti-inflammatory effects of glucocorticoids are generally caused by the down-regulation (transrepression) \nof genes such as those coding for cytokines, whilst the \nunwanted effects are usually caused by up-regulation ( trans -\nactivation ) of metabolic and other genes (e.g. tyrosine amino \ntransferase and phosphoenol pyruvate carboxykinase). \nREFERENCES AND FURTHER READING\nThe hypothalamus and pituitary\nChan,", "start_char_idx": 0, "end_char_idx": 3479, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "005f1136-a4d1-4f71-90bf-76e37b68fbd4": {"__data__": {"id_": "005f1136-a4d1-4f71-90bf-76e37b68fbd4", "embedding": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e130cb5f-021e-4944-bde3-bdb43f2b5c97", "node_type": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cc92b524d9d43506ee9ac939de727914f497b0c72d2f78ed874c01135b7f452d"}, "2": {"node_id": "be2204da-aa24-47c6-a1bf-981bc81dbeac", "node_type": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f6b0ede3d8757f75b90860db325a038608cd0691f2d4d3dde1357d72c85ef92"}, "3": {"node_id": "56c0e92e-a489-4f84-8969-950c69a39d62", "node_type": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a08fc9a8e0ed9f34bde2d2915df43d6e40cb5a37f8b2a00dfcc407b947b33895"}}, "hash": "f3086c67c8b2f4e8e4981d560f46b72c60c6905725dd4fa996eb7db1e6c7b659", "text": "AND FURTHER READING\nThe hypothalamus and pituitary\nChan, L.F., Clark, A.J., Metherell, L.A., 2008. Familial glucocorticoid \ndeficiency: advances in the molecular understanding of ACTH action. \nHorm. Res. 69, 75\u201382. (This paper and the one by the same group below \n(Clark et al.) discuss research into the role of the ACTH signalling system in \nfamilial glucocorticoid deficiency. An expert piece of scientific detective work. \nThe second paper is more accessible)\nChini, B., Manning, M., Guillon, G., 2008. Affinity and efficacy of \nselective agonists and antagonists for vasopressin and oxytocin receptors: an \u2018easy guide\u2019 to receptor pharmacology. Prog. Brain Res. \n170, 513\u2013517. (The title is self-explanatory! Also deals with the prospects for \nnew drugs in this area)\nClark, A.J., Metherell, L.A., Cheetham, M.E., Huebner, A., 2005. \nInherited ACTH insensitivity illuminates the mechanisms of ACTH action. Trends Endocrinol. Metab. 16, 451\u2013457. (\nSee also Chan et al. \nabove)\nDrolet, G., Rivest, S., 2001. Corticotropin-releasing hormone and its \nreceptors; an evaluation at the transcription level in vivo. Peptides 22, \n761\u2013767.\nFreeman, M.E., Kanyicska, B., Lerant, A., Nagy, G., 2000. \nProlactin: structure, function and regulation of secretion. Physiol. \nRes. 80, 1524\u20131585. (Comprehensive review of prolactin and its receptors)\nGetting, S.J., Christian, H.C., Flower, R.J., Perretti, M., 2002. Activation \nof melanocortin type 3 receptor as a molecular mechanism for adrenocorticotropic hormone efficacy in gouty arthritis. Arthritis \nRheum. 46, 2765\u20132775. (Original paper that demonstrates that ACTH has \nintrinsic anti-inflammatory actions that are independent of adrenal stimulation)\nGuillemin, R., 2005. Hypothalamic hormones a.k.a. hypothalamic \nreleasing factors. J. Endocrinol. 184, 11\u201328. (This little review focuses on the history of research in this field and covers the discovery and \ncharacterisation of the principal releasing factors. Something to read if you \nare drawn to this area)\nLamberts, S.W.J., van der Lely, A.J., de Herder, W.W., Hofland, L.J., \n1996. Octreotide. N. Engl. J. Med. 334, 246\u2013254. (A review covering somatostatin receptors, somatostatin analogues and treatment of tumours expressing somatostatin receptors with octreotide)Schneider, F., Tomek, W., Grundker, C., 2006. Gonadotropin-releasing \nhormone (GnRH) and its natural analogues: a review. Theriogenology 66, 691\u2013709. (Focuses mainly on the use of such agents in veterinary \nmedicine)\nThibonnier, M., Coles, P., Thibonnier, A., et al., 2001. The basic and \nclinical pharmacology of nonpeptide vasopressin receptor antagonists. \nAnnu. Rev. Pharmacol. 41, 175\u2013202. (Authoritative account of ADH \nreceptors and the search for new antagonists)\nWikberg, J.E.S., Muceniece, R., Mandrika, I., et al., 2000. New aspects on \nthe melanocortins and their receptors. Pharmacol. Res. 42, 393\u2013420. \n(Detailed review of the varied biological roles of melanocortins and their", "start_char_idx": 3429, "end_char_idx": 6398, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "56c0e92e-a489-4f84-8969-950c69a39d62": {"__data__": {"id_": "56c0e92e-a489-4f84-8969-950c69a39d62", "embedding": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e130cb5f-021e-4944-bde3-bdb43f2b5c97", "node_type": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cc92b524d9d43506ee9ac939de727914f497b0c72d2f78ed874c01135b7f452d"}, "2": {"node_id": "005f1136-a4d1-4f71-90bf-76e37b68fbd4", "node_type": null, "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3086c67c8b2f4e8e4981d560f46b72c60c6905725dd4fa996eb7db1e6c7b659"}}, "hash": "a08fc9a8e0ed9f34bde2d2915df43d6e40cb5a37f8b2a00dfcc407b947b33895", "text": "\n(Detailed review of the varied biological roles of melanocortins and their \nreceptors)\nGlucocorticoids\nBarnes, P.J., 2011. Glucocorticosteroids: current and future directions. \nBr. J. Pharmacol. 163 (1), 29\u201343. (Useful and accessible review focusing on general mechanisms with especial reference to asthma)\nBeaulieu, E., Morand, E.F., 2011. Role of GILZ in immune regulation, \nglucocorticoid actions and rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 340\u2013348. (Details the role of glucocorticoid-induced leucine zipper protein \nin GC action and speculates that it could be used as a stand-alone therapeutic agent with some advantages over GC treament)\nButtgereit, F., Scheffold, A., 2002. Rapid glucocorticoid effects on \nimmune cells. Steroids 67, 529\u2013534. (A short paper which details some of the effects of GCs on cells which can\u2019t be accounted for by genomic \nmechanisms)\nBaxter, J.D., Rousseau, G.G. (Eds.), 1979. Glucocorticoid Hormone \nAction. Monographs on Endocrinology. Springer-Verlag, Berlin, p. 12. (Another very useful source of information although it is somewhat dated \nnow)\nBiggadike, K., Bledsoe, R.K., Coe, D.M., et al., 2009. Design and x-ray \ncrystal structures of high-potency nonsteroidal glucocorticoid agonists exploiting a novel binding site on the receptor. Proc. Natl. Acad. Sci. \nU. S. A. 106, 18114\u201318119. (Explores the design of new non-steroid drugs \nthat bind to the glucocorticoid receptor)\nBuckingham, J.C., 1998. Stress and the hypothalamo\u2013pituitary\u2013immune \naxis. Int. J. Tissue React. 20, 23\u201334. (Excellent review of the complexities of the effect of stress on HPA axis function)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6374, "end_char_idx": 8470, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "08792c8f-b935-4cda-8690-67891a48eb98": {"__data__": {"id_": "08792c8f-b935-4cda-8690-67891a48eb98", "embedding": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c350c827-c430-45af-859a-903d2cb39e48", "node_type": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "072c0476d61bdd7bdcf66ee36a8d5137a76e13d415ae196692217ef2693c2263"}, "3": {"node_id": "6822f32b-1581-4212-92c9-4cf2755192d6", "node_type": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69a42c287549999e5bac309153c785b0278395dfebbbee2a69dd480b34fd42e6"}}, "hash": "bbd6cfb17c632502aab12f22dc39f3855fa3e7cfee1b72ef3c05516693b4dbfe", "text": "34 ThE pITUITARY AND ThE ADRENAl CORTEx\n447Clin. Immunol. 132, 1033\u20131044. ( A fascinating account of the role of splice \nvariants and GR isoforms in glucocorticoid action )\nSpinelli, S.L., Xi, X., McMillan, D.H., et al., 2014. Mapracorat, a selective \nglucocorticoid receptor agonist, upregulates RelB, an \nanti-inflammatory nuclear factor-kappaB protein, in human ocular \ncells. Exp. Eye Res. 127, 290\u2013298.\nReichardt, H.M., Kaestner, K.H., Tuckermann, J., et al., 1998. DNA \nbinding of the glucocorticoid receptor is not essential for survival. \nCell 93, 531\u2013541. ( An account of the work that changed the way we think \nabout glucocorticoid receptor actions )\nSchacke, H., Berger, M., Rehwinkel, H., Asadullah, K., 2007. Selective \nglucocorticoid receptor agonists (SEGRAs): novel ligands with an \nimproved therapeutic index. Mol. Cell. Endocrinol. 275, 109\u2013117. ( This \npaper and the next describe the ideas behind the \u2018SEGRA\u2019 concept and the \ndrugs that have been produced as a result )\nSchacke, H., Zollner, T.M., Docke, W.D., et al., 2009. Characterization of \nZK 245186, a novel, selective glucocorticoid receptor agonist for the \ntopical treatment of inflammatory skin diseases. Br. J. Pharmacol. 158, \n1088\u20131103.\nSong, I.H., Gold, R., Straub, R.H., et al., 2005. New glucocorticoids on \nthe horizon: repress, don\u2019t activate! J. Rheumatol. 32, 1199\u20131207. ( Good \nsummary of the various approaches taken to circumvent glucocorticoid side \neffects )\nStrehl, C., Spies, C.M., Buttgereit, F., 2011. Pharmacodynamics of \nglucocorticoids. Clin. Exp. Rheumatol. 29, S13\u2013S18. ( General review of \nglucocorticoid mechanisms with especial reference to the treatment of \nrheumatic disorders )\nTak, P.P., Firestein, G.S., 2001. NF-kappaB: a key role in inflammatory \ndiseases. J. Clin. Invest. 107, 7\u201311. ( Succinct and very readable account of \nthe role of nuclear factor (NF) \u03ba\u03b2 in inflammation )\nTalaber, G., Jondal, M., Okret, S., 2015. Local glucocorticoid production \nin the thymus. Steroids 103, 58\u201363. ( One of two recent papers [see \nHannen et al. above] that overturn the idea that GCs can only be synthesised \nin the adrenal cortex )\nUings, I.J., Needham, D., Matthews, J., et al., 2013. Discovery of \nGW870086: a potent anti-inflammatory steroid with a unique \npharmacological profile. Br. J. Pharmacol. 169, 1389\u20131403.\nVandevyver, S., Dejager, L., Tuckermann, J., Libert, C., 2013. New \ninsights into the anti-inflammatory mechanisms of glucocorticoids: an \nemerging role for glucocorticoid-receptor-mediated transactivation. \nEndocrinology 154, 993\u20131007.\nMineralocorticoids\nBastl, C., Hayslett, J.P., 1992. The cellular action of aldosterone in target \nepithelia. Kidney Int. 42, 250\u2013264. ( A detailed review covering the \naldosterone receptor and regulation of gene expression, aldosterone action on \nelectrogenic and electroneutral Na+ transport, and on K+ and H+ secretion )\nJaisser, F., Farman,", "start_char_idx": 0, "end_char_idx": 2907, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6822f32b-1581-4212-92c9-4cf2755192d6": {"__data__": {"id_": "6822f32b-1581-4212-92c9-4cf2755192d6", "embedding": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c350c827-c430-45af-859a-903d2cb39e48", "node_type": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "072c0476d61bdd7bdcf66ee36a8d5137a76e13d415ae196692217ef2693c2263"}, "2": {"node_id": "08792c8f-b935-4cda-8690-67891a48eb98", "node_type": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bbd6cfb17c632502aab12f22dc39f3855fa3e7cfee1b72ef3c05516693b4dbfe"}, "3": {"node_id": "59d23f56-810b-473b-8df8-106595807acb", "node_type": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ace92eedb5baad992177b9d742f0c6d041ebf9ed4ce4582ebcdaa57c14c31bf"}}, "hash": "69a42c287549999e5bac309153c785b0278395dfebbbee2a69dd480b34fd42e6", "text": "and on K+ and H+ secretion )\nJaisser, F., Farman, N., 2016. Emerging roles of the mineralocorticoid \nreceptor in pathology: toward new paradigms in clinical \npharmacology. Pharmacol. Rev. 68, 49\u201375. ( This review is an extremely \ncomprehensive account of mineralocorticoid action and whilst it concentrates \non the role of the MR in pathology, it also contains a great deal of basic \ninformation on the physiology and pharmacology of the MR )Clark, A.R., Belvisi, M.G., 2012. Maps and legends: the quest for \ndissociated ligands of the glucocorticoid receptor. Pharmacol. Ther. \n134, 54\u201367. ( Very readable account of the \u2018transrepression\u2019 hypothesis and \nits shortcomings )\nD\u2019Acquisto, F., Perretti, M., Flower, R.J., 2008. Annexin-A1: a pivotal \nregulator of the innate and adaptive immune systems. Br. J. \nPharmacol. 155, 152\u2013169. ( Reviews the role of the glucocorticoid-regulated \nprotein annexin-A1 in mediating anti-inflammatory actions of glucocorticoid \ndrugs )\nDobricic, V., Jacevic, V., Vucicevic, J., Nikolic, K., Vladimirov, S., \nCudina, O., 2017. Evaluation of biological activity and computer-aided \ndesign of new soft glucocorticoids. Arch. Pharm. (Weinheim) 350 (5).\nFiorucci, S., Antonelli, E., Distrutti, E., et al., 2002. NCX-1015, a \nnitric-oxide derivative of prednisolone, enhances regulatory T cells in \nthe lamina propria and protects against 2,4,6-trinitrobenzene sulfonic \nacid-induced colitis in mice. Proc. Natl. Acad. Sci. U. S. A. 99, \n15770\u201315775.\nHannen, R., Udeh-Momoh, C., Upton, J., et al., 2017. Dysfunctional \nskin-derived glucocorticoid synthesis is a pathogenic mechanism of \npsoriasis. J. Invest. Dermatol. ( One of two recent papers (see Talaber et al. \nbelow) that overturn the idea that GCs can only be synthesised in the adrenal \ncortex )\nHayashi, R., Wada, H., Ito, K., Adcock, I.M., 2004. Effects of \nglucocorticoids on gene transcription. Eur. J. Pharmacol. 500, 51\u201362. \n(Good basic review of glucocorticoid action; easy to read )\nHe, Y., Yi, W., Suino-Powell, K., et al., 2014. Structures and mechanism \nfor the design of highly potent glucocorticoids. Cell Res. 24, 713\u2013726.\nJiang, C.L., Liu, L., Tasker, J.G., 2014. Why do we need nongenomic \nglucocorticoid mechanisms? Front. Neuroendocrinol. 35, 72\u201375. \n(Another short, but thought-provoking, paper on the potential role of \nnon-genomic GC actions in the physiological response to stress )\nKirwan, J., Power, L., 2007. Glucocorticoids: action and new therapeutic \ninsights in rheumatoid arthritis. Curr. Opin. Rheumatol. 19, 233\u2013237. \n(Written mainly from the viewpoint of a practising rheumatologist, this \nreview offers interesting insights into the use of these drugs to modify severe \nchronic arthritic disease )\nMunck, A., Guyre, P.M., Holbrook, N.J., 1984. Physiological functions of \nglucocorticoids in stress and their relation to pharmacological actions. \nEndocr. Rev. 5, 25\u201344. ( Seminal review", "start_char_idx": 2867, "end_char_idx": 5774, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "59d23f56-810b-473b-8df8-106595807acb": {"__data__": {"id_": "59d23f56-810b-473b-8df8-106595807acb", "embedding": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c350c827-c430-45af-859a-903d2cb39e48", "node_type": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "072c0476d61bdd7bdcf66ee36a8d5137a76e13d415ae196692217ef2693c2263"}, "2": {"node_id": "6822f32b-1581-4212-92c9-4cf2755192d6", "node_type": null, "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69a42c287549999e5bac309153c785b0278395dfebbbee2a69dd480b34fd42e6"}}, "hash": "1ace92eedb5baad992177b9d742f0c6d041ebf9ed4ce4582ebcdaa57c14c31bf", "text": "actions. \nEndocr. Rev. 5, 25\u201344. ( Seminal review suggesting that the \nanti-inflammatory/immunosuppressive actions of the glucocorticoids have a \nphysiological function; required reading if you want to understand \nglucocorticoid physiology and pharmacology )\nNorman, A.W., Mizwicki, M.T., Norman, D.P., 2004. Steroid-hormone \nrapid actions, membrane receptors and a conformational ensemble \nmodel. Nat. Rev. Drug Discov. 3, 27\u201341. ( Fairly advanced reading but \ncontains many useful tables and excellent diagrams; well worth the effort if \nthis subject interests you )\nOakley, R.H., Cidlowski, J.A., 2001. The glucocorticoid receptor: \nexpression, function and regulation of glucocorticoid responsiveness. \nIn: Goulding, N.J., Flower, R.J. (Eds.), Milestones in Drug Therapy: \nGlucocorticoids. Birkh\u00e4user Verlag, Basle, pp. 55\u201380. ( The book is a \nuseful source of information on all aspects of glucocorticoid biology and \npharmacology, containing chapters by some of the leaders in the field )\nOakley, R.H., Cidlowski, J.A., 2013. The biology of the glucocorticoid \nreceptor: new signaling mechanisms in health and disease. J. Allergy mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5766, "end_char_idx": 7381, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1aab28b8-c555-4611-95f7-262f3e7b4f10": {"__data__": {"id_": "1aab28b8-c555-4611-95f7-262f3e7b4f10", "embedding": null, "metadata": {"page_label": "454", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8573aeb4-ff29-40e7-9cad-8d5fa6308758", "node_type": null, "metadata": {"page_label": "454", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "def4fb77cc264911e0d1e9fad2c8c6f6249b13db895369a7e5162ca5a83a3833"}, "3": {"node_id": "ae9c2a81-ac97-4d2b-8cc4-b9d36d2172ec", "node_type": null, "metadata": {"page_label": "454", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd4a1f3b6b44acdb7c52c088c6ad2c4b29fd4a132f72bd2d601e42f00b0cd2b9"}}, "hash": "2fb88ebed68d68f1527001e7dd947983836cab59d2f9279bc8b9961e767171df", "text": "448\nThe thyroid35 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3\nOVERVIEW\nDiseases of the thyroid gland are common, and in \nthis chapter we deal with drug therapy used to mitigate \nthese disorders. We set the scene by briefly outlining \nthe structure, regulation and physiology of the thyroid, and highlight the most common abnormalities of \nthyroid function. We then consider the drugs that can \nbe used to replace thyroid hormones when these are deficient or cease to function adequately, or which \ndecrease thyroid function when this is excessive.\nSYNTHESIS, STORAGE AND SECRETION \nOF THYROID HORMONES\nThe thyroid gland secretes three main hormones: in this \nchapter we focus on two of these, thyroxine (T 4) and tri-\niodothyronine (T 3). The third hormone secreted by this gland \nis calcitonin, which is involved in the control of plasma \n[Ca2+]. It is used to treat osteoporosis and other metabolic \nbone diseases. It is dealt with in Ch 37. The term \u2018thyroid \nhormones\u2019 will be used here solely to refer to T 4 and T 3.\nBoth T 3 and T 4 circulate in the blood tightly bound ( >99%) \nto plasma proteins, mainly thyroxine binding globulin (TBG). \nThe majority (~85%) of the secreted thyroid hormone is \nT4. This is converted into the (three- to five-fold) more \nactive species, T 3, in a tissue-specific manner. Both hormones \nare critically important for normal growth and development \nand for controlling energy metabolism.\nThe functional unit of the thyroid is the follicle or acinus. \nEach follicle consists of a single layer of epithelial cells surrounding a cavity, the follicle lumen , which is filled with \na thick colloid containing thyroglobulin. Thyroglobulin is a \nlarge glycoprotein, each molecule of which contains about \n115 tyrosine residues. It is synthesised, glycosylated and \nthen secreted into the lumen of the follicle, where iodination of the tyrosine residues occurs. Surrounding the follicles is a dense capillary network and the blood flow through \nthe gland is very high in comparison with other tissues. \nThe main steps in the synthesis, storage and secretion of thyroid hormone (Fig. 35.1) are:\n\u2022\tuptake \tof \tplasma \tiodide \tby \tthe \tfollicle \tcells;\n\u2022\toxidation \tof \tiodide \tand \tiodination \tof \ttyrosine \tresidues \t\nof\tthyroglobulin;\n\u2022\tsecretion \tof \tthyroid \thormone.\nUPTAKE OF PLASMA IODIDE BY THE \nFOLLICLE CELLS\nIodide uptake must occur against a concentration gradient \n(normally about 25 : 1) so it is an energy-dependent process. \nIodide is captured from the blood and moved to the lumen by two transporters: the Na+/I\u2212 symporter (NIS) located \nat the basolateral surface of the thyrocytes (the energy \nbeing provided by Na+/K+-ATPase), and pendrin1 (PDS), an \nI\u2212/Cl\u2212 porter in the apical membranes (Nilsson, 2001). Uptake \nis very rapid: labelled iodide (125I) is found in the lumen \nwithin 40 s of intravenous injection. Numerous mutations \nhave been discovered in the NIS and PDS genes and these \ncontribute to thyroid disease in some patients.\nOXIDATION OF IODIDE AND IODINATION OF \nTYROSINE RESIDUES\nThe oxidation of iodide and its incorporation into thyro -\nglobulin (termed the organification of iodide) is catalysed \nby thyroperoxidase , an enzyme situated", "start_char_idx": 0, "end_char_idx": 3213, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ae9c2a81-ac97-4d2b-8cc4-b9d36d2172ec": {"__data__": {"id_": "ae9c2a81-ac97-4d2b-8cc4-b9d36d2172ec", "embedding": null, "metadata": {"page_label": "454", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8573aeb4-ff29-40e7-9cad-8d5fa6308758", "node_type": null, "metadata": {"page_label": "454", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "def4fb77cc264911e0d1e9fad2c8c6f6249b13db895369a7e5162ca5a83a3833"}, "2": {"node_id": "1aab28b8-c555-4611-95f7-262f3e7b4f10", "node_type": null, "metadata": {"page_label": "454", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2fb88ebed68d68f1527001e7dd947983836cab59d2f9279bc8b9961e767171df"}}, "hash": "dd4a1f3b6b44acdb7c52c088c6ad2c4b29fd4a132f72bd2d601e42f00b0cd2b9", "text": "iodide) is catalysed \nby thyroperoxidase , an enzyme situated at the inner surface \nof the cell at the interface with the colloid. The reaction \nrequires the presence of hydrogen peroxide (H 2O2) as an \noxidising agent. Iodination occurs after the tyrosine has \nbeen incorporated into thyroglobulin. The process is shown \nin Fig. 35.2.\nTyrosine residues are iodinated first at position 3 on the \nring, forming monoiodotyrosine (MIT) and then, in some molecules, at position 5 as well, forming di-iodotyrosine (DIT). While still incorporated into thyroglobulin, these \nmolecules are then coupled in pairs, either MIT with DIT \nto form T\n3, or two DIT molecules to form T 4 (Figs 35.2 and \n35.3). The mechanism for coupling is believed to involve \na peroxidase system similar to the iodination reaction. About \none-fifth of the tyrosine residues in thyroglobulin are iodinated in this way.\nThe iodinated thyroglobulin of the thyroid forms a large \nstore of thyroid hormone within the gland, with a relatively slow turnover. This is in contrast to some other endocrine \nsecretions (e.g. the hormones of the adrenal cortex), which \nare not stored but synthesised and released as required.\nSECRETION OF THYROID HORMONE\nThe thyroglobulin molecule is taken up into the follicle cell by endocytosis. The endocytotic vesicles then fuse with \nlysosomes, and proteolytic enzymes act on thyroglobulin, \nreleasing T\n4 and T 3 to be secreted into the plasma. The \nsurplus MIT and DIT, which are released at the same time, \nare scavenged by the cell and the iodide is removed \nenzymatically and reused.\nREGULATION OF THYROID FUNCTION\nThyrotropin-releasing hormone (TRH), released from the hypothalamus in response to various stimuli, releases \n1So called because it is implicated in the pathophysiology of Pendred \nsyndrome, named after the eponymous English physician who first \ndescribed this autosomal recessive form of familial goitre in association \nwith sensorineural deafness.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3152, "end_char_idx": 5599, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c121baed-ac42-4758-8b81-52a9a8da64b5": {"__data__": {"id_": "c121baed-ac42-4758-8b81-52a9a8da64b5", "embedding": null, "metadata": {"page_label": "455", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bea488a7-f4d3-493f-9046-b7d7b05c3dbe", "node_type": null, "metadata": {"page_label": "455", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "333ea8508fe11ad5a50c1b689bf9573c5d138767f3ddab45a777fa4c72d2580f"}}, "hash": "333ea8508fe11ad5a50c1b689bf9573c5d138767f3ddab45a777fa4c72d2580f", "text": "35 ThE ThYROID\n449T4\nT3Endocytosis\nand secretion\nFOLLICLE LUMEN FOLLICLE CELL PLASMAProtein\nsynthesisThyroperoxidase\n+ H2O2\nP\nPThioureylenes and\nexcess I\u2212\nIodination\nand couplingUptake of\niodide\nTT\nT T\nTTG\nTGTG\nLTGTDITPDS NIS\nT\nMIT MITTT\nMIT\nDITTSH \nstimulates \ntranscription \nof the gene \nfor this \ncarrierI\u2212I\u2212I\u2212\nCC\nScavenger\nroute\nColloid\nFig. 35.1 Diagram of thyroid hormone synthesis and secretion, with the sites of action of some drugs used in the treatment of \nthyroid disorders. Iodide in the blood is transported by the carriers Na+/I\u2212 symporter (NIS) and pendrin (PDS) through the follicular cell and \ninto the colloid-rich lumen, where it is incorporated into tyrosines in thyroglobulin under the influence of the thyroperoxidase enzyme and \nmonoiodotyrosine units are produced and coupled to produce the hormones (see text for details). Thyroid-stimulating hormone (thyrotropin; \nTSH) stimulates the endocytosis of thyroglobulin and the hormones are subsequently cleaved from the globulin by lysosomal enzymes and \nexported into the blood. DIT, di-iodotyrosine; L, lysosome; MIT, monoiodotyrosine; P, pseudopod; T, tyrosine; T3, tri-iodothyronine; T4, \nthyroxine; TG, thyroglobulin. \nOH\nCOOHC\nHH\nH\nH2NOH\nCOOHC\nH H2NOH\nCOOHC\nH H2N\nTyrosine Tyrosine radicalMonoiodotyrosineII\u2212I\u2212e\nThyroperoxidase H2O2\n1234\n5\n6\nFig. 35.2 Iodination of tyrosyl residues by the \nthyroperoxidase\u2013H 2O2 complex. This probably involves two \nsites on the enzyme, one of which removes an electron from \niodide to give the free radical I\u2022; another removes an electron \nfrom tyrosine to give the tyrosyl radical (shown by orange dot) . \nMonoiodotyrosine results from the addition of the two radicals. O\nOO\nO5\n5OH\nTissue 5-iodinase\nOHOH\nOH\nT4T3NH2\nNH2II\nII\nI\nI\nII\nFig. 35.3 The structures of thyroxine T 3 and T 4. The \nposition of the iodine residues are indicated in orange . T4 is \nconverted, in a tissue-specific manner, to the more active \nspecies T 3 by mono de-iodination at position 5 of the ring. The \nbasic tyrosine unit is shaded in yellow . mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2519, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ad8eeea8-b267-4270-a1b0-32781c8c05d8": {"__data__": {"id_": "ad8eeea8-b267-4270-a1b0-32781c8c05d8", "embedding": null, "metadata": {"page_label": "456", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3f3ac97b-c944-478d-a1d9-38e8666f5b90", "node_type": null, "metadata": {"page_label": "456", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "809ecd9e6a3a9fdb99b22f03b0aa7f7c5d025ceaab7f365c301e76ec5a1779ce"}, "3": {"node_id": "b26fdb4f-d9e5-4e46-8354-429d189b3f99", "node_type": null, "metadata": {"page_label": "456", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5dcfa06f6e69de730cda33b1aad8e5d68b8cd621fe8754f2b45f4daaa9abf3c1"}}, "hash": "c371592aac770253d0a8519f3240616de8bd29504ea39376004bfb51b4d85ffc", "text": "35 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n450in TSH produce only small alterations in T 3/T 4. It is impor -\ntant to recognise this, as measurement of TSH is a key \ndiagnostic tool when assessing thyroid function in patients.\nThe other main factor influencing thyroid function is the \nplasma iodide concentration. About 100 nmol of T 4 is \nsynthesised daily, necessitating uptake by the gland of \napproximately 500 nmol of iodide each day (equivalent to \nabout 70 \u00b5g of iodine). A reduced iodine intake, with \nreduced plasma iodide concentration, will result in a decrease of hormone production and an increase in TSH \nsecretion. An increased plasma iodide has the opposite effect, although this may be modified by other factors. The \noverall feedback mechanism responds to changes of iodide \nslowly over fairly long periods of days or weeks, because there is a large reserve capacity for the binding and uptake \nof iodide in the thyroid. The size and vascularity of the \nthyroid are reduced by an increase in plasma iodide and this is exploited therapeutically in preparing hyperthyroid patients for surgery to the gland. Diets deficient in iodine \neventually result in a continuous excessive compensatory \nsecretion of TSH, and eventually in an increase in vascularity and (sometimes gross) hypertrophy of the gland.\n2\nACTIONS OF THE THYROID HORMONES\nThe physiological actions of the thyroid hormones fall into two main categories: those affecting metabolism and those \naffecting growth and development. Both T\n3 and T 4 are \nextensively plasma bound and only the free concentrations of the hormones are active.\nEFFECTS ON METABOLISM\nThe thyroid hormones produce a general increase in the \nmetabolism of carbohydrates, fats and proteins, and regulate \nthese processes in most tissues, T 3 being three to five times \nmore active than T 4 in this respect (Fig. 35.5). Although thyroid-stimulating hormone \t(TSH;\tthyrotrophin) \tfrom \tthe \t\nanterior pituitary (Fig. 35.4), as does the synthetic tripeptide \nprotirelin (pyroglutamyl-histidyl-proline amide), which is \nused in this way for diagnostic purposes. TSH acts on receptors on the membrane of thyroid follicle cells through a mechanism that involves cAMP and phosphatidylinositol \n3-kinase. It has a trophic action on thyroid cells and controls \nall aspects of thyroid hormone synthesis, mainly by stimulat -\ning transcription of the iodide transporter genes, thereby \nincreasing the uptake of iodide by follicle cells. This, in \nturn, controls all aspects of thyroid hormone synthesis including:\n\u2022\tthe\tsynthesis \tand \tsecretion \tof \tthyroglobulin;\n\u2022\tthe\tgeneration \tof \tH2O2\tand\tthe\tiodination \tof \ttyrosine;\n\u2022\tthe\tendocytosis \tand \tproteolysis \tof \tthyroglobulin;\n\u2022\tthe\tactual \tsecretion \tof \tT3 and T 4;\n\u2022\tthe\tblood \tflow \tthrough \tthe \tgland.\nThe production of TSH is also regulated by a negative feedback effect of thyroid hormones on the anterior pituitary \ngland\tand \tthe \thypothalamus; \tT3 is more active than T 4 in \nthis respect. The peptide somatostatin also reduces basal \nTSH release. The control of the secretion of TSH thus depends on a balance between the actions of T\n3/T 4 and \nTRH (and probably also somatostatin) on the pituitary and \nmost likely on the hypothalamus also. However, the relation -\nship between T 3/T", "start_char_idx": 0, "end_char_idx": 3307, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b26fdb4f-d9e5-4e46-8354-429d189b3f99": {"__data__": {"id_": "b26fdb4f-d9e5-4e46-8354-429d189b3f99", "embedding": null, "metadata": {"page_label": "456", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3f3ac97b-c944-478d-a1d9-38e8666f5b90", "node_type": null, "metadata": {"page_label": "456", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "809ecd9e6a3a9fdb99b22f03b0aa7f7c5d025ceaab7f365c301e76ec5a1779ce"}, "2": {"node_id": "ad8eeea8-b267-4270-a1b0-32781c8c05d8", "node_type": null, "metadata": {"page_label": "456", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c371592aac770253d0a8519f3240616de8bd29504ea39376004bfb51b4d85ffc"}}, "hash": "5dcfa06f6e69de730cda33b1aad8e5d68b8cd621fe8754f2b45f4daaa9abf3c1", "text": "likely on the hypothalamus also. However, the relation -\nship between T 3/T 4 concentration and TSH secretion is not \nlinear. Small changes in thyroid hormones can produce very large changes in TSH secretion whilst large changes ThioureylenesIodide (excess)\n131IT3T4ThyrotrophinSomatostatinT RH ProtirelinCold Trauma Stress\nThyroidAnterior pituitaryHypothalamus\nI\u2212 (physiological)\nFig. 35.4 Regulation of thyroid hormone secretion. Iodide \n(I\u2212) is essential for thyroid hormone synthesis, but excess of \nendogenous or exogenous iodide (30 times the daily \nrequirement of iodine) may be used to inhibit the increased thyroid hormone production of thyrotoxicosis. Protirelin, as well as recombinant human thyrotropin-releasing hormone (rhTRH) is sometimes used to stimulate the system for diagnostic purposes. Larger amounts of iodine (as the \n131I isotope) are used \nfor ablation of thyroid tissue (see text for details). T3, tri-\niodothyronine; T4, thyroxine. \n2\u2018Derbyshire neck\u2019 was the name given to this condition in a part of the \nUnited Kingdom where sources of dietary iodine were once scarce.48 12 16 20Basal metabolic rate+5\n\u22125\n\u221215\n\u221225\u221235\n0\nDays after injection720 \u00b5g T4600 \u00b5g T3\nFig. 35.5 The effect of equimolar doses of tri-\niodothyronine (T 3) and thyroxine (T 4) on basal metabolic rate \n(BMR) in a hypothyroid subject. Note that this figure is meant \nonly to illustrate overall differences in effect; thyroxine is not \ngiven clinically in a single bolus dose as here, but in regular daily doses so that the effect builds up to a plateau. The apparent differences in potency really represent differences in kinetics, reflecting the prohormone role of T\n4. (Modified from Blackburn \net al., 1954.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3232, "end_char_idx": 5424, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ffd3c5cf-1124-4a00-81ff-d9e8204a2495": {"__data__": {"id_": "ffd3c5cf-1124-4a00-81ff-d9e8204a2495", "embedding": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "98224aec-f657-4911-9593-9ed0f0716a54", "node_type": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0bf9851afa295eb4426466baa424643632a4b15d345ad2c6ac65efc5acd7e773"}, "3": {"node_id": "88461808-8e4b-4342-8c32-4565c01bbb43", "node_type": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "529d61cb5c4cf4f759628bcfefc1608c60dd13aa2341ec2fc2e43177cb35c1b0"}}, "hash": "86c8f6c73553c62b22d4ff6850d941b34811262d0b33e686f2b0db87b5e8936a", "text": "35 ThE T h YROID\n451ABNORMALITIES OF THYROID FUNCTION\nThyroid disorders are among the most common endocrine \ndiseases in all age groups, including children. Subclinical \nthyroid disease is prevalent in the middle-aged and elderly. \nThyroid disorders are accompanied by many extra-thyroidal symptoms, particularly in the heart, gastrointestinal system \nand skin. One (rare) cause of organ dysfunction is thyroid \ncancer. Many other thyroid disorders have an autoimmune basis \u2013 in fact, autoimmune thyroid disease is the commonest \nautoimmune disease. The reason for this is not clear, \nalthough it may be linked to a breakdown in immune toler -\nance to the TSH receptor, although other factors cannot be \nruled out (Lee et al., 2015). It may be linked to other \nautoimmune conditions such as rheumatoid arthritis.\nThere are two main types of autoimmune thyroid dis-\norder, Graves\u2019 disease4 and Hashimoto\u2019s disease. Both are \nassociated with the production of thyroid autoantibodies \nand immune damage to the gland itself.5 Oddly perhaps, \nthey result in different clinical pictures with Graves\u2019 disease leading to thyrotoxicosis while Hashimoto\u2019s thyroiditis \nleads to hypoactive thyroid. Regardless of causation, thyroid dysfunction is often associated with typical gross enlarge -\nment of the gland, known as goitre . Like other autoimmune \ndiseases, such thyroid disorders are more common in women than men and occur with increased frequency during \npregnancy (Cignini et al., 2012).\nHYPERTHYROIDISM (THYROTOXICOSIS)\nIn thyrotoxicosis there is excessive secretion and activity of the thyroid hormones, resulting in a high metabolic rate, \nan increase in skin temperature and sweating, and heat \nintolerance. Nervousness, tremor, tachycardia and increased appetite associated with loss of weight occur. There are \nseveral types of hyperthyroidism, but only two are common: \nexophthalmic or diffuse toxic goitre (Graves\u2019 disease) and toxic \nnodular goitre.\nDiffuse toxic goitre is an organ-specific autoimmune \ndisease caused by autoantibodies to the TSH receptor which activate it, increasing T\n4 secretion. Constitutively active \nmutations of the TRH receptor may also be involved. As \nis indicated by the name, patients with exophthalmic goitre \nhave protrusion of the eyeballs. The pathogenesis of this condition is not fully understood, but it is thought to be \ncaused by the presence of TSH receptor-like proteins in \norbital tissues. There is also an enhanced sensitivity to catecholamines. Toxic nodular goitre is caused by a benign \ntumour, and may develop in patients with long-standing simple goitre. This condition does not usually have con -\ncomitant exophthalmos. The antidysrhythmic drug ami-\nodarone (Ch. 22) is rich in iodine and can cause either \nhyperthyroidism or hypothyroidism. Some iodine-containing radiocontrast agents, such as iopanoic acid and its conge -\nners, used as imaging agents to visualise the gall bladder, the thyroid hormones directly control the activity of some \nof the enzymes of carbohydrate metabolism, most effects are brought about in conjunction with other hormones, \nsuch as insulin, glucagon, the glucocorticoids and the \ncatecholamines. There is an increase in oxygen consumption and heat production, which is manifested as an increase \nin the measured basal metabolic rate. This reflects the action \nof these hormones on tissues such as heart, kidney, liver and muscle, although not on others, such as the gonads, \nbrain or spleen. This calorigenic action is important as part \nof the response to a cold", "start_char_idx": 0, "end_char_idx": 3557, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "88461808-8e4b-4342-8c32-4565c01bbb43": {"__data__": {"id_": "88461808-8e4b-4342-8c32-4565c01bbb43", "embedding": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "98224aec-f657-4911-9593-9ed0f0716a54", "node_type": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0bf9851afa295eb4426466baa424643632a4b15d345ad2c6ac65efc5acd7e773"}, "2": {"node_id": "ffd3c5cf-1124-4a00-81ff-d9e8204a2495", "node_type": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86c8f6c73553c62b22d4ff6850d941b34811262d0b33e686f2b0db87b5e8936a"}, "3": {"node_id": "bfb24b01-8b56-476d-a156-bb0982ff00cf", "node_type": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "de5a4e807f0210d55ce774fd7da53b0a131bf0114a3c7784832fb348096196d0"}}, "hash": "529d61cb5c4cf4f759628bcfefc1608c60dd13aa2341ec2fc2e43177cb35c1b0", "text": "This calorigenic action is important as part \nof the response to a cold environment. Administration of thyroid hormone results in augmented cardiac rate and output, and increased tendency to dysrhythmias such as \natrial fibrillation.\nEFFECTS ON GROWTH AND DEVELOPMENT\nThe thyroid hormones have a critical effect on growth, \npartly by a direct action on cells, but also indirectly by \ninfluencing growth hormone production and potentiating \nits effects on its target tissues. The hormones are important for a normal response to parathormone (Ch. 37) and calcitonin \nas\twell\tas\tfor\tskeletal\tdevelopment; \tthey\tare\talso\tessential \t\nfor normal growth and maturation of the central nervous system.\nMECHANISM OF ACTION\nWhile there is some evidence for non-genomic actions (see \nBassett et al., 2003), thyroid hormones act mainly through \na specific nuclear receptor, TR (Ch. 3). Two distinct genes, TR\u03b1 and TR \u03b2, code for several receptor isoforms that have \ndistinct functions. T\n4 may be regarded as a prohormone, \nbecause when it enters the cell, it is converted to T 3, which \nthen binds with high affinity to TR. This interaction is likely \nto take place in the nucleus, where TR isoforms generally \nact as a constitutive repressor of target genes. When T 3 is \nbound, these receptors change conformation, the co-repressor \ncomplex is released and a co-activator complex is recruited, \nwhich then activates transcription, resulting in generation of mRNA and protein synthesis. Some rare cases of thyroid \nhormone resistance linked to TR \u03b2 mutations, have been \nreported (Lai et al., 2015).\nTRANSPORT AND METABOLISM OF \nTHYROID HORMONES\nPlasma concentrations of these hormones can be measured \nby radioimmunoassay, and are approximately 1 \u00d7 10\u22127 mol/L \n(T4) and 2 \u00d7 10\u22129 mol/L (T 3). Both are eventually metabolised \nin their target tissues by deiodination, deamination, decar -\nboxylation and conjugation with glucuronic and sulfuric acids. The liver is a major site of metabolism and the free and conjugated forms are excreted partly in the bile and \npartly in the urine. The half-life of T\n3 is a few hours, whereas \nthat of T 4 varies between 3\u20134 days in hyperthyroidism, and \n9\u201310 days in hypothyroidism3. Abnormalities in the \nmetabolism of these hormones may occur naturally or be induced by drugs or heavy metals, and this may give rise \nto a variety of (uncommon) clinical conditions such as the \u2018low T\n3 syndrome\u2019.\n3Correcting hypothyroidism by administration of T 4 therefore takes 2\u20133 \nweeks to reach equilibrium.4After a Dublin physician who connected \u2018violent and long continued \npalpitations in females\u2019 with enlargement of the thyroid gland. Their \ncomplaints of fluttering hearts and lumps in their throats had \npreviously been attributed to hysteria.\n5John F Kennedy Jr suffered from Graves\u2019 disease. He inherited a \npropensity for autoimmune diseases from his father JFK, who himself \nsuffered from the autoimmune Addison\u2019s disease, in which adrenal \nglands are the main organs affected. JFK\u2019s sister Eunice also suffered from Addison\u2019s disease.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3499, "end_char_idx": 6868, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bfb24b01-8b56-476d-a156-bb0982ff00cf": {"__data__": {"id_": "bfb24b01-8b56-476d-a156-bb0982ff00cf", "embedding": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "98224aec-f657-4911-9593-9ed0f0716a54", "node_type": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0bf9851afa295eb4426466baa424643632a4b15d345ad2c6ac65efc5acd7e773"}, "2": {"node_id": "88461808-8e4b-4342-8c32-4565c01bbb43", "node_type": null, "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "529d61cb5c4cf4f759628bcfefc1608c60dd13aa2341ec2fc2e43177cb35c1b0"}}, "hash": "de5a4e807f0210d55ce774fd7da53b0a131bf0114a3c7784832fb348096196d0", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6880, "end_char_idx": 7103, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "387d6fd1-d69f-4289-961b-6abbdc049b56": {"__data__": {"id_": "387d6fd1-d69f-4289-961b-6abbdc049b56", "embedding": null, "metadata": {"page_label": "458", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "22200d52-b191-4236-bc55-72dcb50e180a", "node_type": null, "metadata": {"page_label": "458", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a95fe223cae60c34593b08d52579b0d3f42bbc089f5d9fd113c5a538766f7bc9"}, "3": {"node_id": "3c9eaea3-1dff-46f3-90b4-d7959039393a", "node_type": null, "metadata": {"page_label": "458", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20507094299df5c684b46b4d69639d632638f775ab0cdb99372477328b05f6e9"}}, "hash": "585e7ebea900a7e9288451ad6bc395413b7abfd1fdf365df32de2008d8e44ac1", "text": "35 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n452isotope emits both \u03b2 and \u03b3 radiation. The \u03b3 rays pass through \nthe tissue without causing damage, but the \u03b2 particles have \na\tvery\tshort \trange; \tthey \tare \tabsorbed \tby \tthe \ttissue \tand \t\nexert a powerful cytotoxic action that is restricted to the \ncells of the thyroid follicles, resulting in significant destruc -\ntion of the tissue. 131I has a half-life of 8 days, so by 2 months \nits radioactivity has effectively disappeared. It is given as \none single dose, but its cytotoxic effect on the gland is \ndelayed for 1\u20132 months and does not reach its maximum for a further 2 months.\nHypothyroidism will eventually occur after treatment \nwith radioiodine, particularly in patients with Graves\u2019 disease, but is easily managed by replacement therapy with \nT\n4. Radioiodine is best avoided in children or pregnant \npatients (because of potential damage to the fetus). There is theoretically an increased risk of thyroid cancer but this \nhas not been seen following therapeutic treatment.\nThe uptake of \n131I and other isotopes of iodine is also \nused diagnostically as a test of thyroid function. A tracer \ndose of the isotope is given orally or intravenously and \nthe amount accumulated by the thyroid is measured by a \u03b3-scintillation counter placed over the gland. \n131I is also \nused for the treatment of thyroid cancer.may also interfere with thyroid function. The chronic use of psychotropic agents may precipitate a variety of thyroid \nabnormalities (Bou Khalil & Richa, 2011).\nSIMPLE, NON-TOXIC GOITRE\nA dietary deficiency of iodine, if prolonged, causes a rise \nin plasma TRH and eventually an increase in the size of \nthe gland. This condition is known as simple or non-toxic \ngoitre. Another cause is ingestion of goitrogens (e.g. from cassava root). The enlarged thyroid usually manages to \nproduce normal amounts of thyroid hormone, although if \nthe iodine deficiency is very severe, hypothyroidism may supervene.\nHYPOTHYROIDISM\nA decreased activity of the thyroid results in hypothyroidism, and in severe cases myxoedema. Once again, this disease is \nusually of immunological in origin, and the manifestations include low metabolic rate, slow speech, deep hoarse voice, lethargy, bradycardia, sensitivity to cold and mental impair -\nment. Patients also develop a characteristic thickening of the skin (caused by the subcutaneous deposition of gly -\ncosaminoglycans), which gives myxoedema its name. In \nHashimoto\u2019s thyroiditis, there is an immune reaction against \nthyroglobulin or some other component of thyroid tissue, which can lead to both hypothyroidism and myxoedema. Genetic factors play an important role. Destruction of \nglandular tissue whilst treating thyroid tumours with \nradioiodine is another cause of hypothyroidism. Some drugs (e.g. cholecystographic agents or anti-epileptic drugs) as \nwell as environmental \u2018endocrine disruptors\n6\u2019 may interfere \nwith the normal production of thyroid hormones.\nThyroid deficiency during development, affecting 1 in \n3000\u20134000 births, causes congenital hypothyroidism, \ncharacterised by gross retardation of growth and mental \ndeficiency.7\nDRUGS USED IN DISEASES OF \nTHE THYROID\nHYPERTHYROIDISM\nHyperthyroidism may be treated pharmacologically or \nsurgically. In general, surgery is now used only when there \nare mechanical problems resulting from compression of \nthe trachea by the thyroid. Under such circumstances it is usual to remove only part", "start_char_idx": 0, "end_char_idx": 3472, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3c9eaea3-1dff-46f3-90b4-d7959039393a": {"__data__": {"id_": "3c9eaea3-1dff-46f3-90b4-d7959039393a", "embedding": null, "metadata": {"page_label": "458", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "22200d52-b191-4236-bc55-72dcb50e180a", "node_type": null, "metadata": {"page_label": "458", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a95fe223cae60c34593b08d52579b0d3f42bbc089f5d9fd113c5a538766f7bc9"}, "2": {"node_id": "387d6fd1-d69f-4289-961b-6abbdc049b56", "node_type": null, "metadata": {"page_label": "458", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "585e7ebea900a7e9288451ad6bc395413b7abfd1fdf365df32de2008d8e44ac1"}}, "hash": "20507094299df5c684b46b4d69639d632638f775ab0cdb99372477328b05f6e9", "text": "by the thyroid. Under such circumstances it is usual to remove only part of the organ. Although the \ncondition of hyperthyroidism can be controlled with \nantithyroid drugs, these drugs do not alter the underlying autoimmune mechanisms or improve the exophthalmos \nassociated with Graves\u2019 disease.\nRADIOIODINE\nRadioiodine is a first-line treatment for hyperthyroidism \n(particularly in the United States). The isotope used is 131I \n(usually as the sodium salt), and the dose generally \n5\u201315 mCi. Given orally, it is taken up and processed by \nthe thyroid in the same way as the stable form of iodide, eventually becoming incorporated into thyroglobulin. The The thyroid \n\u2022 Thyroid hormones, tri-iodothyronine (T 3) and thyroxine \n(T4), are synthesised by iodination of tyrosine residues \non thyroglobulin within the lumen of the thyroid follicle.\n\u2022 Hormone synthesis and secretion are regulated by \nthyroid-stimulating hormone (thyrotropin) and \ninfluenced by plasma iodide.\n\u2022 There is a large pool of T 4 in the body; it has a low \nturnover rate and is found mainly in the circulation.\n\u2022 There is a small pool of T 3 in the body; it has a fast \nturnover rate and is found mainly intracellularly.\n\u2022 Within target cells, the T 4 is converted to T 3, which \ninteracts with a nuclear receptor to regulate gene transcription.\n\u2022 T3 and T 4 actions:\n\u2013 stimulation of metabolism, causing increased oxygen \nconsumption and increased metabolic rate;\n\u2013 regulation of growth and development.\n\u2022 Abnormalities of thyroid function include:\n\u2013 hyperthyroidism (thyrotoxicosis): either diffuse toxic \ngoitre or toxic nodular goitre;\n\u2013 hypothyroidism: in adults this causes myxoedema, in \ninfants, gross retardation of growth and mental deficiency;\n\u2013 simple non-toxic goitre caused by dietary iodine \ndeficiency, usually with normal thyroid function.\n6These are man-made chemicals such as pesticides or herbicides (e.g. \npolychlorinated biphenyls) that persist in the environment and are \ningested in foodstuffs. The endocrine system is particularly sensitive to \nthese, especially during development.\n7An older term for this condition, cretinism, has been dropped.THIOUREYLENES\nThis group of drugs comprises carbimazole and propylthi -\nouracil. Chemically, they are related to thiourea, and the \nthiocarbamide (S\u2013C\u2013N) group is essential for antithyroid \nactivity.\nMechanism of action\nThioureylenes decrease the output of thyroid hormones from the gland, and cause a gradual reduction in the signs mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3400, "end_char_idx": 6360, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a4ed3ab9-c675-4068-b345-befe90d1f5ba": {"__data__": {"id_": "a4ed3ab9-c675-4068-b345-befe90d1f5ba", "embedding": null, "metadata": {"page_label": "459", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0cf980e4-13da-4048-9a2c-e2821df2bada", "node_type": null, "metadata": {"page_label": "459", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61dd92a39397321dea8e4de3b7752392d5b862bf65e461cc56b176788c2912e0"}, "3": {"node_id": "839aef15-9423-4a70-afe0-d0d9759ee11f", "node_type": null, "metadata": {"page_label": "459", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5518423e7f78bd0093a7624fb2a6b5e111ac6a61eec745c32f2fb0e6bf2074af"}}, "hash": "ca481472b4e0ac7c38895f3cc7608524de8493375db57c2efc27ca5d34a9d4c9", "text": "35 ThE T h YROID\n453symptoms including headaches, nausea, jaundice and \narthralgia, are common. Rare cases of fetal abnormalities \nhave been reported with carbimazole.\nIODINE/IODIDE\nIodine is converted in vivo to iodide (I\u2212), which temporarily \ninhibits the release of thyroid hormones. When high doses of iodine are given to thyrotoxic patients, the symptoms \nsubside within 1\u20132 days. There is inhibition of the secretion of thyroid hormones and, over a period of 10\u201314 days, a \nmarked reduction in vascularity of the gland, which becomes \nsmaller and firmer. Iodine is often given orally in a solution with potassium iodide (\u2018 Lugol iodine\u2019). With continuous \nadministration, its effect reaches maximum within 10\u201315 days and then decreases. The mechanism of action is not \nentirely\tclear; \tit \tmay \tinhibit \tiodination \tof \tthyroglobulin, \t\npossibly by reducing the H 2O2 generation that is necessary \nfor this process.\nThe main uses of iodine/iodide are for the preparation \nof hyperthyroid subjects for surgical resection of the gland, and as part of the treatment of severe thyrotoxic crisis \n(thyroid storm). It is also used following exposure to acci -\ndental leakage of radioactive iodine from nuclear reactors, \nto reduce uptake of the radioactive isotope in the thyroid. \nAllergic\treactions \tcan \toccur; \tthese \tinclude \tangio-oedema, \t\nrashes and drug fever. Lacrimation, conjunctivitis, pain in the salivary glands and a cold-like syndrome are dose-\nrelated adverse effects connected to the concentration of \niodide by transport mechanisms in tears and saliva.\nOTHER \u2003DRUGS \u2003USED\nThe \u03b2-adrenoceptor antagonists, for example, propranolol \nand nadolol (Ch. 15), are not antithyroid agents as such, \nbut they are useful for decreasing many of the signs and symptoms of hyperthyroidism \u2013 the tachycardia, dysrhyth -\nmias, tremor and agitation. They are used during the \npreparation of thyrotoxic patients for surgery, as well as \nin most hyperthyroid patients during the initial treatment period while the thioureylenes or radioiodine take effect, \nor as part of the treatment of acute hyperthyroid crisis. \nEye drops containing guanethidine, a noradrenergic-\nblocking agent (Ch. 15), are used to mitigate the exoph -\nthalmos of hyperthyroidism (which is not relieved by \nantithyroid \tdrugs); \tit \tacts \tby \trelaxing \tthe \tsympathetically \t\ninnervated smooth muscle that causes eyelid retraction. Glucocorticoids (e.g. prednisolone or hydrocortisone) or \nsurgical decompression may be needed to mitigate severe exophthalmia in Graves\u2019 disease.\nHYPOTHYROIDISM\nThere are no drugs that specifically augment the synthesis or release of thyroid hormones. The only effective treatment \nfor hypothyroidism, unless it is caused by iodine deficiency \n(which is treated with iodide), is to administer the thyroid hormones themselves as replacement therapy. Synthetic \nT\n4 (official name: levothyroxine) and T 3 (official name: \nliothyronine ), identical to the natural hormones, are given \norally. Levothyroxine, as the sodium salt in doses of \n50\u2013100 \u00b5g/day, is the usual first-line drug of choice. Lio -\nthyronine has a faster onset but a shorter duration of action, and is generally reserved for acute emergencies such as \nthe rare condition of myxoedema coma, where these proper -\nties are an", "start_char_idx": 0, "end_char_idx": 3296, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "839aef15-9423-4a70-afe0-d0d9759ee11f": {"__data__": {"id_": "839aef15-9423-4a70-afe0-d0d9759ee11f", "embedding": null, "metadata": {"page_label": "459", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0cf980e4-13da-4048-9a2c-e2821df2bada", "node_type": null, "metadata": {"page_label": "459", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61dd92a39397321dea8e4de3b7752392d5b862bf65e461cc56b176788c2912e0"}, "2": {"node_id": "a4ed3ab9-c675-4068-b345-befe90d1f5ba", "node_type": null, "metadata": {"page_label": "459", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca481472b4e0ac7c38895f3cc7608524de8493375db57c2efc27ca5d34a9d4c9"}}, "hash": "5518423e7f78bd0093a7624fb2a6b5e111ac6a61eec745c32f2fb0e6bf2074af", "text": "condition of myxoedema coma, where these proper -\nties are an advantage.\nUnwanted effects may occur with overdose, and in \naddition to the signs and symptoms of hyperthyroidism and symptoms of thyrotoxicosis, with the basal metabolic rate and pulse rate returning to normal over a period of \n3\u20134 weeks. Their mode of action is not completely under-\nstood, but there is evidence that they reduce the iodination of tyrosyl residues in thyroglobulin (see Figs 35.1 and 35.2) by inhibiting the thyroperoxidase-catalysed oxidation \nreactions, possibly by acting as substrates thus competitively \ninhibiting the interaction with tyrosine. Propylthiouracil has the additional effect of reducing the deiodination of \nT\n4 to T 3 in peripheral tissues.\nPharmacokinetic aspects\nThioureylenes are given orally. Carbimazole is rapidly \nconverted to an active metabolite. An average dose of \ncarbimazole produces more than 90% inhibition of thyroid \nincorporation of iodine within 12 h. The full clinical \nresponse to this and other antithyroid drugs, however, \nmay take several weeks (Fig. 35.6), partly because T 4 has \na long half-life, and also because the thyroid may have \nlarge stores of hormone, which need to be depleted before \nthe drug\u2019s action can be fully manifest. Propylthiouracil is thought to act somewhat more rapidly because of its \nadditional effect as an inhibitor of the peripheral conversion \nof T\n4 to T 3.\nBoth drugs may be used during pregnancy but both can \ncross the placenta and may affect the fetal thyroid gland. \nThey also appear in breast milk, but this effect is less pronounced with propylthiouracil, because it is more \nstrongly bound to plasma protein. After degradation, the \nmetabolites of these drugs are excreted in the urine. The thioureylenes may be concentrated in the thyroid.\nUnwanted effects\nThe most dangerous unwanted effects of thioureylene drugs are neutropenia and agranulocytosis (see Ch. 26). These \nare relatively rare, having an incidence of 0.1%\u20131.2%, and \nare reversible on cessation of treatment. Patients must be warned to report symptoms (especially sore throat) imme -\ndiately and have a blood count. Rashes (2%\u201325%) and other \nBMR %+40\n+30\n+20+10\n0\n\u221210\n20 16 12 8 4 0\nWeeks\nFig. 35.6 Time course of fall of basal metabolic rate \n(BMR) during treatment with an antithyroid drug, \ncarbimazole. The curve is exponential, corresponding to a daily \ndecrease in BMR of 3.4%. (Modified from Furth et al., 1963.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3235, "end_char_idx": 6171, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b497a5ec-1d17-460a-9c46-296d5bc97082": {"__data__": {"id_": "b497a5ec-1d17-460a-9c46-296d5bc97082", "embedding": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "21c50316-5573-46ab-b10d-65561c9917ba", "node_type": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24dc0b73405144d3788dea7e89c1091c353c51a26fb2dea190f671374f446968"}, "3": {"node_id": "278108c2-78f4-4c03-88a3-0af07e5b672a", "node_type": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80f7323b0400c42ce48d498a994769f22fcfb767817f2fdde95b6e26f850b9a2"}}, "hash": "21211eb21f9d72469604c01ad593d0119219b016fa3ec032aecb1e841f0b1912", "text": "35 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n454there is a risk of precipitating angina pectoris, cardiac \ndysrhythmias or even cardiac failure. The effects of less \nsevere\toverdose \tare \tmore \tinsidious; \tthe \tpatient \tfeels \twell \t\nbut bone resorption is increased, leading to osteoporosis (Ch. 37).\nThe use of drugs to treat thyroid cancer is a specialist \nsubject and will not be covered here. Bikas et al. (2016) \nREFERENCES AND FURTHER READING\nBassett, J.H.D., Harvey, C.B., Williams, G.R., 2003. Mechanisms of \nthyroid hormone receptor-specific nuclear and extranuclear actions. \nMol. Cell. Endocrinol. 213, 1\u201311. (An excellent and comprehensive review \ndealing with the actions of thyroid hormones through the nuclear receptor mechanism as well as other actions through G protein-coupled receptors and \nother pathways)\nBikas, A., Vachhani, S., Jensen, K., Vasko, V., Burman, K.D., 2016. \nTargeted therapies in thyroid cancer: an extensive review of the literature. Expert Rev. Clin. Pharmacol. 1\u201315. (This reference reviews the \nproperties of some of the latest generation of drugs to be used in thyroid carcinoma, such as the tyrosine kinase inhibitors)\nBlackburn, C.M., McConahey, W.M., Keating, F.R., Jr., Albert, A., 1954. \nCalorigenic effects of single intravenous doses of L-triiodothyronine and L-thyroxine in myxedematous persons. J. Clin. Invest. 33, \n819\u2013824.\nBou Khalil, R., Richa, S., 2011. Thyroid adverse effects of psychotropic \ndrugs: a review. Clin. Neuropharmacol. 34, 248\u2013255. (Many patients taking psychotropic drugs present with thyroid problems. This review deals \nwith the role played by antipsychotic drugs in this phenomenon)\nCignini, P., Cafa, E.V., Giorlandino, C., Capriglione, S., Spata, A., Dugo, \nN., 2012. Thyroid physiology and common diseases in pregnancy: review of literature. J. Prenat. Med. 6, 64\u201371. (Makes the point that increased rates of thyroid abnormalities are seen in pregnancy and that many \ngo undiagnosed. Also deals with clinical management of these cases)\nFurth, E.D., Becker, D.V., Schwartz, M.S., 1963. Significance of rate of \nresponse of basal metabolic rate and serum cholesterol in hyperthyroid patients receiving neomercazole and other antithyroid \nagents. J. Clin. Endocrinol. Metab. 23, 1130\u20131140.\nHadj Kacem, H., Rebai, A., Kaffel, N., et al., 2003. PDS is a new \nsusceptibility gene to autoimmune thyroid diseases: association and linkage study. J. Clin. Endocrinol. Metab. 88, 2274\u20132280. (Interesting \narticle on the PDS transporter protein and its contribution to disease \nsusceptibility)\nKahaly, G.J., Dillmann, W.H., 2005. Thyroid hormone action in the \nheart. Endocr. Rev. 26, 704\u2013728. (A very interesting review focusing on the cardiac actions of thyroid hormones; much historical detail)\nKelly, G.S., 2000. Peripheral metabolism of thyroid hormones: a review. \nAltern. Med. Rev. 5, 306\u2013333. (This review focuses on the role of peripheral metabolism in thyroid hormone action)\nKojic, K.L., Kojic,", "start_char_idx": 0, "end_char_idx": 2984, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "278108c2-78f4-4c03-88a3-0af07e5b672a": {"__data__": {"id_": "278108c2-78f4-4c03-88a3-0af07e5b672a", "embedding": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "21c50316-5573-46ab-b10d-65561c9917ba", "node_type": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24dc0b73405144d3788dea7e89c1091c353c51a26fb2dea190f671374f446968"}, "2": {"node_id": "b497a5ec-1d17-460a-9c46-296d5bc97082", "node_type": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "21211eb21f9d72469604c01ad593d0119219b016fa3ec032aecb1e841f0b1912"}, "3": {"node_id": "5f98baf9-1e1e-42d8-8711-a7bc3b591cae", "node_type": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7cf8404a718cf9b2485f40cd5864ad78571f9c15748c8d53a5152d77290f2f70"}}, "hash": "80f7323b0400c42ce48d498a994769f22fcfb767817f2fdde95b6e26f850b9a2", "text": "thyroid hormone action)\nKojic, K.L., Kojic, S.L., Wiseman, S.M., 2012. Differentiated thyroid \ncancers: a comprehensive review of novel targeted therapies. Exp. Rev. Anticancer Ther. 12, 345\u2013357. (A review dealing with the pharmacotherapy of the most common type of thyroid cancer, differentiated \nthyroid carcinoma)Lai, S., Zhang, S., Wang, L., et al., 2015. A rare mutation in patients with \nresistance to thyroid hormone and review of therapeutic strategies. \nAm. J. Med. Sci. 350, 167\u2013174. (Worth reading if you are interested in this \nrare disorder)\nLee, H.J., Li, C.W., Hammerstad, S.S., Stefan, M., Tomer, Y., 2015. \nImmunogenetics of autoimmune thyroid diseases: a comprehensive review. J. Autoimmun. 64, 82\u201390. (An immunological view of disorders \nsuch as Graves\u2019 and Hashimoto\u2019s disease. Interesting but moderately complex)\nMastorakos, G., Karoutsou, E.I., Mizamtsidi, M., Creatsas, G., 2007. The \nmenace of endocrine disruptors on thyroid hormone physiology and their impact on intrauterine development. Endocrine 3, 219\u2013237. ( A \nreview of endocrine disrupters and their effects on the thyroid. Not mainstream reading but an interesting topic)\nMcAninch, E.A., Bianco, A.C., 2016. The history and future of \ntreatment of hypothyroidism. Ann. Intern. Med. 164, 50\u201356. (Very comprehensive history of the diagnosis and treatment of hypothyroidism. Good review if you want to go into this subject in \nmore detail)\nNilsson, M., 2001. Iodide handling by the thyroid epithelial cell. Exp. \nClin. Endocrinol. Diabetes 109, 13\u201317. (Useful and readable review of iodide handling by the thyroid gland)\nRoberts, C.G., Ladenson, P.W., 2004. Hypothyroidism. Lancet 363, \n793\u2013803. (Authoritative and accessible review dealing with this thyroid pathology)\nSheehan, M.T., 2016. Biochemical testing of the thyroid: TSH is the best \nand, oftentimes, only test needed - A review for primary care. Clin. Med. Res. 14, 83\u201392. (This review was written primarily for primary care \nphysicians who have to test thyroid function in their patients. However, it contains a small review on the physiology and endocrinology of the thyroid \nas well as a lot of information about abnormal thyroid tests. Easy to read and \nrecommended)\nSurks, M.I., Ortiz, E., Daniels, G.H., et al., 2004. Subclinical thyroid \ndisease: scientific review and guidelines for diagnosis and management. JAMA 291, 228\u2013238. (Discusses and reviews the treatment \nof subclinical thyroid disease in detail; primarily of interest to clinical \nstudents)\nYen, P.M., 2001. Physiological and molecular basis of thyroid hormone \naction. Physiol. Rev. 81, 1097\u20131142. (Comprehensive review of thyroid hormone\u2013receptor interaction and the effects of thyroid hormone on target tissues)\nZhang, J., Lazar, M., 2000. The mechanism of action of thyroid \nhormones. Annu. Rev. Physiol. 62, 439\u2013466. (Detailed review of the molecular aspects of thyroid hormone\u2013receptor interaction)Clinical use of drugs acting on the thyroid \nRadioiodine (131I)\n\u2022 Hyperthyroidism (Graves\u2019 disease, multinodular toxic \ngoitre).\n\u2022 Relapse of hyperthyroidism after failed medical or \nsurgical treatment.\nCarbimazole or propylthiouracil\n\u2022 Hyperthyroidism (diffuse toxic", "start_char_idx": 2946, "end_char_idx": 6134, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5f98baf9-1e1e-42d8-8711-a7bc3b591cae": {"__data__": {"id_": "5f98baf9-1e1e-42d8-8711-a7bc3b591cae", "embedding": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "21c50316-5573-46ab-b10d-65561c9917ba", "node_type": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24dc0b73405144d3788dea7e89c1091c353c51a26fb2dea190f671374f446968"}, "2": {"node_id": "278108c2-78f4-4c03-88a3-0af07e5b672a", "node_type": null, "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80f7323b0400c42ce48d498a994769f22fcfb767817f2fdde95b6e26f850b9a2"}}, "hash": "7cf8404a718cf9b2485f40cd5864ad78571f9c15748c8d53a5152d77290f2f70", "text": "or propylthiouracil\n\u2022 Hyperthyroidism (diffuse toxic goitre); at least 1 year of \ntreatment is needed.\n\u2022 Preliminary to surgery for toxic goitre.\n\u2022 Part of the treatment of thyroid storm (very severe \nhyperthyroidism); propylthiouracil is preferred, combined with a \u03b2-adrenoceptor antagonist (e.g. \npropranolol).\nThyroid hormones and iodine\n\u2022 Levothyroxine (T 4) is the standard replacement therapy \nfor hypothyroidism.\n\u2022 Liothyronine (T 3), administered by slow intravenous \ninjection, is used for myxoedema coma.\n\u2022 Iodine dissolved in aqueous potassium iodide \n(\u2018Lugol iodine\u2019 ) is used short term to control \nthyrotoxicosis preoperatively. It reduces the vascularity \nof the gland.review the latest generation of drugs to be used for this \npurpose.\nFinally, recombinant human thyroid-stimulating hormone \n(rhTSH) is sometimes used for diagnostic purposes following \nsurgery.\nThe use of drugs to treat disorders of the thyroid is \nsummarised in the clinical box.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6121, "end_char_idx": 7566, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cfac263d-925f-4c5a-92f5-4823f3b6a05b": {"__data__": {"id_": "cfac263d-925f-4c5a-92f5-4823f3b6a05b", "embedding": null, "metadata": {"page_label": "461", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ac7325f-441a-47a3-86da-d059b679d783", "node_type": null, "metadata": {"page_label": "461", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9aa477ee715607c4c339ead920246218f211a8c0b788faad63fb93183f1f41d"}, "3": {"node_id": "788d36f0-07aa-451d-bc71-a1455fd80617", "node_type": null, "metadata": {"page_label": "461", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea23111d813fea471b0f1864e0e0779341e8b10082097eb78df3528aeb818273"}}, "hash": "c64e29f67470a0e34a6f636d387efeeee6d0aa9631b014ca1f074c6bf9c4c042", "text": "455\nThe reproductive system 36 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3\nOVERVIEW\nIn this chapter, we describe the endocrine control of \nthe female and male reproductive systems as the \nbasis for understanding drug actions in sex hormone \nreplacement, contraception, treatment of infertility, management of labour and treatment of erectile \ndysfunction.\nINTRODUCTION\nDrugs that affect reproduction (both by preventing concep -\ntion and more recently for treating infertility) transformed \nsociety in the latter half of the last century. In this chapter, \nwe briefly summarise salient points in reproductive endo -\ncrinology as a basis for understanding the numerous \nimportant drugs that work on the male and female reproduc -\ntive systems. Such drugs are used for contraception, to \ntreat infertility, as sex hormone replacement and in obstetric \npractice to influence labour. They are also used to influence \nlifestyle (Ch. 59). The principle of negative feedback is stressed and is central to understanding how hormones interact to control reproduction\n1 \u2013 many drugs, including \nagents used to prevent or assist conception, work by \ninfluencing negative feedback mechanisms. The chapter \nconcludes with a short section on erectile dysfunction.\nENDOCRINE CONTROL OF \nREPRODUCTION\nHormonal control of the reproductive systems in men and \nwomen involves sex steroids from the gonads, hypothalamic \nmediators including the decapeptide gonadotrophin-\nreleasing hormone (GnRH), and glycoprotein gonadotro -\nphins from the anterior pituitary gland (Ch. 34). Kisspeptin, \na protein that is a G protein\u2013coupled receptor ligand for \na receptor known as GPR54, initiates secretion of GnRH at puberty. GnRH is released from the hypothalamus to \nact on the anterior pituitary triggering the release of luteinis -\ning hormone (LH), and follicle-stimulating hormone (FSH). \nThese gonadotrophic hormones control sexual maturation and gametogenesis. Kisspeptin has been linked with sexual \nbonding. Neurokinin B (NKB, Ch. 19) is also implicated in controlling the secretion of GnRH in humans, with possible \nroles in pregnancy, sexual maturation and the menopause. It is present, together with kisspeptin and dynorphin, in \nthe arcuate nucleus of the hypothalamus where these \nmediators are implicated in generating pulsatile release of GnRH. NKB is implicated in menopausal flushing and NK3 \nreceptor block has reduced such flushing (Prague et al., \n2017).\nAnti-M\u00fcllerian hormone (AMH) is a glycoprotein which \ncontrols sexual development in the fetus and follicle forma -\ntion in adult women (Behringer, 1994). It is activated at a specific time in the male fetus and inhibits the development \nof the female reproductive tract (M\u00fcllerian ducts) in the \nmale embryo. AMH is also produced in adult women, regulating follicle formation in the ovaries. It is produced \nby granulosa cells, which surround the eggs, and is a \nbiomarker of ovarian reserve and in disorders such as polycystic ovary syndrome.\nNEUROHORMONAL CONTROL OF THE FEMALE \nREPRODUCTIVE SYSTEM\nIncreased secretion of hypothalamic and anterior pituitary \nhormones occurs in girls at puberty and stimulates secretion \nof oestrogen from the ovaries. This causes maturation of \nthe reproductive organs and development of secondary sexual characteristics, and also accelerated growth followed \nby closure of the epiphyses of the long bones. Sex steroids, \noestrogens and progesterone, are thereafter involved in the \nmenstrual cycle, and in pregnancy. A simplified outline is \ngiven in Figs 36.1 and 36.2.\nThe", "start_char_idx": 0, "end_char_idx": 3562, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "788d36f0-07aa-451d-bc71-a1455fd80617": {"__data__": {"id_": "788d36f0-07aa-451d-bc71-a1455fd80617", "embedding": null, "metadata": {"page_label": "461", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ac7325f-441a-47a3-86da-d059b679d783", "node_type": null, "metadata": {"page_label": "461", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9aa477ee715607c4c339ead920246218f211a8c0b788faad63fb93183f1f41d"}, "2": {"node_id": "cfac263d-925f-4c5a-92f5-4823f3b6a05b", "node_type": null, "metadata": {"page_label": "461", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c64e29f67470a0e34a6f636d387efeeee6d0aa9631b014ca1f074c6bf9c4c042"}}, "hash": "ea23111d813fea471b0f1864e0e0779341e8b10082097eb78df3528aeb818273", "text": "outline is \ngiven in Figs 36.1 and 36.2.\nThe menstrual cycle begins with menstruation, which \nlasts for 3\u20136 days, during which the superficial layer of \nuterine endometrium is shed. The endometrium regenerates \nduring the follicular phase of the cycle after menstrual flow \nhas stopped. A releasing factor, GnRH, is secreted from peptidergic neurons in the hypothalamus which discharge in \na pulsatile fashion, approximately one burst per hour. GnRH \nstimulates the anterior pituitary to release gonadotrophic hormones (see Fig. 36.1) \u2013 FSH and LH. These act on the \novaries to promote development of small groups of follicles, \neach of which contains an ovum. One follicle develops faster than the others and forms the Graafian follicle (see \nFigs 36.1 and 36.2E), which secretes oestrogens, and the \nrest degenerate. The ripening Graafian follicle consists of thecal and granulosa cells surrounding a fluid-filled core, \nwithin which lies an ovum. Oestrogens are responsible \nfor the proliferative phase of endometrial regeneration, which occurs from day 5 or 6 until mid-cycle (see Fig. \n36.2B and F). During this phase, the endometrium increases \nin thickness and vascularity, and at the peak of oestrogen secretion there is a prolific cervical secretion of mucus of pH 8\u20139, rich in protein and carbohydrate, which facilitates \nentry of spermatozoa. Oestrogen has a negative feedback \neffect on the anterior pituitary, decreasing gonadotrophin \n1Recognition that negative feedback is central to endocrine control was \na profound insight, made in 1930 by Dorothy Price, a laboratory \nassistant in the University of Chicago experimenting on effects of \ntestosterone in rats. She referred to it as \u2018reciprocal influence\u2019 and it helps in understanding how many reproductive hormones seem, \nconfusingly, to cause both an effect and its opposite if given in different \ndoses or over different time courses.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3518, "end_char_idx": 5901, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "57099d50-95d3-4a60-9629-988046838331": {"__data__": {"id_": "57099d50-95d3-4a60-9629-988046838331", "embedding": null, "metadata": {"page_label": "462", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7c1c9517-e544-4c5d-a853-3d19c424bbc1", "node_type": null, "metadata": {"page_label": "462", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "55d5f4710c956961d0f5958a48053e6cdc4e2c4812a449f2a68d03c4f17bf6d1"}, "3": {"node_id": "64a16c70-fcca-44d9-a230-6ce17d97a4c3", "node_type": null, "metadata": {"page_label": "462", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c46ddbec5c5f7959bf46061e0cb98acd0782be5880e46bdd9dbbd55a9ad61e90"}}, "hash": "33979cdef2be6097b0bd31de639073d107571b431aeb07e9309fb36b6b6a5b2d", "text": "36 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n456physiologically obvious, HCG has an additional pharm -\nacological action, exploited therapeutically in treating \ninfertility (see p. 463), of stimulating ovulation. As pregnancy \nproceeds, the placenta develops further hormonal functions and secretes a variety of hormones, including gonadotro -\nphins, progesterone and oestrogens. Progesterone secreted release during chronic administration of oestrogen as oral contraception (see pp. 463\u2013464). In contrast, the spike of endogenous oestrogen secretion just before mid-cycle \nsensitises LH-releasing cells of the pituitary to the action \nof the GnRH and causes the mid-cycle surge of LH secretion (see Fig. 36.2C). This, in turn, causes rapid swelling and \nrupture of the Graafian follicle, resulting in ovulation. If \nfertilisation occurs, the fertilised ovum passes down the fallopian tubes to the uterus, starting to divide as it goes.\nStimulated by LH, cells of the ruptured follicle proliferate \nand develop into the corpus luteum , which secretes proges -\nterone. Progesterone acts, in turn, on oestrogen-primed \nendometrium, stimulating the secretory phase of the cycle, \nwhich renders the endometrium suitable for the implantation of a fertilised ovum. During this phase, cervical mucus becomes more viscous, less alkaline, less copious and in \ngeneral less welcoming for sperm. Progesterone exerts \nnegative feedback on the hypothalamus and pituitary, decreasing the release of LH. It also has a thermogenic \neffect, causing a rise in body temperature of about 0.5\u00b0C \nat ovulation, which is maintained until the end of the cycle.\nIf implantation of a fertilised ovum does not occur, \nprogesterone secretion stops, triggering menstruation. If implantation does occur the corpus luteum continues to secrete progesterone which, by its effect on the hypothala -\nmus and anterior pituitary, prevents further ovulation. The chorion (an antecedent of the placenta) secretes human chorionic gonadotrophin (HCG), which maintains the lining \nof the uterus during pregnancy. For reasons that are not GnRH\nFSH LH\nOvary\nMaturation\nGF\nOestrogens\nAct on reproductive tract and other tissuesHypothalamus\nAnterior pituitary\nCL\nProgesterone\nFig. 36.1 Hormonal control of the female reproductive \nsystem. The Graafian follicle (GF) is shown developing on the \nleft, then involuting to form the corpus luteum (CL) on the right, after the ovum (\u2022) has been released. FSH, follicle-stimulating \nhormone; GnRH, gonadotrophin-releasing hormone; LH, \nluteinising hormone. Progesterone\n0102028(ng/mL)LH1800\n15001200\n900600300\n0(ng/mL)Oestrogens600\n400200\n0(pg/mL)Follicular\nphaseLuteal\nphase\nFSH1200\n800\n400\n0(ng/mL)\nV AEndometrium\nBlood\nvessels\nDay of menstrual cycle28 21 14 7 0FollicleOvulationA\nB\nC\nD\nE\nF\nFig. 36.2 Plasma concentrations of ovarian hormones and \ngonadotrophins in women during normal menstrual cycles. \nValues are the mean \u00b1 standard deviation of 40 women. The \nshaded areas indicate the entire range of observations. Day 1 \nis the onset of menstruation. Mean plasma hormone \nconcentrations", "start_char_idx": 0, "end_char_idx": 3106, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "64a16c70-fcca-44d9-a230-6ce17d97a4c3": {"__data__": {"id_": "64a16c70-fcca-44d9-a230-6ce17d97a4c3", "embedding": null, "metadata": {"page_label": "462", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7c1c9517-e544-4c5d-a853-3d19c424bbc1", "node_type": null, "metadata": {"page_label": "462", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "55d5f4710c956961d0f5958a48053e6cdc4e2c4812a449f2a68d03c4f17bf6d1"}, "2": {"node_id": "57099d50-95d3-4a60-9629-988046838331", "node_type": null, "metadata": {"page_label": "462", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "33979cdef2be6097b0bd31de639073d107571b431aeb07e9309fb36b6b6a5b2d"}}, "hash": "c46ddbec5c5f7959bf46061e0cb98acd0782be5880e46bdd9dbbd55a9ad61e90", "text": "the onset of menstruation. Mean plasma hormone \nconcentrations (A\u2013D) are shown in relation to day of menstrual cycle. (E and F) show diagrammatically the changes in the ovarian follicle and the endometrium during the cycle. Ovulation on day 14 of the menstrual cycle occurs with the mid-cycle peak of luteinising hormone (LH), represented by the vertical \ndashed line . A, arterioles; FSH, follicle-stimulating hormone; V, \nvenules. (After van de Wiele, R. L., Dyrenfurth, I. 1974. Pharmacol. Rev. 25, 189\u2013217.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3044, "end_char_idx": 4034, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "94b40922-f839-49bd-9fe1-f142a349e4b2": {"__data__": {"id_": "94b40922-f839-49bd-9fe1-f142a349e4b2", "embedding": null, "metadata": {"page_label": "463", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6ca7a83b-3fa0-4094-a157-aa9483abc836", "node_type": null, "metadata": {"page_label": "463", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e1e7213a8a2850e1658eb8ebf909902b28e6865cc6325928cf736616b4f1ba6e"}, "3": {"node_id": "5f9f747d-5e4d-4594-82e1-2a983d95988e", "node_type": null, "metadata": {"page_label": "463", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9939266f8c684e66c0ce6f7f35c44c39919d4280a7ef886637595690233d91cb"}}, "hash": "1c26d8a50f43f8a89bd4d65a3575261c07d2d683bada2d59145995ec388ccbde", "text": "36 ThE RE p RODUCTI v E SYSTEM\n457A simplified outline is given in Fig. 36.4. GnRH controls \nthe secretion of gonadotrophins by the anterior pituitary. \nThis secretion is not cyclical as in menstruating women, \nalthough it is pulsatile in both sexes, as with other ante -\nrior pituitary hormones (see Ch. 34). FSH is responsible \nfor the integrity of the seminiferous tubules, and after \npuberty is important in gametogenesis through an action on Sertoli cells, which nourish and support developing \nspermatozoa. LH, which in the male is also called interstitial \ncell-stimulating hormone (ICSH), stimulates the interstitial \ncells (Leydig cells) to secrete androgens \u2013 in particular during pregnancy controls the development of the secretory \nalveoli in the mammary gland, while oestrogen stimulates \nthe lactiferous ducts. After parturition oestrogen, along with prolactin (see Ch. 34), is responsible for stimulating and maintaining lactation, whereas supraphysiological \ndoses of oestrogen suppress lactation.\nOestrogens, progestogens (progesterone-like drugs), \nandrogens and the gonadotrophins are described below \u2013 see Fig. 36.3 for biosynthetic pathways.Aromatase\nDihydrotestosterone TestosteroneAndrostenedione\nOestradiolOestrone\nAnastrozole Finasteride\n5\u03b1-ReductaseOestriol Cholesterol Progesterone\nAromataseFig. 36.3 The biosynthetic \npathway for the androgens and \noestrogens, with sites of drug action. (See also Fig. 34.5.) Finasteride is used in benign prostatic hyperplasia, and anastrozole to treat breast cancer in postmenopausal women. \nHormonal control of the female \nreproductive system \n\u2022\tThe\tmenstrual \tcycle \tstarts \twith \tmenstruation.\n\u2022\tGonadotrophin-releasing \thormone, \treleased \tfrom \tthe \t\nhypothalamus, acts on the anterior pituitary to release \nfollicle-stimulating hormone (FSH) and luteinising hormone (LH).\n\u2022\tFSH\tand \tLH \tstimulate \tfollicle \tdevelopment \tin \tthe \t\novary. FSH is the main hormone stimulating oestrogen release. LH stimulates ovulation at mid-cycle and is the main hormone controlling subsequent progesterone secretion from the corpus luteum.\n\u2022\tOestrogen \tcontrols \tthe \tproliferative \tphase \tof \tthe \t\nendometrium and has negative feedback effects on the anterior pituitary. Progesterone controls the later secretory phase, and has negative feedback effects on \nboth the hypothalamus and anterior pituitary.\n\u2022\tIf\ta\tfertilised \tovum \tis \timplanted, \tthe \tcorpus \tluteum \t\ncontinues to secrete progesterone.\n\u2022\tAfter\timplantation, \thuman \tchorionic \tgonadotrophin \t\n(HCG) from the chorion becomes important, and later \nin pregnancy progesterone, HCG and other hormones \nare secreted by the placenta.Sertoli\ncellGnRH\nFSH ICSHHypothalamus\nAnterior pituitary\nTESTIS\nGametogenesis\nin the\nseminiferous\ntubulesTestosterone\nDihydrotestosterone\nSecondary sex organsInterstitial\ncells\nFig. 36.4 Hormonal control of the male reproductive \nsystem. FSH, follicle-stimulating hormone; GnRH, \ngonadotrophin-releasing hormone; ICSH, interstitial cell-\nstimulating hormone. \nNEUROHORMONAL CONTROL OF THE MALE \nREPRODUCTIVE SYSTEM\nAs in women, hypothalamic, anterior pituitary and \ngonadal hormones control the male reproductive system. mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3187, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5f9f747d-5e4d-4594-82e1-2a983d95988e": {"__data__": {"id_": "5f9f747d-5e4d-4594-82e1-2a983d95988e", "embedding": null, "metadata": {"page_label": "463", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6ca7a83b-3fa0-4094-a157-aa9483abc836", "node_type": null, "metadata": {"page_label": "463", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e1e7213a8a2850e1658eb8ebf909902b28e6865cc6325928cf736616b4f1ba6e"}, "2": {"node_id": "94b40922-f839-49bd-9fe1-f142a349e4b2", "node_type": null, "metadata": {"page_label": "463", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c26d8a50f43f8a89bd4d65a3575261c07d2d683bada2d59145995ec388ccbde"}}, "hash": "9939266f8c684e66c0ce6f7f35c44c39919d4280a7ef886637595690233d91cb", "text": "and \ngonadal hormones control the male reproductive system. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3112, "end_char_idx": 3651, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cb037d7e-539e-472c-8222-3d963184d4ab": {"__data__": {"id_": "cb037d7e-539e-472c-8222-3d963184d4ab", "embedding": null, "metadata": {"page_label": "464", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6b65e8ab-70ee-4a2d-931a-c4103bf783ec", "node_type": null, "metadata": {"page_label": "464", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed287bc29eba59f6d5cc8203d4d80628634149765291459735e52f13f513ca72"}, "3": {"node_id": "bf996fdd-bc20-4e96-a0fa-5ead3bbf7d1a", "node_type": null, "metadata": {"page_label": "464", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0bc9755d8220a23228d3a7b2cde0c79e2699002764e469f2ad71072681060c2"}}, "hash": "f2e12d5ee8636339b7696193ab1add68f01b818d83a99dbb3522a2027c3ec8ba", "text": "36 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n458the principal oestrogen secreted by the ovary. At the begin -\nning of the menstrual cycle, the plasma concentration is \n0.2 nmol/L, rising to ~2.2 nmol/L in mid-cycle.\nActions\nOestrogen acts in concert with progesterone, and induces \nsynthesis of progesterone receptors in uterus, vagina, \nanterior pituitary and hypothalamus. Conversely, proges -\nterone decreases oestrogen receptor expression in the \nreproductive tract. Prolactin (see Ch. 34) also influences \noestrogen action by increasing the numbers of oestrogen receptors in the mammary gland, but has no effect on oestrogen receptor expression in the uterus.\nEffects of exogenous oestrogen in females depend on \nthe state of sexual maturity when the oestrogen is administered:\n\u2022\tIn primary hypogonadism: oestrogen stimulates \ndevelopment of secondary sexual characteristics and accelerates growth.\n\u2022\tIn adults with primary amenorrhoea: oestrogen, given cyclically with a progestogen, induces an artificial cycle.\n\u2022\tIn sexually mature women: oestrogen (with a progestogen) is contraceptive.\n\u2022\tAt or after the menopause: oestrogen replacement prevents menopausal symptoms and bone loss.\nOestrogens have several metabolic actions, including mineralocorticoid (retention of salt and water) and mild \nanabolic actions. They increase plasma concentrations of \nhigh-density lipoproteins, a potentially beneficial effect (Ch. 24) that may contribute to the relatively low risk of ather -\nomatous disease in premenopausal women compared with men of the same age. However, oestrogens also increase the coagulability of blood, and increase the risk of thromboembolism.\nMechanism of action\nOestrogen binds to nuclear receptors, as do other steroid hormones (Ch. 3). There are at least two types of oestrogen \nreceptor, termed ER \u03b1 and ER \u03b2. Binding is followed by \ninteraction of the resultant complexes with nuclear sites \nand subsequent genomic effects. In addition to these \n\u2018classic\u2019 intracellular receptors, some oestrogen effects, \nin particular its rapid vascular actions, are initiated by interaction with membrane receptors, including a G \nprotein\u2013coupled oestrogen receptor (GPER), which was \ncloned from vascular endothelial cells and plays a part in regulating vascular tone and cell growth as well as lipid and glucose homeostasis (Barton & Prossnitz, 2015). Acute \nvasodilatation caused by 17- \u03b2-oestradiol is mediated by \nnitric oxide, and a plant-derived (phyto-) oestrogen called \ngenistein (which is selective for ER \u03b2, as well as having \nquite distinct effects due to inhibition of protein kinase C) is as potent as 17- \u03b2-oestradiol in this regard (Walker \net al., 2001). Oestrogen receptor modulators (receptor-\nselective oestrogen agonists or antagonists) are mentioned \nlater.\nPreparations\nMany preparations (oral, transdermal, intramuscular, implantable and topical) of oestrogens are available for a \nwide range of indications. These include natural (e.g. \noestradiol, oestriol) and synthetic (e.g. mestranol, ethi-\nnylestradiol, diethylstilbestrol) oestrogens. Oestrogens are testosterone . LH/ICSH secretion begins at puberty, and the \nconsequent secretion of testosterone causes maturation of \nthe reproductive organs and development of secondary \nsexual characteristics. Thereafter, the primary function of testosterone is the maintenance of spermatogenesis \nand hence fertility \u2013 an action mediated by Sertoli cells.", "start_char_idx": 0, "end_char_idx": 3451, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bf996fdd-bc20-4e96-a0fa-5ead3bbf7d1a": {"__data__": {"id_": "bf996fdd-bc20-4e96-a0fa-5ead3bbf7d1a", "embedding": null, "metadata": {"page_label": "464", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6b65e8ab-70ee-4a2d-931a-c4103bf783ec", "node_type": null, "metadata": {"page_label": "464", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed287bc29eba59f6d5cc8203d4d80628634149765291459735e52f13f513ca72"}, "2": {"node_id": "cb037d7e-539e-472c-8222-3d963184d4ab", "node_type": null, "metadata": {"page_label": "464", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f2e12d5ee8636339b7696193ab1add68f01b818d83a99dbb3522a2027c3ec8ba"}}, "hash": "d0bc9755d8220a23228d3a7b2cde0c79e2699002764e469f2ad71072681060c2", "text": "spermatogenesis \nand hence fertility \u2013 an action mediated by Sertoli cells. \nTestosterone is also important in the maturation of sper -\nmatozoa as they pass through the epididymis and vas \ndeferens. A further action is a feedback effect on the anterior \npituitary, modulating its sensitivity to GnRH and thus influencing secretion of LH/ICSH. Testosterone has marked anabolic effects, causing development of the musculature \nand increased bone growth which results in the pubertal \ngrowth spurt, followed by closure of the epiphyses of the \nlong bones.\nSecretion of testosterone is mainly controlled by LH/\nICSH, but FSH also plays a part, possibly by releasing a factor similar to GnRH from the Sertoli cells which are its \nprimary target. The interstitial cells that synthesise testos -\nterone also have receptors for prolactin, which may influence \ntestosterone production by increasing the number of \nreceptors for LH/ICSH.\nBEHAVIOURAL EFFECTS OF SEX HORMONES\nAs well as controlling the menstrual cycle, sex steroids \naffect sexual behaviour. Two types of control are recognised: \norganisational and activational.\nOrganisational control refers to the fact that sexual dif-\nferentiation of the brain can be permanently altered by the presence or absence of sex steroids at key stages in develop -\nment. In rats, administration of androgens to females within \na few days of birth results in long-term virilisation of \nbehaviour. Conversely, neonatal castration of male rats \ncauses them to develop behaviourally as females. Brain development in the absence of sex steroids follows female lines, but is switched to the male pattern by exposure of \nthe hypothalamus to androgen at a key stage of develop -\nment. Similar but less complete behavioural virilisation of \nfemale offspring has been demonstrated following androgen \nadministration in non-human primates, and probably also \noccurs in humans if pregnant women are exposed to exces -\nsive androgen.\nThe activational effect of sex steroids refers to their ability \nto modify sexual behaviour after brain development is complete. In general, oestrogens and androgens increase \nsexual activity in the appropriate sex. Oxytocin, which is \nimportant during parturition (see pp. 465\u2013466), also has \nroles in mating and parenting behaviours, its action in the \ncentral nervous system being regulated by oestrogen (see \nCh. 34).\nDRUGS AFFECTING REPRODUCTIVE \nFUNCTION\nOESTROGENS\nOestrogens are synthesised by the ovary and placenta, and \nin small amounts by the testis and adrenal cortex. The \nstarting substance for synthesis of oestrogen and other \nsteroids is cholesterol. The immediate precursors to the oestrogens are androgenic substances \u2013 androstenedione \nor testosterone (see Fig. 36.3). There are three main \nendogenous oestrogens in humans: oestradiol, oestrone and \noestriol (see Fig. 36.3). Oestradiol is the most potent and is mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3376, "end_char_idx": 6748, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1ad6fcde-990f-40e1-b3ea-9b36da3795d3": {"__data__": {"id_": "1ad6fcde-990f-40e1-b3ea-9b36da3795d3", "embedding": null, "metadata": {"page_label": "465", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0ed360c5-3f13-4686-a627-f0fc85dcbd22", "node_type": null, "metadata": {"page_label": "465", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "865a15c3323dd97c1f9d95c5ce780f912ae8b5dc160e4a14a340ea3bfe35df9a"}, "3": {"node_id": "89360432-824c-4330-90fc-793ef7d764b1", "node_type": null, "metadata": {"page_label": "465", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aac5fa87e68029f853120c810edf21fc6991734046d9451d6dc2ffb662bbda67"}}, "hash": "8a10dc41f43ee118eb84b2ce64347bb0a36b971813438ec187954a0822fafe9c", "text": "36 ThE RE p RODUCTI v E SYSTEM\n459malignancy, and that also has a role in controlling the \nbalance between bone-producing osteoblasts and bone-\nresorbing osteoclasts (Ch. 37).\nThe use of tamoxifen to treat and prevent breast cancer \nis discussed further in Chapter 57.\nANTIOESTROGENS\nAntioestrogens compete with natural oestrogens for recep -\ntors in target organs; in addition to SERMs (raloxifene, tamoxifen), which are partial agonists in some tissues and \nantagonists in others, there are drugs that are pure oestrogen receptor antagonists.\nClomiphene inhibits oestrogen binding in the anterior \npituitary, so preventing negative feedback and acutely increasing secretion of GnRH and gonadotrophins. This \nstimulates and enlarges the ovaries, increases oestrogen \nsecretion and induces ovulation. It is used in treating infertility caused by lack of ovulation. Twins are common, but multiple pregnancy is unusual.\nSee the clinical box on oestrogens and antioestrogens for \na summary of clinical uses.\nPROGESTOGENS\nThe natural progestational hormone (progestogen) is progesterone (see Figs 36.2 and 36.3). This is secreted by the \ncorpus luteum in the second part of the menstrual cycle, and by the placenta during pregnancy. Small amounts are also secreted by the testis and adrenal cortex.\nProgestogens act, as do other steroid hormones, on nuclear \nreceptors. The density of progesterone receptors is controlled by oestrogens (see p. 458).\nPreparations\nThere are two main groups of progestogens:\n1. The naturally occurring hormone and its derivatives \n(e.g. hydroxyprogesterone, medroxyprogesterone, \ndydrogesterone). Progesterone itself is virtually \ninactive orally, because of presystemic hepatic \nmetabolism. Other derivatives are available for oral administration, intramuscular injection or \nadministration via the vagina or rectum.\n2. Testosterone derivatives (e.g. norethisterone, \nnorgestrel and ethynodiol) can be given orally. The first two have some androgenic activity and are \nmetabolised to give oestrogenic products. Newer progestogens used in contraception include \ndesogestrel and gestodene; they may have fewer \nadverse effects on lipids than ethynodiol and may be considered for women who experience side effects \nsuch as acne, depression or breakthrough bleeding \nwith the older drugs. However, these newer drugs have been associated with higher risks of venous thromboembolic disease (see later).\nActions\nThe pharmacological actions of the progestogens are in essence the same as the physiological actions of progesterone \ndescribed previously. Specific effects relevant to contracep -\ntion are detailed later.\nPharmacokinetic aspects\nInjected progesterone is bound to albumin, not to the sex steroid-binding globulin. Some is stored in adipose tissue. \nIt is metabolised in the liver, and the products, pregnanolone presented either as single agents or combined with progestogen.\nPharmacokinetic aspects\nNatural and synthetic oestrogens are well absorbed in the \ngastrointestinal (GI) tract, but after absorption the natural \noestrogens are rapidly metabolised in the liver, whereas \nsynthetic oestrogens are degraded less rapidly. There is variable enterohepatic cycling. Most oestrogens are readily \nabsorbed from skin and mucous membranes. They may \nbe given as intravaginal creams or pessaries for local effect. In the plasma, natural oestrogens are bound to albumin \nand to a sex steroid-binding globulin. Natural oestrogens \nare excreted in the urine as glucuronides", "start_char_idx": 0, "end_char_idx": 3503, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "89360432-824c-4330-90fc-793ef7d764b1": {"__data__": {"id_": "89360432-824c-4330-90fc-793ef7d764b1", "embedding": null, "metadata": {"page_label": "465", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0ed360c5-3f13-4686-a627-f0fc85dcbd22", "node_type": null, "metadata": {"page_label": "465", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "865a15c3323dd97c1f9d95c5ce780f912ae8b5dc160e4a14a340ea3bfe35df9a"}, "2": {"node_id": "1ad6fcde-990f-40e1-b3ea-9b36da3795d3", "node_type": null, "metadata": {"page_label": "465", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a10dc41f43ee118eb84b2ce64347bb0a36b971813438ec187954a0822fafe9c"}}, "hash": "aac5fa87e68029f853120c810edf21fc6991734046d9451d6dc2ffb662bbda67", "text": "Natural oestrogens \nare excreted in the urine as glucuronides and sulfates.\nUnwanted effects\nUnwanted effects of oestrogens range from the common and tiresome to the life-threatening but rare: breast tender -\nness, nausea, vomiting, anorexia, retention of salt and water with resultant oedema, and increased risk of thrombo-embolism. More details of the unwanted effects of oral \ncontraceptives are given later.\nUsed intermittently for postmenopausal replacement \ntherapy, oestrogens cause menstruation-like bleeding. Oestrogen causes endometrial hyperplasia unless given \ncyclically with a progestogen. When administered to males, oestrogens result in feminisation.\nThere is current concern regarding environmental effects \nof oestrogens, including various pesticides that act on oestrogen receptors as well as oestrogens excreted in urine. Either of these sources of oestrogen can pollute groundwater \nand damage aquatic wildlife as well as posing risks to \nhuman health (Adeel et al., 2017; McLachlan, 2016).\nOestrogen administration to pregnant women can cause \ngenital abnormalities in their offspring: carcinoma of the vagina was more common in young women whose mothers \nwere given diethylstilbestrol in early pregnancy in a misguided attempt to prevent miscarriage (see Ch. 58).\nThe clinical uses of oestrogens and antioestrogens are \nsummarised in the box (p. 460). In addition, see the section later on postmenopausal hormone replacement therapy \n(HRT).\nOESTROGEN \u2003RECEPTOR \u2003MODULATORS\nRaloxifene, a \u2018selective [o]estrogen receptor modulator\u2019 \n(SERM), has anti-oestrogenic effects on breast and uterus \nbut oestrogenic effects on bone, lipid metabolism and blood \ncoagulation. It is used for prevention and treatment of postmenopausal osteoporosis (Ch. 37) and reduces the \nincidence of oestrogen receptor-positive breast cancer \nsimilarly to tamoxifen but with fewer adverse events \n(Barrett-Connor et al., 2006; Vogel et al., 2006). The US FDA \nhas supported its use to reduce the risk of invasive breast cancer in postmenopausal women with osteoporosis and \nin postmenopausal women at high risk for invasive breast \ncancer. Unlike oestrogen, it does not prevent menopausal flushes.\nTamoxifen has an antioestrogenic action on mammary \ntissue but oestrogenic actions on plasma lipids, endometrium and bone. It produces mild oestrogen-like adverse effects \nconsistent with partial agonist activity. The tamoxifen\u2013\noestrogen receptor complex does not readily dissociate, so there is interference with the recycling of receptors.\nTamoxifen upregulates transforming growth factor- \u03b2 \n(TGF-\u03b2), a cytokine that retards the progression of mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3442, "end_char_idx": 6568, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f78ecb36-2dd7-4907-a0f4-f2affd3091af": {"__data__": {"id_": "f78ecb36-2dd7-4907-a0f4-f2affd3091af", "embedding": null, "metadata": {"page_label": "466", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e6f3dd1d-a05d-47d2-b7b8-5f349822a71f", "node_type": null, "metadata": {"page_label": "466", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9610972bbbc89ce120e2d80a1158ced14d2ad9b9f4b3bd661edbe662c7af318"}, "3": {"node_id": "7cee7c56-369a-424e-b512-d739cfd777a3", "node_type": null, "metadata": {"page_label": "466", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "413874abe811b3a430ac8af1c03e57573f75fceeac6de128f602e204718bb238"}}, "hash": "a34b5292dce7cde5b62df82f9f91f8a3f3f2a8faa5cbebad883635733d2481bf", "text": "36 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n460Clinical uses of progestogens are summarised in the next \nbox.\nANTIPROGESTOGENS\nMifepristone is a partial agonist at progesterone receptors. \nIt sensitises the uterus to the action of prostaglandins. It \nis given orally and has a plasma half-life of 21 h. Mifepris -\ntone is used, in combination with a prostaglandin (e.g. \ngemeprost ; see p. 466), as a medical alternative to surgical \ntermination of pregnancy (see clinical box).\nProgestogens and \nantiprogestogens \n\u2022\tThe\tendogenous \thormone \tis \tprogesterone. \tExamples \t\nof synthetic drugs are the progesterone derivative \nmedroxyprogesterone and the testosterone derivative norethisterone.\n\u2022\tMechanism \tof \taction \tinvolves \tintracellular \treceptor/\naltered\tgene \texpression. \tOestrogen \tstimulates \t\nsynthesis of progesterone receptors, whereas progesterone inhibits synthesis of oestrogen receptors.\n\u2022\tMain\ttherapeutic \tuses \tare \tin \toral \tcontraception \tand \t\noestrogen replacement regimens, and to treat endometriosis.\n\u2022\tThe\tantiprogestogen \tmifepristone, in combination \nwith prostaglandin analogues, is an effective medical alternative to surgical termination of early pregnancy.\nClinical uses of progestogens and \nantiprogestogens \nProgestogens\n\u2022\tContraception:\n\u2013 with oestrogen in combined oral contraceptive pill ;\n\u2013 as progesterone-only contraceptive pill ;\n\u2013 as injectable or implantable progesterone-only \ncontraception;\n\u2013 as part of an intrauterine contraceptive system.\n\u2022\tCombined \twith \toestrogen for oestrogen replacement \ntherapy in women with an intact uterus, to prevent endometrial hyperplasia and carcinoma.\n\u2022\tFor\tendometriosis.\n\u2022\tIn\tendometrial carcinoma ; use in breast and renal \ncancer has declined.\n\u2022\tPoorly\tvalidated \tuses \thave \tincluded \tvarious \tmenstrual \t\ndisorders.\nAntiprogestogens\n\u2022\tMedical \ttermination \tof \tpregnancy: \tmifepristone \n(partial agonist) combined with a prostaglandin (e.g. gemeprost).Oestrogens and antioestrogens \n\u2022\tThe\tendogenous \toestrogens \tare \toestradiol \t(the \tmost \t\npotent), oestrone and oestriol; there are numerous \nexogenous \tsynthetic \tforms \t(e.g. \tethinylestradiol).\n\u2022\tMechanism \tof \taction \tinvolves \tinteraction \twith \tnuclear \t\nreceptors (ER\u03b1 or ER \u03b2) in target tissues, resulting in \nmodification of gene transcription. Some of the rapid vascular and metabolic effects of oestrogens are \nmediated by a G protein\u2013coupled [o]estrogen receptor \n(GPER).\n\u2022\tTheir\tpharmacological \teffects \tdepend \ton \tthe \tsexual \t\nmaturity\tof \tthe \trecipient:\n\u2013 before puberty, they stimulate development of \nsecondary \tsexual \tcharacteristics;\n\u2013 given cyclically in the female adult, they induce an \nartificial menstrual cycle and are used for contraception;\n\u2013 given at or after the menopause, they prevent \nmenopausal symptoms and protect against osteoporosis, but increase thromboembolism.\n\u2022\tAntioestrogens \tare \tcompetitive \tantagonists \tor \tpartial \t\nagonists. Tamoxifen is used in oestrogen-dependent \nbreast cancer. Clomiphene induces ovulation by \ninhibiting the negative feedback effects on the \nhypothalamus and anterior pituitary.\n\u2022\tSelective \tmodulators \tof \tthe", "start_char_idx": 0, "end_char_idx": 3139, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7cee7c56-369a-424e-b512-d739cfd777a3": {"__data__": {"id_": "7cee7c56-369a-424e-b512-d739cfd777a3", "embedding": null, "metadata": {"page_label": "466", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e6f3dd1d-a05d-47d2-b7b8-5f349822a71f", "node_type": null, "metadata": {"page_label": "466", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9610972bbbc89ce120e2d80a1158ced14d2ad9b9f4b3bd661edbe662c7af318"}, "2": {"node_id": "f78ecb36-2dd7-4907-a0f4-f2affd3091af", "node_type": null, "metadata": {"page_label": "466", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a34b5292dce7cde5b62df82f9f91f8a3f3f2a8faa5cbebad883635733d2481bf"}}, "hash": "413874abe811b3a430ac8af1c03e57573f75fceeac6de128f602e204718bb238", "text": "and anterior pituitary.\n\u2022\tSelective \tmodulators \tof \tthe \toestrogen \treceptor \tare \t\noestrogen agonists in some tissues but antagonists in \nothers. Raloxifene (one such drug) is used to treat \nand prevent osteoporosis.\nClinical uses of oestrogens and \nantioestrogens \nOestrogens\n\u2022\tReplacement \ttherapy:\n\u2013 primary ovarian failure (e.g. Turner\u2019s syndrome);\n\u2013 secondary ovarian failure (menopause) for flushing, \nvaginal dryness and to preserve bone mass.\n\u2022\tContraception.\n\u2022\tProstate \tand \tbreast \tcancer \t(these \tuses \thave \tlargely \t\nbeen superseded by other hormonal manipulations; see Ch. 57).\nAntioestrogens\n\u2022\tTo\ttreat \toestrogen-sensitive \tbreast \tcancer \t\n(tamoxifen).\n\u2022\tTo\tinduce \tovulation \t(clomiphene) in treating infertility.\nand pregnanediol, are conjugated with glucuronic acid and \nexcreted in the urine.\nUnwanted effects\nUnwanted effects of progestogens include weak androgenic \nactions. Other unwanted effects include acne, fluid retention, \nweight change, depression, change in libido, breast dis -\ncomfort, premenstrual symptoms, irregular menstrual cycles \nand breakthrough bleeding. There is an increased incidence \nof thromboembolism.POSTMENOPAUSAL HORMONE \nREPLACEMENT THERAPY (HRT)\nAt the menopause, whether natural or surgically induced, \novarian function decreases and oestrogen levels fall. There \nis a long history of disagreement regarding the pros and \ncons of HRT in this context, with the prevailing wisdom mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3083, "end_char_idx": 4999, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4da1771e-5e52-4661-bf99-ef6d6f5ea7b1": {"__data__": {"id_": "4da1771e-5e52-4661-bf99-ef6d6f5ea7b1", "embedding": null, "metadata": {"page_label": "467", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54cd3a27-ee22-49c2-980d-9f286473132c", "node_type": null, "metadata": {"page_label": "467", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01ee028b0fddf8d6bf9c2747c49ec265dc94f7beaf375f0696ec6b68a6ca72f9"}, "3": {"node_id": "7919f8a8-9eba-454e-b6b1-1904d34aad43", "node_type": null, "metadata": {"page_label": "467", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "faa5864aad1f515817090c7cc3cdb090c85101e911ec0aedd30922e581aa824a"}}, "hash": "b88f71149192f646277f2f2594b7d0c9e745b0c28134a520fb9c12e66eea8bf7", "text": "36 ThE RE p RODUCTI v E SYSTEM\n461the usual increase in height that occurs year on year in \nyounger children, followed by fusion of the bony epiphyses \nand cessation of linear growth. In adults, the anabolic effects \ncan be accompanied by retention of salt and water. The skin thickens and may darken, and sebaceous glands become \nmore active, predisposing to acne. Body weight and muscle \nmass increase, partly due to water retention. Androgens cause a feeling of well-being and an increase in physical \nvigour, and may increase libido. Whether they are respon -\nsible for sexual behaviour as such is controversial, as is \ntheir contribution to aggressive behaviour. Paradoxically, testosterone administration inhibits spermatogenesis, so \nreducing male fertility.\nMechanism of action\nIn most target cells, testosterone works through an active \nmetabolite, dihydrotestosterone, to which it is converted \nlocally by a 5 \u03b1-reductase enzyme. In contrast, testosterone \nitself causes virilisation of the genital tract in the male \nembryo and regulates LH/ICSH production in anterior \npituitary cells. Testosterone and dihydrotestosterone modify \ngene transcription by interacting with nuclear receptors.\nPreparations\nTestosterone itself can be given by subcutaneous implanta -\ntion or by transdermal patches (male replacement dose \napproximately 2.5 mg/day). Various esters (e.g. enanthate \nand propionate) are given by intramuscular depot injection. Testosterone undecanoate and mesterolone can be given \norally.\nPharmacokinetic aspects\nIf given orally, testosterone is rapidly metabolised in the \nliver. Virtually all testosterone in the circulation is bound \nto plasma protein \u2013 mainly to the sex steroid-binding \nglobulin. Approximately 90% of endogenous testosterone is eliminated as metabolites. The elimination half-life of \nthe free hormone is short (10\u201320 min). It is converted in \nthe liver to androstenedione (see Fig. 36.3), which has weak androgenic activity. Synthetic androgens are less rapidly \nmetabolised, and some are excreted in the urine unchanged.\nUnwanted effects\nUnwanted effects of androgens include decreased gonado -\ntrophin release during continued use, with resultant male infertility,\n2 and salt and water retention leading to oedema. \nAdenocarcinoma of the liver has been reported. Androgens impair growth in children (via premature fusion of epi -\nphyses), cause acne and lead to masculinisation in girls. \nAdverse effects of testosterone replacement and monitoring \nfor these are reviewed by Rhoden and Morgentaler (2004).\nThe clinical uses of androgens are given in the clinical \nbox.\nANABOLIC STEROIDS\nAndrogens can be modified chemically to alter the balance \nof anabolic and other effects. \u2018Anabolic steroids\u2019 (e.g. \nnandrolone ) increase protein synthesis and muscle develop -\nment disproportionately, but clinical use (e.g. in debilitating \nor muscle wasting disease) has been disappointing. They undergoing several revisions over the years (see Davis et al., \n2005). HRT normally involves the cyclic or continuous administration of low doses of one or more oestrogens, \nwith or without a progestogen. Short-term HRT has some \nclear-cut benefits:\n\u2022\timprovement \tof \tsymptoms \tcaused \tby \treduced \t\noestrogen, for example, hot flushes and vaginal dryness;\n\u2022\tprevention \tand \ttreatment \tof \tosteoporosis, \tbut \tother \t\ndrugs are usually preferable for this (Ch. 37).\nOestrogen replacement does not reduce the risk of coronary \nheart disease, despite earlier hopes, nor is there evidence \nthat it", "start_char_idx": 0, "end_char_idx": 3535, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7919f8a8-9eba-454e-b6b1-1904d34aad43": {"__data__": {"id_": "7919f8a8-9eba-454e-b6b1-1904d34aad43", "embedding": null, "metadata": {"page_label": "467", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54cd3a27-ee22-49c2-980d-9f286473132c", "node_type": null, "metadata": {"page_label": "467", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "01ee028b0fddf8d6bf9c2747c49ec265dc94f7beaf375f0696ec6b68a6ca72f9"}, "2": {"node_id": "4da1771e-5e52-4661-bf99-ef6d6f5ea7b1", "node_type": null, "metadata": {"page_label": "467", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b88f71149192f646277f2f2594b7d0c9e745b0c28134a520fb9c12e66eea8bf7"}}, "hash": "faa5864aad1f515817090c7cc3cdb090c85101e911ec0aedd30922e581aa824a", "text": "\nheart disease, despite earlier hopes, nor is there evidence \nthat it reduces age-related decline in cognitive function. Drawbacks include:\n\u2022\tcyclical \twithdrawal \tbleeding;\n\u2022\tadverse \teffects \trelated \tto \tprogestogen \t(see \tlater);\n\u2022\tincreased \trisk \tof \tendometrial \tcancer \tif \toestrogen \tis \t\ngiven unopposed by progestogen;\n\u2022\tincreased \trisk \tof \tbreast \tcancer, \trelated \tto \tthe \tduration \t\nof HRT use and disappearing within 5 years of stopping;\n\u2022\tincreased \trisk \tof \tvenous \tthromboembolism \t(risk \t\napproximately doubled in women using combined HRT for 5 years).\nThe web links in the reference list provide best estimates of risks of cancer (breast, endometrium, ovary), venous thromboembolism, stroke and coronary artery disease in \nrelation to age and duration of HRT use.\nOestrogens used in HRT can be given orally (conjugated \noestrogens, oestradiol, oestriol), vaginally (oestriol), by transdermal patch (oestradiol) or by subcutaneous implant \n(oestradiol). Tibolone is marketed for the short-term treat -\nment of symptoms of oestrogen deficiency and for post -\nmenopausal prophylaxis of osteoporosis in women at high risk of fracture when other prophylaxis is contraindicated or not tolerated. It has oestrogenic, progestogenic and weak \nandrogenic activity, and can be used continuously without \ncyclical progesterone (avoiding the inconvenience of withdrawal bleeding).\nANDROGENS\nTestosterone is the main natural androgen. It is synthesised \nmainly by the interstitial cells of the testis, and in smaller \namounts by the ovaries and adrenal cortex. Adrenal \nandrogen production is influenced by adrenocorticotrophic hormone (ACTH, corticotrophin). As for other steroid \nhormones, cholesterol is the starting substance. Dehydroe -\npiandrosterone and androstenedione are important \nintermediates. They are released from the gonads and the \nadrenal cortex, and converted to testosterone in the liver \n(see Fig. 36.3).\nActions\nIn general, the effects of exogenous androgens are the same as those of testosterone, and depend on the age and sex of \nthe recipient. If prepubertal boys are given androgens, they \ndo not reach their full predicted height because of premature closure of the epiphyses of the long bones. In boys at the \nage of puberty, there is rapid development of secondary \nsexual characteristics (i.e. growth of facial, axillary and pubic hair, deepening of the voice), maturation of the \nreproductive organs and a marked increase in muscular \nstrength. There is a growth spurt with an acceleration in \n2Large doses of androgens also adversely affect female fertility, but \nphysiological concentrations of androgen are now believed to be \nimportant for female fertility (Prizant et al., 2014)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3466, "end_char_idx": 6672, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dafe0f41-bd82-478a-b223-83bcb572ebcc": {"__data__": {"id_": "dafe0f41-bd82-478a-b223-83bcb572ebcc", "embedding": null, "metadata": {"page_label": "468", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "737ee5e7-9f0a-4b9b-a303-ab10e318d0d8", "node_type": null, "metadata": {"page_label": "468", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b031e2f877fa93cb233f7da1e87d6ac3aa74bcad4c9d9638bf65c79bfb0cceb7"}, "3": {"node_id": "14d5611b-3b76-47ce-8308-9f8ef0a7bd53", "node_type": null, "metadata": {"page_label": "468", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7bfae15085c9e365d4640ede575127acc20a0c67d026def9991ea50946f39a06"}}, "hash": "acc8a947282c313a50f3372744b21bfdf5c502044f3264341307a77574b6157b", "text": "36 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n462Drugs can have anti-androgen action by inhibiting \nsynthetic enzymes. Finasteride inhibits the enzyme \n(5\u03b1-reductase) that converts testosterone to dihydro -\ntestosterone (see Fig. 36.3). This active metabolite has greater \naffinity than testosterone for androgen receptors in the \nprostate gland. Finasteride is well absorbed after oral \nadministration, has a half-life of about 7 h, and is excreted \nin the urine and faeces. It is used to treat benign prostatic \nhyperplasia, although \u03b11-adrenoceptor antagonists, for \nexample, terazosin or tamsulosin (Chs 15 and 30), are more \neffective (working by the entirely different mechanism of relaxing smooth muscle in the capsule of the prostate gland and opposing \u03b1\n1-adrenoceptor-mediated prostatic growth). \nSurgery is another option.\nGONADOTROPHIN-RELEASING HORMONE: \nAGONISTS AND ANTAGONISTS\nGnRH (previously known as luteinising hormone-releasing \nhormone, LHRH) is a decapeptide that controls the secretion \nof FSH and LH by the anterior pituitary. Secretion of GnRH \nis controlled by neural input from other parts of the brain, and through negative feedback by the sex steroids (Figs \n36.1 and 36.5). Exogenous androgens, oestrogens and \nprogestogens all inhibit GnRH secretion, but only progesto -\ngens exert this effect at doses that do not have marked \nhormonal actions on peripheral tissues, presumably because \nprogesterone receptors in the reproductive tract are sparse unless they have been induced by previous exposure to oestrogen. Danazol (see later) is a synthetic steroid that \ninhibits release of GnRH and, consequently, of gonadotro -\nphins (FSH and LH). Clomiphene is an oestrogen antagonist \nthat stimulates gonadotrophin release by inhibiting the \nnegative feedback effects of endogenous oestrogen; it is \nused to treat infertility (see clinical box, p. 460, and \nFig. 36.5).\nSynthetic GnRH is termed gonadorelin. Numerous \nanalogues of GnRH, both agonists and antagonists, have \nHypothalamus\nAnterior pituitary\nClomiphene\nCyclofenilGnRHGnRH\nagonists\nGnRH\nantagonistsPulsatileContinuous\nGnRHR\nFSH LHOestrogen\nFig. 36.5 Regulation of gonadotrophin (follicle-stimulating \nhormone, FSH; luteinising hormone, LH) release from the \nanterior pituitary. GnRHR, gonadotrophin-releasing hormone receptor. 3Very different doses are used for these different conditions, for \nexample, 2 mg/day for acne, 100 mg/day for hypersexuality and \n300 mg/day for prostatic cancer.Androgens and the hormonal \ncontrol of the male reproductive \nsystem \n\u2022\tGonadotrophin-releasing \thormone \tfrom \tthe \t\nhypothalamus acts on the anterior pituitary to release \nboth follicle-stimulating hormone, which stimulates gametogenesis, and luteinising hormone (also called \ninterstitial cell-stimulating hormone), which stimulates \nandrogen secretion.\n\u2022\tThe\tendogenous \thormone \tis \ttestosterone; \t\nintramuscular depot injections of testosterone esters are used for replacement therapy.\n\u2022\tMechanism \tof \taction \tis \tvia \tintracellular \treceptors.\n\u2022\tEffects\tdepend \ton \tage/sex, \tand \tinclude \tdevelopment \t\nof\tmale\tsecondary \tsexual \tcharacteristics \tin \tprepubertal", "start_char_idx": 0, "end_char_idx": 3169, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "14d5611b-3b76-47ce-8308-9f8ef0a7bd53": {"__data__": {"id_": "14d5611b-3b76-47ce-8308-9f8ef0a7bd53", "embedding": null, "metadata": {"page_label": "468", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "737ee5e7-9f0a-4b9b-a303-ab10e318d0d8", "node_type": null, "metadata": {"page_label": "468", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b031e2f877fa93cb233f7da1e87d6ac3aa74bcad4c9d9638bf65c79bfb0cceb7"}, "2": {"node_id": "dafe0f41-bd82-478a-b223-83bcb572ebcc", "node_type": null, "metadata": {"page_label": "468", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "acc8a947282c313a50f3372744b21bfdf5c502044f3264341307a77574b6157b"}}, "hash": "7bfae15085c9e365d4640ede575127acc20a0c67d026def9991ea50946f39a06", "text": "\t\nof\tmale\tsecondary \tsexual \tcharacteristics \tin \tprepubertal \t\nboys and masculinisation in women.\nClinical uses of androgens and \nanti-androgens \n\u2022\tAndrogens \t(testosterone preparations) as hormone \nreplacement \tin:\n\u2013 male hypogonadism due to pituitary or testicular \ndisease (e.g. 50\u2013100 mg per day as gel applied to \nthe skin)\n\u2022\tAnti-androgens \t(e.g. \tflutamide, cyproterone) are \nused as part of the treatment of prostatic cancer.\n\u2022\t5\u03b1-Reductase inhibitors (e.g. finasteride) are used in \nbenign prostatic hyperplasia.\nare used in the therapy of aplastic anaemia and (notoriously) \nabused by some athletes (Ch. 59), as is testosterone itself. \nUnwanted effects are described above, under Androgens. \nIn addition, cholestatic jaundice, liver tumours and increased \nrisk of coronary heart disease are recognised adverse effects of high-dose anabolic steroids.\nANTI-ANDROGENS\nBoth oestrogens and progestogens have anti-androgen activity, oestrogens mainly by inhibiting gonadotrophin \nsecretion and progestogens by competing at androgen \nreceptors in target organs. Cyproterone is a derivative of \nprogesterone and has weak progestational activity. It is a \npartial agonist at androgen receptors, competing with \ndihydrotestosterone for receptors in androgen-sensitive target tissues. Through its effect in the hypothalamus, it \ndepresses the synthesis of gonadotrophins. It is used as an \nadjunct in the treatment of prostatic cancer during initiation of GnRH agonist treatment (see later). It is also used in the therapy of precocious puberty in males, and of masculinisa -\ntion and acne in women. It also has a central nervous system effect, decreasing libido, and has been used to treat hyper -\nsexuality in male sexual offenders.\n3\nFlutamide is a non-steroidal anti-androgen used with \nGnRH agonists in the treatment of prostate cancer.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3108, "end_char_idx": 5430, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2546deb7-6133-4a4c-9c5a-e70f757c555f": {"__data__": {"id_": "2546deb7-6133-4a4c-9c5a-e70f757c555f", "embedding": null, "metadata": {"page_label": "469", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9578f030-ebc2-46cf-9b78-b3cc1bc692a5", "node_type": null, "metadata": {"page_label": "469", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4464563b9ed985acee9f3b4d0ccc4a1f7384e3474ec7ea4f1e23e3969110d6bf"}, "3": {"node_id": "152ef194-4a83-484e-bbad-040229f7e09b", "node_type": null, "metadata": {"page_label": "469", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c5e71105e2d4f066bef5f4afb3c30036b6e9c64702dac9bad6249ab49846b60b"}}, "hash": "eb8527b2b15e309c421e1a1ba624486e6684866aafff835b967e41a5f7cecca6", "text": "36 ThE RE p RODUCTI v E SYSTEM\n463Preparations\nGonadotrophins are extracted from urine of pregnant (HCG) \nor postmenopausal women (human menopausal gonado-\ntrophin, which contains a mixture of FSH and LH). \nRecombinant FSH ( follitropin ) and LH ( lutropin ) are also \navailable.\nPharmacokinetics and clinical use\nGonadotrophin preparations are given by injection. They are used to treat infertility caused by lack of ovulation as \na result of hypopituitarism, or following failure of treatment \nwith clomiphene ; they are also used by specialists to induce \novulation to enable eggs to be collected for in vitro fertilisa -\ntion. For this use, gonadotrophin is usually administered after secretion of endogenous FSH and LH has been sup -\npressed (see p. 463). Gonadotrophins are also sometimes \nused in men with infertility caused by a low sperm count \nas a result of hypogonadotrophic hypogonadism (a disorder that is sometimes accompanied by lifelong anosmia, i.e. lack of sense of smell). (Gonadotrophins do not, of course, \nwork for patients whose low sperm count is the result of \nprimary testicular failure.) HCG has been used to stimulate testosterone synthesis in boys with delayed puberty, but \ntestosterone is usually preferred.been synthesised. Buserelin, leuprorelin, goserelin and \nnafarelin are agonists, the last being 200 times more potent \nthan endogenous GnRH.\nPharmacokinetics and clinical use\nGnRH agonists, given by subcutaneous infusion in pulses to \nmimic physiological secretion of GnRH, stimulate gonado -\ntrophin release (see Fig. 36.5) and induce ovulation. They are absorbed intact following nasal administration (Ch. 9). Continuous use, by nasal spray or as depot preparations, \nstimulates gonadotrophin release transiently, but then \nparadoxically inhibits gonadotrophin release (see Fig. 36.5) because of down-regulation (desensitisation) of GnRH \nreceptors in the pituitary. GnRH analogues are given in \nthis fashion to cause gonadal suppression in various sex hormone-dependent conditions, including prostate and breast cancers, endometriosis (endometrial tissue outside \nthe uterine cavity) and large uterine fibroids. Continuous, \nnon-pulsatile administration inhibits spermatogenesis and ovulation. GnRH agonists are used by specialists in \ninfertility treatment, not to stimulate ovulation (which \nis achieved using gonadotrophin preparations) but to suppress the pituitary before administration of FSH \nor HCG.\nUnwanted effects of GnRH analogues\nUnwanted effects of GnRH agonists in women, for example, flushing, vaginal dryness and bone loss, result from hypo-\noestrogenism. The initial stimulation of gonadotrophin \nsecretion on starting treatment can transiently worsen pain from bone metastases in men with prostate cancer, so \ntreatment is started only after the patient has received an \nandrogen receptor antagonist such as flutamide (see earlier \nand Ch. 57).\nDANAZOL\nActions and pharmacokinetics\nDanazol inhibits gonadotrophin secretion (especially the mid-cycle surge), and consequently reduces oestrogen \nsynthesis in the ovary (see Fig. 36.5). In men, it reduces \nandrogen synthesis and spermatogenesis. It has androgenic activity. It is orally active and metabolised in the liver.\nDanazol is used in sex hormone-dependent conditions \nincluding endometriosis, breast dysplasia (benign breast lumps) and gynaecomastia. An additional special use is \nto reduce attacks of", "start_char_idx": 0, "end_char_idx": 3421, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "152ef194-4a83-484e-bbad-040229f7e09b": {"__data__": {"id_": "152ef194-4a83-484e-bbad-040229f7e09b", "embedding": null, "metadata": {"page_label": "469", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9578f030-ebc2-46cf-9b78-b3cc1bc692a5", "node_type": null, "metadata": {"page_label": "469", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4464563b9ed985acee9f3b4d0ccc4a1f7384e3474ec7ea4f1e23e3969110d6bf"}, "2": {"node_id": "2546deb7-6133-4a4c-9c5a-e70f757c555f", "node_type": null, "metadata": {"page_label": "469", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eb8527b2b15e309c421e1a1ba624486e6684866aafff835b967e41a5f7cecca6"}}, "hash": "c5e71105e2d4f066bef5f4afb3c30036b6e9c64702dac9bad6249ab49846b60b", "text": "and gynaecomastia. An additional special use is \nto reduce attacks of swelling in hereditary angio-oedema \n(Ch. 29).\nUnwanted effects are common, and include GI distur -\nbances, weight gain, fluid retention, dizziness, menopausal symptoms, muscle cramps and headache. Danazol is virilis -\ning in women.\nGONADOTROPHINS AND ANALOGUES\nGonadotrophins (FSH, LH and HCG) are glycoproteins \nproduced and secreted by the anterior pituitary (FSH and \nLH, see Ch. 34) or chorion and placenta (HCG). Large \namounts of gonadotrophins are present in the urine of women following the menopause, in whom oestrogen no \nlonger exerts feedback inhibition on the pituitary, which \nconsequently secretes large amounts of FSH and LH.\n4Gonadotrophin-releasing hormone \nand gonadotrophins \n\u2022\tGonadotrophin-releasing \thormone \tis \ta \tdecapeptide; \t\ngonadorelin is the synthetic form. Nafarelin is a \npotent analogue.\n\u2022\tGiven\tin \tpulsatile \tfashion, \tthey \tstimulate \tgonadotrophin \t\nrelease; given continuously, they inhibit it.\n\u2022\tThe\tgonadotrophins, \tfollicle-stimulating \thormone \tand \t\nluteinising hormone, are glycoproteins.\n\u2022\tPreparations \tof \tgonadotrophins \t(e.g. \tchorionic \t\ngonadotrophin) are used to treat infertility caused by \nfailure of ovulation.\n\u2022\tDanazol is a modified progestogen that inhibits \ngonadotrophin production by actions on the \nhypothalamus and anterior pituitary.\n4This forms the basis for the standard blood test, estimation of plasma \nLH/FSH concentrations, to confirm whether a woman is \npostmenopausal.5The first-generation pills, containing more than 50 \u00b5g of oestrogen, \nwere shown in the 1970s to be associated with an increased risk of deep vein thrombosis and pulmonary embolism.DRUGS USED FOR CONTRACEPTION\nORAL CONTRACEPTIVES\nThere are two main types of oral contraceptives:\n1. Combinations of an oestrogen with a progestogen (the \ncombined pill).\n2. Progestogen alone (the progestogen-only pill).\nTHE\u2003COMBINED \u2003PILL\nThe combined oral contraceptive pill is extremely effective, \nat least in the absence of intercurrent illness and of treatment \nwith potentially interacting drugs (see p. 464). The oestrogen \nin most combined preparations (second-generation pills)5 \nis ethinylestradiol, although a few preparations contain mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3352, "end_char_idx": 6074, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ffad4f42-eb16-431f-9dc7-6ae28546b4b7": {"__data__": {"id_": "ffad4f42-eb16-431f-9dc7-6ae28546b4b7", "embedding": null, "metadata": {"page_label": "470", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "03dbb60f-b29e-4421-9ba0-7b5caaf5ee40", "node_type": null, "metadata": {"page_label": "470", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9900767ac049c86e5f26c0346c0a7229d0f5057e76f67bd93283b7bf35e9db03"}, "3": {"node_id": "59ee4a62-52ff-473a-8b50-16326b8cc87d", "node_type": null, "metadata": {"page_label": "470", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b68c134e44bb7ec4aa536acbfaad8df707f745a434610cadb5556d8923fdf3d8"}}, "hash": "0468ca1ff180c8070aa03c78df7d8e8e5a8b3ab1dc9aa3a331c8beff43ec9ada", "text": "36 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n464unwanted pregnancy. In general, provided risk factors, e.g. \nsmoking, hypertension and obesity, have been identified, \ncombined oral contraceptives are safe for most women for \nmost of their reproductive lives.\nIs cancer risk affected?\nOvarian and endometrial cancer risk is reduced.\nIs blood pressure increased?\nA marked increase in arterial blood pressure occurs in a small percentage of women shortly after starting the combined oral contraceptive pill. This is associated with \nincreased circulating angiotensinogen, and disappears when \ntreatment is stopped. Blood pressure is therefore monitored when oral contraceptive treatment is started, and an alterna -\ntive contraceptive substituted if necessary.\nBeneficial effects\nBesides avoiding unwanted pregnancy, other desirable effects of the combined contraceptive pill include decreased \nmenstrual symptoms such as irregular periods and inter -\nmenstrual bleeding. Iron deficiency anaemia and premen -\nstrual tension are reduced, as are benign breast disease, uterine fibroids and functional cysts of the ovaries.\nTHE\u2003PROGESTOGEN-ONLY \u2003PILL\nThe drugs used in progestogen-only pills include nore-\nthisterone , levonorgestrel or ethynodiol . The pill is taken \ndaily without interruption. The mode of action is primarily on the cervical mucus, which is made inhospitable to sperm. The progestogen probably also hinders implantation through \nits effect on the endometrium (see Fig. 36.2) and on the \nmotility and secretions of the fallopian tubes (see p. 456).\nPotential beneficial and unwanted effects\nProgestogen-only contraceptives offer a suitable alternative to the combined pill for some women in whom oestrogen \nis contraindicated, and are suitable for women whose blood \npressure increases unacceptably during treatment with oestrogen. However, their contraceptive effect is less reliable \nthan that of the combination pill, and missing a dose may \nresult in conception. Disturbances of menstruation (espe -\ncially irregular bleeding) are common. Only a small propor -\ntion of women use this form of contraception, so long-term safety data are less reliable than for the combined pill.\nPHARMACOKINETICS \u2003OF \u2003ORAL \u2003CONTRACEPTIVES: \u2003\nDRUG \u2003INTERACTIONS\nCombined and progestogen-only oral contraceptives are metabolised by hepatic cytochrome P450 enzymes. Because \nthe minimum effective dose of oestrogen is used (to avoid \nexcess risk of thromboembolism), any increase in its clear -\nance may result in contraceptive failure, and indeed \nenzyme-inducing drugs can have this effect, not only for \ncombined but also for progesterone-only pills. Such drugs include rifampicin and rifabutin , as well as carbamazepine , \nphenytoin and others, including the herbal preparation St \nJohn\u2019s Wort (Ch. 48).\nOTHER DRUG REGIMENS USED FOR \nCONTRACEPTION\nPOSTCOITAL \u2003(EMERGENCY) \u2003CONTRACEPTION\nOral administration of levonorgestrel, alone or combined \nwith oestrogen, is effective if taken within 72 h of mestranol instead. The progestogen may be norethisterone , \nlevonorgestrel , ethynodiol , or \u2013 in \u2018third-generation\u2019 pills \n\u2013 desogestrel or gestodene, which are more potent, have \nless androgenic action and cause less change in lipoprotein \nmetabolism, but which probably cause a greater risk of \nthromboembolism than do second-generation preparations. \nThe oestrogen content is generally 20\u201350 \u00b5g of ethinyle -\nstradiol or its equivalent, and a preparation is", "start_char_idx": 0, "end_char_idx": 3476, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "59ee4a62-52ff-473a-8b50-16326b8cc87d": {"__data__": {"id_": "59ee4a62-52ff-473a-8b50-16326b8cc87d", "embedding": null, "metadata": {"page_label": "470", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "03dbb60f-b29e-4421-9ba0-7b5caaf5ee40", "node_type": null, "metadata": {"page_label": "470", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9900767ac049c86e5f26c0346c0a7229d0f5057e76f67bd93283b7bf35e9db03"}, "2": {"node_id": "ffad4f42-eb16-431f-9dc7-6ae28546b4b7", "node_type": null, "metadata": {"page_label": "470", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0468ca1ff180c8070aa03c78df7d8e8e5a8b3ab1dc9aa3a331c8beff43ec9ada"}}, "hash": "b68c134e44bb7ec4aa536acbfaad8df707f745a434610cadb5556d8923fdf3d8", "text": "of ethinyle -\nstradiol or its equivalent, and a preparation is chosen with the lowest oestrogen and progestogen content that is well \ntolerated and gives good cycle control. This combined pill is taken for 21 consecutive days followed by 7 pill-free \ndays, which causes a withdrawal bleed. Normal cycles of \nmenstruation usually commence fairly soon after discontinu -\ning treatment, and permanent loss of fertility (which may \nbe a result of early menopause rather than a long-term \nconsequence of the contraceptive pill) is rare.The mode of action is as follows:\n\u2022\tOestrogen \tinhibits \tsecretion \tof \tFSH \tvia \tnegative \t\nfeedback on the anterior pituitary, and thus suppresses development of the ovarian follicle.\n\u2022\tProgestogen \tinhibits \tsecretion \tof \tLH \tand \tthus \t\nprevents ovulation; it also makes the cervical mucus less suitable for the passage of sperm.\n\u2022\tOestrogen \tand \tprogestogen \tact \tin \tconcert \tto \talter \tthe \t\nendometrium in such a way as to discourage implantation.\nThey may also interfere with the coordinated contractions of the cervix, uterus and fallopian tubes that facilitate fertilisation and implantation.\nHundreds of millions of women worldwide have used \nthis method since the 1960s, and in general the combined pill constitutes a safe and effective method of contraception. \nThere are distinct health benefits from taking the pill (see \nbelow), and serious adverse effects are rare. However, minor unwanted effects constitute drawbacks to its use, and several \nimportant questions need to be considered.\nCommon adverse effects\nThe common adverse effects are:\n\u2022\tweight \tgain, \towing \tto \tfluid \tretention \tor \tan \tanabolic \t\neffect, or both;\n\u2022\tmild\tnausea, \tflushing, \tdizziness, \tdepression \tor \t\nirritability;\n\u2022\tskin\tchanges \t(e.g. \tacne \tand/or \tan \tincrease \tin \t\npigmentation);\n\u2022\tamenorrhoea \tof \tvariable \tduration \ton \tcessation \tof \t\ntaking the pill.\nQuestions that need to be considered\nIs there an increased risk of cardiovascular disease (venous \nthromboembolism, myocardial infarction, stroke)?\nWith second-generation pills (oestrogen content less than \n50 \u00b5g), the risk of thromboembolism is small (incidence \napproximately 15 per 100,000 users per year, compared with 5 per 100,000 non-pregnant non-users per year or 60 episodes \nof thromboembolism per 100,000 pregnancies). The risk is greatest in subgroups with additional factors, such as smoking \n(which increases risk substantially) and long-continued use \nof the pill, especially in women over 35 years of age. The incidence of thromboembolic disease is approximately 25 \nper 100,000 users per year in users of preparations containing \ndesogestrel or gestodene, which is still a small absolute risk compared with the risk of thromboembolism in an mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3414, "end_char_idx": 6643, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4e5b909d-fee4-4cd4-bbd2-ea93e2c9c956": {"__data__": {"id_": "4e5b909d-fee4-4cd4-bbd2-ea93e2c9c956", "embedding": null, "metadata": {"page_label": "471", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c5708c93-982a-4a2c-83be-40839cc174be", "node_type": null, "metadata": {"page_label": "471", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "292bcbf2c790f0fcab11c9e756bfc657157485f7e641ec5f269b65a147645532"}, "3": {"node_id": "1b66140b-37f5-4690-b369-603b00e66121", "node_type": null, "metadata": {"page_label": "471", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8b32304f7adf474314d2b2653264075a2f597ebfe447082787e054334ed33f28"}}, "hash": "e8fc4012080e0ac48124c78b4f83c135fe6e22ab2c7cb50595b0b117a7da8ce3", "text": "36 ThE RE p RODUCTI v E SYSTEM\n465THE MOTILITY OF THE UTERUS\nUterine muscle contracts rhythmically both in vitro and in \nvivo, contractions originating in the muscle itself. Myome -\ntrial cells in the fundus act as pacemakers and give rise to conducted action potentials. The electrophysiological activity of these pacemaker cells is regulated by the sex hormones.\nThe non-pregnant human uterus contracts spontaneously \nbut weakly during the first part of the cycle, and more strongly during the luteal phase and during menstruation. \nUterine movements are depressed in early pregnancy because \noestrogen, potentiated by progesterone, hyperpolarises myometrial cells. This suppresses spontaneous contractions. Towards the end of gestation, however, contractions recom -\nmence; these increase in force and frequency, and become fully coordinated during parturition. The nerve supply to the uterus includes both excitatory and inhibitory sympathetic \ncomponents: adrenaline, acting on \u03b2\n2 adrenoceptors, inhibits \nuterine contraction, whereas noradrenaline, acting on \u03b1 \nadrenoceptors, stimulates contraction.\nDRUGS THAT STIMULATE THE UTERUS\nDrugs that stimulate the pregnant uterus and are impor-\ntant in obstetrics include oxytocin, ergometrine and \nprostaglandins.\nOXYTOCIN\nThe neurohypophyseal hormone oxytocin (an octapeptide) regulates myometrial activity, causing uterine contraction \n(Ch. 34). Oxytocin release is stimulated by cervical dilatation, \nand by suckling; its role in parturition is incompletely understood but the fact that an antagonist ( atosiban, see \nlater) is effective in delaying the onset of labour implicates it in the physiology of parturition.\nOestrogen induces oxytocin receptor synthesis and, \nconsequently, the uterus at term is highly sensitive to this hormone. Given by slow intravenous infusion to induce labour, oxytocin causes regular coordinated contractions that travel from fundus to cervix. Both amplitude and \nfrequency of these contractions are related to dose, the \nuterus relaxing completely between contractions during low-dose infusion. Larger doses further increase the fre -\nquency of the contractions, and there is incomplete relaxation between them. Still higher doses cause sustained contractions that interfere with blood flow through the placenta and \ncause fetal distress or death.\nOxytocin contracts myoepithelial cells in the mammary \ngland, which causes \u2018milk let-down\u2019 \u2013 the expression of milk from the alveoli and ducts. It also has a vasodilator \naction. A weak antidiuretic action can result in water retention, which can be problematic in patients with cardiac \nor renal disease, or with pre-eclampsia.\n6 Oxytocin and \noxytocin receptors are also found in the brain, particularly in the limbic system, and are believed to play a role in \nmating and parenting behaviour.\nThe clinical use of synthetic oxytocin is given in the box \non p. 467.\nOxytocin can be given by intravenous injection or \nintramuscularly, but is most often given by intravenous \ninfusion. It is inactivated in the liver and kidneys, and by \ncirculating placental oxytocinase.Oral contraceptives \nThe combined pill\n\u2022\tThe\tcombined \tpill \tcontains \tan \toestrogen \tand \ta \t\nprogestogen. It is taken for 21 consecutive days out \nof 28.\n\u2022\tMode\tof \taction: \tthe \toestrogen \tinhibits \tfollicle-\nstimulating hormone release and therefore follicle \ndevelopment; the progestogen inhibits luteinising hormone release", "start_char_idx": 0, "end_char_idx": 3439, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1b66140b-37f5-4690-b369-603b00e66121": {"__data__": {"id_": "1b66140b-37f5-4690-b369-603b00e66121", "embedding": null, "metadata": {"page_label": "471", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c5708c93-982a-4a2c-83be-40839cc174be", "node_type": null, "metadata": {"page_label": "471", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "292bcbf2c790f0fcab11c9e756bfc657157485f7e641ec5f269b65a147645532"}, "2": {"node_id": "4e5b909d-fee4-4cd4-bbd2-ea93e2c9c956", "node_type": null, "metadata": {"page_label": "471", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e8fc4012080e0ac48124c78b4f83c135fe6e22ab2c7cb50595b0b117a7da8ce3"}}, "hash": "8b32304f7adf474314d2b2653264075a2f597ebfe447082787e054334ed33f28", "text": "\ndevelopment; the progestogen inhibits luteinising hormone release and therefore ovulation, and makes \ncervical mucus inhospitable for sperm; together, they \nrender the endometrium unsuitable for implantation.\n\u2022\tDrawbacks: \tweight \tgain, \tnausea, \tmood \tchanges \tand \t\nskin pigmentation can occur.\n\u2022\tSerious \tunwanted \teffects \tare \trare. \tA \tsmall \tproportion \t\nof women develop reversible hypertension; there is a small increase in diagnosis of breast cancer, possibly attributable to earlier diagnosis, and of cervical cancer. \nThere is an increased risk of thromboembolism with \nthird-generation pills, especially in women with additional risk factors (e.g. smoking) and with prolonged use.\n\u2022\tThere\tare \tseveral \tbeneficial \teffects, \tnot \tleast \tthe \t\navoidance of unwanted pregnancy, which itself carries risks to health.\nThe progestogen-only pill\n\u2022\tThe\tprogestogen-only \tpill \tis \ttaken \tcontinuously. \tIt \t\ndiffers from the combined pill in that the contraceptive effect is less reliable and is mainly a result of the alteration of cervical mucus. Irregular bleeding is \ncommon.\n6Eclampsia is a pathological condition (involving, among other things, \nhigh blood pressure, swelling and seizures) that occurs in pregnant \nwomen \u2013 it is usually preceded by milder changes (\u2018pre-eclampsia\u2019).unprotected intercourse and repeated 12 h later. Nausea \nand vomiting are common (and the pills may then be lost: \nreplacement tablets can be taken with an antiemetic such \nas domperidone). Insertion of an intrauterine device is \nmore effective than hormonal methods, and works up to \n5 days after intercourse.\nLONG-ACTING \u2003PROGESTOGEN-ONLY \u2003\nCONTRACEPTION\nMedroxyprogesterone can be given intramuscularly as a contraceptive. This is effective and safe. However, menstrual \nirregularities are common, and infertility may persist for \nmany months after the final dose.\nLevonorgestrel implanted subcutaneously in non-\nbiodegradable capsules is used by approximately 3 million women worldwide. This route of administration avoids first-pass metabolism. The capsules release their progestogen \ncontent slowly over 5 years. Irregular bleeding and headache \nare common.\nA levonorgestrel-impregnated intrauterine system provides \nprolonged, reliable contraception and, in contrast to standard \ncopper containing devices, reduces menstrual bleeding.\nTHE UTERUS\nThe physiological and pharmacological responses of the \nuterus vary at different stages of the menstrual cycle and \nduring pregnancy.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3373, "end_char_idx": 6334, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "70a7777b-27d7-4a37-a89e-3568398db9a0": {"__data__": {"id_": "70a7777b-27d7-4a37-a89e-3568398db9a0", "embedding": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ec86f52-80b5-41bb-b362-0ea24d2ebf4b", "node_type": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c6cd52205ea83538c188603eb204236627878952ac6103a32c79e0a99a09180"}, "3": {"node_id": "0543bf5d-4617-4c69-a3f7-cf8f89015305", "node_type": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06d04e0ee5b87e7813b46a8e569ac1d7c1c90ea48faf3fab29956f7e51a2f56b"}}, "hash": "9b2531f09871ae6f13e00d327615d44aa3e038a3c7c2ab348bb9c6e16e769206", "text": "36 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n466aggregation) could impair haemostasis as well as causing \nvasodilatation. Non-steroidal anti-inflammatory drugs (e.g. \nmefenamic acid ) are used to treat menorrhagia as well as \ndysmenorrhoea.\nProstaglandin preparations\nProstaglandins of the E and F series promote coordinated \ncontractions of the body of the pregnant uterus, while \nrelaxing the cervix. E and F prostaglandins reliably cause \nabortion in early and middle pregnancy, unlike oxytocin \nwhich generally does not cause expulsion of the uterine \ncontents at this stage. The prostaglandins used in obstetrics \nare dinoprostone (PGE 2), carboprost (15-methyl PGF 2\u03b1) and \ngemeprost or misoprostol (PGE 1 analogues). Dinoprostone \ncan be given intravaginally as a gel or as tablets. Carboprost \nis given by deep intramuscular injection. Gemeprost or \nmisoprostol are given intravaginally.\nUnwanted effects\nUnwanted effects include uterine pain, nausea and vomiting, \nand diarrhoea. Dinoprost can cause hypotension. When \ncombined with mifepristone, a progestogen antagonist that \nsensitises the uterus to prostaglandins, lower doses of the \nprostaglandins (e.g. misoprostol) can be used to terminate \npregnancy and side effects are reduced.\nThe clinical box shows the clinical uses of prostaglandins \n(also Ch. 18).Unwanted effects of oxytocin include dose-related \nhypotension, due to vasodilatation, with associated reflex \ntachycardia. Its antidiuretic hormone-like effect on water \nexcretion by the kidney causes water retention and, unless \nwater intake is curtailed, consequent hyponatraemia.\nERGOMETRINE\nErgot ( Claviceps purpurea ) is a fungus that grows on rye \nand contains a surprising variety of pharmacologically \nactive substances (see Ch. 16). Ergot poisoning, which was \nonce common, was often associated with abortion. In 1935, \nergometrine was isolated and recognised as the oxytocic \nprinciple in ergot.\nErgometrine contracts the human uterus. This action \ndepends partly on the contractile state of the organ. On a \ncontracted uterus (the normal state following delivery), \nergometrine has relatively little effect. However, if the uterus \nis inappropriately relaxed, ergometrine initiates strong \ncontraction and reduces bleeding from the placental bed \n(the raw surface from which the placenta has detached). \nErgometrine also has a moderate vasoconstrictor action.\nThe mechanism of action of ergometrine on smooth \nmuscle is not understood. It is possible that it acts partly \non \u03b1 adrenoceptors, like the related alkaloid ergotamine \n(see Ch. 15), and partly on 5-hydroxytryptamine receptors.\nThe clinical use of ergometrine is given in the box on \np. 467.\nErgometrine can be given orally, intramuscularly or \nintravenously. It has a very rapid onset of action and its \neffect lasts for 3\u20136 h.\nErgometrine can produce vomiting, probably by an effect \non dopamine D 2 receptors in the chemoreceptor trigger \nzone (see Ch. 31, Fig. 31.5). Vasoconstriction with an increase \nin blood pressure associated with nausea, blurred vision \nand headache can occur, as can vasospasm of the coronary \narteries, resulting in angina.\nPROSTAGLANDINS\nProstaglandins are discussed in detail in Chapter 18. The \nendometrium and myometrium have substantial", "start_char_idx": 0, "end_char_idx": 3279, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0543bf5d-4617-4c69-a3f7-cf8f89015305": {"__data__": {"id_": "0543bf5d-4617-4c69-a3f7-cf8f89015305", "embedding": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ec86f52-80b5-41bb-b362-0ea24d2ebf4b", "node_type": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c6cd52205ea83538c188603eb204236627878952ac6103a32c79e0a99a09180"}, "2": {"node_id": "70a7777b-27d7-4a37-a89e-3568398db9a0", "node_type": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9b2531f09871ae6f13e00d327615d44aa3e038a3c7c2ab348bb9c6e16e769206"}, "3": {"node_id": "beeb9469-8724-4f57-930d-f3b13bf6d755", "node_type": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "715b21f71e24064f543287b5f640058fdbf36df78742bf6806d69b1fec45f4d2"}}, "hash": "06d04e0ee5b87e7813b46a8e569ac1d7c1c90ea48faf3fab29956f7e51a2f56b", "text": "discussed in detail in Chapter 18. The \nendometrium and myometrium have substantial \nprostaglandin-synthesising capacity, particularly in the \nsecond, proliferative phase of the menstrual cycle. Prosta -\nglandin (PG)F 2\u03b1 is generated in large amounts, and has \nbeen implicated in the ischaemic necrosis of the endome -\ntrium that precedes menstruation (although it has relatively \nlittle vasoconstrictor action on many human blood vessels, \nin contrast to some other mammalian species). Vasodilator \nprostaglandins, PGE 2 and PGI 2 (prostacyclin), are also \ngenerated by the uterus.\nIn addition to their vasoactive properties, the E and F \nprostaglandins contract uterine smooth muscle, whose \nsensitivity to these prostaglandins increases during gestation. \nTheir role in parturition is not fully understood, but as \ncyclo-oxygenase inhibitors can delay labour (see later), they \nprobably play some part in this.\nProstaglandins also play a part in two of the main dis -\norders of menstruation: dysmenorrhoea (painful menstrua -\ntion) and menorrhagia (excessive blood loss). Dysmenorrhoea \nis associated with increased production of PGE 2 and PGF 2\u03b1; \nnon-steroidal anti-inflammatory drugs, which inhibit \nprostaglandin biosynthesis (see Ch. 27), are used to treat \ndysmenorrhoea. Menorrhagia, in the absence of other uterine \npathology, may be caused by a combination of increased \nvasodilatation and reduced haemostasis. Increased gen-\neration by the uterus of PGI 2 (which inhibits platelet Drugs acting on the uterus \n\u2022\tAt\tparturition,\t oxytocin causes regular coordinated \nuterine\tcontractions,\t each\tfollowed\tby\trelaxation;\t\nergometrine , an ergot alkaloid, causes uterine \ncontractions with an increase in basal tone. Atosiban , \nan\tantagonist\t of\toxytocin,\t delays\tlabour.\n\u2022\tProstaglandin\t (PG)\tanalogues,\t for\texample,\t\ndinoprostone (PGE 2) and dinoprost (PGF 2\u03b1), contract \nthe\tpregnant\t uterus\tbut\trelax\tthe\tcervix.\tCyclo-\noxygenase\t inhibitors\t inhibit\tPG\tsynthesis\t and\tdelay\t\nlabour. They also alleviate symptoms of \ndysmenorrhoea and menorrhagia.\n\u2022\tThe\t \u03b22-adrenoceptor agonists (e.g. ritodrine ) inhibit \nspontaneous\t and\toxytocin-induced\t contractions\t of\tthe\t\npregnant uterus.\nDRUGS THAT INHIBIT UTERINE CONTRACTION\nSelective \u03b22-adrenoceptor agonists, such as ritodrine or \nsalbutamol , inhibit spontaneous or oxytocin-induced \ncontractions of the pregnant uterus. These uterine relaxants \nare used in selected patients to prevent premature labour \noccurring between 22 and 33 weeks of gestation in otherwise \nuncomplicated pregnancies. They can delay delivery by \n48 h, time that can be used to administer glucocorticoid \ntherapy to the mother so as to mature the lungs of the baby \nand reduce neonatal respiratory distress. It has been difficult \nto demonstrate that any of the drugs used to delay labour \nimprove the outcome for the baby. Risks to the mother, \nespecially pulmonary oedema, increase after 48 h, and \nmyometrial response is reduced, so prolonged treatment \nis avoided. Cyclo-oxygenase inhibitors (e.g. indometacin ) \ninhibit labour, but their use could cause problems in the \nbaby, including renal dysfunction and delayed closure of", "start_char_idx": 3208, "end_char_idx": 6380, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "beeb9469-8724-4f57-930d-f3b13bf6d755": {"__data__": {"id_": "beeb9469-8724-4f57-930d-f3b13bf6d755", "embedding": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ec86f52-80b5-41bb-b362-0ea24d2ebf4b", "node_type": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c6cd52205ea83538c188603eb204236627878952ac6103a32c79e0a99a09180"}, "2": {"node_id": "0543bf5d-4617-4c69-a3f7-cf8f89015305", "node_type": null, "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "06d04e0ee5b87e7813b46a8e569ac1d7c1c90ea48faf3fab29956f7e51a2f56b"}}, "hash": "715b21f71e24064f543287b5f640058fdbf36df78742bf6806d69b1fec45f4d2", "text": "could cause problems in the \nbaby, including renal dysfunction and delayed closure of mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6367, "end_char_idx": 6932, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "73af8a0e-13ba-4012-a842-948c8c3338bb": {"__data__": {"id_": "73af8a0e-13ba-4012-a842-948c8c3338bb", "embedding": null, "metadata": {"page_label": "473", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "203809e9-b2bf-460d-ad91-9c7cd697612d", "node_type": null, "metadata": {"page_label": "473", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bdee4a362ad72205c476ef2cafe9517b4ae65c5986ed923ae5ea90471324a02f"}, "3": {"node_id": "d07354eb-ba33-4c32-86d9-62f72e6b88dd", "node_type": null, "metadata": {"page_label": "473", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1038d5860010c38c7114de2e00134c33c19cd325f4b4e4a8bcbcd25f11dffa43"}}, "hash": "c9a9cc8c31a93c414789338b76f88549761b16bc667a731711099be78db76c07", "text": "36 ThE RE p RODUCTI v E SYSTEM\n467p. 462), hyperprolactinaemia (see Ch. 34), arterial disease \nand various causes of neuropathy (most commonly diabetes), \nbut often no organic cause is identified.\nOver the centuries, there has been a huge trade in parts \nof various creatures that have the misfortune to bear some fancied resemblance to human genitalia, in the pathetic \nbelief that consuming these will restore virility or act as an aphrodisiac (i.e. a drug that stimulates libido). Alcohol \n(Ch. 50) \u2018provokes the desire but takes away the perfor -\nmance\u2019, and cannabis (Ch. 20) can also release inhibitions \nand probably does the same. Yohimbine (an \u03b1\n2-adrenoceptor \nantagonist; Ch. 15) may have some positive effect in this \nregard, but trials have proved inconclusive. Apomorphine \n(a dopamine agonist; Ch. 39) causes erections in humans \nas well as in rodents when injected subcutaneously, but it \nis a powerful emetic, a disadvantage in this context. The \npicture picked up somewhat when it was found that injecting vasodilator drugs directly into the corpora cavernosa causes \npenile erection. Papaverine (Ch. 23), if necessary with the \naddition of phentolamine , was used in this way. The route \nof administration is not acceptable to most men, but diabetics in particular are often not needle-shy, and this approach \nwas a real boon to many such patients. PGE\n1 (alprostadil ) \nis often combined with other vasodilators when given intracavernosally. It can also be given transurethrally as \nan alternative (albeit still a somewhat unromantic one) to injection. Adverse effects of all these drugs include priapism \n(prolonged and painful erection with risk of permanent \ntissue damage), which is no joke. Treatment consists of aspiration of blood and, if necessary, cautious intracaver -\nnosal administration of a vasoconstrictor such as phenyle-\nphrine . Intracavernosal and transurethral preparations are \nstill available to treat erectile failure, but orally active phosphodiesterase inhibitors are now generally the drugs \nof choice.\nPHOSPHODIESTERASE \u2003TYPE \u2003V \u2003INHIBITORS\nSildenafil, the first selective phosphodiesterase type V \ninhibitor (see also Chs 21 and 23), was found accidentally \nto influence erectile function.8 Tadalafil and vardenafil are \nsimilar. Tadalafil is longer acting than sildenafil. In contrast to intracavernosal vasodilators, phosphodiesterase type V \ninhibitors do not cause erection independent of sexual desire, but enhance the erectile response to sexual stimula -\ntion. They have transformed the treatment of erectile dysfunction.\nMechanism of action\nPhosphodiesterase V is the isoform that inactivates cGMP. Nitrergic nerves release nitric oxide (or a related nitrosothiol) \nwhich diffuses into smooth muscle cells, where it activates \nguanylyl cyclase. The resulting increase in cytoplasmic cGMP mediates vasodilatation via activation of protein \nkinase G (Ch. 4, Fig. 4.10). Consequently, inhibition of \nphosphodiesterase V potentiates the effect on penile vascular smooth muscle of endothelium-derived nitric oxide and \nof nitrergic nerves that are activated by sexual stimulation \n(Fig. 36.6). Other vascular beds are also affected, suggesting other possible uses, notably in pulmonary hypertension (Ch. 23).ERECTILE DYSFUNCTION\nErectile function depends on complex interactions between physiological and psychological factors. Erection is caused \nby vasorelaxation in the arteries and", "start_char_idx": 0, "end_char_idx": 3439, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d07354eb-ba33-4c32-86d9-62f72e6b88dd": {"__data__": {"id_": "d07354eb-ba33-4c32-86d9-62f72e6b88dd", "embedding": null, "metadata": {"page_label": "473", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "203809e9-b2bf-460d-ad91-9c7cd697612d", "node_type": null, "metadata": {"page_label": "473", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bdee4a362ad72205c476ef2cafe9517b4ae65c5986ed923ae5ea90471324a02f"}, "2": {"node_id": "73af8a0e-13ba-4012-a842-948c8c3338bb", "node_type": null, "metadata": {"page_label": "473", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9a9cc8c31a93c414789338b76f88549761b16bc667a731711099be78db76c07"}}, "hash": "1038d5860010c38c7114de2e00134c33c19cd325f4b4e4a8bcbcd25f11dffa43", "text": "factors. Erection is caused \nby vasorelaxation in the arteries and arterioles supplying \nthe erectile tissue. This increases penile blood flow; the consequent increase in sinusoidal filling compresses the \nvenules, occluding venous outflow and causing erection. \nDuring sexual intercourse, reflex contraction of the ischio -\ncavernosus muscles compresses the base of the corpora \ncavernosa, and the intracavernosal pressure can reach several \nhundred millimetres of mercury during this phase of rigid erection. Innervation of the penis includes autonomic and somatic nerves. Nitric oxide is probably the main mediator \nof erection and is released both from nitrergic nerves and \nfrom endothelium (Ch. 21, Fig. 21.6).\nErectile function is adversely affected by several thera -\npeutic drugs (including many antipsychotic, antidepressant and antihypertensive agents), and psychiatric and vascular disease (especially in association with endothelial dysfunc -\ntion) can themselves cause erectile dysfunction, which is common in middle-aged and older men, even if they have no psychiatric or cardiovascular problems.\n7 There are several \norganic causes, including hypogonadism (see clinical box, Clinical uses of drugs acting on \nthe uterus \nMyometrial stimulants (oxytocics)\n\u2022\tOxytocin is used to induce or augment labour when \nthe uterine muscle is not functioning adequately. It can \nalso be used to treat postpartum haemorrhage.\n\u2022\tErgometrine is used to treat postpartum \nhaemorrhage. Carboprost can be used if patients do \nnot respond to ergometrine.\n\u2022\tA\tpreparation \tcontaining \tboth \toxytocin and \nergometrine is used for the management of the third stage of labour; the two agents together can also be \nused, before surgery, to control bleeding due to \nincomplete abortion.\n\u2022\tGemeprost (intravaginally) or misoprostol (following \nmifepristone) are used to terminate pregnancy.\nMyometrial relaxants\n\u2022\tThe\t\u03b2-adrenoceptor agonists (e.g. ritodrine) are used \nto delay preterm labour.\n\u2022\tAtosiban \t(oxytocin\tantagonist) \talso \tdelays \tpreterm \t\nlabour.\n7In randomised controlled trials, an appreciable proportion of men who \ndiscontinued treatment because of erectile dysfunction had been \nreceiving placebo.8Sildenafil was originally intended to treat angina, but bulging \nbedclothes were noticed in early clinical trials, providing the opportunity for the drug to be developed for a less crowded and more \nprofitable indication than angina.the ductus arteriosus, both of which are influenced by \nendogenous prostaglandins.\nAn oxytocin receptor antagonist, atosiban, provides an \nalternative to a \u03b22-adrenoceptor agonist. It is given as an \nintravenous bolus followed by an intravenous infusion for \nnot more than 48 h. Adverse effects include vasodilatation, \nnausea, vomiting and hyperglycaemia.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3373, "end_char_idx": 6650, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "182ae4ad-1172-4f43-ae67-080183f317cf": {"__data__": {"id_": "182ae4ad-1172-4f43-ae67-080183f317cf", "embedding": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d07d5e36-89ca-4a85-9806-ea5cba2db0f8", "node_type": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7bfe40dceabfb1f7bcdf04d59c5b5ca90415eece7aab9b3b017dd4f6f3482cfd"}, "3": {"node_id": "7f73123d-fdf5-4d88-89c6-b43d4a196b2f", "node_type": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e34d6edc98263920e623e3740ef968334810caa80bf026d19615f4ca9d9e940"}}, "hash": "c5b256f8ff7fa7bfa069fbe046197c609b9e7c99456b600217d4e3cc4e7b908d", "text": "36 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n468Pharmacokinetic aspects and drug interactions\nPeak plasma concentrations of sildenafil occur approximately \n30\u2013120 min after an oral dose and are delayed by eating, \nso it is taken an hour or more before sexual activity. It is \ngiven as a single dose as needed. It is metabolised by \nCYP3A4, which is induced by carbamazepine , rifampicin \nand barbiturates, and inhibited by cimetidine, macrolide \nantibiotics, antifungal imidazolines and some antiviral drugs (such as ritonavir ). These drugs can interact with sildenafil. \nTadalafil has a longer half-life than sildenafil, so can be \ntaken longer before sexual activity. A clinically important \npharmacodynamic interaction of all phosphodiesterase V \ninhibitors occurs with all organic nitrates, which work through increasing cGMP (Ch. 21) and are therefore mark -\nedly potentiated by sildenafil (see Fig. 36.6). Consequently, \nconcurrent nitrate use, including use of nicorandil, con-\ntraindicates the concurrent use of any phosphodiesterase \ntype V inhibitor.\n9\nUnwanted effects\nMany of the unwanted effects of phosphodiesterase type V inhibitors are caused by vasodilatation in other vascular \nbeds; these effects include hypotension, flushing and \nheadache. Visual disturbances have occasionally been reported and are of concern because sildenafil has some \naction on phosphodiesterase VI, which is present in the \nretina and important in vision (a cGMP-dependent process too). The manufacturers advise that sildenafil should not \nbe used in patients with hereditary retinal degenerative \ndiseases (such as retinitis pigmentosa) because of the theo -\nretical risk posed by this. Vardenafil is more selective for the type V isozyme than is sildenafil (reviewed by Doggrell, \n2005), but is also contraindicated in patients with hereditary retinal disorders.Nitric oxide (NO)\nPDE V\ninhibitor \u2013\nsildenafil, etc.Organic\nnitrates \u2013\nGTN etc\nGuanylyl cyclase\nPDE VGTP cGMP PKG\nVasodilatation\nPenile\nerectionInactive\nproductNitrergic\nnervesEndotheliumSexual\nstimulation\nFig. 36.6 Mechanism of phosphodiesterase V (PDE V) \ninhibitors on penile erection, and of the interaction of PDE V \ninhibitors with organic nitrates. The large grey rectangle \ndenotes a vascular smooth muscle cell in the corpora \ncavernosa. \tSexual \tstimulation \treleases \tnitric \toxide \t(NO) \tfrom \t\nnitrergic nerves and this activates guanylyl cyclase, increasing cGMP production and hence activating protein kinase G (PKG), causing vasodilatation and penile erection. cGMP is inactivated \nby\tPDE\tV, \tso \tPDE \tV \tinhibitors \t(e.g. \tsildenafil) \tpotentiate \tNO \tand \t\npromote\tpenile \terection. \tNO \tfrom \torganic \tnitrates \tsuch \tas \t\nglyceryl\ttrinitrate \t(GTN) \tis \talso \tpotentiated \tleading \tto \tgeneralised \t\nvasodilatation and hypotension. 9This is important not only for sufferers from angina who take nitrates \nsuch as glyceryl trinitrate or isosorbide mononitrate therapeutically or \nprophylactically and are at risk of hypotension because of coronary \nartery disease, but also asymptomatic individuals who take amyl nitrate recreationally (\u2018poppers\u2019) because of its effect on pelvic blood vessels.\nREFERENCES AND", "start_char_idx": 0, "end_char_idx": 3202, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7f73123d-fdf5-4d88-89c6-b43d4a196b2f": {"__data__": {"id_": "7f73123d-fdf5-4d88-89c6-b43d4a196b2f", "embedding": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d07d5e36-89ca-4a85-9806-ea5cba2db0f8", "node_type": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7bfe40dceabfb1f7bcdf04d59c5b5ca90415eece7aab9b3b017dd4f6f3482cfd"}, "2": {"node_id": "182ae4ad-1172-4f43-ae67-080183f317cf", "node_type": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c5b256f8ff7fa7bfa069fbe046197c609b9e7c99456b600217d4e3cc4e7b908d"}, "3": {"node_id": "5621fa90-822c-473e-aef9-c6b28309d39b", "node_type": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b91486b9302a9dc68f1da5cd74ba029ebd780c39ff02c023cb8073d41b15fa81"}}, "hash": "3e34d6edc98263920e623e3740ef968334810caa80bf026d19615f4ca9d9e940", "text": "because of its effect on pelvic blood vessels.\nREFERENCES AND FURTHER READING\nSex hormones and their control\nAdeel, M., Song, X., Wang, Y., Dennis Francis, D., Yang, Y., 2017. \nEnvironmental impact of estrogens on human, animal and plant life: a \ncritical review. Environ. Int. 99, 107\u2013119. (Review of environmental issues)\nBarrett-Connor, E., Mosca, L., Collins, P., et al., 2006. Effects of \nraloxifene on cardiovascular events and breast cancer in \npostmenopausal women. N. Engl. J. Med. 355, 125\u2013137. (Reduced breast \ncancer)\nBarton, M., Prossnitz, E.R., 2015. Emerging roles of GPER in diabetes \nand atherosclerosis. Trends Endocrinol. Metab. 26, 185\u2013192. (Evidence for a central role of GPER in a wide range of vascular and metabolic \nprocesses)\nBehringer, R.R., 1994. The in vivo roles of M\u00fcllerian-inhibiting \nsubstance. Curr. Top. Dev. Biol. 29, 171\u2013187. (Known as Anti-M\u00fcllerian hormone, AMH)\nChen, Z., Yuhanna, I.S., Galcheva-Gargova, Z., et al., 1999. Estrogen \nreceptor-alpha mediates the nongenomic activation of endothelial nitric oxide synthase by estrogen. J. Clin. Invest. 103, 401\u2013406. ( Acute \nvasodilator action of oestrogen may involve membrane ER rather than the classic intracellular receptor pathway)\nGruber, C.J., Tschugguel, W., Schneeberger, C., Huber, J.C., 2002. \nProduction and actions of estrogens. N. Engl. J. Med. 346, 340\u2013352. (Review focusing on the new biochemical aspects of the action of oestrogen \u2013 including phyto-oestrogens and selective oestrogen receptor modulators \n\u2013 as well as physiological and clinical aspects)McLachlan, J.A., 2016. Environmental signaling: from environmental \nestrogens to endocrine-disrupting chemicals and beyond. Andrology \n4, 684\u2013694. (Review, including epigenetic mechanisms of inter-generational adverse effects)\nPrizant, H., Gleicher, N., Sen, A., 2014. Androgen actions in the ovary: \nbalance is key. J. Endocrinol. 222, R141\u2013R151. (Androgens play an important role in female fertility)\nRhoden, E.L., Morgentaler, A., 2004. Risks of testosterone-replacement \ntherapy and recommendations for monitoring. N. Engl. J. Med. 350, 482\u2013492. (Review)\nVogel, V., Constantino, J., Wickerman, L., et al., 2006. Effects of \ntamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes. JAMA 295, 2727\u20132741. (Raloxifene \nhad similar efficacy as tamoxifen with fewer thrombotic events)\nWalker, H.A., Dean, T.S., Sanders, T.A.B., et al., 2001. The \nphytoestrogen genistein produces acute nitric oxide-dependent \ndilation of human forearm vasculature with similar potency to 17 \nbeta-estradiol. Circulation 103, 258\u2013262.\nContraceptives\nDjerassi, C., 2001. This Man\u2019s Pill: Reflections on the 50th Birthday of the \nPill. Oxford University Press, New York. (Scientific and autobiographical memoir by polymath steroid chemist who worked on \u2018the pill\u2019 at its inception \nunder Syntex in Mexico, and has continued thinking about human reproduction in a broad biological and biosocial sense ever since)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3150, "end_char_idx": 6259, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5621fa90-822c-473e-aef9-c6b28309d39b": {"__data__": {"id_": "5621fa90-822c-473e-aef9-c6b28309d39b", "embedding": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d07d5e36-89ca-4a85-9806-ea5cba2db0f8", "node_type": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7bfe40dceabfb1f7bcdf04d59c5b5ca90415eece7aab9b3b017dd4f6f3482cfd"}, "2": {"node_id": "7f73123d-fdf5-4d88-89c6-b43d4a196b2f", "node_type": null, "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e34d6edc98263920e623e3740ef968334810caa80bf026d19615f4ca9d9e940"}}, "hash": "b91486b9302a9dc68f1da5cd74ba029ebd780c39ff02c023cb8073d41b15fa81", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6265, "end_char_idx": 6680, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f5d1afa9-b3e7-4077-8c4b-f29ecbdb16ad": {"__data__": {"id_": "f5d1afa9-b3e7-4077-8c4b-f29ecbdb16ad", "embedding": null, "metadata": {"page_label": "475", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "243040ca-57e0-488c-b5c7-d57198a11ee1", "node_type": null, "metadata": {"page_label": "475", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a7ce68ba5197059d1bba8d78c93d6abbca43f2d41b560b075a59e9d904101fc6"}}, "hash": "a7ce68ba5197059d1bba8d78c93d6abbca43f2d41b560b075a59e9d904101fc6", "text": "36 ThE RE p RODUCTI v E SYSTEM\n469Thornton, S., Vatish, M., Slater, D., 2001. Oxytocin antagonists: clinical \nand scientific considerations. Exp. Physiol. 86, 297\u2013302. (Reviews \nrationale for uterine relaxants in preterm labour; evidence for administering \natosiban; and the role of oxytocin, vasopressin and their receptors in the onset of labour)\nErectile dysfunction\nDoggrell, S.A., 2005. Comparison of clinical trials with sildenafil, \nvardenafil and tadalafil in erectile dysfunction. Expert Opin. \nPharmacother. 6, 75\u201384. (Vardenafil is similarly effective to sildenafil. Its \nonly advantage is that it does not inhibit phosphodiesterase VI to alter colour perception, a rare side effect that sometimes occurs with sildenafil. Tadalafil \nhas a longer duration of action)\nUseful Web resource\nhttps://www.gov.uk/drug-safety-update/hormone-replacement-therap\ny-updated-advice. (Risks of cancer [breast, endometrium, ovary], venous thromboembolism, stroke and coronary artery disease in relation to age and \nduration of HRT use)Postmenopausal aspects\nDavis, S.R., Dinatale, I., Rivera-Woll, L., Davison, S., 2005. \nPostmenopausal hormone therapy: from monkey glands to \ntransdermal patches. J. Endocrinol. 185, 207\u2013222. (Reviews the history of \nknowledge of the menopause and the development of hormonal therapy for climacteric complaints, and summarises current evidence for specific benefits \nand risks of hormone treatment)\nHulley, S., Grady, D., Bush, T., et al., 1998. Randomized trial of estrogen \nplus progestin for secondary prevention of coronary heart disease in \npostmenopausal women. JAMA 280, 605\u2013613. (Study showing that \nincidence of fatal myocardial infarction was similar in the two groups, \ndespite favourable changes in low- and high-density-lipoprotein cholesterol in the HRT group. Venous thromboembolism was increased by a factor of 2.89 \nin the active group)\nPrague, J.K., Roberts, R.E., Comninos, A.N., 2017. Neurokinin 3 receptor \nantagonism as a novel treatment for menopausal hot flushes: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet 389, \n1809\u20131820. (A neurokinin 3 receptor antagonist relieved hot flush symptoms without the need for oestrogen exposure)\nThe uterus\nNorwitz, E.R., Robinson, J.N., Challis, J.R., 1999. The control of labor. N. \nEngl. J. Med. 341, 660\u2013666. (Review)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2816, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "073f1ff8-8c0c-4b8b-a48e-d122e8c1610c": {"__data__": {"id_": "073f1ff8-8c0c-4b8b-a48e-d122e8c1610c", "embedding": null, "metadata": {"page_label": "476", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "126b3c54-b015-48a2-9895-99a035c444d7", "node_type": null, "metadata": {"page_label": "476", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57b4234eaf682a87eae95e3affc4a0fe5c30bcc8b137ba189d749425388016bd"}, "3": {"node_id": "b829a60b-4681-4744-8507-25a4c0d4bbf1", "node_type": null, "metadata": {"page_label": "476", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "761ef8804796e71cdddca4670c4d90c64a8aa5c339d51638e2417f82df51d89e"}}, "hash": "36424f6575d9db602dd84a3b0c4e2733f59711bc03c106a32e810d676c771471", "text": "470\nBone metabolism37 DRUGS AFFECTING MAJOR ORGAN SYSTEMS SECTION 3\nOVERVIEW\nIn this chapter we consider first the cellular and \nbiochemical processes involved in bone remodelling, \nand the various mediators that regulate these pro -\ncesses. We then describe the drugs used to treat \ndisorders of bone, including new agents.\nINTRODUCTION\nThe human skeleton undergoes a continuous process of \nremodelling throughout life \u2013 some bone being resorbed \nand new bone being laid down continuously \u2013 resulting \nin the complete skeleton being replaced every 10 years. Structural deterioration and decreased bone mass (osteo -\nporosis) occur with advancing age and constitute a world-wide health problem. Other conditions that lead to treatable pathological changes in bone include nutritional deficiencies \nand malignancy. There have recently been significant \nadvances in the understanding of bone biology, which have led in turn to several valuable new drugs.\nBONE STRUCTURE AND COMPOSITION\nThe human skeleton consists of 80% cortical bone and 20% trabecular bone. Cortical bone is the dense, compact outer \npart and trabecular bone, the inner meshwork. The former \npredominates in the shafts of long bones, the latter in the vertebrae, the epiphyses of long bones and the iliac crest. \nTrabecular bone, having a large surface area, is metabolically \nmore active and more affected by factors that lead to bone loss (see later).\nThe main minerals in bone are calcium and phosphates. \nMore than 99% of the calcium in the body is in the skeleton, mostly as crystalline hydroxyapatite but some as non-crystalline phosphates and carbonates; together, these make \nup half the bone mass.\nThe main bone cells are osteoblasts, osteoclasts and \nosteocytes.\n\u2022\tOsteoblasts \tare \tbone-forming \tcells \tderived \tfrom \t\nprecursor cells in the bone marrow and the \nperiosteum: they secrete important components \n(particularly collagen) of the extracellular matrix of \nbone \u2013 which is known as osteoid. They also have a role in the activation of osteoclasts (Figs 37.1 and 37.2).\n\u2022\tOsteoclasts \tare \tmultinucleated \tbone-resorbing \tcells \t\nderived from precursor cells of the macrophage/monocyte lineage.\n\u2022\tOsteocytes \tare \tderived \tfrom \tosteoblasts \twhich, \tduring \t\nthe formation of new bone, become embedded in the bony matrix and differentiate into osteocytes. These cells form a connected cellular network that, along \nwith nerve fibres located in bone, influences the \nresponse to mechanical loading. Osteocytes sense mechanical strain, and respond by triggering bone \nremodelling (see later) and secreting sclerostin, a \nglycoprotein that binds to receptors on osteoblasts to inhibit bone formation (McClung, 2017).\n\u2022\tOther\timportant \tcells \tin \tbone \tinclude \tmonocytes/\nmacrophages, lymphocytes and vascular endothelial cells; these secrete cytokines and other mediators \nimplicated in bone remodelling.\nOsteoid is the organic matrix of bone and its principal component is collagen. Other components such as proteo-\nglycans, osteocalcin and various phosphoproteins are also \nimportant; one of these, osteonectin, binds to both calcium and collagen and thus links these two major constituents \nof bone matrix.\nCalcium phosphate crystals are deposited as hydroxy -\napatite [Ca\n10(PO 4)6(OH) 2] in the osteoid, converting it into \nhard bone matrix.\nIn addition to its structural function, bone plays a major \nrole in calcium homeostasis.\nBONE REMODELLING\nThere has been substantial progress in our understanding of bone remodelling (see reviews by Harslof &", "start_char_idx": 0, "end_char_idx": 3539, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b829a60b-4681-4744-8507-25a4c0d4bbf1": {"__data__": {"id_": "b829a60b-4681-4744-8507-25a4c0d4bbf1", "embedding": null, "metadata": {"page_label": "476", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "126b3c54-b015-48a2-9895-99a035c444d7", "node_type": null, "metadata": {"page_label": "476", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57b4234eaf682a87eae95e3affc4a0fe5c30bcc8b137ba189d749425388016bd"}, "2": {"node_id": "073f1ff8-8c0c-4b8b-a48e-d122e8c1610c", "node_type": null, "metadata": {"page_label": "476", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "36424f6575d9db602dd84a3b0c4e2733f59711bc03c106a32e810d676c771471"}}, "hash": "761ef8804796e71cdddca4670c4d90c64a8aa5c339d51638e2417f82df51d89e", "text": "progress in our understanding of bone remodelling (see reviews by Harslof & Langdahl, \n2016; Tabatabaei-Malazy, 2017.)\nThe process of remodelling involves:\n\u2022\tactivity \tof \tosteoblasts \tand \tosteoclasts \t(see \tFig. \t37.1);\n\u2022\tactions \tof \tvarious \tcytokines \t(see \tFigs \t37.1 \tand \t37.2);\n\u2022\tturnover \tof \tbone \tminerals \t\u2013 \tparticularly \tcalcium \tand \t\nphosphate;\n\u2022\tactions \tof \tseveral \thormones: \tparathyroid \thormone \t\n(PTH), the vitamin D family, oestrogens, growth \nhormone, steroids, calcitonin and various cytokines.\nDiet, drugs and physical factors (exercise, loading) also affect remodelling. Bone loss \u2013 of 0.5%\u20131% per year \u2013 starts aged 35\u201340 years in both sexes, and accelerates by as much \nas 10-fold during the menopause in women or with castra -\ntion in men, and then gradually settles at 1%\u20133% per year. \nThe loss during the menopause is due to increased osteoclast \nactivity and affects mainly trabecular bone; the later loss \nin both sexes with increasing age is due to decreased osteoblast numbers and affects mainly cortical bone.\nTHE ACTION OF CELLS AND CYTOKINES\nA cycle of remodelling starts with recruitment of osteoclast precursors followed by cytokine-induced differentiation \nof these to mature multinucleated osteoclasts (see Fig. 37.1). mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3464, "end_char_idx": 5207, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6e65ae73-8411-4469-bebc-ac3dd6d7af6d": {"__data__": {"id_": "6e65ae73-8411-4469-bebc-ac3dd6d7af6d", "embedding": null, "metadata": {"page_label": "477", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f1322f1-b094-4c2d-a6bd-1bd24c26f0d0", "node_type": null, "metadata": {"page_label": "477", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c6e55804ecaa87724225f742604b7c5cd23708ec766affcfc320946b730f8984"}}, "hash": "c6e55804ecaa87724225f742604b7c5cd23708ec766affcfc320946b730f8984", "text": "37 BONE METABOlISM\n471OC precursor cell\nPTHCalcitriol\nTeriparatideOestrogens,\nraloxifeneCytokines\n(e.g. ILs)\nCytokines\nand hormones\nNew\nosteoid\nQuiescent trabecular boneOB action\nIGFRecruitment of\nOC precursors\nDifferentiation\nto OCsDifferentiation\nto OBs\nIGFOBs OCsGlucocorticoidsBisphosphonates\nBone resorption Bone formationBPs\nOsteocyte TGF-\u03b2OB precursor cell\nFig. 37.1 The bone-remodelling cycle and the action of hormones, cytokines and drugs. Quiescent trabecular bone: Cytokines \nsuch as insulin-like growth factor (IGF) and transforming growth factor (TGF)- \u03b2, shown as dots, are embedded in the bone matrix. Bone \nresorption and bone formation are illustrated. Embedded bisphosphonates (BPs), are ingested by osteoclasts (OCs) when bone is resorbed \n(not shown). IL, interleukin; OB, osteoblasts; PTH, parathyroid hormone. \nOsteoblast\nM-CSF\nRANKL\nr-OPGRANK\nDenosumab BisphosphonatesBoneOsteoclast\nprogenitorCalcitriol,\nPTH, ILs\nMolecules\nof OPGSclerostinMultinucleated osteoclast\nresorbing bone\nArea of bone\nresorption\nFig. 37.2 Schematic diagram of the role of the osteoblast and cytokines in the differentiation and activation of the osteoclast \nand the action of drugs thereon. The osteoblast is stimulated to express a surface ligand, the RANK ligand (RANKL). RANKL interacts \nwith a receptor on the osteoclast \u2013 an osteoclast differentiation and activation receptor termed RANK (receptor activator of nuclear factor \n\u03baB), which causes differentiation and activation of the osteoclast progenitors to form mature osteoclasts. Bisphosphonates inhibit bone \nresorption by osteoclasts. Anti-RANKL antibodies (e.g. denosumab) bind RANKL and prevent the RANK\u2013RANKL interaction. Sclerostin \ninhibits proliferation of osteoblasts and stimulates RANKL secretion. Drugs used clinically are in red-bordered boxes . IL, interleukin; M-CSF, \nmacrophage colony-stimulating factor; OPG, osteoprotegerin; PTH, parathyroid hormone. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2422, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "de7d3cc7-00b6-46fd-a52b-0f0f4a44c5ad": {"__data__": {"id_": "de7d3cc7-00b6-46fd-a52b-0f0f4a44c5ad", "embedding": null, "metadata": {"page_label": "478", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "889937f8-cf3a-49e4-8519-e3a2d74f1ae3", "node_type": null, "metadata": {"page_label": "478", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b854e0f6c4cb7ec6e1b34150f92c7b78a4ba16d9fc7e92d94e1919324270430"}, "3": {"node_id": "1b6e1170-577d-4e51-8e9d-d46a2e5700da", "node_type": null, "metadata": {"page_label": "478", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1271c09dedc5cfacb2411519e4878036c54b20fe289e9f1fa67ea9e963c6520d"}}, "hash": "ce31cf5ae14ccce3dd3817e484e53e2366137b98d83f25092448468b6b4f5f1f", "text": "37 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n472the osteoclast precursor cell (see Fig. 37.2). The ratio of RANKL to \nOPG is critical in the formation and activity of osteoclasts and the \nRANK, RANKL, OPG system is fundamental to bone remodelling \n(reviewed by Boyce & Xing, 2008; Wright et al., 2009). Denusomab \nis an antibody directed against RANKL that is used clinically to treat osteoporosis.\nTHE TURNOVER OF BONE MINERALS\nThe main bone minerals are calcium and phosphates.\nCALCIUM \u2003METABOLISM\nThe daily turnover of bone minerals during remodelling \ninvolves about 700 mg of calcium. Calcium has numerous \nroles in physiological functioning. Intracellular Ca2+ is part \nof the signal transduction mechanism of many cells (see \nCh. 4), so the concentration of Ca2+ in the extracellular fluid \nand the plasma, normally about 2.5 mmol/L, needs to be \ncontrolled with great precision. The plasma Ca2+ concentra -\ntion is regulated by interactions between PTH and various forms of vitamin D (Figs 37.3 and 37.4); calcitonin also \nplays a part.\nCalcium absorption in the intestine involves a Ca\n2+-binding \nprotein, the synthesis of which is regulated by calcitriol \n(see Fig. 37.3 ). It is probable that the overall calcium content \nof the body is regulated largely by this absorption mecha -\nnism, because urinary Ca2+ excretion normally remains more \nor less constant. However, with high blood Ca2+ concentra -\ntions urinary excretion increases, and with low blood concentrations urinary excretion can be reduced by PTH \nand calcitriol, both of which enhance Ca\n2+ reabsorption in \nthe renal tubules (see Fig. 37.3).\nPHOSPHATE \u2003METABOLISM\nPhosphates are important constituents of bone, and are also critically important in the structure and function of \nall the cells of the body. They are constituents of nucleic \nacids, provide energy in the form of ATP, and control The osteoclasts adhere to an area of trabecular bone, developing a ruffled border at the attachment site. They move along the bone, digging a pit by secreting hydrogen \nions and proteolytic enzymes, mainly cathepsin K. This \nprocess gradually liberates cytokines such as insulin-like \ngrowth factor (IGF)-1 and transforming growth factor (TGF)-\u03b2, which have been embedded in the osteoid (see \nFig. 37.1); these in turn recruit and activate successive teams \nof osteoblasts that have been stimulated to develop from precursor cells and are awaiting the call to duty (see Fig. \n37.1). The osteoblasts invade the site, synthesising and \nsecreting osteoid and secreting IGF-1 and TGF- \u03b2 (which \nbecome embedded in the osteoid; see earlier). Some osteo -\nblasts become embedded in the osteoid, forming osteocytes; others interact with and activate osteoclast precursors \u2013 and we are back to the beginning of the cycle.\nCytokines other than IGF-1 and TGF- \u03b2 involved in bone \nremodelling include other members of the TGF- \u03b2 family, \nincluding bone morphogenic proteins (BMPs), several inter -\nleukins, various hormones and members of the tumour necrosis factor (TNF) family. A member of this last family \u2013 a ligand for a receptor on the osteoclast precursor cell \n\u2013 is of particular importance. The receptor is termed (wait \nfor it \u2013 biological terminology has fallen over its own feet here) RANK, which stands for receptor activator of nuclear \nfactor kappa", "start_char_idx": 0, "end_char_idx": 3337, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1b6e1170-577d-4e51-8e9d-d46a2e5700da": {"__data__": {"id_": "1b6e1170-577d-4e51-8e9d-d46a2e5700da", "embedding": null, "metadata": {"page_label": "478", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "889937f8-cf3a-49e4-8519-e3a2d74f1ae3", "node_type": null, "metadata": {"page_label": "478", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b854e0f6c4cb7ec6e1b34150f92c7b78a4ba16d9fc7e92d94e1919324270430"}, "2": {"node_id": "de7d3cc7-00b6-46fd-a52b-0f0f4a44c5ad", "node_type": null, "metadata": {"page_label": "478", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce31cf5ae14ccce3dd3817e484e53e2366137b98d83f25092448468b6b4f5f1f"}}, "hash": "1271c09dedc5cfacb2411519e4878036c54b20fe289e9f1fa67ea9e963c6520d", "text": "feet here) RANK, which stands for receptor activator of nuclear \nfactor kappa B (NF- \u03baB), NF- \u03baB being the principal transcrip -\ntion factor involved in osteoclast differentiation and activa -\ntion. And the ligand is termed, unsurprisingly, RANK ligand (RANKL).\n\u25bc Osteoblasts synthesise and release osteoprotegerin (OPG) which is \nidentical with RANK and functions as a decoy receptor. In a sibling-\nundermining process by osteoblast and osteoclast precursor cells, \nOPG can bind to RANKL1 (generated by the very same cells as OPG) \nand inhibit RANKL\u2019s binding to the functional receptor, RANK, on Vitamin D\nPTH\n+++\n+\n+\u2212\n\u2212\u2212\n\u2212\u2212\n+\nBone Ca2+\nTeriparatide\nabaloparatideDietary Ca2+\nPlasma Ca2+\nCaSR\nCinacalcetSalcatoninParathyroid\nglandCalcitriol\nExcretion\nin urine\nFig. 37.3 The main factors involved in maintaining the concentration of Ca2+ in the plasma and the action of drugs. The calcium \nreceptor on the parathyroid cell is a G protein\u2013coupled receptor. Endogenous calcitonin, secreted by the thyroid, inhibits Ca2+ mobilisation \nfrom bone and decreases its reabsorption in the kidney, thus reducing blood Ca2+. CaSR, calcium-sensing receptor; PTH, parathyroid \nhormone. \n1RANKL is also sometimes confusingly termed OPG ligand .mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3260, "end_char_idx": 4973, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d038776f-fd91-49bb-809f-6dad6da79690": {"__data__": {"id_": "d038776f-fd91-49bb-809f-6dad6da79690", "embedding": null, "metadata": {"page_label": "479", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "94581969-5096-4860-a484-42d2aa0cd7c3", "node_type": null, "metadata": {"page_label": "479", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "579c09e934c9d8ba640441efea28097320712f4d3cc3508a59f7d72e5726b5bd"}, "3": {"node_id": "1d50f054-3b75-4975-9b64-ad919fe1d27b", "node_type": null, "metadata": {"page_label": "479", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9a32e388d0d9114ba421884baeb5d40da78a1e3c3015f2bdbf5f55a753b50dc"}}, "hash": "0395791429e6f756166ed49027b101b53c83b5117cfcc88cee80e6edc4c92dc6", "text": "37 BONE METABOlISM\n473\u2013 through phosphorylation \u2013 the activity of many functional \nproteins. They also have roles as intracellular buffers and \nin the excretion of hydrogen ions in the kidney.\nPhosphate absorption is an energy-requiring process \nregulated by calcitriol . Phosphate deposition in bone, as \nhydroxyapatite, depends on the plasma concentration of \nPTH, which, with calcitriol, mobilises both Ca2+ and phos -\nphate from the bone matrix. Phosphate is excreted by the \nkidney; here PTH inhibits reabsorption and thus increases \nexcretion.\nHORMONES INVOLVED IN BONE METABOLISM \nAND REMODELLING\nThe main hormones involved in bone metabolism and \nremodelling are PTH, members of the vitamin D family, \noestrogens and calcitonin. Glucocorticoids and thyroid \nhormone also affect bone.\nPARATHYROID\u2003 HORMONE\nPTH, which consists of a single-chain polypeptide of 84 \namino acids, is an important physiological regulator of UV\nExogenous\ncalcitriolDecreased\nblood PO4\u2212\nDecreased\nblood calcium\nIncreased\nblood calcium25(OH)D3 (calcifediol)Liver\nKidneySkin\n25(OH)D3\n1,25(OH)2D3\n(calcitriol)7-dehydro-cholesterol\nVit D3 (cholecalciferol)Vit D3\nExogenous\nergocalciferol\n(vit D 2)\nParathyroid\nhormone\nBiological actions:Calcitriol\nin blood\nIntracellular actions:\ncell differentiation,\nactivation of OBsCalcium and\nphosphate\nhomeostasisExogenous\ncalcifediolAlfacalcidol\nParathyroid\nFig. 37.4 Summary of the actions of the vitamin D endocrine system and the action of drugs. Exogenous ergocalciferol, vitamin \n(vit) D 2 (formed in plants by ultraviolet [UV] light), is converted to the corresponding D 2 metabolites in liver and kidney, as is the D 2 analogue \ndihydrotachysterol (not shown). Calcifediol and calcitriol are metabolites of vitamin D 3 and constitute the \u2018hormones\u2019 25-hydroxy-vitamin D 3 \nand 1,25-dihydroxy-vitamin D 3, respectively. Alfacalcidol (1 \u03b1-hydroxycholecalciferol) is 25-hydroxylated to calcitriol in the liver. OB, \nosteoblast. \nBone remodelling \n\u2022\tBone\tis\tcontinuously\t remodelled\t throughout\t life.\tThe\t\nevents of the remodelling cycle are as follows:\n\u2013 osteoclasts, having been activated by osteoblasts, \nresorb bone by digging pits in trabecular bone. Into \nthese pits the bone-forming osteoblasts secrete \nosteoid (bone matrix), which consists mainly of \ncollagen but also contains osteocalcin, osteonectin, \nphosphoproteins and the cytokines insulin growth \nfactor (IGF) and transforming growth factor (TGF)- \u03b2;\n\u2013 the osteoid is then mineralised, i.e. complex calcium \nphosphate crystals (hydroxyapatites) are deposited.\n\u2022\tBone\tmetabolism\t and\tmineralisation\t involve\tthe\taction\t\nof parathyroid hormone, the vitamin D family, and \nvarious cytokines (e.g. IGF, the TGF- \u03b2 family and \ninterleukins). Declining physiological levels of \noestrogens and therapeutic levels of glucocorticoids \ncan result in bone resorption not balanced by bone \nformation \u2013 leading to osteoporosis.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2969, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1d50f054-3b75-4975-9b64-ad919fe1d27b": {"__data__": {"id_": "1d50f054-3b75-4975-9b64-ad919fe1d27b", "embedding": null, "metadata": {"page_label": "479", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "94581969-5096-4860-a484-42d2aa0cd7c3", "node_type": null, "metadata": {"page_label": "479", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "579c09e934c9d8ba640441efea28097320712f4d3cc3508a59f7d72e5726b5bd"}, "2": {"node_id": "d038776f-fd91-49bb-809f-6dad6da79690", "node_type": null, "metadata": {"page_label": "479", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0395791429e6f756166ed49027b101b53c83b5117cfcc88cee80e6edc4c92dc6"}}, "hash": "d9a32e388d0d9114ba421884baeb5d40da78a1e3c3015f2bdbf5f55a753b50dc", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2922, "end_char_idx": 3385, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a640613-e9cd-4e90-993d-de240e14ddb5": {"__data__": {"id_": "7a640613-e9cd-4e90-993d-de240e14ddb5", "embedding": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cc7fd213-5eb7-4f40-8341-2856d1d6f409", "node_type": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "297524476f80e34265c1f7a618ce61b64a4c6f76371e824ccee622686c09a0e5"}, "3": {"node_id": "36f5403e-5b5b-4bec-843c-cab3a4d5bcd1", "node_type": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14f94f799b2469cc9d16268749a5ec4deb2d445a68622138a3ba6d93e5a73334"}}, "hash": "bb32920ef4521a28e65b8b23703ee248720c5695ae793814710a1bf7d3fd176c", "text": "37 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n474Cholecalciferol is converted to calcifediol (25-hydroxy-vitamin \nD3) in the liver, and this is converted to a series of other \nmetabolites of varying activity in the kidney, the most potent \nof which is calcitriol (1,25-dihydroxy-vitamin D 3); see \nFig. 37.4.\nThe synthesis of calcitriol from calcifediol is regulated \nby PTH, and is also influenced by the phosphate concentra -\ntion in the plasma and by the calcitriol concentration itself through a negative feedback mechanism (see Fig. 37.4). \nReceptors for calcitriol are ubiquitous, and calcitriol is important in the functioning of many cell types.\nThe main actions of calcitriol are to stimulate absorption \nof Ca\n2+ and phosphate in the intestine, and to mobilise Ca2+ \nfrom bone, but it also increases Ca2+ reabsorption in the \nkidney tubules (see Fig. 37.3). It promotes maturation \nof osteoclasts and stimulates their activity (see Figs 37.1 and 37.3). It decreases collagen synthesis by osteoblasts. However, the effect on bone is complex and not confined \nto mobilising Ca\n2+, because in clinical vitamin D deficiency \n(see p. 477), in which the mineralisation of bone is impaired, administration of vitamin D restores bone formation. One \nexplanation may lie in the fact that calcitriol stimulates synthesis of osteocalcin, the Ca\n2+-binding protein of bone \nmatrix.\nOESTROGENS\nOestrogens have an important role in maintaining bone integrity in adult women, acting on osteoblasts and osteo -\nclasts. Oestrogen inhibits the cytokines that recruit osteoclasts and opposes the bone-resorbing, Ca\n2+-mobilising action of \nPTH. It increases osteoblast proliferation, augments produc -\ntion of TGF- \u03b2 and BMPs, and inhibits apoptosis. Withdrawal \nof oestrogen, as happens physiologically at the menopause, frequently leads to osteoporosis.\nCALCITONIN\nCalcitonin is a peptide hormone secreted by \u2018C\u2019 cells found in the thyroid follicles (see Ch. 35).\nThe main action of calcitonin is on bone; it inhibits bone \nresorption by binding to an inhibitory receptor on osteo -\nclasts. In the kidney, it decreases the reabsorption of Ca\n2+ \nand phosphate in the proximal tubules. Its overall effect \nis to decrease the plasma Ca2+ concentration (see Fig. 37.3).\nSecretion is determined mainly by the plasma Ca2+ \nconcentration. A calcitonin analogue, salcatonin, is used \nclinically (see later).\nOTHER \u2003HORMONES\nPhysiological concentrations of glucocorticoids are required \nfor osteoblast differentiation. Higher concentrations inhibit \nbone formation by inhibiting osteoblast differentiation and \nactivity, and may stimulate osteoclast action \u2013 leading to osteoporosis, which is a feature of Cushing\u2019s syndrome \n(Fig. 34.7) and an important adverse effect of glucocorticoid \nadministration (Ch. 34).\nThyroxine stimulates osteoclast action, reducing bone \ndensity and liberating Ca\n2+. Osteoporosis occurs in association \nwith thyrotoxicosis, and it is important not to use excessive \nthyroxine for treating hypothyroidism (see Ch. 35).\nDISORDERS OF BONE\nThe reduction of bone mass with distortion of the micro -\narchitecture is termed osteoporosis ; a reduction in the", "start_char_idx": 0, "end_char_idx": 3178, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "36f5403e-5b5b-4bec-843c-cab3a4d5bcd1": {"__data__": {"id_": "36f5403e-5b5b-4bec-843c-cab3a4d5bcd1", "embedding": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cc7fd213-5eb7-4f40-8341-2856d1d6f409", "node_type": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "297524476f80e34265c1f7a618ce61b64a4c6f76371e824ccee622686c09a0e5"}, "2": {"node_id": "7a640613-e9cd-4e90-993d-de240e14ddb5", "node_type": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bb32920ef4521a28e65b8b23703ee248720c5695ae793814710a1bf7d3fd176c"}, "3": {"node_id": "29873970-1bcf-4dfe-8dc3-4556c8f6a61a", "node_type": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a042ceb18c6487bf8e586b96537f38e9f1153f14d5afa6ffe71cbf3c47c9e9c"}}, "hash": "14f94f799b2469cc9d16268749a5ec4deb2d445a68622138a3ba6d93e5a73334", "text": "micro -\narchitecture is termed osteoporosis ; a reduction in the mineral Ca2+ metabolism. It acts on PTH type 1 receptor,2 G protein\u2013\ncoupled receptors present in various tissues, especially bone \u2013 where it is expressed on osteoblast cell membranes and \nkidney to maintain the plasma Ca\n2+ concentration via \nactivation of adenylyl cyclase and phospholipase C. A \nclosely related molecule, known as parathyroid hormone-\nrelated peptide (PTHrP) bears the same N-terminal end as PTH, and can activate PTH receptors in broadly similar \nways (Harslof & Langdahl, 2016). When PTH activates the \nosteoblast PTH type 1 receptor, osteoblasts express RANKL, which binds to RANK on osteoclasts, activating them and \nincreasing the resorption rate.\nPTH mobilises Ca\n2+ from bone, promotes its reabsorption \nby the kidney and stimulates the synthesis of calcitriol, which in turn increases Ca\n2+ absorption from the intestine \nand synergises with PTH in mobilising bone Ca2+ (see Figs \n37.3 and 37.4). PTH promotes phosphate excretion, and thus its net effect is to increase the concentration of Ca\n2+ \nin the plasma and lower that of phosphate.\nPTH receptors exist in two conformations (R0 and RG). \nShorter duration of activation (and anabolic effect) is seen \nwith ligands that have greater affinity for the RG conforma -\ntion, whereas ligands that bind to the R0 state have a more prolonged duration of action that leads to bone resorption. Sustained levels of PTH mobilise Ca\n2+ from bone and reduce \nrenal Ca2+ excretion. In contrast, low intermittent therapeutic \ndoses of PTH stimulate osteoblast activity and enhance \nbone formation.\nParathyroid hormone is synthesised in the cells of the \nparathyroid glands and stored in vesicles. The principal factor controlling secretion is the concentration of ionised \ncalcium in the plasma, low plasma Ca\n2+ stimulating secretion, \nhigh plasma Ca2+ decreasing it by binding to and activating \na Ca2+-sensing G protein\u2013coupled surface receptor (CaSR, \nsee Ch. 3 and Fig. 37.3). (For reviews, see Stewart, 2004; \nDeal, 2009.) Cinacalcet increases the sensitivity of CaSR to \nplasma Ca2+, thereby reducing PTH secretion.\nTeriparatide and abaloparatide are clinically licensed \nshorter-chain synthetic analogues of PTH and PTHrP, \nrespectively.\nVITAMIN \u2003D\nVitamin D (calciferol) consists of a group of lipophilic precursors that are converted in the body into biologically \nactive metabolites that function as true hormones, circulating \nin the blood and regulating the activities of various cell \ntypes (see Reichel et al., 1989). Their main action, mediated \nby nuclear receptors of the steroid receptor superfamily (see Ch. 3), is the maintenance of plasma Ca\n2+ by increasing \nCa2+ absorption in the intestine, mobilising Ca2+ from bone \nand decreasing its renal excretion (see Fig. 37.3). In humans, \nthere are two important forms of vitamin D, termed D 2 \nand D 3:\n1. Dietary ergocalciferol (D 2), derived from ergosterol in \nplants.\n2. Cholecalciferol (D 3), generated in the skin from \n7-dehydrocholesterol by the action of ultraviolet irradiation during sun exposure, or formed from \ncholesterol in the wall of the intestine.\n2The type 1 receptor is the main one; the PTH type 2 receptor is also a \ntransmembrane-spanning G protein\u2013coupled", "start_char_idx": 3124, "end_char_idx": 6410, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "29873970-1bcf-4dfe-8dc3-4556c8f6a61a": {"__data__": {"id_": "29873970-1bcf-4dfe-8dc3-4556c8f6a61a", "embedding": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cc7fd213-5eb7-4f40-8341-2856d1d6f409", "node_type": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "297524476f80e34265c1f7a618ce61b64a4c6f76371e824ccee622686c09a0e5"}, "2": {"node_id": "36f5403e-5b5b-4bec-843c-cab3a4d5bcd1", "node_type": null, "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14f94f799b2469cc9d16268749a5ec4deb2d445a68622138a3ba6d93e5a73334"}}, "hash": "5a042ceb18c6487bf8e586b96537f38e9f1153f14d5afa6ffe71cbf3c47c9e9c", "text": "2 receptor is also a \ntransmembrane-spanning G protein\u2013coupled receptor expressed in a \nnumber of tissues including central nervous system, pancreas, testis and \nplacenta. Its functions are less well understood.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6403, "end_char_idx": 7093, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8a06d58d-5579-4352-8c3f-a3e702134a3c": {"__data__": {"id_": "8a06d58d-5579-4352-8c3f-a3e702134a3c", "embedding": null, "metadata": {"page_label": "481", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5decbd03-1b78-4c43-9b15-28bc0722a205", "node_type": null, "metadata": {"page_label": "481", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "235d9d01a08353ba89c129a83951a3fe70c650be4ab67c1c36f37529b5276992"}, "3": {"node_id": "fbd99928-8119-4733-a0eb-e4e820168e73", "node_type": null, "metadata": {"page_label": "481", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c416ac67a4967e4cd570748f3fee095660545f8e49c314848d5f9260e58ff7e2"}}, "hash": "c944b9a5bf94d863c93e0b5412925b6f2afedb3fa6f4ec78b5551d225409a257", "text": "37 BONE METABO l ISM\n475Rickets and osteomalacia are treated with vitamin D \npreparations.\nPaget\u2019s disease is common but only a small percentage \nof patients are symptomatic; if medical treatment is needed for symptoms such as bone pain, intermittent courses of \nbisphosphonates such as risedronate, pamidronate or \nzoledronate (see later) can provide benefit that lasts for a \nnumber of years, and are much more convenient than \nfrequent injections of salcatonin, previously the only \neffective medical treatment.\nBISPHOSPHONATES\nBisphosphonates (Fig. 37.5) are enzyme-resistant analogues \nof pyrophosphate, a normal constituent of tissue fluids that \naccumulates in bone and has a role in regulating bone \nresorption. Bisphosphonates inhibit bone resorption by an action mainly on the osteoclasts. They form tight complexes \nwith calcium in the bone matrix, and are released slowly \nas bone is resorbed by the osteoclasts, which are thus exposed to high local bisphosphonate concentrations.\nMechanism of action\nBisphosphonates reduce the rate of bone turnover. They can be grouped into two classes:\n1. Simple compounds that are very similar to \npyrophosphate (e.g. etidronate, clodronate). These are incorporated into ATP analogues that accumulate \nwithin the osteoclasts and promote their apoptosis.\n2. Potent amino-bisphosphonates (e.g. pamidronate, \nalendronate, risedronate, ibandronate, zoledronate). \nThese prevent bone resorption by interfering with the \nanchoring of cell surface proteins to the osteoclast membrane by prenylation, thereby preventing \nosteoclast attachment to bone (see Strewler, 2005).content is termed osteopenia. Dual-energy X-ray absorpti-\nometry (DXA) and quantitative computed tomography are \nthe standard methods for assessing osteoporosis severity \nand monitoring the effect of treatment (Riggs et al., 2012). \nOsteoporotic bone fractures easily after minimal trauma. \nThe commonest causes of osteoporosis are postmenopausal \ndeficiency of oestrogen and age-related deterioration in \nbone homeostasis. It is estimated that 50% of women and 20% of men over the age of 50 will have a fracture due to \nosteoporosis. With increasing life expectancy, osteoporosis \nhas increased to epidemic proportions and is an important public health problem, affecting about 75 million people \nin the United States, Japan and Europe. Other predisposing \nfactors include catabolic hormones that favour protein breakdown such as excessive thyroxine or glucocorticoid administration. Other preventable or treatable diseases of \nbone include osteomalacia and rickets (the juvenile form of \nosteomalacia), in which there are defects in bone mineralisa -\ntion due to vitamin D deficiency, either due to dietary deficiency of vitamin D and lack of sunlight, or to renal \ndisease resulting in reduced synthesis of the active calcitriol hormone (Ch. 30) and Paget\u2019s disease, in which there is \ndistortion of the processes of bone resorption and remodel -\nling as a consequence of mutation in the gene that codes \nfor a ubiquitin-binding protein\n3 called sequestosome 1 (Rea \net al., 2013), which is a scaffold protein in the RANK/NF- \u03baB \nsignalling pathway (see p. 472).\nDRUGS USED IN BONE DISORDERS\nTwo types of agent are currently used for treatment of osteoporosis:\n1. Antiresorptive drugs that decrease bone loss, e.g. bisphosphonates, calcitonin, selective", "start_char_idx": 0, "end_char_idx": 3372, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fbd99928-8119-4733-a0eb-e4e820168e73": {"__data__": {"id_": "fbd99928-8119-4733-a0eb-e4e820168e73", "embedding": null, "metadata": {"page_label": "481", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5decbd03-1b78-4c43-9b15-28bc0722a205", "node_type": null, "metadata": {"page_label": "481", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "235d9d01a08353ba89c129a83951a3fe70c650be4ab67c1c36f37529b5276992"}, "2": {"node_id": "8a06d58d-5579-4352-8c3f-a3e702134a3c", "node_type": null, "metadata": {"page_label": "481", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c944b9a5bf94d863c93e0b5412925b6f2afedb3fa6f4ec78b5551d225409a257"}}, "hash": "c416ac67a4967e4cd570748f3fee095660545f8e49c314848d5f9260e58ff7e2", "text": "bone loss, e.g. bisphosphonates, calcitonin, selective [o]estrogen \nreceptor modulators (SERMs), denusomab, calcium.\n2. Anabolic agents that increase bone formation, e.g. PTH, \nteriparatide.Parathyroid hormone, vitamin D \nand bone mineral homeostasis \n\u2022\tThe\tvitamin \tD \tfamily \tgive \trise \tto \ttrue \thormones; \t\nprecursors are converted to calcifediol in the liver, then \nto the main hormone, calcitriol, in the kidney.\n\u2022\tCalcitriol \tincreases \tplasma \tCa2+ by mobilising it from \nbone, increasing its absorption in the intestine and decreasing its excretion by the kidney.\n\u2022\tParathyroid \thormone \t(PTH) \tacts \tmainly \ton \tthe \tPTH \t\ntype 1 receptor on osteoblasts and in the kidney. \nIntermittent \tstimulation \tof \tPTH \treceptors \twith \tsynthetic \t\nPTH\tanalogues \tstimulates \tbone \tformation.\n\u2022\tCalcitonin \t(secreted \tfrom \tthe \tthyroid) \treduces \tCa2+ \nresorption from bone by inhibiting osteoclast activity.\nOH\nOHOO POHOHPCH\n3\nOHP\nNN\nEtidronate\n(first-generation\nbisphosphonate)\nOHOHOO POHOHPCH\n2CH2\nOHC\nZoldronate\n(first-generation\nbisphosphonate)OHOH\nOO POHOHP O\nPyrophosphate\n(endogenous regulator\nof bone resorption)\nFig. 37.5 Structure of bisphosphonates. Replacement of \nthe oxygen atom in pyrophosphate renders the compounds \nenzyme-resistant. Addition of an N-containing side chain alters the mechanism of action (see text) and greatly increases potency. 3Ubiquitin (Ch. 6) is a small regulatory protein present in almost all \ncells of the body (\u2018ubiquitous\u2019). It directs proteins to compartments in \nthe cell, including the proteasome which destroys and recycles proteins. \nUbiquitin-binding proteins interact with ubiquitinated targets and regulate diverse biological processes, including endocytosis, signal \ntransduction, transcription and DNA repair.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3318, "end_char_idx": 5565, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6196bbd0-1ae2-482e-8806-aab25a8ccad2": {"__data__": {"id_": "6196bbd0-1ae2-482e-8806-aab25a8ccad2", "embedding": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "109d1ad3-db27-4f8b-80d3-05e1148ebaf7", "node_type": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1232c1f35b8357f8ff731b6d2a1e269f2d7c843ce0985ed5567da516f355d370"}, "3": {"node_id": "ab4e0310-cc54-4f38-96ba-a0b984e5dd1f", "node_type": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d208cff62aa023add4018a403102a6776f1f613d172e8a0b1957774cc4275d2e"}}, "hash": "65242918b358ea88820ae23083370b279869f8ac5d43b55f7fd7213cb8bd57be", "text": "37 SECTION 3 \u2003\u2003DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n476OESTROGENS AND RELATED COMPOUNDS\nThe decline in endogenous oestrogen is a major factor in \npostmenopausal osteoporosis, and there is evidence that \ngiving oestrogen as hormone replacement therapy (HRT; \nsee Ch. 36) can ameliorate this. But HRT has actions on \nmany systems, and newer agents (e.g. raloxifene , see Ch. \n36) have been developed that exhibit agonist actions on \nsome tissues and antagonist actions on others. These are \ntermed selective o estrogen receptor modulators (SERMs).\nRALOXIFENE\nRaloxifene is a SERM that stimulates osteoblasts and inhibits \nosteoclasts. It also has agonist actions on the cardiovascular \nsystem, and antagonist activity on mammary tissue and \nthe uterus.\nIt is well absorbed in the GI tract, and undergoes extensive \nfirst-pass metabolism in the liver, yielding the glucuronide, \nwhich undergoes enterohepatic recycling. Overall bioavail -\nability is only about 2%. Despite the low plasma concentra -\ntion, raloxifene is concentrated in tissues, and is converted \nto an active metabolite in liver, lungs, bone, spleen, uterus \nand kidney. Its half-life averages 32 h. It is excreted mainly \nin the faeces.\nUnwanted effects include hot flushes, leg cramps, flu-like \nsymptoms and peripheral oedema. Less common are \nthrombophlebitis and thromboembolism. Other rarer \nadverse effects are thrombocytopenia, GI disturbances, \nrashes, raised blood pressure and arterial thromboembolism. \nRaloxifene is not recommended for primary prevention of \nosteoporotic fractures, but is one alternative to a bisphos -\nphonate for secondary prevention in postmenopausal \nwomen who cannot tolerate a bisphosphonate.\nPARATHYROID HORMONE AND TERIPARATIDE\nPTH and fragments of PTH given in small doses paradoxi -\ncally stimulate osteoblast activity and enhance bone formation, \nand are used treat osteoporosis, especially in those who \nare receiving systemic corticosteroids. The main compound Pharmacokinetic aspects\nBisphosphonates are given orally on an empty stomach \nwith plenty of water in a sitting or standing position at \nleast 30 min before breakfast because of their propensity \nto cause severe oesophageal problems or, in the case of \npamidronate, ibandronate and of zoledronate, intravenously. \nThey are poorly absorbed from the gut. About 50% of \nabsorbed drug accumulates at sites of bone mineralisation, \nwhere it remains adsorbed onto hydroxyapatite crystals, \npotentially for months or years, until the bone is resorbed. \nThe free drug is excreted unchanged by the kidney.\nAbsorption is impaired by food, particularly milk, so \nthe drugs must be taken on an empty stomach.\nUnwanted effects include gastrointestinal (GI) disturbances \nincluding peptic ulcers and oesophagitis (sometimes with \nerosions or stricture formation). Bone pain occurs occasion -\nally. Atypical femoral fractures are described during \nlong-term treatment, especially of osteoporosis, and the \nneed for continued use should be re-evaluated periodically \n(e.g. after 5 years). Given intravenously, some bisphospho -\nnates (in particular zoledronate) can lead to osteonecrosis \n(literally \u2018death of bone\u2019) of the jaw, especially in patients \nwith malignant disease; a dental check is needed before \ntreatment (followed by any indicated remedial work). After \nzoledronate", "start_char_idx": 0, "end_char_idx": 3338, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ab4e0310-cc54-4f38-96ba-a0b984e5dd1f": {"__data__": {"id_": "ab4e0310-cc54-4f38-96ba-a0b984e5dd1f", "embedding": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "109d1ad3-db27-4f8b-80d3-05e1148ebaf7", "node_type": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1232c1f35b8357f8ff731b6d2a1e269f2d7c843ce0985ed5567da516f355d370"}, "2": {"node_id": "6196bbd0-1ae2-482e-8806-aab25a8ccad2", "node_type": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "65242918b358ea88820ae23083370b279869f8ac5d43b55f7fd7213cb8bd57be"}, "3": {"node_id": "a2b174e3-f6b4-4828-a565-483e93e78805", "node_type": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "40ec5aab11f1f6ae53a726ff2d98576fc6cef85684e279ccbdb3ce65d626e135"}}, "hash": "d208cff62aa023add4018a403102a6776f1f613d172e8a0b1957774cc4275d2e", "text": "\ntreatment (followed by any indicated remedial work). After \nzoledronate infusion supplemental calcium and vitamin \nD are administered for at least 10 days.\nClinical use\nAlendronate, ibandronate and risedronate are given orally \nfor prophylaxis and treatment of osteoporosis. Etidronate \nis an alternative. Clodronate is used in patients with \nmalignant disease involving bone and pamidronate is given \nby intravenous infusion to treat hypercalcaemia of malig -\nnancy or to treat Paget\u2019s disease. Ibandronate is given \nintravenously every 3\u20134 weeks in patients with breast cancer \nmetastatic to bone, or every 3 months to treat postmeno -\npausal osteoporosis. Zoledronate, which is given as an \nintravenous infusion, is used for advanced malignancy \ninvolving bone, for Paget\u2019s disease and for selected cases \nof osteoporosis (postmenopausal or in men) when it is \nadministered once a year or even less frequently (see clinical \nbox below).\nBisphosphonates \n\u2022\tOrally\tactive,\tstable\tanalogues\t of\tpyrophosphate,\t\nwhich are incorporated into remodelling bone and \nremain there for months to years.\n\u2022\tReleased\t when\tosteoclast-mediated\t bone\tresorption\t\noccurs, exposing osteoclasts to their effects.\n\u2022\tFirst-generation\t compounds\t (e.g.\t etidronate ) act by \npromoting apoptosis of osteoclasts.\n\u2022\tSecond-generation\t compounds\t (e.g.\t risedronate ) \nwith N-containing side chains are much more potent, \nand prevent osteoclast action by inhibiting prenylation \nreactions required for membrane anchoring of \nfunctional proteins.\n\u2022\tUsed\tlong\tterm\tfor\tprevention\t and\ttreatment\t of\t\nosteoporosis, and for symptomatic Paget\u2019s disease.\n\u2022\tMain\tunwanted\t effect\tis\tgastrointestinal\t (especially\t\noesophageal) disturbance; a rare but serious adverse \neffect of the most potent drugs (notably zoledronate ) \nis osteonecrosis of the jaw.Clinical uses of bisphosphonates \n\u2022\tOsteoporosis :\n\u2013 \u2018primary\u2019 prevention of fractures in high-risk \nindividuals (e.g. with established osteoporosis, \nseveral risk factors for osteoporosis, chronic \ntreatment with systemic glucocorticoids);\n\u2013 \u2018secondary\u2019 prevention after an osteoporotic fracture;\n\u2013 alendronate by mouth, given daily or once weekly \nin addition to calcium with vitamin D 3. Risedronate \nor etidronate are alternatives; zoledronate is given \nannually or even less often by intravenous infusion; it \nis the most potent bisphosphonate and more likely \nto cause osteonecrosis of the jaw \u2013 dental check \nand remedial dental work are prerequisites of \ntreatment.\n\u2022\tMalignant disease involving bone (e.g. metastatic \nbreast cancer, multiple myeloma):\n\u2013 to reduce bone damage, pain and hypercalcaemia \n(e.g. clodronate , ibandronate , zoledronate ).\n\u2022\tPaget\u2019s disease of bone (e.g. risedronate , \npamidronate ) administered intermittently as required \nin patients who are symptomatic.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3275, "end_char_idx": 6352, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a2b174e3-f6b4-4828-a565-483e93e78805": {"__data__": {"id_": "a2b174e3-f6b4-4828-a565-483e93e78805", "embedding": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "109d1ad3-db27-4f8b-80d3-05e1148ebaf7", "node_type": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1232c1f35b8357f8ff731b6d2a1e269f2d7c843ce0985ed5567da516f355d370"}, "2": {"node_id": "ab4e0310-cc54-4f38-96ba-a0b984e5dd1f", "node_type": null, "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d208cff62aa023add4018a403102a6776f1f613d172e8a0b1957774cc4275d2e"}}, "hash": "40ec5aab11f1f6ae53a726ff2d98576fc6cef85684e279ccbdb3ce65d626e135", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6369, "end_char_idx": 6640, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "81247d50-9525-4bb2-af42-7dc74d3e448a": {"__data__": {"id_": "81247d50-9525-4bb2-af42-7dc74d3e448a", "embedding": null, "metadata": {"page_label": "483", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3e88b904-0319-47b3-bec9-c439177d307e", "node_type": null, "metadata": {"page_label": "483", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "579a8539d4e97019ea1cfa02bc99ebb0d736b637364567288f75620d9885fcd7"}, "3": {"node_id": "389fae5d-261f-4d84-9e62-6938e6e47a29", "node_type": null, "metadata": {"page_label": "483", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61e203be45d71a01a141b695c3ebb090b96336add8dd8052054c81ebca7f2156"}}, "hash": "218a899fddd9c89fd7868fdd1c1dc5cef144602877de3be5101069f72b8e3cd1", "text": "37 BONE METABO l ISM\n477BIOPHARMACEUTICALS\nDenosumab is a recombinant human monoclonal antibody \nthat inhibits RANKL, the primary signal for bone resorption \n(see p. 472), and is particularly useful when bisphosphonates \nare not appropriate. It is licensed for use in men and postmenopausal women with osteoporosis who are at high \nrisk of fracture. Denusomab can be used for prevention of \nskeleton-related adverse events in patients with bone metastases from solid tumours, as well as to treat bone \nloss in patients who are receiving hormone ablation therapy \nfor breast or prostate cancer. Calcium and vitamin D deficiencies need to be corrected and necessary dental work needs to be undertaken before treatment with denosumab \nto reduce the risk of osteonecrosis of the jaw (as with potent \nbisphosphonates, see clinical box, p. 476). It is administered \nas subcutaneous injections (60 mg) every 6 months for \nwomen with postmenopausal osteoporosis or men with prostate cancer at increased risk of osteoporosis because \nof hormone ablation, or more frequently (monthly) in \npatients with bone metastases. Adverse effects include altered bowel habit (diarrhoea or constipation), dyspnoea, \nhypocalcaemia, hypophosphataemia, infection (including \nrespiratory, ear, cellulitis) or rash as well as (rarely) oste-onecrosis of the jaw.\nCALCITONIN\nThe main preparation available for clinical use (see the clinical box) is salcatonin (synthetic salmon calcitonin). \nSynthetic human calcitonin is also available. Calcitonin is given by subcutaneous or intramuscular injection, and there may be a local inflammatory action at the injection site. It \ncan also be given intranasally, which is more convenient \nbut less effective. Its plasma half-life is 4\u201312 min, but its \naction lasts for several hours.\nUnwanted effects include nausea and vomiting. Facial \nflushing may occur, as may a tingling sensation in the hands \nand an unpleasant taste in the mouth.currently used is teriparatide \u2013 the peptide fragment (1\u201334) \nof recombinant PTH. A closely related molecule, abalo -\nparatide (consisting of the 34 amino acids in human PTH-related peptide), has recently been licensed in the United \nStates for postmenopausal women with osteoporosis who \nare at high risk of fracture, or unable to take other available therapies. It is thought that the greater affinity of abalo-paratide for the RG conformation of the PTH-1 receptor \nwill result in increased bone formation without provoking \nbone resorption (Harslof & Langdahl, 2016).\nTeriparatide reverses osteoporosis by stimulating new \nbone formation. It increases bone mass, structural integrity and bone strength by increasing the number of osteoblasts and by activating those osteoblasts already in bone. It also \nreduces osteoblast apoptosis.\nTeriparatide is given subcutaneously once daily. It is \nwell tolerated, and serious adverse effects are few. Nausea, dizziness, headache and arthralgias can occur. Mild hyper -\ncalcaemia, transient orthostatic hypotension and leg cramps \nhave been reported. Owing to concerns regarding long-term \nefficacy and safety, the maximal treatment duration of \nteriparatide should be limited to 24 months, and must not be repeated.\nVITAMIN D PREPARATIONS\nVitamin D preparations are used in the treatment of vitamin D deficiencies, bone problems associated with renal failure \n(\u2018renal osteodystrophy\u2019) and hypoparathyroidism \u2013 acute \nhypoparathyroidism is treated with intravenous", "start_char_idx": 0, "end_char_idx": 3464, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "389fae5d-261f-4d84-9e62-6938e6e47a29": {"__data__": {"id_": "389fae5d-261f-4d84-9e62-6938e6e47a29", "embedding": null, "metadata": {"page_label": "483", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3e88b904-0319-47b3-bec9-c439177d307e", "node_type": null, "metadata": {"page_label": "483", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "579a8539d4e97019ea1cfa02bc99ebb0d736b637364567288f75620d9885fcd7"}, "2": {"node_id": "81247d50-9525-4bb2-af42-7dc74d3e448a", "node_type": null, "metadata": {"page_label": "483", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "218a899fddd9c89fd7868fdd1c1dc5cef144602877de3be5101069f72b8e3cd1"}}, "hash": "61e203be45d71a01a141b695c3ebb090b96336add8dd8052054c81ebca7f2156", "text": "\u2013 acute \nhypoparathyroidism is treated with intravenous calcium and injectable vitamin D preparations.\nThe main vitamin D preparation used clinically is ergo-\ncalciferol . Other preparations are alfacalcidol and calcitriol . \nAll can be given orally and are well absorbed unless there \nis obstructive liver disease (vitamin D is fat soluble, and \nbile salts are necessary for absorption). Paricalcitol, a \nsynthetic vitamin D analogue with less potential to cause hypercalcaemia, is used to treat and prevent the secondary \nhyperparathyroidism that occurs in patients with chronic \nrenal failure because of associated hyperphosphataemia (Salusky, 2005).\nGiven orally, vitamin D is bound to a specific \u03b1-globulin \nin the blood and exogenous vitamin D persists in fat for many months after dosing. The main route of elimination \nis in the faeces.\nThe clinical uses of vitamin D preparations are given in \nthe box.\nExcessive intake of vitamin D causes hypercalcaemia. If \nhypercalcaemia persists, especially in the presence of elevated \nphosphate concentrations, calcium salts are deposited in \nthe kidney and urine, causing renal failure and kidney stones.\nClinical uses of vitamin D \n\u2022\tDeficiency \tstates: \tprevention \tand \ttreatment \tof \trickets, \nosteomalacia \tand\tvitamin \tD \tdeficiency \towing \tto \t\nmalabsorption and liver disease (ergocalciferol).\n\u2022\tHypocalcaemia \tcaused \tby \thypoparathyroidism \n(ergocalciferol).\n\u2022\tOsteodystrophy of chronic renal failure , which is the \nconsequence of decreased calcitriol generation \n(calcitriol or alphacalcidol).\nPlasma Ca2+ levels should be monitored during therapy \nwith vitamin D.Clinical uses of calcitonin/\nsalcatonin \nThese agents are now less used.\u2022\tHypercalcaemia (e.g. associated with neoplasia).\n\u2022\tPaget\u2019s disease of bone (to relieve pain and reduce \nneurological complications) \u2013 but it is much less convenient than an injected high-potency bisphosphonate.\n\u2022\tPostmenopausal \tand \tcorticosteroid-induced \t\nosteoporosis (with other agents).\nCALCIUM SALTS\nCalcium salts used therapeutically include calcium gluco -\nnate and calcium lactate , given orally. Calcium gluconate \nis also used for intravenous injection in emergency treatment \nof hyperkalaemia (Ch. 30); intramuscular injection is not used because it causes local necrosis.\nCalcium carbonate, an antacid and phosphate binder \n(Ch. 30), is usually very little absorbed from the gut (an advantage since an effect within the stomach or intestine \nis the desired outcome for a drug intended to buffer gastric \nacid and to reduce ileal phosphate absorption), but there mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3409, "end_char_idx": 6467, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0b129ffc-6be2-418c-9e20-05dafcb61533": {"__data__": {"id_": "0b129ffc-6be2-418c-9e20-05dafcb61533", "embedding": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "15e7e7ad-c2e6-4d63-810e-b75bfc4eecc7", "node_type": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c484ab1575cf0985fb153e37e8d65cf60d143f8a40f56f7ea65c75177164d99"}, "3": {"node_id": "623508c9-5bff-4ee2-bb5c-827ad6993e5a", "node_type": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "608215853389523e0ddfcc09c25aec4580f792fc4e9ab87c612d1f45cf7f6213"}}, "hash": "7fe80f11cec1fce795b2a8a02dfb20ed52e55a1e2c49e65e6e362bf442caceac", "text": "37 SECTION 3\u2003\u2003 DRUGS AFFECTING MAJOR ORGAN SYSTEMS\n478CALCIMIMETIC COMPOUNDS\nCalcimimetics enhance the sensitivity of the parathyroid \nCa2+-sensing receptor to the concentration of blood Ca2+, \nwith a consequent decrease in secretion of PTH and reduc -\ntion in serum Ca2+ concentration. There are two types of \ncalcimimetics:\n1. Type I are agonists, and include various inorganic \nand organic cations; Sr2+ is an example.\n2. Type II are allosteric activators (see Ch. 3) that \nactivate the receptor indirectly. Examples include cinacalcet, which is an oral preparation used for the \ntreatment of hyperparathyroidism (see Fig. 37.3; \nPeacock et al., 2005), and etelcalcetide, a recently \nlicensed injectable formulation that has a longer elimination half-life than cinacalcet (Hamano et al., \n2017).\nPOTENTIAL NEW THERAPIES\nRomosozumab is a monoclonal antibody that increases bone formation and reduces bone resorption through \ninhibition of sclerostin which is produced by osteoclasts \n(McClung, 2017). Although romosozumab appears to be more efficacious than alendronate in preventing fractures, \nthere are safety concerns that have slowed progress towards \nlicensing.Clinical uses of calcium salts \n\u2022\tDietary\tdeficiency.\n\u2022\tHypocalcaemia \tcaused \tby \thypoparathyroidism or \nmalabsorption (intravenous for acute tetany).\n\u2022\tCalcium \tcarbonate \tis \tan \tantacid; \tit \tis \tpoorly \tabsorbed \t\nand binds phosphate in the gut. It is used to treat \nhyperphosphataemia (Ch. 30).\n\u2022\tPrevention \tand \ttreatment \tof \tosteoporosis (often with \noestrogen or selective oestrogen receptor modulators \n(SERMs)\tin \twomen, \tbisphosphonate, \tvitamin \tD).\n\u2022\tCardiac \tdysrhythmias \tcaused \tby \tsevere \thyperkalaemia \n(intravenous; see Ch. 30).is concern that low-level systemic absorption has the \npotential to cause arterial calcification in patients with renal \nfailure, especially if complicated by hyperphosphataemia \n(the product of calcium and phosphate ion concentrations \nis sometimes used clinically to estimate the risk of tissue deposition of insoluble calcium phosphate).\nUnwanted effects : oral calcium salts can cause GI disturbance. \nIntravenous administration in emergency treatment of hyperkalaemia requires care, especially in patients receiving \ncardiac glycosides, the toxicity of which is influenced by \nextracellular calcium ion concentration (see Ch. 22).\nThe clinical uses of calcium salts are given in the clinical \nbox.\nREFERENCES AND FURTHER READING\nBone disorders and bone remodelling\nBoyce, B.F., Xing, L., 2008. Functions of RANKL/RANK/OPG in bone \nmodeling and remodeling. Arch. Biochem. Biophys. 473, 139\u2013146. \n(Good review of the role of the RANK/RANKL/OPG in osteoclast formation \nand the transcription factors involved)\nDeal, C., 2009. Potential new drug targets for osteoporosis. Nat. Clin. \nPract. Rheumatol. 5, 174\u2013180. (Outstanding review; good diagrams)\nDeftos, L.J., 2005. Treatment of Paget\u2019s disease \u2013 taming the wild \nosteoclast. N. Engl. J. Med. 353, 872\u2013875. (Editorial covering the use of \nOPG and zoledronic acid for Paget\u2019s disease. See also article by Cundy et al. \nin", "start_char_idx": 0, "end_char_idx": 3102, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "623508c9-5bff-4ee2-bb5c-827ad6993e5a": {"__data__": {"id_": "623508c9-5bff-4ee2-bb5c-827ad6993e5a", "embedding": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "15e7e7ad-c2e6-4d63-810e-b75bfc4eecc7", "node_type": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c484ab1575cf0985fb153e37e8d65cf60d143f8a40f56f7ea65c75177164d99"}, "2": {"node_id": "0b129ffc-6be2-418c-9e20-05dafcb61533", "node_type": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7fe80f11cec1fce795b2a8a02dfb20ed52e55a1e2c49e65e6e362bf442caceac"}, "3": {"node_id": "a52e7a1e-330b-4703-8814-2d553e38210d", "node_type": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd1bc192951c0bdc86d17e90c0b4ef17080bb965ebe8c28b9d1ee9413226ff61"}}, "hash": "608215853389523e0ddfcc09c25aec4580f792fc4e9ab87c612d1f45cf7f6213", "text": "disease. See also article by Cundy et al. \nin the same issue, pp. 918\u2013923)\nImai, Y., Youn, M.Y., Inoue, K., 2013. Nuclear receptors in bone \nphysiology and diseases. Physiol. Rev. 93, 481\u2013523. (Reviews roles of various nuclear receptor-mediated signalling pathways in bone physiology and disease)\nKhosla, S., Westendorf, J.J., Oursler, M.J., 2008. Building bone to reverse \nosteoporosis and repair fractures. J. Clin. Invest. 118, 421\u2013428. (Good review; covers the role of Wnt signalling and sclerostin secretion)\nMcClung, M.R., 2017. Clinical utility of anti-sclerostin antibodies. Bone \n96, 3\u20137. (Describes new advances in the understanding of drugs targeted at sclerostin)\nRea, S.L., Walsh, J.P., Layfield, R., Ratajczak, T., Xu, J., 2013. New \ninsights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of Paget\u2019s disease of bone. Endocrine Rev. 34, 501\u2013524. \n(Outlines recent advances in understanding of the multiple \npathophysiological roles of SQSTM1/p62 protein, with particular emphasis on their relationship to Paget\u2019s disease of bone)\nReichel, H., Koeftler, H.P., Norman, A.W., 1989. The role of the vitamin \nD endocrine system in health and disease. N. Engl. J. Med. 320, 980\u2013991. (Classic)\nReid, R., 2008. Anti-resorptive therapies for osteoporosis. Semin. Cell \nDev. Biol. 19, 5473\u20135478. (Excellent review of the actions of current and novel anti-resorptive drugs)\nRiggs, B.L., Khosla, S., Melton, L.J., 2012. Better tools for assessing \nosteoporosis. J. Clin. Invest. 122, 4323\u20134324. (Describes the current gold standard methods of dual-energy X-ray absorptiometry (DXA) and \nquantitative computed tomography)Stewart, J.F., 2004. Translational implications of the parathyroid calcium \nreceptor. N. Engl. J. Med. 351, 324\u2013326. (Succinct article with useful \ndiagrams)\nWright, H.L., McCarthy, H.S., Middleton, J., Marshall, M.J., 2009. \nRANK, RANKL and osteoprotegerin in bone biology and disease. Curr. Rev. Musculoskelet. Med. 2, 56\u201364. (Synopsis of the structures of RANK, RANKL and OPG, and the intracellular RANK/RANKL signalling \npathways with a review of diseases linked to their malfunction)\nDrugs used to treat bone disorders\nClemett, D., Spenser, C.M., 2000. Raloxifene: a review of its use in \npostmenopausal osteoporosis. Drugs 60, 379\u2013411. (Comprehensive review covering the mechanism of action, pharmacology, pharmacokinetic \naspects, therapeutic use and adverse effects of raloxifene)\nCummings, S.R., San Martin, J., McClung, M.R., et al., 2009. Denosumab \nfor prevention of fractures in postmenopausal women with osteoporosis. N. Engl. J. Med. 361, 818\u2013820. (\u2018Freedom Trial\u2019 with 239 \ncollaborators. Denosumab was effective in reducing fracture risk in women \nwith osteoporosis)\nHamano, N., Komaba, H., Fukagawa, M., 2017. Etelcalcetide for the \ntreatment of secondary hyperparathyroidism. Expert Opin. Pharmacother.", "start_char_idx": 3066, "end_char_idx": 5936, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a52e7a1e-330b-4703-8814-2d553e38210d": {"__data__": {"id_": "a52e7a1e-330b-4703-8814-2d553e38210d", "embedding": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "15e7e7ad-c2e6-4d63-810e-b75bfc4eecc7", "node_type": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c484ab1575cf0985fb153e37e8d65cf60d143f8a40f56f7ea65c75177164d99"}, "2": {"node_id": "623508c9-5bff-4ee2-bb5c-827ad6993e5a", "node_type": null, "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "608215853389523e0ddfcc09c25aec4580f792fc4e9ab87c612d1f45cf7f6213"}}, "hash": "dd1bc192951c0bdc86d17e90c0b4ef17080bb965ebe8c28b9d1ee9413226ff61", "text": "the \ntreatment of secondary hyperparathyroidism. Expert Opin. Pharmacother. 18, 529\u2013534.\nHarslof, T., Langdahl, B.L., 2016. New horizons in osteoporosis \ntherapies. Curr. Opin. Pharmacol. 28, 38\u201342. (Comprehensive review of the mechanisms and targets of new treatments for osteoporosis)\nKhosla, S., 2009. Increasing options for the treatment of osteoporosis. N. \nEngl. J. Med. 361, 818\u2013820. (Editorial)\nNemeth, E.F., Heaton, W.H., Miller, M., et al., 2004. Pharmacodynamics \nof the type II calcimimetic compound cinacalcet HCl. J. Pharmacol. Exp. Ther. 398, 627\u2013635. (Detailed study of pharmacokinetic aspects and \nthe pharmacological action of cinacalcet hydrochloride)\nPeacock, M., Bilezikian, J.P., Klassen, P.S., et al., 2005. Cinacalcet \nhydrochloride maintains long-term normocalcaemia in patients with \nprimary hyperparathyroidism. J. Clin. Endocrinol. Metab. 90, 135\u2013141.\nReginster, J.Y., Deroisy, R., Neuprez, A., et al., 2009. Strontium ranelate: \nnew data on fracture prevention and mechanisms of action. Curr. Osteoporos. Rep. 7, 96\u2013102. (Stresses that in 5-year studies this drug has mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5898, "end_char_idx": 7477, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "22ade394-a97a-448e-b988-c2ebbda51816": {"__data__": {"id_": "22ade394-a97a-448e-b988-c2ebbda51816", "embedding": null, "metadata": {"page_label": "485", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "06da3ba8-f7df-429d-a061-d9b1c45abb46", "node_type": null, "metadata": {"page_label": "485", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0500be07f0c7be710290e526bd7f733a97e918e5a6a744b76ed963df5a177c48"}}, "hash": "0500be07f0c7be710290e526bd7f733a97e918e5a6a744b76ed963df5a177c48", "text": "37 BONE METABOlISM\n479Strewler, G.J., 2005. Decimal point \u2013 osteoporosis therapy at the 10-year \nmark. N. Engl. J. Med. 350, 1172\u20131174. ( Crisp article concentrating \nmainly on bisphosphonates )\nTabatabaei-Malazy, O., Salari, P., Khashayar, P., LarijanI, B., 2017. New \nhorizons in treatment of osteoporosis. Daru 25, 2. ( Comprehensive \noverview of recent developments in drug therapy )proved efficacious in both decreasing bone reabsorption and stimulating bone \nformation, and has a positive risk\u2013benefit ratio )\nRogers, M.J., 2003. New insights into the mechanisms of action of the \nbisphosphonates. Curr. Pharm. Des. 9, 2643\u20132658. ( Covers the different \nmechanisms of action of the simple bisphosphonates and the \nnitrogen-containing bisphosphonates )\nSalusky, I.B., 2005. Are new vitamin D analogues in renal bone disease \nsuperior to calcitriol? Pediatr. Nephrol. 20, 393\u2013398.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1363, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "10e011fe-7498-47e4-bdcd-2e69216e2bd4": {"__data__": {"id_": "10e011fe-7498-47e4-bdcd-2e69216e2bd4", "embedding": null, "metadata": {"page_label": "486", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d4adc45b-f76d-4538-8d80-1f050c69bdeb", "node_type": null, "metadata": {"page_label": "486", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4a9289d33c6674c7e111f83f76ffd11a89341064419acb4a2945ef344989471"}, "3": {"node_id": "bf3ac2ab-8cb9-46ae-822c-be8a09568526", "node_type": null, "metadata": {"page_label": "486", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "08a712ff5baadfb95aabd764868081434eca6cda156664788c24ae3cefd8da97"}}, "hash": "62926200206430ccaea9625ebfb14576d237a658f9d2f3b3a9cb42b6a331bd28", "text": "480\nChemical transmission and \ndrug action in the central \nnervous system38 NERVOUS SYSTEM SECTION 4 \nOVERVIEW\nBrain function is the single most important aspect of \nphysiology that defines the difference between humans \nand other species. Disorders of brain function, whether \nprimary or secondary to malfunction of other systems, are a major concern of human society, and a field \nin which pharmacological intervention plays a key \nrole. In this chapter we introduce some basic principles of neuropharmacology that underlie much of the \nmaterial in the other chapters describing drug action \non the central nervous system.\nINTRODUCTION\nThere are two reasons why understanding the action of \ndrugs on the central nervous system (CNS) presents a \nparticularly challenging problem. The first is that centrally \nacting drugs are of special significance to humankind. Not only are they of major therapeutic importance,\n1 but they \nare also the drugs that humans most commonly administer \nto themselves for non-medical reasons (e.g. alcohol, tea \nand coffee, nicotine, cannabis, MDMA [ecstasy], opioids, cocaine, amphetamines and so on). The second reason is \nthat the CNS is functionally far more complex than any \nother system in the body (also uniquely protected by a blood\u2013brain barrier), and this makes the understanding of \ndrug effects very much more difficult. The relationship \nbetween the behaviour of individual cells and that of the organ as a whole is far less direct in the brain than in other organs. Currently, the links between a drug\u2019s action at the \nbiochemical and cellular level and its effects on brain \nfunction remain largely mysterious. Functional brain imaging is beginning to reveal relationships between brain \nactivity in specific regions and mental function, and this \ntool is being used increasingly to probe drug effects. Despite sustained progress in understanding the cellular and \nbiochemical effects produced by centrally acting drugs, \nand the increasing use of brain imaging to study brain function and drug effects, the gulf between our understand -\ning of drug action at the cellular level and at the functional and behavioural level remains, for the most part, very wide.\nIn some instances, our understanding of brain function \nand how drugs alter it is more advanced. Thus, the relation -\nship between dopaminergic pathways in the extrapyramidal system and the effects of drugs in alleviating or exacerbating \nthe symptoms of Parkinson\u2019s disease (see Ch. 41) is clear \ncut. Many CNS drugs are used to treat psychiatric disorders that are defined according to their symptomatology rather \nthan on the basis of causative factors or clinical signs and investigations. What is called \u2018schizophrenia\u2019 or \u2018depression\u2019 \non the basis of particular symptoms is likely to consist of \nseveral distinct disorders caused by different mechanisms and responding to drugs in different ways. Furthermore, \nin disorders such as schizophrenia and depression, disease-\ninduced cognitive deficits may contribute to the behavioural symptoms and in chronic pain the affective state (mood) \nof the sufferer may be changed and exacerbate the painful \ncondition. Much effort is going into pinning down the biological basis of psychiatric disorders \u2013 a necessary step to improve the design of better drugs for clinical use \u2013 but \nthe task is daunting and progress is slow.\nIn this chapter we outline the general principles governing \nthe action of drugs on the CNS. Most neuroactive drugs work by interfering with the chemical signals that underlie \nbrain function, and the next two chapters discuss the major CNS transmitter systems and the ways in which drugs affect \nthem. In Chapter 41, we focus on neurodegenerative diseases, \nand the remaining chapters in this section deal with the main classes of neuroactive drugs that are currently in use.\nBackground information will be found in neurobiology \nand neuropharmacology textbooks such as Iversen et al. \n(2009), Kandel et al.", "start_char_idx": 0, "end_char_idx": 3995, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bf3ac2ab-8cb9-46ae-822c-be8a09568526": {"__data__": {"id_": "bf3ac2ab-8cb9-46ae-822c-be8a09568526", "embedding": null, "metadata": {"page_label": "486", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d4adc45b-f76d-4538-8d80-1f050c69bdeb", "node_type": null, "metadata": {"page_label": "486", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4a9289d33c6674c7e111f83f76ffd11a89341064419acb4a2945ef344989471"}, "2": {"node_id": "10e011fe-7498-47e4-bdcd-2e69216e2bd4", "node_type": null, "metadata": {"page_label": "486", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "62926200206430ccaea9625ebfb14576d237a658f9d2f3b3a9cb42b6a331bd28"}}, "hash": "08a712ff5baadfb95aabd764868081434eca6cda156664788c24ae3cefd8da97", "text": "such as Iversen et al. \n(2009), Kandel et al. (2013) and Nestler et al. (2015).\nCHEMICAL SIGNALLING IN THE \nNERVOUS SYSTEM\nThe brain (like every other organ in the body!) is basically \na chemical machine; it controls the main functions of a \nhigher animal across timescales ranging from milliseconds \n(e.g. returning a 100 mph tennis serve) to years (e.g. remembering how to ride a bicycle).\n2 The chemical signalling \nmechanisms cover a correspondingly wide dynamic range, \nas summarised, in a very general way, in Fig. 38.1. Currently, \nwe understand much about drug effects on events at the fast end of the spectrum \u2013 synaptic transmission and \nneuromodulation \u2013 but much less about long-term adaptive \nprocesses, although it is quite evident that the latter are of great importance for the neurological and psychiatric \ndisorders that are susceptible to drug treatment.\nThe original concept of neurotransmission envisaged a \nsubstance released by one neuron and acting rapidly, briefly \nand at short range on the membrane of an adjacent (post -\nsynaptic) neuron, causing excitation or inhibition. The principles outlined in Chapter 13 apply to the central as well as the peripheral nervous system. It is now clear that \n1In England and Wales in 2015, over 200 million prescriptions (about \n20% of all prescriptions), costing \u00a31.93 billion, were for CNS drugs as \ndefined by the British National Formulary. This amounted to over three \nprescriptions per person across the whole population.2Memory of drug names and the basic facts of pharmacology seems to \ncome somewhere in the middle of this range (skewed towards the short \nend).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3948, "end_char_idx": 6065, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1b2be3a4-548d-438e-b1ab-db6bf9cc1f0e": {"__data__": {"id_": "1b2be3a4-548d-438e-b1ab-db6bf9cc1f0e", "embedding": null, "metadata": {"page_label": "487", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fba39d8d-914f-4dcd-92e8-a54373e14b4f", "node_type": null, "metadata": {"page_label": "487", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50d8338f9e0d3c1731de05b00ae3c5892b40143caf5eb9c86275cacdd685806d"}, "3": {"node_id": "ea676f44-1b16-44d0-956a-29f53a44e950", "node_type": null, "metadata": {"page_label": "487", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7370e87a849c49c5d8ccad836245498ca316c1404149f59e6c3b8999fbb63bc0"}}, "hash": "ae1ce823580f97d8666cf27ee053033e33b60b3200ef2f4918a586995d8ec0fb", "text": "38 ChEMiCal TR a NSM i SS i ON a N d d RU g a CT i ON i N T h E CENTR al NERVOUS SYSTEM\n481Glial cells, particularly astrocytes, which are the main \nnon-neuronal cells in the CNS and outnumber neurons by \n10 to 1, also play an important signalling role. Once thought \nof mainly as housekeeping cells, whose function was merely to look after the fastidious neurons, they are increasingly \nseen as \u2018inexcitable neurons\u2019 with a major communications \nrole (see Matsas & Tsacopolous, 2013; Vasile et al., 2017), \nalbeit on a slower timescale than that of neuronal com -\nmunication. These cells express a range of receptors and transporters, and also release a wide variety of mediators, \nincluding glutamate, D-serine, ATP, lipid mediators and growth factors. They respond to chemical signals from \nneurons, and also from neighbouring astrocytes and \nmicroglial cells (the CNS equivalent of macrophages, which function much like inflammatory cells in peripheral tissues). \nElectrical coupling between astrocytes causes them often \nto respond in concert in a particular brain region, thus controlling the chemical environment in which the neurons operate. Although they do not conduct action potentials, \nand do not send signals to other parts of the body, astrocytes \nare otherwise very similar to neurons and play a crucial communication role within the brain. This is a rapidly \nexpanding area of research and drug development. It is \nan area to watch closely.chemical mediators within the brain can produce slow and long-lasting effects; that they can act rather diffusely, at a considerable distance from their site of release (e.g. GABA \nacting at extrasynaptic GABA\nA receptors, see Ch. 39); and \nthat they can also produce other diverse effects, for example, on transmitter synthesis, on the expression of neurotransmit -\nter receptors and on neuronal morphology, in addition to \naffecting the ionic conductance of the postsynaptic cell \nmembrane. The term neuromodulator is often used to denote \na mediator, the actions of which do not conform to the \noriginal neurotransmitter concept. The term is not clearly \ndefined, and it covers not only the diffusely acting neuro-\npeptide mediators, but also mediators such as nitric oxide (NO, Ch. 21) and arachidonic acid metabolites (Ch. 18), which are not stored and released like conventional neu -\nrotransmitters, and may come from non-neuronal cells, particularly glia, as well as neurons. In general, neuromodula -\ntion relates to synaptic plasticity, including short-term \nphysiological events such as the regulation of presynaptic \ntransmitter release or postsynaptic excitability. Longer-term neurotrophic effects are involved in regulating the growth \nand morphology of neurons, as well as their functional \nproperties. Table 38.1 summarises the types of chemical mediator that operate in the CNS.month/yeardayhminsmsTimescale\nStructural remodellingPharmacological toleranceDelayed pharmacological\neffectsSynaptic plasticityNeuromodulationSlow synaptic transmissionFast synaptic transmissionTransmitter releaseImpulse conductionProcess\n[Ca2+]iNoneChemical mediators\nLigand-gated ion channels (Ch. 3)Exocytosis (Ch. 4)Molecular mechanisms\nVoltage-gated ion channels (Ch. 4)\nG protein-coupled receptors (Ch. \n3) linked to ion channels, [Ca2+]i, \nsecond messengersSoluble guanylyl cyclase (Ch. 21)\nReceptor up-/down-regulation\n? Altered gene expression\nKinase-linked receptors \ncontrolling gene expressionFast transmitters(e.g. glutamate, GABA, ACh)\nSlow transmitters\n(e.g. monoamines,", "start_char_idx": 0, "end_char_idx": 3545, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ea676f44-1b16-44d0-956a-29f53a44e950": {"__data__": {"id_": "ea676f44-1b16-44d0-956a-29f53a44e950", "embedding": null, "metadata": {"page_label": "487", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fba39d8d-914f-4dcd-92e8-a54373e14b4f", "node_type": null, "metadata": {"page_label": "487", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50d8338f9e0d3c1731de05b00ae3c5892b40143caf5eb9c86275cacdd685806d"}, "2": {"node_id": "1b2be3a4-548d-438e-b1ab-db6bf9cc1f0e", "node_type": null, "metadata": {"page_label": "487", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ae1ce823580f97d8666cf27ee053033e33b60b3200ef2f4918a586995d8ec0fb"}}, "hash": "7370e87a849c49c5d8ccad836245498ca316c1404149f59e6c3b8999fbb63bc0", "text": "ACh)\nSlow transmitters\n(e.g. monoamines, peptides, ACh)\nSlow transmitters + others (e.g. NO,\narachidonic acid metabolites)\nMany neuroactive drugs\n(e.g. antidepressants, Ch. 48)\nMany neuroactive drugs (Ch. 50)\n(e.g. opioids, benzodiazepines)\nChemokines\nCytokinesGrowth factors? Adhesion molecules? Steroids Degeneration, regeneration and repair(very limited in CNS)\nFig. 38.1 Chemical signalling in the nervous system. Knowledge of the mediators and mechanisms becomes sparser as we move \nfrom the rapid events of synaptic transmission to the slower ones involving remodelling and alterations of gene expression. ACh, \nacetylcholine; CNS, central nervous system; NO, nitric oxide. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3505, "end_char_idx": 4666, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "86073e8e-51a2-449e-b3fd-689d7942be63": {"__data__": {"id_": "86073e8e-51a2-449e-b3fd-689d7942be63", "embedding": null, "metadata": {"page_label": "488", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2787f3dc-3f6a-4e50-be71-a85d1c8e01ba", "node_type": null, "metadata": {"page_label": "488", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "88fa11621512bab9c1269fc00bdb0cbc7700e0029b052df4d3626e79fb979776"}, "3": {"node_id": "8af10762-b99b-4e5a-84ad-3fe4431892e9", "node_type": null, "metadata": {"page_label": "488", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e957351eb2d3003697b18ace182808e51c6fc09fce816815908b4a783a8a72e"}}, "hash": "c36607425c0eaa2d55e8667412f726ad04124c09cbf6221e41de090c9f383d54", "text": "38 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n482TARGETS FOR DRUG ACTION\n\u25bc To recapitulate what was discussed in Chapters 2 and 3, neuroactive \ndrugs act primarily on one of four types of target proteins, namely \nion channels, receptors, enzymes and transport proteins. Of the four \nmain receptor families \u2013 ionotropic receptors, G protein\u2013coupled \nreceptors, kinase-linked receptors and nuclear receptors \u2013 current neuroactive drugs target mainly the first two.\nIn the last three decades, knowledge about these targets \nin the CNS has accumulated rapidly, particularly as follows:\n\u2022\tAs\twell \tas \t40 \tor \tmore \tsmall-molecule \tand \tpeptide \t\nmediators, the importance of other \u2018non-classical\u2019 \nmediators \u2013 NO, eicosanoids, growth factors, etc. \u2013 has \nbecome apparent.\n\u2022\tConsiderable \tmolecular \tdiversity \tof \tknown \treceptor \t\nmolecules and ion channels (see Ch. 3) has been \nrevealed.\n\u2022\tReceptors \tand \tchannels \tare \teach \texpressed \tin \tseveral \t\nsubtypes, and many possess sites for allosteric modulation and exist in multiple heteromeric \ncomplexes, all of which add to the diversity of \npotential drug targets. In most cases, we are only beginning to discover what this diversity means at a \nfunctional level. The molecular diversity of such \ntargets raises the possibility of developing drugs with improved selectivity of action, e.g. interacting with \none kind of GABA\nA receptor without affecting others \n(see Ch. 45). The potential of these new approaches in terms of improved drugs for neurological and \npsychiatric diseases is large but as yet unrealised.\nOur knowledge of the neurobiology of epilepsy, schizo -\nphrenia and depressive illnesses is advancing and hopefully this will result in new strategies for treating these disabling conditions. The pathophysiology and genetic causes of \nneurodegeneration are beginning to be understood (see \nCh. 41) ushering in long-awaited gene therapies for CNS disorders. In this regard, nusinersen, an antisense oligo -\nnucleotide that corrects the genetic defect that causes spinal muscular atrophy, has recently been approved for clinical use.Table 38.1 Types of chemical mediators in the central nervous system\nMediator typeaExamples Targets Main functional role\nConventional \nsmall-molecule mediatorsGlutamate, GABA, acetylcholine, dopamine, 5-hydroxytryptamine, etc.Ligand-gated ion channelsG protein\u2013coupled receptorsFast and slow synaptic neurotransmissionNeuromodulation\nNeuropeptides Substance P, neuropeptide Y, endorphins, orexins, corticotrophin-releasing factor, etc.G protein\u2013coupled receptors Neuromodulation\nLipid mediators Prostaglandins, endocannabinoids G protein\u2013coupled receptors Neuromodulation\n\u2018Gaseous\u2019 mediators Nitric oxide, carbon monoxide, hydrogen sulfide, etcGuanylyl cyclase Neuromodulation\nNeurotrophins, cytokinesNerve growth factor, brain-derived neurotrophic factor, interleukin-1Kinase-linked receptors Neuronal growth, survival and functional plasticity\nSteroids Androgens, oestrogens Nuclear and membrane receptors Functional plasticity\naMost central nervous system pharmacology has been centred on small-molecule mediators and, less commonly, neuropeptides. Other \nmediator types are now being targeted for therapeutic purposes.\nChemical transmission in the \ncentral nervous system \n\u2022\tThe\tbasic \tprocesses \tof \tsynaptic \ttransmission \tin \tthe \t\ncentral nervous", "start_char_idx": 0, "end_char_idx": 3341, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8af10762-b99b-4e5a-84ad-3fe4431892e9": {"__data__": {"id_": "8af10762-b99b-4e5a-84ad-3fe4431892e9", "embedding": null, "metadata": {"page_label": "488", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2787f3dc-3f6a-4e50-be71-a85d1c8e01ba", "node_type": null, "metadata": {"page_label": "488", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "88fa11621512bab9c1269fc00bdb0cbc7700e0029b052df4d3626e79fb979776"}, "2": {"node_id": "86073e8e-51a2-449e-b3fd-689d7942be63", "node_type": null, "metadata": {"page_label": "488", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c36607425c0eaa2d55e8667412f726ad04124c09cbf6221e41de090c9f383d54"}}, "hash": "3e957351eb2d3003697b18ace182808e51c6fc09fce816815908b4a783a8a72e", "text": "\tof \tsynaptic \ttransmission \tin \tthe \t\ncentral nervous system are essentially similar to those \noperating in the periphery (Ch. 13).\n\u2022\tGlial\tcells, \tparticularly \tastrocytes, \tparticipate \tactively \tin \t\nchemical signalling, functioning essentially as \u2018inexcitable neurons\u2019.\n\u2022\tThe\tterms \tneurotransmitter, neuromodulator and \nneurotrophic factor refer to chemical mediators that operate over different timescales. In general:\n\u2013 neurotransmitters are released by presynaptic terminals and produce rapid excitatory or inhibitory responses in postsynaptic neurons;\n\u2013\tfast\tneurotransmitters \t(e.g. \tglutamate, \tGABA) \t\noperate through ligand-gated ion channels\n\u2013 slow neurotransmitters and neuromodulators (e.g. \ndopamine, neuropeptides, prostanoids) operate \nmainly\tthrough \tG \tprotein\u2013coupled \treceptors;\n\u2013 neuromodulators are released by neurons and by astrocytes, and produce slower pre- or postsynaptic responses;\n\u2013 neurotrophic factors are released mainly by non-neuronal cells and act on tyrosine kinase-linked receptors that regulate gene expression and control \nneuronal growth and phenotypic characteristics.\n\u2022\tThe\tsame \tagent \t(e.g. \tglutamate, \t5-hydroxytryptamine, \t\nacetylcholine) may act through both ligand-gated \nchannels\tand \tG \tprotein\u2013coupled \treceptors, \tand \t\nfunction as both neurotransmitter and neuromodulator.\n\u2022\tMany\tchemical \tmediators, \tincluding \tglutamate, \tnitric \t\noxide and arachidonic acid metabolites, are produced \nby glia as well as neurons.\n\u2022\tMany\tmediators \t(e.g. \tcytokines, \tchemokines, \tgrowth \t\nfactors and steroids) control long-term changes in the brain (e.g. synaptic plasticity and remodelling), mainly by affecting gene transcription.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3287, "end_char_idx": 5444, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dbc84f8b-dae9-401d-907a-1ac129cb736d": {"__data__": {"id_": "dbc84f8b-dae9-401d-907a-1ac129cb736d", "embedding": null, "metadata": {"page_label": "489", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "75bc9aac-619e-486d-b3b9-46e5ea82f0cc", "node_type": null, "metadata": {"page_label": "489", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39ca67726e587e1d89955af99f9d6d830b872388b8a2745b631848edced4b4a5"}, "3": {"node_id": "88d1d145-2281-45e9-b443-1d2aa411405a", "node_type": null, "metadata": {"page_label": "489", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f0b02b45dfca5d9e5ffd9f0ebec64ed910e78a929ac2abc8337da63d2515a12"}}, "hash": "b7fdc5c8015826f4df8bb31c1f8876825afad69ee0939c426a8121bb47348d9f", "text": "38 ChEMiCal TR a NSM i SS i ON a N d d RU g a CT i ON i N T h E CENTR al NERVOUS SYSTEM\n483this secondary response, rather than the primary effect, \nwhich leads to clinical benefit.\nBLOOD\u2013BRAIN BARRIER\n\u25bc A key factor in CNS pharmacology is the blood\u2013brain barrier (see \nCh. 9), penetration of which requires molecules to traverse the vascular \nendothelial cells rather than going between them. Inflammation can \ndisrupt the integrity of the blood\u2013brain barrier, allowing previously \nimpermeable drugs such as penicillin to cross. In general, only small \nnon-polar molecules can diffuse passively across cell membranes. \nSome neuroactive drugs penetrate the blood\u2013brain barrier in this \nway, but many do so via transporters, which either facilitate entry into the brain or diminish it by pumping the compound from the \nendothelial cell interior back into the bloodstream. Drugs that gain \nentry in this way include levodopa (Ch. 41), valproate (Ch. 46) and \nvarious sedative histamine antagonists (Ch. 18). Active extrusion of \ndrugs from the brain occurs via P-glycoprotein, an ATP-driven drug efflux transporter, and related transporter proteins (see Ch. 9). Many \nantibacterial and anticancer drugs are excluded from the brain while \nsome CNS-acting drugs \u2013 including certain opioid, antidepressant, antipsychotic and anti-epileptic drugs \u2013 are actively extruded from \nthe brain (see Linnet & Ejsing, 2008). Variation in the activity of efflux \ntransporters between individuals is an important consideration (Chs 9 and 12).DRUG ACTION IN THE CENTRAL \nNERVOUS SYSTEM\nAs already emphasised, the molecular and cellular mecha -\nnisms underlying drug action in the CNS and in the \nperiphery have much in common. Understanding how \ndrugs affect brain function is, however, problematic. One difficulty is the complexity of neuronal interconnections \nin the brain \u2013 the wiring diagram. Fig. 38.2 illustrates in a \nschematic way the kind of interconnections that typically exist for, say, a noradrenergic neuron in the locus coeruleus \n(see Ch. 40), shown as neuron 1 in the diagram, releasing \ntransmitter a\n\tat\tits\tterminals. \tRelease \tof \ta affects neuron \n2 (which releases transmitter b), and also affects neuron 1 \nby direct feedback and, indirectly, by affecting presynaptic inputs impinging on neuron 1. The firing pattern of neuron 2 also affects the system, partly through interneuronal \nconnections (neuron 3, releasing transmitter c). Even at \nthis grossly oversimplified level, the effects on the system \nof blocking or enhancing the release or actions of one or \nother of the transmitters are difficult to predict, and will \ndepend greatly on the relative strength of the various excitatory and inhibitory synaptic connections, and on external inputs ( x and y in the diagram). Added to this \ncomplexity is the influence of glial cells, mentioned previously.\nA further important complicating factor is that a range \nof secondary, adaptive responses is generally set in train by any drug-induced perturbation of the system. Typically, an increase in transmitter release, or interference with \ntransmitter reuptake, is countered by inhibition of transmit -\nter synthesis, enhanced transporter expression or decreased \nreceptor expression. These changes, which involve altered \ngene expression, generally take time (hours, days or weeks) \nto develop and are not evident in acute pharmacological experiments.\nIn the clinical situation, the effects of psychotropic drugs \noften take weeks to develop, so it is likely that they reflect adaptive responses and slowly developing changes in \nperception rather than the immediate pharmacodynamic \neffects of the drug. This is well", "start_char_idx": 0, "end_char_idx": 3685, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "88d1d145-2281-45e9-b443-1d2aa411405a": {"__data__": {"id_": "88d1d145-2281-45e9-b443-1d2aa411405a", "embedding": null, "metadata": {"page_label": "489", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "75bc9aac-619e-486d-b3b9-46e5ea82f0cc", "node_type": null, "metadata": {"page_label": "489", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39ca67726e587e1d89955af99f9d6d830b872388b8a2745b631848edced4b4a5"}, "2": {"node_id": "dbc84f8b-dae9-401d-907a-1ac129cb736d", "node_type": null, "metadata": {"page_label": "489", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b7fdc5c8015826f4df8bb31c1f8876825afad69ee0939c426a8121bb47348d9f"}}, "hash": "6f0b02b45dfca5d9e5ffd9f0ebec64ed910e78a929ac2abc8337da63d2515a12", "text": "\nperception rather than the immediate pharmacodynamic \neffects of the drug. This is well documented for antipsychotic and antidepressant drugs (Chs 47 and 48). The development of dependence on opioids, benzodiazepines and psycho -\nstimulants is similarly gradual in onset (Ch. 50). Thus one has to take into account not only the primary interaction of the drug with its target, but also the longer-term second -\nary response of the brain to this primary effect; it is often \n3\n2 1 yxcb\nba\na\naaFig. 38.2 Simplified scheme of neuronal \ninterconnections in the central nervous system. \nNeurons 1, 2 and 3 are shown releasing transmitters a, b \nand c, respectively, which may be excitatory or inhibitory. \nBoutons\tof \tneuron \t1 terminate on neuron 2, but also on \nneuron 1 itself, and on presynaptic terminals of other \nneurons that make synaptic connections with neuron 1. \nNeuron 2 also feeds back on neuron 1 via interneuron 3. \nTransmitters \t(x and y) released by other neurons are also \nshown impinging on neuron 1. Even with such a simple \nnetwork, the effects of drug-induced interference with \nspecific transmitter systems can be difficult to predict. Drug action in the central \nnervous system \n\u2022\tThe\tbasic \ttypes \tof \tdrug \ttarget \t(ion \tchannels, \t\nreceptors, enzymes and transporter proteins) \ndescribed in Chapter 3 apply in the central nervous system, as elsewhere.\n\u2022\tMost\tof \tthese \ttargets \toccur \tin \tseveral \tdifferent \t\nmolecular isoforms, giving rise to subtle differences in function and pharmacology.\n\u2022\tMany\tof \tthe \tcurrently \tavailable \tneuroactive \tdrugs \tare \t\nrelatively non-specific, affecting several different targets, the principal ones being receptors, ion channels and transporters.\n\u2022\tThe\trelationship \tbetween \tthe \tpharmacological \tprofile \t\nand the therapeutic effect of neuroactive drugs is often unclear.\n\u2022\tSlowly\tdeveloping \tsecondary \tresponses \tto \tthe \tprimary \t\ninteraction of the drug with its target are often important (e.g. the delayed efficacy of antidepressant drugs, and tolerance and dependence with opioids).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3597, "end_char_idx": 6136, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bf090f23-e16a-48d1-a2e9-c25d029f5667": {"__data__": {"id_": "bf090f23-e16a-48d1-a2e9-c25d029f5667", "embedding": null, "metadata": {"page_label": "490", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e6e6b521-0007-4d47-849b-14e1ce997dd7", "node_type": null, "metadata": {"page_label": "490", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a7764b66d27e6eef3e18ec4f394a1294ac03dc89e6fcf73b7559a04755d0c6c"}, "3": {"node_id": "ab30ceac-14e6-4335-984a-a6210459de25", "node_type": null, "metadata": {"page_label": "490", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "88bced7089f7d6e73a8effa80620c85bb31e7a7197972dca9434115c5077e87d"}}, "hash": "b3d2c4ed12b103cc6ca0c6991e19593539212582bd482430aa2ac59dc17590ae", "text": "38 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n484manic depressive psychosis, and ketamine (see Ch. 42), \nwhich is classed as a dissociative anaesthetic but produces \npsychotropic effects rather similar to those produced by \nphencyclidine (PCP, Ch. 49).\nTable 38.2 provides a general classification of centrally \nacting drugs. In practice, the use of drugs in psychiatric illness frequently cuts across specific therapeutic categories. For example, it is common for antipsychotic drugs to be \nused as \u2018tranquillisers\u2019 to pacify extremely anxious or unruly \npatients, or to treat bipolar depression (Ch. 48). Antidepres -\nsant drugs are often used to treat anxiety (Ch. 45) and neuropathic pain (Ch. 43), and certain psychostimulants \nare of proven efficacy for treating hyperactive children (Ch. \n49). Here we will adhere to the conventional pharmacological categories, but it needs to be emphasised that in clinical \nuse these distinctions are often disregarded.THE CLASSIFICATION OF \nPSYCHOTROPIC DRUGS\nPsychotropic drugs are defined as those that affect mood \nand behaviour. Because these indices of brain function are \ndifficult to define and measure, there is no consistent basis \nfor classifying psychotropic drugs. Instead, we find a confusing m\u00eal\u00e9e of terms relating to chemical structure \n(benzodiazepines, butyrophenones, etc.), biochemical target \n(monoamine oxidase inhibitors, serotonin reuptake inhibitors, \netc.), behavioural effect ( hallucinogens , psychomotor stimulants ) \nor clinical use ( antidepressants, antipsychotic agents, anti-\nepileptic drugs , etc.), together with a number of indefinable \nrogue categories ( atypical antipsychotic drugs , nootropic drugs ) \nthrown in for good measure.\nSome drugs defy classification in this scheme, for example \nlithium (see Ch. 48), which is used in the treatment of Table 38.2 General classification of drugs acting on the central nervous system\nClass Definition ExamplesSee \nchapter\nGeneral anaesthetic agents Drugs used to produce surgical \nanaesthesiaIsoflurane, desflurane, propofol, etomidate 42\nAnalgesic drugsDrugs used clinically for controlling painOpiates\nNeuropathic pain \u2013 carbamazepine, \ngabapentin, amitriptyline, duloxetine43\nAnxiolytics and sedatives Drugs that reduce anxiety and cause sleepBenzodiazepines (e.g. diazepam, \nchlordiazepoxide, flurazepam, clonazepam)45\nAnti-epileptic drugsSynonym: anticonvulsantsDrugs used to reduce seizures Carbamazepine, valproate, lamotrigine 46\nAntipsychotic drugsSynonym: antischizophrenic drugsDrugs used to relieve the symptoms of schizophrenic illnessClozapine, haloperidol, risperidone 47\nAntidepressant drugs Drugs that alleviate the symptoms of depressive illnessSelective serotonin reuptake inhibitors, tricyclic \nantidepressants, monoamine oxidase inhibitors48\nPsychomotor stimulants Synonym: psychostimulantsDrugs that cause wakefulness and euphoriaAmphetamine, cocaine, methylphenidate, \ncaffeine49\nPsychotomimetic drugsSynonym: hallucinogensDrugs that cause disturbance of perception (particularly visual hallucinations) and of behaviour in ways that cannot be simply characterised as sedative or stimulant effectsLysergic acid diethylamide, mescaline, MDMA \n(ecstasy)49\nCognition enhancersSynonym: nootropic drugsDrugs that improve memory and cognitive performanceAcetylcholinesterase inhibitors: donepezil, \ngalantamine, rivastigmine41\nNMDA receptor antagonists: memantine\nOthers: piracetam,", "start_char_idx": 0, "end_char_idx": 3412, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ab30ceac-14e6-4335-984a-a6210459de25": {"__data__": {"id_": "ab30ceac-14e6-4335-984a-a6210459de25", "embedding": null, "metadata": {"page_label": "490", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e6e6b521-0007-4d47-849b-14e1ce997dd7", "node_type": null, "metadata": {"page_label": "490", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a7764b66d27e6eef3e18ec4f394a1294ac03dc89e6fcf73b7559a04755d0c6c"}, "2": {"node_id": "bf090f23-e16a-48d1-a2e9-c25d029f5667", "node_type": null, "metadata": {"page_label": "490", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3d2c4ed12b103cc6ca0c6991e19593539212582bd482430aa2ac59dc17590ae"}}, "hash": "88bced7089f7d6e73a8effa80620c85bb31e7a7197972dca9434115c5077e87d", "text": "receptor antagonists: memantine\nOthers: piracetam, modafinil39\nNMDA, N-methyl-D-aspartate.\nREFERENCES AND FURTHER READING\nIversen,\tL.L., \tIversen, \tS.D., \tBloom, \tF.E., \tRoth, \tR.H., \t2009. \tIntroduction \t\nto Neuropsychopharmacology. Oxford University Press, New York. \n(Excellent and readable account focusing on basic rather than clinical \naspects)Kandel, E., Schwartz, J.H., Jessell, T.M., 2013. Principles of \nNeural Science, fifth ed. Elsevier, New York. (Excellent and \ndetailed standard text on neurobiology \u2013 little emphasis on \npharmacology)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3362, "end_char_idx": 4394, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "749407bb-b8ca-464c-b27e-03104da3c38a": {"__data__": {"id_": "749407bb-b8ca-464c-b27e-03104da3c38a", "embedding": null, "metadata": {"page_label": "491", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6320fa5f-f3e5-4a16-9fd7-6be49257980e", "node_type": null, "metadata": {"page_label": "491", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "babecb9bd618f374d92b8a9310a64076c0163d3b0a57a4f01682e2bdea8be88f"}}, "hash": "babecb9bd618f374d92b8a9310a64076c0163d3b0a57a4f01682e2bdea8be88f", "text": "38 ChEMiCal TRaNSMiSSiON aNd dRUg aCTiON iN ThE CENTRal NERVOUS SYSTEM\n485Linnet, K., Ejsing, T.B., 2008. A review on the impact of P-glycoprotein on \nthe penetration of drugs into the brain. Focus on psychotropic drugs. \nEur. Neuropsychopharmacol. 18, 157\u2013169. ( Review of how P-glycoprotein \ncan limit the brain concentration of antidepressant and antipsychotic drugs )\nMatsas,\tR.,\tTsacopolous,\t M.,\t2013.\tThe\tfunctional\t roles\tof\tglial\tcells\tin\t\nhealth and disease: dialogue between glia and neurons. Adv. Exp. \nBiol. Med. 468. ( This volume contains a number of chapters on the \nemerging view of glial cell function )Nestler,\t E.J.,\tHyman,\t S.E.,\tHolzman,\t M.,\tMalenka,\t R.C.,\t2015.\tMolecular\t\nNeuropharmacology, third ed. McGraw-Hill, New York. ( Good \ntextbook )\nVasile,\tF.,\tDossi,\tE.,\tRouach,\t N.,\t2017.\tHuman\tastrocytes:\t structure\t and\t\nfunction in the healthy brain. Brain Struct. Funct. 222, 2017\u20132029. \n(Informative review )\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1416, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "30f77fa8-9c8f-4697-9575-5a4aeccaa6bd": {"__data__": {"id_": "30f77fa8-9c8f-4697-9575-5a4aeccaa6bd", "embedding": null, "metadata": {"page_label": "492", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7a39621e-7e24-46fb-b5b5-8624b7a664e1", "node_type": null, "metadata": {"page_label": "492", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "604280425071d867ddce9fd358dedcddde2d76e33a25d3ad037ce18c226a74ff"}, "3": {"node_id": "235c4ba7-5af9-453c-81fa-ebd8d713ffbb", "node_type": null, "metadata": {"page_label": "492", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b39e0bfb8c9945e2f1909f4ff58e545e671790ff05cd69156b7e46e0f1f96fa3"}}, "hash": "1c7876efdf9a61389dc9d72fdf531c377c9590f06d63817510b8c33fac3cc1c4", "text": "486\nAmino acid transmitters39 NERVOUS SYSTEM SECTION 4\nOVERVIEW\nIn this chapter we discuss the major neurotransmit -\nters in the central nervous system (CNS), namely the \nexcitatory transmitter, glutamate, and the inhibitory \ntransmitters, GABA and glycine. It is an area in which scientific interest has been intense in recent \nyears. Unravelling the complexities of amino acid \nreceptors and signalling mechanisms has thrown considerable light on their role in brain function and \ntheir likely involvement in CNS disease. Drugs that \ntarget specific receptors and transporters have been developed, but translating this knowledge into drugs \nfor therapeutic use is only now beginning to happen. \nHere, we present the pharmacological principles and include recent references for those seeking more \ndetail.\nEXCITATORY AMINO ACIDS\nEXCITATORY AMINO ACIDS AS \nCNS TRANSMITTERS\nL-Glutamate is the principal and ubiquitous excitatory \ntransmitter in the central nervous system.\n\u25bc The realisation of glutamate\u2019s importance came slowly (see \nWatkins & Jane, 2006). By the 1950s, work on the peripheral nervous \nsystem had highlighted the transmitter roles of acetylcholine and \ncatecholamines and, as the brain also contained these substances, there \nseemed little reason to look further. The presence of \u03b3-aminobutyric \nacid (GABA; see p. 493) in the brain, and its powerful inhibitory \neffect on neurons, were discovered in the 1950s, and its transmitter \nrole was postulated. At the same time, work by Curtis\u2019s group in Canberra showed that glutamate and various other acidic amino acids \nproduced a strong excitatory effect, but it seemed inconceivable that \nsuch workaday metabolites could actually be transmitters. Through \nthe 1960s, GABA and excitatory amino acids (EAAs) were thought, \neven by their discoverers, to be mere pharmacological curiosities. In the 1970s, the humblest amino acid, glycine, was established as \nan inhibitory transmitter in the spinal cord, giving the lie to the \nidea that transmitters had to be exotic molecules, too beautiful for any role but to sink into the arms of a receptor. Once glycine had \nbeen accepted, the rest quickly followed. A major advance was the \ndiscovery of EAA antagonists, based on the work of Watkins in Bristol, which enabled the physiological role of glutamate to be established \nunequivocally, and also led to the realisation that EAA receptors are \nheterogeneous.\nTo do justice to the wealth of discovery in this field in the past 25 \nyears is beyond the range of this book; for more detail see Traynelis \net al. (2010) and Nicoletti et al. (2011). Here we concentrate on \npharmacological aspects. With regard to novel drug development, many promising new compounds interacting with EAAs commenced \ndevelopment for the treatment of a wide range of neurological and \npsychiatric disorders but have failed because of lack of efficacy or adverse effects, and only a few drugs\n1 have made it into clinical use. \nThe field has yet to make a major impact on therapeutics. The major \nproblem has been that EAA-mediated neurotransmission is ubiquitous \nin the brain and so agonist and antagonist drugs exert effects at many sites, giving rise not only to therapeutically beneficial effects, but also \nto other, unwanted, harmful effects.\nMETABOLISM AND RELEASE OF EXCITATORY \nAMINO ACIDS\nGlutamate is widely and fairly uniformly distributed in the \nCNS, where its concentration is much higher than in other \ntissues. It has an important metabolic role, the metabolic \nand neurotransmitter pools being linked by transaminase enzymes that catalyse the interconversion of glutamate and", "start_char_idx": 0, "end_char_idx": 3636, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "235c4ba7-5af9-453c-81fa-ebd8d713ffbb": {"__data__": {"id_": "235c4ba7-5af9-453c-81fa-ebd8d713ffbb", "embedding": null, "metadata": {"page_label": "492", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7a39621e-7e24-46fb-b5b5-8624b7a664e1", "node_type": null, "metadata": {"page_label": "492", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "604280425071d867ddce9fd358dedcddde2d76e33a25d3ad037ce18c226a74ff"}, "2": {"node_id": "30f77fa8-9c8f-4697-9575-5a4aeccaa6bd", "node_type": null, "metadata": {"page_label": "492", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c7876efdf9a61389dc9d72fdf531c377c9590f06d63817510b8c33fac3cc1c4"}}, "hash": "b39e0bfb8c9945e2f1909f4ff58e545e671790ff05cd69156b7e46e0f1f96fa3", "text": "linked by transaminase enzymes that catalyse the interconversion of glutamate and \n\u03b1-ketoglutarate (Fig. 39.1). Glutamate in the CNS comes \nmainly from either glucose, via the Krebs cycle, or glutamine, which is synthesised by glial cells and taken up by the \nneurons; very little comes from the periphery. The intercon -\nnection between the pathways for the synthesis of EAAs \nand inhibitory amino acids (GABA and glycine), shown in Fig. 39.1, makes it difficult to use experimental manipula -\ntions of transmitter synthesis to study the functional role of individual amino acids, because disturbance of any one step will affect both excitatory and inhibitory mediators.\nIn common with other fast neurotransmitters, glutamate is \nstored in synaptic vesicles and released by Ca\n2+-dependent \nexocytosis; specific transporter proteins account for its \nuptake by neurons and other cells, and for its accumulation \nby synaptic vesicles (see Ch. 13). Released glutamate is taken up into nerve terminals and neighbouring astrocytes (Fig. \n39.2) by Na\n+/H+/K+ dependent transporters (cf. monoamine \ntransporters \u2013 Chs 13 and 14), and transported into synaptic vesicles, by a different transporter driven by the proton \ngradient across the vesicle membrane. Several EAA trans-porters have been cloned and characterised in detail (see \nJensen et al., 2015). Glutamate transport can, under some \ncircumstances (e.g. depolarisation by increased extracellular [K\n+]), operate in reverse and constitute a source of glutamate \nrelease, a process that may occur under pathological condi -\ntions such as brain ischaemia (see Ch. 41). Glutamate taken up by astrocytes is converted to glutamine and recycled, via transporters, back to the neurons, which convert the \nglutamine back to glutamate (see Fig. 39.2). Glutamine, \nwhich lacks the pharmacological activity of glutamate, thus serves as a pool of inactive transmitter under the regulatory \ncontrol of the astrocytes, which act as ball boys, returning \n1Perampanel, a non-competitive AMPA receptor antagonist, has been \napproved for the treatment of epilepsy (Ch. 46). Memantine, an NMDA \nantagonist, licensed for the treatment of moderate to severe Alzheimer\u2019s \ndisease (Ch. 41), has been used for some time, as has the dissociative anaesthetic ketamine, an NMDA channel blocker (Ch. 42).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3555, "end_char_idx": 6363, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d35fc882-eb72-4db6-af09-797b2906238f": {"__data__": {"id_": "d35fc882-eb72-4db6-af09-797b2906238f", "embedding": null, "metadata": {"page_label": "493", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ade4fa21-fdd3-459a-9f8b-8d3a08fc7e0a", "node_type": null, "metadata": {"page_label": "493", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e1fd66ab5cc3344ac7bf1412e5f8e80e236c98437698cbd9c412ed87042a85e2"}, "3": {"node_id": "95400e49-a559-4ed0-aed0-476031306c1f", "node_type": null, "metadata": {"page_label": "493", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9cd3c52adf6bd12a823f7329f5148b25446b2c8899525fc715b763b7e8fd04ef"}}, "hash": "f2dc3eeceb3982c5311e82d7d424e8f72738af374edbef51da029ea7fc867f2f", "text": "39 AMiNO A cid TRANSM i TTERS\n487situation with monoamine synthesis and transport (Chs \n15 and 40), few drugs (none in clinical use) are known that \ninterfere specifically with glutamate metabolism.\nGLUTAMATE\nGLUTAMATE RECEPTOR SUBTYPES\nGlutamate and related EAAs, such as aspartate and homo -\ncysteate, activate both ionotropic (ligand-gated cation channels) and metabotropic (G protein\u2013coupled) receptors \n(see Ch. 3 for a general description of ionotropic and metabotropic receptors).\nIONOTROPIC GLUTAMATE RECEPTORS\nOn the basis of studies with selective agonists and antagonists (Fig. 39.3 and Table 39.1), three main subtypes of ionotropic \nreceptors for glutamate can be distinguished: NMDA , AMPA \nand kainate\n2 receptors, named originally according to their \nspecific agonists. These ligand-gated channels comprise four subunits, each with the \u2018pore loop\u2019 structure shown in Fig. \n3.5 (Ch. 3). There are some 16 different receptor subunits and their nomenclature has, until recently, been somewhat \nconfusing.\n3 Here, in this brief, general description, we use \nthe International Union of Basic and Clinical Pharmacology (IUPHAR) recommended terminology because it simplifies \nthe subject considerably, but beware confusion when reading older papers. NMDA receptors are heteromers assembled \nfrom seven types of subunit (GluN1, GluN2A, GluN2B, \nGluN2C, GluN2D, GluN3A, GluN3B). The subunits com -\nprising AMPA receptors (GluA1\u20134) and kainate receptors \n(GluK1\u20135) are closely related to, but distinct from, GluN \nsubunits. AMPA and kainite receptors can be homomeric or heteromeric. Receptors comprising different subunits can have different pharmacological and physiological charac -\nteristics, e.g. AMPA receptors lacking the GluA2 subunit have much higher permeability to Ca\n2+ than the others, \nwhich has important functional consequences (see Ch. 4). \nAMPA receptor subunits are also subject to other kinds \nof variation, namely alternative splicing, giving rise to the engagingly named flip and flop variants, RNA editing at the \nsingle amino acid level, and associated auxiliary subunits, all of which contribute yet more functional diversity to this diverse family.\nAMPA receptors, and in certain brain regions kainate \nreceptors, serve to mediate fast excitatory synaptic transmis -\nsion in the CNS \u2013 absolutely essential for our brains to function. NMDA receptors (which often coexist with AMPA \nreceptors) contribute a slow component to the excitatory \nsynaptic potential (Fig. 39.4B), the magnitude of which varies in different pathways. NMDA, kainate and AMPA \nreceptors are also expressed on nerve terminals where they \ncan enhance or reduce transmitter release.\n4 AMPA receptors \nthe ammunition in harmless form in order to rearm the neurons.\nThere may be value in developing enhancers and inhibi -\ntors of glutamate uptake for the treatment of CNS disorders in which the level of extracellular glutamate may be abnormal, e.g. neurodegeneration (see Ch. 41), schizophrenia \n(see Ch. 47) and depression (see Ch. 48). In contrast to the GABAGAD\nGABA-T TransaminaseGlutaminase\nTransaminaseGlyoxylate\nGlycine \u03b1-Ketoglutarate\nSuccinateSuccinic\nsemialdehyde\nAspartate OxaloacetateGlutamine\nGlutamine\nsynthase\nTRICARBOXYLIC\nACID\nCYCLEGlutamate\nFig. 39.1 ", "start_char_idx": 0, "end_char_idx": 3270, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "95400e49-a559-4ed0-aed0-476031306c1f": {"__data__": {"id_": "95400e49-a559-4ed0-aed0-476031306c1f", "embedding": null, "metadata": {"page_label": "493", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ade4fa21-fdd3-459a-9f8b-8d3a08fc7e0a", "node_type": null, "metadata": {"page_label": "493", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e1fd66ab5cc3344ac7bf1412e5f8e80e236c98437698cbd9c412ed87042a85e2"}, "2": {"node_id": "d35fc882-eb72-4db6-af09-797b2906238f", "node_type": null, "metadata": {"page_label": "493", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f2dc3eeceb3982c5311e82d7d424e8f72738af374edbef51da029ea7fc867f2f"}}, "hash": "9cd3c52adf6bd12a823f7329f5148b25446b2c8899525fc715b763b7e8fd04ef", "text": "39.1 Metabolism of transmitter amino acids in the \nbrain. Transmitter substances are marked with green boxes . \nGABA-T, GABA transaminase; GAD, glutamic acid \ndecarboxylase. \nVGluTGlnT\nEAAT\nEAATGlnT\nGlutaminaseGln\nGluGlu\nGlutamine\nsynthaseGln\nGlu\nGlu\nGluNEURON ASTROCYTE\nFig. 39.2 Transport of glutamate (Glu) and glutamine (Gln) \nby neurons and astrocytes. Released glutamate is captured \npartly by neurons and partly by astrocytes, which convert most \nof it to glutamine. EAAT, excitatory amino acid transporter; GlnT, \nglutamine transporter; VGluT, vesicular glutamate transporter. \n2In the past, AMPA and kainate receptors were often lumped together \nas AMPA/kainate or non-NMDA receptors, but they each have distinct \nsubunit compositions and should not be grouped together.\n3An international committee has sought to bring order to the area but, \ndespite the logic of their recommendations, how generally accepted \nthey will be remains to be seen (see Collingridge et al., 2009 and ). Scientists can get very stuck in their ways.\n4In the CNS, presynaptic ligand-gated ion channels such as kainate and \nNMDA receptors as well as nicotinic and P2X receptors (see Ch. 40) control neurotransmitter release. An explanation of how this control can \nbe either facilitatory or inhibitory is given in Khahk and Henderson (2000).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3265, "end_char_idx": 5102, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d2e8838f-a8b6-43ca-b3f5-955091c2cee1": {"__data__": {"id_": "d2e8838f-a8b6-43ca-b3f5-955091c2cee1", "embedding": null, "metadata": {"page_label": "494", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c5ba3c2b-278c-4c6e-94b3-a54d5e583e59", "node_type": null, "metadata": {"page_label": "494", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "005b99ecd8bb6fd1e7cfaeed7f05c2664d894e88946a2b00aa82bf960dbab900"}, "3": {"node_id": "0895fde4-c357-418b-b44c-0cdb1082809c", "node_type": null, "metadata": {"page_label": "494", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "94a812d1a5300a47c3a0ac07006c0a2267d8e6ed4eb6ddd56b62409b34e21a04"}}, "hash": "ef4038b97838dec943b949c849a7b0a56addb90bbb635f7dd420724eced45ebf", "text": "39 SECTION 4 NERVOUS SYSTEM\n488H2NH\nH2NH\nL-Glutamate L-Aspartate\nN\nHH\nH\nNMDAH2NH3C\nCO2HOH\nAMPACO2HCO2H\nN\nH\nKainateH3C\nL-AP-4NH2CO2H\nBaclofenNH2ONHO\nMuscimolGlycineNH2 NH2CO2H\nCO2H\nGABATRANSMITTERS\nSYNTHETIC\nANALOGUESINHIBITORY EXCITATORY\nCO2HC O2HHO2CCO2H\nH2NH\nCO2HPO3H2\nCO2HCO2HO\nN\nCl\nFig. 39.3 Structures of agonists acting on glutamate, GABA and glycine receptors. The receptor specificity of these compounds is \nshown in Tables 39.1 and 39.2. AMPA, ( S)-\u03b1-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; L-AP4, L-2-amino-4-\nphosphonopentanoic acid; NMDA, N-methyl-D-aspartic acid. \nTable 39.1 Properties of ionotropic glutamate receptors\nNMDA AMPA Kainate\nSubunit \ncompositionTetramers consisting of GluN1\u20133 subunitsTetramers consisting of GluA1\u20134 subunits (variants splicing and RNA editing)Tetramers consisting of GluK1\u20135 subunits\nReceptor site Modulatory site (glycine)\nEndogenous agonist(s)GlutamateAspartateGlycineD-SerineGlutamate Glutamate\nOther agonist(s)\naNMDA D-Cycloserine AMPA KainateDomoate\nb\nAntagonist(s)aAP5, CPP 7-Chloro-kynurenic acid, HA-966NBQX NBQXACET\nOther modulatorsPolyamines (e.g. spermine, spermidine)Mg\n2+, Zn2+CyclothiazidePerampanelPiracetamCX-516\u2014\nChannel blockersDizocilpine (MK801)Phencyclidine, ketamineRemacemideMemantineMg\n2+\u2014 \u2014\nEffector mechanismLigand-gated cation channel (slow kinetics, high Ca\n2+ permeability)Ligand-gated cation channel (fast kinetics; channels possessing GluA2 subunits show low Ca\n2+ permeability)Ligand-gated cation channel (fast kinetics, low Ca\n2+ permeability)\nLocation Postsynaptic (some presynaptic, also glial)Wide distributionPostsynaptic (also glial) Pre- and postsynaptic\nFunctionSlow epspSynaptic plasticity (long-term potentiation, long-term depression)ExcitotoxicityFast epspWide distributionFast epspPresynaptic inhibitionLimited distribution\naStructures of experimental compounds can be found in Brauner-Osborne et al. (2002).\nbA neurotoxin from mussels (see Ch. 41).\nACET, -(S)-1-(2-amino-2-carboxyethyl)-3-(2-carboxy-5-phenylthiophene-3-yl-methyl)-5-methylpyrimidine-2,4-dione; AP5, 2-amino-5-\nphosphonopentanoic acid; CPP, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid; CX-516, 1-(quinoxalin-6-ylcarbonyl)-piperidine; \nepsp, excitatory postsynaptic potential; NBQX, 2,3-dihydro-6-nitro-7-sulfamoyl-benzoquinoxaline; NMDA, N-methyl-D-aspartic acid. (Other \nstructures are shown in Fig. 39.3.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2455, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0895fde4-c357-418b-b44c-0cdb1082809c": {"__data__": {"id_": "0895fde4-c357-418b-b44c-0cdb1082809c", "embedding": null, "metadata": {"page_label": "494", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c5ba3c2b-278c-4c6e-94b3-a54d5e583e59", "node_type": null, "metadata": {"page_label": "494", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "005b99ecd8bb6fd1e7cfaeed7f05c2664d894e88946a2b00aa82bf960dbab900"}, "2": {"node_id": "d2e8838f-a8b6-43ca-b3f5-955091c2cee1", "node_type": null, "metadata": {"page_label": "494", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef4038b97838dec943b949c849a7b0a56addb90bbb635f7dd420724eced45ebf"}}, "hash": "94a812d1a5300a47c3a0ac07006c0a2267d8e6ed4eb6ddd56b62409b34e21a04", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2408, "end_char_idx": 2871, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "43e45e40-fede-492c-9332-1858c94e8642": {"__data__": {"id_": "43e45e40-fede-492c-9332-1858c94e8642", "embedding": null, "metadata": {"page_label": "495", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e141a14e-c6a7-488e-b761-956334ac2e30", "node_type": null, "metadata": {"page_label": "495", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6781a9f641f039d7e39713dc59e518de252f70a4fb29414cd37f0a340b122719"}, "3": {"node_id": "fc9b2eed-5bb3-454f-9884-d77dda2804c2", "node_type": null, "metadata": {"page_label": "495", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db4d3da07e9c5fba5a74ddd59a45de8ad62b6a9c6eaab6e10cba1c404cdb8fa2"}}, "hash": "db27d7dec94e49963feeb1a81b4c11ac6e67cc18492dfb28a7afe488b244b846", "text": "39 AMiNO A cid TRANSM i TTERS\n489occur on astrocytes as well as on neurons, and these cells \nplay an important role in communication in the brain.\nBinding studies show that ionotropic glutamate receptors \nare most abundant in the cortex, basal ganglia and sensory pathways. NMDA and AMPA receptors are generally \nco-localised, but kainate receptors have a much more \nrestricted distribution. Expression of the many different receptor subtypes in the brain also shows distinct regional \ndifferences, but we have hardly begun to understand the \nsignificance of this extreme organisational complexity.\nSpecial features of NMDA receptors\nNMDA receptors and their associated channels have been studied in more detail than the other types and show special \nAfterBefore BeforeAPV Control\n10 ms0.5 mV\n100150200250\n60 45 30 15 0Conditioning train\nMinutesControlepsp amplitude (% control)\nCNQX (5 \u00b5mol/L)CNQX (5 \u00b5mol/L)\nAPV (50 \u00b5mol/L)Control\n50 ms20 mVAPVAfterA\nB\nFig. 39.4 Effects of excitatory amino acid receptor \nantagonists on synaptic transmission. (A) AP5 ( N-methyl-D-\naspartic acid [NMDA] antagonist) prevents long-term potentiation \n(LTP) in the rat hippocampus without affecting the fast excitatory postsynaptic potential (epsp). Top records show the extracellularly recorded fast epsp (downward deflection) before, \nand 50 min after, a conditioning train of stimuli (100 Hz for 2 s). \nThe presence of LTP in the control preparation is indicated by the increase in epsp amplitude. In the presence of AP5 \n(50 \u00b5mol/L), the normal epsp is unchanged, but LTP does not \noccur. Lower trace shows epsp amplitude as a function of time. The conditioning train produces a short-lasting increase in epsp amplitude, which still occurs in the presence of AP5, but the long-lasting effect is prevented. (B) Block of fast and slow components of epsp by CNQX (6-cyano-7-nitroquinoxaline-2,3-dione; AMPA receptor antagonist) and AP5 (NMDA receptor antagonist). The epsp (upward deflection) in a hippocampal \nneuron recorded with intracellular electrode is partly blocked by \nCNQX (5 \u00b5mol/L), leaving behind a slow component, which is \nblocked by AP5 (50 \u00b5mol/L). (Panel [A] from Malinow, R., \nMadison, D., Tsien, R.W., 1988. Nature 335, 821; panel [B] from Andreasen, M., Lambert, J. D., Jensen, M. S., 1989. J. Physiol. 414, 317\u2013336.)GlutamateGlycine\nPolyamines\nNMDA receptorNa+\nCa2+\nMg2+NMDA\nantagonists\nChannel-blocking\ndrugsGlycine\nantagonists\nPolyamine\nantagonistsRECEPTOR\nSITEMODULATORY\nSITES\nGABAA receptorCl\u2212\nGABAGABA\nantagonists\nChannel-blocking\ndrugsBenzodiazepine\nagonists\nAntagonists\nBenzodiazepine\ninverse agonists\n\u2018Channel\nmodulators\u2019RECEPTOR\nSITEMODULATORY\nSITE\nFig. 39.5 Main sites of drug action on N-methyl-D-\naspartic acid (NMDA) and GABA A receptors. Both receptors \nare multimeric ligand-gated ion channels. Drugs can act as agonists or antagonists at the neurotransmitter receptor site or at modulatory sites associated with the receptor. They can also act to block the ion channel at one or more distinct sites. In the case of the GABA\nA receptor, the mechanism by which \u2018channel", "start_char_idx": 0, "end_char_idx": 3103, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fc9b2eed-5bb3-454f-9884-d77dda2804c2": {"__data__": {"id_": "fc9b2eed-5bb3-454f-9884-d77dda2804c2", "embedding": null, "metadata": {"page_label": "495", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e141a14e-c6a7-488e-b761-956334ac2e30", "node_type": null, "metadata": {"page_label": "495", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6781a9f641f039d7e39713dc59e518de252f70a4fb29414cd37f0a340b122719"}, "2": {"node_id": "43e45e40-fede-492c-9332-1858c94e8642", "node_type": null, "metadata": {"page_label": "495", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db27d7dec94e49963feeb1a81b4c11ac6e67cc18492dfb28a7afe488b244b846"}}, "hash": "db4d3da07e9c5fba5a74ddd59a45de8ad62b6a9c6eaab6e10cba1c404cdb8fa2", "text": "the case of the GABA\nA receptor, the mechanism by which \u2018channel \nmodulators\u2019 (e.g. ethanol, anaesthetic agents, neurosteroids) facilitate channel opening is uncertain; they may affect both ligand-binding and channel sites. The location of the different binding sites shown in the figure is largely imaginary, although study of mutated receptors is revealing where they actually reside. Examples of the different drug classes are given in Tables 39.1 and 39.3. \npharmacological properties, summarised in Fig. 39.5, that are \npostulated to play a role in pathophysiological mechanisms.\n\u2022\tThey\tare \thighly \tpermeable \tto \tCa2+, as well as to other \ncations, so activation of NMDA receptors is \nparticularly effective in promoting Ca2+ entry.\n\u2022\tThey\tare \treadily \tblocked \tby \tMg2+, and this block \nshows marked voltage dependence. It occurs at mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3039, "end_char_idx": 4360, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1eeb523c-eca8-4cde-9bd8-2e90e653650c": {"__data__": {"id_": "1eeb523c-eca8-4cde-9bd8-2e90e653650c", "embedding": null, "metadata": {"page_label": "496", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d6c5149c-a967-4043-98e6-8466ac2de86e", "node_type": null, "metadata": {"page_label": "496", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c283af50239921b359850bc2e6974b75a2209219067a1cb8d7471ea0d19048e9"}, "3": {"node_id": "bce40c4d-5fc0-4f4d-b5b6-2eac81aa2b75", "node_type": null, "metadata": {"page_label": "496", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "45cee60eca5f55a6738b85bd06ebbf678451e628149b3a6abbbfab687db3f323"}}, "hash": "7bf548d0ddadd47f950030ca02264135c134bb21a3f424120666e00bb502f8bf", "text": "39 SECTION 4 NERVOUS SYSTEM\n490selectivity have been discovered (Zhu & Paoletti, \n2015).\n\u2022\tAspartate and homocysteate activate NMDA receptors and may be endogenous activators in certain brain regions.\n\u2022\tSome\twell-known \tanaesthetic \tand \tpsychotomimetic \t\nagents, such as ketamine (Ch. 42) and phencyclidine (Ch. 49), are selective blocking agents for \nNMDA-operated channels. The experimental \ncompound dizocilpine shares this property.\nMETABOTROPIC GLUTAMATE RECEPTORS\nThere are eight different metabotropic glutamate receptors (mGlu\n1\u20138) which are unusual in showing no sequence \nhomology with other G protein\u2013coupled receptors (Ferraguti \n& Shigemoto, 2006). They function as homo- and heterodi -\nmers6 (see Ch. 3) cross-linked by a disulfide bridge across \nthe extracellular domain of each protein (see Goudet et al., \n2009). They are members of class C G protein\u2013coupled receptors, possessing a large extracellular N-terminus \ndomain that forms a Venus fly trap-like structure into which \nglutamate binds. They can be divided into three groups on the basis of their sequence homology, G protein coupling \nand pharmacology (Table 39.2). Alternatively, spliced \nreceptor variants have been reported.\nmGlu receptors are widely distributed throughout the \nCNS (see Ferraguti & Shigemoto, 2006) on neurons, where they regulate cell excitability and synaptic transmission, and on glia. Neuronal group 1 mGlu receptors are located postsynaptically and are largely excitatory. By raising \nintracellular [Ca\n2+], they modify responses through physiological Mg2+ concentrations when the cell is \nnormally polarised, but disappears if the cell is depolarised.\n\u2022\tActivation \tof \tNMDA \treceptors \trequires \tglycine \tas \t\nwell as glutamate (Fig. 39.6). The binding site for \nglycine is distinct from the glutamate binding site, i.e. \nglycine is an allosteric modulator (see Ch. 2), and both \nhave to be occupied for the channel to open. This discovery by Johnson and Ascher caused a stir, \nbecause glycine had hitherto been recognised as an \ninhibitory transmitter (see p. 497), so to find it facilitating excitation ran counter to the prevailing \ndoctrine. The concentration of glycine required \ndepends on the subunit composition of the NMDA receptor: for some NMDA receptor subtypes, physiological variation of the glycine concentration \nmay serve as a regulatory mechanism, whereas others \nare fully activated at all physiological glycine concentrations. Competitive antagonists at the glycine \nsite (see Table 39.1) indirectly inhibit the action of \nglutamate. D-serine, somewhat surprisingly,\n5 may \nalso function as an endogenous activator of the \nglycine site on the NMDA receptor.\n\u2022\tSome\tendogenous \tpolyamines \t(e.g. \tspermine, \nspermidine) act at an allosteric site distinct from that of glycine to facilitate channel opening. The \nexperimental drugs ifenprodil and eliprodil block their action.\n\u2022\tOther\tallosteric \tsites \thave \tbeen \tidentified \ton \tthe \t\nNMDA receptor and positive and negative allosteric modulators with novel patterns of GluN2 subunit \n5Surprising, because it is the \u2018wrong\u2019 enantiomer for amino acids of \nhigher organisms. Nevertheless, vertebrates possess specific enzymes \nand transporters for this D-amino acid, which is abundant in the brain.6It has been suggested that mGlu receptors may form heterodimers with \nnon mGlu receptors such as the 5-HT 2A", "start_char_idx": 0, "end_char_idx": 3386, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bce40c4d-5fc0-4f4d-b5b6-2eac81aa2b75": {"__data__": {"id_": "bce40c4d-5fc0-4f4d-b5b6-2eac81aa2b75", "embedding": null, "metadata": {"page_label": "496", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d6c5149c-a967-4043-98e6-8466ac2de86e", "node_type": null, "metadata": {"page_label": "496", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c283af50239921b359850bc2e6974b75a2209219067a1cb8d7471ea0d19048e9"}, "2": {"node_id": "1eeb523c-eca8-4cde-9bd8-2e90e653650c", "node_type": null, "metadata": {"page_label": "496", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7bf548d0ddadd47f950030ca02264135c134bb21a3f424120666e00bb502f8bf"}}, "hash": "45cee60eca5f55a6738b85bd06ebbf678451e628149b3a6abbbfab687db3f323", "text": "with \nnon mGlu receptors such as the 5-HT 2A receptor (Gonz\u00e1lez-Maeso et al., \n2008).Kai\n+ GlyKaiQuis\n+ Gly QuisGlu\n+ GlyGluNMDA\n+ Gly Gly NMDA\n5 s100 pAA B\nC D\nFig. 39.6 Facilitation of N-methyl-D-aspartic acid (NMDA) by glycine. Recordings from mouse brain neurons in culture (whole-cell \npatch clamp technique). Downward deflections represent inward current through excitatory amino acid-activated ion channels. (A) NMDA \n(10 \u00b5mol/L) or glycine (1 \u00b5mol/L) applied separately had little or no effect, but together produced a response. (B) The response to \nglutamate (Glu,10 \u00b5mol/L) was strongly potentiated by glycine (Gly, 1 \u00b5mol/L). (C and D) Responses of AMPA and kainate receptors to \nquisqualate (Quis) and kainate (Kai) were unaffected by glycine. (From Johnson, J.W., Ascher, P., 1987. Glycine potentiates the NMDA \nresponse in cultured mouse brain neurons. Nature 325, 529\u2013531.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3342, "end_char_idx": 4715, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ae07f997-c440-414d-8284-c46faf5acbe5": {"__data__": {"id_": "ae07f997-c440-414d-8284-c46faf5acbe5", "embedding": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "57ea7ac2-7e22-4a51-82e2-d12bb9d444dc", "node_type": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a84077ed51f5ebe35e0ee4dcacc9aacdef250cd4a176ddb54e4cebfe42fb857c"}, "3": {"node_id": "872064ff-1e7e-493e-afcb-b5de0bd00cd8", "node_type": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9be6b629e4c626eb893514a4eb1796eaae10f991d50186bc9fd5c3e5aa047840"}}, "hash": "a9628b0c6725231b83b07fb60578f5e93d25f4c0c7f2916d8a919114f37ff524", "text": "39 AMiNO A cid TRANSM i TTERS\n491has been argued that \u2018learning\u2019, in the synaptic sense, can occur if \nsynaptic strength is enhanced following simultaneous activity in both \npre- and postsynaptic neurons. LTP shows this characteristic; it does \nnot occur if presynaptic activity fails to excite the postsynaptic neuron, or if the latter is activated independently, for instance by a different \npresynaptic input. The mechanisms underlying both LTP and LTD \ndiffer somewhat at different synapses in the brain (see Bear et al., \n2015). Here only a brief, generic view of the underlying events is \ngiven. LTP initiation may involve both presynaptic and postsynaptic \ncomponents, and results from enhanced activation of postsynaptic \nAMPA receptors at glutamatergic synapses and (probably) to enhanced glutamate release (although the argument rumbles on about whether \nincreased transmitter release does or does not occur in LTP; see Nicoll, \n2017). The response of postsynaptic AMPA receptors to glutamate is \nincreased due to phosphorylation of the AMPA receptor subunits by \nkinases such as Ca\n2+/calmodulin-dependent protein kinase (CaMKII) \nand protein kinase C (PKC), thus enhancing their conductance, as well as to increased expression and trafficking of AMPA receptors \nto synaptic sites. LTD, on the other hand, results from modest Ca\n2+ \nentry into the cell activating phosphatases that reduce AMPA receptor \nphosphorylation and enhance AMPA receptor internalisation (see \nConnor & Wang, 2016).\nLTP is reduced by agents that block the synthesis or effects of \nnitric oxide or arachidonic acid. These mediators (see Chs 18 and 21) may act as retrograde messengers through which events in the \npostsynaptic cell are able to influence the presynaptic nerve terminal. \nEndogenous cannabinoids released by the postsynaptic cell, may also act as retrograde messengers to enhance glutamate release (see Chs 20 \nand 40).\nTwo special properties of the NMDA receptor underlie its involvement \nin LTP, namely voltage-dependent channel block by Mg\n2+ and its \nhigh Ca2+ permeability. At normal membrane potentials, the NMDA \nchannel is blocked by Mg2+; a sustained postsynaptic depolarisation \nproduced by glutamate acting repeatedly on AMPA receptors, however, removes the Mg\n2+ block, and NMDA receptor activation then allows \nCa2+ to enter the cell. Activation of group 1 mGlu receptors also \ncontributes to the increase in [Ca2+]i. This rise in [Ca2+]i in the post -\nsynaptic cell activates protein kinases, phospholipases and nitric oxide synthase, which act jointly with other cellular processes to facilitate \ntransmission via AMPA receptors. Initially, during the induction phase of LTP, phosphorylation of AMPA receptors increases their \nresponsiveness to glutamate. Later, during the maintenance phase, \nmore AMPA receptors are recruited to the membrane of postsynaptic dendritic spines as a result of altered receptor trafficking; later still, \nvarious other mediators and signalling pathways are activated, causing \nstructural changes and leading to a permanent increase in the number \nof synaptic contacts.\nThe general descriptions of LTP and LTD given earlier are intended \nto provide the uninitiated reader with an overview of the topic. There \nare subtle differences in their forms and in the mechanisms underlying \nthem at different synapses in the CNS. How LTP and LTD, in all of their guises, relate to different forms of memory is slowly being worked \nout (see Kessels & Malinow, 2009 ; Connor & Wang, 2016). Thus there \nis hope that drugs capable of modifying LTP and LTD may improve learning and memory.\nDRUGS", "start_char_idx": 0, "end_char_idx": 3628, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "872064ff-1e7e-493e-afcb-b5de0bd00cd8": {"__data__": {"id_": "872064ff-1e7e-493e-afcb-b5de0bd00cd8", "embedding": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "57ea7ac2-7e22-4a51-82e2-d12bb9d444dc", "node_type": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a84077ed51f5ebe35e0ee4dcacc9aacdef250cd4a176ddb54e4cebfe42fb857c"}, "2": {"node_id": "ae07f997-c440-414d-8284-c46faf5acbe5", "node_type": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a9628b0c6725231b83b07fb60578f5e93d25f4c0c7f2916d8a919114f37ff524"}, "3": {"node_id": "a2729c9d-d0fc-4c24-9af5-6089def794ff", "node_type": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "981cf9b3fcdf2a4768c5045acf15b7e764e48ec63fb92d855d495d83a7d1b184"}}, "hash": "9be6b629e4c626eb893514a4eb1796eaae10f991d50186bc9fd5c3e5aa047840", "text": "capable of modifying LTP and LTD may improve learning and memory.\nDRUGS ACTING ON GLUTAMATE RECEPTORS\nANTAGONISTS AND NEGATIVE MODULATORS\nInotropic glutamate receptor antagonists\nThe main types and examples of ionotropic glutamate \nantagonists are shown in Table 39.1. They are selective for \nthe main receptor types but generally not for specific \nsubtypes. Many of these compounds, although very useful as experimental tools in vitro, are unable to penetrate the \nblood\u2013brain barrier, so they are not effective when given \nsystemically.\nNMDA receptors, as discussed before, require glycine \nas well as NMDA to activate them, so blocking the glycine site is an alternative way to produce antagonism. Kynurenic Table 39.2 Metabotropic glutamate receptors\nGroup 1 Group 2 Group 3\nMembers mGlu 1, mGlu 5 mGlu 2, mGlu 3mGlu 4, \nmGlu 6,a \nmGlu 7, \nmGlu 8\nG protein \ncouplingGq Gi/Go Gi/Go\nAgonistDHPGCHPG\nb EglumegadcL-AP4(S)-3,4-DCPG\nd\nAntagonist LY367385e\nS-4-CPGLY341495 CPPG\nNeuronal locationSomatodendriticSomatodendritic and nerve terminalsNerve terminals\namGlu 6 is found only in the retina.\nbmGlu 5 selective.\ncFormerly known as LY354740.\ndmGlu 8 selective.\nemGlu 1 selective.\nCHPG, (RS)-2-chloro-5-hydroxyphenylglycine; CPPG, (RS)- \u03b1-\ncyclopropyl-4-phosphonophenylglycine; DHPG, \n3,5-dihydroxyphenylglycine; L-AP4, 2-amino-4-\nphosphonobutyrate; (S)-3,4-DCPG, (S)-3,4-\ndicarboxyphenylglycine; S-4-CPG, (S)-4-carboxyphenylglycine.\nionotropic glutamate receptors (Fig. 39.7). Group 2 and 3 \nmGlu receptors are mostly presynaptic receptors and their \nactivation tends to reduce synaptic transmission and \nneuronal excitability. They can be autoreceptors, involved in reducing glutamate release or heteroreceptors, e.g. when \npresent on GABA-containing terminals.\nSYNAPTIC PLASTICITY AND LONG-TERM \nPOTENTIATION\n\u25bc As well as participating in synaptic transmission, glutamate \nreceptors play a role in long-term adaptive and pathological changes \nin the brain, and are of particular interest as potential drug targets.\nIn this context, two aspects of glutamate receptor function are of \nparticular pathophysiological importance, namely synaptic plasticity, \ndiscussed here, and excitotoxicity (discussed in Ch. 41).\nSynaptic plasticity is a general term used to describe long-term changes \nin synaptic connectivity and efficacy, either following physiological \nalterations in neuronal activity (as in learning and memory), or resulting \nfrom pathological disturbances (as in epilepsy, chronic pain or drug \ndependence). Synaptic plasticity underlies much of what we call \u2018brain \nfunction\u2019, allowing it to be influenced by past experience. Needless to say, no single mechanism is responsible; however, one significant \nand much-studied component is long-term potentiation (LTP), a phe-\nnomenon in which AMPA and NMDA receptors play a central role.\nLTP (see Bear et al., 2015; Bliss & Cooke, 2011) is a prolonged (hours \nin vitro, days or weeks in vivo) enhancement of synaptic transmission \nthat occurs at various CNS synapses following a short (conditioning) \nburst of", "start_char_idx": 3568, "end_char_idx": 6637, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a2729c9d-d0fc-4c24-9af5-6089def794ff": {"__data__": {"id_": "a2729c9d-d0fc-4c24-9af5-6089def794ff", "embedding": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "57ea7ac2-7e22-4a51-82e2-d12bb9d444dc", "node_type": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a84077ed51f5ebe35e0ee4dcacc9aacdef250cd4a176ddb54e4cebfe42fb857c"}, "2": {"node_id": "872064ff-1e7e-493e-afcb-b5de0bd00cd8", "node_type": null, "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9be6b629e4c626eb893514a4eb1796eaae10f991d50186bc9fd5c3e5aa047840"}}, "hash": "981cf9b3fcdf2a4768c5045acf15b7e764e48ec63fb92d855d495d83a7d1b184", "text": "occurs at various CNS synapses following a short (conditioning) \nburst of high-frequency presynaptic stimulation. Its counterpart is \nlong-term depression (LTD), which is produced at some synapses by a longer train of stimuli at lower frequency (see Massey & Bashir, \n2007; Bliss & Cooke, 2011). These phenomena have been studied at various synapses in the CNS, most especially in the hippocampus, which plays a central role in learning and memory (see Fig. 39.4). It mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6625, "end_char_idx": 7572, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0335c563-7c2e-4d7c-83f1-e55068b34454": {"__data__": {"id_": "0335c563-7c2e-4d7c-83f1-e55068b34454", "embedding": null, "metadata": {"page_label": "498", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "32ffde5c-b016-4163-b482-9f3e4308eb58", "node_type": null, "metadata": {"page_label": "498", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b5a6c18e8fb0d00ae4a92d2d58547c36585f185724928b2091e8f5f5da561400"}, "3": {"node_id": "5262362d-2916-4443-8edf-f0590784d342", "node_type": null, "metadata": {"page_label": "498", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e16a1d9349ec9cdd298218f8414808eaced370c70123b0bf23f1c12b534f0a7d"}}, "hash": "d119d0b1d37ddef2dd25a57d9d7114e1b444999acb6a8c75c029dc25f64da30a", "text": "39 SECTION 4 NERVOUS SYSTEM\n492as in the treatment of epilepsy (Ch. 46) and Alzheimer\u2019s \ndisease (Ch. 41). They have also been considered for indica -\ntions such as drug dependence (Ch. 50), schizophrenia (Ch. \n47) and depression (Ch. 48). Trials with NMDA antagonists \nand channel blockers have so far proved disappointing, and \na serious drawback of these agents is their tendency to cause \nhallucinatory and other disturbances (also a feature of phen -\ncyclidine; Ch. 49). Only two NMDA receptor antagonists, acid and the more potent analogue 7-chloro-kynurenic \nacid act in this way. Another site of block is the channel \nitself, where substances such as ketamine, phencyclidine \nand memantine act. These agents are lipid soluble and \nthus able to cross the blood\u2013brain barrier.\nThe potential therapeutic interest in ionotropic glutamate \nreceptor antagonists lies mainly in the reduction of brain \ndamage following strokes and head injury (Ch. 41), as well Depolarisation\n(brief)Depolarisation\n(sustained)\nKinase\nactivation\nCaMKII\nPKC\n(other kinases)\nAltered gene expression,\nStructural alterationsNa+\nDendritic\nspine\nDendriteMg2+G\nNa+Na+Na+Na+\nMg2+\nCa2+PI IP3\nNOS\nArg NOCa+\nEXCITATIONEXCITATION\nPhosphorylation\nand insertion of\nAMPA channelsG\nRetrograde\nmessage\nAMPA mGlu1 NMDAAfter conditioning train\n\u2022 AMPA, NMDA, mGlu1 receptors activated\n\u2022 increased [Ca2+]i\n\u2022 Activation of CaMKII, PKC and NOSNormal transmission\n\u2022 only AMPA receptors activatedA B\nFig. 39.7 Mechanisms of long-term potentiation. (A) With infrequent synaptic activity, glutamate (G) activates mainly AMPA receptors. \nThere is insufficient glutamate to activate metabotropic receptors, and N-methyl-D-aspartic acid NMDA receptor channels are blocked by \nMg2+. (B) After a conditioning train of stimuli, enough glutamate is released to activate metabotropic receptors, and NMDA channels are \nunblocked by the sustained depolarisation. The resulting increase in [Ca2+]i activates various enzymes, including the following: \n\u2022\t Ca2+/calmodulin-dependent protein kinase (CaMKII) and protein kinase C (PKC) phosphorylate various proteins, including AMPA \nreceptors (causing them to be trafficked to areas of synaptic contact on dendritic spines and facilitation of transmitter action) and other \nsignal transduction molecules controlling gene transcription (not shown) in the postsynaptic cell.\n\u2022\t Nitric\toxide\tsynthase\t(NOS);\trelease\tof\tnitric\toxide\t(NO)\tfacilitates\t glutamate\t release\t(retrograde\t signalling,\t otherwise\t known\tas\tNO\t\nturning back).\n\u2022\t Phospholipase\t A2 (not shown) catalyses the formation of arachidonic acid (Ch. 18), a retrograde messenger that increases presynaptic \nglutamate release.\n\u2022\t A\tphospholipase\t (NAPE-PLD,\t not\tshown)\tthat\tcatalyses\t production\t of\tthe\tendocannabinoids\t (Ch.\t20)\tthat\tact\tas\tretrograde\t\nmessengers to enhance glutamate release.\n\u2022\t Brain-derived\t neurotrophic\t factor\t(BDNF)\treleased\tfrom\tnerve\tterminals\t and\tpostsynaptic\t structures\t (not\tshown)\tplays\ta\tmultimodal\t role\t\nin the early and later stages of LTP. Arg, Arginine; IP3, inositol", "start_char_idx": 0, "end_char_idx": 3068, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5262362d-2916-4443-8edf-f0590784d342": {"__data__": {"id_": "5262362d-2916-4443-8edf-f0590784d342", "embedding": null, "metadata": {"page_label": "498", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "32ffde5c-b016-4163-b482-9f3e4308eb58", "node_type": null, "metadata": {"page_label": "498", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b5a6c18e8fb0d00ae4a92d2d58547c36585f185724928b2091e8f5f5da561400"}, "2": {"node_id": "0335c563-7c2e-4d7c-83f1-e55068b34454", "node_type": null, "metadata": {"page_label": "498", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d119d0b1d37ddef2dd25a57d9d7114e1b444999acb6a8c75c029dc25f64da30a"}}, "hash": "e16a1d9349ec9cdd298218f8414808eaced370c70123b0bf23f1c12b534f0a7d", "text": "and later stages of LTP. Arg, Arginine; IP3, inositol (1,4,5) trisphosphate; NO, nitric oxide; PI, phosphatidylinositol. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3015, "end_char_idx": 3615, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8295accd-af00-4fcf-b890-84e34613793e": {"__data__": {"id_": "8295accd-af00-4fcf-b890-84e34613793e", "embedding": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4fd8461f-640b-41e3-a871-ff1d9f01ec61", "node_type": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "440495c6bd8df25a6aac4e87d47416491ba9f5cec1af0d639b87a9fb8ce93c7e"}, "3": {"node_id": "0b49f314-9421-4338-bd2a-bf1d2fc10007", "node_type": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dc85de5a4965484cde530ea7c5735c4764f126df2d1e6acdf0a2cba8557a5542"}}, "hash": "cbb8e4e1f1c620a8b5ab3300a21e55399ea7224fe51b46afaed3e09b2223194a", "text": "39 AMiNO A cid TRANSM i TTERS\n493thought to have therapeutic potential as cognition enhancers \n(nootropics or \u2018smart drugs\u2019) and for the treatment of \nschizophrenia, depression, attention deficit hyperactivity \ndisorder (ADHD) and Parkinson\u2019s disease (see Lynch, 2006) but so far clinical trials have been disappointing. A more \nrecently developed ampakine, CX1739, is in clinical trial \nfor the treatment of drug-induced respiratory depression. Inhibition of the glycine transporter GlyT1 leads to an \nelevation of extracellular glycine levels throughout the brain \nand, through potentiation of NMDA receptor-mediated responses, could be beneficial in the treatment of various neurological disorders (see Harvey & Yee, 2013).\nMetabotropic glutamate receptors\nDeveloping selective agonists of mGlu receptors has proven to be quite difficult; recently, selective positive \nallosteric modulators have been developed (see Nicoletti \net al., 2011). Group 2 and 3 mGlu receptors are located \npresynaptically on nerve terminals and agonists at these \nreceptors decrease glutamate release. Group 2 mGlu agonists \nand positive allosteric modulators were therefore thought \nto have therapeutic potential to decrease neuronal cell death in stroke and in the treatment of epilepsy, but to \ndate clinical trials have been disappointing. Agonists and \npositive allosteric modulators may be useful in treating anxiety as well as in controlling the positive symptoms \nof schizophrenia. Group 3 mGlu receptor positive allos -\nteric modulators may be useful in treating anxiety and \nParkinson\u2019s disease.\n\u03b3-AMINOBUTYRIC ACID (GABA)\nGABA is the main inhibitory transmitter in the brain. In \nthe spinal cord and brain stem, glycine is also important \n(see p. 497).\nSYNTHESIS, STORAGE AND FUNCTION\nGABA occurs in brain tissue but not in other mammalian \ntissues, except in trace amounts. It is particularly abundant \n(about 10 \u00b5mol/g tissue) in the nigrostriatal system, but \noccurs at lower concentrations (2\u20135 \u00b5mol/g) throughout \nthe grey matter.\nGABA is formed from glutamate (see Fig. 39.1) by the \naction of glutamic acid decarboxylase (GAD), an enzyme found only in GABA-synthesising neurons in the brain.\n8 \nImmunohistochemical labelling of GAD is used to map the \nGABA pathways in the brain. GABAergic neurons and \nastrocytes take up GABA via specific transporters, thus removing GABA after it has been released. GAT1 is the \npredominant GABA transporter in the brain and is located \nprimarily on GABAergic nerve terminals where it recycles GABA. GAT3 is located predominantly on astrocytes around \nthe GABAergic synapse. GABA transport is inhibited by \nguvacine, nipecotic acid and tiagabine. Tiagabine is used \nto treat epilepsy (Ch. 46). In astrocytes GABA can be destroyed by a transamination reaction in which the amino \ngroup is transferred to \u03b1-oxoglutaric acid (to yield gluta -\nmate), with the production of succinic semialdehyde and ketamine (anaesthesia, analgesia and depression; see Chs \n42, 43 and 48) and memantine (Alzheimer\u2019s disease; Ch. 41), are in clinical use. Ketamine is also used for its psychoac -\ntive properties (see Ch. 49) inducing feelings akin to an \u2018out-of-body\u2019 experience (going \u2018through the K-hole\u2019). It is possible that antagonists selective for NMDA receptors \ncontaining the GluN2B subunit, which is highly", "start_char_idx": 0, "end_char_idx": 3335, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0b49f314-9421-4338-bd2a-bf1d2fc10007": {"__data__": {"id_": "0b49f314-9421-4338-bd2a-bf1d2fc10007", "embedding": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4fd8461f-640b-41e3-a871-ff1d9f01ec61", "node_type": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "440495c6bd8df25a6aac4e87d47416491ba9f5cec1af0d639b87a9fb8ce93c7e"}, "2": {"node_id": "8295accd-af00-4fcf-b890-84e34613793e", "node_type": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cbb8e4e1f1c620a8b5ab3300a21e55399ea7224fe51b46afaed3e09b2223194a"}, "3": {"node_id": "2fe4aac7-e942-491b-b9e3-e387b5a891df", "node_type": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6983fa0cecd694fc68d5fec81cea9875e24b2f91f63010310fb6782a1a6965e5"}}, "hash": "dc85de5a4965484cde530ea7c5735c4764f126df2d1e6acdf0a2cba8557a5542", "text": "for NMDA receptors \ncontaining the GluN2B subunit, which is highly Ca\n2+ perme -\nable, may be effective for treating neurodegeneration and have fewer CNS side effects. The non-competitive AMPA \nreceptor antagonist perampanel has been introduced as an \nanti-epileptic drug (see Ch. 46). The prospects for kainate \nreceptor antagonists appear promising \u2013 antagonists for \nGluK1 have shown potential for the treatment of pain, \nmigraine, epilepsy, stroke and anxiety (see Jane et al., \n2009).\nOverall, the promise foreseen for ionotropic glutamate \nreceptor antagonists in the clinic has been less successful than was hoped. The problem may be that glutamate is \nsuch a ubiquitous and multifunctional mediator \u2013 involved, \nit seems, in almost every aspect of brain function \u2013 that attempting to improve a specific malfunction by flooding \nthe brain with a compound that affects the glutamate system \nin some way is just too crude a strategy. The new hope is that subunit selective negative allosteric modulators may have fewer side effects than previous generations of \northosteric antagonists.\nMetabotropic glutamate receptor antagonists\nWhile antagonists that discriminate between the different \ngroups of mGlu receptors are available (see Table 39.2), it \nhas proven more difficult to develop selective antagonists \nfor the subtypes within the groups. mGlu receptors, like many G protein\u2013coupled receptors, possess allosteric \nmodulatory sites, which can be either inhibitory or facilita -\ntory (see Ch. 3). Antagonists or negative allosteric modula -\ntors acting at group 1 mGlu receptors have potential for the treatment of fragile X syndrome,\n7 various pain states, \nParkinson\u2019s disease (including the control of levodopa-\ninduced dyskinesias, see Ch. 41), neuroprotection, epilepsy \nand drug abuse; whereas antagonists or negative allosteric modulators of group 2 mGlu receptors have potential as \ncognition enhancers (see Nicoletti et al., 2011).\nAGONISTS AND POSITIVE MODULATORS\nIonotropic glutamate receptors\nVarious agonists at ionotropic glutamate receptors that are used experimentally are shown in Table 39.1. From the \nclinical perspective, interest centres on the theory that \npositive AMPA receptor modulators may improve memory and cognitive performance. Early examples include cyclo -\nthiazide, piracetam (approved for use in certain forms of \nepilepsy, see Ch. 46) and CX-516 ( Ampalex ). These positive \nallosteric modulators, known as ampakines , can act in subtly \ndifferent ways to increase response amplitude, slow deac -\ntivation and attenuate desensitisation of AMPA receptor-mediated currents. They therefore increase AMPA-mediated synaptic responses and enhance LTP as well as up-regulating \nthe production of nerve growth factors such as brain-derived \nneurotrophic factor (BDNF). Originally, ampakines were \n7Fragile X syndrome is caused by mutation of a single gene on the X \nchromosome. It affects about 1 : 4000 children of either sex, causing \nmental retardation, autism and motor disturbances.8It has been suggested that GABA can also be synthesised in the brain \nfrom putrescine by the action of diamine oxidase and aldehyde \ndehydrogenase.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3279, "end_char_idx": 6810, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2fe4aac7-e942-491b-b9e3-e387b5a891df": {"__data__": {"id_": "2fe4aac7-e942-491b-b9e3-e387b5a891df", "embedding": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4fd8461f-640b-41e3-a871-ff1d9f01ec61", "node_type": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "440495c6bd8df25a6aac4e87d47416491ba9f5cec1af0d639b87a9fb8ce93c7e"}, "2": {"node_id": "0b49f314-9421-4338-bd2a-bf1d2fc10007", "node_type": null, "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dc85de5a4965484cde530ea7c5735c4764f126df2d1e6acdf0a2cba8557a5542"}}, "hash": "6983fa0cecd694fc68d5fec81cea9875e24b2f91f63010310fb6782a1a6965e5", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6820, "end_char_idx": 6995, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cbfded63-befa-4959-9336-69364fbf2d3b": {"__data__": {"id_": "cbfded63-befa-4959-9336-69364fbf2d3b", "embedding": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7868f618-471b-4071-bb6b-b026e466b7fc", "node_type": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "28bb3eb7eb3310a8575311357b3fd98aa4c077f7b346a225f57c3b64d984c95f"}, "3": {"node_id": "7c33ca19-cffe-4e65-bea1-3e9cc470406a", "node_type": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b26d280663b98266fede0e97b59674cf34b886e38ad01c5078680a7ece48a034"}}, "hash": "b1f3859803dc4a43edda940140563ea2b65485f7ec53b98ac7e6fbba816006a7", "text": "39 SECTION 4 NERVOUS SYSTEM\n494The widespread distribution of GABA \u2013 GABA serves as \na transmitter at about 30% of all the synapses in the CNS \n\u2013 and the fact that virtually all neurons are sensitive to its \ninhibitory effect suggests that its function is ubiquitous in the brain. That antagonists such as bicuculline induce \nseizures illustrates the important, ongoing inhibitory role of GABA in the brain.\nGABA RECEPTORS: STRUCTURE AND \nPHARMACOLOGY\nGABA acts on two distinct types of receptor: GABA A \nreceptors are ligand-gated ion channels whereas GABA B \nreceptors are G protein\u2013coupled.\nGABA A RECEPTORS\nGABA A receptors9 are members of the cys-loop family of \nreceptors that also includes the glycine, nicotinic and 5-HT 3 \nreceptors (see Ch. 3, Fig. 3.5). The GABA A receptors are \npentamers made up of different subunits.\nThe reader should not despair when informed that 19 \nGABA A receptor subunits have been cloned ( \u03b11\u20136, \u03b21\u20133, \n\u03b31\u20133, \u03b4, \u03b5, \u03b8, \u03c0 and \u03c11\u20133) and that splice variants of some \nsubunits also exist. Although the number of possible \ncombinations is large, only a few dozen have been shown to exist. The most common are \u03b11\u03b22\u03b32 (by far the most \nabundant), \u03b12\u03b23\u03b32 and \u03b13\u03b23\u03b32 subunits. To make up the \npentamer, each receptor contains two \u03b1, two \u03b2 and one \u03b3 \nsubunit arranged in a circle in the sequence \u03b1\u2013\u03b2\u2013\u03b1\u2013\u03b2\u2013\u03b3 \naround the pore when viewed from the extracellular side of the membrane. GABA binds at each of the interfaces between the \u03b1 and \u03b2 subunits whereas benzodiazepines \n(see Ch. 45) bind at the \u03b1/\u03b3 interface. A novel benzodiaz -\nepine binding site at the \u03b1/\u03b2 interface has recently been \ndescribed but its function is unclear at present. Receptors containing different \u03b1 and \u03b3 subunits exhibit differential \nsensitivity to benzodiazepines and mediate different behavioural responses to these drugs. This raises the tantalis -\ning prospect of developing new agents with greater \nselectivity and potentially fewer side effects. The GABA\nA \nreceptor should therefore be thought of as a group of receptors exhibiting subtle differences in their physiological \nand pharmacological properties.\nGABA\nA receptors are primarily located postsynaptically \nand mediate both fast and tonic postsynaptic inhibition. \nThe GABA A channel is selectively permeable to Cl\u2212 and \nbecause the equilibrium membrane potential for Cl\u2212 is \nusually negative to the resting potential, increasing Cl\u2212 per-\nmeability hyperpolarises the cell as Cl\u2212 ions enter, thereby \nreducing its excitability.10 In the postsynaptic cell, GABA A \nreceptors are located both at areas of synaptic contact and extrasynaptically (Fig. 39.8 and see Farrant & Nusser, 2005). \nthen succinic acid. This reaction is catalysed by GABA \ntransaminase, an enzyme located primarily in astrocytes. It is inhibited by vigabatrin, another compound used to \ntreat epilepsy (Ch. 46).\nGABA functions as an inhibitory transmitter in many \ndifferent CNS pathways. About 20% of CNS neurons are GABAergic; most are short interneurons, but there are some \nlong GABAergic tracts, e.g. from the striatum to the sub -\nstantia nigra and globus pallidus (see Ch. 41 and Fig. 41.4). Excitatory amino acids \n\u2022\tGlutamate \tis \tthe \tmain \tfast \texcitatory \ttransmitters \tin \t\nthe central nervous system.\n\u2022\tGlutamate \tis \tformed \tmainly \tfrom \tthe \tKrebs \tcycle", "start_char_idx": 0, "end_char_idx": 3314, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7c33ca19-cffe-4e65-bea1-3e9cc470406a": {"__data__": {"id_": "7c33ca19-cffe-4e65-bea1-3e9cc470406a", "embedding": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7868f618-471b-4071-bb6b-b026e466b7fc", "node_type": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "28bb3eb7eb3310a8575311357b3fd98aa4c077f7b346a225f57c3b64d984c95f"}, "2": {"node_id": "cbfded63-befa-4959-9336-69364fbf2d3b", "node_type": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b1f3859803dc4a43edda940140563ea2b65485f7ec53b98ac7e6fbba816006a7"}, "3": {"node_id": "663f4875-5629-4660-a067-10f17a61712d", "node_type": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "997edd0b01876d56769a3050047a63900a7f451c08c73ba928d4928c3f771b84"}}, "hash": "b26d280663b98266fede0e97b59674cf34b886e38ad01c5078680a7ece48a034", "text": "\tis \tformed \tmainly \tfrom \tthe \tKrebs \tcycle \t\nintermediate \u03b1-ketoglutarate by the action of GABA \ntransaminase.\n\u2022\tThere\tare \tthree \tmain \tionotropic \tglutamate \treceptors \t\nand eight metabotropic receptors.\n\u2022\tN-methyl-D-aspartic acid (NMDA), (S)-\u03b1-amino-3-\nhydroxy-5-methylisoxazole-4-propionic acid (AMPA) \nand kainate receptors are ionotropic receptors \nregulating cation channels.\n\u2022\tThe\tchannels \tcontrolled \tby \tNMDA \treceptors \tare \thighly \t\npermeable to Ca2+ and are blocked by Mg2+.\n\u2022\tAMPA\tand \tkainate \treceptors \tare \tinvolved \tin \tfast \t\nexcitatory transmission; NMDA receptors mediate slower excitatory responses and, through their effect in controlling Ca\n2+ entry, play a more complex role in \ncontrolling synaptic plasticity (e.g. long-term \npotentiation).\n\u2022\tCompetitive \tNMDA \treceptor \tantagonists \tinclude \tAP5 \n(2-amino-5-phosphonopentanoic acid) and CPP \n(3-(2-carboxypirazin-4-yl)-propyl-1-phosphonic acid); the NMDA-operated ion channel is blocked by \nketamine and phencyclidine.\n\u2022\tNBQX (2,3-dihydro-6-nitro-7-sulfamoyl-benzoquinoxaline) is an AMPA and kainate receptor \nantagonist.\n\u2022\tNMDA\treceptors \trequire \tlow \tconcentrations \tof \tglycine \t\nas a co-agonist, in addition to glutamate; \n7-chlorokynurenic acid blocks this action of glycine.\n\u2022\tNMDA\treceptor \tactivation \tis \tincreased \tby \tendogenous \t\npolyamines, such as spermine, acting on a \nmodulatory site that is blocked by ifenprodil.\n\u2022\tThe\tentry \tof \texcessive \tamounts \tof \tCa2+ produced by \nNMDA receptor activation can result in cell death \u2013 excitotoxicity (see Ch. 41).\n\u2022\tMetabotropic \tglutamate \treceptors \t(mGlu 1\u20138) are \ndimeric G protein\u2013coupled receptors. mGlu 1 and \nmGlu 5 receptors couple through G q to inositol \ntrisphosphate formation and intracellular Ca2+ release. \nThey play a part in glutamate-mediated synaptic plasticity and excitotoxicity. The other mGlu receptors \ncouple to G\ni/Go and inhibit neurotransmitter release, \nmost importantly glutamate release.\n\u2022\tSome\tspecific \tmetabotropic \tglutamate \treceptor \t\nagonists and antagonists are available, as are positive \nand negative allosteric modulators.\n9The IUPHAR Nomenclature Committee has recommended (see Olsen \n& Sieghart, 2008) that the receptors previously referred to as \u2018GABA C\u2019 \nreceptors, because they were insensitive to bicuculline, benzodiazepines \nand baclofen, should be subtypes of the GABA A receptor family as they \nare pentameric Cl\u2212-permeable ligand-gated channels comprising \nhomo- or heteromeric assemblies of \u03c1 subunits. They are referred to as GABA\nA-rho or GABA A-\u03c1 receptors. Their pharmacology and functional \nsignificance is slowly being worked out (see Naffaa et al., 2017).\n10During early brain development (in which GABA plays an important \nrole), and also in some regions of the adult brain, GABA has an excitatory rather than an inhibitory effect, because the intracellular \nCl\n\u2212 concentration is relatively high, so that the equilibrium potential is \npositive to the resting membrane potential.mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3277, "end_char_idx": 6309, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "663f4875-5629-4660-a067-10f17a61712d": {"__data__": {"id_": "663f4875-5629-4660-a067-10f17a61712d", "embedding": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7868f618-471b-4071-bb6b-b026e466b7fc", "node_type": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "28bb3eb7eb3310a8575311357b3fd98aa4c077f7b346a225f57c3b64d984c95f"}, "2": {"node_id": "7c33ca19-cffe-4e65-bea1-3e9cc470406a", "node_type": null, "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b26d280663b98266fede0e97b59674cf34b886e38ad01c5078680a7ece48a034"}}, "hash": "997edd0b01876d56769a3050047a63900a7f451c08c73ba928d4928c3f771b84", "text": "potential.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6290, "end_char_idx": 6779, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2b83b099-a5ec-4c1b-82cc-9b8f175eceb4": {"__data__": {"id_": "2b83b099-a5ec-4c1b-82cc-9b8f175eceb4", "embedding": null, "metadata": {"page_label": "501", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ee18826a-548f-4901-8715-7af39e7753bb", "node_type": null, "metadata": {"page_label": "501", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e8dca80bfb8e3ba32f532cc763d2a492ac3bd086c5fa39183735148cd6e3c4b"}, "3": {"node_id": "f38b3875-f105-425b-b007-b45951af1c5f", "node_type": null, "metadata": {"page_label": "501", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ab3cd6d4888d61c2df43fa372796d57c4950500f4471410c53faf78a9adbd89a"}}, "hash": "476a7740335195989ce1bc2f6bd39389a736af337427ef1bc96ac237c7134813", "text": "39 AMiNO A cid TRANSM i TTERS\n495Thus GABA produces inhibition by acting both as a fast \n\u2018point-to-point\u2019 transmitter and as an \u2018action-at-a-distance\u2019 \nneuromodulator, as the extrasynaptic GABA A receptors can \nbe tonically activated by GABA that has diffused away from its site of release. Extrasynaptic GABA\nA receptors \ncontain \u03b14 and \u03b16 subunits as well as the \u03b4 subunit. They \nhave higher affinity for GABA and show less desensitisa -\ntion than synaptic receptors, and are also highly sensitive \nto general anaesthetic agents (see Ch. 42) and ethanol \n(see Ch. 49),\nGABA B RECEPTORS\nGABA B receptors (see Bettler et al., 2004) are located pre- and \npostsynaptically. They are class C G protein\u2013coupled receptors that couple through G\ni/G o to inhibit voltage-gated \nCa2+ channels (thus reducing transmitter release), to open \npotassium channels (thus reducing postsynaptic excitability) \nand to inhibit adenylyl cyclase.\n\u25bc For GABA B receptors, the functional receptor is a dimer (see \nCh. 3) consisting of two different seven-transmembrane subunits, \nB1 and B2, held together by a coil/coil interaction between their \nC-terminal tails. In the absence of B2, the B1 subunit does not traffic to the plasma membrane as it possesses an endoplasmic reticulum \nretention signal. Interaction of B1 with B2 masks the retention signal \nand facilitates trafficking to the membrane. Activation of the dimer results from GABA binding to the extracellular, \u2018Venus fly trap\u2019 domain \nof B1 (even although the B2 subunit possesses a similar domain) \nwhereas it is the B2 subunit that interacts with and activates the G \nprotein (Fig. 39.9). \n \n \n \n \nExtrasynaptic SynapticGABA\n10 pA \n25 s10 pA \n10 ms\nSR95531A\nBC\nFig. 39.8 Synaptic and extrasynaptic GABA A receptors. (A) Diagram depicting GABA A receptors at synaptic and extrasynaptic sites in \nthe plasma membrane. The blue dots represent GABA molecules. (B) Tonic activation of extrasynaptic GABA A receptors gives rise to a \nsteady-state inward current (distance from the baseline indicated by the dashed line) and increased \u2018noise\u2019 on the trace. The current is \nblocked on application of the GABA A receptor antagonist SR95531. (C) Phasic release of GABA from the presynaptic terminal evokes a \nfast synaptic current (rapid downward deflection). Note the different timescales in (B) and (C). (Figure courtesy M. Usowicz.)\nGABAB1RGABA\nGABAB2R\nG protein\nFig. 39.9 Dimeric structure of the GABA B receptor. The \nreceptor is made up of two seven-transmembrane domain \nsubunits held together by a coil/coil interaction between their C-terminal tails. Activation of the receptor occurs when GABA binds to the extracellular domain of the B1 subunit (known as the Venus fly trap, because it snaps shut when GABA binds). This produces an allosteric change in the B2 subunit which is coupled to the G protein. (Adapted from Kubo, Y., Tateyama, M., 2005. Towards a view of functioning dimeric metabotropic receptors. Curr. Opin. Neurobiol. 15, 289\u2013295.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3144, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f38b3875-f105-425b-b007-b45951af1c5f": {"__data__": {"id_": "f38b3875-f105-425b-b007-b45951af1c5f", "embedding": null, "metadata": {"page_label": "501", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ee18826a-548f-4901-8715-7af39e7753bb", "node_type": null, "metadata": {"page_label": "501", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e8dca80bfb8e3ba32f532cc763d2a492ac3bd086c5fa39183735148cd6e3c4b"}, "2": {"node_id": "2b83b099-a5ec-4c1b-82cc-9b8f175eceb4", "node_type": null, "metadata": {"page_label": "501", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "476a7740335195989ce1bc2f6bd39389a736af337427ef1bc96ac237c7134813"}}, "hash": "ab3cd6d4888d61c2df43fa372796d57c4950500f4471410c53faf78a9adbd89a", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3097, "end_char_idx": 3480, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0d29a955-d3d4-47c4-bf5b-aaaaffbd1eab": {"__data__": {"id_": "0d29a955-d3d4-47c4-bf5b-aaaaffbd1eab", "embedding": null, "metadata": {"page_label": "502", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "90dee43c-9eb6-41d0-ac8b-e0f68cacb276", "node_type": null, "metadata": {"page_label": "502", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "959a20256db86e3f71426742341d6acc627214d1ac5c7392e156df80eb2647ad"}, "3": {"node_id": "82d6ba15-8906-445f-9bc9-7f2e26269716", "node_type": null, "metadata": {"page_label": "502", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed9b53495cb24d303dcea3c7b0b9a0686b504e79d15495536082fbca95bc24f7"}}, "hash": "05eb1888bb49221ddae8b4e3fb92eb17453fb43119d6850a25db06da0c598659", "text": "39 SECTION 4 NERVOUS SYSTEM\n496Table 39.3 Properties of inhibitory amino acid receptors\nGABA A\nGABA B Glycine Receptor siteModulatory site \n(benzodiazepine)Modulatory site (others)\nEndogenous \nagonistsGABAUnknown, several postulated (see text)Various neurosteroids (e.g. progesterone metabolites)GABAGlycine\u03b2-AlanineTaurine\nOther agonist(s)MuscimolGaboxadol(THIP,\na a \npartial agonist)Anxiolytic benzodiazepines (e.g. diazepam)Barbiturates\nSteroid anaesthetics \n(e.g. alphaxalone)Baclofen \u2014\nAntagonist(s) BicucullineGabazineFlumazenil (inverse agonist?)\u2014 2-Hydroxy-saclofenCGP 35348 and othersStrychnine\nChannel blocker Picrotoxin\nbNot applicable \u2014\nEffector mechanism(s)Ligand-gated chloride channelG protein\u2013coupled receptor; inhibition of Ca\n2+ channels, \nactivation of K+ channels, \ninhibition of adenylyl cyclaseLigand-gated chloride channel\nLocation Widespread; primarily postsynapticPre- and postsynapticWidespreadPostsynapticMainly in brain stem and spinal cord\nFunction Postsynaptic inhibition (fast ipsp and tonic inhibition)Presynaptic inhibition (decreased Ca\n2+ entry)\nPostsynaptic inhibition (increased K\n+ permeability)Postsynaptic inhibition (fast ipsp)\naTHIP is an abbreviation of the chemical name of gaboxadol. It is reported to have preference for \u03b4 subunit-containing extrasynaptic GABA A \nreceptors.\nbPicrotoxin also blocks some glycine receptors.\nipsp, inhibitory postsynaptic potential.DRUGS ACTING ON GABA RECEPTORSGABA\nA RECEPTORS\nGABA A receptors resemble NMDA receptors in that drugs \nmay act at several different sites (see Fig. 39.5). These \ninclude:\n\u2022\tthe\tGABA-binding \tsite\n\u2022\tseveral \tmodulatory \tsites\n\u2022\tthe\tion \tchannel\nThere is growing evidence that the different receptor \nsubtypes differ in their pharmacological properties.\nGABA A receptors are the target for several important \ncentrally acting drugs, notably benzodiazepines (see Ch. \n45), alcohol (see Ch. 49), barbiturates, neurosteroids (see \nlater, Table 39.3) and many general anaesthetics (see Ch. 42). The main agonists, antagonists and modulatory substances \nthat act on GABA receptors are shown in Table 39.3.\nMuscimol, derived from a hallucinogenic mushroom, \nresembles GABA chemically (see Fig. 39.3) and is a powerful GABA\nA receptor agonist. A synthetic analogue, gaboxadol \nis a partial agonist that was developed as a hypnotic drug (Ch. 45) but has now been withdrawn. Bicuculline , a natu -\nrally occurring convulsant compound, is a specific antagonist \nthat blocks the fast inhibitory synaptic potential in most \nCNS synapses. Gabazine, a synthetic GABA analogue, is similar. These compounds are useful experimental tools \nbut have no therapeutic uses.\nBenzodiazepines , which have powerful sedative, anxio -\nlytic and anticonvulsant effects (see Ch. 45), selectively potentiate the effects of GABA on some GABA\nA receptors \ndepending upon the subunit composition of the receptor. \nThey bind with high affinity to an accessory allosteric site \non the GABA A receptor, in such a way that the binding of \nGABA is facilitated and its agonist effect is enhanced. \nConversely, inverse agonists at the benzodiazepine site (e.g. \nRo15-4513) reduce GABA binding and are anxiogenic and", "start_char_idx": 0, "end_char_idx": 3187, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "82d6ba15-8906-445f-9bc9-7f2e26269716": {"__data__": {"id_": "82d6ba15-8906-445f-9bc9-7f2e26269716", "embedding": null, "metadata": {"page_label": "502", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "90dee43c-9eb6-41d0-ac8b-e0f68cacb276", "node_type": null, "metadata": {"page_label": "502", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "959a20256db86e3f71426742341d6acc627214d1ac5c7392e156df80eb2647ad"}, "2": {"node_id": "0d29a955-d3d4-47c4-bf5b-aaaaffbd1eab", "node_type": null, "metadata": {"page_label": "502", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "05eb1888bb49221ddae8b4e3fb92eb17453fb43119d6850a25db06da0c598659"}}, "hash": "ed9b53495cb24d303dcea3c7b0b9a0686b504e79d15495536082fbca95bc24f7", "text": "\nRo15-4513) reduce GABA binding and are anxiogenic and proconvulsant \u2013 they are unlikely to be therapeutically \nuseful!\nModulators that also enhance the action of GABA, but \nwhose site of action is less well defined than that of benzodiazepines (shown as \u2018channel modulators\u2019 in Fig. \n39.5), include other CNS depressants such as barbiturates, anaesthetic agents (Ch. 42) and neurosteroids. Neurosteroids \n(see Lambert et al., 2009) are compounds that are related \nto steroid hormones but that act to enhance activation of GABA\nA receptors \u2013 those containing \u03b4 subunits appear most \nsensitive. Interestingly, they include metabolites of pro -\ngesterone and androgens that are formed in the nervous system, and are believed to have a physiological role. Synthetic neurosteroids include alphaxalone, developed \nas an anaesthetic agent (Ch. 42).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3133, "end_char_idx": 4455, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "63e97bdd-ca7d-4632-b8fa-e5ad162ba8b2": {"__data__": {"id_": "63e97bdd-ca7d-4632-b8fa-e5ad162ba8b2", "embedding": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "456b5bfe-4173-4f2d-9215-9872ec72401e", "node_type": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "71f1de0dcb07271c6437afa0d5db63100faab798cc5ed5f79a169d5692c392ce"}, "3": {"node_id": "8e2c3a76-b867-4673-912f-160364e6253d", "node_type": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c537d414a0791d9290e959e41f3d94d6b7b6634ef48993fd788dd175155dede"}}, "hash": "fb1aca63d2608389a434ae22f1d6eebe6bf5f2435c8fa1029f78c03c267c05c9", "text": "39 AMiNO A cid TRANSM i TTERS\n497a pattern of distribution very similar to those of glycine, \nbut its action is not blocked by strychnine.\nThe inhibitory effect of glycine is quite distinct from \nits role in facilitating activation of NMDA receptors (see \np. 490).\n\u25bc The glycine receptor (see Dutertre et al., 2012) resembles the GABA A \nreceptor in that it is a cys-loop, pentameric ligand-gated chloride \nchannel. There are no specific metabotropic receptors for glycine. \nFive glycine receptor subunits have been cloned (\u03b11\u20134, \u03b2) and it \nappears that in the adult brain the main form of glycine receptor is \na heteromeric complex of \u03b1 and \u03b2 subunits, probably with a stoichi-\nometry of 2 \u03b1 and 3 \u03b2. Homomers formed of only \u03b1 subunits can form \nand are sensitive to glycine and strychnine, indicating that the binding site for these drugs is on the \u03b1 subunit. They are also much more \nsensitive to channel block by picrotoxin than are receptors comprised \nof \u03b1 and \u03b2 subunits.\nGlycine receptors are involved in the regulation of respiratory rhythms, \nmotor control and muscle tone as well as in the processing of pain \nsignals. Mutations of the receptor have been identified in some inherited \nneurological disorders associated with muscle spasm and reflex hyperexcitability. There are as yet no therapeutic drugs that act \nspecifically by modifying glycine receptors.\nTetanus toxin, a bacterial toxin resembling botulinum \ntoxin (Ch. 14), acts selectively to prevent glycine release \nfrom inhibitory interneurons in the spinal cord, causing \nexcessive reflex hyperexcitability and violent muscle spasms (lockjaw).\n11\nGlycine is removed from the extracellular space by two \ntransporters, GlyT1 and GlyT2 (Eulenburg et al., 2005). \nGlyT1 is located primarily on astrocytes and expressed throughout most regions of the CNS. GlyT2, on the other \nhand is expressed on glycinergic neurons in the spinal cord, \nbrain stem and cerebellum. The GlyT1 inhibitor bitopertin \nfailed in phase III clinical trials for the treatment of negative \nsymptoms of schizophrenia (see Ch. 47). GlyT2 inhibitors \nwere thought to have potential as analgesics.\nCONCLUDING REMARKS\nThe study of amino acids and their receptors in the brain has been one of the most active fields of research in the \npast 30 years, and the amount of information available is \nprodigious. These signalling systems have been speculatively implicated in almost every kind of neurological and psy -\nchiatric disorder, and the pharmaceutical industry has put a great deal of effort into identifying specific ligands \u2013 agonists, antagonists, modulators, enzyme inhibitors, \ntransport inhibitors \u2013 designed to influence them. While a \nlarge number of pharmacologically unimpeachable com -\npounds have emerged, and many clinical trials have been undertaken, due to lack of efficacy and serious adverse \neffects there have been few therapeutic breakthroughs. The \noptimistic view is that a better understanding of the par -\nticular functions of the many molecular subtypes of these \ntargets, and the design of more subtype-specific ligands, \nwill lead to future breakthroughs. Expectations have, however, undoubtedly dimmed in recent years.Picrotoxin, a plant product, is a convulsant that acts by \nblocking the GABA A receptor chloride channel, thus blocking \nthe postsynaptic inhibitory effect of GABA. It also blocks \nglycine receptors. It has no therapeutic uses.\nGABA B RECEPTORS\nWhen the importance of GABA as an inhibitory transmitter \nwas recognised, it was thought that a GABA-like", "start_char_idx": 0, "end_char_idx": 3542, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e2c3a76-b867-4673-912f-160364e6253d": {"__data__": {"id_": "8e2c3a76-b867-4673-912f-160364e6253d", "embedding": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "456b5bfe-4173-4f2d-9215-9872ec72401e", "node_type": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "71f1de0dcb07271c6437afa0d5db63100faab798cc5ed5f79a169d5692c392ce"}, "2": {"node_id": "63e97bdd-ca7d-4632-b8fa-e5ad162ba8b2", "node_type": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb1aca63d2608389a434ae22f1d6eebe6bf5f2435c8fa1029f78c03c267c05c9"}, "3": {"node_id": "72d46f46-dd5c-43c6-9fe9-31c3a8d6e731", "node_type": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53cf289e65a14769f3552cc6c95ee2a999c3731f01e22efe0b4c2e6dc7708673"}}, "hash": "4c537d414a0791d9290e959e41f3d94d6b7b6634ef48993fd788dd175155dede", "text": "an inhibitory transmitter \nwas recognised, it was thought that a GABA-like substance \nmight prove to be effective in controlling epilepsy and \nother convulsive states; because GABA itself fails to pen -\netrate the blood\u2013brain barrier, more lipophilic GABA \nanalogues were sought, one of which, baclofen (see Fig. \n39.3), was introduced in 1972. Unlike GABA, its actions \nare not blocked by bicuculline. These findings led to the \nrecognition of the GABA B receptor, for which baclofen is \na selective agonist. Baclofen is used to treat spasticity and related motor disorders (Ch. 46); it has been tested for \ntreating alcohol and opioid dependence (see Ch. 50) but results so far are inconclusive.\nCompetitive antagonists for the GABA\nB receptor include \na number of experimental compounds (e.g. 2-hydroxy-\nsaclofen and more potent compounds with improved brain penetration, such as CGP 35348). Tests in animals showed that these compounds produce only slight effects \non CNS function (in contrast to the powerful convulsant \neffects of GABA\nA antagonists). The main effect observed, \nparadoxically, was an anti-epileptic action, specifically \nin an animal model of absence seizures (see Ch. 46), \ntogether with enhanced cognitive performance. However, as in many areas of pharmacology, such preclinical \npromise has not resulted in the development of a new \ntherapeutic drug.\n\u03b3-HYDROXYBUTYRATE\n\u03b3-Hydroxybutyrate (sodium oxybate or GHB; see Wong \net al., 2004) occurs naturally in the brain as a side product \nof GABA synthesis. As a synthetic drug it can be used to \ntreat narcolepsy and alcoholism. In addition, it has found \nfavour with bodybuilders, based on its ability to evoke the \nrelease of growth hormone, and with party-goers, based on its euphoric and disinhibitory effects. It is also used as \nan intoxicant and \u2018date rape\u2019 drug, but is fatal in higher \ndoses. In common with many abused drugs (see Ch. 50), it activates \u2018reward pathways\u2019 in the brain, and its use is \nnow illegal in most countries. GHB is an agonist at GABA\nA \nreceptors containing \u03b14 and \u03b4 subunits and a weak partial \nagonist at GABA B receptors. A specific GHB receptor has \nalso been postulated but the evidence for its existence is not yet convincing.\nGLYCINE\nGlycine is an important inhibitory neurotransmitter in the \nspinal cord and brain stem. It is present in particularly \nhigh concentration (5 \u00b5mol/g) in the grey matter of the \nspinal cord. Applied ionophoretically to motor neurons or \ninterneurons, it produces an inhibitory hyperpolarisation \nthat is indistinguishable from the inhibitory synaptic response. Strychnine , a convulsant poison that acts mainly \non the spinal cord, blocks both the synaptic inhibitory response and the response to glycine. This, together with direct measurements of glycine release in response to nerve \nstimulation, provides strong evidence for its physiological \ntransmitter role. \u03b2-Alanine has pharmacological effects and 11Botulinum toxin (also known as botox), then tetanus toxin, hold the \nprize for the two deadliest substances, with LD 50s of ~1 and 3 ng/kg. \nThat means 1 g of each is enough to kill over 8 million people, or 935 g \ncould potentially wipe out the entire global population!!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3479, "end_char_idx": 6934, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "72d46f46-dd5c-43c6-9fe9-31c3a8d6e731": {"__data__": {"id_": "72d46f46-dd5c-43c6-9fe9-31c3a8d6e731", "embedding": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "456b5bfe-4173-4f2d-9215-9872ec72401e", "node_type": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "71f1de0dcb07271c6437afa0d5db63100faab798cc5ed5f79a169d5692c392ce"}, "2": {"node_id": "8e2c3a76-b867-4673-912f-160364e6253d", "node_type": null, "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c537d414a0791d9290e959e41f3d94d6b7b6634ef48993fd788dd175155dede"}}, "hash": "53cf289e65a14769f3552cc6c95ee2a999c3731f01e22efe0b4c2e6dc7708673", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6951, "end_char_idx": 7254, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "16d28f75-0773-4204-aa77-5d62cd6a40ad": {"__data__": {"id_": "16d28f75-0773-4204-aa77-5d62cd6a40ad", "embedding": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "288888be-56cd-4ec1-aa99-2068f429e7d5", "node_type": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "75d796b4167c67f08abecb712f5c557a590b0e33271d17d00720a861dd88c38e"}, "3": {"node_id": "1f3d164c-de35-489e-aef9-596ea8525b8e", "node_type": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7825aa7dffa839032cfdf1e692694722dfcd8e131ab56df99affc7c4b75f66c4"}}, "hash": "1c964bd81144b445af2f659b7ecd28c96261f2eb2d99e5b39b916301f5ec8bbb", "text": "39 SECTION 4 NERVOUS SYSTEM\n498REFERENCES AND FURTHER READING\nExcitatory amino acids\nBr\u00e4uner-Osborne, H., Egebjerg, J., Nielsen, E.\u00d8., Madsen, U., \nKrogsgaard-Larsen, P., 2000. Ligands for glutamate receptors: design \nand therapeutic prospects. J. Med. Chem. 43, 2609\u20132645.\nCollingridge, G.L., Olsen, R.W., Peters, J., Spedding, M., 2009. A \nnomenclature for ligand-gated ion channels. Neuropharmacology 56, \n2\u20135.\nFerraguti, F., Shigemoto, R., 2006. Metabotropic glutamate receptors. \nCell Tissue Res. 326, 483\u2013504.\nGonz\u00e1lez-Maeso, J., Ang, R.L., Yuen, T., et al., 2008. Identification of a \nserotonin/glutamate receptor complex implicated in psychosis. \nNature 452, 93\u201399.\nGoudet, C., Magnaghi, V., Landry, M., et al., 2009. Metabotropic \nreceptors for glutamate and GABA in pain. Brain Res. Rev. 60, \n43\u201356.\nHarvey, R.J., Yee, B.K., 2013. Glycine transporters as novel therapeutic \ntargets in schizophrenia, alcohol dependence and pain. Nat. Rev. \nDrug Discov. 12, 866\u2013885.\nJensen, A.A., Fahlke, C., Bj\u00f8rn-Yoshimoto, W.E., Bunch, L., 2015. \nExcitatory amino acid transporters: recent insights into molecular \nmechanisms, novel modes of modulation and new therapeutic \npossibilities. Curr. Opin. Pharmacol. 20, 116\u2013123.\nJane, D.E., Lodge, D., Collingridge, G.L., 2009. Kainate receptors: \npharmacology, function and therapeutic potential. \nNeuropharmacology 56, 90\u2013113.\nLynch, G., 2006. Glutamate-based therapeutic approaches: ampakines. Curr. \nOpin. Pharmacol. 6, 82\u201388. ( Report of new allosteric sites on NMDA receptors )\nNicoletti, F., Bockaert, J., Collingridge, G.L., et al., 2011. Metabotropic \nglutamate receptors: from the workbench to the bedside. \nNeuropharmacology 60, 1017\u20131041. ( Extensive review of the scientific \ndevelopments in this field and their potential clinical significance in relation \nto the development of new drugs )\nTraynelis, S.F., Wollmuth, L.P., McBain, C.J., et al., 2010. Glutamate \nreceptor ion channels: structure, regulation and function. Pharmacol. \nRev. 62, 405\u2013496.\nWatkins, J.C., Jane, D.E., 2006. The glutamate story. Br. J. Pharmacol. \n147 (Suppl. 1), S100\u2013S108. ( A brief and engaging history by one of the \npioneers in the discovery of glutamate as a CNS transmitter )\nZhu, S., Paoletti, P., 2015. Allosteric modulators of NMDA receptors: \nmultiple sites and mechanisms. Curr. Opin. Pharmacol. 20, 14\u201323. \n(Review of allosteric sites on NMDA receptors )\nInhibitory amino acids\nBettler, B., Kaupmann, K., Mosbacher, J., Gassmann, M., 2004. \nMolecular structure and function of GABA B receptors. Physiol. Rev. \n84, 835\u2013867. ( Comprehensive review article by the team that first cloned the \nGABA B receptor and discovered its unusual heterodimeric structure )Dutertre, S., Becker, C.M., Betz, H., 2012.", "start_char_idx": 0, "end_char_idx": 2749, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1f3d164c-de35-489e-aef9-596ea8525b8e": {"__data__": {"id_": "1f3d164c-de35-489e-aef9-596ea8525b8e", "embedding": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "288888be-56cd-4ec1-aa99-2068f429e7d5", "node_type": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "75d796b4167c67f08abecb712f5c557a590b0e33271d17d00720a861dd88c38e"}, "2": {"node_id": "16d28f75-0773-4204-aa77-5d62cd6a40ad", "node_type": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c964bd81144b445af2f659b7ecd28c96261f2eb2d99e5b39b916301f5ec8bbb"}, "3": {"node_id": "5883cf82-c9ea-4e4a-9653-178537ddd533", "node_type": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "edd3dbbdaeabcbf3547bf55b73601609d34561345468366e483e7f43d1f9d1b9"}}, "hash": "7825aa7dffa839032cfdf1e692694722dfcd8e131ab56df99affc7c4b75f66c4", "text": "S., Becker, C.M., Betz, H., 2012. Inhibitory glycine receptors: \nan update. J. Biol. Chem. 287, 40216\u201340223.\nEulenburg, V., Armsen, W., Betz, H., Gomez, J., 2005. Glycine \ntransporters: essential regulators of neurotransmission. Trends \nBiochem. Sci. 30, 325\u2013333.\nFarrant, M., Nusser, Z., 2005. Variations on an inhibitory theme: phasic \nand tonic activation of GABA A receptors. Nat. Rev. Neurosci. 6, \n215\u2013229.\nLambert, J.J., Cooper, M.A., Simmons, R.D., Weir, C.J., Belelli, D., 2009. \nNeurosteroids: endogenous allosteric modulators of GABA(A) \nreceptors. Psychoneuroendocrinology 34 (Suppl. 1), S48\u2013S58.\nNaffaa, M.M., Hung, S., Chebib, M., Johnston, G.A.R., Hanrahan, J.R., \n2017. GABA- \u03c1 receptors: distinctive functions and molecular \npharmacology. Br. J. Pharmacol. 174, 1881\u20131894.\nOlsen, R.W., Sieghart, W., 2008. International Union of Pharmacology. \nLXX. Subtypes of \u03b3-aminobutyric acid A receptors: classification on the \nbasis of subunit composition, pharmacology, and function. Update. \nPharmacol. Rev. 60, 243\u2013260. ( IUPHAR Nomenclature Subcommittee \nreport containing an extensive discussion of the subtypes of GABA A receptor \ndepending upon subunit composition. It also contains the recommendation \nthat GABA C receptors should be considered as subtypes of the GABA A \nreceptor )\nWong, C.G.T., Gibson, K.M., Snead, O.C., 2004. From street to brain: \nneurobiology of the recreational drug gamma-hydroxybutyric acid. \nTrends Pharmacol. Sci. 25, 29\u201334. ( Short review article )\nPhysiological aspects\nBear, M.F., Connors, B.W., Paradiso, M.A., 2015. Neuroscience: \nExploring the Brain, fourth ed. Lippincott, Williams & Wilkins, \nBaltimore. ( Major neuroscience textbook that discusses in detail long-term \npotentiation and memory mechanisms )\nBliss, T.V., Cooke, S.F., 2011. Long-term potentiation and long-term \ndepression: a clinical perspective. Clinics (Sao Paulo) 66 (Suppl. 1), 3\u201317.\nConnor, S.A., Wang, Y.T., 2016. A place at the table: LTD as a mediator \nof memory genesis. Neuroscientist 22, 359\u2013371. ( An update on the role \nof LTD in memory )\nKessels, H.W., Malinow, R., 2009. Synaptic AMPA receptor plasticity \nand behavior. Neuron 61, 340\u2013350.\nKhahk, B.S., Henderson, G., 2000. Modulation of fast synaptic \ntransmission by presynaptic ligand-gated cation channels. J. Auton. \nNerv. Syst. 81, 110\u2013121. ( Describes how activation of presynaptic \nligand-gated cation channels can either enhance or inhibit neurotransmitter \nrelease )\nMassey, P.V., Bashir, Z.I., 2007. Long-term depression: multiple forms \nand implications for brain function. Trends Neurosci. 30, 176\u2013184.\nNicoll, R.A., 2017. A brief history of long-term potentiation. Neuron 93, \n281\u2013290.Inhibitory amino acids: GABA and glycine \n\u2022\tGABA\tis\tthe\tmain\tinhibitory\ttransmitter\t in\tthe\tbrain.\n\u2022\tIt\tis\tpresent\tfairly\tuniformly\t", "start_char_idx": 2722, "end_char_idx": 5535, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5883cf82-c9ea-4e4a-9653-178537ddd533": {"__data__": {"id_": "5883cf82-c9ea-4e4a-9653-178537ddd533", "embedding": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "288888be-56cd-4ec1-aa99-2068f429e7d5", "node_type": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "75d796b4167c67f08abecb712f5c557a590b0e33271d17d00720a861dd88c38e"}, "2": {"node_id": "1f3d164c-de35-489e-aef9-596ea8525b8e", "node_type": null, "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7825aa7dffa839032cfdf1e692694722dfcd8e131ab56df99affc7c4b75f66c4"}}, "hash": "edd3dbbdaeabcbf3547bf55b73601609d34561345468366e483e7f43d1f9d1b9", "text": "throughout\t the\tbrain;\tthere\tis\t\nvery little in peripheral tissues.\n\u2022\tGABA\tis\tformed\tfrom\tglutamate\t by\tthe\taction\tof\t\nglutamic acid decarboxylase. Its action is terminated \nmainly by reuptake, but also by deamination, catalysed \nby GABA transaminase.\n\u2022\tThere\tare\ttwo\tmain\ttypes\tof\tGABA\treceptor:\t GABA A and \nGABA B.\n\u2022\tGABA A receptors, which occur mainly \npostsynaptically, are directly coupled to chloride \nchannels, the opening of which reduces membrane \nexcitability.\n\u2022\tMuscimol is a specific GABA A agonist, and the \nconvulsant bicuculline is an antagonist.\n\u2022\tOther\tdrugs\tthat\tinteract\twith\tGABA A receptors and \nchannels include:\n\u2013 benzodiazepines, which act at an allosteric binding site \nto facilitate the action of GABA;\u2013 convulsants such as picrotoxin , which block the \nanion channel;\n\u2013 neurosteroids, including endogenous progesterone \nmetabolites;\n\u2013 central nervous system depressants, such as \nbarbiturates and many general anaesthetic agents, \nwhich facilitate the action of GABA.\n\u2022\tGABA B receptors are heterodimeric G protein\u2013coupled \nreceptors. They cause pre- and postsynaptic inhibition \nby inhibiting Ca2+ channel opening and increasing K+ \nconductance. Baclofen is a GABA B receptor agonist \nused to treat spasticity. GABA B antagonists are not in \nclinical use.\n\u2022\tGlycine\t is\tan\tinhibitory\ttransmitter\t mainly\tin\tthe\tspinal\t\ncord, acting on its own receptor, structurally and \nfunctionally similar to the GABA A receptor.\n\u2022\tThe\tconvulsant\t drug\t strychnine is a competitive glycine \nantagonist. Tetanus toxin acts mainly by interfering with \nglycine release.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5564, "end_char_idx": 7630, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4c16e553-57f8-4c96-9f69-6c4bb906a13e": {"__data__": {"id_": "4c16e553-57f8-4c96-9f69-6c4bb906a13e", "embedding": null, "metadata": {"page_label": "505", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "95ef8d6a-ef6f-4a11-b774-6a31b0b888f8", "node_type": null, "metadata": {"page_label": "505", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c13369c82509bd98f2c244664b66827f4dc888c0066d3a6303252607a264dd5"}, "3": {"node_id": "79d048c3-31d2-471c-b65a-afd8cfa1a0d8", "node_type": null, "metadata": {"page_label": "505", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f0fe605df633f3a8aca1c2f413b52d970a5a8f5f443c57633fff261e8f01239"}}, "hash": "63dc4c3aa7709476ae25ff01a3bcd4424faff1c255ee15f4852becbb04daecbb", "text": "499\nOVERVIEW\nThe principal \u2018amine\u2019 transmitters in the central \nnervous system (CNS), namely noradrenaline, dopa -\nmine, 5-hydroxytryptamine (5-HT, serotonin) and acetylcholine (ACh), are described in this chapter, with briefer coverage of other mediators, including hista -\nmine, melatonin and purines. The monoamines were the first CNS transmitters to be identified, and during the 1960s a combination of neurochemistry and \nneuropharmacology led to many important discoveries \nabout their role, and about the ability of drugs to influence these systems. Amine mediators differ from \nthe amino acid transmitters discussed in Chapter 39 \nin being localised to small populations of neurons \nwith cell bodies in the brain stem and basal forebrain, \nwhich project diffusely both rostrally to cortical and \nother areas, and in some cases caudally to the spinal cord. These amine-containing neurons are broadly \nassociated with high-level behaviours (e.g. emotion, \ncognition and awareness), rather than with localised synaptic excitation or inhibition.\n1 More recently, \n\u2018gaseotransmitters\u2019 - such as nitric oxide (NO), carbon \ndioxide and hydrogen sulfide ( Ch. 21 ) - and endocan -\nnabinoids ( Ch. 20 ) have come on the scene, and they \nare discussed at the end of the chapter. The other major class of CNS mediators, the neuropeptides (e.g. \nendorphins, neurokinins and orexins) appear in later chapters in this section.\nINTRODUCTION\nAlthough we know much about the many different media -\ntors, their cognate receptors and signalling mechanisms at \nthe cellular level, when describing their effects on brain \nfunction and behaviour we fall back on relatively crude terms \u2013 psychopharmacologists will be at our throats for \nso under-rating the sophistication of their measurements \n\u2013 such as \u2018motor coordination\u2019, \u2018arousal\u2019, \u2018cognitive impair -\nment\u2019 and \u2018exploratory behaviour\u2019. The gap between these \ntwo levels of understanding still frustrates the best efforts \nto link drug action at the molecular level to drug action at the therapeutic level. Modern approaches, such as the use of transgenic animal technology (see Ch. 8) and non-invasive imaging techniques, are helping to forge links, but there is still a long way to go.\nMore detail on the content of this chapter can be found \nin Iversen et al. (2009) and Nestler et al. (2015).\nNORADRENALINE\nThe basic processes responsible for the synthesis, storage and release of noradrenaline are the same in the CNS \nas in the periphery (Ch. 15). In the CNS, inactivation of \nreleased noradrenaline is by neuronal reuptake or by metabolism, largely through the monamine oxidase, alde-\nhyde reductase and catechol-O-methyl transferase mediated \npathway to 3-hydroxy-4-methoxyphenylglycol (MHPG) (see \nFig. 15.3).\nNORADRENERGIC PATHWAYS IN THE CNS\nAlthough the transmitter role of noradrenaline in the brain was suspected in the 1950s, detailed analysis of its neuronal \ndistribution became possible only when a technique, based \non the formation of fluorescent catecholamine derivatives when tissues are exposed to formaldehyde, was devised \nby Falck and Hillarp. Detailed maps of the pathway of \nnoradrenergic, dopaminergic and serotonergic neurons in laboratory animals were produced and later confirmed in \nhuman brains. The cell bodies of noradrenergic neurons \noccur in small clusters in the pons and medulla, and they \nsend extensively branching axons to many other parts of the brain and spinal cord (Fig. 40.1). The most prominent", "start_char_idx": 0, "end_char_idx": 3491, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "79d048c3-31d2-471c-b65a-afd8cfa1a0d8": {"__data__": {"id_": "79d048c3-31d2-471c-b65a-afd8cfa1a0d8", "embedding": null, "metadata": {"page_label": "505", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "95ef8d6a-ef6f-4a11-b774-6a31b0b888f8", "node_type": null, "metadata": {"page_label": "505", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c13369c82509bd98f2c244664b66827f4dc888c0066d3a6303252607a264dd5"}, "2": {"node_id": "4c16e553-57f8-4c96-9f69-6c4bb906a13e", "node_type": null, "metadata": {"page_label": "505", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "63dc4c3aa7709476ae25ff01a3bcd4424faff1c255ee15f4852becbb04daecbb"}}, "hash": "8f0fe605df633f3a8aca1c2f413b52d970a5a8f5f443c57633fff261e8f01239", "text": "parts of the brain and spinal cord (Fig. 40.1). The most prominent \ncluster is the locus coeruleus (LC), located in the pons. \nAlthough it contains only about 10,000 neurons in humans, the axons, running in a discrete medial forebrain \nbundle, give rise to many millions of noradrenergic nerve \nterminals throughout the cortex, hippocampus, thalamus, hypothalamus and cerebellum. These nerve terminals do \nnot form distinct synaptic contacts but appear to release \ntransmitter somewhat diffusely. The LC also projects to the spinal cord and is involved in the descending control \nof pain (Ch. 43).\nOther noradrenergic neurons lie close to the LC in the \npons and project to the amygdala, hypothalamus, hip -\npocampus and other parts of the forebrain, as well as to the spinal cord. A small cluster of adrenergic neurons, which release adrenaline rather than noradrenaline, lies more \nventrally in the brain stem. These cells contain phenyle -\nthanolamine N-methyl transferase, the enzyme that converts \nnoradrenaline to adrenaline (see Ch. 15), and project mainly \nto the pons, medulla and hypothalamus. Rather little is \nknown about them, but they are believed to be important \nin cardiovascular control.Other transmitters and modulators 40 NERVOUS SYSTEM SECTION 4\n1They are, if you like, voices from the nether regions, which make you \nhappy or sad, sleepy or alert, cautious or adventurous, energetic or \nlazy, although you do not quite know why \u2013 very much the stuff of \nmental illness.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3425, "end_char_idx": 5396, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "14cf9598-ee91-4f98-8a76-3c14ace29516": {"__data__": {"id_": "14cf9598-ee91-4f98-8a76-3c14ace29516", "embedding": null, "metadata": {"page_label": "506", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ef85af9-740e-4229-b599-d8d4e85ce41c", "node_type": null, "metadata": {"page_label": "506", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4cdb3a03e33258ffe2ad73b21eeec276a1c98e59af3dd2797fd0edae37d860d1"}, "3": {"node_id": "6145253a-df1e-4918-88b4-4fbd411cf09c", "node_type": null, "metadata": {"page_label": "506", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86cf61d237ed1b4ea271bea5df9e358cc53d042d8a6ca2084ec7038f9e265cf0"}}, "hash": "619c23f634c23bc9dba62c07faf5d50b4ec17694421bdc886e5dccb52bea0409", "text": "40 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n500Arousal and mood\nAttention has focused mainly on the LC, which is the source \nof most of the noradrenaline released in the brain, and \nfrom which neuronal activity can be measured by implanted \nelectrodes. LC neurons are silent during sleep, and their activity increases with behavioural arousal. \u2018Wake-up\u2019 \nstimuli of an unfamiliar or threatening kind excite these \nneurons much more effectively than familiar stimuli. Amphetamine-like drugs, which release catecholamines in \nthe brain, increase wakefulness, alertness and exploratory \nactivity (although, in this case, firing of LC neurons is actually reduced by feedback mechanisms; see Ch. 49).\nThere is a close relationship between mood and state of \narousal; depressed individuals are typically lethargic and unresponsive to external stimuli. The catecholamine hypothesis of depression (see Ch. 48) suggested that it \nresults from a functional deficiency of noradrenaline in \ncertain parts of the brain, while mania results from an excess. This remains controversial, and subsequent findings suggest \nthat 5-HT may be more important than noradrenaline in \nrelation to mood.\nBlood pressure regulation\nThe role of central, as well as peripheral, noradrenergic synapses in blood pressure control is shown by the action \nof hypotensive drugs such as clonidine and methyldopa \n(see Chs 15 and 23), which decrease the discharge of \nsympathetic nerves emerging from the CNS. They cause \nhypotension when injected locally into the medulla or fourth \nventricle, in much smaller amounts than are required when the drugs are given systemically. Noradrenaline and other \n\u03b1\n2-adrenoceptor agonists have the same effect when injected \nlocally. Noradrenergic synapses in the medulla probably form part of the baroreceptor reflex pathway, because \nstimulation or antagonism of \u03b1\n2 adrenoceptors in this part \nof the brain has a powerful effect on the activity of baro -\nreceptor reflexes.\nAscending noradrenergic fibres run to the hypothalamus, \nand descending fibres run to the lateral horn region of the \nspinal cord, acting to increase sympathetic discharge in \nthe periphery. It has been suggested that these regulatory neurons may release adrenaline rather than noradrenaline \nas inhibition of phenylethanolamine N-methyl transferase, \nthe enzyme that converts noradrenaline to adrenaline, \ninterferes with the baroreceptor reflex.\nMoxonidine and rilmenidine are reported to be I\n1-receptor \nagonists with less activity at \u03b1 2 adrenoceptors; they act \ncentrally to reduce peripheral sympathetic activity, thus \ndecreasing peripheral vascular resistance (see Ch. 23).\nDOPAMINE\nDopamine is particularly important in relation to neuro-\npharmacology, because it is involved in several common \ndisorders of brain function, notably Parkinson\u2019s disease, \nschizophrenia and attention deficit disorder, as well as in drug dependence and certain endocrine disorders. Many \nof the drugs used clinically to treat these conditions work \nby influencing dopamine transmission.\nThe distribution of dopamine in the brain is more \nrestricted than that of noradrenaline. Dopamine is most abundant in the corpus striatum , a part of the extrapyramidal \nmotor system concerned with the coordination of movement (see Ch. 41), and high concentrations also occur in certain FUNCTIONAL ASPECTS\nWith the exception of the \u03b2 3 adrenoceptor, all of the \nadrenoceptors (\u03b1 1A, \u03b11B, \u03b11D, \u03b12A, \u03b12B, \u03b12C, \u03b21 and \u03b22)2 are \nexpressed in the CNS (see Bylund, 2007). They are G \nprotein\u2013coupled receptors that interact with a", "start_char_idx": 0, "end_char_idx": 3568, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6145253a-df1e-4918-88b4-4fbd411cf09c": {"__data__": {"id_": "6145253a-df1e-4918-88b4-4fbd411cf09c", "embedding": null, "metadata": {"page_label": "506", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ef85af9-740e-4229-b599-d8d4e85ce41c", "node_type": null, "metadata": {"page_label": "506", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4cdb3a03e33258ffe2ad73b21eeec276a1c98e59af3dd2797fd0edae37d860d1"}, "2": {"node_id": "14cf9598-ee91-4f98-8a76-3c14ace29516", "node_type": null, "metadata": {"page_label": "506", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "619c23f634c23bc9dba62c07faf5d50b4ec17694421bdc886e5dccb52bea0409"}}, "hash": "86cf61d237ed1b4ea271bea5df9e358cc53d042d8a6ca2084ec7038f9e265cf0", "text": "2007). They are G \nprotein\u2013coupled receptors that interact with a variety of \neffector mechanisms (see Table 15.1). The role of \u03b11 receptors \nin the CNS is poorly understood. They are widely distrib -\nuted, located both on postsynaptic neurons and on glial cells, and may be involved in motor control, cognition and fear. \u03b1\n2 Adrenoceptors are located on noradrenergic neurons \n(in both somatodendritic and nerve terminal regions where \nthey function as inhibitory autoreceptors activated by locally \nreleased noradrenaline), as well as on postsynaptic non-noradrenergic neurons. They are involved in blood pressure \ncontrol (see later), sedation (\n\u03b12 agonists such as medeto-\nmidine are used as anaesthetics in veterinary practice) and \nanalgesia. \u03b21 Receptors are found in the cortex, striatum \nand hippocampus whereas \u03b22 receptors are largely found \nin the cerebellum. They have been implicated in the long-term effects of antidepressant drugs but quite how remains \na mystery (see Ch. 48).\nResearch on the \u03b1\n2-adrenoceptor antagonist idazoxan \nled to the identification of other putative \u2018imidazoline \nreceptors\u2019 (see Nikolic & Agbaba, 2012). These are the I 1 \nreceptor, which plays a role in the central control of blood pressure (see Ch. 23); the I\n2 receptor, which is not a true \npharmacological receptor (see Ch. 1) at all but an allosteric binding site on the enzyme monoamine oxidase, and the \nI\n3 receptor, present in the pancreas with a role in regulating \ninsulin secretion.MFB\nNORADRENALINE\nSpinal cordNTSCHyp\nLTALC\nAmHipThStr\nSep\nFig. 40.1 Simplified diagram of the noradrenaline \npathways in the brain. The location of the main groups of cell \nbodies and fibre tracts is in solid colour . Light-shaded areas \nshow the location of noradrenergic terminals. Am, amygdaloid \nnucleus; C, cerebellum; Hip, hippocampus; Hyp, hypothalamus; \nLC, locus coeruleus; LTA, lateral tegmental area, part of the \nreticular formation; MFB, medial forebrain bundle; NTS, nucleus \nof the tractus solitarius (vagal sensory nucleus); Sep, septum; \nStr, corpus striatum; Th, thalamus. \n2The \u03b11C receptor was subsequently found to be identical to \u03b1 1A \nreceptor.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3503, "end_char_idx": 6141, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "181a4561-5be0-47e5-ba01-aca57604e7c9": {"__data__": {"id_": "181a4561-5be0-47e5-ba01-aca57604e7c9", "embedding": null, "metadata": {"page_label": "507", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a3ad0988-0f22-4a8e-b9e3-1d5897a4ebd5", "node_type": null, "metadata": {"page_label": "507", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bea30235435ac419e595bd90f54f1c32e558edfe96df5e2918e098a28b7cd9c9"}, "3": {"node_id": "b853f3df-d10f-454e-9b38-4f94c449eb3e", "node_type": null, "metadata": {"page_label": "507", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "03ed68daa7af995c4a3cdac8f1d713a126cada2c1f86fe7b217114933ddcd624"}}, "hash": "e6b461a552b6145cdee3f9f4e4f16763233a18353886c407964d417c8a350305", "text": "40 OThER TR a NSM i TTERS a N d MO d U la TORS\n501Noradrenaline in the central \nnervous system \n\u2022\tMechanisms \tfor \tsynthesis, \tstorage, \trelease \tand \t\nreuptake of noradrenaline in the central nervous \nsystem (CNS) are essentially the same as in the periphery, as are the receptors (Ch. 15).\n\u2022\tNoradrenergic \tcell \tbodies \toccur \tin \tdiscrete \tclusters, \t\nmainly in the pons and medulla, one important such cell group being the locus coeruleus.\n\u2022\tNoradrenergic \tpathways, \trunning \tmainly \tin \tthe \tmedial \t\nforebrain bundle and descending spinal tracts, terminate diffusely in the cortex, hippocampus, hypothalamus, cerebellum and spinal cord.\n\u2022\tThe\tactions \tof \tnoradrenaline \tare \tmediated \tthrough \t\u03b11, \n\u03b12, \u03b21 and \u03b22 receptors.\n\u2022\tNoradrenergic \ttransmission \tis \tbelieved \tto \tbe \timportant \t\nin:\n\u2013 the \u2018arousal\u2019 system, controlling wakefulness and \nalertness;\n\u2013 blood pressure regulation;\n\u2013 control of mood (functional deficiency contributing to \ndepression).\n\u2022\tPsychotropic \tdrugs \tthat \tact \tpartly \tor \tmainly \ton \t\nnoradrenergic transmission in the CNS include antidepressants, cocaine and amphetamine. Some \nantihypertensive drugs (e.g. clonidine, methyldopa) \nact mainly on noradrenergic transmission in the CNS.MAO\nAldehyde\ndehydrogenaseCOMT\nCOMT\nCOMTHO CH3O\nCH3O\nCH3OHO\nHOHO HO\nHO HO\nHO HOCH2CH2NH2 CH2CH2NH2\nCH2CHOC H2CHO\nCH2COOH CH2COOHDopamine 3-Methoxydopamine\nDihydroxyphenylacetic aci d\n(DOPAC)Homovanillic acid\n(HVA)MAO\nAldehyde\ndehydrogenase\nFig. 40.2 The main pathways for dopamine metabolism in \nthe brain. COMT, catechol- O-methyl transferase; MAO, \nmonoamine oxidase. \nTuberohypophyseal\npathway\nMesolimbic\npathwayNigrostriatal\npathway\nMesocortical\npathway\nDOPAMINECHyp\nAmHipVTAAc\nPSNStr\nSep\nFig. 40.3 Simplified diagram of the dopamine pathways in \nthe brain, drawn as in Fig. 40.1.\tThe\tpituitary \tgland \t(P) \tis \t\nshown, innervated with dopaminergic fibres from the \nhypothalamus. Ac, nucleus accumbens; SN, substantia nigra; \nVTA, ventral tegmental area; other abbreviations as in Fig. 40.1. parts of the frontal cortex, limbic system and hypothalamus \n(where its release into the pituitary blood supply inhibits \nsecretion of prolactin; Ch. 34).\nThe synthesis of dopamine follows the same route as \nthat of noradrenaline (see Fig. 15.1), namely conversion of tyrosine to dopa (the rate-limiting step), followed by \ndecarboxylation to form dopamine. Dopaminergic neurons lack dopamine \u03b2-hydroxylase, and thus do not convert \ndopamine to noradrenaline.\nDopamine is largely recaptured, following its release \nfrom nerve terminals, by a specific dopamine transporter, one of the large family of monoamine transporters (see \nCh. 15). It is metabolised by monoamine oxidase and \ncatechol- O-methyl transferase (Fig. 40.2), the main products \nbeing dihydroxyphenylacetic acid (DOPAC) and", "start_char_idx": 0, "end_char_idx": 2812, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b853f3df-d10f-454e-9b38-4f94c449eb3e": {"__data__": {"id_": "b853f3df-d10f-454e-9b38-4f94c449eb3e", "embedding": null, "metadata": {"page_label": "507", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a3ad0988-0f22-4a8e-b9e3-1d5897a4ebd5", "node_type": null, "metadata": {"page_label": "507", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bea30235435ac419e595bd90f54f1c32e558edfe96df5e2918e098a28b7cd9c9"}, "2": {"node_id": "181a4561-5be0-47e5-ba01-aca57604e7c9", "node_type": null, "metadata": {"page_label": "507", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e6b461a552b6145cdee3f9f4e4f16763233a18353886c407964d417c8a350305"}}, "hash": "03ed68daa7af995c4a3cdac8f1d713a126cada2c1f86fe7b217114933ddcd624", "text": "main products \nbeing dihydroxyphenylacetic acid (DOPAC) and homovanil-\nlic acid (HVA), the methoxy derivative of DOPAC. The brain content of HVA is often used in animal experiments as an index of dopamine turnover. Drugs that cause \nthe release of dopamine increase HVA, often without \nchanging the content of dopamine. DOPAC and HVA, and their sulfate conjugates, are excreted in the urine, \nwhich provides an index of dopamine release in human \nsubjects.\n6-Hydroxydopamine, which selectively destroys dopa -\nminergic nerve terminals, is used as a research tool. It is \ntaken up by the dopamine transporter and converted to a reactive metabolite that causes oxidative cytotoxicity.\nDOPAMINERGIC PATHWAYS IN THE CNS\nThere are four main dopaminergic pathways in the brain (Fig. 40.3):1. The nigrostriatal pathway, accounting for about 75% \nof the dopamine in the brain, consists of cell bodies \nlargely in the substantia nigra whose axons terminate \nin the corpus striatum. These fibres run in the medial forebrain bundle along with other \nmonoamine-containing fibres. The abundance of \ndopamine-containing neurons in the human striatum can be appreciated from the image shown in Fig. 40.4, \nwhich was obtained by injecting a dopa derivative mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2753, "end_char_idx": 4474, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0a3c86f6-5ef7-42e4-92b8-8841ab1832a7": {"__data__": {"id_": "0a3c86f6-5ef7-42e4-92b8-8841ab1832a7", "embedding": null, "metadata": {"page_label": "508", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "136a9f79-7451-4ba6-a160-f2b8ef4dadca", "node_type": null, "metadata": {"page_label": "508", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a6de943e1e0c8d039ad1f340067d207b245bb949332a657e612d6033805f223b"}, "3": {"node_id": "2b3ea4b8-9798-40e7-9216-c65e4ffc299a", "node_type": null, "metadata": {"page_label": "508", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a72e19a2a7bb8ab25e89a5e2ac2cf4cff28897b9407db4df75d600aacd29163"}}, "hash": "fcb7430a4d118ad2fdd5dcd4d8649d4fc30f6f4bcfa0ab4f8c626f09d624eb8a", "text": "40 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n502cloning revealed further subgroups, D 1 to D 5. The original \nD1 family now includes D 1 and D 5, while the D 2 family \nconsists of D 2, D 3 and D 4 (Table 40.1). Splice variants, leading \nto long and short forms of D 2, and genetic polymorphisms, \nparticularly of D 4, have subsequently been identified.\n\u25bc All belong to the family of G protein\u2013coupled transmembrane \nreceptors described in Chapter 3. D 1 and D 5 receptors link through \nGs to stimulate adenylyl cyclase and activate protein kinase A (PKA). \nPKA mediates many of the effects of D 1 and D 5 receptors by phos-\nphorylating a wide array of proteins, including voltage-activated \nsodium, potassium and calcium channels, as well as ionotropic \nglutamate and GABA receptors. D 2, D 3, and D 4 receptors link through \nGi/G o and activate potassium channels as well as inhibiting calcium \nchannels and adenylyl cyclase, and can also affect other cellular second \nmessenger cascades (see Ch. 3). When intracellular cAMP is increased \nthrough activation of D 1 receptors, activating PKA, DARPP-32 (a \ncAMP-regulated phosphoprotein also known as protein phosphatase 1 \nregulatory subunit 1B) is phosphorylated. Phosphorylated DARPP-32 inhibits protein phosphatase-1, thus acting in concert with protein kinases as an amplifying mechanism favouring protein phosphoryla -\ntion. In general, activation of D\n2 receptors opposes the effects of D 1 \nreceptor activation.\nDopamine receptors are expressed in the brain in distinct \nbut overlapping areas. D 1 receptors are the most abundant \nand widespread in areas receiving a dopaminergic innerva -\ntion (namely the striatum, limbic system, thalamus and hypothalamus; see Fig. 40.3), as are D\n2 receptors, which \nalso occur in the pituitary gland. D 2 receptors are found \nnot only on dopaminergic neurons (on the soma, dendrites \nand nerve terminals), where they function as inhibitory \nautoreceptors activated by locally released dopamine, but also on glutamatergic, GABAergic and cholinergic nerve \nterminals (see De Mei et al., 2009). D 3 receptors occur in \nthe limbic system but not in the striatum. The D 4 receptor \nis much more weakly expressed, mainly in the cortex and \nlimbic systems.\nDopamine receptors also mediate various effects in the \nperiphery (mediated by D 1 receptors), notably renal \nvasodilatation and increased myocardial contractility (dopamine itself has been used clinically in the treatment \nof circulatory shock; see Ch. 23).\nFUNCTIONAL ASPECTS\nThe functions of dopaminergic pathways divide broadly into:\n\u2022\tmotor\tcontrol \t(nigrostriatal \tsystem)\n\u2022\tbehavioural \teffects \t(mesolimbic \tand \tmesocortical \t\nsystems)\n\u2022\tendocrine \tcontrol \t(tuberohypophyseal \tsystem)\nDopamine and motor systems\nUngerstedt showed, in 1968, that bilateral ablation of the substantia nigra in rats, which destroys the nigrostriatal \nneurons, causes profound catalepsy, the animals becoming \nso inactive that they die of starvation unless artificially fed. Parkinson\u2019s disease (Ch. 41) is a disorder of motor control, \nassociated with a deficiency of dopamine in the nigrostriatal \npathway.\nIn treating CNS disorders, it is often desired that a certain \nreceptor type be activated or inhibited only in one part of the brain, but the problem", "start_char_idx": 0, "end_char_idx": 3279, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2b3ea4b8-9798-40e7-9216-c65e4ffc299a": {"__data__": {"id_": "2b3ea4b8-9798-40e7-9216-c65e4ffc299a", "embedding": null, "metadata": {"page_label": "508", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "136a9f79-7451-4ba6-a160-f2b8ef4dadca", "node_type": null, "metadata": {"page_label": "508", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a6de943e1e0c8d039ad1f340067d207b245bb949332a657e612d6033805f223b"}, "2": {"node_id": "0a3c86f6-5ef7-42e4-92b8-8841ab1832a7", "node_type": null, "metadata": {"page_label": "508", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fcb7430a4d118ad2fdd5dcd4d8649d4fc30f6f4bcfa0ab4f8c626f09d624eb8a"}}, "hash": "6a72e19a2a7bb8ab25e89a5e2ac2cf4cff28897b9407db4df75d600aacd29163", "text": "\nreceptor type be activated or inhibited only in one part of the brain, but the problem is that drugs are rarely brain-region selective and will affect a given receptor type throughout the brain. For example, many antipsychotic \ndrugs (see Ch. 47) are D\n2 receptor antagonists, exerting a \nbeneficial effect by blocking D 2 receptors in the mesolimbic containing radioactive fluorine, and scanning for \nradioactivity 3 h later by positron emission \ntomography (PET) scanning.\n2. The mesolimbic pathway, whose cell bodies occur in \nthe midbrain ventral tegmental area (VTA), adjacent to the substantia nigra, and whose fibres project via \nthe medial forebrain bundle to parts of the limbic system, especially the nucleus accumbens and the \namygdaloid nucleus.\n3. The mesocortical pathway, whose cell bodies also lie \nin the VTA and which project via the medial forebrain bundle to the frontal cortex.\n4. The tuberohypophyseal (or tuberoinfundibular) \nsystem is a group of short neurons running from the ventral hypothalamus to the median eminence \nand pituitary gland, the secretions of which they regulate.\nThere are also dopaminergic neurons in other brain regions and in the retina. For a more complete description, see \nBj\u00f6rklund and Dunnett (2007). The functions of the main \ndopaminergic pathways are discussed later.\nDOPAMINE RECEPTORS\nTwo types of receptor, D 1 and D 2, were originally distin-\nguished on pharmacological and biochemical grounds. Gene \nFig. 40.4 Dopamine in the basal ganglia of a human \nsubject. The subject was injected with 5-fluoro-dopa labelled \nwith the positron-emitting isotope 18F, which was localised 3 h \nlater by the technique of positron emission tomography. The \nisotope is accumulated (white areas) by the dopa uptake system \nof the neurons of the basal ganglia, and to a smaller extent in the frontal cortex. It is also seen in the scalp and temporalis muscles. (From Garnett, E.S., Firnau, G., Nahmias, C., 1983. Nature 305, 137\u2013138.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3192, "end_char_idx": 5651, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "eb6841e6-ea8a-4fbc-a970-d78856b95b3a": {"__data__": {"id_": "eb6841e6-ea8a-4fbc-a970-d78856b95b3a", "embedding": null, "metadata": {"page_label": "509", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a1f1ff96-8b29-4f81-87d0-d3c8e3d30826", "node_type": null, "metadata": {"page_label": "509", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "070920d600c2f0e7aa7d8eb96b60ad8c8ba03da95467143dc22e40d758bd7b63"}, "3": {"node_id": "17437a2b-2322-4ab0-ab87-3231ab7ff932", "node_type": null, "metadata": {"page_label": "509", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f5d4d85cd2db92cac2848ced36293b8387d8a7163def709fae1586b474e14f8"}}, "hash": "3185e846eea5dc0e4aa76a98a379824b75d4e57fdffeae1a6e06fb3b473771eb", "text": "40 OThER TR a NSM i TTERS a N d MO d U la TORS\n503reduced food intake and insensitivity to amphetamine and \ncocaine.\nNeuroendocrine function\nThe tuberohypophyseal dopaminergic pathway (see Fig. 40.3) inhibits prolactin secretion via dopamine release. This \nsystem is of clinical importance. Many antipsychotic drugs \n(see Ch. 47), by blocking D\n2 receptors, increase prolactin \nsecretion and can cause breast development and lactation, \neven in males. Bromocriptine , a dopamine-receptor agonist \nderived from ergot, is used clinically to suppress prolactin \nsecretion by tumours of the pituitary gland.\nGrowth hormone production is increased in normal \nsubjects by dopamine, but bromocriptine paradoxically inhibits the excessive secretion responsible for acromegaly \n(probably because it desensitises dopamine receptors, \nin contrast to the physiological release of dopamine, which is pulsatile) and has a useful therapeutic effect, provided it is given before excessive growth has taken \nplace. It is now rarely used, as other agents are more \neffective (see Ch. 34). Bromocriptine and other dopamine agonists, such as cabergoline, enhance libido and sexual \nperformance.pathway. However, their D\n2 antagonist property also gives \nrise to their major side effect, which is to cause movement \ndisorders, by simultaneously blocking D 2 receptors in the \nnigrostriatal pathway.\nBehavioural effects\nAdministration of amphetamine to rats, which releases \nboth dopamine and noradrenaline, causes a cessation of normal \u2018ratty\u2019 behaviour (exploration and grooming), and \nthe appearance of repeated \u2018stereotyped\u2019 behaviour (rearing, gnawing and so on) unrelated to external stimuli. These \namphetamine-induced motor disturbances in rats probably \nreflect hyperactivity in the nigrostriatal dopaminergic system, and are prevented by dopamine antagonists and \nby destruction of dopamine-containing cell bodies in the \nmidbrain, but not by drugs that inhibit the noradrenergic system.\nAmphetamine and cocaine (which inhibit the dopamine \ntransporter) and also other drugs of abuse (Chs 49 and 50) activate mesolimbic dopaminergic \u2018reward\u2019 pathways to produce feelings of euphoria in humans. The main receptor \ninvolved appears to be D\n1, and transgenic mice lacking D 1 \nreceptors behave as though generally demotivated, with Table 40.1 Dopamine receptors\nFunctional roleD1 type D2 type\nD1 D5 D2 D3 D4\nDistribution\nCortex Arousal, mood +++ \u2014 ++ \u2014 +\nLimbic system Emotion, stereotypic \nbehaviour+++ + ++ + +\nStriatum Prolactin secretion +++ + ++ + +\nVentral hypothalamus and anterior pituitaryProlactin secretion \u2014 \u2014 ++ + \u2014\nAgonists\na\nDopamine FA FA FA FA FA\nApomorphine FA PA PA PA PA\nBromocriptine PA FA FA PA Ant\nQuinpirole Inactive Inactive FA FA FA\nAntagonists\nChlorpromazine ++ ++ ++ ++ ++\nHaloperidol ++ + +++ ++ +++\nSpiperone ++ + +++ +++ +++\nSulpiride \u2014 \u2014 ++ ++ +\nClozapine + + + + ++\nAripiprazole \u2014 \u2014 +++ (PA) \u2014 ++\nRaclopride \u2014 \u2014 +++ ++ +\nSignal transductionGs coupled \u2013 activates \nadenylyl cyclaseGi/Go coupled \u2013 inhibits adenylyl \ncyclase, activates K+ channels, \ninhibits Ca2+ channels, may also \nactivate phospholipase C\nEffectMainly postsynaptic \ninhibitionPre- and postsynaptic inhibitionStimulation/inhibition of hormone release\naAgonists generally", "start_char_idx": 0, "end_char_idx": 3260, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "17437a2b-2322-4ab0-ab87-3231ab7ff932": {"__data__": {"id_": "17437a2b-2322-4ab0-ab87-3231ab7ff932", "embedding": null, "metadata": {"page_label": "509", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a1f1ff96-8b29-4f81-87d0-d3c8e3d30826", "node_type": null, "metadata": {"page_label": "509", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "070920d600c2f0e7aa7d8eb96b60ad8c8ba03da95467143dc22e40d758bd7b63"}, "2": {"node_id": "eb6841e6-ea8a-4fbc-a970-d78856b95b3a", "node_type": null, "metadata": {"page_label": "509", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3185e846eea5dc0e4aa76a98a379824b75d4e57fdffeae1a6e06fb3b473771eb"}}, "hash": "8f5d4d85cd2db92cac2848ced36293b8387d8a7163def709fae1586b474e14f8", "text": "inhibitionStimulation/inhibition of hormone release\naAgonists generally exhibit lower potency at D 1 and D 5 receptors compared with D 2, D 3 and D 4 receptors.\nAnt, antagonist; FA, full agonist; PA, partial agonist. \n(Data\tbased \ton \tthat \tcontained \tin \tthe \tIUPHAR/BPS \tGuide \tto \tPharmacology \tdatabase www.guidetopharmacology.org.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3189, "end_char_idx": 4005, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6f4d6c02-80e2-4510-9ef6-1e1b838a9a35": {"__data__": {"id_": "6f4d6c02-80e2-4510-9ef6-1e1b838a9a35", "embedding": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "383319f0-3b67-49c0-9800-00c18fb1d6b7", "node_type": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a53d61b190f62dbaca6c5b389f7edd0b6aa93ed9b00c0e68672ff4fd11f38bd0"}, "3": {"node_id": "82d7bc62-352e-470b-a70c-aa247a962ff6", "node_type": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5f86fe296db6a09e5d275791a20a60734e849cd4b7b840c9f2b3184199478c35"}}, "hash": "c436c9948ca2dc51541b5458c443ea23f5c684233803bed2fc492c6053bfec3e", "text": "40 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n504(see Iversen et al., 2009; Muller & Jacobs, 2009). 5-HT is \ninvolved in various physiological processes, including \nsleep, appetite, thermoregulation and pain perception as \nwell as in disorders such as migraine, depression, mania, \nanxiety, obsessive\u2013compulsive disorders, schizophrenia, autism and drug abuse.\nIn its formation, storage and release, 5-HT resembles \nnoradrenaline. Its precursor is tryptophan, an amino acid derived from dietary protein, the plasma content of which \nvaries considerably according to food intake and time of \nday. 5-HT does not cross the blood\u2013brain barrier and is synthesised in the CNS. Tryptophan is actively taken up into neurons, converted by tryptophan hydroxylase to \n5-hydroxytryptophan (see Fig. 16.1), and then decarboxy -\nlated by a non-specific amino acid decarboxylase to form \n5-HT. Tryptophan hydroxylase can be selectively and \nirreversibly inhibited by p-chlorophenylalanine (PCPA). \nAvailability of tryptophan and the activity of tryptophan \nhydroxylase are thought to be the main factors that regulate \n5-HT synthesis. The decarboxylase is very similar, if not \nidentical, to dopa decarboxylase, and does not play any role in regulating 5-HT synthesis. Following release, 5-HT \nis largely recovered by neuronal uptake, through a specific \ntransporter (see Ch. 3) similar to, but not identical with, those that take up noradrenaline and dopamine. 5-HT \nreuptake is specifically inhibited by selective serotonin reuptake \ninhibitors (SSRIs) such as fluoxetine and, less specifically, \nby many of the drugs that inhibit catecholamine uptake (e.g. tricyclic antidepressants). SSRIs (see Chs 45 and 48) \nconstitute an important group of antidepressant and \nantianxiety drugs. 5-HT is degraded almost entirely by monoamine oxidase (Fig. 16.1), which converts it to \n5-hydroxyindole acetaldehyde, most of which is then \ndehydrogenated to form 5-hydroxyindole acetic acid (5-HIAA) and excreted in the urine.\n5-HT PATHWAYS IN THE CNS\nThe distribution of 5-HT-containing neurons (Fig. 40.5) resembles that of noradrenergic neurons. The cell bodies \nare grouped in the pons and upper medulla, close to the \nmidline (raphe), and are often referred to as raphe nuclei. The rostrally situated nuclei project, via the medial forebrain \nbundle, to many parts of the cortex, hippocampus, basal \nganglia, limbic system and hypothalamus. The caudally situated cells project to the cerebellum, medulla and spinal \ncord.\n5-HT RECEPTORS IN THE CNS\nThe main 5-HT receptor types are shown in Table 16.1. All \nare G protein\u2013coupled receptors except for 5-HT 3, which \nis a ligand-gated cation channel (see later). All are expressed \nin the CNS, and their functional roles have been extensively \nanalysed. With some 14 identified subtypes plus numerous splice variants, and a large number of pharmacological \ntools of relatively low specificity, assigning clear-cut func -\ntions to 5-HT receptors is not simple. Our present state of \nknowledge is described by Filip and Bader (2009).\nCertain generalisations can be made:\n\u2022\t5-HT\n1 receptors (5-HT 1A, 5-HT 1B, 5-HT 1D, 5-HT 1E, \n5-HT 1F)3 are predominantly inhibitory in their effects. Vomiting\nPharmacological evidence strongly", "start_char_idx": 0, "end_char_idx": 3238, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "82d7bc62-352e-470b-a70c-aa247a962ff6": {"__data__": {"id_": "82d7bc62-352e-470b-a70c-aa247a962ff6", "embedding": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "383319f0-3b67-49c0-9800-00c18fb1d6b7", "node_type": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a53d61b190f62dbaca6c5b389f7edd0b6aa93ed9b00c0e68672ff4fd11f38bd0"}, "2": {"node_id": "6f4d6c02-80e2-4510-9ef6-1e1b838a9a35", "node_type": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c436c9948ca2dc51541b5458c443ea23f5c684233803bed2fc492c6053bfec3e"}, "3": {"node_id": "119f7fe3-05ae-426b-a48a-6a82da0ecef5", "node_type": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3463b2e186da3d382a4bcd938698c72b08290019ba02ecec0e5f42858d934ab2"}}, "hash": "5f86fe296db6a09e5d275791a20a60734e849cd4b7b840c9f2b3184199478c35", "text": "predominantly inhibitory in their effects. Vomiting\nPharmacological evidence strongly suggests that dopamin -\nergic neurons have a role in the production of nausea and \nvomiting. Thus nearly all dopamine-receptor agonists (e.g. \nbromocriptine) and other drugs that increase dopamine release in the brain (e.g. levodopa; Ch. 41) cause nausea \nand vomiting as side effects, while many dopamine antago -\nnists (e.g. phenothiazines, metoclopramide; Ch. 31) have \nantiemetic activity. D\n2 receptors occur in the area of the \nmedulla (the chemoreceptor trigger zone) associated with \nthe initiation of vomiting (Ch. 31), and are assumed to \nmediate this effect.\nDopamine in the central nervous \nsystem \n\u2022\tDopamine \tis \ta \tneurotransmitter \tas \twell \tas \tbeing \tthe \t\nprecursor for noradrenaline. It is degraded in a similar \nfashion to noradrenaline, giving rise mainly to dihydroxyphenylacetic acid and homovanillic acid, \nwhich are excreted in the urine.\n\u2022\tThere\tare \tfour \tmain \tdopaminergic \tpathways:\n\u2013 nigrostriatal pathway, important in motor control;\n\u2013 mesolimbic pathway, running from groups of cells in \nthe midbrain to parts of the limbic system, especially \nthe nucleus accumbens, involved in emotion and drug-induced reward;\n\u2013 mesocortical pathway, running from the midbrain to \nthe cortex, involved in emotion;\n\u2013 tuberohypophyseal neurons, running from the \nhypothalamus to the pituitary gland, whose secretions they regulate.\n\u2022\tThere\tare \tfive \tdopamine-receptor \tsubtypes. \tD1 and D 5 \nreceptors are linked to stimulation of adenylyl cyclase. D\n2, D 3 and D 4 receptors are linked to activation of K+ \nchannels and inhibition of Ca2+ channels as well as to \ninhibition of adenylyl cyclase.\n\u2022\tD 2 receptors may be implicated in the positive \nsymptoms and D 1 receptors in the negative symptoms \nof schizophrenia.\n\u2022\tParkinson\u2019s \tdisease \tis \tassociated \twith \ta \tdeficiency \tof \t\nnigrostriatal dopaminergic neurons.\n\u2022\tHormone \trelease \tfrom \tthe \tanterior \tpituitary \tgland \tis \t\nregulated by dopamine, especially prolactin release (inhibited) and growth hormone release (stimulated).\n\u2022\tDopamine \tacts \ton \tthe \tchemoreceptor \ttrigger \tzone \tto \t\ncause nausea and vomiting.\n3There is no 5-HT 1C receptor. The original 5-HT 1C receptor has been \nreclassified as 5-HT 2C.5-HYDROXYTRYPTAMINE\nThe occurrence and functions of 5-HT (serotonin) in the \nperiphery are described in Chapter 16. Interest in 5-HT as a \npossible CNS transmitter dates from 1953, when Gaddum \nfound that lysergic acid diethylamide (LSD), a powerful \nhallucinogen (see Ch. 49), acted as a 5-HT antagonist on \nperipheral tissues, and suggested that its central effects \nmight also be related to this action. The presence of 5-HT in the brain was demonstrated a few years later. Even \nthough brain 5-HT accounts for only about 1% of the \ntotal body content, 5-HT is an important CNS transmitter mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3161, "end_char_idx": 6335, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "119f7fe3-05ae-426b-a48a-6a82da0ecef5": {"__data__": {"id_": "119f7fe3-05ae-426b-a48a-6a82da0ecef5", "embedding": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "383319f0-3b67-49c0-9800-00c18fb1d6b7", "node_type": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a53d61b190f62dbaca6c5b389f7edd0b6aa93ed9b00c0e68672ff4fd11f38bd0"}, "2": {"node_id": "82d7bc62-352e-470b-a70c-aa247a962ff6", "node_type": null, "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5f86fe296db6a09e5d275791a20a60734e849cd4b7b840c9f2b3184199478c35"}}, "hash": "3463b2e186da3d382a4bcd938698c72b08290019ba02ecec0e5f42858d934ab2", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6366, "end_char_idx": 6589, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dd078166-e654-415d-ace0-4023a048c9a3": {"__data__": {"id_": "dd078166-e654-415d-ace0-4023a048c9a3", "embedding": null, "metadata": {"page_label": "511", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e298e071-cfd8-4e38-bf2b-80db3becb0b9", "node_type": null, "metadata": {"page_label": "511", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ee35e5efdfa3553afdb8d10df86bfb7bf84dfa284e18c7d000450d176160a55"}, "3": {"node_id": "26654bb4-cb62-4e28-934f-3f4bb3c7e548", "node_type": null, "metadata": {"page_label": "511", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27dc1c223dacfeb76d905026d555203aef187bf3b77174c76a62d3393d3df49d"}}, "hash": "0dacb8c3a62b571c298449e54a0e4d1229c87a7af8f2e6edd37e19e71d201cf3", "text": "40 OThER TR a NSM i TTERS a N d MO d U la TORS\n505see Chs 16 and 31) are used to treat nausea and \nvomiting.\n\u2022\t5-HT 4 receptors are important in the gastrointestinal \n(GI) tract (see Chs 16 and 31), and are also expressed \nin the brain, particularly in the limbic system, basal \nganglia, hippocampus and substantia nigra. They are located at both pre- and postsynaptic sites. They exert \na presynaptic facilitatory effect, particularly on ACh \nrelease, thus enhancing cognitive performance (see Chs 41 and 49). Activation of medullary 5-HT\n4 \nreceptors opposes the respiratory depressant actions \nof opioids (see Ch. 43).\n\u2022\tThere\tare \ttwo \t5-HT 5 receptors, 5-HT 5A and 5-HT 5B. In \nthe human, only 5-HT 5A is functional. Antagonists \nmay have anxiolytic, antidepressant and antipsychotic activity.\n\u2022\t5-HT\n6 receptors occur primarily in the CNS, \nparticularly in the hippocampus, cortex and limbic system. Blockade of 5-HT\n6 receptors increases \nglutamate and ACh release and 5HT 6-antagonists are \nconsidered potential drugs to improve cognition or relieve symptoms of schizophrenia.\n\u2022\t5-HT\n7 receptors occur in the hippocampus, cortex, \namygdala, thalamus and hypothalamus. They are found on the soma and axon terminals of GABAergic \nneurons. They are also expressed in blood vessels and the GI tract. Likely CNS functions include \nthermoregulation and endocrine regulation, as well as \nsuspected involvement in mood, cognitive function and sleep. The antipsychotic drug, lurasidone (see Ch. \n47), has slightly higher affinity for 5-HT\n7 receptors \nthan for D 2 receptors. Selective antagonists are being \ndeveloped for clinical use in a variety of potential indications.\nFUNCTIONAL ASPECTS\nThe precise localisation of 5-HT neurons in the brain \nstem has allowed their electrical activity to be studied in \ndetail and correlated with behavioural and other effects \nproduced by drugs thought to affect 5-HT-mediated transmission. 5-HT cells show an unusual, highly regular, \nslow discharge pattern, and are strongly inhibited by 5-HT\n1 \nreceptor agonists, suggesting a local inhibitory feedback \nmechanism.\nIn vertebrates, certain physiological and behavioural \nfunctions relate particularly to 5-HT pathways, namely:\n\u2022\thallucinations \tand \tbehavioural \tchanges\n\u2022\tsleep,\twakefulness \tand \tmood\n\u2022\tfeeding \tbehaviour\n\u2022\tcontrol \tof \tsensory \ttransmission \t(especially \tpain \t\npathways; see Ch. 43)\nHallucinatory effects\nMany hallucinogenic drugs (e.g. LSD; Ch. 49) are agonists \nat 5-HT 2A receptors. It is suggested that a loss of corti-\ncal inhibition underlies the hallucinogenic effect. Many \nantipsychotic drugs (Ch. 47) are antagonists at 5-HT 2A \nreceptors in addition to blocking dopamine D 2 recep-\ntors. The psychostimulant properties of MDMA (3,4- methylenedioxymethamphetamine, see Ch. 49) are due \npartly to its ability to release 5-HT. MDMA is taken up by the serotonin transporter, and displaces 5-HT from \nstorage vesicles \u2013 a mechanism analogous to the action of \namphetamine on noradrenergic nerve terminals (Ch. 15).5-HT\n1A receptors are expressed on the soma and \ndendrites of 5-HT neurons in the raphe nuclei and are \nactivated by locally released 5-HT. This inhibitory \neffect tends to limit the rate of firing of these", "start_char_idx": 0, "end_char_idx": 3241, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "26654bb4-cb62-4e28-934f-3f4bb3c7e548": {"__data__": {"id_": "26654bb4-cb62-4e28-934f-3f4bb3c7e548", "embedding": null, "metadata": {"page_label": "511", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e298e071-cfd8-4e38-bf2b-80db3becb0b9", "node_type": null, "metadata": {"page_label": "511", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ee35e5efdfa3553afdb8d10df86bfb7bf84dfa284e18c7d000450d176160a55"}, "2": {"node_id": "dd078166-e654-415d-ace0-4023a048c9a3", "node_type": null, "metadata": {"page_label": "511", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0dacb8c3a62b571c298449e54a0e4d1229c87a7af8f2e6edd37e19e71d201cf3"}}, "hash": "27dc1c223dacfeb76d905026d555203aef187bf3b77174c76a62d3393d3df49d", "text": "This inhibitory \neffect tends to limit the rate of firing of these cells. They are also widely distributed in the limbic system, \nand are believed to be a major target for drugs used to \ntreat anxiety and depression (see Chs 45 and 48). 5-HT\n1B and 5-HT 1D receptors are found mainly as \npresynaptic inhibitory receptors on both \n5-HT-containing and other nerve terminals in the \nbasal ganglia and cortex. Agonists acting on 5-HT 1B \nand 5-HT 1D receptors such as sumatriptan are used to \ntreat migraine (see Ch. 16).\n\u2022\t5-HT 2 receptors (5-HT 2A, 5-HT 2B and 5-HT 2C) are \nabundant in the cortex and limbic system, where they \nare located at both pre- and postsynaptic sites. They \ncan exert excitatory or inhibitory effects by enhancing the release of glutamate and GABA. They are believed \nto be the target of some antidepressants (see Ch. 48) \nand antipsychotic drugs (see Ch. 47) as well as various hallucinogenic drugs (see Ch. 49). Lorcaserin, \na 5-HT\n2C agonist is an anti-obesity drug (see Ch. 33). \nThe use of 5-HT 2 receptor antagonists such as \nmethysergide in treating migraine is discussed in Chapter 16.\n\u2022\t5-HT\n3 receptors are pentameric ligand-gated cation \nchannels that can be either homomeric or heteromeric complexes of different 5-HT\n3 receptor subunits (see \nPeters et al., 2005). While 5-HT3A and 5-HT3B \nsubunits are the most extensively studied, the roles of \nother subunits remain to be fully investigated (see \nJensen et al., 2008). In the brain, 5-HT 3 receptors are \nfound in the area postrema (a region of the medulla \ninvolved in vomiting; see Ch. 31) and other parts of \nthe brain stem, extending to the dorsal horn of the spinal cord. They are also present in certain parts \nof the cortex, as well as in the peripheral nervous \nsystem. They are excitatory ionotropic receptors, and specific antagonists (e.g. granisetron and ondansetron; Raphe nucleiSEROTONIN\nSpinal cordCHyp\nAmHipThStr\nSep\nFig. 40.5 Simplified diagram of the 5-hydroxytryptamine \npathways in the brain, drawn as in Fig. 40.1. Abbreviations as \nin Fig. 40.1. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3175, "end_char_idx": 5717, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5ad0bc53-d13d-4c6d-b78d-94d1d0ed1950": {"__data__": {"id_": "5ad0bc53-d13d-4c6d-b78d-94d1d0ed1950", "embedding": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c23ea36b-b45a-43b5-90da-c01ccbbd3cb3", "node_type": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50b60bfdfa16f3f5bf2b01a9107e0727982557253b5805a5358184e46463fa41"}, "3": {"node_id": "917bfb27-bd46-4121-a814-3f78a5f15f8a", "node_type": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d951e18aeb491f1365c783c5bfdf28d03ee2973fab3f4723515df5023f8684af"}}, "hash": "42c1be7f6154738df1af63a91c683676a02073d327be13bdbea008b07611897f", "text": "40 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n506ACETYLCHOLINE\nThere are numerous cholinergic neurons in the CNS, and \nthe basic processes by which ACh is synthesised, stored \nand released are the same as in the periphery (see Ch. 14). \nVarious biochemical markers have been used to locate cholinergic neurons in the brain, the most useful being Sleep, wakefulness and mood\nLesions of the raphe nuclei, or depletion of 5-HT by PCPA administration, abolish sleep in experimental animals, \nwhereas microinjection of 5-HT at specific points in the \nbrain stem induces sleep. 5-HT\n7 receptor antagonists \ninhibit \u2018rapid-eye-movement\u2019 (REM) sleep and increase the \nlatency to onset of REM sleep. Attempts to cure insomnia \nin humans by giving 5-HT precursors (tryptophan or 5-hydroxytryptophan) have, however, proved unsuccessful. \nThere is strong evidence that 5-HT, as well as noradrenaline, \nmay be involved in the control of mood (see Ch. 48), and the use of tryptophan to enhance 5-HT synthesis has been \ntried in depression, with equivocal results.\nFeeding and appetite\nIn experimental animals, 5-HT 1A agonists such as 8-hydroxy-\n2-(di-n-propylamino)-tetralin (8-OH-DPAT) cause hyper -\nphagia, leading to obesity. Antagonists acting on 5-HT 2 \nreceptors, including several antipsychotic drugs used clinically, also increase appetite and cause weight gain. \nHowever, antidepressant drugs that inhibit 5-HT uptake (see Ch. 48) cause loss of appetite, as does the 5-HT\n2C \nreceptor agonist lorcaserin.\nSensory transmission\nAfter lesions of the raphe nuclei or administration of PCPA, animals show exaggerated responses to many forms of \nsensory stimulus. They are startled much more easily, and \nalso quickly develop avoidance responses to stimuli that would not normally bother them. It appears that the normal \nability to disregard irrelevant forms of sensory input requires \nintact 5-HT pathways. The \u2018sensory enhancement\u2019 produced by hallucinogenic drugs may be partly due to loss of this \ngatekeeper function of 5-HT. 5-HT also exerts an inhibitory \neffect on transmission in the pain pathway, both in the spinal cord and in the brain, and there is a synergistic effect between 5-HT and analgesics such as morphine (see Ch. \n43). Thus depletion of 5-HT by PCPA, or selective lesions to the descending 5-HT-containing neurons that run to the dorsal horn, antagonise the analgesic effect of morphine, \nwhile inhibitors of 5-HT uptake have the opposite effect.\nOther roles\nOther roles of 5-HT include various autonomic and endo -\ncrine functions, such as the regulation of body temperature, blood pressure and sexual function. Further information \ncan be found in Iversen et al. (2009).\nCLINICALLY USED DRUGS\nSeveral classes of drugs used clinically influence 5-HT-\nmediated transmission. They include:\n\u2022\t5-HT\treuptake \tinhibitors, \tsuch \tas \tfluoxetine, \tused \tas \t\nantidepressants (Ch. 48) and anxiolytic agents (Ch. 45)\n\u2022\t5-HT 1D receptor agonists, such as sumatriptan, used to \ntreat migraine (Ch. 16)\n\u2022\t5-HT 2 antagonists, such as pizotifen, used to treat \nmigraine (Ch. 16)\n\u2022\tbuspirone, \ta \t5-HT 1A receptor agonist used in treating \nanxiety (Ch. 45)\n\u2022\t5-HT 3 receptor antagonists, such as ondansetron, used \nas", "start_char_idx": 0, "end_char_idx": 3204, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "917bfb27-bd46-4121-a814-3f78a5f15f8a": {"__data__": {"id_": "917bfb27-bd46-4121-a814-3f78a5f15f8a", "embedding": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c23ea36b-b45a-43b5-90da-c01ccbbd3cb3", "node_type": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50b60bfdfa16f3f5bf2b01a9107e0727982557253b5805a5358184e46463fa41"}, "2": {"node_id": "5ad0bc53-d13d-4c6d-b78d-94d1d0ed1950", "node_type": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42c1be7f6154738df1af63a91c683676a02073d327be13bdbea008b07611897f"}, "3": {"node_id": "8ae5bc58-3fb9-4339-950d-db7f889a1826", "node_type": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb226680046db0736e82c92740863d4e9e3cdb09450143892fec7b28f58fd737"}}, "hash": "d951e18aeb491f1365c783c5bfdf28d03ee2973fab3f4723515df5023f8684af", "text": "3 receptor antagonists, such as ondansetron, used \nas antiemetic agents (see Ch. 31)\n\u2022\tantipsychotic \tdrugs \t(e.g. \tclozapine, \tCh. \t47), \twhich \t\nowe their efficacy partly to an action on 5-HT receptors5-Hydroxytryptamine in the central \nnervous system \n\u2022\tThe\tprocesses \tof \tsynthesis, \tstorage, \trelease, \treuptake \t\nand\tdegradation \tof \t5-hydroxytryptamine \t(5-HT) \tin \tthe \t\nbrain are very similar to events in the periphery (Ch. \n16).\n\u2022\tAvailability \tof \ttryptophan \tis \tthe \tmain \tfactor \tregulating \t\nsynthesis.\n\u2022\tUrinary\texcretion \tof \t5-hydroxyindole \tacetic \tacid \t\nprovides\ta \tmeasure \tof \t5-HT \tturnover.\n\u2022\t5-HT\tneurons \tare \tconcentrated \tin \tthe \tmidline \traphe \t\nnuclei in the brain stem projecting diffusely to the cortex, limbic system, hypothalamus and spinal cord, similar to the noradrenergic projections.\n\u2022\tFunctions \tassociated \twith \t5-HT \tpathways \tinclude:\n\u2013 various behavioural responses (e.g. hallucinatory \nbehaviour, \u2018wet dog shakes\u2019)\n\u2013 feeding behaviour\n\u2013 control of mood and emotion\n\u2013\tcontrol\tof \tsleep/wakefulness\n\u2013 control of sensory pathways, including nociception\n\u2013 control of body temperature\n\u2013 vomiting\n\u2022\t5-HT\tcan \texert \tinhibitory \tor \texcitatory \teffects \ton \t\nindividual neurons, acting either presynaptically or postsynaptically.\n\u2022\tThe\tmain \treceptor \tsubtypes \t(see \tTable \t16.1) \tin \tthe \t\ncentral\tnervous \tsystem \t(CNS) \tare \t5-HT 1A,\t5-HT1B, \n5-HT 1D,\t5-HT 2A,\t5-HT 2C\tand\t5-HT 3. Associations of \nbehavioural and physiological functions with these receptors have been partly worked out. Other receptor \ntypes\t(5-HT 4\u20137) also occur in the CNS, but less is \nknown about their function.\n\u2022\tDrugs\tacting \tselectively \ton \t5-HT \treceptors \tor \t\ntransporters include:\n\u2013 buspirone ,\t5-HT 1A receptor agonist used to treat \nanxiety (see Ch. 45);\n\u2013\t\u2018triptans\u2019 \t(e.g. \tsumatriptan), \t5-HT 1D agonists used to \ntreat migraine (see Ch. 16);\n\u2013\t5-HT 2 antagonists (e.g. pizotifen) used for migraine \nprophylaxis (see Ch. 16);\n\u2013 selective serotonin uptake inhibitors (e.g. fluoxetine) \nused to treat depression (see Ch. 48);\n\u2013 ondansetron ,\ta\t5-HT 3 antagonist, used to treat \nchemotherapy-induced emesis (see Chs 16 \nand 31);\n\u2013 MDMA\t(ecstasy), \ta \tsubstrate \tfor \tthe \t5-HT \t\ntransporter. \tIt \tthen \tdisplaces \t5-HT \tfrom \tnerve \t\nterminals\tonto \t5-HT \treceptors \tto \tproduce \tits \t\nmood-altering effects (see Ch. 49).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3159, "end_char_idx": 5733, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ae5bc58-3fb9-4339-950d-db7f889a1826": {"__data__": {"id_": "8ae5bc58-3fb9-4339-950d-db7f889a1826", "embedding": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c23ea36b-b45a-43b5-90da-c01ccbbd3cb3", "node_type": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50b60bfdfa16f3f5bf2b01a9107e0727982557253b5805a5358184e46463fa41"}, "2": {"node_id": "917bfb27-bd46-4121-a814-3f78a5f15f8a", "node_type": null, "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d951e18aeb491f1365c783c5bfdf28d03ee2973fab3f4723515df5023f8684af"}}, "hash": "cb226680046db0736e82c92740863d4e9e3cdb09450143892fec7b28f58fd737", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5780, "end_char_idx": 6035, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "46f51e5d-5d8e-422e-9694-b9c6bb6c9d28": {"__data__": {"id_": "46f51e5d-5d8e-422e-9694-b9c6bb6c9d28", "embedding": null, "metadata": {"page_label": "513", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f76cae65-7d50-4032-ada5-1c4d1ac41c56", "node_type": null, "metadata": {"page_label": "513", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f0c5e7f6895b4664f5edfc4b2e1ec44c653d156013bd918a55664acf72f5c72"}, "3": {"node_id": "a74e732c-8e9c-450a-b494-926f1628715a", "node_type": null, "metadata": {"page_label": "513", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b18fabd8370a7a541368a5fa7e4c83b6fde8814b4328817b792efbd933e31a1"}}, "hash": "5f001d69fd0935504c81ed3ff381584cb60d8ef8fe1d9e64f7998fe83c6a4cf7", "text": "40 OThER TR a NSM i TTERS a N d MO d U la TORS\n507inhibition of voltage-sensitive Ca2+ channels. mAChRs on \ncholinergic terminals function to inhibit ACh release, and \nmuscarinic antagonists, by blocking this inhibition, markedly \nincrease ACh release. Many of the behavioural effects associated with cholinergic pathways seem to be produced \nby ACh acting on mAChRs. Positive allosteric modulators \n(see Ch. 2) selective for different muscarinic receptors are under development.\nNicotinic ACh receptors (nAChRs) are ligand-gated cation \nchannels permeable to Na\n+, K+ and Ca2+ ions (see Chs 3 \nand 14). They are pentamers and can be formed as homo -\nmeric or heteromeric combinations of \u03b1 (\u03b12\u20137) and \u03b2 (\u03b22\u20134) \nsubunits (Ch. 3; see Gotti et al., 2008) distributed widely \nthroughout the brain (Table 40.2). Nicotine (see Ch. 49) exerts its central effects by agonist action on nAChRs. The \nheteromeric \u03b14\u03b22 and the homomeric \u03b17 subtypes are the \nmost extensively characterised. Subtype-specific agonists \nand positive allosteric modulators have been developed \nbut initial results from clinical trials for cognitive enhance -\nment have so far not lived up to expectation.\nnAChRs are located both pre- and postsynaptically. \nPresynaptic nAChRs act usually to facilitate the release of \nother transmitters such as glutamate, dopamine and GABA.\n4 \nPostsynaptic nAChRs mediate fast excitatory transmission, \nas in the periphery (see Ch.14).\nMany of the drugs that block nAChRs (e.g. tubocurarine ; \nsee Ch. 14) do not cross the blood\u2013brain barrier, and even those that do (e.g. mecamylamine) produce only modest \nCNS effects. Various nAChR knock-out mouse strains \nhave been produced and studied. Deletion of the various \nCNS-specific nAChR subtypes generally has rather little \neffect, although some cognitive impairment can be detected. Mutations in nAChRs may be the cause of some forms of epilepsy and changes in nAChR expression may occur in \ndisorders such as schizophrenia, attention deficit hyperactiv -\nity disorder, depression and anxiety, as well as following \nneurodegeneration in Alzheimer\u2019s and Parkinson\u2019s diseases.\nFUNCTIONAL ASPECTS\nThe main functions ascribed to cholinergic pathways are related to arousal, reward, learning and memory, and motor \ncontrol. The cholinergic projection from the ventral forebrain \nto the cortex is thought to mediate arousal, whereas the septohippocampal pathway is involved in learning and \nshort-term memory (see Hasselmo, 2006). Cholinergic \ninterneurons in the striatum are involved in motor control (see Ch. 41).\nMuscarinic agonists have been shown to partially restore \nlearning and memory deficits induced in experimental animals by lesions of the septohippocampal cholinergic pathway. Hyoscine, a muscarinic antagonist, impairs \nmemory in human subjects and causes amnesia when used as preanaesthetic medication. M\n1 receptor knock-out mice, \nhowever, show only slight impairment of learning and \nmemory (see Wess, 2004).\nNicotine increases alertness and also enhances learning \nand memory, as do various synthetic agonists at neuronal nAChRs. Conversely, CNS-active nAChR antagonists such \nas mecamylamine cause detectable, although slight, impair -\nment of learning and memory. Transgenic mice with choline acetyltransferase, the enzyme responsible for ACh synthesis, and the transporters that capture choline and \npackage ACh, which can be labelled by immunofluorescence.", "start_char_idx": 0, "end_char_idx": 3429, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a74e732c-8e9c-450a-b494-926f1628715a": {"__data__": {"id_": "a74e732c-8e9c-450a-b494-926f1628715a", "embedding": null, "metadata": {"page_label": "513", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f76cae65-7d50-4032-ada5-1c4d1ac41c56", "node_type": null, "metadata": {"page_label": "513", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f0c5e7f6895b4664f5edfc4b2e1ec44c653d156013bd918a55664acf72f5c72"}, "2": {"node_id": "46f51e5d-5d8e-422e-9694-b9c6bb6c9d28", "node_type": null, "metadata": {"page_label": "513", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5f001d69fd0935504c81ed3ff381584cb60d8ef8fe1d9e64f7998fe83c6a4cf7"}}, "hash": "6b18fabd8370a7a541368a5fa7e4c83b6fde8814b4328817b792efbd933e31a1", "text": "choline and \npackage ACh, which can be labelled by immunofluorescence. \nBiochemical studies on ACh precursors and metabolites are generally more difficult than corresponding studies on \nother amine transmitters, because the relevant substances, \ncholine and acetate, are involved in many processes other than ACh metabolism.\nCHOLINERGIC PATHWAYS IN THE CNS\nACh is very widely distributed in the brain, occurring in all parts of the forebrain (including the cortex), midbrain \nand brain stem, although there is little in the cerebellum. \nCholinergic neurons in the forebrain and brain stem send diffuse projections to many parts of the brain (Fig. 40.6). \nCholinergic neurons in the forebrain lie in a discrete area, \nforming the magnocellular forebrain nuclei (so called because the cell bodies are conspicuously large). Degeneration of \none of these, the nucleus basalis of Meynert , which projects \nmainly to the cortex, is associated with Alzheimer\u2019s disease \n(Ch. 41). Another cluster, the septohippocampal nucleus, \nprovides the main cholinergic input to the hippocampus, \nand is also involved in memory. In addition, there are \u2013 in \ncontrast to noradrenaline, dopamine and 5-HT-containing pathways \u2013 many local cholinergic interneurons, particularly \nin the corpus striatum, these being important in relation \nto Parkinson\u2019s disease and Huntington\u2019s chorea (Ch. 41).\nACETYLCHOLINE RECEPTORS\nAcetylcholine acts on both muscarinic (G protein\u2013coupled) and nicotinic (ionotropic) receptors in the CNS (see Ch. 14).\nThe muscarinic ACh receptors (mAChRs) in the brain \nare predominantly of the G\nq\u2013coupled M 1 class (i.e. M 1, M 3 \nand M 5 subtypes; see Ch. 14). Activation of these receptors \ncan result in excitation through blockade of M-type (KCNQ/\nKv7) K+ channels (see Delmas & Brown, 2005). G i/G o\u2013\ncoupled M 2 and M 4 receptors, however, are inhibitory \nthrough activation of inwardly rectifying K+ channels and Septohippocampal\npathwayNucleus\nbasalisStriatal\ninterneurons\nACETYLCHOLINECHyp\nHip\nPPT/\nLDThStr\nSep\nFig. 40.6 Simplified diagram of the acetylcholine \npathways in the brain, drawn as in Fig. 40.1. PPT/LD, \npedunculopontine and laterodorsal tegmental nuclei; other \nabbreviations as in Fig. 40.1. \n4See Khakh & Henderson (2000) for a description of how presynaptic \ncation-selective ligand-gated channels can, under different \ncircumstances, facilitate or enhance neurotransmitter release.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3359, "end_char_idx": 6248, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "35a70b95-0920-4c3c-9f28-b7408f203ddc": {"__data__": {"id_": "35a70b95-0920-4c3c-9f28-b7408f203ddc", "embedding": null, "metadata": {"page_label": "514", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0fdf224e-99d0-4940-9fcc-d3ea8d0422c7", "node_type": null, "metadata": {"page_label": "514", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c1ae0f7aaac839ec7141879b663b29cda23e2aa0a5be328f2b5f2a084495596"}, "3": {"node_id": "6c917109-6d6b-437e-a476-4b6e10d2963c", "node_type": null, "metadata": {"page_label": "514", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4fd0bb92bb8b9e87e68857d899ed4e35912891e2a0fdde38b0650acd3837a21f"}}, "hash": "8ee6f2dd843f07a803f85f215715bc9d7dcbfb178f127074e5cc6d2195e51d6a", "text": "40 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n508neuronal damage but it is also quickly converted to adeno -\nsine, which exerts a protective effect. These special char-\nacteristics of purine metabolism suggest that adenosine \nserves mainly as a safety mechanism, protecting the neurons from damage when their viability is threatened, for example disruption of brain nAChRs are only slightly impaired in spatial learning tasks. In the dopaminergic VTA to accum -\nbens \u2018reward\u2019 pathway, nicotine affects neuronal firing at the level of the cell soma in the VTA and modulates dopamine release from terminals in the nucleus accumbens \nto modify dopamine release in this reward pathway (see \nCh. 50).\nIn conclusion, both nAChRs and mAChRs may play a \nrole in learning and memory, while nAChRs also mediate behavioural arousal. Receptor knock-out mice are surpris -\ningly little affected, suggesting that alternative mechanisms may be able to compensate for the loss of ACh receptor \nsignalling.\nThe importance of cholinergic neurons in neurodegenera -\ntive conditions such as dementia and Parkinson\u2019s disease is discussed in Chapter 41. The role of nAChRs in addiction \nto nicotine is described in Chapter 49 and their role in modulating pain transmission in the CNS is described in \nChapter 43.\nPURINES\nBoth adenosine and ATP act as transmitters and/or modu -\nlators in the CNS (for review, see Fredholm et al., 2005; \nKhakh & North, 2012) as they do in the periphery (Ch. \n17). Mapping the pathways is difficult, because purinergic \nneurons are not easily identifiable histochemically. It is \nlikely that adenosine and ATP serve as neuromodulators.\nAdenosine is produced intracellularly from ATP. It is \nnot packaged into vesicles but is released mainly by carrier-mediated transport. Because the intracellular concentration of ATP (several mmol/L) greatly exceeds that of adenosine, \nconversion of a small proportion of ATP results in a large \nincrease in adenosine. ATP is packaged into vesicles and released by exocytosis as a conventional transmitter, but can also leak out of cells in large amounts under conditions \nof tissue damage. In high concentrations, ATP can act as \nan excitotoxin (like glutamate; see Ch. 41) and cause further Table 40.2 Presence of nicotinic receptors of different subunit composition in selected regions of the central \nnervous system\nBrain regionNicotinic receptors\n\u03b17 \u03b13\u03b22 \u03b13\u03b24 \u03b14\u03b22 \u03b14\u03b15\u03b2 \u03b16\u03b22\u03b23 \u03b16\u03b14\u03b22\u03b23\nCortex + + +\nHippocampus + + + +\nStriatum + + + +\nAmygdala + +\nThalamus +\nHypothalamus + +\nSubstantia nigra + + + + +\nCerebellum + + + +\nSpinal cord + + +\n\u03b17 may also form heteromeric receptors with \u03b22\tsubunits. \tnAChRs \tcomprising \t\u03b12\u03b22 and \u03b13\u03b23\u03b24 are found in some other areas of the \nbrain. \n(Data taken from Gotti et al., 2008.)\nAcetylcholine in the central \nnervous system \n\u2022\tSynthesis, \tstorage \tand \trelease \tof \tacetylcholine \t(ACh) \t\nin the central nervous system (CNS) are essentially the \nsame as in the periphery (Ch. 14).\n\u2022\tACh\tis\twidely \tdistributed \tin \tthe \tCNS, \timportant \t\npathways being:\n\u2013 basal forebrain (magnocellular) nuclei, which send a \ndiffuse projection to most forebrain structures, including the cortex;\n\u2013", "start_char_idx": 0, "end_char_idx": 3163, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6c917109-6d6b-437e-a476-4b6e10d2963c": {"__data__": {"id_": "6c917109-6d6b-437e-a476-4b6e10d2963c", "embedding": null, "metadata": {"page_label": "514", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0fdf224e-99d0-4940-9fcc-d3ea8d0422c7", "node_type": null, "metadata": {"page_label": "514", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c1ae0f7aaac839ec7141879b663b29cda23e2aa0a5be328f2b5f2a084495596"}, "2": {"node_id": "35a70b95-0920-4c3c-9f28-b7408f203ddc", "node_type": null, "metadata": {"page_label": "514", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8ee6f2dd843f07a803f85f215715bc9d7dcbfb178f127074e5cc6d2195e51d6a"}}, "hash": "4fd0bb92bb8b9e87e68857d899ed4e35912891e2a0fdde38b0650acd3837a21f", "text": "a \ndiffuse projection to most forebrain structures, including the cortex;\n\u2013 septohippocampal projection;\n\u2013 short interneurons in the striatum and nucleus \naccumbens.\n\u2022\tCertain\tneurodegenerative \tdiseases, \tespecially \t\ndementia\tand \tParkinson\u2019s \tdisease \t(see \tCh. \t41), \tare \t\nassociated with abnormalities in cholinergic pathways.\n\u2022\tBoth\tnicotinic \tand \tmuscarinic \t(predominantly \tM1) ACh \nreceptors occur in the CNS. The former mediate the central effects of nicotine. Nicotinic receptors are \nmainly located presynaptically; there are few examples \nof transmission mediated by postsynaptic nicotinic receptors.\n\u2022\tMuscarinic \treceptors \tappear \tto \tmediate \tthe \tmain \t\nbehavioural effects associated with ACh, namely effects on arousal, and on learning and short-term memory.\n\u2022\tMuscarinic \tantagonists \t(e.g. \thyoscine) cause \namnesia.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3088, "end_char_idx": 4407, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b57d5c18-9b63-4843-a108-d9c3d49290d0": {"__data__": {"id_": "b57d5c18-9b63-4843-a108-d9c3d49290d0", "embedding": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "206472a5-ae06-4c7d-8216-14b3408803bd", "node_type": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69235f4e0fbc083cb132a6d88662ffd9f7262c005439fd04509c5c011029bbf4"}, "3": {"node_id": "38bc94b2-7109-41c9-badf-52c26cd005f0", "node_type": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f9bdc4ede621862a1aaa1725b6f4a48ae63fc1ae53fa6d8909bd2a9309b41376"}}, "hash": "10e527ec5f1c2e815692ef2b914edb759619d15c3e35653941e5339e703f24cb", "text": "40 OThER TR a NSM i TTERS a N d MO d U la TORS\n509receptor antagonists, as they may have potential for the treatment of \ncognitive impairment associated with Alzheimer\u2019s disease (see Ch. \n41), schizophrenia (see Ch. 47), attention deficit hyperactivity disorder \n(see Ch. 49) and Parkinson\u2019s disease (see Ch. 41) as well as for the treatment of narcolepsy, obesity and pain states (Ellenbrock & Ghiabi, \n2014).\nOTHER CNS MEDIATORS\nWe now move from the familiar neuropharmacological \nterritory of the \u2018classic\u2019 monoamines to some of the odder \nagents which challenge many of our preconceived ideas \nof how neurotransmission functions. Useful drugs interact -\ning with some of these mediators are starting to be approved \nfor clinical use.\nMELATONIN\n\u25bc Melatonin ( N-acetyl-5-methoxytryptamine) (reviewed by \nDubocovich et al., 2010) is synthesised exclusively in the pineal, an \nendocrine gland that plays a role in establishing circadian rhythms. \nThe gland contains two enzymes, not found elsewhere, which convert \n5-HT by acetylation and O-methylation to melatonin, its hormonal \nproduct.\nThere are two well-defined melatonin receptors (MT 1 and MT 2) which \nare G protein\u2013coupled receptors \u2013 both coupling to G i/G o \u2013 found \nmainly in the brain and retina but also in peripheral tissues (see \nJockers et al., 2016). Another type (termed MT 3) has been suggested \nto be the enzyme quinone reductase 2 (QR2). The function of the \ninteraction between melatonin and QR2 is unclear.\nMelatonin secretion (in all animals studied, whether diurnal or \nnocturnal in their habits) is high at night and low by day. This rhythm \nis controlled by input from the retina via a noradrenergic retinohy -\npothalamic tract that terminates in the suprachiasmatic nucleus (SCN) \nin the hypothalamus, a structure often termed the \u2018biological clock\u2019, \nwhich generates the circadian rhythm. Activation of MT 1 receptors \ninhibits neuronal firing in the SCN and prolactin secretion from the \npituitary. Activation of MT 2 receptors phase shifts circadian rhythms \ngenerated within the SCN. Melatonin has antioxidant properties and may be neuroprotective in Alzheimer\u2019s disease and Parkinson\u2019s disease \n(see Ch. 41).\nGiven orally, melatonin is well absorbed but quickly metabolised, \nits plasma half-life being a few minutes. Based on its ability to reset the circadian clock, it has been promoted for various uses, such as \ncontrolling jet lag, improving the performance of night-shift workers, \ntreating insomnia in the elderly, and controlling sleep disorders in children with autism or attention deficit hyperactivity disorder (ADHD) \nclinical trials have been unconvincing. Ramelteon , an agonist at MT\n1 \nand MT 2 receptors, is used to treat insomnia (see Ch. 45) and ago-\nmelatine, which also has agonist actions at MT 1 and MT 2 receptors \nas well as antagonist actions at 5-HT 2C receptors, is a novel antidepres -\nsant drug (see Ch. 48).\nNITRIC OXIDE\nNO as a peripheral mediator is discussed in Chapter 21. \nIts significance as an important chemical mediator in the \nnervous system has demanded a considerable readjustment \nof our views about neurotransmission and neuromodulation \n(for review, see Chachlaki et al., 2017). The main defining \ncriteria for transmitter substances \u2013 namely that neurons should possess machinery for synthesising and storing the \nsubstance, that it should", "start_char_idx": 0, "end_char_idx": 3376, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "38bc94b2-7109-41c9-badf-52c26cd005f0": {"__data__": {"id_": "38bc94b2-7109-41c9-badf-52c26cd005f0", "embedding": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "206472a5-ae06-4c7d-8216-14b3408803bd", "node_type": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69235f4e0fbc083cb132a6d88662ffd9f7262c005439fd04509c5c011029bbf4"}, "2": {"node_id": "b57d5c18-9b63-4843-a108-d9c3d49290d0", "node_type": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10e527ec5f1c2e815692ef2b914edb759619d15c3e35653941e5339e703f24cb"}, "3": {"node_id": "58a29694-20d1-4992-87bc-277748883e79", "node_type": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0789154c302cf40fc3e89c2c6a16e49c848823efd86f696e60ad10c640185925"}}, "hash": "f9bdc4ede621862a1aaa1725b6f4a48ae63fc1ae53fa6d8909bd2a9309b41376", "text": "machinery for synthesising and storing the \nsubstance, that it should be released from neurons by \nexocytosis, that it should interact with specific membrane receptors and that there should be mechanisms for its \ninactivation \u2013 do not apply to NO. Moreover, it is an \ninorganic gas, not at all like the kind of molecule pharma -\ncologists are used to. The mediator function of NO is now by ischaemia or seizure activity. It has been suggested that adenosine deficiency may underlie a number of CNS \ndisorders such as some epilepsies as well as Alzheimer\u2019s \nand Parkinson\u2019s diseases (Boison & Aronica, 2015).\nAdenosine produces its effects through G protein\u2013coupled \nadenosine A receptors (see Ch. 17). There are four adenosine receptors \u2013 A\n1, A 2A, A 2B and A 3 \u2013 distributed throughout \nthe CNS. The overall effect of adenosine, or of various \nadenosine receptor agonists, is inhibitory, leading to effects \nsuch as drowsiness and sedation, motor incoordination, analgesia and anticonvulsant activity. Xanthines, such as \ncaffeine (Ch. 49), which are antagonists at A\n2 receptors, \nproduce arousal and alertness.\nFor ATP there are two forms of receptor \u2013 P2X and P2Y \nreceptors (see Ch. 17 also). P2X receptor subunits (P2X1-7) \nare trimeric ligand-gated cation channels that can be \nhomomeric or heteromeric in composition. The evidence \nin favour of ATP acting on postsynaptic P2X receptors mediating fast synaptic transmission in the brain remains \nweak. P2X receptors are located on the postsynaptic cell \nmembrane away from sites of synaptic contact, on nerve terminals and on astrocytes. Like acetylcholine at nicotinic receptors (see p. 507), ATP acting on nerve terminal P2X \nreceptors appears to play a neuromodulatory role. There \nare eight P2Y receptors,\n5 all are G protein coupled (see \nTable 17.1).\nWhile there is little doubt that purinergic signalling plays \na significant role in CNS function, our understanding is still very limited. There is optimism that purinergic receptor \nligands \u2013 both agonists and antagonists \u2013 will prove useful \nin a wide range of CNS disorders (see Chen et al., 2013; \nJacobson & M\u0171ller, 2016).\nHISTAMINE\n\u25bc Histamine is present in the brain in much smaller amounts than \nin other tissues, such as skin and lung, but undoubtedly serves a \nneurotransmitter role (see Brown et al., 2001). The cell bodies of \nhistaminergic neurons, which also synthesise and release a variety \nof other transmitters, are restricted to a small part of the hypothalamus, \nand their axons run to virtually all parts of the brain. Unusually, no \nuptake mechanism for histamine is present, its action being terminated instead by enzymic methylation. Histamine\u2019s prolonged extracellular \npresence may explain its involvement in homeostatic process such \nas the sleep/wake cycle, food and water intake and temperature regulation.\nHistamine acts on four types of receptor (H\n1\u20134; Ch. 18) in the brain. \nH1\u2013H 3 occur in most brain regions, H 4 has a more restricted dis -\ntribution. All are G protein coupled \u2013 H 1 receptors to G q, H 2 to G s \nand H 3 and H 4 to G i/Go. H 3 receptors are inhibitory receptors on \nhistamine-releasing neurons as well as on terminals releasing other \nneurotransmitters.\nLike other monoamine transmitters, histamine is involved in many \ndifferent CNS functions. Histamine release follows a distinct circadian \npattern, the neurons being active", "start_char_idx": 3317, "end_char_idx": 6714, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "58a29694-20d1-4992-87bc-277748883e79": {"__data__": {"id_": "58a29694-20d1-4992-87bc-277748883e79", "embedding": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "206472a5-ae06-4c7d-8216-14b3408803bd", "node_type": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "69235f4e0fbc083cb132a6d88662ffd9f7262c005439fd04509c5c011029bbf4"}, "2": {"node_id": "38bc94b2-7109-41c9-badf-52c26cd005f0", "node_type": null, "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f9bdc4ede621862a1aaa1725b6f4a48ae63fc1ae53fa6d8909bd2a9309b41376"}}, "hash": "0789154c302cf40fc3e89c2c6a16e49c848823efd86f696e60ad10c640185925", "text": "Histamine release follows a distinct circadian \npattern, the neurons being active by day and silent by night. H 1 \nreceptors in the cortex and reticular activating system contribute to \narousal and wakefulness, and H 1 receptor antagonists that access the \nCNS produce sedation (see Ch. 45). Antihistamines are widely used to control nausea and vomiting, for example, in motion sickness and \nmiddle ear disorders, as well as to induce sleep. Recent pharmaceutical industry activity has centred on the development of selective H\n3 \n5Unfortunately the nomenclature for P2Y receptors has developed in a \nrather haphazard manner. There is compelling evidence for the \nexistence of P2Y 1,2,4,6,11,12,13 and 14 receptors, but not for others.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6693, "end_char_idx": 7908, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aad80dfc-dbf0-487a-ac74-ab9aa48851f2": {"__data__": {"id_": "aad80dfc-dbf0-487a-ac74-ab9aa48851f2", "embedding": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e895e8ae-bbf3-4933-8651-67ec9949c758", "node_type": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e13a02b30ee62c1a33d3b0ecc5c6d8f7a53dc9351c923eaf0793091a3ec89660"}, "3": {"node_id": "3ac28c5d-8e8a-4968-8271-2216f469b561", "node_type": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44b1892d847959d5172daab40f77b84e635a849140e8ce1362226c90ca2cd4b2"}}, "hash": "5a638030749a8151c4473def198887704f0d8b8fa6754e2c454d66d81ade6c89", "text": "40 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n510Hydrogen sulfide (H 2S) has been postulated to be involved in learning, \nmemory and pain perception but then again so has almost every \nother neurotransmitter or neuromodulator! It has been suggested that \nbrain H 2S concentrations are lowered in Alzheimer\u2019s and Parkinson\u2019s \ndiseases but the relevance of such observations still needs to be \nworked out.\nLIPID MEDIATORS\n\u25bc T he formation of arachidonic acid, and its conversion to eicosanoids \n(mainly prostaglandins, leukotrienes and hydroxyeicosatetraenoic acids (HETEs) \u2013 see Ch. 18) and to endocannabinoids, anandamide \nand 2-arachidonoylglycerol (see Ch. 20), also take place in the CNS.\nPhospholipid cleavage, leading to arachidonic acid production, occurs \nin neurons in response to receptor activation by many different \nmediators, including neurotransmitters. The arachidonic acid so formed can act directly as an intracellular messenger, controlling both ion \nchannels and various parts of the protein kinase cascade (see Ch. 3), \nproducing both rapid and delayed effects on neuronal function. Both arachidonic acid itself and its products escape readily from the cell \nof origin and can affect neighbouring structures, including presynaptic \nterminals (retrograde signalling) and adjacent cells (paracrine signal -\nling), by acting on receptors or by acting directly as intracellular \nmessengers. Fig. 40.7 shows a schematic view of the variety of different \nroles these agents can play at the synapse.\nArachidonic acid can be metabolised to eicosanoids, some of which \n(principally the HETEs) can also act as intracellular messengers acting in the same cell. Eicosanoids can also exert an autocrine \neffect via membrane receptors expressed by the cell (see Ch. 18). The \neicosanoids play important roles in neural function including pain, temperature regulation, sleep induction, synaptic plasticity and spatial \nlearning.\nIt is now generally accepted that endocannabinoids, such as anan -\ndamide and 2-arachidonylglycerol, act as retrograde synaptic mes -\nsengers in the CNS (see Pertwee, 2015 and Ch. 20). They are synthesised \nand secreted in response to a rise in intracellular Ca\n2+ and activate \npresynaptic CB 1 receptors inhibiting the release of neurotransmitters \nsuch as glutamate and GABA. CB 1 receptors are widely distributed \nin the brain and spinal cord, not only on neurons but also on astrocytes \nand microglia, whereas CB 2 receptor expression is much less but may \nbe up-regulated under pathological conditions. Agonists at CB 1 \nreceptors have therapeutic potential for the treatment of vomiting, pain (CB\n2 receptor agonists may also be effective in some pain states), \nmuscle spasms as occur in conditions such as multiple sclerosis and anxiety, as well as in other brain disorders including Alzheimer\u2019s \ndisease and tardive dyskinesias. Endocannabinoids released into the extracellular space are removed into cells by facilitated transport, for \nwhich inhibitors have been developed, and then metabolised (Cascio \n& Marini, 2015). Anandamide is metabolised by fatty acid amide \nhydrolase (FAAH; see Ch. 20). Inhibitors of FAAH potentiate the \neffects of endocannabinoids and were shown to be effective analgesics \nin animal models of pain (Roques et al., 2012).6 The CB 1-receptor \nantagonist rimonabant was introduced as an anti-obesity agent but \nsubsequently had to be withdrawn because of negative effects on \nmood (see Ch. 20). Endocannabinoids, besides", "start_char_idx": 0, "end_char_idx": 3483, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3ac28c5d-8e8a-4968-8271-2216f469b561": {"__data__": {"id_": "3ac28c5d-8e8a-4968-8271-2216f469b561", "embedding": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e895e8ae-bbf3-4933-8651-67ec9949c758", "node_type": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e13a02b30ee62c1a33d3b0ecc5c6d8f7a53dc9351c923eaf0793091a3ec89660"}, "2": {"node_id": "aad80dfc-dbf0-487a-ac74-ab9aa48851f2", "node_type": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a638030749a8151c4473def198887704f0d8b8fa6754e2c454d66d81ade6c89"}, "3": {"node_id": "f33ac858-ff8e-435b-8ba9-329de00088ef", "node_type": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6eb857e35ff0b519c136051f06bf4c46c2cbf4227a4c31cd8d71657359baa039"}}, "hash": "44b1892d847959d5172daab40f77b84e635a849140e8ce1362226c90ca2cd4b2", "text": "of negative effects on \nmood (see Ch. 20). Endocannabinoids, besides being agonists at cannabinoid receptors, also interact with a variety of ion channels \nincluding TRPV1 channels (see Fig. 40.7 and Ch. 43), 5-HT3 receptors \n(see pp. 504\u2013505), calcium channels and potassium channels (Pertwee, \n2015)\nLysophosphatidic acid and sphingosine 1-phosphate are phospholipids \nwith important signalling functions in the brain and elsewhere \nthroughout the body. Their effects are mediated by multiple G \nprotein\u2013coupled receptors (LPA1-6 and S1P1-5). Agonists at S1P1 receptors are in phase III clinical trials for the treatment of multiple \nsclerosis (see Ch. 41).well established (Zhou & Zhu, 2009). NO diffuses rapidly \nthrough cell membranes, and its action is not highly \nlocalised. Its half-life depends greatly on the chemical \nenvironment, ranging from seconds in blood to several minutes in normal tissues. The rate of inactivation of NO \n(see Ch. 21, reaction 21.1) increases disproportionately with \nNO concentration, so low levels of NO are relatively stable. The presence of superoxide, with which NO reacts (see \nlater), shortens its half-life considerably.\nNO in the nervous system is produced mainly by the \nconstitutive neuronal form of NO synthase (nNOS; see Ch. \n21), which can be detected either histochemically or by immunolabelling. This enzyme is present in roughly 2% of \nneurons, both short interneurons and long-tract neurons, in virtually all brain areas, with particular concentrations in \nthe cerebellum and hippocampus. It occurs in cell bodies \nand dendrites, as well as in axon terminals, suggesting that NO may be produced both pre- and postsynaptically. \nnNOS is calmodulin-dependent and is activated by a rise \nin intracellular Ca\n2+ concentration, which can occur by \nmany mechanisms (see Ch. 4), including action potential \nconduction and neurotransmitter action, especially by \nglutamate activation of NMDA receptors. NO is not stored, but released as it is made. Many studies have shown that \nNO production is increased by activation of synaptic \npathways, or by other events, such as brain ischaemia (see \nCh. 41).\nNO exerts pre- and postsynaptic actions on neurons as \nwell as acting on glial cells (Garthwaite, 2008). It produces its effects in two main ways:\n1. By activation of soluble guanylyl cyclase, leading to \nthe production of cGMP, which itself or through activation of protein kinase G can affect membrane \nion channels (Steinert et al., 2010). This \u2018physiological\u2019 \ncontrol mechanism operates at low NO concentrations \nof about 0.1 \u00b5mol/L.\n2. By reacting with the superoxide free radical to \ngenerate peroxynitrite, a highly toxic anion that acts by oxidising various intracellular proteins. This \nrequires concentrations of 1\u201310 \u00b5mol/L, which are \nachieved in brain ischaemia.\nThere is good evidence that NO plays a role in synaptic plasticity (see Ch. 39), because long-term potentiation and depression are reduced or prevented by NOS inhibitors \nand are absent in transgenic mice in which the nNOS gene \nhas been disrupted.\nBased on the same kind of evidence, NO is also believed \nto play an important part in the mechanisms by which \nischaemia causes neuronal death (see Ch. 41). There is also evidence that it may be involved in other processes, includ -\ning neurodegeneration in Parkinson\u2019s disease, senile dementia and amyotrophic lateral sclerosis, and the local control of blood flow linked to neuronal", "start_char_idx": 3425, "end_char_idx": 6890, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f33ac858-ff8e-435b-8ba9-329de00088ef": {"__data__": {"id_": "f33ac858-ff8e-435b-8ba9-329de00088ef", "embedding": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e895e8ae-bbf3-4933-8651-67ec9949c758", "node_type": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e13a02b30ee62c1a33d3b0ecc5c6d8f7a53dc9351c923eaf0793091a3ec89660"}, "2": {"node_id": "3ac28c5d-8e8a-4968-8271-2216f469b561", "node_type": null, "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44b1892d847959d5172daab40f77b84e635a849140e8ce1362226c90ca2cd4b2"}}, "hash": "6eb857e35ff0b519c136051f06bf4c46c2cbf4227a4c31cd8d71657359baa039", "text": "amyotrophic lateral sclerosis, and the local control of blood flow linked to neuronal activity.\n\u25bc Other \u2018gaseotransmitters\u2019. These include carbon monoxide, \nhydrogen sulfide and, more recently, ammonia (see Ch. 21 and Wang, \n2014). While evidence is accumulating for their roles in CNS disorders, \ntheir pharmacology is still at a very preliminary stage.\nCarbon monoxide (CO) is best known as a poisonous gas present in \nvehicle exhaust, which binds strongly to haemoglobin, causing tissue anoxia. However, it is also formed endogenously and has many features \nin common with NO. Neurons and other cells contain a CO-generating \nenzyme, haem oxygenase, and CO, like NO, activates guanylyl cyclase. There is some evidence that CO plays a role in memory mechanisms \nin the hippocampus (see Cutajar & Edwards, 2007).6Readers may recall the tragic phase I clinical trial of one FAAH \ninhibitor, BIA 10-2474, that caused sudden, severe CNS damage and \nresulted in one subject being brain dead and four others having \npermanent brain damage. In this instance the adverse effects were due to actions of the drug on other lipases.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6864, "end_char_idx": 8466, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3b83f416-979c-438f-8f32-c01cee635913": {"__data__": {"id_": "3b83f416-979c-438f-8f32-c01cee635913", "embedding": null, "metadata": {"page_label": "517", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd36e499-6c1c-4c7d-9b35-1398b655577a", "node_type": null, "metadata": {"page_label": "517", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d811f12562ab647ba994ed6f7bbda3b75822a1f12c9befb006c62dbd2190063a"}, "3": {"node_id": "f8bdb659-9543-4785-9ee0-68f2d02d5d02", "node_type": null, "metadata": {"page_label": "517", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6e2ef5d3c332c3fafb585b479b7d27fba23e6821467d369e396550446301ac04"}}, "hash": "db45cd8992251063363b89573695f34f1d9e48c1d416d7c4eb09a8ea28fe96e0", "text": "40 OThER TRaNSMiTTERS aNd MOdUlaTORS\n511Ion channels,\nkinases, etc.\nFunctional\neffectsPL\nECs\nEicTransmitters\nModulators\nTRPV1\nOTHER CELLS\n(NEURONS, GLIA)Paracrine\nsignallingRetrograde\nsignallingAutocrine\nsignalling\nPRESYNAPTIC\nTERMINAL\nAA\nIntracellular\nsignalling\nFig. 40.7 Postulated modes of signalling by lipid mediators. Arachidonic acid (AA) is formed by receptor-mediated cleavage of \nmembrane phospholipid. It can act directly as an intracellular messenger on ion channels or components of different kinase cascades, \nproducing various long- and short-term effects. It can also be converted to eicosanoids (prostaglandins, leukotrienes or \nhydroxyeicosatetraenoic\t acids\t[HETEs])\tor\tto\tthe\tendocannabinoids\t (ECs),\tanandamide\t and\t2-arachidonoylglycerol.\t ECs\tcan\talso\tact\tas\t\nintracellular\t messengers\t to\tactivate\tTRPV1\tchannels.\t HETEs\tcan\talso\tact\tdirectly\tas\tintracellular\t messengers.\t All\tthese\tmediators\t also\t\ndiffuse out of the cell, and exert effects on presynaptic terminals and neighbouring cells, acting either on extracellular receptors or \nintracellularly. There are examples of most of these modes of signalling, but only limited information about their functional significance in the \nnervous system. Eic, eicosanoids; PL, membrane phospholipid. \nOther transmitters and modulators \nPurines\n\u2022\tATP\tfunctions\t as\ta\tneurotransmitter,\t being\tstored\tin\t\nvesicles and released by exocytosis. It acts via ionotropic \nP2X\treceptors\t and\tmetabotropic\t P2Y\treceptors.\n\u2022\tCytosolic\t ATP\tis\tpresent\tat\trelatively\thigh\tconcentration\t\nand can be released directly if neuronal viability is \ncompromised (e.g. in stroke). Excessive release may be \nneurotoxic.\n\u2022\tReleased\t ATP\tis\trapidly\tconverted\t to\tADP,\tAMP\tand\t\nadenosine.\n\u2022\tAdenosine\t is\tnot\tstored\tin\tvesicles\tbut\tis\treleased\tby\t\ncarrier\tmechanisms\t or\tgenerated\t from\treleased\tATP,\t\nmainly under pathological conditions.\n\u2022\tAdenosine\t exerts\tmainly\tinhibitory\teffects,\tthrough\tA1 \nand A 2 receptors, resulting in sedative, anticonvulsant \nand neuroprotective effects, and acting as a safety \nmechanism.\n\u2022\tMethylxanthines\t (e.g.\t caffeine ) are antagonists at A 2 \nreceptors and increase wakefulness.\nHistamine\n\u2022\tHistamine\t fulfils\tthe\tcriteria\tfor\ta\tneurotransmitter.\t\nHistaminergic\t neurons\toriginate\tin\ta\tsmall\tarea\tof\tthe\t\nhypothalamus and have a widespread distribution.\u2022\tH 1,\tH2\tand\tH3 receptors are widespread in the brain.\n\u2022\tThe\tfunctions\t of\thistamine\t are\tnot\twell\tunderstood,\t the\t\nmain clues being that histaminergic neurons are active \nduring\twaking\thours,\tand\tH1 receptor antagonists are \nstrongly sedative.\n\u2022\tH 1 receptor antagonists are antiemetic.\nMelatonin\n\u2022\tMelatonin\t is\tsynthesised\t from\t5-hydroxytryptamine,\t\nmainly in the pineal gland, from which it is released as a \ncirculating hormone.\n\u2022\tSecretion\t is\tcontrolled\t", "start_char_idx": 0, "end_char_idx": 2802, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f8bdb659-9543-4785-9ee0-68f2d02d5d02": {"__data__": {"id_": "f8bdb659-9543-4785-9ee0-68f2d02d5d02", "embedding": null, "metadata": {"page_label": "517", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd36e499-6c1c-4c7d-9b35-1398b655577a", "node_type": null, "metadata": {"page_label": "517", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d811f12562ab647ba994ed6f7bbda3b75822a1f12c9befb006c62dbd2190063a"}, "2": {"node_id": "3b83f416-979c-438f-8f32-c01cee635913", "node_type": null, "metadata": {"page_label": "517", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "db45cd8992251063363b89573695f34f1d9e48c1d416d7c4eb09a8ea28fe96e0"}}, "hash": "6e2ef5d3c332c3fafb585b479b7d27fba23e6821467d369e396550446301ac04", "text": "released as a \ncirculating hormone.\n\u2022\tSecretion\t is\tcontrolled\t by\tlight\tintensity,\tbeing\tlow\tby\tday\t\nand high by night. Fibres from the retina run to the \nsuprachiasmatic nucleus (\u2018biological clock\u2019), which \ncontrols the pineal gland via its sympathetic \ninnervation.\n\u2022\tMelatonin\t acts\ton\tMT 1\tand\tMT 2 receptors in the brain.\n\u2022\tAgonists\t at\tmelatonin\t receptors\t induce\tsleep\tand\thave\t\nantidepressant properties.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2739, "end_char_idx": 3633, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5233d938-e6df-4175-9cc0-fc0db9f00357": {"__data__": {"id_": "5233d938-e6df-4175-9cc0-fc0db9f00357", "embedding": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ee278a6-3fc5-4738-82cb-01b3efec6ae9", "node_type": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19bac947751b45acc24bf1c8856f8200c2aa0f647f2bdbe6cd50e78cc4425897"}, "3": {"node_id": "4a7738a4-a5fa-48be-8e17-f72615187bc6", "node_type": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b00f3bd3ac13061bf0713197b96c778511420ab4c8cd0c95257b1f639370546"}}, "hash": "184fec15066f4eb207d2aa77191d10177d15fc25015a04c98efb38d527b77110", "text": "40 SECTION 4 \u2003\u2003NERVOUS SYSTEM\n512A FINAL MESSAGE\nIn the last two chapters we have taken a long and tortu -\nous tour through the brain and its chemistry, with two \nquestions at the back of our minds. What mediators and \nwhat receptors play a key role in what brain functions? \nHow does the information relate to existing and future \ndrugs that aim to correct malfunctions? Through the efforts \nof a huge army of researchers deploying an arsenal of \npowerful modern techniques, the answers to these questions \nare slowly being produced. The array of potential CNS \ntargets \u2013 comprising multiple receptor subtypes, many \nwith the added complexity of heteromeric assemblies, \nsplice variants, etc., along with regulatory mechanisms \nthat control their expression and localisation \u2013 continues \nto grow in complexity. Speculation about the best target \nto aim at in order to ameliorate the effect of a particular brain malfunction, such as stroke or schizophrenia, has \nbecome less focused, even if better informed, than it was \ntwo decades ago. In the ensuing chapters in this section we \nshall find that most of the therapeutic successes have come \nfrom chance discoveries that were followed up empirically; \nfew have followed a logical, mechanism-based route to \nsuccess. The optimistic view is that this is changing, and \nthat future therapeutic discoveries will depend less on luck \nand more on molecular logic. But the revolution is slow \nin coming. One of the key problems, perhaps, is that the \nbrain puts cells, organelles and molecules exactly where \nthey are needed, and uses the same molecules to perform \ndifferent functions in different locations. Drug discovery \nscientists are getting quite good at devising molecule-\nspecific ligands (see Ch. 60), but we lack delivery systems \nable to target them anatomically even to macroscopic \nbrain regions, let alone to specific cells and subcellular \nstructures.\nREFERENCES AND FURTHER READING\nGeneral references\nIversen, L.L., Iversen, S.D., Bloom, F.E., Roth, R.H., 2009. Introduction \nto Neuropsychopharmacology. Oxford University Press, New York. \n(Clear and well-written textbook giving more detailed information on many \ntopics covered in this chapter )\nNestler, E.J., Hyman, S.E., Holtzman, M., Malenka, R.C., 2015. \nMolecular Neuropharmacology: A Foundation for Clinical \nNeuroscience, third ed. McGraw-Hill, New York. ( Good textbook )\nNoradrenaline\nBylund, D.B., 2007. Receptors for norepinephrine and signal \ntransduction pathways. In: Ordway, G.A., Schwartz, M.A.Frazer, A. \n(Eds.), Brain Norepinephrine. Cambridge University Press, \nLondon.\nNikolic, K., Agbaba, D., 2012. Imidazoline antihypertensive drugs: \nselective I 1-imidazoline receptor activation. Cardiovasc. Ther. 30, \n209\u2013216. ( An update on the potential usefulness of drugs acting at the \nmysterious imidazoline receptors )\nDopamine\nBj\u00f6rklund, A., Dunnett, S.B., 2007. Dopamine neuron systems in the \nbrain: an update. Trends Neurosci. 30, 194\u2013202. ( Short review of the \nanatomy of dopaminergic neurons in the central nervous system )\nDe Mei, C., Ramos, M., Iitaka, C., Borrelli, E., 2009. Getting specialized: \npresynaptic and postsynaptic dopamine D 2 receptors. Curr. Opin. \nPharmacol. 9, 53\u201358.Girault, J.A., Greengard, P., 2004. The neurobiology of dopamine \nsignalling. Arch. Neurol. 61, 641\u2013644. ( Short review", "start_char_idx": 0, "end_char_idx": 3348, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4a7738a4-a5fa-48be-8e17-f72615187bc6": {"__data__": {"id_": "4a7738a4-a5fa-48be-8e17-f72615187bc6", "embedding": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ee278a6-3fc5-4738-82cb-01b3efec6ae9", "node_type": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19bac947751b45acc24bf1c8856f8200c2aa0f647f2bdbe6cd50e78cc4425897"}, "2": {"node_id": "5233d938-e6df-4175-9cc0-fc0db9f00357", "node_type": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "184fec15066f4eb207d2aa77191d10177d15fc25015a04c98efb38d527b77110"}, "3": {"node_id": "ffc6920d-0050-4702-b504-b8c222d5492b", "node_type": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe7b109679b64b558e2fbaba7c2d3a78b906e852aa2ccaf9dcf1cb26b0e3cf5e"}}, "hash": "0b00f3bd3ac13061bf0713197b96c778511420ab4c8cd0c95257b1f639370546", "text": "\nsignalling. Arch. Neurol. 61, 641\u2013644. ( Short review article )\n5-Hydroxytryptamine\nFilip, M., Bader, M., 2009. Overview of 5-HT receptors and their role in \nphysiology and pathology of the central nervous system. Pharm. Rep. \n61, 761\u2013777.\nJensen, A.A., Davies, P.A., Br\u00e4uner-Osborne, H., Krzywkowski, K., \n2008. 3B but which 3B? And that\u2019s just one of the questions: the \nheterogeneity of human 5-HT 3 receptors. Trends Pharmacol. Sci. 29, \n437\u2013444. ( Discusses the potential complexity of 5-HT 3 receptors now that \nnew subunits have been discovered )\nMuller, C., Jacobs, B., 2009. Handbook of Behavioral Neurobiology of \nSerotonin, vol. 18, (Handbook of Behavioral Neuroscience). Academic \nPress, Oxford. ( Extensive coverage of the role of 5-HT in the brain )\nPeters, J.A., Hales, T.G., Lambert, J.J., 2005. Molecular determinants of \nsingle-channel conductance and ion selectivity in the Cys-loop family: \ninsights from the 5-HT 3 receptor. Trends Pharmacol. Sci. 26, 587\u2013594. \n(For those who thought ligand-gated ion channels were just simple pores \nopened by neurotransmitters, this review will contain a few surprises! )\nAcetylcholine\nDelmas, P., Brown, D.A., 2005. Pathways modulating neural KCNQ/M \n(Kv7) potassium channels. Nat. Rev. Neurosci. 6, 850\u2013862. ( Gives \ninformation on the functional significance of the \u2018M-current\u2019 and the \ntherapeutic potential of drugs that modify it )Other mediators \nNitric oxide (see Ch. 21)\n\u2022\tNeuronal\t nitric\toxide\tsynthase\t(nNOS)\tis\tpresent\tin\tmany\t\ncentral nervous system neurons, and nitric oxide (NO) \nproduction is increased by mechanisms (e.g. transmitter \naction) that raise intracellular Ca2+.\n\u2022\tNO\taffects\tneuronal\tfunction\tby\tincreasing\t cGMP\t\nformation, producing both inhibitory and excitatory \neffects on neurons.\n\u2022\tIn\tlarger\tamounts,\t NO\tforms\tperoxynitrite,\t which\t\ncontributes to neurotoxicity.\n\u2022\tInhibition\t of\tnNOS\treduces\tlong-term\t potentiation\t \nand long-term depression, probably because NO \nfunctions as a retrograde messenger. Inhibition of \nnNOS also protects against ischaemic brain damage in \nanimal models.\u2022\tCarbon\t monoxide\t and\thydrogen\t sulfide\tmay\talso\tbe\t\nneural mediators.\nLipid mediators\n\u2022\tArachidonic\t acid\tis\tproduced\t in\tneurons\tby\treceptor-\nmediated hydrolysis of phospholipid. It is converted to \nvarious eicosanoids and endocannabinoids.\n\u2022\tArachidonic\t acid\titself,\tas\twell\tas\tits\tactive\tproducts,\t can\t\nproduce rapid and slow effects by regulation of ion \nchannels and protein kinase cascades. Such effects can \noccur in the donor cell or in adjacent cells and nerve \nterminals.\n\u2022\tAnandamide\t and\t2-arachidonoylglycerol\t are\tendogenous\t\nactivators\t of\tcannabinoid\t CB 1\tand\tCB 2 receptors (Ch. \n20)\tand\talso\tof\tthe\tTRPV1\treceptor\t(Ch.\t43).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3302, "end_char_idx": 6176, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ffc6920d-0050-4702-b504-b8c222d5492b": {"__data__": {"id_": "ffc6920d-0050-4702-b504-b8c222d5492b", "embedding": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ee278a6-3fc5-4738-82cb-01b3efec6ae9", "node_type": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19bac947751b45acc24bf1c8856f8200c2aa0f647f2bdbe6cd50e78cc4425897"}, "2": {"node_id": "4a7738a4-a5fa-48be-8e17-f72615187bc6", "node_type": null, "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b00f3bd3ac13061bf0713197b96c778511420ab4c8cd0c95257b1f639370546"}}, "hash": "fe7b109679b64b558e2fbaba7c2d3a78b906e852aa2ccaf9dcf1cb26b0e3cf5e", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6176, "end_char_idx": 6559, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6f6c68a6-1d04-4e89-bfbb-bd39194fd9cc": {"__data__": {"id_": "6f6c68a6-1d04-4e89-bfbb-bd39194fd9cc", "embedding": null, "metadata": {"page_label": "519", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0f2be16c-6fb1-47c4-85fb-07308a9cae35", "node_type": null, "metadata": {"page_label": "519", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e63643b84dbcbd99ff3fc9a6db7f0c429773836fd04aa524e6c6bd7d5b84280"}, "3": {"node_id": "4d71c198-8091-405d-ba4b-cec3a2cf630c", "node_type": null, "metadata": {"page_label": "519", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7d0328d3dabee7f3c8152e0efc115525158aab66c3a4776595544c4d2e48ee7d"}}, "hash": "a0f0b714e0722e44e0c642b59fac9f0378b9be0d81dc8cd766811a99913fb7cd", "text": "40 OThER TRaNSMiTTERS aNd MOdUlaTORS\n513Dubocovich, M.L., Delagrange, P., Krause, D.N., Sugden, D., Cardinali, \nD.P., Olcese, J., 2010. International Union of Basic and Clinical \nPharmacology. LXXV. Nomenclature, classification, and \npharmacology of G protein-coupled melatonin receptors. Pharmacol. \nRev. 62, 343\u2013380.\nEllenbroek, B.A., Ghiabi, B., 2014. The other side of the histamine H3 \nreceptor. Trends Neurosci. 37, 191\u2013199.\nFredholm, B.B., Chen, J.F., Masino, S.A., Vaugeois, J.M., 2005. Actions of \nadenosine at its receptors in the CNS: insights from knockouts and \nfrom drugs. Annu. Rev. Pharmacol. Toxicol. 45, 395\u2013412.\nGarthwaite, J., 2008. Concepts of neural nitric oxide-mediated \ntransmission. Eur. J. Neurosci. 27, 2783\u20132802.\nJacobson, K.A., Muller, C.E., 2016. Medicinal chemistry of adenosine, \nP2Y and P2X receptors. Neuropharmacology 104, 31\u201349.\nJockers, R., Delagrange, P., Dubocovich, M.L., et al., 2016. Update on \nmelatonin receptors: IUPHAR Review 20. Br. J. Pharmacol. 173, \n2702\u20132725.\nKhakh, B.S., North, R.A., 2012. Neuromodulation by extracellular ATP \nand P2X receptors in the CNS. Neuron 76, 51\u201369.\nPertwee, R.G., 2015. Endocannabinoids and their pharmacological \naction. In \u2018Endocannabinoids\u2019, Pertwee R.G. (Ed.), Handb. Exp. \nPharmacol. 231, 1\u201338.\nRoques, B.P., Fourni\u00e9-Zaluski, M.C., Wurm, M., 2012. Inhibiting the \nbreakdown of endogenous opioids and cannabinoids to alleviate pain. \nNat. Rev. Drug Discov. 11, 292\u2013310. ( Interesting review of potential for \nsuch inhibitors to reduce pain )\nSteinert, J.R., Chernova, T., Forsythe, I.D., 2010. Nitric oxide signaling in \nbrain function, dysfunction, and dementia. Neuroscientist 16, 435\u2013452.\nWang, R., 2014. Gasotransmitters: growing pains and joys. Trends \nBiochem. Sci. 39, 227\u2013232.\nZhou, L., Zhu, D.Y., 2009. Neuronal nitric oxide synthase: structure, \nsubcellular localization, regulation and clinical implications. Nitric \nOxide 20, 223\u2013230.Gotti, C., Zoli, M., Clementi, F., 2008. Brain nicotinic acetylcholine \nreceptors: native subtypes and their relevance. Trends Pharmacol. Sci. \n27, 482\u2013491.\nHasselmo, M.E., 2006. The role of acetylcholine in learning and \nmemory. Curr. Opin. Neurobiol. 16, 710\u2013715.\nKhakh, B.S., Henderson, G., 2000. Modulation of fast synaptic \ntransmission by presynaptic ligand-gated cation channels. J. Auton. \nNerv. Syst. 81, 110\u2013121. ( Describes how activation of presynaptic \nligand-gated cation channels can either enhance or inhibit neurotransmitter \nrelease )\nWess, J., 2004. Muscarinic acetylcholine receptor knockout mice: novel \nphenotypes and clinical implications. Annu. Rev. Pharmacol. Toxicol. \n44, 423\u2013450. ( Description of functional effects of deleting various peripheral \nand central", "start_char_idx": 0, "end_char_idx": 2718, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4d71c198-8091-405d-ba4b-cec3a2cf630c": {"__data__": {"id_": "4d71c198-8091-405d-ba4b-cec3a2cf630c", "embedding": null, "metadata": {"page_label": "519", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0f2be16c-6fb1-47c4-85fb-07308a9cae35", "node_type": null, "metadata": {"page_label": "519", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e63643b84dbcbd99ff3fc9a6db7f0c429773836fd04aa524e6c6bd7d5b84280"}, "2": {"node_id": "6f6c68a6-1d04-4e89-bfbb-bd39194fd9cc", "node_type": null, "metadata": {"page_label": "519", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a0f0b714e0722e44e0c642b59fac9f0378b9be0d81dc8cd766811a99913fb7cd"}}, "hash": "7d0328d3dabee7f3c8152e0efc115525158aab66c3a4776595544c4d2e48ee7d", "text": "( Description of functional effects of deleting various peripheral \nand central mAChR isoforms )\nOther messengers\nBoison, D., Aronica, E., 2015. Comorbidities in neurology: is adenosine \nthe common link? Neuropharmacology 97, 18\u201334.\nBrown, R.E., Stevens, D.R., Haas, H.L., 2001. The physiology of brain \nhistamine. Prog. Neurobiol. 63, 637\u2013672. ( Useful review article )\nBuscemi, N., Vandermeer, B., Hooton, N., et al., 2006. Efficacy and \nsafety of exogenous melatonin for secondary sleep disorders and \nsleep disorders accompanying sleep restriction: meta-analysis. BMJ \n332, 385\u2013393.\nCascio, M.G., Marini, P., 2015. Biosynthesis and fate of \nendocannabinoids. In \u2018Endocannabinoids\u2019, Pertwee R.G. (Ed.), Handb. \nExp. Pharmacol. 231, 39\u201358.\nCastillo, P.E., Younts, T.J., Ch\u00e1vez, A.E., Hashimotodani, Y., 2012. \nEndocannabinoid signaling and synaptic function. Neuron 76, 70\u201381.\nChachlaki, K., Garthwaite, J., Prevot, V., 2017. The gentle art of saying \nNO: how nitric oxide gets things done in the hypothalamus. Nat. Rev. \nEndocrinol. 13, 521\u2013535.\nChen, J.F., Eltzschig, H.K., Fredholm, B.B., 2013. Adenosine receptors as \ndrug targets \u2013 what are the challenges? Nat. Rev. Drug Discov. 12, \n265\u2013286.\nCutajar, M.C., Edwards, T.M., 2007. Evidence for the role of endogenous \ncarbon monoxide in memory processing. J. Cogn. Neurosci. 19, \n557\u2013562.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2639, "end_char_idx": 4462, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3cac20d2-ddf7-42c6-84e8-df656b850d06": {"__data__": {"id_": "3cac20d2-ddf7-42c6-84e8-df656b850d06", "embedding": null, "metadata": {"page_label": "520", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ece04c1-2b93-4e9b-a7e5-5d0ce8380f43", "node_type": null, "metadata": {"page_label": "520", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20a16c631a35e30f47384a71897afe10bc43f5efd879e631c0233a27883394af"}, "3": {"node_id": "2232da1a-70cc-427b-910b-2c3d83272bd1", "node_type": null, "metadata": {"page_label": "520", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0e68ecf9b71d5d1448224cacd0f91fb080aad104452373a593459a7809510b3d"}}, "hash": "4d54215b691c7f18e1448a7bb3edd3c4f0e22cc95b7962210f7283ecb6bdbebd", "text": "514\nOVERVIEW\nAs a rule, dead neurons in the adult central nervous \nsystem (CNS) are not replaced,1 nor can their terminals \nregenerate when their axons are interrupted. Therefore \nany pathological process causing neuronal death \ngenerally has irreversible consequences. At first sight, this appears to be very unpromising territory for \npharmacological intervention, and indeed drug therapy \nis currently very limited, except in the case of Par -\nkinson\u2019s disease (PD). Nevertheless, the incidence and \nsocial impact of neurodegenerative brain disorders \nin ageing populations has resulted in a massive research effort in recent years.\nIn this chapter, a number of neurodegenerative \nconditions are described: ischaemic brain damage (stroke), Alzheimer\u2019s disease (AD), PD, Huntington\u2019s \ndisease (HD), amyotrophic lateral sclerosis (ALS), spinal \nmuscular atrophy (SMA) and multiple sclerosis (MS).\nThe main topics discussed in this chapter are:\n\u2022\n mechanisms responsible for neuronal death, focusing on genetic defects, protein aggregation (e.g. amy -\nloidosis), excitotoxicity, oxidative stress and apoptosis;\n\u2022\n pharmacological approaches to neuroprotection, based on the above mechanisms;\n\u2022\n pharmacological approaches to compensation for neuronal loss (applicable mainly to AD and PD).\nPROTEIN MISFOLDING AND \nAGGREGATION IN CHRONIC NEURODEGENERATIVE DISEASES\nProtein misfolding and aggregation is the first step in many \nneurodegenerative diseases (see Peden & Ironside, 2012). \nMisfolding means the adoption of abnormal conformations, \nby certain normally expressed proteins, such that they tend to form large insoluble aggregates (Fig. 41.1). The conversion \nof the linear amino acid chain produced by the ribosome \ninto a functional protein requires it to be folded correctly into a compact conformation with specific amino acids correctly located on its surface. This complicated stepwise sequence can easily go wrong and lead to misfolded variants \nthat are unable to find a way back to the correct \u2018native\u2019 \nconformation. The misfolded molecules lack the normal function of the protein, but can nonetheless make mischief \nwithin the cell. The misfolding often means that hydrophobic \nresidues that would normally be buried in the core of the protein are exposed on its surface, which gives the molecules \na strong tendency to stick to cell membranes and aggregate, \ninitially as oligomers and then as insoluble microscopic aggregates (see Fig. 41.1), leading to the death of neurons. The tendency to adopt such conformations may be favoured \nby specific mutations of the protein in question, or by \ninfection with prions.\n2\nMisfolded conformations can be generated spontaneously \nat a low rate throughout life, so that aggregates accumulate \ngradually with age. In the nervous system, the aggregates \noften form distinct structures, generally known as amyloid \ndeposits, that are visible under the microscope and are \ncharacteristic of neurodegenerative disease. Although the \nmechanisms are not clear, such aggregates, or the misfolded protein precursors, lead to neuronal death. Examples of \nneurodegenerative diseases that are caused by such protein \nmisfolding and aggregation are shown in Table 41.1.\nThe brain possesses a variety of protective mechanisms \nthat limit the accumulation of such protein aggregates. The \nmain ones involve the production of \u2018chaperone\u2019 proteins, \nwhich bind to newly synthesised or misfolded proteins and encourage them to fold correctly, and the \u2018ubiquitina -\ntion\u2019 reaction, which prepares proteins for destruction within the cell. Accumulation of protein deposits occurs when these", "start_char_idx": 0, "end_char_idx": 3630, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2232da1a-70cc-427b-910b-2c3d83272bd1": {"__data__": {"id_": "2232da1a-70cc-427b-910b-2c3d83272bd1", "embedding": null, "metadata": {"page_label": "520", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ece04c1-2b93-4e9b-a7e5-5d0ce8380f43", "node_type": null, "metadata": {"page_label": "520", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20a16c631a35e30f47384a71897afe10bc43f5efd879e631c0233a27883394af"}, "2": {"node_id": "3cac20d2-ddf7-42c6-84e8-df656b850d06", "node_type": null, "metadata": {"page_label": "520", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4d54215b691c7f18e1448a7bb3edd3c4f0e22cc95b7962210f7283ecb6bdbebd"}}, "hash": "0e68ecf9b71d5d1448224cacd0f91fb080aad104452373a593459a7809510b3d", "text": "for destruction within the cell. Accumulation of protein deposits occurs when these protective mechanisms are unable to cope.\nMECHANISMS OF NEURONAL DEATH\nAcute injury to cells causes them to undergo necrosis, \nrecognised pathologically by cell swelling, vacuolisation \nand lysis, and associated with Ca2+ overload of the cells \nand membrane damage (see p. 516). Necrotic cells typically spill their contents into the surrounding tissue, evoking an \ninflammatory response. Chronic inflammation is a feature of most neurodegenerative disorders (see Schwab & McGeer, \n2008), and a possible target for therapeutic intervention.\nCells can also die by apoptosis (programmed cell death, \nsee Ch. 6), a mechanism that is essential for many processes Neurodegenerative diseases41 NERVOUS SYSTEM SECTION 4\n1It is recognised that new neurons are formed from progenitor cells \n(neurogenesis) in certain regions of the adult brain and can become \nfunctionally integrated, even in primates (see Rakic, 2002; Zhao et al., \n2008). Neurogenesis in the hippocampus is thought to play a role in \nlearning and memory, but plays little if any role in brain repair. \nHowever, learning how to harness the inherent ability of neuronal \nprogenitors (stem cells) to form new neurons is seen as an obvious approach to treating neurodegenerative disorders.2Such prion diseases include Creutzfeldt\u2013Jakob\u2019s disease (CJD) and the \nnew variant CJD that results from eating, or close contact with, beef or \nhuman tissue infected with bovine spongiform encephalopathy (BSE). \nSadly, no pharmacological treatments that prevent disease progression are yet available and treatment is aimed at ameliorating the symptoms.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3547, "end_char_idx": 5711, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bbdb89c0-3702-4318-9dff-fccad67c1121": {"__data__": {"id_": "bbdb89c0-3702-4318-9dff-fccad67c1121", "embedding": null, "metadata": {"page_label": "521", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d8f6a3b-ee1d-4986-9479-d8e27475f128", "node_type": null, "metadata": {"page_label": "521", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b892173be96a653f3dcbeb014c38de30bf38a6d86b713cdef29231d58a80a63"}, "3": {"node_id": "7a50d2c6-1f76-4887-858a-1a7d94fd68c2", "node_type": null, "metadata": {"page_label": "521", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ed45e652c1bd3501e69dbc795dc3e3292dceb52f9f8d39f85f3e0dfbad194bb"}}, "hash": "be5c9c99cda1c4e4d7a0eb3f27fd35bde6368cbee8b1e8be7d0a13fb97c3eea0", "text": "41 NEURO dEgENER aTiVE diSEaSES\n515Native\nproteinMisfolded\nproteinOligomer Insoluble\naggregate\nNEUROTOXICITYMutations\nExternal factors\nMolecular\n chaperonesCellular disposal\nmechanismsExtracellular\ndepositsIntracellular\ndeposits\nFig. 41.1 Protein misfolding: a process \ninvolved in many chronic \nneurodegenerative diseases. \nTable 41.1 Examples of neurodegenerative diseases associated with protein misfolding and aggregationa\nDisease ProteinCharacteristic \npathology Notes\nAlzheimer\u2019s disease \u03b2-Amyloid (A\u03b2) Amyloid plaques A\u03b2 mutations occur in rare familial forms of Alzheimer\u2019s \ndisease\nTau Neurofibrillary tangles Implicated in other pathologies (\u2018tauopathies\u2019) as well as Alzheimer\u2019s disease\nParkinson\u2019s disease \u03b1-Synuclein Lewy bodies \u03b1-Synuclein mutations occur in some types of familial Parkinson\u2019s disease\nCreutzfeldt\u2013Jakob\u2019s diseasePrion protein Insoluble aggregates of prion proteinTransmitted by infection with prion protein in its misfolded state\nHuntington\u2019s disease Huntingtin No gross lesions One of several genetic \u2018polyglutamine repeat\u2019 disorders\nAmyotrophic lateral sclerosis (a form of motor neuron disease)Superoxide dismutaseLoss of motor neuronsMutated superoxide dismutase tends to form aggregates; loss of enzyme function increases susceptibility to oxidative stress\naProtein aggregation disorders are often collectively known as amyloidoses and commonly affect organs other than the brain.\nProtein misfolding \n\u2022\tMany\tchronic \tneurodegenerative \tdiseases \tinvolve \tthe \t\nmisfolding \tof \tnormal \tor \tmutated \tforms \tof \tphysiological \t\nproteins.\tExamples \tinclude \tAlzheimer\u2019s \tdisease, \t\nParkinson\u2019s \tdisease, \tamyotrophic \tlateral \tsclerosis \tand \t\nmany less common diseases.\n\u2022\tMisfolded \tproteins \tare \tnormally \tremoved \tby \tintracellular \t\ndegradation \tpathways, \twhich \tmay \tbe \taltered \tin \t\nneurodegenerative \tdisorders.\n\u2022\tMisfolded \tproteins \ttend \tto \taggregate, \tinitially \tas \tsoluble \t\noligomers, \tlater \tas \tlarge \tinsoluble \taggregates \tthat \taccumulate \tintracellularly \tor \textracellularly \tas \tmicroscopic \t\ndeposits,\twhich \tare \tstable \tand \tresistant \tto \tproteolysis.\n\u2022\tMisfolded \tproteins \toften \tpresent \thydrophobic \tsurface \t\nresidues\tthat \tpromote \taggregation \tand \tassociation \twith \t\nmembranes.\n\u2022\tThe\tmechanisms \tresponsible \tfor \tneuronal \tdeath \tare \t\nunclear,\tbut \tthere \tis \tevidence \tthat \tboth \tthe \tsoluble \t\naggregates \tand \tthe \tmicroscopic \tdeposits \tmay \tbe \t\nneurotoxic.\nthroughout life, including development, immune regulation \nand tissue remodelling. Apoptosis, as well as necrosis, occurs \nin both acute neurodegenerative disorders (such as stroke \nand head injury) and chronic ones (such as Alzheimer\u2019s and \nParkinson\u2019s disease). The distinction between necrosis and apoptosis as processes leading to neurodegeneration is not absolute, for challenges such as excitotoxicity and oxidative stress may be enough to kill cells directly by necrosis or, if less intense, may induce them to undergo apoptosis. Both \nprocesses therefore represent possible targets for putative \nneuroprotective drug therapy. Pharmacological interference with the", "start_char_idx": 0, "end_char_idx": 3110, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a50d2c6-1f76-4887-858a-1a7d94fd68c2": {"__data__": {"id_": "7a50d2c6-1f76-4887-858a-1a7d94fd68c2", "embedding": null, "metadata": {"page_label": "521", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d8f6a3b-ee1d-4986-9479-d8e27475f128", "node_type": null, "metadata": {"page_label": "521", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b892173be96a653f3dcbeb014c38de30bf38a6d86b713cdef29231d58a80a63"}, "2": {"node_id": "bbdb89c0-3702-4318-9dff-fccad67c1121", "node_type": null, "metadata": {"page_label": "521", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be5c9c99cda1c4e4d7a0eb3f27fd35bde6368cbee8b1e8be7d0a13fb97c3eea0"}}, "hash": "7ed45e652c1bd3501e69dbc795dc3e3292dceb52f9f8d39f85f3e0dfbad194bb", "text": "for putative \nneuroprotective drug therapy. Pharmacological interference with the apoptotic pathway may become possible in the mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3029, "end_char_idx": 3635, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "420054b3-e979-4111-bd16-a182b1f543e2": {"__data__": {"id_": "420054b3-e979-4111-bd16-a182b1f543e2", "embedding": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "20fec5c3-caac-421e-ac1e-aa8e9f3f4836", "node_type": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea37624d8715d6bb0313a00bb6c3d369120f6002ca2745cfa44209696d3da5f6"}, "3": {"node_id": "cdf35c44-6bb9-4e54-b592-c5d03f9f57c6", "node_type": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67e3098d04cae606b899c170a9dbfb39d5d9d8a3a4287fafe7f853fa8a3fb0a4"}}, "hash": "c64c162a0d5203c33041b9789f9327584314dba7dc3c4dfab6e04233ef127177", "text": "41 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n516Glutamate and Ca2+ are arguably the two most ubiquitous \nchemical signals, extracellular and intracellular, respectively, \nunderlying brain function, so it is disconcerting that such \ncytotoxic mayhem can be unleashed when they get out of control. Both are stored in dangerous amounts in subcellular \norganelles, like hand grenades in an ammunition store. \nDefence against excitotoxicity is clearly essential if our brains are to have any chance of staying alive. Mitochondrial \nenergy metabolism provides one line of defence (see p. \n518), and impaired mitochondrial function, by rendering neurons vulnerable to excitotoxic damage, may be a factor in various neurodegenerative conditions, including PD. \nFurthermore, impaired mitochondrial function can cause \nrelease of cytochrome C, which is an important initiator of apoptosis.\nThe role of excitotoxicity in ischaemic brain damage is \nwell established (see p. 518), and it is also believed to be a factor in other neurodegenerative diseases, such as those \ndiscussed below.\n\u25bc There are several examples of neurodegenerative conditions caused \nby environmental toxins acting as agonists on glutamate receptors. \nDomoic acid is a glutamate analogue produced by mussels, which \nwas identified as the cause of an epidemic of severe mental and neurological deterioration in a group of Newfoundlanders in 1987. \nOn the island of Guam, a syndrome combining the features of dementia, \nparalysis and PD was traced to an excitotoxic amino acid, \u03b2-methylamino-alanine, in the seeds of a local plant. Discouraging \nthe consumption of these seeds has largely eliminated the disease.\nDisappointingly, intense effort, based on the mechanisms described \nearlier, to find effective drugs for a range of neurodegenerative \ndisorders in which excitotoxicity is believed to play a part has had very limited success. Riluzole retards to some degree the deterioration \nof patients with ALS (see p. 528). Its precise mechanism of action is unclear. Memantine, a compound first described 40 years ago, is a \nweak NMDA-receptor antagonist that produces slight improvement \nin moderate-to-severe cases of AD.\nAPOPTOSIS\nApoptosis can be initiated by various cell surface signals \n(see Ch. 6). The cell is systematically dismantled, and the \nshrunken remnants are removed by macrophages without \ncausing inflammation. Apoptotic cells can be identified by a staining technique that detects the characteristic DNA \nbreaks. Many different signalling pathways can result in \napoptosis, but in all cases the final pathway resulting in cell death is the activation of a family of proteases (caspases), \nwhich inactivate various intracellular proteins. Neural \napoptosis is normally prevented by neuronal growth factors, including nerve growth factor and brain-derived neurotrophic \nfactor, secreted proteins that are required for the survival \nof different populations of neurons in the CNS. These growth \nfactors regulate the expression of the two gene products, Bax and Bcl-2, Bax being proapoptotic and Bcl-2 being \nantiapoptotic (see Ch. 6). Blocking apoptosis by interfering \nat specific points on these pathways represents an attractive strategy for developing neuroprotective drugs, but one that \nhas yet to bear fruit.\nOXIDATIVE STRESS\nThe brain has high energy needs, which are met almost \nentirely by mitochondrial oxidative phosphorylation, \ngenerating ATP at the same time as reducing molecular \nO2 to H 2O. Under certain conditions, highly ROS, for \nexample, oxygen and hydroxyl free radicals and H 2O2, may \nbe generated as side products of this process (see Barnham \net al.,", "start_char_idx": 0, "end_char_idx": 3646, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cdf35c44-6bb9-4e54-b592-c5d03f9f57c6": {"__data__": {"id_": "cdf35c44-6bb9-4e54-b592-c5d03f9f57c6", "embedding": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "20fec5c3-caac-421e-ac1e-aa8e9f3f4836", "node_type": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea37624d8715d6bb0313a00bb6c3d369120f6002ca2745cfa44209696d3da5f6"}, "2": {"node_id": "420054b3-e979-4111-bd16-a182b1f543e2", "node_type": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c64c162a0d5203c33041b9789f9327584314dba7dc3c4dfab6e04233ef127177"}, "3": {"node_id": "01a5a2b6-c32d-42a8-8893-49fb8f3b7fd7", "node_type": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e43b4b8bd181004d09a3f8545cd75c0d7c697ecce15d1893398434857c9687c"}}, "hash": "67e3098d04cae606b899c170a9dbfb39d5d9d8a3a4287fafe7f853fa8a3fb0a4", "text": "may \nbe generated as side products of this process (see Barnham \net al., 2004). Oxidative stress is the result of excessive future, but for the present most efforts are directed at the processes involved in cell necrosis, and at compensating \npharmacologically for the neuronal loss.\nEXCITOTOXICITY\nDespite its ubiquitous role as a neurotransmitter, glutamate \nis highly toxic to neurons, a phenomenon dubbed excitotoxic -\nity (see Ch. 39). A low concentration of glutamate applied to \nneurons in culture kills the cells, and the finding in the 1970s that glutamate given orally produces neurodegeneration in \nvivo caused considerable alarm because of the widespread \nuse of glutamate as a \u2018taste-enhancing\u2019 food additive. The \u2018Chinese restaurant syndrome\u2019 \u2013 an acute attack of neck \nstiffness and chest pain \u2013 is well known, but so far, the \npossibility of more serious neurotoxicity is only hypothetical.\nLocal injection of the glutamate receptor agonist kainic \nacid is used experimentally to produce neurotoxic lesions. \nIt acts by excitation of local glutamate-releasing neurons, \nand the release of glutamate, acting on NMDA receptors, and also metabotropic receptors (Ch. 39), leads to neuronal \ndeath.\nCalcium overload is the essential factor in excitotoxicity. \nThe mechanisms by which this occurs and leads to cell death are as follows (see also Fig. 41.2):\n\u2022\tGlutamate \tactivates \tNMDA, \tAMPA \tand \tmetabotropic \t\nreceptors (sites 1, 2 and 3 in Fig. 41.2). Activation of \nAMPA receptors depolarises the cell, which removes \nthe Mg2+ block of NMDA channels (see Ch. 39), \npermitting Ca2+ entry. Depolarisation also opens \nvoltage-dependent calcium channels (site 4). Metabotropic receptors cause the release of \nintracellular Ca\n2+ from the endoplasmic reticulum. Na+ \nentry further contributes to Ca2+ entry by stimulating \nCa2+/Na+ exchange (site 5). Depolarisation inhibits or \nreverses glutamate uptake (site 6), thus increasing the \nextracellular glutamate concentration.\n\u2022\tThe\tmechanisms \tthat \tnormally \toperate \tto \tcounteract \t\nthe rise in cytosolic free Ca2+ concentration, [Ca2+]i, \ninclude the Ca2+ efflux pump (site 7) and, indirectly, \nthe Na+ pump (site 8).\n\u2022\tThe\tmitochondria \tand \tendoplasmic \treticulum \tact \tas \t\ncapacious sinks for Ca2+ and normally keep [Ca2+]i \nunder control. Loading of the mitochondrial stores beyond a certain point, however, disrupts \nmitochondrial function, reducing ATP synthesis, thus reducing the energy available for the membrane \npumps and for Ca\n2+ accumulation by the endoplasmic \nreticulum. Formation of reactive oxygen species (ROS) is also enhanced. This represents the danger point at \nwhich positive feedback exaggerates the process.\n\u2022\tRaised \t[Ca2+]i affects many processes, the chief ones \nrelevant to neurotoxicity being:\n\u2013 increased glutamate release from nerve terminals;\n\u2013 activation of proteases (calpains) and lipases, \ncausing membrane damage;\n\u2013 activation of nitric oxide synthase; while low \nconcentrations of nitric oxide are neuroprotective, high concentrations in the presence of ROS generate \nperoxynitrite and hydroxyl free radicals, which \ndamage many important biomolecules, including membrane lipids, proteins and DNA;\n\u2013 increased arachidonic acid release, which increases \nfree radical and inflammatory mediator production and also inhibits glutamate uptake (site", "start_char_idx": 3587, "end_char_idx": 6938, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "01a5a2b6-c32d-42a8-8893-49fb8f3b7fd7": {"__data__": {"id_": "01a5a2b6-c32d-42a8-8893-49fb8f3b7fd7", "embedding": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "20fec5c3-caac-421e-ac1e-aa8e9f3f4836", "node_type": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea37624d8715d6bb0313a00bb6c3d369120f6002ca2745cfa44209696d3da5f6"}, "2": {"node_id": "cdf35c44-6bb9-4e54-b592-c5d03f9f57c6", "node_type": null, "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67e3098d04cae606b899c170a9dbfb39d5d9d8a3a4287fafe7f853fa8a3fb0a4"}}, "hash": "2e43b4b8bd181004d09a3f8545cd75c0d7c697ecce15d1893398434857c9687c", "text": "\nfree radical and inflammatory mediator production and also inhibits glutamate uptake (site 6).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6907, "end_char_idx": 7481, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "74416f9f-cfcd-40d1-967f-2fa199f1ef68": {"__data__": {"id_": "74416f9f-cfcd-40d1-967f-2fa199f1ef68", "embedding": null, "metadata": {"page_label": "523", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8e59cf09-9e77-4cde-9e35-b57022769458", "node_type": null, "metadata": {"page_label": "523", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3aaa442b4b063af4ebff3f8a450a522dd46f1b6c6c3a6b1a7bf38159426bcb1"}}, "hash": "c3aaa442b4b063af4ebff3f8a450a522dd46f1b6c6c3a6b1a7bf38159426bcb1", "text": "41 NEUROdEgENERaTiVE diSEaSES\n517Na+/Ca2+\nNa+Ca2+\nCa2+Ca2+Na+/K+\nGluK+\nInactive\nproducts\nSOD\nFree radical\nscavengersNO\nsynthase\ninhibitors\nProtease\ninhibitorsmGluR\nantagonists\nGlutamate\nrelease\ninhibitors5 8\n7\n6\nMembrane\ndamageM3\nIP321 4 Na+Ca2+Ca2+\nER\nMITOCHONDRION\nAA\nreleaseNMDA VDCCNMDA\nreceptor\nantagonistsCalcium\nchannel\ninhibitorsGLUTAMATE\nHEROES VILLAINS[Ca2+]i\nROSProteasesNORelief of \nMg2+-block\nDepolarisation\nATP\nFig. 41.2 Mechanisms of excitotoxicity. \tMembrane\t receptors,\t ion\tchannels\tand\ttransporters,\t identified\tby\tnumbers\t1\u20138,\tare\tdiscussed\t\nin\tthe\ttext.\tPossible\tsites\tof\taction\tof\tneuroprotective\t drugs\t(not\tyet\tof\tproven\tclinical\tvalue)\tare\thighlighted .\tMechanisms\t on\tthe\tleft \n(villains)\tare\tthose\tthat\tfavour\tcell\tdeath,\twhile\tthose\ton\tthe\tright\t(heroes)\tare\tprotective.\t See\ttext\tfor\tdetails.\t AA, arachidonic acid; ER, \nendoplasmic\t reticulum;\t Glu,\tglutamate\t uptake;\t IP3,\tinositol\ttrisphosphate;\t M, mGluR, \tmetabotropic\t glutamate\t receptor;\t NO,\tnitric\toxide;\t\nROS,\treactive\toxygen\tspecies;\t SOD,\tsuperoxide\t dismutase;\t VDCC,\tvoltage-dependent\t calcium\tchannel.\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1578, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d29b5f79-da19-4734-9fd5-60e5799911ba": {"__data__": {"id_": "d29b5f79-da19-4734-9fd5-60e5799911ba", "embedding": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ab42f691-4637-42fb-ab92-2aaf0adbfce6", "node_type": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "df8738eb878a8dc5d279b7b49e9ea60f69c4e53275c5f2e830b45e9d9c95cde4"}, "3": {"node_id": "ac5ba062-cf0c-4cf3-b081-504ee5d30016", "node_type": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c42115b3693247f3f94dee46b3a23702ee6f6766b32d79a89c5b825d0f61cd7a"}}, "hash": "6b277d5e4f9483dab23dd0aeea8f7fbd8932514033734ba539bbea78c49c76c1", "text": "41 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n518inability to talk, double vision and dizziness. These symp -\ntoms usually resolve within 24 hours but serve as a warning \nthat a full stroke may occur in the near future and that \nmeasures should be taken to prevent further atherosclerosis (see p. 519). The other type of stroke is haemorrhagic, due \nto rupture of a cerebral artery.\nPATHOPHYSIOLOGY\nProlonged interruption of blood supply to the brain initi -\nates the cascade of neuronal events shown in Fig. 41.2, \nwhich lead in turn to later consequences, including cerebral \noedema and inflammation, which can also contribute to brain damage. Further damage can occur following reperfusion,\n4 \nbecause of the production of ROS when the oxygenation \nis restored. Reperfusion injury may be an important com -\nponent in stroke patients. These secondary processes often \ntake hours to develop, providing a window of opportunity \nfor therapeutic intervention. The lesion produced by occlu -\nsion of a major cerebral artery consists of a central core in \nwhich the neurons quickly undergo irreversible necrosis, production of these reactive species. They can also be produced as a byproduct of other biochemical pathways, \nincluding nitric oxide synthesis and arachidonic acid \nmetabolism (which are implicated in excitotoxicity; see p. 516), as well as the P450 mono-oxygenase system (see Ch. \n10). Unchecked, reactive oxygen radicals attack many key \nmolecules, including enzymes, membrane lipids and DNA. During periods of tissue reperfusion following ischaemia \n(e.g. in stroke), delinquent leukocytes may exacerbate this \nproblem by releasing their own cytotoxic oxygen products. Not surprisingly, defence mechanisms are provided, in the form of enzymes such as superoxide dismutase (SOD) and \ncatalase, as well as antioxidants such as ascorbic acid, glutathione and \u03b1-tocopherol (vitamin E), which normally \nkeep these reactive species in check. Some cytokines, \nespecially tumour necrosis factor (TNF)- \u03b1, which is produced \nin conditions of brain ischaemia or inflammation (Ch.19), \nexert a protective effect, partly by increasing the expression \nof SOD. Transgenic animals lacking TNF receptors show \nenhanced susceptibility to brain ischaemia. Mutations of the gene encoding SOD (see Fig. 41.2) are associated with \nALS, a fatal, paralytic disease resulting from progressive \ndegeneration of motor neurons (see p. 528), and transgenic mice expressing mutated SOD develop a similar condition.\n3 \nAccumulation of aggregates of misfolded mutated SOD \nmay also contribute to neurodegeneration.\nMitochondria play a central role in energy metabolism, \nfailure of which leads to oxidative stress. Damage to mitochondria, leading to the release of cytochrome C into \nthe cytosol, also initiates apoptosis. Mitochondrial integrity is therefore essential for neuronal survival, and mitochon-\ndrial dysfunction is seen as a major factor in many neuro -\ndegenerative disorders (see Itoh et al., 2013). It is possible \nthat accumulated or inherited mutations in enzymes such \nas those of the mitochondrial respiratory chain lead to a \ncongenital or age-related increase in susceptibility to oxida -\ntive stress, which is manifest in different kinds of inherited \nneurodegenerative disorders (such as HD), and in age-\nrelated neurodegeneration.\nOxidative stress is both a cause and consequence of \ninflammation (Ch. 7), which is a general feature of neuro -\ndegenerative disease and is thought to contribute to neuronal \ndamage (see Schwab & McGeer, 2008).\nSeveral possible", "start_char_idx": 0, "end_char_idx": 3553, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ac5ba062-cf0c-4cf3-b081-504ee5d30016": {"__data__": {"id_": "ac5ba062-cf0c-4cf3-b081-504ee5d30016", "embedding": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ab42f691-4637-42fb-ab92-2aaf0adbfce6", "node_type": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "df8738eb878a8dc5d279b7b49e9ea60f69c4e53275c5f2e830b45e9d9c95cde4"}, "2": {"node_id": "d29b5f79-da19-4734-9fd5-60e5799911ba", "node_type": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b277d5e4f9483dab23dd0aeea8f7fbd8932514033734ba539bbea78c49c76c1"}, "3": {"node_id": "096c5d53-d60c-4fd4-b49a-e8abcc602866", "node_type": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3865c9cce81eddba61711e42dfcbac86599269d2b089818f14b3e7bb5273c8de"}}, "hash": "c42115b3693247f3f94dee46b3a23702ee6f6766b32d79a89c5b825d0f61cd7a", "text": "\ndamage (see Schwab & McGeer, 2008).\nSeveral possible targets for therapeutic intervention with \nneuroprotective drugs are shown in Fig. 41.2.\nISCHAEMIC BRAIN DAMAGE\nAfter heart disease and cancer, strokes are the commonest cause of death in Europe and North America, and the 70% \nthat are non-fatal are the commonest cause of disability. \nApproximately 85% of strokes are ischaemic, usually due to cerebral arterial occlusion caused by local thrombus \nformation or by a circulating embolus lodging at a narrowing \nof the vessel. Ischaemic stroke may be preceded by transient ischaemic attacks (TIAs) or \u2018mini-strokes\u2019, resulting from \nbrief episodes of inadequate blood flow. TIAs produce \nsymptoms such as sudden limb or facial muscle weakness, Excitotoxicity and oxidative stress \n\u2022\tExcitatory \tamino \tacids, \tespecially \tglutamate, \tcan \t\ncause\tneuronal \tdeath.\n\u2022\tExcitotoxicity \tis \tassociated \tmainly \twith \tactivation \tof \t\nNMDA\treceptors, \tbut \tother \ttypes \tof \texcitatory \tamino \t\nacid\treceptors \talso \tcontribute.\n\u2022\tExcitotoxicity \tresults \tfrom \ta \tsustained \trise \tin \t\nintracellular \tCa2+\tconcentration \t(Ca2+\toverload).\n\u2022\tExcitotoxicity \tcan \toccur \tunder \tpathological \tconditions \t\n(e.g.\tcerebral \tischaemia, \tepilepsy) \tin \twhich \texcessive \t\nglutamate \trelease \toccurs. \tIt \tcan \talso \toccur \twhen \t\nchemicals \tsuch \tas \tkainic acid are administered.\n\u2022\tRaised\tintracellular \tCa2+\tcauses\tcell \tdeath \tby \tvarious \t\nmechanisms, \tincluding \tactivation \tof \tproteases, \t\nformation\tof \tfree \tradicals \tand \tlipid \tperoxidation. \t\nFormation \tof \tnitric \toxide \tand \tarachidonic \tacid \tare \talso \t\ninvolved.\n\u2022\tVarious \tmechanisms \tact \tnormally \tto \tprotect \tneurons \t\nagainst\texcitotoxicity, \tthe \tmain \tones \tbeing \tCa2+ \ntransport\tsystems, \tmitochondrial \tfunction \tand \tthe \t\nproduction \tof \tfree \tradical \tscavengers.\n\u2022\tOxidative \tstress \trefers \tto \tconditions \t(e.g. \thypoxia) \tin \t\nwhich\tthe \tprotective \tmechanisms \tare \tcompromised, \t\nreactive\toxygen \tspecies \taccumulate \tand \tneurons \t\nbecome\tmore \tsusceptible \tto \texcitotoxic \tdamage.\n\u2022\tExcitotoxicity \tdue \tto \tenvironmental \tchemicals \tmay \t\ncontribute \tto \tsome \tneurodegenerative \tdisorders.\n\u2022\tMeasures \tdesigned \tto \treduce \texcitotoxicity \tinclude \tthe \t\nuse\tof\tglutamate \tantagonists, \tcalcium \tchannel-\nblocking\tdrugs \tand \tfree \tradical \tscavengers; \tnone \tis \t\nyet\tproven \tfor \tclinical \tuse.\n\u2022\tMitochondrial \tdysfunction, \tassociated \twith \tageing, \t\nenvironmental \ttoxins \tand \tgenetic \tabnormalities, \tleads \t\nto\toxidative \tstress \tand \tis \ta \tcommon \tfeature \tof", "start_char_idx": 3507, "end_char_idx": 6060, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "096c5d53-d60c-4fd4-b49a-e8abcc602866": {"__data__": {"id_": "096c5d53-d60c-4fd4-b49a-e8abcc602866", "embedding": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ab42f691-4637-42fb-ab92-2aaf0adbfce6", "node_type": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "df8738eb878a8dc5d279b7b49e9ea60f69c4e53275c5f2e830b45e9d9c95cde4"}, "2": {"node_id": "ac5ba062-cf0c-4cf3-b081-504ee5d30016", "node_type": null, "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c42115b3693247f3f94dee46b3a23702ee6f6766b32d79a89c5b825d0f61cd7a"}}, "hash": "3865c9cce81eddba61711e42dfcbac86599269d2b089818f14b3e7bb5273c8de", "text": "\t\nneurodegenerative \tdiseases.\n3Surprisingly, some SOD mutations associated with ALS are more, \nrather than less, active than the normal enzyme. The mechanism \nresponsible for neurodegeneration probably involves abnormal \naccumulation of the enzyme in mitochondria.4Nevertheless, early reperfusion (within 4.5 h of the thrombosis) is \nclearly beneficial, based on clinical evidence with fibrinolytic drugs.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6108, "end_char_idx": 6994, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b7fe66c7-30ab-4365-9771-3b109ef7554d": {"__data__": {"id_": "b7fe66c7-30ab-4365-9771-3b109ef7554d", "embedding": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1888d106-872a-4cf0-b9f8-085025dd26a6", "node_type": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a89028c9a6ca44b5c0a713de1789a69d8522ccd8b463a7b56dc67a563b7b032f"}, "3": {"node_id": "f51c4678-8da5-471e-ab1d-1c95aeaa45b0", "node_type": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b00ac14c5af072b1ccd94613186e03335bc4a6bb54c7387ee952cf20e45d35cc"}}, "hash": "4fe11026da802c26634d93c536b728af4f1d4d279c185e519602dc84e9cfd6b9", "text": "41 NEURO dEgENER aTiVE diSEaSES\n519more on prevention (e.g. by controlling blood pressure, \ntaking aspirin, statins or ticagrelor to prevent atherosclerosis \n[see Ch. 25]) than on treatment.5\nOne area of promise is the use of subanaesthetic doses \nof xenon , which has NMDA-receptor antagonist properties \n(Ch. 42), in combination with hypothermia to treat hypoxia-\ninduced brain damage in neonates (Esencan et al., 2013).surrounded by a penumbra of compromised tissue in which inflammation and apoptotic cell death develop over \na period of several hours. It is assumed that neuroprotec -\ntive therapies, given within a few hours, might inhibit this \nsecondary penumbral damage.\nGlutamate excitotoxicity plays a critical role in brain \nischaemia. Ischaemia causes depolarisation of neurons, and the release of large amounts of glutamate. Ca\n2+ accumulation \noccurs, partly as a result of glutamate acting on NMDA \nreceptors, as both Ca2+ entry and cell death following cerebral \nischaemia are inhibited by drugs that block NMDA receptors or channels (see Ch. 39). Nitric oxide is also produced in \namounts much greater than result from normal neuronal activity (i.e. to levels that are toxic rather than modulatory).\nTHERAPEUTIC APPROACHES\nThe only drug currently approved for treating strokes is a recombinant tissue plasminogen activator, alteplase, given \nintravenously, which helps to restore blood flow by dispers -\ning the thrombus (see Ch. 25). Clinical trials have found that it did not reduce mortality, but gave significant \nfunctional benefit to patients who survive. To be effective, \nit must be given within about 4.5 h of the thrombotic \nepisode. Also, it must not be given in the 15% of cases \nwhere the cause is haemorrhage rather than thrombosis, \nso preliminary computerised tomography (CT) scanning \nis essential. These stringent requirements seriously limit the use of fibrinolytic agents for treating stroke, except \nwhere specialised rapid response facilities are available. \nThe use of intra-arterial clot retrieval devices (mechanical thrombectomy), in combination with alteplase, has yielded \ngreater benefits and this technology is being rolled out in \nspecialised acute stroke treatment centres.\nAn alternative approach would be to use neuroprotective \nagents aimed at rescuing cells in the penumbral region of \nthe lesion, which are otherwise likely to die. In animal \nmodels involving cerebral artery occlusion, many drugs targeted at the mechanisms shown in Fig. 41.2 (not to \nmention many others that have been tested on the basis of \nmore far-flung theories) act in this way to reduce the size of the infarct. These include glutamate antagonists, calcium \nand sodium-channel inhibitors, free radical scavengers, \nanti-inflammatory drugs, protease inhibitors and others (see Green, 2008). It seems that almost anything works in \nthese animal models. However, of the many drugs that \nhave been tested in over 100 clinical trials, none was effective. The dispiriting list of failures includes calcium- and \nsodium-channel blockers (e.g. nimodipine , fosphenytoin ), \nNMDA-receptor antagonists ( selfotel, eliprodil, dex-\ntromethorphan), drugs that inhibit glutamate release (adenosine analogues, lubeluzole), drugs that enhance \nGABA effects (e.g. chlormethiazole), 5-HT antagonists, \nmetal chelators and various free radical scavengers (e.g. tirilazad ). There was hope that mGlu1-receptor antagonists \nor negative allosteric modulators might be effective in the treatment of ischaemic brain damage", "start_char_idx": 0, "end_char_idx": 3532, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f51c4678-8da5-471e-ab1d-1c95aeaa45b0": {"__data__": {"id_": "f51c4678-8da5-471e-ab1d-1c95aeaa45b0", "embedding": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1888d106-872a-4cf0-b9f8-085025dd26a6", "node_type": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a89028c9a6ca44b5c0a713de1789a69d8522ccd8b463a7b56dc67a563b7b032f"}, "2": {"node_id": "b7fe66c7-30ab-4365-9771-3b109ef7554d", "node_type": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4fe11026da802c26634d93c536b728af4f1d4d279c185e519602dc84e9cfd6b9"}, "3": {"node_id": "060cf403-5f3b-4657-b81c-c55185cfa465", "node_type": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cc88c18e9119da441f4e8e389807fd92ff1a8e6c746099e84e4ab898dc041efe"}}, "hash": "b00ac14c5af072b1ccd94613186e03335bc4a6bb54c7387ee952cf20e45d35cc", "text": "\nor negative allosteric modulators might be effective in the treatment of ischaemic brain damage but things have gone quiet on that front recently.\nControlled clinical trials on stroke patients are problematic \nand very expensive, partly because of the large variability of outcome in terms of functional recovery, which means \nthat large groups of patients (typically thousands) need to \nbe observed for several months. The need to start therapy within hours of the attack is an additional problem.\nStroke treatment is certainly not \u2013 so far at least \u2013 one \nof pharmacology\u2019s success stories, and medical hopes rest Stroke \n\u2022\tAssociated \twith \tintracerebral \tthrombosis \tor \t\nhaemorrhage \t(less \tcommon), \tresulting \tin \trapid \tdeath \t\nof\tneurons \tby \tnecrosis \tin \tthe \tcentre \tof \tthe \tlesion, \t\nfollowed\tby \tmore \tgradual \t(hours) \tdegeneration \tof \tcells \t\nin\tthe\tpenumbra \tdue \tto \texcitotoxicity \tand \t\ninflammation.\n\u2022\tSpontaneous \tfunctional \trecovery \toccurs \tto \ta \thighly \t\nvariable degree.\n\u2022\tAlthough \tmany \ttypes \tof \tdrug \tthat \tinterfere \twith \t\nexcitotoxicity \tare \table \tto \treduce \tinfarct \tsize \tin \t\nexperimental \tanimals, \tnone \tof \tthese \thas \tso \tfar \tproved \t\nefficacious \tin \thumans.\n\u2022\tRecombinant \ttissue \tplasminogen \tactivator \t(alteplase ),\t\nwhich\tdisperses \tblood \tclots, \tis \tbeneficial \tif \tit \tis \tgiven \t\nwithin\t4.5 \th; \thaemorrhagic \tstroke \tmust \tbe \texcluded \t\nby imaging before its administration.\n5Eating dark chocolate is believed to reduce the risk of stroke. \nFlavonoids in the chocolate may be protective due to antioxidant, \nanti-clotting and anti-inflammatory properties. However, this is not a \nreason to overindulge!ALZHEIMER\u2019S DISEASE\nLoss of cognitive ability with age is considered to be a \nnormal process whose rate and extent is very variable. AD \nwas originally defined as presenile dementia, but it now \nappears that the same pathology underlies the dementia irrespective of the age of onset. AD refers to dementia of \ngradual onset in adulthood, that may follow earlier brain \ninjury, but often has no known antecedent cause. Its prevalence rises sharply with age, from about 2% in those \naged 65\u201369 to 20% in those aged 85\u201389. Common symptoms \nof AD are difficulty remembering names and recent events, loss of executive functioning, apathy and depression. Age-related dementia was originally considered to result from \nthe steady loss of neurons that normally goes on throughout \nlife, possibly accelerated by a failing blood supply associated with atherosclerosis. Studies in recent years have, however, \nrevealed specific genetic and molecular mechanisms \nunderlying AD (see Frigero & De Strooper, 2016). These advances raised hopes of more effective treatments, but \nsuccess has proved elusive, in part because multiple factors \nrather than a single cause contribute to the disease and because the symptoms of the disease only become obvious \nafter the underlying pathology has progressed.\nPATHOGENESIS OF ALZHEIMER\u2019S DISEASE\nAD is associated with brain shrinkage and loss of neurons \nin many brain regions, but especially in the hippocampus mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3450, "end_char_idx": 6838, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "060cf403-5f3b-4657-b81c-c55185cfa465": {"__data__": {"id_": "060cf403-5f3b-4657-b81c-c55185cfa465", "embedding": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1888d106-872a-4cf0-b9f8-085025dd26a6", "node_type": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a89028c9a6ca44b5c0a713de1789a69d8522ccd8b463a7b56dc67a563b7b032f"}, "2": {"node_id": "f51c4678-8da5-471e-ab1d-1c95aeaa45b0", "node_type": null, "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b00ac14c5af072b1ccd94613186e03335bc4a6bb54c7387ee952cf20e45d35cc"}}, "hash": "cc88c18e9119da441f4e8e389807fd92ff1a8e6c746099e84e4ab898dc041efe", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6890, "end_char_idx": 7113, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c6a0e017-cc07-48d9-b990-3c7b3c5adb43": {"__data__": {"id_": "c6a0e017-cc07-48d9-b990-3c7b3c5adb43", "embedding": null, "metadata": {"page_label": "526", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6a8c1287-8d7e-43b8-84ce-6fb9b28b07c8", "node_type": null, "metadata": {"page_label": "526", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "454ab386a8cfcca9b149fabba335007cb0e20a7d1fa4c4de316db18fd0305fc8"}, "3": {"node_id": "19679262-5efa-49ec-a4b0-82546671406c", "node_type": null, "metadata": {"page_label": "526", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cf0dcfe338c95ee56a95090dacd49911991ee813e9919f2af2925a771b8a9f99"}}, "hash": "0dec9c5dfc0402377d5f2d4b7882866f605ec5b8b2c5d188a0bfa81aea860638", "text": "41 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n520of certain, relatively rare, types of familial AD, in which \nmutations of the APP gene, or of other genes (e.g. for \npresenilins and sortilin-related receptor 1 ) that control amyloid \nprocessing, have been discovered.6\n\u25bc Amyloid deposits consist of aggregates of A\u03b2 (Fig. 41.3), a 40- or \n42-residue segment of APP, generated by the action of specific proteases \n(secretases). A\u03b240 is produced normally in small amounts, whereas \nA\u03b242 is overproduced as a result of the genetic mutations mentioned \nabove. Both proteins aggregate to form amyloid plaques, but A\u03b242 \nshows a stronger tendency than A \u03b240 to do so, and appears to be \nthe main culprit in amyloid formation. APP is a 770-amino acid membrane protein normally expressed by many cells, including CNS \nneurons. Cleavage by \u03b1-secretase releases the large extracellular and basal forebrain. The loss of cholinergic neurons in the \nhippocampus and frontal cortex is a feature of the disease, \nand is thought to underlie the cognitive deficit and loss of \nshort-term memory that occur. Two microscopic features are characteristic of the disease, namely extracellular amyloid \nplaques, consisting of amorphous extracellular deposits \nof \u03b2-amyloid protein (known as A \u03b2), and intraneuronal \nneurofibrillary tangles , comprising filaments of a phosphoryl -\nated form of a microtubule-associated protein (Tau). Both of these deposits are protein aggregates that result from misfolding of native proteins, as discussed previously. They appear also in normal brains, although in smaller numbers. \nThe early appearance of amyloid deposits presages the \ndevelopment of AD, although symptoms may not develop for many years. Altered processing of amyloid protein from \nits precursor ( amyloid precursor protein , APP) has been \nimplicated in the pathogenesis of AD. This is based on \nseveral lines of evidence, particularly the genetic analysis \n6The APP gene resides on chromosome 21, of which an extra copy is the \ncause of Down\u2019s syndrome, in which early AD-like dementia occurs in \nassociation with overexpression of APP.APPsAPPA\u03b240/42\u03b3 \u03b1\u03b2Cleavage\nby secretases\nSites of\namyloidogenicmutationsA B\nPHYSIOLOGICAL\nPATHWAYAMYLOIDOGENIC\nPATHWAY\nClearance\nNEURONAL DEATHAPP\nAPP and presenilin mutations\nfavour A\u03b2 formation,\nespecially A 42\nApoE4 mutations\ninhibit A clearance\nTau mutations favour \nhyperphosphorylationAggregationsAPP\nGrowth factor\nfunction\u03b1-Secretase \u03b2/\u03b3-Secretases\nA\u03b242 A\u03b240\n?\nNEUROFIBRILLARY\nTANGLESTau-PPP Tau\nInflammation\nMitochondrial damage\nOxidative stressPaired helical\nfilamentsKinases\nPhosphatases\n?OLIGOMERS\nAMYLOID\nPLAQUES\nFig. 41.3 Pathogenesis of Alzheimer\u2019s disease. \t(A)\tStructure \tof \tamyloid \tprecursor \tprotein \t(APP), \tshowing \torigin \tof \tsecreted \tAPP \t\n(sAPP)\tand \tA\u03b2\tamyloid\tprotein. \tThe \tregions \tinvolved \tin \tamyloidogenic \tmutations \tdiscovered \tin \tsome \tcases \tof \tfamilial \tAlzheimer\u2019s \tdisease \t\nare\tshown \tflanking \tthe \tA\u03b2\tsequence. \tAPP \tcleavage \tinvolves \tthree \tproteases: \tsecretases \t\u03b1,\t\u03b2 and \u03b3. \u03b1-Secretase \tproduces \tsoluble \tAPP, \t\nwhereas \u03b2- and \u03b3-secretases \tgenerate \tA\u03b2\tamyloid\tprotein.", "start_char_idx": 0, "end_char_idx": 3134, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "19679262-5efa-49ec-a4b0-82546671406c": {"__data__": {"id_": "19679262-5efa-49ec-a4b0-82546671406c", "embedding": null, "metadata": {"page_label": "526", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6a8c1287-8d7e-43b8-84ce-6fb9b28b07c8", "node_type": null, "metadata": {"page_label": "526", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "454ab386a8cfcca9b149fabba335007cb0e20a7d1fa4c4de316db18fd0305fc8"}, "2": {"node_id": "c6a0e017-cc07-48d9-b990-3c7b3c5adb43", "node_type": null, "metadata": {"page_label": "526", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0dec9c5dfc0402377d5f2d4b7882866f605ec5b8b2c5d188a0bfa81aea860638"}}, "hash": "cf0dcfe338c95ee56a95090dacd49911991ee813e9919f2af2925a771b8a9f99", "text": "\u03b2- and \u03b3-secretases \tgenerate \tA\u03b2\tamyloid\tprotein. \t\u03b3-Secretase \tcan \tcut \tat \tdifferent \tpoints, \tgenerating \tA\u03b2\tpeptides\tof \tvarying \t\nlengths,\tincluding \tA\u03b240\tand\tA\u03b242,\tthe\tlatter \thaving \ta \thigh \ttendency \tto \taggregate \tas \tamyloid \tplaques. \t(B) \tProcessing \tof \tAPP. \tThe \tmain \t\n\u2018physiological\u2019 \tpathway \tgives \trise \tto \tsAPP, \twhich \texerts \ta \tnumber \tof \ttrophic \tfunctions. \tCleavage \tof \tAPP \tat \tdifferent \tsites \tgives \trise \tto \tA\u03b2,\t\nthe\tpredominant \tform \tnormally \tbeing \tA\u03b240,\twhich \tis \tweakly \tamyloidogenic. \tMutations \tin \tAPP \tor \tpresenilins \tincrease \tthe \tproportion \tof \tAPP, \t\nwhich\tis\tdegraded \tvia \tthe \tamyloidogenic \tpathway, \tand \talso \tincrease \tthe \tproportion \tconverted \tto \tthe \tmuch \tmore \tstrongly \tamyloidogenic \t\nform\tA\u03b242.\tClearance \tof \tA\u03b2\tis\timpaired \tby \tmutations \tin \tthe \tapoE4 \tgene. \tHyperphosphorylated \tTau \tresults \tin \tdissociation \tof \tTau \tfrom \t\nmicrotubules, \tmisfolding \tand \taggregation \tto \tform \tpaired \thelical \tfilaments, \twhich \tenhance \tA\u03b2\ttoxicity.\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3084, "end_char_idx": 4583, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "df7c7077-3849-45cd-89d4-9a6f3977adec": {"__data__": {"id_": "df7c7077-3849-45cd-89d4-9a6f3977adec", "embedding": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f5c4958-b80d-4500-92aa-b5b304c99594", "node_type": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "176b0421239df45e01dba61a18bb43b2076dc7f39d1fbb47f2e806b502845f6a"}, "3": {"node_id": "e5a7d0f9-b51f-49dc-ac31-0fe73005e961", "node_type": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef380b0140135f7e8a4d478725f5a351669e01901e3bd1d3ac3a2c4d219b3f35"}}, "hash": "492e35b334f1067ffe712d8fd0464891cde0c5c38d4b299446051a4651e801f9", "text": "41 NEURO dEgENER aTiVE diSEaSES\n521THERAPEUTIC APPROACHES\nCurrently, cholinesterase inhibitors (see Ch. 14) and \nmemantine are the only drugs approved for treating AD. \nNo new treatments have been introduced since 2003 despite \nintensive research into the underlying causes of the disease and huge investment in drug development. Unravelling \nthe mechanism of neurodegeneration in AD has yet to result \nin therapies able to retard it and, with some spectacular failures having occurred in expensive clinical trials of new \ndrugs, optimism is waning about an effective new therapy \nbeing just around the corner.\nCHOLINESTERASE \u2003INHIBITORS\nTacrine was the first drug approved for treating AD but because of its hepatotoxicity and the subsequent availability \nof other anticholinesterase agents use of tacrine has been \ndiscontinued. Later compounds include donepezil, riv-\nastigmine and galantamine (Table 41.2). Clinical trials have \ndemonstrated modest improvements in tests of memory \nand cognition but no sustained effect on disease progression or improvement in other behavioural and psychological \nmeasures that affect quality of life.\nOther drugs aimed at improving cholinergic function \nthat are being investigated include other cholinesterase \ninhibitors and a variety of muscarinic and nicotinic receptor \nagonists. To date, the lack of selectivity of muscarinic \northosteric agonists has hindered their use to treat CNS disorders due to the incidence of side effects, but the hope \nis that positive allosteric modulators (see Ch. 3) that are \nselective (e.g. for the M\n1 receptor) will be developed.\nMEMANTINE\nThe other drug currently approved for the treatment of AD is memantine, an orally active weak antagonist at domain as soluble APP, which is believed to serve a physiological \ntrophic function. Formation of A \u03b2 involves cleavage at two different \npoints, including one in the intramembrane domain of APP, by \u03b2- and \n\u03b3-secretases (see Fig. 41.3). \u03b3-Secretase is a clumsy enzyme \u2013 actually a large intramembrane complex of several proteins \u2013 that lacks precision \nand cuts APP at different points in the transmembrane domain, \ngenerating A\u03b2 fragments of different lengths, including A \u03b240 and \n42. Mutations in this region of the APP gene affect the preferred \ncleavage point, tending to favour formation of A \u03b242. Mutations of \nthe unrelated presenilin genes result in increased activity of \u03b3-secretase, \nbecause the presenilin proteins form part of the \u03b3-secretase complex. \nThese different AD-related mutations increase the ratio of A \u03b242:A\u03b240, \nwhich can be detected in plasma, serving as a marker for familial AD. Mutations in another gene, that for the lipid transport protein \nApoE4 which facilitates the clearance of A \u03b2 oligomers, also predispose \nto AD, probably because the mutant form of ApoE4 proteins are less \neffective in this function.\nIt is uncertain exactly how A\u03b2 accumulation would cause neurode-\ngeneration, and whether the damage is done by soluble A \u03b2 monomers \nor oligomers or by amyloid plaques. There is evidence that the cells \ndie by apoptosis, although an inflammatory response is also evident. \nExpression of Alzheimer\u2019s mutations in transgenic animals (see G\u00f6tz & \nIttner, 2008) causes plaque formation and neurodegeneration, and also \nincreases the susceptibility of CNS neurons to other challenges, such \nas ischaemia, excitotoxicity and oxidative stress, and this increased \nvulnerability may be the cause of the progressive neurodegeneration in AD. However, the fact that several novel potential therapies designed \nto reduce A\u03b2 production (see p. 522) have so far proven to be inef", "start_char_idx": 0, "end_char_idx": 3635, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e5a7d0f9-b51f-49dc-ac31-0fe73005e961": {"__data__": {"id_": "e5a7d0f9-b51f-49dc-ac31-0fe73005e961", "embedding": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f5c4958-b80d-4500-92aa-b5b304c99594", "node_type": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "176b0421239df45e01dba61a18bb43b2076dc7f39d1fbb47f2e806b502845f6a"}, "2": {"node_id": "df7c7077-3849-45cd-89d4-9a6f3977adec", "node_type": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "492e35b334f1067ffe712d8fd0464891cde0c5c38d4b299446051a4651e801f9"}, "3": {"node_id": "495145ca-75a4-40eb-a4ed-b1bd2759d842", "node_type": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "478898e3c87863778c86786b84bab173c6a76e00b70cb65c0e2da0e0c33f02cc"}}, "hash": "ef380b0140135f7e8a4d478725f5a351669e01901e3bd1d3ac3a2c4d219b3f35", "text": "reduce A\u03b2 production (see p. 522) have so far proven to be inef -\nfective in clinical trials on AD patients has led some to question the \nimportance of amyloid plaque formation in AD (see Herrup, 2015 for a \ncritical view).\nThe other main player on the biochemical stage is Tau, the protein \nof which the neurofibrillary tangles are composed (see Fig. 41.3). Its \nrole in neurodegeneration is unclear, although similar \u2018tauopathies\u2019 \noccur in many neurodegenerative conditions (see Brunden et al., \n2009; Hanger et al., 2009). Tau is a normal constituent of neurons, \nbeing associated with the intracellular microtubules that serve as tracks for transporting materials along nerve axons. In AD and other \ntauopathies, Tau is abnormally phosphorylated by the action of various \nkinases, including glycogen synthase kinase-3 \u03b2 (GSK-3 \u03b2) and cyclin-\ndependent kinase 5 (CDK5), and dissociates from microtubules to be \ndeposited intracellularly as paired helical filaments with a characteristic \nmicroscopic appearance. When the cells die, these filaments aggre -\ngate as extracellular neurofibrillary tangles . Tau phosphorylation is \nenhanced by the presence of A\u03b2, possibly by activation of kinases. \nConversely, hyperphosphorylated Tau favours the formation of \namyloid deposits. Whether hyperphosphorylation and intracellular \ndeposition of Tau directly harms the cell is not certain, although it is known that it impairs fast axonal transport, a process that depends on \nmicrotubules.\nLoss of cholinergic neurons\nAlthough changes in many transmitter systems have been \nobserved, mainly from measurements on postmortem AD \nbrain tissue, a relatively selective loss of cholinergic neurons \nin the basal forebrain nuclei (Ch. 40) is characteristic. This discovery, made in 1976, implied that pharmacological \napproaches to restoring cholinergic function might be \nfeasible, leading to the use of cholinesterase inhibitors to treat AD (see later).\nCholine acetyl transferase activity, acetylcholine content \nand acetylcholinesterase and choline transport in the cortex and hippocampus are all reduced considerably in AD but not in other disorders, such as depression or schizophre -\nnia. Muscarinic receptor density, determined by binding studies, is not affected, but nicotinic receptors, particularly in the cortex, are reduced. The reason for the selective loss \nof cholinergic neurons resulting from A\u03b2 formation is \nnot known.Alzheimer\u2019s disease \n\u2022\tAlzheimer\u2019s \tdisease \t(AD) \tis \ta \tcommon \tage-related \t\ndementia, \tdistinct \tfrom \tvascular \tdementia \tassociated \t\nwith brain infarction.\n\u2022\tThe\tmain \tpathological \tfeatures \tof \tAD \tcomprise \t\namyloid\tplaques, \tneurofibrillary \ttangles \tand \ta \tloss \tof \t\nneurons\t(particularly \tcholinergic \tneurons \tof \tthe \tbasal \t\nforebrain).\n\u2022\tAmyloid \tplaques \tconsist \tof \taggregates \tof \tthe \tA\u03b2 \nfragment\tof \tamyloid \tprecursor \tprotein \t(APP), \ta \tnormal \t\nneuronal\tmembrane \tprotein, \tproduced \tby \tthe \taction \tof \t\n\u03b2- and \u03b3-secretases. \tAD \tis \tassociated \twith \texcessive \t\nA\u03b2\tformation, \tresulting \tin \tneurotoxicity.\n\u2022\tFamilial\tAD \t(rare) \tresults \tfrom \tmutations \tin \tthe \tAPP \t\ngene,\tor\tin \tpresenilin \tgenes \t(involved \tin \t\u03b3-secretase \nfunction),\tboth \tof \twhich \tcause \tincreased", "start_char_idx": 3585, "end_char_idx": 6830, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "495145ca-75a4-40eb-a4ed-b1bd2759d842": {"__data__": {"id_": "495145ca-75a4-40eb-a4ed-b1bd2759d842", "embedding": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f5c4958-b80d-4500-92aa-b5b304c99594", "node_type": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "176b0421239df45e01dba61a18bb43b2076dc7f39d1fbb47f2e806b502845f6a"}, "2": {"node_id": "e5a7d0f9-b51f-49dc-ac31-0fe73005e961", "node_type": null, "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef380b0140135f7e8a4d478725f5a351669e01901e3bd1d3ac3a2c4d219b3f35"}}, "hash": "478898e3c87863778c86786b84bab173c6a76e00b70cb65c0e2da0e0c33f02cc", "text": "\t\u03b3-secretase \nfunction),\tboth \tof \twhich \tcause \tincreased \tA\u03b2 formation.\n\u2022\tMutations \tin \tthe \tlipoprotein \tApoE4 \tincrease \tthe \trisk \tof \t\ndeveloping \tAD, \tprobably \tby \tinterfering \twith \tA\u03b2 \nclearance.\n\u2022\tNeurofibrillary \ttangles \tcomprise \tintracellular \taggregates \t\nof\ta\thighly \tphosphorylated \tform \tof \ta \tnormal \tneuronal \t\nprotein\t(Tau). \tHyperphosphorylated \tTau \tand \tA\u03b2 act \nsynergistically \tto \tcause \tneurodegeneration.\n\u2022\tLoss\tof \tcholinergic \tneurons \tis \tbelieved \tto \taccount \tfor \t\nmuch\tof\tthe \tlearning \tand \tmemory \tdeficit \tin \tAD.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6823, "end_char_idx": 7856, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e45a520c-c83d-4ded-a584-e07a0dc26b10": {"__data__": {"id_": "e45a520c-c83d-4ded-a584-e07a0dc26b10", "embedding": null, "metadata": {"page_label": "528", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f561b82a-8bc5-4431-9b4c-92fe880a0e0d", "node_type": null, "metadata": {"page_label": "528", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "afae27aabc5cd3804817ea94b77b245c4b1a915c6887a1ec8bf20bad5bf746a7"}, "3": {"node_id": "aff212c9-a712-4527-a4c7-1ae6b845a020", "node_type": null, "metadata": {"page_label": "528", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "68cd3f47fbdb90c4fe30c797f55836569e43ce06ed02c8b25271ef85745d3b19"}}, "hash": "a15f6c5f60919a53255c584f33d53cb9a8a711d2ed852c9cc4df9a1ef766dd6b", "text": "41 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n522models of AD on which compounds can be tested, subsequent clinical \ntrials of drugs targeting these processes have been disappointing. \nExamples of drugs that proved not to be as effective in stopping or \nreversing the progress of AD as had been hoped are:\n\u2022\tverubecestat, a \u03b2-secretase 1 (BACE1) inhibitor;\n\u2022\tsolanezumab, a monoclonal antibody against A\u03b2 peptide.\nThere is still some hope that these or similarly acting agents (e.g. \naducanumab) may prove effective if given at an early stage of disease \ndevelopment.\nThat treatment strategies targeted at reducing A \u03b2 have failed to reverse \nthe progression of AD suggests that the disease is the result of a more \ncomplex pathophysiology and that targeting A\u03b2 alone may not be \nsufficient to treat AD.\nDetails of over 100 drugs in various stages of clinical trial for either \nsymptomatic relief or disease-modifying activity in AD are given in \nCummings et al. (2017). Cognitive deficits occur in other CNS disorders \nsuch as PD, schizophrenia and depression. The development of \ncognition-enhancing drugs that may be useful across these disorders \nis described in Chapter 49.\nPARKINSON\u2019S DISEASE\nFEATURES OF PARKINSON\u2019S DISEASE\nPD is a progressive disorder of movement that occurs mainly \nin the elderly. It was first described in 1817 by James \nParkinson. Przedborski (2017) describes in detail how \nunderstanding of the disorder and its treatment have evolved over the subsequent 200 years.\nThe chief symptoms are:\n\u2022\tsuppression \tof \tvoluntary \tmovements \t(bradykinesia), \ndue partly to muscle rigidity and partly to an inherent \ninertia of the motor system, which means that motor \nactivity is difficult to stop as well as to initiate;\n\u2022\ttremor \tat \trest, \tusually \tstarting \tin \tthe \thands \t\n(\u2018pill-rolling\u2019 tremor), which tends to diminish during voluntary activity;\n\u2022\tmuscle \trigidity, \tdetectable \tas \tan \tincreased \tresistance \t\nin passive limb movement;\n\u2022\ta\tvariable \tdegree \tof \tcognitive \timpairment.\nParkinsonian patients walk with a characteristic shuffling gait. They find it hard to start, and once in progress they \ncannot quickly stop or change direction. PD is commonly NMDA receptors. It was originally introduced as an antiviral drug, and resurrected as a potential inhibitor of excitotoxic -\nity. It produces \u2013 surprisingly \u2013 a modest cognitive improve -\nment in moderate or severe AD, but does not appear to be neuroprotective. It may work by selectively inhibiting \nexcessive, pathological NMDA-receptor activation while preserving more physiological activation. It has a long \nplasma half-life, and its adverse effects include headache, \ndizziness, drowsiness, constipation, shortness of breath and hypertension as well as a raft of less common problems. \nThe potential for other drugs acting as agonists or allosteric \nmodulators at NMDA receptors to enhance cognition is \ndiscussed by Collingridge et al. (2013).Table 41.2 Cholinesterase inhibitors used in the treatment of Alzheimer\u2019s diseasea\nDrug Type of inhibitionDuration of action \nand dosage Main side effects Notes\nDonepezil CNS, AChE selective ~24 h\nOnce-daily oral dosageSlight cholinergic \nside effects\u2014\nRivastigmine CNS selective~8 h\nTwice-daily oral dosageCholinergic side effects that tend \nto subside with continuing treatmentGradual dose escalation to minimise side effectsAvailable in a transdermal patch\nGalantamineAffects both AChE and BuChEAlso enhances", "start_char_idx": 0, "end_char_idx": 3443, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aff212c9-a712-4527-a4c7-1ae6b845a020": {"__data__": {"id_": "aff212c9-a712-4527-a4c7-1ae6b845a020", "embedding": null, "metadata": {"page_label": "528", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f561b82a-8bc5-4431-9b4c-92fe880a0e0d", "node_type": null, "metadata": {"page_label": "528", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "afae27aabc5cd3804817ea94b77b245c4b1a915c6887a1ec8bf20bad5bf746a7"}, "2": {"node_id": "e45a520c-c83d-4ded-a584-e07a0dc26b10", "node_type": null, "metadata": {"page_label": "528", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a15f6c5f60919a53255c584f33d53cb9a8a711d2ed852c9cc4df9a1ef766dd6b"}}, "hash": "68cd3f47fbdb90c4fe30c797f55836569e43ce06ed02c8b25271ef85745d3b19", "text": "patch\nGalantamineAffects both AChE and BuChEAlso enhances nicotinic ACh receptor activation by allosteric action\n~8 h\nTwice-daily oral dosageSlight cholinergic side effects\u2014\naSimilar\tlevel \tof \tlimited \tclinical \tbenefit \tfor \tall \tdrugs. \tNo \tclinical \tevidence \tfor \tretardation \tof \tdisease \tprocess, \talthough \tanimal \ttests \tsuggest \t\ndiminution \tof \tA\u03b2\tand\tplaque \tformation \tby \ta \tmechanism \tnot \trelated \tto \tcholinesterase \tinhibition.\nAChE, acetylcholinesterase; BuChE,\tbutyryl\tcholinesterase; \tCNS,\tcentral\tnervous \tsystem.\nClinical use of drugs in dementia \n\u2022\tAcetylcholinesterase \tinhibitors \tand \tNMDA \tantagonists \t\ndetectably \timprove \tcognitive \timpairment \tin \tclinical \t\ntrials\tbut\thave \tsignificant \tadverse \teffects \tand \tare \tof \t\nlimited\tuse \tclinically. \tThey \thave \tnot \tbeen \tshown \tto \t\nretard\tneurodegeneration.\n\u2022\tEfficacy \tis \tmonitored \tperiodically \tin \tindividual \tpatients, \t\nand\tadministration \tcontinued \tonly \tif \tthe \tdrugs \tare \t\nbelieved to be working and their effect in slowing \nfunctional\tand \tcognitive \tdeterioration \tis \tjudged \tto \t\noutweigh\tadverse \teffects.\nAcetylcholinesterase inhibitors:\n\u2022\tDonepezil ,\tgalantamine ,\trivastigmine. Unwanted \ncholinergic \teffects \tmay \tbe \ttroublesome.\n\u2022\tUsed\tin \tmild \tto \tmoderate \tAlzheimer\u2019s \tdisease.\nNMDA-receptor antagonists:\n\u2022\tFor\texample, \tmemantine \t(see\tCh.\t39).\n\u2022\tUsed\tin \tmoderate-to-severe \tAlzheimer\u2019s \tdisease.\nFuture drug development\n\u25bc For most of the disorders discussed in this chapter, including AD, \nthe Holy Grail, which so far eludes us, would be a drug that retards \nneurodegeneration. Although several well-characterised targets were \nidentified, such as A \u03b2 formation by \u03b2- and \u03b3-secretases, A \u03b2 aggregation \nand A\u03b2 neurotoxicity, together with a range of transgenic animal mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3386, "end_char_idx": 5648, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0f0dc202-17ec-48a0-b3b0-7bd1e57be964": {"__data__": {"id_": "0f0dc202-17ec-48a0-b3b0-7bd1e57be964", "embedding": null, "metadata": {"page_label": "529", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ebdc26ee-d582-44b5-a69d-65a38e7c0b8c", "node_type": null, "metadata": {"page_label": "529", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e44ff261c29721a97bc705865ae81e3eb86bd319dd88d933a528e7c348ed1b8"}, "3": {"node_id": "964746b8-c8ac-4c03-b601-084f87d0c280", "node_type": null, "metadata": {"page_label": "529", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fd44efab4da83f9e28b54810f69b9aeb345ec1422336c84655a9f660fe6b0781"}}, "hash": "a9903b30b5f5ce5c58ee9e6cd5a34013754d5f8e0546cec77e446833ea50d683", "text": "41 NEURO dEgENER aTiVE diSEaSES\n523dopaminergic and cholinergic neurons are, up to a point, \nbeneficial.\nPATHOGENESIS OF PARKINSON\u2019S DISEASE\nAs with other neurodegenerative disorders, the neuronal damage in PD is caused by protein misfolding and aggrega -\ntion, aided and abetted by other familiar villains, namely excitotoxicity, mitochondrial dysfunction, oxidative stress, inflammation and apoptosis. Aspects of the pathogenesis \nand animal models of PD are described by Duty and Jenner \n(2011).\nNeurotoxins\nNew light was thrown on the possible aetiology of \nPD by a chance event. In 1982, a group of young drug \naddicts in California suddenly developed an exception -\nally severe form of PD (known as the \u2018frozen addict\u2019 \nsyndrome), and the cause was traced to the compound associated with dementia, depression, hallucinations and autonomic dysfunction, because the degenerative process \nis not confined to the basal ganglia but also affects other \nparts of the brain. Non-motor symptoms may appear before motor symptoms and often predominate in the later stages \nof the disease.\nPD often occurs with no obvious underlying cause, but it \nmay be the result of cerebral ischaemia, viral encephalitis, head injury or other types of pathological damage. The \nsymptoms can also be drug-induced, the main drugs involved being those that block dopamine receptors (e.g. \nantiemetic and antipsychotic drugs such as chlorpromazine ; \nsee Chs 31 and 47). There are rare instances of familial \nearly-onset PD, and several gene mutations have been identified, including those encoding synuclein and parkin \n(see p. 524). Mutations in the gene encoding leucine-\nrich repeat kinase 2 (LRRK2) have also been associated with PD. Study of gene mutations has given some clues \nabout the mechanism underlying the neurodegenerative \nprocess.\nNeurochemical changes\nPD affects the basal ganglia, and its neurochemical origin \nwas discovered in 1960 by Hornykiewicz, who showed \nthat the dopamine content of the substantia nigra and \ncorpus striatum (see Ch. 40) in postmortem brains of PD patients was extremely low (usually less than 10% of \nnormal), associated with a loss of dopaminergic neurons in \nthe substantia nigra and degeneration of nerve terminals in the striatum.\n7 Neurons containing other monoamines \nsuch as noradrenaline and 5-hydroxytryptamine are also \naffected. Gradual loss of dopamine occurs over several years, \nwith symptoms of PD appearing only when the striatal dopamine content has fallen to 20%\u201340% of normal. Lesions \nof the nigrostriatal tract or chemically induced depletion of \ndopamine in experimental animals also produce symptoms of PD. The symptom most clearly related to dopamine \ndeficiency is bradykinesia, which occurs immediately \nand invariably in lesioned animals. Rigidity and tremor involve more complex neurochemical disturbances of other transmitters (particularly acetylcholine, noradrenaline, \n5-hydroxytryptamine and GABA) as well as dopamine. \nIn experimental lesions, two secondary consequences follow damage to the nigrostriatal tract, namely a hyperactivity \nof the remaining dopaminergic neurons, which show an \nincreased rate of transmitter turnover, and an increase in the number of dopamine receptors, which produces a state \nof denervation hypersensitivity (see Ch. 13). Neurons in the \nstriatum expresses mainly D\n1 (excitatory) and D 2 (inhibitory) \nreceptors (see Ch. 40), but fewer D 3 and D 4 receptors. A \nsimplified diagram of the", "start_char_idx": 0, "end_char_idx": 3479, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "964746b8-c8ac-4c03-b601-084f87d0c280": {"__data__": {"id_": "964746b8-c8ac-4c03-b601-084f87d0c280", "embedding": null, "metadata": {"page_label": "529", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ebdc26ee-d582-44b5-a69d-65a38e7c0b8c", "node_type": null, "metadata": {"page_label": "529", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e44ff261c29721a97bc705865ae81e3eb86bd319dd88d933a528e7c348ed1b8"}, "2": {"node_id": "0f0dc202-17ec-48a0-b3b0-7bd1e57be964", "node_type": null, "metadata": {"page_label": "529", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a9903b30b5f5ce5c58ee9e6cd5a34013754d5f8e0546cec77e446833ea50d683"}}, "hash": "fd44efab4da83f9e28b54810f69b9aeb345ec1422336c84655a9f660fe6b0781", "text": "fewer D 3 and D 4 receptors. A \nsimplified diagram of the neuronal circuitry involved, and \nthe pathways primarily affected in PD and HD, is shown \nin Fig. 41.4.\nCholinergic interneurons of the corpus striatum (not \nshown in Fig. 41.4) are also involved in PD and HD. Acetylcholine release from the striatum is strongly inhibited by dopamine, and it is suggested that hyperactivity of these \ncholinergic neurons contributes to the symptoms of PD. \nThe opposite happens in HD, and in both conditions therapies aimed at redressing the balance between the Corpus striatum\nThalamusMotor cortex\nPCPD\nPRGlobus\npallidusHuntington\u2019s\ndisease\nSTN = Subthalamic nucleus\nPR = Substantia nigra\n(pars reticulata)\nPC = Substantia nigra\n(pars compacta)STN\nDopaminergicneuron\nGABAergicneuron\nGlutamatergic\nneuronSubstantia\nnigra\nFig. 41.4 Simplified diagram of the organisation of the \nextrapyramidal motor system and the defects that occur in \nParkinson\u2019s disease (PD) and Huntington\u2019s disease. \nNormally,\tactivity \tin \tnigrostriatal \tdopamine \tneurons \tcauses \t\nexcitation\tof \tstriatonigral \tneurons \tand \tinhibition \tof \tstriatal \t\nneurons\tthat \tproject \tto \tthe \tglobus \tpallidus. \tBecause \tof \tthe \t\ndifferent\tpathways \tinvolved, \tthe \tactivity \tof \tGABAergic \tneurons \tin \t\nthe\tsubstantia \tnigra \tis \tsuppressed, \treleasing \tthe \trestraint \ton \tthe \t\nthalamus\tand \tcortex, \tcausing \tmotor \tstimulation. \tIn \tPD, \tthe \t\ndopaminergic \tpathway \tfrom \tthe \tsubstantia \tnigra \t(pars \t\ncompacta) \tto \tthe \tstriatum \tis \timpaired. \tIn \tHuntington\u2019s \tdisease, \t\nthe\tGABAergic \tstriatopallidal \tpathway \tis \timpaired, \tproducing \t\neffects\topposite \tto \tthe \tchanges \tin \tPD. \t\n7It is emerging that other types of neuron are also affected. Here we \nconcentrate on the dopaminergic nigrostriatal pathway as it is the most \nimportant in relation to current therapies.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3422, "end_char_idx": 5747, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c5635610-57e6-4b60-b55e-45e8a1e2b372": {"__data__": {"id_": "c5635610-57e6-4b60-b55e-45e8a1e2b372", "embedding": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bca26671-473a-4482-9631-c71294d51d7b", "node_type": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b204c9c41113786d4358bd622e47373baf67b643158cd6f11b4f85c66a08c899"}, "3": {"node_id": "1870ee1a-b7c9-4457-833a-0dfecb6b93f1", "node_type": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8c6df0237051dafbffd47ffe4692446169ba46fd044366ac7bd1362c864a9a9b"}}, "hash": "593cf3078f1c248eb3af0683dd12d72fad7f4a9efb84c5b459dffcf11ec42892", "text": "41 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n524making cells more susceptible to oxidative stress. Thus, a picture \nsimilar to AD pathogenesis is slowly emerging. Misfolded \u03b1-synuclein, \nfacilitated by overexpression, genetic mutations or possibly by environmental factors, builds up in the cell as a result of impaired protein degradation (resulting from defective parkin) in the form of \nLewy bodies, which, by unknown mechanisms, compromise cell \nsurvival. If oxidative stress is increased, as a result of ischaemia, mitochondrial poisons or mutations of certain mitochondrial proteins, \nthe result is cell death.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP), which \nwas a contaminant in the illegal preparation of a heroin \nsubstitute (see Langston, 1985). MPTP causes irreversible \ndestruction of nigrostriatal dopaminergic neurons in various species, and produces a PD-like state in primates. MPTP \nacts by being converted to a toxic metabolite, MPP\n+, by \nthe enzyme monoamine oxidase (MAO, specifically by the MAO-B subtype that is located in glial cells; see Chs 15 \nand 48). MPP\n+ is then taken up by the dopamine trans-\nport system, and thus acts selectively on dopaminergic \nneurons; it inhibits mitochondrial oxidation reactions, \nproducing oxidative stress. MPTP appears to be selective in destroying nigrostriatal neurons and does not affect \ndopaminergic neurons elsewhere \u2013 the reason for this is \nunknown. It is also less effective in rats than in primates, yet mice show some susceptibility. Selegiline, a selective \nMAO-B inhibitor, prevents MPTP-induced neurotoxicity by blocking its conversion to MPP\n+. Selegiline is also used \nin treating PD (see p. 526); as well as inhibiting dopamine \nbreakdown, it might also work by blocking the metabolic \nactivation of a putative endogenous, or environmental, MPTP-like substance, which is involved in the causation \nof PD. It is possible that dopamine itself could be the culprit, \nbecause oxidation of dopamine gives rise to potentially toxic metabolites. Whether or not the action of MPTP reflects \nthe natural pathogenesis of PD, the MPTP model is a very \nuseful experimental tool for testing possible therapies.\nImpaired mitochondrial function is a feature of the disease \nin humans. Various herbicides, such as rotenone, that \nselectively inhibit mitochondrial function cause a PD-like syndrome in animals. PD in humans is more common in agricultural areas than in cities, suggesting that environ -\nmental toxins could be a factor in its causation.\nMolecular aspects\n\u25bc PD, as well as several other neurodegenerative disorders, is \nassociated with the development of intracellular protein aggregates \nknown as Lewy bodies in various parts of the brain. They consist \nlargely of \u03b1-synuclein, a synaptic protein, present in large amounts in normal brains. Recent evidence suggests that \u03b1-synuclein may \nact as a prion-like protein and that PD is in fact a prion-like disease (Olanow & Brundin, 2013). \u03b1-Synuclein normally exists in an \u03b1-helical \nconformation. However, under certain circumstances, such as genetic \nduplication or triplication or genetic mutation, it can undergo a \nconformational change to a \u03b2-sheet-rich structure that polymerises \nto form toxic aggregates and amyloid plaques. Mutations occur in rare \ntypes of hereditary PD (see p. 523). It is believed that misfolding and aggregation renders the protein resistant to degradation within cells, \ncausing it to pile up in Lewy bodies. In", "start_char_idx": 0, "end_char_idx": 3465, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1870ee1a-b7c9-4457-833a-0dfecb6b93f1": {"__data__": {"id_": "1870ee1a-b7c9-4457-833a-0dfecb6b93f1", "embedding": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bca26671-473a-4482-9631-c71294d51d7b", "node_type": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b204c9c41113786d4358bd622e47373baf67b643158cd6f11b4f85c66a08c899"}, "2": {"node_id": "c5635610-57e6-4b60-b55e-45e8a1e2b372", "node_type": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "593cf3078f1c248eb3af0683dd12d72fad7f4a9efb84c5b459dffcf11ec42892"}, "3": {"node_id": "4e926dce-421c-40e8-a95c-7e8a21bed2cf", "node_type": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "04cc7b590cbd81785445f689794f614ae647004e22eaab17a26adf60dcd3ff2c"}}, "hash": "8c6df0237051dafbffd47ffe4692446169ba46fd044366ac7bd1362c864a9a9b", "text": "within cells, \ncausing it to pile up in Lewy bodies. In parkinsonian patients who \nreceived fetal dopaminergic neuron grafts, (see p. 527) the grafted neurons, over time, developed Lewy bodies. Misfolded \u03b1-synuclein \nis thought to have migrated from the native tissue to the grafted \ntissue.\nIt is possible (see Lotharius & Brundin, 2002) that the normal \nfunction of \u03b1-synuclein is related to synaptic vesicle recy -\ncling, and that the misfolded form loses this functionality, with the result that vesicular storage of dopamine is impaired. This may lead to an increase in cytosolic dopa-\nmine, degradation of which produces ROS and hence \nneurotoxicity. Consistent with the \u03b1-synuclein hypothesis, \nanother mutation associated with PD ( parkin ) also involves \na protein that participates in the intracellular degradation of rogue proteins.\n\u25bc Other gene mutations that have been identified as risk factors for \nearly-onset PD code for proteins involved in mitochondrial function, Parkinson\u2019s disease \n\u2022\tDegenerative \tdisease \tof \tthe \tbasal \tganglia \tcausing \t\nhypokinesia, \ttremor \tat \trest \tand \tmuscle \trigidity, \toften \t\nwith\tdementia \tand \tautonomic \tdysfunction.\n\u2022\tAssociated \twith \taggregation \tof \t\u03b1-synuclein \t(a \tprotein \t\nnormally\tinvolved \tin \tvesicle \trecycling) \tin \tthe \tform \tof \t\ncharacteristic \tLewy \tbodies.\n\u2022\tOften\tidiopathic \tbut \tmay \tfollow \tstroke \tor \tvirus \t\ninfection;\tcan \tbe \tdrug-induced \t(antipsychotic \tdrugs). \t\nRare\tfamilial \tforms \talso \toccur, \tassociated \twith \tvarious \t\ngene\tmutations, \tincluding \t\u03b1-synuclein.\n\u2022\tAssociated \twith \tdegeneration \tof \tdopaminergic \t\nnigrostriatal \tneurons \tthat \tgives \trise \tto \tthe \tmotor \t\nsymptoms, \tas \twell \tas \tmore \tgeneral \tneurodegeneration \t\nresulting\tin \tdementia \tand \tdepression.\n\u2022\tCan\tbe \tinduced \tby \t1-methyl-4-phenyl-1,2,3,6-\ntetrahydropyridine \t(MPTP),\ta\tneurotoxin \taffecting \t\ndopamine \tneurons. \tSimilar \tenvironmental \tneurotoxins, \t\nas\twell\tas \tgenetic \tfactors, \tmay \tbe \tinvolved \tin \thuman \t\nParkinson\u2019s \tdisease.\nDRUG TREATMENT OF PARKINSON\u2019S DISEASE\nCurrently, the main drugs used (Fig. 41.5) are:\n\u2022\tlevodopa (sometimes in combination with carbidopa \nand entacapone);\n\u2022\tdopamine \tagonists \t(e.g. \tpramipexole, ropinirole, \nbromocriptine);\n\u2022\tMAO-B \tinhibitors \t(e.g. \tselegiline, rasagiline);\n\u2022\tmuscarinic \tACh \treceptor \tantagonists \t(e.g. \t\norphenadrine, procyclidine and trihexyphenidyl) are \noccasionally used.\nNone of the drugs used to treat PD affect the progression of the disease.\nLEVODOPA\nLevodopa is the first-line treatment for PD and is combined \nwith a peripherally acting dopa decarboxylase inhibitor, \nsuch as carbidopa or benserazide , which reduces the dose \nneeded by about 10-fold and diminishes the peripheral \nside effects. It is well absorbed from the small intestine, a \nprocess that relies on", "start_char_idx": 3421, "end_char_idx": 6241, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4e926dce-421c-40e8-a95c-7e8a21bed2cf": {"__data__": {"id_": "4e926dce-421c-40e8-a95c-7e8a21bed2cf", "embedding": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bca26671-473a-4482-9631-c71294d51d7b", "node_type": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b204c9c41113786d4358bd622e47373baf67b643158cd6f11b4f85c66a08c899"}, "2": {"node_id": "1870ee1a-b7c9-4457-833a-0dfecb6b93f1", "node_type": null, "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8c6df0237051dafbffd47ffe4692446169ba46fd044366ac7bd1362c864a9a9b"}}, "hash": "04cc7b590cbd81785445f689794f614ae647004e22eaab17a26adf60dcd3ff2c", "text": "active transport, although much of \nit is inactivated by MAO in the wall of the intestine. The \nplasma half-life is short (about 2 h ). Oral and subcutaneous \nslow-release preparations have been developed. Conversion to dopamine in the periphery, which would otherwise \naccount for about 95% of the levodopa dose and cause \ntroublesome side effects, is largely prevented by the decarboxylase inhibitor. Decarboxylation occurs rapidly \nwithin the brain, because the decarboxylase inhibitors do \nnot penetrate the blood\u2013brain barrier. It is not certain mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6287, "end_char_idx": 7318, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "07a87240-386a-45a7-9e21-27a906de8649": {"__data__": {"id_": "07a87240-386a-45a7-9e21-27a906de8649", "embedding": null, "metadata": {"page_label": "531", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "35bbddcf-6a73-46ab-ab1f-0d50be6a00f9", "node_type": null, "metadata": {"page_label": "531", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca5bed3b01c728abc80b936ad6be433c0eb71240fd40e4c6d56e735310063950"}, "3": {"node_id": "dbddadde-a0a0-40e8-937c-25f0264f56b3", "node_type": null, "metadata": {"page_label": "531", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a5f1708342db44a4da410e2cbbdddf76ad9cd00156088548c37dc044f6f8f918"}}, "hash": "1f8742fe125b4c0c07d883192a09aa0c2ccd91872a10d45e4231ce20b34a5606", "text": "41 NEURO dEgENER aTiVE diSEaSES\n525accelerate the neurodegenerative process through overpro -\nduction of dopamine, as was suspected on theoretical \ngrounds. Overall, levodopa increases the life expectancy \nof PD patients, probably as a result of improved motor function, although some symptoms (e.g. dysphagia, cogni-\ntive decline) are not improved.\nUnwanted effects\nThere are two main types of unwanted effect:\n1. Involuntary movements (dyskinesia), which do not \nappear initially but develop in the majority of patients \nwithin 2 years of starting levodopa therapy. These \nmovements usually affect the face and limbs, and can \nbecome very severe. They occur at the time of the peak therapeutic effect, and the margin between the \nbeneficial and the dyskinetic effect becomes \nprogressively narrower. Levodopa is short acting, and the fluctuating plasma concentration of the drug may \nfavour the development of dyskinesias, as \nlonger-acting dopamine agonists are less problematic in this regard.\n2. Rapid fluctuations in clinical state, where bradykinesia \nand rigidity may suddenly worsen for anything from a few minutes to a few hours, and then improve again. \nThis \u2018on\u2013off effect\u2019 is not seen in untreated PD patients \nor with other anti-PD drugs. The \u2018off effect\u2019 can be so sudden that the patient stops while walking and feels \nrooted to the spot, or is unable to rise from a chair, whether the effect depends on an increased release of \ndopamine from the few surviving dopaminergic neurons or on a \u2018flooding\u2019 of the synapse with dopamine formed \nelsewhere. Because synthetic dopamine agonists (see p. \n526) are equally effective, the latter explanation is more likely, and animal studies suggest that levodopa can act \neven when no dopaminergic nerve terminals are present. \nOn the other hand, the therapeutic effectiveness of levodopa decreases as the disease advances, so part of its action may \nrely on the presence of functional dopaminergic neurons. \nCombination of levodopa plus a dopa decarboxylase inhibi -\ntor with a catechol- O-methyl transferase (COMT) inhibitor \n(e.g. entacapone, tolcapone or opicapone, see Ch. 15) to \ninhibit its degradation, is used in patients troubled by \u2018end of dose\u2019 motor fluctuations.\nTherapeutic effectiveness\nAbout 80% of patients show initial improvement with levodopa, particularly of rigidity and bradykinesia, and \nabout 20% are restored virtually to normal motor function. \nAs time progresses, the effectiveness of levodopa gradually declines (Fig. 41.6). In a typical study of 100 patients treated \nwith levodopa for 5 years, only 34 were better than they \nhad been at the beginning of the trial, 32 patients having died and 21 having withdrawn from the trial. It is likely \nthat the loss of effectiveness of levodopa mainly reflects \nthe natural progression of the disease, but receptor down-regulation and other compensatory mechanisms may also contribute. There is no evidence that levodopa can actually DDC COMTEntacapone\nTolcapone\nLevodopa\nDopamine 3-MT3-MDopa DopaminePERIPHERY\nBRAIN\nDOPACCarbidopa\nBenserazide\nMAO-BSelegiline\nRasagiline\nPramipexole\nRopinirole\nRotigotine\nBromocriptine\nApomorphineCOMTTolcaponeLevodopa\nD1, D2 receptors\nTherapeutic\neffect\nFig. 41.5 Sites of action of drugs used to treat Parkinson\u2019s disease. \tLevodopa \tenters \tthe \tbrain \tand \tis \tconverted \tto", "start_char_idx": 0, "end_char_idx": 3341, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dbddadde-a0a0-40e8-937c-25f0264f56b3": {"__data__": {"id_": "dbddadde-a0a0-40e8-937c-25f0264f56b3", "embedding": null, "metadata": {"page_label": "531", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "35bbddcf-6a73-46ab-ab1f-0d50be6a00f9", "node_type": null, "metadata": {"page_label": "531", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca5bed3b01c728abc80b936ad6be433c0eb71240fd40e4c6d56e735310063950"}, "2": {"node_id": "07a87240-386a-45a7-9e21-27a906de8649", "node_type": null, "metadata": {"page_label": "531", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1f8742fe125b4c0c07d883192a09aa0c2ccd91872a10d45e4231ce20b34a5606"}}, "hash": "a5f1708342db44a4da410e2cbbdddf76ad9cd00156088548c37dc044f6f8f918", "text": "\tLevodopa \tenters \tthe \tbrain \tand \tis \tconverted \tto \tdopamine \t(the \t\ndeficient\tneurotransmitter). \tInactivation \tof \tlevodopa \tin \tthe \tperiphery \tis \tprevented \tby \tinhibitors \tof \tdopa \tdecarboxylase \t(DDC) \tand \tcatechol-\nO-methyl\ttransferase \t(COMT). \tInactivation \tin \tthe \tbrain \tis \tprevented \tby \tinhibitors \tof \tCOMT \tand \tmonoamine \toxidase-B \t(MAO-B). \tDopamine \t\nagonists\tact \tdirectly \ton \tstriatal \tdopamine \treceptors. \t3-MDopa, \t3-methoxydopa; \t3-MT,\t3-methoxytyrosine; \tDOPAC,\tdihydroxyphenylacetic \t\nacid. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3288, "end_char_idx": 4294, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f680157d-b7af-4f59-8de1-7b1afedbfe3a": {"__data__": {"id_": "f680157d-b7af-4f59-8de1-7b1afedbfe3a", "embedding": null, "metadata": {"page_label": "532", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "38724542-862c-43e4-96fe-6488ed65a759", "node_type": null, "metadata": {"page_label": "532", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f24695b7a4ebd43a65653e4a694ac3b479ad494ef78bb01dc4c5075ef4f4bbb"}, "3": {"node_id": "ee8d2be4-3926-49d8-b603-ae98d96bc13c", "node_type": null, "metadata": {"page_label": "532", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b2403eaae4c86bf9f5c814be548f5b1a5d25b833a9a396ce11929aa1b9e3873"}}, "hash": "3c116f73f5e310c97e01c47bcc1cddf3fbe32fcb841eb3565b4cb8cfcf9b7de9", "text": "41 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n526DOPAMINE \u2003AGONISTS\nBromocriptine, pergolide and cabergoline exhibit slight \nselectivity for D 2/3 over D 1 receptors (see Ch. 40). \nBromocriptine, which inhibits the release of prolactin \nfrom the anterior pituitary gland, was first introduced for \nthe treatment of galactorrhoea and gynaecomastia (Ch. 34). Though effective in controlling the symptoms of PD, \ntheir usefulness is limited by side effects, such as nausea \nand vomiting, somnolence and a risk of fibrotic reactions in the lungs, retroperitoneum and pericardium. These \ndisadvantages have led to the replacement of these drugs \nby pramipexole and ropinirole, which are D\n2/3 selective \nand better tolerated, and do not show the fluctuations \nin efficacy associated with levodopa. They do, however, \ncause somnolence and sometimes hallucinations, and recent evidence suggests that they may predispose to compulsive \nbehaviours, such as excessive gambling,\n8 over-eating and \nsexual excess, related to the \u2018reward\u2019 functions of dopamine \n(see Ch. 50).\nA disadvantage of current dopamine agonists is their \nshort plasma half-life (6\u20138 h), requiring three-times daily \ndosage, though slow-release once-daily formulations are \nnow available.\nRotigotine is a newer agent, delivered as a transdermal \npatch, with similar efficacy and side effects.\nApomorphine, given by injection, is sometimes used to \ncontrol the \u2018off effect\u2019 with levodopa. Because of its powerful emetic action, it must be combined with an oral antiemetic drug. It has other serious adverse effects (mood and \nbehavioural changes, cardiac dysrhythmias, hypotension) \nand is a last resort if other drugs fail.\nMAO-B \u2003INHIBITORS\nSelegiline is a selective MAO-B9 inhibitor, which lacks the \nunwanted peripheral effects of non-selective MAO inhibi -\ntors used to treat depression (Ch. 48) and, in contrast to them, does not provoke the \u2018cheese reaction\u2019 or interact so frequently with other drugs. Inhibition of MAO-B \nprotects dopamine from extraneuronal degradation and \nwas initially used as an adjunct to levodopa. Long-term trials showed that the combination of selegiline and levo -\ndopa was more effective than levodopa alone in relieving symptoms and prolonging life. Recognition of the role of MAO-B in neurotoxicity (see p. 524) suggested that selegiline might be neuroprotective rather than merely \nenhancing the action of levodopa, but clinical studies do \nnot support this. A large-scale trial (see Fig. 41.6) showed no difference when selegiline was added to levodopa/\nbenserazide treatment. Selegiline is metabolised to ampheta -\nmine, and sometimes causes excitement, anxiety and \ninsomnia. Rasagiline, a very similar drug, does not have \nthis unwanted effect, and may somewhat retard disease \nprogression, as well as alleviating symptoms (Olanow et al., \n2009). Safinamide inhibits both MAO-B and dopamine \nreuptake.having sat down normally a few moments earlier. As with the dyskinesias, the problem seems to reflect the \nfluctuating plasma concentration of levodopa, and it is \nsuggested that as the disease advances, the ability of neurons to store dopamine is lost, so the therapeutic \nbenefit of levodopa depends increasingly on the \ncontinuous formation of extraneuronal dopamine, which requires a continuous supply of levodopa. The", "start_char_idx": 0, "end_char_idx": 3319, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ee8d2be4-3926-49d8-b603-ae98d96bc13c": {"__data__": {"id_": "ee8d2be4-3926-49d8-b603-ae98d96bc13c", "embedding": null, "metadata": {"page_label": "532", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "38724542-862c-43e4-96fe-6488ed65a759", "node_type": null, "metadata": {"page_label": "532", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f24695b7a4ebd43a65653e4a694ac3b479ad494ef78bb01dc4c5075ef4f4bbb"}, "2": {"node_id": "f680157d-b7af-4f59-8de1-7b1afedbfe3a", "node_type": null, "metadata": {"page_label": "532", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3c116f73f5e310c97e01c47bcc1cddf3fbe32fcb841eb3565b4cb8cfcf9b7de9"}}, "hash": "6b2403eaae4c86bf9f5c814be548f5b1a5d25b833a9a396ce11929aa1b9e3873", "text": "dopamine, which requires a continuous supply of levodopa. The \nuse of sustained-release preparations, or \nco-administration of COMT inhibitors such as entacapone, may be used to counteract the \nfluctuations in plasma concentration of levodopa.\nIn addition to these slowly developing side effects, levodopa \nproduces several acute effects, which are experienced by most patients at first but tend to disappear after a few \nweeks. The main ones are as follows:\n\u2022\tNausea \tand \tanorexia. \tDomperidone, a dopamine \nantagonist that works in the chemoreceptor trigger zone (where the blood\u2013brain barrier is leaky) but does \nnot gain access to the basal ganglia, may be useful in preventing this effect.\n\u2022\tHypotension. \tPostural \thypotension \tis \ta \trecognised \t\nproblem, particularly in older patients.\n\u2022\tPsychological \teffects. \tLevodopa, \tby \tincreasing \t\ndopamine activity in the brain, can produce a schizophrenia-like syndrome (see Ch. 47) with \ndelusions and hallucinations. More commonly, in \nabout 20% of patients, it causes confusion, disorientation, insomnia or nightmares.\u22123\u22122\u2212101234\n72 60 48 36 24 12 0\nNumber of months since entryChange in disability scoreLevodopa + benserazide + selegiline\nBromocriptineLevodopa + benserazide\nFig. 41.6 Comparison of levodopa/benserazide, levodopa/\nbenserazide/selegiline and bromocriptine on progression of \nParkinson\u2019s disease symptoms. \tPatients\t(249\u2013271 \tin \teach \t\ntreatment\tgroup) \twere \tassessed \ton \ta \tstandard \tdisability \trating \t\nscore.\tBefore \ttreatment, \tthe \taverage \trate \tof \tdecline \twas \t0.7 \t\nunits/year. \tAll \tthree \ttreatments \tproduced \timprovement \tover \tthe \t\ninitial\trating \tfor \t2\u20133 \tyears, \tbut \tthe \teffect \tdeclined, \teither \tbecause \t\nof\trefractoriness \tto \tthe \tdrugs \tor \tdisease \tprogression. \t\nBromocriptine \tappeared \tslightly \tless \teffective \tthan \tlevodopa \t\nregimens, \tand \tthere \twas \ta \thigher \tdrop-out \trate \tdue \tto \tside \t\neffects\tin\tthis \tgroup. \t(From \tParkinson\u2019s \tDisease \tResearch \t\nGroup,\t1993. \tBr. \tMed. \tJ. \t307, \t469\u2013472.)\n8In 2008 a plaintiff was awarded $8.2 million damages by a United \nStates court, having become a compulsive gambler (and losing a lot of \nmoney) after taking pramipexole for PD \u2013 a side effect of which the \npharmaceutical company had been aware.\n9MAO-B in the brain is located mainly in glial cells, and also in 5-HT \nneurons (though, surprisingly, it does not appear to be expressed in \ndopamine neurons).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3258, "end_char_idx": 6164, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "86b4aea9-4542-49b9-ab71-a31cf1e705b5": {"__data__": {"id_": "86b4aea9-4542-49b9-ab71-a31cf1e705b5", "embedding": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "41e81d24-56f7-45b7-9d04-a7bc8ea13350", "node_type": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ac2d499e7a7f2161561d73b60fd14feb0331ac8fc99361c704e605580841c552"}, "3": {"node_id": "55bed8a5-fe81-4860-9330-86602def3760", "node_type": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "362c909977cc48734f06697e9f2d56d643ea7724c8c5b67ad2962bff72f636e0"}}, "hash": "5140331916463b996675f2c2fbdd11cb324e2a84286d60915ae68a0f7cd343ca", "text": "41 NEURO dEgENER aTiVE diSEaSES\n527NEURAL \u2003TRANSPLANTATION, \u2003GENE \u2003THERAPY \u2003AND\u2003\nBRAIN \u2003STIMULATION\n\u25bc Parkinson\u2019s disease is the first neurodegenerative disease for which \nneural transplantation was attempted in 1982, amid much publicity. \nVarious transplantation approaches have been tried, based on the \ninjection of dissociated fetal cells (neuroblasts) directly into the striatum. \nTrials in patients with PD (Barker et al., 2013) have mainly involved \ninjection of midbrain cells from aborted human fetuses. Although such transplants have been shown to survive and establish functional \ndopaminergic connections, this approach has fallen out of favour \nrecently. Some patients have gone on to develop serious dyskinesias, possibly due to dopamine overproduction. The use of fetal material \nis, of course, fraught with ethical difficulties (usually cells from five \nor more fetuses are needed for one transplant) and hopes for the future rest mainly on developing stem cell transplants (Nishimura \net al., 2013); small clinical trials are underway.\nGene therapy (see Ch. 5) for PD is aimed at increasing the synthesis of neurotransmitters and neurotrophic factors such as:\n\u2022\tdopamine \tin \tthe \tstriatum \t\u2013 \tby \texpressing \ttyrosine \thydroxylase \t\nor dopa decarboxylase;\n\u2022\tGABA \tin \tthe \tsubthalamic \tnucleus \t\u2013 \tby \toverexpression \tof \t\nglutamic acid decarboxylase (to reduce the excitatory input to the substantia nigra) (see Fig. 41.4);\n\u2022\tneurotrophic \tfactors \tsuch \tas \tneurturin, \ta \tglial-derived \t\nneurotrophic factor (GDNF) analogue.\nElectrical stimulation of the subthalamic nuclei with implanted electrodes (which inhibits ongoing neural activity, equivalent to reversible ablation) is used in severe cases, and can improve motor \ndysfunction in PD, but does not improve cognitive and other symptoms \nand does not stop the neurodegenerative process (see Okun, 2012).\nHUNTINGTON\u2019S DISEASE\n\u25bcHD is an inherited (autosomal dominant) disorder resulting in progressive brain degeneration, starting in adulthood and causing \nrapid deterioration and death. As well as dementia, it causes severe \nmotor symptoms in the form of choreiform (i.e. rapid, jerky invol -\nuntary) movements, especially of fingers, face or tongue. It is the \ncommonest of a group of so-called trinucleotide repeat neurodegenerative \ndiseases, associated with the expansion of the number of repeats of \nthe CAG sequence in specific genes, and hence the number (50 or \nmore) of consecutive glutamine residues at the N-terminal of the \nexpressed protein (see Walker, 2007). The larger the number of repeats, \nthe earlier the appearance of symptoms. The protein coded by the \nHD gene , huntingtin , which normally possesses a chain of fewer than \n30 glutamine residues, is a soluble cytosolic protein of unknown \nfunction found in all cells. HD develops when the mutant protein \ncontains 40 or more repeats. The long poly-Gln chains reduce the solubility of huntingtin, and favour the formation of aggregates, which \nare formed by proteolytic cleavage of the mutant protein, releasing \nN-terminal fragments that include the poly-Gln region. As with AD \nand PD, aggregation is probably responsible for the neuronal loss, \nwhich affects mainly the cortex and the striatum, resulting in progres -\nsive dementia and severe involuntary choreiform movements. Studies \non postmortem brains", "start_char_idx": 0, "end_char_idx": 3360, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "55bed8a5-fe81-4860-9330-86602def3760": {"__data__": {"id_": "55bed8a5-fe81-4860-9330-86602def3760", "embedding": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "41e81d24-56f7-45b7-9d04-a7bc8ea13350", "node_type": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ac2d499e7a7f2161561d73b60fd14feb0331ac8fc99361c704e605580841c552"}, "2": {"node_id": "86b4aea9-4542-49b9-ab71-a31cf1e705b5", "node_type": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5140331916463b996675f2c2fbdd11cb324e2a84286d60915ae68a0f7cd343ca"}, "3": {"node_id": "99847d07-ccec-4f99-b893-ccdbb02a7a19", "node_type": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "052eb69bda0bc5a543b6da47f0f7a2cbac0b9232b638db012534aa9a78af7f6c"}}, "hash": "362c909977cc48734f06697e9f2d56d643ea7724c8c5b67ad2962bff72f636e0", "text": "and severe involuntary choreiform movements. Studies \non postmortem brains showed that the dopamine content of the \nstriatum was normal or slightly increased, while there was a 75% reduction in the activity of glutamic acid decarboxylase, the enzyme \nresponsible for GABA synthesis (Ch. 39). It is believed that the loss \nof GABA-mediated inhibition in the basal ganglia produces a hyper -\nactivity of dopaminergic synapses, so the syndrome is in some senses a mirror image of PD (see Fig. 41.4).\nThe effects of drugs that influence dopaminergic transmission are \ncorrespondingly the opposite of those that are observed in PD, \ndopamine antagonists being effective in reducing the involuntary movements, while drugs such as levodopa and bromocriptine make \nthem worse. Drugs used to alleviate the motor symptoms include \ntetrabenazine (an inhibitor of the vesicular monoamine transporter) \n(see Ch. 15) that reduces dopamine storage, dopamine antagonists \nsuch as chlorpromazine and haloperidol (Ch. 47) and the GABA\nB OTHER \u2003DRUGS \u2003USED \u2003IN \u2003PARKINSON\u2019S \u2003DISEASE\nAmantadine\n\u25bc Amantadine was introduced as an antiviral drug and discovered by accident in 1969 to be beneficial in PD. Many possible mechanisms \nfor its action have been suggested based on neurochemical evidence \nof increased dopamine release, inhibition of amine uptake or a direct action on dopamine receptors. More recently block of NMDA receptors \nby stabilising closed states of the channel has been described and \nthis may be a novel target for antiparkinsonian drugs.\nAmantadine is less effective than levodopa or bromocriptine in treating \nPD, but it is effective in reducing the dyskinesias induced by prolonged levodopa treatment (see p. 525).\nAcetylcholine antagonists\n\u25bc For more than a century, until levodopa was discovered, atropine and related drugs were the main form of treatment for PD. Muscarinic \nacetylcholine receptors exert an inhibitory effect on dopaminergic nerve \nterminals, suppression of which compensates for a lack of dopamine. The side effects of muscarinic antagonists (Ch. 14) \u2013 dry mouth, con -\nstipation, impaired vision, urinary retention \u2013 are troublesome, and they are now rarely used, except to treat parkinsonian symptoms in \npatients receiving antipsychotic drugs (which are dopamine antagonists \nand thus nullify the effect of levodopa; see Ch. 47). Drugs used are \norphenadrine, procyclidine and trihexyphenidyl.\nNEW \u2003PHARMACOLOGICAL \u2003APPROACHES\n\u25bc Potential new treatments for PD at various stages of clinical trial are \nreviewed by Oertel and Schulz (2016). Active and passive immunisa -\ntion against \u03b1-synuclein and inhibitors or modulators of \u03b1-synuclein \naggregation may prevent the progression of the disease. Other, pharmacological approaches are aimed at symptomatic relief after the \ndisease has developed. For example, pimavanserin , a 5-HT\n2A receptor \ninverse agonist, has recently been introduced to treat hallucinations and delusions associated with psychosis in PD. Other potential treatments \ninclude adenosine A\n2A receptor antagonists (e.g. istradefylline and \npreladenant ), 5-HT 1A antagonists (e.g. sarizotan ) and glutamate receptor \nantagonists or negative allosteric modulators (acting at mGluR5, AMPA \nor NMDA receptors) as well as new, improved COMT inhibitors.\nDrugs used in Parkinson\u2019s disease \n\u2022\tDrugs\tact \tby \tcounteracting \tdeficiency \tof \tdopamine \tin", "start_char_idx": 3295, "end_char_idx": 6685, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "99847d07-ccec-4f99-b893-ccdbb02a7a19": {"__data__": {"id_": "99847d07-ccec-4f99-b893-ccdbb02a7a19", "embedding": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "41e81d24-56f7-45b7-9d04-a7bc8ea13350", "node_type": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ac2d499e7a7f2161561d73b60fd14feb0331ac8fc99361c704e605580841c552"}, "2": {"node_id": "55bed8a5-fe81-4860-9330-86602def3760", "node_type": null, "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "362c909977cc48734f06697e9f2d56d643ea7724c8c5b67ad2962bff72f636e0"}}, "hash": "052eb69bda0bc5a543b6da47f0f7a2cbac0b9232b638db012534aa9a78af7f6c", "text": "\tby \tcounteracting \tdeficiency \tof \tdopamine \tin \t\nbasal\tganglia \tor \tby \tblocking \tmuscarinic \treceptors. \t\nNone\tof\tthe \tavailable \tdrugs \taffect \tthe \tunderlying \t\nneurodegeneration.\n\u2022\tDrugs\tinclude:\n\u2013\tlevodopa \t(dopamine \tprecursor; \tCh. \t15), \tgiven \twith \t\nan\tinhibitor \tof \tperipheral \tdopa \tdecarboxylase \t(e.g. \t\ncarbidopa )\tto\tminimise \tside \teffects; \tsometimes \ta \t\ncatechol-O -methyl\ttransferase \tinhibitor \t(e.g. \t\nentacapone )\tis\talso\tgiven, \tespecially \tto \tpatients \t\nwith\t\u2018end\tof \tdose\u2019 \tmotor \tfluctuations;\n\u2013\tdopamine \treceptor \tagonists \t(pramipexole ,\t\nropinirole ,\trotigotine ,\tbromocriptine );\trotigotine \nis\tavailable \tas \ta \ttransdermal \tpatch;\n\u2013\tmonoamine \toxidase-B \tinhibitors \t(selegiline ,\t\nrasagiline);\n\u2013\tamantadine \t(which\tmay \tenhance \tdopamine \t\nrelease);\n\u2013\torphenadrine \t(muscarinic \treceptor \tantagonist \tused \t\nfor\tparkinsonism \tcaused \tby \tantipsychotic \tdrugs).\n\u2022\tNeurotransplantation, \tstill \tin \tan \texperimental \tphase, \t\nmay\tbe\teffective \tbut \tresults \tare \tvariable, \tand \tslowly \t\ndeveloping \tdyskinesias \tmay \toccur.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6703, "end_char_idx": 8244, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d71744e3-b3d5-41be-b311-7ce8306d1ba3": {"__data__": {"id_": "d71744e3-b3d5-41be-b311-7ce8306d1ba3", "embedding": null, "metadata": {"page_label": "534", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f7163ddc-984c-4354-8171-36f85c0a366d", "node_type": null, "metadata": {"page_label": "534", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8c8beac89607e2010afe120ceb7dc3d67a0794ff0e611d1dffcd8ec9ca9b6a7f"}, "3": {"node_id": "a4887108-c041-4e51-a001-fd1493499a52", "node_type": null, "metadata": {"page_label": "534", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7dd176660d1a3ee9bce014e321209ef01dc5dadb65340caacd2a3a282eee51e9"}}, "hash": "ebf01717a362b2625928cfebd88da46f3be0a21083ac72846d54b8f938460171", "text": "41 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n528not produce much functional SMN. Nusinersen prevents \nthe skipping thus allowing the cell to produce SMN.\nMULTIPLE SCLEROSIS\nMS is a disease associated with demyelination of nerve axons and neuronal degeneration resulting in lesions that \nmay occur throughout the CNS. Symptoms usually start \nto develop between 20 and 30 years of age and depend upon the location of the lesions. Common symptoms include \nproblems with vision, dizziness, balance, walking, fatigue, \nincontinence, muscle stiffness and painful muscle spasms. MS can also affect cognitive processing and mood. It affects \nalmost three times as many women as men. There are two \nforms of the disease , relapse\u2013remitting, in which sufferers \nhave attacks of symptoms which subsequently fade away partially or completely but then relapse at a later date, and \nprimary progressive, in which the symptoms persist and \nincrease over time. Relapse\u2013remitting may, however, develop into secondary progressive in later life. The cause \nof MS is unknown; like other neurodegenerative conditions \nit may result from a combination of predisposing genetic factors (Hollenbach & Oksenberg, 2015) and exposure to \nenvironmental factors such as infection.\nMS has long been considered an autoimmune demyelinat -\ning disease, although the proteins, lipids and gangliosides in myelin that act as antigens have not been identified. \nInflammation (see Ch. 27), enhanced permeability of blood\u2013brain barrier, demyelination and axonal degeneration \nare common pathological features. It is, however, still unclear \nwhether MS is a primary autoimmune disease that affects the CNS or a neurodegenerative disease with secondary \ninflammatory demyelination (see Trapp & Nave, 2008). \nCurrent therapies are aimed at moderating the acute inflam -\nmatory components of MS ( Table 41.3 ), but they are limited \nin effectiveness. They may reduce the rate of clinical \ndeterioration and incidence of relapses but by and large \nthey do not reverse the neurodegeneration that has occurred. Several (natalizumab, alemtuzumab, daclizumab and \nocrelizumab) are monoclonal antibodies that target specific proteins expressed on B and T lymphocytes to limit their spread into the brain and spinal cord where they attack \nthe myelin sheath around motor nerves. Monoclonal \nantibody therapy does, however, carry the risk of serious autoimmune complications (see Ch. 5) that need to be \nmonitored. The pathological mechanisms underlying the \nneurodegeneration, which renders the disease irreversible, are still not well understood but may hold the key to finding \ndisease-curing treatments. Symptomatic treatment of MS \nincludes baclofen and nabiximols, a botanical extract of \ncannabis containing tetrahydrocannabinol (THC) and \ncannabidiol (CBD) (see Ch. 20), for spasticity, nabiximols \n(a botanical extract containing tetrahydrocannabinol and \ncannabidiol ) for spasticity, and fampridine (a potassium-\nchannel blocker that enhances action potential propagation in demyelinated axons) for a modest improvement in \nwalking speed.receptor agonist baclofen (Ch. 39). Other drug treatments include \nantidepressants, mood stabilisers (see Ch. 48) and benzodiazepines \n(see Ch. 45) to reduce the depression, mood swings and anxiety \nassociated with the disorder. None of these drugs affects dementia or retards the course of the disease. It is possible that drugs that \ninhibit excitotoxicity, antisense to reduce mutant huntingtin expression, \nor possibly neural transplantation procedures when these become available, may", "start_char_idx": 0, "end_char_idx": 3573, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a4887108-c041-4e51-a001-fd1493499a52": {"__data__": {"id_": "a4887108-c041-4e51-a001-fd1493499a52", "embedding": null, "metadata": {"page_label": "534", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f7163ddc-984c-4354-8171-36f85c0a366d", "node_type": null, "metadata": {"page_label": "534", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8c8beac89607e2010afe120ceb7dc3d67a0794ff0e611d1dffcd8ec9ca9b6a7f"}, "2": {"node_id": "d71744e3-b3d5-41be-b311-7ce8306d1ba3", "node_type": null, "metadata": {"page_label": "534", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ebf01717a362b2625928cfebd88da46f3be0a21083ac72846d54b8f938460171"}}, "hash": "7dd176660d1a3ee9bce014e321209ef01dc5dadb65340caacd2a3a282eee51e9", "text": "expression, \nor possibly neural transplantation procedures when these become available, may prove useful.\nAMYOTROPHIC LATERAL SCLEROSIS\nALS is the most common form of motor neuron disease, \nin which degeneration of motor neurons leads to paralysis \nand eventual death. In ALS, degeneration occurs in both \nupper motor neurons, those projecting from higher centres to the spinal cord and in lower motor neurons, those project -\ning from the ventral horn of the spinal cord to skeletal muscle. The causes of ALS are not known, but there is evidence that both genetic and environmental factors such \nas exposure to bacterial toxins, heavy metals, pesticides \nand trauma are involved.\n10 Mutations in several genes \u2013 \nSOD1, C9orf72 and NEK1 \u2013 have been associated with \nsome cases of familial ALS (see Pochet, 2017).\nThe drugs currently used in ALS treatment are riluzole \nand edaravone . Riluzole may work by reducing glutamate \nrelease whereas edaravone may reduce oxidative stress. \nHowever, these drugs only provide limited improvement. Antisense oligonucleotide therapies, designed to suppress \nthe expression of mutated genes, and stem cell therapies \nare undergoing clinical trials.\nSPINAL MUSCULAR ATROPHY\nSMA is a group of inherited neuromuscular disorders in which there is degeneration of motor neurons and progres -\nsive muscle wasting. It is the most common genetic cause of infant death. Motor neurons require expression of a protein, appropriately called survival motorneuron protein \n(SMN), for them to survive and function normally. SMA \nis caused by a genetic defect in the SMN-1 gene encoding for SMN. Nusinersen, introduced in 2016, is a novel gene \ntherapy for the disorder, reported in early trials to halt disease progression in some patients. It is an antisense oligoneucleotide sequence (see Ch. 5) given by intrathecal injection, that facilitates SMN expression, not from the \nmutated SMN-1 gene but from SMN-2, a \u2018backup\u2019 gene \nthat under normal conditions, due to exon skipping, does \n10Intense physical exercise has been suggested to be one potential \nenvironmental factor and there are examples of leading sportspersons \nsuccumbing to the disease in later life, for example, Joost van der \nWesthuizen, the great South African scrum half, and Doddie Weir who played for Scotland and the British and Irish Lions.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3482, "end_char_idx": 6297, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "684eeb2f-b37e-46ed-be3c-e5e9f18cef91": {"__data__": {"id_": "684eeb2f-b37e-46ed-be3c-e5e9f18cef91", "embedding": null, "metadata": {"page_label": "535", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f5c6c4d-288f-4418-9eea-2fd9b93f0c73", "node_type": null, "metadata": {"page_label": "535", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2828d53d1bc61af0c148b86829bbd934e4bb7337c04b30fd9548c4f764a68d55"}, "3": {"node_id": "459080be-f09b-4460-bddc-90116d224f28", "node_type": null, "metadata": {"page_label": "535", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ee0e827ffd118049f2ad6d0ece45d9e73ce533e2bbd1da457dd70b67fae1c4d6"}}, "hash": "f2acc0752cf499f664300f8cfaf7dec6320306592dd565a3df60ebce96c61f4a", "text": "41 NEUROdEgENERaTiVE diSEaSES\n529Drug treatment of multiple sclerosis \nSeveral\tnew\tand\tefficacious\t agents\thave\temerged\tin\tthe\t\ntreatment\t of\tmultiple\tsclerosis\t(MS),\tbut\tthese\ttreatments\t\nalso\tbring\twith\tthem\ta\tsignificant\t risk\tof\tserious\tadverse\t\neffects.\tAs\tthe\tseverity\tand\tcourse\tof\tMS\tvaries\t\nsubstantially\t amongst\tindividuals,\t selection\tof\tappropriate\t\ntherapy\tmust\tconsider\tnot\tonly\tbenefit\tand\tharm\tof\tthe\t\nproposed\t agents,\tbut\talso\tthe\tpatient\u2019s\tclinical\tcondition\t\nand co-morbidities.\nPrompt\tuse\tof\tdisease-modifying\t therapies\t is\t\nrecommended\t in\tpatients\twho\thave\tclinical\tand/or\t\nradiological\t evidence\tof\tactive\tdisease.\tExamples\t of\t\ntherapeutic\t options\tfor\tpatients\twith\tactive\trelapsing\u2013\nremitting\tMS\tare:\u2022\tDrugs\tof\tmoderate\t efficacy\tsuch\tas\tinterferon-beta or \nglatiramer acetate \tby\tinjection.\t Teriflunomide or \ndimethylfumarate \tcan\tbe\tused\tif\toral\ttherapy\tis\t\npreferred.\n\u2022\tDrugs\tof\thigh\tefficacy\tsuch\tas\tnatalizumab or \nalemtuzumab may be considered in those with more \nactive disease.\nThere\tis\tlimited\tevidence\tfor\tinterferon\t in\tprogressive\t MS,\t\nbut\tocrelizumab \tis\tan\temerging\t option\tfor\tprimary\t\nprogressive\t disease.\nDrugs\tthat\tare\tused\tto\tmanage\tsymptoms\t or\tdisease\t\ncomplications\t in\tmultiple\tsclerosis\tinclude\t baclofen\t(for\t\nmuscle\tspasticity)\t and\tamitriptyline \t(for\temotional\t lability).\nTable 41.3 Disease-modifying treatments for multiple sclerosis\nDrug Mechanism of actionRoute(s) and frequency \nof administration Notes\nGlatiramer acetateA random polymer (approx. \n6 kD) of four amino acids \nthought to interfere with the \nimmune response to myelinSubcutaneous (usually \nadministered daily)Reduces relapses\nDimethyl fumarate Unknown Oral (twice a day) Reduces relapse rate and slows \nprogression\nFingolimodInhibits cytotoxic CD8 \nexpressing T cells \nPhosphorylated derivative is \nan agonist at S1P receptors.Oral (daily)Reduces the rate of relapses\nIncreased risk of progressive \nmultifocal leukoencephalopathy and \nserious ventricular arrhythmias\nBeta interferons (IFN- \u03b2)\n(see Ch. 19)Modulation of immune \nfunctionSubcutaneous (three times \na week)\nIntramuscular (once a week)Reduce relapses by approximately \n30% but not all patients respond\nNatalizumab\n(see Ch. 27)Humanised monoclonal \nantibody targeting \u03b14-integrin\n(see Table 27.3)Intravenous infusion (every \n4 weeks)Slows the progression of disability in \nrelapsing multiple sclerosis\nMay cause progressive multifocal \nleukoencephalopathy in some cases\nAlemtuzumab\n(see Chs 27, 57 and \nTable 27.3)Humanised monoclonal \nantibody targeting CD52 on \nB and T lymphocytesIntravenous infusion (5-day \nshort courses, 12 months \napart)Also used in the treatment of \nlymphocytic leukaemia\nDaclizumab\n(see Ch. 27)Humanised monoclonal \nantibody targeting CD25, the \nalpha subunit of the IL-2 \nreceptor on T cellsSubcutaneous (once a \nmonth)Risk of serious liver toxicity; this \ndrug is now restricted", "start_char_idx": 0, "end_char_idx": 2901, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "459080be-f09b-4460-bddc-90116d224f28": {"__data__": {"id_": "459080be-f09b-4460-bddc-90116d224f28", "embedding": null, "metadata": {"page_label": "535", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2f5c6c4d-288f-4418-9eea-2fd9b93f0c73", "node_type": null, "metadata": {"page_label": "535", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2828d53d1bc61af0c148b86829bbd934e4bb7337c04b30fd9548c4f764a68d55"}, "2": {"node_id": "684eeb2f-b37e-46ed-be3c-e5e9f18cef91", "node_type": null, "metadata": {"page_label": "535", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f2acc0752cf499f664300f8cfaf7dec6320306592dd565a3df60ebce96c61f4a"}}, "hash": "ee0e827ffd118049f2ad6d0ece45d9e73ce533e2bbd1da457dd70b67fae1c4d6", "text": "a \nmonth)Risk of serious liver toxicity; this \ndrug is now restricted to patients \nwho are not suitable for other \ntherapies\nOcrelizumabHumanised monoclonal \nantibody targeting CD20 on \nB lymphocytesIntravenous infusion (every \n6 months after initial \ntreatments)Superior to beta-interferon in \nrelapsing and progressive multiple \nsclerosis\nTeriflunomideImmunosuppressant. Active \nmetabolite of leflunomide \n(see Ch. 27)Oral (once a day) Modest efficacy in reducing relapse\nCladribinePurine nucleoside analogue \nthat has immunosuppressant \neffects through depletion of \nlymphocytesOral therapy given as two \nshort courses in a 2-year \nperiodUsed in rapidly evolving or severe \nrelapsing\u2013remitting MS. Also has a \nrole in hairy cell leukaemiamebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2832, "end_char_idx": 4052, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e64479f7-1f9e-47ec-8d5c-7c060c2999a0": {"__data__": {"id_": "e64479f7-1f9e-47ec-8d5c-7c060c2999a0", "embedding": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6823750a-63c4-48a3-aa0c-96bfb96965f9", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92e612b4a759cfed078ba41af36af87b0c50c023fe1a0825851b12b308ef4b8a"}, "3": {"node_id": "36ded081-1f7a-46bd-85a9-34abb4396ddd", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a2584c4cf03abd52329b6d2180e0d541645f5c816fbf1dd8f7a24168261f477"}}, "hash": "a14688b2d447c03aa81aed477c68ddbb1257df85050901a05fc62ed2a47c7f63", "text": "41 SECTION 4 \u2003\u2003NERVOUS SYSTEM\n530REFERENCES AND FURTHER READING\nGeneral mechanisms of neurodegeneration\nBarnham, K.J., Masters, C.L., Bush, A.I., 2004. Neurodegenerative \ndiseases and oxidative stress. Nat. Rev. Drug Discov. 3, 205\u2013214. \n(Describes the oxidative stress model of neurodegeneration, including \nevidence based on various transgenic animal models )\nBrunden, K., Trojanowski, J.O., Lee, V.M.Y., 2009. Advances in \nTau-focused drug discovery for Alzheimer\u2019s disease and related \ntauopathies. Nat. Rev. Drug Discov. 8, 783\u2013793. ( Good detailed review of \nthe current status of Tau-directed drug discovery efforts, with a realistic \nassessment of the problems that have to be overcome )\nCoyle, J.T., Puttfarken, P., 1993. Oxidative stress, glutamate and \nneurodegenerative disorders. Science 262, 689\u2013695. ( Good review \narticle )\nHanger, D.P., Anderton, B.H., Noble, W., 2009. Tau phosphorylation: \nthe therapeutic challenge for neurodegenerative disease. Trends Mol. \nMed. 15, 112\u2013119.\nItoh, K., Nakamura, K., Iijima, M., Sesaki, H., 2013. Mitochondrial \ndynamics in neurodegeneration. Trends Cell Biol. 23, 64\u201371. \n(Summarises evidence for the involvement of mitochondrial dysfunction in \nseveral neurodegenerative diseases )\nOkouchi, M., Ekshyyan, O., Maracine, M., Aw, T.Y., 2007. Neuronal \napoptosis in neurodegeneration. Antioxid. Redox Signal. 9, 1059\u20131096. \n(Detailed review describing the role of apoptosis, the factors that induce it \nand possible therapeutic strategies aimed at preventing it, in various \nneurodegenerative disorders )\nPeden, A.H., Ironside, J.W., 2012. Molecular pathology in \nneurodegenerative diseases. Curr. Drug Targets 13, 1548\u20131559. \n(Compares the molecular pathology of neurodegenerative and prion-mediated \ndisorders )\nZhao, C., Deng, W., Gage, F.H., 2008. Mechanisms and functional \nimplications of adult neurogenesis. Cell 132, 645\u2013660. ( Review by one of \nthe pioneers in this controversial field. Neurogenesis probably contributes to \nlearning, but evidence for involvement in neural repair is weak )\nAlzheimer\u2019s disease\nBreitner, J.C., Baker, L.D., Montine, T.J., et al., 2011. Extended results of \nthe Alzheimer\u2019s disease anti-inflammatory prevention trial. \nAlzheimers Dement. 7, 402\u2013411. ( Reports on a long-term trial of NSAIDs \nin AD )\nBrioni, J.D., Esbenshade, T.A., Garrison, T.R., 2011. Discovery of \nhistamine H 3 antagonists for the treatment of cognitive disorders and \nAlzheimer\u2019s disease. J. Pharmacol. Exp. Ther. 336, 38\u201346. ( Reviews \npreclinical and clinical data on the effectiveness of H 3 antagonists to treat a \nvariety of CNS disorders )\nCollingridge, G.L., Volianskis, A., Bannister, N., et al., 2013. The NMDA \nreceptor as a target for cognitive enhancement. Neuropharmacology \n64, 13\u201326. ( Reviews the preclinical evidence that various types of drug \nacting at the NMDA receptor might improve cognition )\nCorbett, A., Pickett, J., Burns, A., et al., 2012. Drug repositioning for \nAlzheimer\u2019s", "start_char_idx": 0, "end_char_idx": 2968, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "36ded081-1f7a-46bd-85a9-34abb4396ddd": {"__data__": {"id_": "36ded081-1f7a-46bd-85a9-34abb4396ddd", "embedding": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6823750a-63c4-48a3-aa0c-96bfb96965f9", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92e612b4a759cfed078ba41af36af87b0c50c023fe1a0825851b12b308ef4b8a"}, "2": {"node_id": "e64479f7-1f9e-47ec-8d5c-7c060c2999a0", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a14688b2d447c03aa81aed477c68ddbb1257df85050901a05fc62ed2a47c7f63"}, "3": {"node_id": "ac7b08f4-a1a8-4947-b1e9-66bc88c34867", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "701884394f0cd53a44572c2e83242b4a50c0dc36531c7d6f5f589e388bc3b74e"}}, "hash": "0a2584c4cf03abd52329b6d2180e0d541645f5c816fbf1dd8f7a24168261f477", "text": "A., et al., 2012. Drug repositioning for \nAlzheimer\u2019s disease. Nat. Rev. Drug Discov. 11, 833\u2013846. ( Describes \nrecent failures in drug development and discusses how drugs currently used \nfor other conditions might be effective in treating AD )\nCummings, J., Lee, G., Mortsdorf, T., Ritter, A., Zhong, K., 2017. \nAlzheimer\u2019s disease drug development pipeline. Alzheimers Dement. \n(N Y) 3, 367\u2013384. ( Describes the drugs in development for AD that are \neither symptom reducing or disease modifying agents )\nFrigero, C., De Strooper, B., 2016. Alzheimer\u2019s disease mechanisms and \nemerging roads to novel therapeutics. Ann. Rev. Neurosci. 39, 57\u201379. \n(Discusses how genetics, in vitro models and improved animal models will \naid the development of new medicines)\nG\u00f6tz, J., Ittner, L.M., 2008. Animal models of Alzheimer\u2019s disease and \nfrontotemporal dementia. Nat. Rev. Neurosci. 9, 532\u2013544. ( Detailed \nreview focusing on transgenic models )\nHerrup, K., 2015. The case for rejecting the amyloid cascade hypothesis. \nNat. Nerosci. 18, 794\u2013799. ( Makes a strong case that Alzheimer\u2019s disease is \nnot just a disorder resulting from altered amyloid processing )\nQuerfurth, H.W., LaFerla, F.M., 2010. Mechanisms of disease: \nAlzheimer\u2019s disease. N. Engl. J. Med. 362, 329\u2013344.\nRakic, P., 2002. Neurogenesis in the primate cortex: an evaluation of the \nevidence. Nat. Rev. Neurosci. 3, 65\u201371.\nSchenk, D., Barbour, R., Dunn, W., et al., 1999. Immunization with \namyloid-beta attenuates Alzheimer-disease-like pathology in the \nPDAPP mouse. Nature 400, 173\u2013177. ( Report of an ingenious experiment \nthat could have implications for AD treatment in humans )\nSchwab, C., McGeer, P.L., 2008. Inflammatory aspects of Alzheimer\u2019s \ndisease and other neurodegenerative disorders. J. Alzheimer Dis. 13, 359\u2013369. ( Discusses the role of inflammation in neurodegeneration and \nrepair )\nWeggen, S., Rogers, M., Eriksen, J., 2007. NSAIDs: small molecules for \nprevention of Alzheimer\u2019s disease or precursors for future drug \ndevelopment. Trends Pharmacol. Sci. 28, 536\u2013543. ( Summarises data \nrelating to effects of NSAIDs on AD and concludes that mechanisms other \nthan cyclo-oxygenase inhibition may be relevant in the search for new \nanti-AD drugs )\nParkinson\u2019s disease\nBarker, R.A., Barrett, J., Mason, S.L., Bj\u00f6rklund, A., 2013. Fetal \ndopaminergic transplantation trials and the future of neural grafting \nin Parkinson\u2019s disease. Lancet Neurol. 12, 84\u201391. ( Update by pioneers in \nthe field )\nDuty, S., Jenner, P., 2011. Animal models of Parkinson\u2019s disease: a \nsource of novel treatments and clues to the cause of the disease. Br. J. \nPharmacol. 164, 1357\u20131391. ( Describes the value of various animal models \nin the search for new therapies for PD )\nLangston, W.J., 1985. MPTP and Parkinson\u2019s disease. Trends Neurosci. \n8, 79\u201383. ( Readable account of the MPTP story by its discoverer )\nLotharius, J., Brundin,", "start_char_idx": 2923, "end_char_idx": 5819, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ac7b08f4-a1a8-4947-b1e9-66bc88c34867": {"__data__": {"id_": "ac7b08f4-a1a8-4947-b1e9-66bc88c34867", "embedding": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6823750a-63c4-48a3-aa0c-96bfb96965f9", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92e612b4a759cfed078ba41af36af87b0c50c023fe1a0825851b12b308ef4b8a"}, "2": {"node_id": "36ded081-1f7a-46bd-85a9-34abb4396ddd", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a2584c4cf03abd52329b6d2180e0d541645f5c816fbf1dd8f7a24168261f477"}, "3": {"node_id": "dbf3dedb-9044-4f3d-a797-babbeca5dd57", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6255aaab5b8c0cfdad852157b05286eb637ce782a3739d36900ca4adb75edf5"}}, "hash": "701884394f0cd53a44572c2e83242b4a50c0dc36531c7d6f5f589e388bc3b74e", "text": "story by its discoverer )\nLotharius, J., Brundin, P., 2002. Pathogenesis of Parkinson\u2019s disease: \ndopamine, vesicles and \u03b1-synuclein. Nat. Rev. Neurosci. 3, 833\u2013842. \n(Review of PD pathogenesis, emphasising the possible role of dopamine itself \nas a likely source of neurotoxic metabolites )\nNishimura, K., Takahashi, J., 2013. Therapeutic application of stem cell \ntechnology toward the treatment of Parkinson\u2019s disease. Biol. Pharm. \nBull. 36, 171\u2013175.\nOertel, W., Schulz, J.B., 2016. Current and experimental treatments of \nParkinson disease: A guide for neuroscientists. J. Neurochem. 139, S1, \n325\u2013337. ( Discusses current therapeutic approaches and drugs recently \napproved or in clinical trials for treatment of PD )\nOkun, M.S., 2012. Deep-brain stimulation for Parkinson\u2019s disease. N. \nEngl. J. Med. 367, 1529\u20131538. ( Review of the clinical use of deep brain \nstimulation to treat Parkinson\u2019s disease )\nOlanow, C.W., Brundin, P., 2013. Parkinson\u2019s disease and alpha \nsynuclein: is Parkinson\u2019s disease a prion-like disorder? Mov. Disord. \n28, 31\u201340.\nOlanow, C.W., Rascol, O., Hauser, R., et al., 2009. A double-blind, \ndelayed-start trial of rasagiline in Parkinson\u2019s disease. N. Engl. J. Med. \n139, 1268\u20131278. ( Well-conducted trial showing that rasagiline can \nsignificantly retard disease progression in patients with early PD )\nPrzedborski, S., 2017. The two-century journey of Parkinson disease \nresearch. Nat. Rev. Neurosci. 18, 251\u2013259. ( Extensive review of the 200 \nyear timeline of PD research )\nSchapira, A.H.V., 2009. Neurobiology and treatment of Parkinson\u2019s \ndisease. Trends Pharmacol. Sci. 30, 41\u201347. ( Short review of \npathophysiology and treatment of PD )\nStroke\nEsencan, E., Yuksel, S., Tosun, Y.B., Robinot, A., Solaroglu, I., Zhang, \nJ.H., 2013. Xenon in medical area: emphasis on neuroprotection in \nhypoxia and anesthesia. Med. Gas Res. 3, 4. ( Outlines the potential for \nxenon as a neurprotective agent )\nGreen, A.R., 2008. Pharmacological approaches to acute ischaemic \nstroke: reperfusion certainly, neuroprotection possibly. Br. J. \nPharmacol. 153 (Suppl. 1), S325\u2013S338. ( The theories were good but \nsubsequent efforts to develop them into neuroprotective agents for human \nmedicine have proven unsuccessful )\nHuntington\u2019s disease\nWalker, F.O., 2007. Huntington\u2019s disease. Lancet 369, 218\u2013228. ( General \nreview of genetics, pathogenesis and treatment of HD )\nAmyotrophic lateral sclerosis\nPochet, R., 2017. Genetics and ALS: cause for optimism. Cerebrum 2017, \n1\u201313.\nMotor neuron disease\nTrapp, B.D., Nave, K.A., 2008. Multiple sclerosis: an immune or \nneurodegenerative disorder. Ann. Rev. Neurosci. 31, 247\u2013269. ( Reviews \nthe evidence for MS being a primary neurodegenerative disorder with \nsecondary inflammation )\nMultiple sclerosis\nHollenbach, J.A., Oksenberg, J.R., 2015. The immunogenetics of multiple \nsclerosis: A comprehensive review. J. Autoimmun. 64, 13\u201325.mebooksfree.net mebooksfree.net", "start_char_idx": 5823, "end_char_idx": 8760, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dbf3dedb-9044-4f3d-a797-babbeca5dd57": {"__data__": {"id_": "dbf3dedb-9044-4f3d-a797-babbeca5dd57", "embedding": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6823750a-63c4-48a3-aa0c-96bfb96965f9", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92e612b4a759cfed078ba41af36af87b0c50c023fe1a0825851b12b308ef4b8a"}, "2": {"node_id": "ac7b08f4-a1a8-4947-b1e9-66bc88c34867", "node_type": null, "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "701884394f0cd53a44572c2e83242b4a50c0dc36531c7d6f5f589e388bc3b74e"}}, "hash": "d6255aaab5b8c0cfdad852157b05286eb637ce782a3739d36900ca4adb75edf5", "text": "Autoimmun. 64, 13\u201325.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 8751, "end_char_idx": 9251, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "67e45801-4275-488f-8e69-f2928cf1854d": {"__data__": {"id_": "67e45801-4275-488f-8e69-f2928cf1854d", "embedding": null, "metadata": {"page_label": "537", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5c8a8cc-b0ff-434c-a1ed-dc6866eb42c8", "node_type": null, "metadata": {"page_label": "537", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7eae16115f9adcc3f6fa36dbee7501322b2be6c6636a388d4436d66cfe6bb98e"}, "3": {"node_id": "2330513c-15ae-410c-b2f7-e52032a402b1", "node_type": null, "metadata": {"page_label": "537", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "52a12a9b2f377ebcc8ff0fb63211b3fd0cdf96441255c3e81f27501851c4c3e6"}}, "hash": "3ae405f72235e1e442eaf976fd0f95c3c3d1341e9a2f60cb083fbf9008a706e1", "text": "531\nOVERVIEW\nGeneral anaesthesia aims to provide balanced anaes -\nthesia, meeting the requirements of amnesia, analgesia \nand relaxation tailored for the intended medical \nprocedure. Different general anaesthetic agents provide varying amounts of the components of bal -\nanced anaesthesia but they are rarely used nowadays in isolation. Neuromuscular-blocking drugs ( Ch. 14), \nsedative and anxiolytic drugs ( Ch. 45), and analgesic \ndrugs ( Ch. 43 ) are frequently co-administered. General \nanaesthetics are given systemically and exert their main effects on the central nervous system (CNS), in \ncontrast to local anaesthetics ( Ch. 44). Although we \nnow take them for granted, general anaesthetics are \nthe drugs that paved the way for modern surgery. \nWithout them, much of modern medicine would be \nimpossible.\nIn this chapter we first describe the pharmacology \nof the main agents in current use, which fall into two groups: intravenous agents and inhalation agents (gases and volatile liquids). The use of anaesthetics \nin combination with other drugs to produce balanced \nanaesthesia is discussed at the end of the chapter. Detailed information on the clinical pharmacol -\nogy and use of anaesthetic agents can be found in specialised textbooks (e.g. \nAitkenhead et al., \n2013).\nINTRODUCTION\nIt was only when inhalation anaesthetics were first discov -\nered, in 1846, that most surgical operations became a \npractical possibility. Until that time, surgeons relied on \nbeing able to operate on struggling patients at lightning speed, and most operations were amputations.\n\u25bc The use of nitrous oxide to relieve the pain of surgery was suggested \nby Humphrey Davy in 1800. He was the first person to make nitrous \noxide, and he tested its effects on several people, including himself and \nthe Prime Minister, noting that it caused euphoria, analgesia and loss of consciousness. The use of nitrous oxide, billed as \u2018laughing gas\u2019, \nbecame a popular fairground entertainment and came to the notice \nof an American dentist, Horace Wells, who had a tooth extracted under its influence, while he himself squeezed the inhalation bag. \nEther also first gained publicity in a disreputable way, through the \nspread of \u2018ether frolics\u2019, at which it was used to produce euphoria \namong the guests. William Morton, also a dentist and a student at \nHarvard Medical School, used it successfully to extract a tooth in 1846 and then suggested to Warren, the illustrious chief surgeon \nat Massachusetts General Hospital, that he should administer it for \none of Warren\u2019s operations. Warren grudgingly agreed, and on 16 October 1846 a large audience was gathered in the main operating theatre1; after some preliminary fumbling, Morton\u2019s demonstration \nwas a spectacular success. \u2018Gentlemen, this is no humbug\u2019, was the \nmost gracious comment that Warren could bring himself to make to \nthe assembled audience.\nIn the same year, James Simpson, Professor of Midwifery at Edinburgh \nUniversity, used chloroform to relieve the pain of childbirth, bringing on himself fierce denunciation from the clergy, one of whom wrote: \n\u2018Chloroform is a decoy of Satan, apparently offering itself to bless \nwomen; but in the end it will harden society and rob God of the deep, earnest cries which arise in time of trouble, for help.\u2019 Opposition \nwas effectively silenced in 1853, when Queen Victoria gave birth to \nher seventh child under the influence of chloroform, and the procedure became known as anaesth\u00e9sie \u00e0 la reine.\nThe second half of the 20th century saw the introduction \ninto clinical practice of a number of new general anaesthetic \nagents, most notably", "start_char_idx": 0, "end_char_idx": 3642, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2330513c-15ae-410c-b2f7-e52032a402b1": {"__data__": {"id_": "2330513c-15ae-410c-b2f7-e52032a402b1", "embedding": null, "metadata": {"page_label": "537", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e5c8a8cc-b0ff-434c-a1ed-dc6866eb42c8", "node_type": null, "metadata": {"page_label": "537", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7eae16115f9adcc3f6fa36dbee7501322b2be6c6636a388d4436d66cfe6bb98e"}, "2": {"node_id": "67e45801-4275-488f-8e69-f2928cf1854d", "node_type": null, "metadata": {"page_label": "537", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ae405f72235e1e442eaf976fd0f95c3c3d1341e9a2f60cb083fbf9008a706e1"}}, "hash": "52a12a9b2f377ebcc8ff0fb63211b3fd0cdf96441255c3e81f27501851c4c3e6", "text": "introduction \ninto clinical practice of a number of new general anaesthetic \nagents, most notably isoflurane and propofol, that were \nmarkedly superior to earlier agents such as nitrous oxide \nand thiopental. Despite the need for further improvement \nthe pipeline has all but dried up in the 21st century, with \nonly fospropofol being introduced.\nMECHANISM OF ACTION OF \nANAESTHETIC DRUGS\nUnlike most drugs, anaesthetics, which include substances \nas diverse as simple gases (e.g. nitrous oxide and xenon), \nhalogenated hydrocarbons (e.g. isoflurane), barbiturates \n(e.g. thiopental ) and steroids (e.g. alphaxalone ), belong to \nno recognisable chemical class. At one time it appeared \nthat the shape and electronic configuration of the molecule \nwere relatively unimportant, and the pharmacological action required only that the molecule had certain physicochemical \nproperties. We now know much more about how different \nanaesthetics interact with neuronal membrane proteins and have come to realise that there are multiple mechanisms by which anaesthesia can be produced and that different \nanaesthetics work by different mechanisms.\nAs the concentration of an anaesthetic is increased, the \nswitch from being conscious to unconscious occurs over a very narrow concentration range (approximately 0.2 of a \nlog unit). This is a much steeper concentration\u2013response curve than that seen with drugs that interact as agonists \nor antagonists at classical receptors (see Ch. 2).\nLIPID SOLUBILITY\n\u25bc Overton and Meyer, at the turn of the 20th century, showed a \nclose correlation between anaesthetic potency and lipid solubility in \na diverse group of simple and unreactive organic compounds that General anaesthetic agents 42 NERVOUS SYSTEM SECTION 4\n1Now preserved as the Ether Dome, a museum piece at Massachusetts \nGeneral Hospital.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3545, "end_char_idx": 5856, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ae43b9b3-6085-47d0-a392-dc200e20355d": {"__data__": {"id_": "ae43b9b3-6085-47d0-a392-dc200e20355d", "embedding": null, "metadata": {"page_label": "538", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d4287f0c-96e1-482a-95e4-290e0dce98de", "node_type": null, "metadata": {"page_label": "538", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c29090404c7536aa4b6e5efdaa2f22efda5f96fec2b3d7249a2b30805bb1dbb"}, "3": {"node_id": "2ae996da-80c7-4ff8-a00f-5c9a68385eaf", "node_type": null, "metadata": {"page_label": "538", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f45b834b2a0b8e719e034794685bb56c192be877d249bbad0bf168e66911d0f"}}, "hash": "319e46527aabc30c6c7312f5de53a6d17931cb60d05d573dc377e652c8e44560", "text": "42 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n532xenon2) potentiate the action of GABA at GABA A receptors \n(Antkowiak & Rudolph, 2016). As described in detail in \nChapter 39, GABA A receptors are ligand-gated Cl\u2212 channels \nmade up of five subunits (generally comprising two \u03b1, two \n\u03b2 and one \u03b3 or \u03b4 subunit). Anaesthetics can bind to hydro -\nphobic pockets within different GABA A receptor subunits \nto act as positive allosteric modulators.\n\u25bc Specific mutations of the amino acid sequence of the \u03b1 subunit \ninhibit the actions of volatile anaesthetics but not those of intravenous \nanaesthetics, whereas mutations of the \u03b2 subunit inhibit both volatile \nand intravenous anaesthetics (see Franks, 2008). This suggest that \nvolatile anaesthetics may bind at the interface between \u03b1 and \u03b2 subunits \n(analogous to benzodiazepines that bind at the interface between \u03b1 \nand \u03b3/\u03b4 subunits, see Ch. 39), whereas the intravenous anaesthetics \nsuch as propofol may bind only on the \u03b2 subunit (Fig. 42.2). However, \nphotoaffinity labelling experiments suggest that etomidate may bind \nto amino acid residues on both the \u03b1 and \u03b2 subunits. A further level \nof complexity arises because there are different subtypes of each subunit (see Ch. 39). Different subunit compositions give rise to subtly different subtypes of GABA\nA receptor and these may be involved in \ndifferent aspects of anaesthetic action. GABA A receptors clustered at were tested for their ability to immobilise tadpoles. This led to a bold \ntheory, formulated by Meyer in 1937: \u2018Narcosis commences when \nany chemically indifferent substance has attained a certain molar concentration in the lipids of the cell.\u2019\nThe relationship between anaesthetic activity and lipid solubility has \nbeen repeatedly confirmed for a diverse array of agents. Anaesthetic potency in humans is usually expressed as the minimal alveolar \nconcentration (MAC) required to abolish the response to surgical \nincision in 50% of subjects. Fig. 42.1 shows the correlation between \nMAC (inversely proportional to potency) and lipid solubility, expressed \nas the oil:gas partition coefficient, for a wide range of inhalation anaesthetics. The Overton\u2013Meyer studies did not suggest any par -\nticular mechanism, but revealed an impressive correlation, for which any theory of anaesthesia needs to account. Oil:gas partition was assumed to predict partition into membrane lipids, consistent with \nthe suggestion that anaesthesia results from an alteration of membrane \nfunction.\nHow the simple introduction of inert foreign molecules into the lipid \nbilayer could cause a functional disturbance was not explained. Two possible mechanisms, namely volume expansion and increased \nmembrane fluidity, have been suggested and tested experimentally, \nbut both are now largely discredited and attention has swung from lipids to proteins, the correlation of potency with lipid solubility \nbeing explained by molecules of anaesthetic binding to hydrophobic \npockets within specific membrane protein targets.\nEFFECTS ON ION CHANNELS\nFollowing early studies that showed that anaesthetics can \nbind to various proteins as well as lipids, it was found that \nanaesthetics affect several different types of ion channels \n(see Franks, 2008). For most anaesthetics, there are no known competitive antagonists, so this approach to identify sites \nof action is denied. Therefore the main criterion for identify -\ning putative mechanisms of action of general anaesthetics \nis that, for a cellular effect to be relevant to the anaesthetic \nor analgesic actions of these agents, it must occur at thera -\npeutically relevant concentrations.\nCys-loop ligand-gated ion channels. Almost all anaesthet -\nics", "start_char_idx": 0, "end_char_idx": 3691, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2ae996da-80c7-4ff8-a00f-5c9a68385eaf": {"__data__": {"id_": "2ae996da-80c7-4ff8-a00f-5c9a68385eaf", "embedding": null, "metadata": {"page_label": "538", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d4287f0c-96e1-482a-95e4-290e0dce98de", "node_type": null, "metadata": {"page_label": "538", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c29090404c7536aa4b6e5efdaa2f22efda5f96fec2b3d7249a2b30805bb1dbb"}, "2": {"node_id": "ae43b9b3-6085-47d0-a392-dc200e20355d", "node_type": null, "metadata": {"page_label": "538", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "319e46527aabc30c6c7312f5de53a6d17931cb60d05d573dc377e652c8e44560"}}, "hash": "9f45b834b2a0b8e719e034794685bb56c192be877d249bbad0bf168e66911d0f", "text": "ligand-gated ion channels. Almost all anaesthet -\nics (with the exceptions of cyclopropane, ketamine and MethoxyfluraneChloroformHalothaneEtherFluroxeneCyclopropaneXenonNitrous oxideSulfur hexafluorideCarbon tetrafluoride\n0.0010.010.111050\nMAC (atm)\n0.1 1 10 100 1000 5000\nOil:gas partition coefficient (37 \u00b0C)\nFig. 42.1 Correlation of anaesthetic potency with oil:gas \npartition coefficient. Anaesthetic potency in humans is \nexpressed as minimum alveolar partial pressure (MAC) required to produce surgical anaesthesia. There is a close correlation with lipid solubility, expressed as the oil:gas partition coefficient. (From Halsey, M.J., 1989. Physicochemical properties of inhalation anaesthetics. In: Nunn, J.F., Utting, J.E., Brown, B.R. (Eds), General Anaesthesia, Butterworth, London.)\nTransmembrane\ndomainPropofol\nFig. 42.2 Putative propofol binding site on the \u03b2 subunit \nof the GABA A receptor. A molecular model showing the \napproximate binding position of propofol at the interface \nbetween the transmembrane domain and the extracellular domain of the \u03b2 subunit. (Based on the original report by Yip \net al., 2013. Nat. Chem. Biol. 9, 715\u2013720.)\n2There is some controversy about whether or not xenon potentiates \nGABA A responses but at present the weight of evidence suggests it does \nnot.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3637, "end_char_idx": 5422, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d24ab3dd-04f7-4217-8dba-8fb16ba8947d": {"__data__": {"id_": "d24ab3dd-04f7-4217-8dba-8fb16ba8947d", "embedding": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "01451183-24ed-4c12-966c-3f4bede6aedd", "node_type": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "281b9d3424099b667e6a7e28ee861cdf420654e26e55db45bb4aa3373359c911"}, "3": {"node_id": "6d4372e0-d0b4-472d-afb3-715f65f8d9ea", "node_type": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4f10702869eb7a16c73314a5633860d354398f754add2c87b41fac87e6c2497"}}, "hash": "99f8231e38f72098d70e85fd0e5b154fcc04120a3cfeceb5147b8602f91c3461", "text": "42 GENER al aNaESThETic aGENTS\n533a lesser extent, parts of the cortex. Inhibition of these regions \nresults in unconsciousness and analgesia. Some anaesthetics \n\u2013 particularly volatile anaesthetics \u2013 cause inhibition at the \nspinal level, producing a loss of reflex responses to painful stimuli, although, in practice, neuromuscular-blocking drugs \n(Ch. 14) are used as an adjunct to produce muscle relaxation \nrather than relying on the anaesthetic alone. Anaesthetics, even in low concentrations, cause short-term amnesia. It \nis likely that interference with hippocampal function \nproduces this effect, because the hippocampus is involved in short-term memory, and certain hippocampal synapses are highly susceptible to inhibition by anaesthetics.\nAs the anaesthetic concentration is increased, all brain \nfunctions are progressively affected, including motor control and reflex activity, respiration and autonomic regulation. \nTherefore it is not possible to identify a critical \u2018target \nsite\u2019 in the brain responsible for all the phenomena of \nanaesthesia.\nHigh concentrations of any general anaesthetic affect all \nparts of the CNS, causing profound inhibition which, in the absence of artificial respiration, leads to death from \nrespiratory failure. The margin between surgical anaesthesia \nand potentially fatal respiratory and circulatory depression is quite narrow, requiring careful monitoring by the \nanaesthetist and adjustment of the level of anaesthesia.\nEFFECTS ON THE CARDIOVASCULAR AND \nRESPIRATORY SYSTEMS\nMost anaesthetics decrease cardiac contractility, but their \neffects on cardiac output and blood pressure vary because \nof concomitant actions on the sympathetic nervous system \nand vascular smooth muscle. Isoflurane and other halogen -\nated anaesthetics inhibit sympathetic outflow, reduce arterial \nand venous tone and thus decrease arterial pressure and \nvenous pressure. By contrast, nitrous oxide and ketamine \nincrease sympathetic discharge and plasma noradrenaline \nconcentration and, if used alone, increase heart rate and \nmaintain blood pressure.\nHalogenated anaesthetics cause ventricular extrasystoles. \nThe mechanism involves sensitisation to adrenaline. \nElectrocardiogram monitoring shows that extrasystolic beats \noccur commonly in patients under anaesthesia, with no harm coming to the patient. If catecholamine secretion is the synapse have different pharmacological and kinetic properties \nfrom those that are distributed elsewhere across the cell (extrasynaptic \nreceptors; see Ch. 39). Extrasynaptic GABA A receptors contain \u03b14 \nand \u03b16 subunits as well as the \u03b4 subunit, and anaesthetics appear to \nhave a greater potentiating effect on these extrasynaptic GABA A \nreceptors.\nGeneral anaesthetics also affect other neuronal cys-loop \nligand-gated channels such as those activated by glycine \n(Ch. 39), acetylcholine and 5-hydroxytryptamine (Ch. 40). \nTheir actions on these channels are similar to those on GABA\nA receptors but the relative importance of such actions \nto general anaesthesia is still to be determined.\nTwo-pore domain K+ channels. These belong to a family \nof \u2018background\u2019 K+ channels that modulate neuronal excit -\nability. They are homomeric or heteromeric assemblies of \na family of structurally related subunits (Bayliss & Barrett, \n2008). Channels made up of TREK1, TREK2, TASK1, TASK3 \nor TRESK (see Ch. 4, Table 4.2) subunits can be directly \nactivated by low concentrations of volatile and gaseous \nanaesthetics, thus reducing membrane excitability (see Franks, 2008). This may contribute to the analgesic, hypnotic \nand immobilising effects of these agents. Two-pore", "start_char_idx": 0, "end_char_idx": 3644, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d4372e0-d0b4-472d-afb3-715f65f8d9ea": {"__data__": {"id_": "6d4372e0-d0b4-472d-afb3-715f65f8d9ea", "embedding": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "01451183-24ed-4c12-966c-3f4bede6aedd", "node_type": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "281b9d3424099b667e6a7e28ee861cdf420654e26e55db45bb4aa3373359c911"}, "2": {"node_id": "d24ab3dd-04f7-4217-8dba-8fb16ba8947d", "node_type": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "99f8231e38f72098d70e85fd0e5b154fcc04120a3cfeceb5147b8602f91c3461"}, "3": {"node_id": "e3cd60cd-3749-45df-82fd-f948facb39da", "node_type": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b72186de8352f4ec156f471b9516c094093bd3a1fb7e297a06391622c0ce583e"}}, "hash": "b4f10702869eb7a16c73314a5633860d354398f754add2c87b41fac87e6c2497", "text": "hypnotic \nand immobilising effects of these agents. Two-pore domain \nK\n+ channels do not appear to be affected by intravenous \nanaesthetics.\nNMDA receptors. Glutamate, the major excitatory \nneurotransmitter in the CNS, activates three main classes \nof ionotropic receptor \u2013 AMPA, kainate and NMDA recep -\ntors (see Ch. 39). NMDA receptors are an important site \nof action for anaesthetics such as nitrous oxide , xenon and \nketamine which act, in different ways, to reduce NMDA receptor-mediated responses. Xenon appears to inhibit NMDA receptors by competing with glycine for its regula -\ntory site on this receptor whereas ketamine blocks the pore of the channel (see Ch. 39). Other inhalation anaesthetics may also exert effects on the NMDA receptor in addition to their effects on other proteins such as the GABA\nA \nreceptor.\nOther ion channels. Anaesthetics may also exert actions \nat cyclic nucleotide-gated K+ channels and K ATP channels. \nSome general anaesthetics inhibit certain subtypes of \nvoltage-gated Na+ channels. Inhibition of presynaptic Na+ \nchannels may give rise to the inhibition of transmitter release at excitatory synapses.\nIt may be overly simplistic to think of each anaesthetic \nas having only one mechanism of action: individual anaes -\nthetics differ in their actions and affect cellular function in \nseveral different ways, so a single mechanism is unlikely to be sufficient.\nComprehensive reviews of the molecular and cellular \nactions of general anaesthetics can be found in Sch\u00fcttler and Schwilden (2008).\nEFFECTS ON THE NERVOUS SYSTEM\nAt the cellular level, the effects of anaesthetics are to enhance tonic inhibition (through enhancing the actions of GABA), \nreduce excitation (opening K\n+ channels) and to inhibit \nexcitatory synaptic transmission (by depressing transmitter release and inhibiting ligand-gated ion channels). Effects \non axonal conduction are relatively unimportant.\nThe anaesthetised state comprises several components, \nincluding unconsciousness , loss of reflexes ( muscle relaxation ) \nand analgesia. Much effort has gone into identifying the \nbrain regions on which anaesthetics act to produce these \neffects. The most sensitive regions appear to be the midbrain \nreticular formation, thalamic sensory relay nuclei and, to Theories of anaesthesia \n\u2022\tMany\tsimple, \tunreactive \tcompounds \tproduce \tgeneral \t\nanaesthesia, the extreme example being the inert gas \nxenon.\n\u2022\tAnaesthetic \tpotency \tis \tclosely \tcorrelated \twith \tlipid \t\nsolubility (Overton\u2013Meyer correlation), not with chemical structure.\n\u2022\tEarlier\ttheories \tof \tanaesthesia \tpostulated \tinteraction \t\nwith the lipid membrane bilayer. Recent work favours interaction with membrane ion channels.\n\u2022\tMost\tanaesthetics \tenhance \tthe \tactivity \tof \tinhibitory \t\nGABA A receptors and other cys-loop ligand-gated ion \nchannels. Other important effects are the activation of a subfamily of potassium channels (the two-pore \ndomain K\n+ channels) and inhibition of excitatory NMDA \nreceptors.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3592, "end_char_idx": 7058, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e3cd60cd-3749-45df-82fd-f948facb39da": {"__data__": {"id_": "e3cd60cd-3749-45df-82fd-f948facb39da", "embedding": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "01451183-24ed-4c12-966c-3f4bede6aedd", "node_type": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "281b9d3424099b667e6a7e28ee861cdf420654e26e55db45bb4aa3373359c911"}, "2": {"node_id": "6d4372e0-d0b4-472d-afb3-715f65f8d9ea", "node_type": null, "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4f10702869eb7a16c73314a5633860d354398f754add2c87b41fac87e6c2497"}}, "hash": "b72186de8352f4ec156f471b9516c094093bd3a1fb7e297a06391622c0ce583e", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7064, "end_char_idx": 7127, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bd0fab0d-4123-4c3e-91a4-d2fd94423609": {"__data__": {"id_": "bd0fab0d-4123-4c3e-91a4-d2fd94423609", "embedding": null, "metadata": {"page_label": "540", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "acb4637a-ee59-47d3-8d55-7a5a0c4e6728", "node_type": null, "metadata": {"page_label": "540", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7d92725573895b2785f7bff9a8a6546bacf102adc82ab5c6017fa5f749d26a3d"}, "3": {"node_id": "ce69aa69-4166-4b95-a31d-2b59d76c9f6e", "node_type": null, "metadata": {"page_label": "540", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80f0117a046517173a9fe1f89eee42a1724cfad6dc0bc313f53f6910b1bca0bd"}}, "hash": "91028c6406ab315da874c7c27b75bf4dff36f4ae1e5086e6654b2cacb83faf41", "text": "42 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n534the duration of action of ketamine is sufficient that it can \nbe administered as a single bolus for short operations \nwithout the need for an inhalation agent. Under these \ncircumstances a short-acting opioid such as alfentanil or \nremifentanil (Ch. 43) may be co-administered to provide \nanalgesia.\nThe properties of the main intravenous anaesthetics are \nsummarised in Table 42.1.3\nPROPOFOL\nPropofol, introduced in 1983, has now largely replaced \nthiopental as an induction agent. It has a rapid onset of \naction (approximately 30 s) and a rapid rate of redistribution \n(t1/2 2\u20134 min), which makes it short acting. Because of its \nlow water solubility, it is administered as an oil-in-water emulsion, which can cause pain on injection, and supports \nmicrobial growth. Fospropofol is a recently developed \nwater-soluble derivative that is less painful on injection and rapidly converted by alkaline phosphatases to propofol \nin the body. Propofol metabolism to inactive conjugates \nand quinols follows first-order kinetics, in contrast to thio -\npental (see later), resulting in more rapid recovery and less \nhangover effect than occurs with thiopental. It has a \ncardiovascular depressant effect that may lead to hypoten -\nsion and bradycardia. Respiratory depression may also occur. It is particularly useful for day-case surgery, especially \nas it causes less nausea and vomiting than do inhalation \nanaesthetics.\nThere have been reports of a propofol infusion syndrome \noccurring in approximately 1 in 300 patients when it has been given for a prolonged period to maintain sedation, particularly to sick patients \u2013 especially children in whom \nit is contraindicated in this setting \u2013 in intensive care units. \nThis is characterised by severe metabolic acidosis, skeletal muscle necrosis (rhabdomyolysis), hyperkalaemia, lipaemia, \nhepatomegaly, renal failure, arrhythmia and cardiovascular \ncollapse.\nPropofol can be taken as a drug of abuse, especially by \nthose, such as anaesthetists, who have ready access to the drug. Using propofol to obtain a sedative high is a risky business given its steep concentration\u2013response curve.\n4\nTHIOPENTAL\nThiopental is the only remaining barbiturate in common use. It has very high lipid solubility, and this accounts for \nthe speed of onset and transience of its effect when it is \ninjected intravenously. The free acid is insoluble in water, so thiopental is given as the sodium salt. On intravenous \ninjection, thiopental causes unconsciousness within about \n20 s, lasting for 5\u201310 min. The anaesthetic effect closely \nparallels the concentration of thiopental in the blood reach -\ning the brain, because its high lipid solubility allows it to cross the blood\u2013brain barrier without noticeable delay.\nThe blood concentration of thiopental declines rapidly, \nby about 80% within 1\u20132 min, following the initial peak \nafter intravenous injection, because the drug is redistributed, \nfirst to tissues with a large blood flow (liver, kidneys, brain, excessive, however ( par excellence in phaeochromocytoma, \na neuroendocrine tumour that secretes catecholamines into the circulation; see Ch. 15), there is a risk of precipitating \nventricular fibrillation.\nWith the exception of nitrous oxide, ketamine and xenon , \nall anaesthetics depress respiration markedly and increase \narterial P\nCO 2. Nitrous oxide has much less effect, in part \nbecause its low potency prevents very deep anaesthesia \nfrom being produced with this drug. Some inhalation \nanaesthetics are pungent, particularly", "start_char_idx": 0, "end_char_idx": 3565, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ce69aa69-4166-4b95-a31d-2b59d76c9f6e": {"__data__": {"id_": "ce69aa69-4166-4b95-a31d-2b59d76c9f6e", "embedding": null, "metadata": {"page_label": "540", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "acb4637a-ee59-47d3-8d55-7a5a0c4e6728", "node_type": null, "metadata": {"page_label": "540", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7d92725573895b2785f7bff9a8a6546bacf102adc82ab5c6017fa5f749d26a3d"}, "2": {"node_id": "bd0fab0d-4123-4c3e-91a4-d2fd94423609", "node_type": null, "metadata": {"page_label": "540", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91028c6406ab315da874c7c27b75bf4dff36f4ae1e5086e6654b2cacb83faf41"}}, "hash": "80f0117a046517173a9fe1f89eee42a1724cfad6dc0bc313f53f6910b1bca0bd", "text": "being produced with this drug. Some inhalation \nanaesthetics are pungent, particularly desflurane, which \nis liable to cause coughing, laryngospasm and bronchos -\npasm, so desflurane is not used for induction of anaesthesia but only for maintenance.\nPharmacological effects of \nanaesthetic agents \n\u2022\tAnaesthesia \tinvolves \tthree \tmain \tneurophysiological \t\nchanges: unconsciousness, loss of response to painful \nstimulation and loss of reflexes (motor and autonomic).\n\u2022\tAt\tsupra-anaesthetic \tdoses, \tall \tanaesthetic \tagents \tcan \t\ncause death by loss of cardiovascular reflexes and respiratory paralysis.\n\u2022\tAt\tthe\tcellular \tlevel, \tanaesthetic \tagents \taffect \tsynaptic \t\ntransmission and neuronal excitability rather than axonal conduction. GABA-mediated inhibitory transmission is enhanced by most anaesthetics. The \nrelease of excitatory transmitters and the response of \nthe postsynaptic receptors are also inhibited.\n\u2022\tAlthough \tall \tparts \tof \tthe \tnervous \tsystem \tare \taffected \t\nby anaesthetic agents, the main targets appear to be the cortex, thalamus, hippocampus, midbrain reticular formation and spinal cord.\n\u2022\tMost\tanaesthetic \tagents \t(with \tthe \texception \tof \t\nketamine, nitrous oxide and xenon) produce similar \nneurophysiological effects and differ mainly in respect of their pharmacokinetic properties and toxicity.\n\u2022\tMost\tanaesthetic \tagents \tcause \tcardiovascular \t\ndepression by effects on the myocardium and blood vessels, as well as on the nervous system. Halogenated anaesthetic agents are likely to cause \ncardiac dysrhythmias, accentuated by circulating \ncatecholamines.\n3Propanidid and alphaxalone were withdrawn because of allergic \nreactions including hypotension and bronchoconstriction \u2013 probably \nattributable to the solvent Cremophor \u2013 but a new formulation of \nalphaxalone has been reintroduced to veterinary medicine and is thought to be less allergenic.\n4Propofol is referred to as the \u2018milk of amnesia\u2019. The singer Michael \nJackson died of a propofol overdose.INTRAVENOUS ANAESTHETIC AGENTS\nEven the fastest-acting inhalation anaesthetics take a few \nminutes to act and cause a period of excitement before \nanaesthesia is induced. Intravenous anaesthetics act more \nrapidly, producing unconsciousness in about 20 s, as soon \nas the drug reaches the brain from its site of injection. These \ndrugs (e.g. propofol , thiopental and etomidate ) are normally \nused for induction of anaesthesia. They are preferred by many patients because injection generally lacks the menacing quality associated with a face mask in an apprehensive \nindividual. With propofol, recovery is also fast due to rapid \nmetabolism.\nAlthough many intravenous anaesthetics are not suitable \nfor maintaining anaesthesia because their elimination from the body is relatively slow compared with that of inhalation agents, propofol can be used as a continuous infusion, and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3479, "end_char_idx": 6840, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ecca81ee-8aa7-411d-8edd-460d916a8fe5": {"__data__": {"id_": "ecca81ee-8aa7-411d-8edd-460d916a8fe5", "embedding": null, "metadata": {"page_label": "541", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a90e0185-cd48-4b2d-aa95-6a1b21bb3694", "node_type": null, "metadata": {"page_label": "541", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d22cf97d82ba6a75be5a53ab04d47e0f41e9dbfecc615ea30dcb95a70ef1d60"}, "3": {"node_id": "a9c52cae-0d40-40f4-9e99-4d787a1b21f2", "node_type": null, "metadata": {"page_label": "541", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d73034bf2fa5ad881050d6eaab6984e0f99d973c56af0a2f9116be3b2fbbef3b"}}, "hash": "26a334cbe5f95bb65d7dbf14b2f144440b1462137e3c8a2ac31d6c1a6c00f11d", "text": "42 GENERal aNaESThETic aGENTS\n535with a slowly declining plasma concentration, means that \ndrowsiness and some degree of respiratory depression \npersist for some hours.\nThiopental, like other barbiturates, induces production \nof various liver enzymes, including those involved in haem \nsynthesis, and can precipitate attacks of porphyria in patients \nsuffering from this genetic disorder.\nETOMIDATE\nEtomidate has gained favour over thiopental on account \nof the larger margin between the anaesthetic dose and the \ndose needed to produce cardiovascular depression. It is \nmore rapidly metabolised than thiopental, and thus less \nlikely to cause a prolonged hangover. It causes less hypoten -\nsion than propofol or thiopental. In other respects, etomidate \nis very similar to thiopental, although involuntary move -\nments during induction, postoperative nausea and vomiting, \nand pain at the injection site are problems with its use. \nEtomidate suppresses the production of adrenal steroids, \nan effect that has been associated with an increase in \nmortality in severely ill patients. It should be avoided in \npatients at risk of having adrenal insufficiency, e.g. in sepsis. \nIt is preferable to thiopental in patients at risk of circulatory \nfailure.\nOTHER INTRAVENOUS AGENTS\nKETAMINE\n\u25bc Ketamine closely resembles phencyclidine , both chemically and \npharmacologically. Both are used recreationally for their pronounced \neffects on sensory perception (see Ch. 49). Both drugs are believed \nto act by blocking activation of the NMDA receptor (see Ch. 39). They \nproduce a similar anaesthesia-like state and profound analgesia, but \nketamine produces less euphoria and sensory distortion than phen -\ncyclidine and is thus more useful in anaesthesia. Ketamine can be \nused in lower doses as an analgesic (Ch. 43) and as an acute treatment \nfor depression (Ch. 48).\nGiven intravenously, ketamine takes effect more slowly (1\u20132 min) \nthan thiopental, and produces a different effect, known as \u2018dissociative \nanaesthesia\u2019, in which there is a marked sensory loss and analgesia, etc.) and more slowly to muscle. Uptake into body fat, \nalthough favoured by the high lipid solubility of thiopental, \noccurs only slowly, because of the low blood flow to this \ntissue. After several hours, however, most of the thiopental \npresent in the body will have accumulated in body fat, the \nrest having been metabolised. Recovery from the anaesthetic \neffect of a bolus dose occurs within about 5 min, governed \nentirely by redistribution of the drug to well-perfused \ntissues; very little is metabolised in this time. After the \ninitial rapid decline, the blood concentration drops more \nslowly, over several hours, as the drug is taken up by body \nfat and metabolised in the liver. Consequently, thiopental \nproduces a long-lasting hangover. Thiopental metabolism \nshows saturation kinetics (see Ch. 11). Because of this, large \ndoses or repeated intravenous doses cause progressively \nlonger periods of anaesthesia, as the plateau in blood \nconcentration becomes progressively more elevated as more \ndrug accumulates in the body and metabolism saturates. \nFor this reason, thiopental is not used to maintain surgical \nanaesthesia but only as an induction agent. It is also still \nused to terminate status epilepticus (see Ch. 46) or (in \npatients with a secured airway) to lower intracranial \npressure.\nThiopental binds to plasma albumin (roughly 85% of the \nblood content normally being bound). The fraction bound \nis less in states of malnutrition, liver disease or renal", "start_char_idx": 0, "end_char_idx": 3558, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a9c52cae-0d40-40f4-9e99-4d787a1b21f2": {"__data__": {"id_": "a9c52cae-0d40-40f4-9e99-4d787a1b21f2", "embedding": null, "metadata": {"page_label": "541", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a90e0185-cd48-4b2d-aa95-6a1b21bb3694", "node_type": null, "metadata": {"page_label": "541", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d22cf97d82ba6a75be5a53ab04d47e0f41e9dbfecc615ea30dcb95a70ef1d60"}, "2": {"node_id": "ecca81ee-8aa7-411d-8edd-460d916a8fe5", "node_type": null, "metadata": {"page_label": "541", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "26a334cbe5f95bb65d7dbf14b2f144440b1462137e3c8a2ac31d6c1a6c00f11d"}}, "hash": "d73034bf2fa5ad881050d6eaab6984e0f99d973c56af0a2f9116be3b2fbbef3b", "text": "fraction bound \nis less in states of malnutrition, liver disease or renal disease, \nwhich affect the concentration and drug-binding properties \nof plasma albumin, and this can appreciably reduce the \ndose needed for induction of anaesthesia.\nIf thiopental \u2013 a strongly alkaline solution \u2013 is accidentally \ninjected around rather than into a vein, or into an artery, \nthis can cause pain, local tissue necrosis and ulceration or \nsevere arterial spasm that can result in gangrene.\nThe actions of thiopental on the nervous system are very \nsimilar to those of inhalation anaesthetics, although it has \nlittle analgesic effect and can cause profound respiratory \ndepression, even in amounts that fail to abolish reflex \nresponses to painful stimuli. Its long after-effect, associated Table 42.1 Properties of intravenous anaesthetic agents\nDrugSpeed of induction and \nrecovery Main unwanted effect(s) Notes\nPropofolFast onset, very fast \nrecoveryCardiovascular and \nrespiratory depressionRapidly metabolised\nPossible to use as continuous infusion\nCauses pain at injection site\nFospropofol is a prodrug, less painful on injection\nThiopentalFast (accumulation occurs, \ngiving slow recovery)\n\u2018Hangover\u2019Cardiovascular and \nrespiratory depressionLargely replaced by propofol\nCauses pain at injection site\nRisk of precipitating porphyria in susceptible \npatients\nEtomidateFast onset, fairly fast \nrecoveryExcitatory effects during \ninduction and recovery\nAdrenocortical suppressionLess cardiovascular and respiratory depression \nthan with thiopental\nCauses pain at injection site\nKetamineSlow onset, after effects \ncommon during recoveryPsychotomimetic effects \nfollowing recovery\nPostoperative nausea, \nvomiting and salivation\nRaised intracranial pressureProduces good analgesia and amnesia with little \nrespiratory depression\nMidazolam Slower than other agents \u2014 Amnesia, but little analgesia\nLittle respiratory or cardiovascular depressionmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3485, "end_char_idx": 5898, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a5575c21-7471-4608-aa19-99b317071bdd": {"__data__": {"id_": "a5575c21-7471-4608-aa19-99b317071bdd", "embedding": null, "metadata": {"page_label": "542", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3978a3fa-e428-4ee7-8368-52ac860684d7", "node_type": null, "metadata": {"page_label": "542", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b17fca575c0fd98a093f65742937c070b1b1b62a80e34c1e289674ca2ec5aac5"}, "3": {"node_id": "245fffde-5b96-4d47-95f5-e40b59910fd1", "node_type": null, "metadata": {"page_label": "542", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "72dfaaced433be48537ceb4c150d0b7c55b12dc0691f0159d246628c563ce9a0"}}, "hash": "e992155bf04d05867722424c7ad7b5da9613e5c9ccfb7c5cfce134813237600a", "text": "42 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n536as well as amnesia, without complete loss of consciousness. During \ninduction and recovery, involuntary movements and peculiar sensory \nexperiences often occur. Ketamine does not act simply as a CNS \ndepressant, and it produces cardiovascular and respiratory effects quite different from those of most anaesthetics. Blood pressure and \nheart rate are usually increased, and respiration is unaffected by \neffective anaesthetic doses. This makes it relatively safe to use in low-technology healthcare situations or in accident and emergency \nsituations where it can be administered intramuscularly if intravenous \nadministration is not possible.\n5 However, ketamine, unlike other \nintravenous anaesthetic drugs, can increase intracranial pressure, so \nit should not be given to patients with raised intracranial pressure \nor at risk of cerebral ischaemia. The other main drawback of ketamine is that hallucinations, and sometimes delirium and irrational behaviour, \nare common during recovery. These after effects limit the usefulness \nof ketamine but are said to be less marked in children,\n6 and ketamine, \noften in conjunction with a benzodiazepine, is sometimes still used \nfor minor procedures in paediatrics.\nMIDAZOLAM\nMidazolam, a benzodiazepine (see Ch. 45), is slower in \nonset and offset than the drugs discussed above but, like \nketamine, causes less respiratory or cardiovascular depres -\nsion. Midazolam (or diazepam ) is often used as a preopera -\ntive sedative and during procedures such as endoscopy, where full anaesthesia is not required. It can be administered \nin combination with an analgesic such as alfentanil . In the \nevent of overdose it can be reversed by flumazenil (see \nCh. 45).\nINHALATION ANAESTHETICS\nMany inhalation anaesthetics that were once widely used, \nsuch as ether, chloroform, trichloroethylene, cyclopropane, \nmethoxyflurane and enflurane, have now been replaced \nin clinical practice, particularly by isoflurane , sevoflurane \nand desflurane, which have improved pharmacokinetic \nproperties, fewer side effects and are non-flammable. Of the older agents, nitrous oxide is still used widely (especially in obstetric practice), and halothane now only \noccasionally.\nPHARMACOKINETIC ASPECTS\nAn important characteristic of an inhalation anaesthetic is the speed at which the arterial blood concentration, which \ngoverns the pharmacological effect in the brain, follows \nchanges in the partial pressure of the drug in the inspired gas mixture. Ideally, the blood concentration should follow \nas quickly as possible, so that the depth of anaesthesia can \nbe controlled rapidly. In particular, the blood concentration should fall to a subanaesthetic level rapidly when admin -\nistration is stopped, so that the patient recovers conscious -\nness with minimal delay. A prolonged semi-comatose state, in which vomiting is likely and respiratory reflexes are weak or absent, is particularly hazardous.\nThe lungs are the only quantitatively important route \nby which inhalation anaesthetics enter and leave the body. Intravenous anaesthetic agents \n\u2022\tMost\tcommonly \tused \tfor \tinduction \tof \tanaesthesia, \t\nfollowed by inhalation agent. Propofol can also be \nused to maintain anaesthesia during surgery.\n\u2022\tPropofol, thiopental and etomidate are most \ncommonly used; all act within 20\u201330 s if given \nintravenously.\n\u2022\tPropofol:\n\u2013 potent;\n\u2013 rapid onset and distribution;\n\u2013 rapidly metabolised;\n\u2013 very rapid recovery, limited cumulative effect;\n\u2013 useful for day-case surgery;\n\u2013 low incidence of nausea and vomiting;\n\u2013 risk", "start_char_idx": 0, "end_char_idx": 3584, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "245fffde-5b96-4d47-95f5-e40b59910fd1": {"__data__": {"id_": "245fffde-5b96-4d47-95f5-e40b59910fd1", "embedding": null, "metadata": {"page_label": "542", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3978a3fa-e428-4ee7-8368-52ac860684d7", "node_type": null, "metadata": {"page_label": "542", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b17fca575c0fd98a093f65742937c070b1b1b62a80e34c1e289674ca2ec5aac5"}, "2": {"node_id": "a5575c21-7471-4608-aa19-99b317071bdd", "node_type": null, "metadata": {"page_label": "542", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e992155bf04d05867722424c7ad7b5da9613e5c9ccfb7c5cfce134813237600a"}}, "hash": "72dfaaced433be48537ceb4c150d0b7c55b12dc0691f0159d246628c563ce9a0", "text": "surgery;\n\u2013 low incidence of nausea and vomiting;\n\u2013 risk of bradycardia;\n\u2013 may induce an adverse \u2018propofol infusion syndrome\u2019 \nwhen administered at high doses for prolonged \nperiods of time.\n\u2022\tThiopental:\n\u2013 barbiturate with very high lipid solubility;\n\u2013 rapid action due to rapid transfer across blood\u2013brain \nbarrier; short duration (about 5 min) due to \nredistribution, mainly to muscle;\n\u2013 reduces intracranial pressure;\n\u2013 slowly metabolised and liable to accumulate in body \nfat, therefore may cause prolonged effect if given repeatedly;\n\u2013 narrow margin between anaesthetic dose and dose \ncausing cardiovascular depression;\n\u2013 risk of tissue damage if accidentally injected \nextravascularly or into an artery;\n\u2013 can precipitate an attack of porphyria in susceptible \nindividuals (see Ch. 12).\n\u2022\tEtomidate:\n\u2013 similar to thiopental but more quickly metabolised;\n\u2013 less risk of cardiovascular depression;\n\u2013 may cause involuntary movements during induction \nand high incidence of nausea;\n\u2013 possible risk of adrenocortical suppression.\n\u2022\tKetamine:\n\u2013 analogue of phencyclidine, with similar properties;\n\u2013 action differs from other agents, probably related to \ninhibition of NMDA receptors;\n\u2013 onset of effect is relatively slow (1\u20132 min);\n\u2013 powerful analgesic;\n\u2013 produces \u2018dissociative\u2019 anaesthesia, in which the \npatient may remain conscious although amnesic and insensitive to pain;\n\u2013 high incidence of dysphoria, hallucinations, etc. \nduring recovery; used mainly for minor procedures in children;\n\u2013 can raise intracranial pressure.\n5An anaesthetist colleague tells of coming across a motorway accident \nwhere most of a victim was hidden under a mass of distorted metal but \nenough of a limb was available for an injection of ketamine to be given.\n6A cautionary note: many adverse effects are claimed to be less marked \nin children, perhaps because they cannot verbalise their experiences. At one time, muscle relaxants alone were used without anaesthesia during \ncardiac surgery in neonates. The babies did not complain of pain, but their circulating catecholamines reached extreme levels.For modern inhalation anaesthetics, metabolic degradation \nis generally insignificant in determining their duration of \naction. Inhalation anaesthetics are all small, lipid-soluble \nmolecules that readily cross alveolar membranes. It is therefore the rates of delivery of drug to and from the mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3529, "end_char_idx": 6389, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d37ce0c7-2d45-405a-8843-b6fefc40b734": {"__data__": {"id_": "d37ce0c7-2d45-405a-8843-b6fefc40b734", "embedding": null, "metadata": {"page_label": "543", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c66949e2-9b14-4fac-8dac-d07f94f8dead", "node_type": null, "metadata": {"page_label": "543", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "08ea113984c9fe4fd1bfbaebd27651abb3bf8fa2d3ef9ddae3d14932581ebca9"}, "3": {"node_id": "650f5690-0681-4094-a25a-2f5f27494dee", "node_type": null, "metadata": {"page_label": "543", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4fd1a3d62fede7961a4fe244870cadfc34b6e0ceffa981073593885f81227b45"}}, "hash": "649e995d7ec5b83b79f4fe81613f4c455b314b02ff1ece625f09c05c2eec71ae", "text": "42 GENER al aNaESThETic aGENTS\n537This is because it is the partial pressure of the gas in the \nalveolar space that governs the concentration in the blood. \nThe lower the blood:gas partition coefficient, the more \nrapidly the partial pressure of the gas in the alveolar space will equal that being administered in the inspired air (see \nlater).\nThe oil:gas partition coefficient , a measure of fat solubil -\nity, determines the potency of an anaesthetic (as already discussed) and also influences the kinetics of its distribu -\ntion in the body, the main effect being that high lipid \nsolubility, by causing accumulation in body fat, delays recovery from anaesthesia. Values of blood:gas and oil:gas \npartition coefficients for some anaesthetics are given in \nTable 42.2.\nINDUCTION \u2003AND \u2003RECOVERY\nCerebral blood flow is a substantial fraction of cardiac output \n(~15%), and the blood\u2013brain barrier is freely permeable to \nanaesthetics, so the concentration of anaesthetic in the brain \nclosely tracks that in the arterial blood. The kinetics of transfer of anaesthetic between the inspired air and the \narterial blood therefore determine the kinetics of the \npharmacological effect.\nWhen a volatile anaesthetic is first administered, the \ninitial breaths are diluted into the residual gas volume in lungs, via (respectively) the inspired air and bloodstream, which determine the overall kinetic behaviour of an \nanaesthetic. The reason that anaesthetics vary in their kinetic \nbehaviour is that their relative solubilities in blood, and in body fat, vary between one drug and another.\nThe main factors that determine the speed of induction \nand recovery can be summarised as follows:\n\u2022\tProperties of the anaesthetic:\n\u2013 blood:gas partition coefficient (i.e. solubility in \nblood)\n\u2013 oil:gas partition coefficient (i.e. solubility in fat)\n\u2022\tPhysiological factors:\n\u2013 alveolar ventilation rate\n\u2013 cardiac output\nSOLUBILITY \u2003OF \u2003INHALATION \u2003ANAESTHETICS\nInhalation anaesthetics can be regarded physicochemically as ideal gases: their solubility in different media is expressed \nas partition coefficients , defined as the ratio of the concentra -\ntion of the agent in two phases at equilibrium.\nThe blood:gas partition coefficient is the main factor that \ndetermines the rate of induction and recovery of an inhala -\ntion anaesthetic, and the lower the blood:gas partition \ncoefficient, the faster is induction and recovery (Table 42.2). \nTable 42.2 Characteristics of inhalation anaesthetics\nDrugPartition \ncoefficientMinimum \nalveolar concentration (% v/v)Induction/recoveryMain adverse effect(s) and disadvantage(s) Notes Blood:gas Oil:gas\nNitrous oxide 0.5 1.4 100aFastFew adverse effects\nRisk of anaemia (with prolonged or repeated use)Accumulation in gaseous cavitiesGood analgesic effectLow potency precludes use as sole anaesthetic agent \u2013 normally combined with other inhalation agents\nlsoflurane 1.4 91 1.2 MediumFew adverse effectsPossible risk of coronary ischaemia in susceptible patientsWidely usedHas replaced halothane\nDesflurane 0.4 23 6.1 FastRespiratory tract irritation, cough, bronchospasmUsed for day-case surgery because of fast onset and recovery (comparable with nitrous oxide)\nSevoflurane 0.6 53 2.1 FastFew reportedTheoretical risk of renal toxicity owing to fluorideSimilar to desflurane\nHalothane 2.4 220 0.8 MediumHypotensionCardiac arrhythmiasHepatotoxicity (with repeated use)Malignant hyperthermia (rare)Little used nowadaysSignificant metabolism to", "start_char_idx": 0, "end_char_idx": 3476, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "650f5690-0681-4094-a25a-2f5f27494dee": {"__data__": {"id_": "650f5690-0681-4094-a25a-2f5f27494dee", "embedding": null, "metadata": {"page_label": "543", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c66949e2-9b14-4fac-8dac-d07f94f8dead", "node_type": null, "metadata": {"page_label": "543", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "08ea113984c9fe4fd1bfbaebd27651abb3bf8fa2d3ef9ddae3d14932581ebca9"}, "2": {"node_id": "d37ce0c7-2d45-405a-8843-b6fefc40b734", "node_type": null, "metadata": {"page_label": "543", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "649e995d7ec5b83b79f4fe81613f4c455b314b02ff1ece625f09c05c2eec71ae"}}, "hash": "4fd1a3d62fede7961a4fe244870cadfc34b6e0ceffa981073593885f81227b45", "text": "hyperthermia (rare)Little used nowadaysSignificant metabolism to trifluoracetate\nEnflurane 1.9 98 1.7 Medium Risk of convulsions (slight)Malignant hyperthermia (rare)Has declined in useMay induce seizures\nEther 12.0 65 1.9 SlowRespiratory irritationNausea and vomitingExplosion riskNow obsolete, except where modern facilities are lacking\naTheoretical value based on experiments under hyperbaric conditions.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3412, "end_char_idx": 4298, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f9d073d0-f261-4d0b-9998-7f79e50bfb63": {"__data__": {"id_": "f9d073d0-f261-4d0b-9998-7f79e50bfb63", "embedding": null, "metadata": {"page_label": "544", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f65edeea-34e8-4a21-aee1-2351e87dcb25", "node_type": null, "metadata": {"page_label": "544", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "175921160e93e10e7115b9a15dcbf768c4ea226390ae69279a675b945245c5f6"}, "3": {"node_id": "4a46de18-32c9-4d56-ba99-046f9da01015", "node_type": null, "metadata": {"page_label": "544", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2250cf06a8587f50245a5b3a7e0f3652da50848ab0cd05e5f0ef2b3865d421df"}}, "hash": "88b93aa3fba44417dda94f2918b4b8458edc88aca157875138c0ff20cb50a64a", "text": "42 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n538the lungs resulting in a reduction in the alveolar partial \npressure of the anaesthetic as compared with the inspired \ngas mixture. With subsequent breaths, the alveolar partial \npressure rises towards equilibrium. For an anaesthetic with a low blood:gas partition coefficient, the absorption into \nthe blood will be slower, so with repeated breaths the partial \npressure in the alveolar space will rise faster than with an agent of high blood:gas partition coefficient. Thus a smaller \nnumber of breaths (i.e. a shorter time) will be needed to \nreach equilibrium. Therefore, contrary to what one might intuitively suppose, the lower the solubility in blood, the faster is the process of equilibration. Fig. 42.3 shows the \nmuch faster equilibration for nitrous oxide , a low-solubility \nagent, than for ether, a high-solubility agent.\n\u25bc The rate of absorption into the blood can be enhanced by administer -\ning a volatile anaesthetic along with nitrous oxide. The rapid movement \nof nitrous oxide from the alveoli into the blood concentrates the volatile \nanaesthetic in the alveoli which will increase its movement into the blood \u2013 referred to as the concentration effect . Furthermore, the volume \nof nitrous oxide taken up from the alveoli into the blood is replaced by inspired gas, thus augmenting the delivery to the alveoli of the volatile anaesthetic, and speeding its absorption \u2013 referred to as the \nsecond gas effect.\nThe transfer of anaesthetic between blood and tissues \nalso affects the kinetics of equilibration. Fig. 42.4 shows a \nvery simple model of the circulation, in which two tissue \ncompartments are included. Body fat has a low blood flow but has a high capacity to take up anaesthetics, and con -\nstitutes about 20% of the volume of a non-obese human. Therefore for a drug such as halothane, which is about \n100 times more soluble in fat than in water, the amount \npresent in fat after complete equilibration would be roughly \n95% of the total amount in the body. Because of the low blood flow to adipose tissue, it takes many hours for the drug to enter and leave the fat, which results in a pro -\nnounced slow phase of equilibration following the rapid phase associated with the blood\u2013gas exchanges (see Fig. 42.3). The more fat-soluble the anaesthetic and the fatter 0102030405060708090100\n30 20 10 0MinutesEtherHalothaneIsofluraneSevofluraneDesfluraneAlveolar concentration (% of inspired concentration)N2O\nFig. 42.3 Rate of equilibration of inhalation anaesthetics \nin humans. The curves show alveolar concentration (which \nclosely reflects arterial blood concentration) as a function of time \nduring induction. The initial rate of equilibration reflects solubility in blood. There is also a slow phase of equilibration, most marked with highly lipid-soluble drugs (ether and halothane), owing to the slow transfer between blood and fat (see Fig. 42.4). (Adapted from Yasuda, N., Lockhart, S.H., Eger, E.I. II \net al., 1991. Comparison of kinetics of sevoflurane and \nisoflurane in humans. Anesth. Analg. 72, 316\u2013324.)\nFATLean\ntissuesSlow equilibrationLarge partition coefficientSlow perfusion\nRapid equilibrationSmall partition coefficientFast perfusionCardiac outputAlveolar ventilation\nFig. 42.4 Factors affecting the rate of equilibration of inhalation anaesthetics in the body. The body is represented as two \ncompartments. Lean tissues, including the brain, have a large blood flow and low partition coefficient for anaesthetics, and therefore \nequilibrate rapidly with the blood. Fat tissues have a small blood flow and large partition coefficient, and therefore equilibrate slowly, acting as", "start_char_idx": 0, "end_char_idx": 3668, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4a46de18-32c9-4d56-ba99-046f9da01015": {"__data__": {"id_": "4a46de18-32c9-4d56-ba99-046f9da01015", "embedding": null, "metadata": {"page_label": "544", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f65edeea-34e8-4a21-aee1-2351e87dcb25", "node_type": null, "metadata": {"page_label": "544", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "175921160e93e10e7115b9a15dcbf768c4ea226390ae69279a675b945245c5f6"}, "2": {"node_id": "f9d073d0-f261-4d0b-9998-7f79e50bfb63", "node_type": null, "metadata": {"page_label": "544", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "88b93aa3fba44417dda94f2918b4b8458edc88aca157875138c0ff20cb50a64a"}}, "hash": "2250cf06a8587f50245a5b3a7e0f3652da50848ab0cd05e5f0ef2b3865d421df", "text": "flow and large partition coefficient, and therefore equilibrate slowly, acting as a reservoir of drug during the recovery phase. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3587, "end_char_idx": 4195, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ed4519ef-a96a-4bf9-b799-32bd0ae68fc3": {"__data__": {"id_": "ed4519ef-a96a-4bf9-b799-32bd0ae68fc3", "embedding": null, "metadata": {"page_label": "545", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "145c297e-2aaa-4607-ba09-dd3c2fa951e0", "node_type": null, "metadata": {"page_label": "545", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa070aa600dc0fb2467ca0744e242e8e25602ca786d7773dc2f0ce131a0cacb3"}, "3": {"node_id": "559a87c0-f31f-453f-b7ac-daa089ac521e", "node_type": null, "metadata": {"page_label": "545", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ea5284408985e315195ba8b596282039abe13c182e701e2e6af7b2e078715e5"}}, "hash": "f67b2a12e0a8a85e5e745a4113d94d76d836c2ca8865567de549d845e27991d4", "text": "42 GENER al aNaESThETic aGENTS\n539but its relatively low potency and high cost are disadvan-\ntages. It may also be neuroprotective in neonatal hypoxia \n(see Ch. 41).\nISOFLURANE, DESFLURANE, SEVOFLURANE, \nENFLURANE AND HALOTHANE\nIsoflurane is now the most widely used volatile anaesthetic. \nIt is not appreciably metabolised and lacks the proconvulsive \nproperty of enflurane. It can cause hypotension and is a \npowerful coronary vasodilator. Paradoxically, this can exacerbate cardiac ischaemia in patients with coronary \ndisease, because of the \u2018steal\u2019 phenomenon (see Ch. 22).\nDesflurane is chemically similar to isoflurane, but its \nlower solubility in blood and fat means that adjustment of anaesthetic depth and recovery are faster, so it is increasingly \nused as an anaesthetic in obese patients undergoing bariatric surgery and for day-case surgery. It is not appreciably metabolised. It is less potent than the drugs described above. \nAt the concentrations used for induction of anaesthesia \n(about 10%), desflurane causes some respiratory tract irritation, which can lead to coughing and bronchospasm. \nRapid increases in the depth of desflurane anaesthesia can \nbe associated with a striking increase in sympathetic activ -\nity, which is undesirable in patients with ischaemic heart \ndisease.\nSevoflurane resembles desflurane but is more potent \nand does not cause the same degree of respiratory irritation. \nIt is partially (about 3%) metabolised, and detectable levels \nof fluoride are produced, although this does not appear to be sufficient to cause toxicity.\nEnflurane has a moderate speed of induction but is little \nused nowadays. It was originally introduced as an alterna -\ntive to methoxyflurane. It can cause seizures, either during \ninduction or following recovery from anaesthesia, especially \nin patients suffering from epilepsy. In this connection, it is interesting that a related substance, the fluorine-substituted the patient, the more pronounced this slow phase becomes and recovery will also be delayed.\nOf the physiological factors affecting the rate of equilibra -\ntion of inhalation anaesthetics, alveolar ventilation is the most important. The greater the minute volume (respiration \nrate \u00d7 tidal volume), the faster is equilibration, particularly \nfor drugs that have high blood:gas partition coefficients. \nRespiratory depressant drugs such as morphine (see Ch. \n43) can thus retard recovery from anaesthesia. The effect of changes in cardiac output on the rate of equilibration is more complex. By reducing alveolar perfusion, a reduction of cardiac output reduces alveolar absorption of the anaes -\nthetic, and thus speeds up induction, but this is partially offset by a reduction of cerebral blood flow slowing down delivery to the brain.\nRecovery from anaesthesia involves the same processes \nas induction but in reverse, the rapid phase of recovery being followed by a slow \u2018hangover\u2019. Because of these kinetic \nfactors, the search for improved inhalation anaesthetics \nhas focused on agents with low blood and tissue solubility. Newer drugs, which show kinetic properties similar to \nthose of nitrous oxide but have higher potency, include \nsevoflurane and desflurane (see Table 42.2 and Fig. 42.3).\nMETABOLISM \u2003AND \u2003TOXICITY\nMetabolism, although not quantitatively important as a route of elimination of inhalation anaesthetics, can generate \ntoxic metabolites (Ch. 58).\n7 This is the main reason that \nagents that are now obsolete or obsolescent, such as chlo -\nroform,", "start_char_idx": 0, "end_char_idx": 3516, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "559a87c0-f31f-453f-b7ac-daa089ac521e": {"__data__": {"id_": "559a87c0-f31f-453f-b7ac-daa089ac521e", "embedding": null, "metadata": {"page_label": "545", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "145c297e-2aaa-4607-ba09-dd3c2fa951e0", "node_type": null, "metadata": {"page_label": "545", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa070aa600dc0fb2467ca0744e242e8e25602ca786d7773dc2f0ce131a0cacb3"}, "2": {"node_id": "ed4519ef-a96a-4bf9-b799-32bd0ae68fc3", "node_type": null, "metadata": {"page_label": "545", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f67b2a12e0a8a85e5e745a4113d94d76d836c2ca8865567de549d845e27991d4"}}, "hash": "3ea5284408985e315195ba8b596282039abe13c182e701e2e6af7b2e078715e5", "text": "\nagents that are now obsolete or obsolescent, such as chlo -\nroform, methoxyflurane and halothane, have been replaced \nby the less toxic alternatives described below.\nMalignant hyperthermia is an important but rare idiosyn-\ncratic reaction (see Ch. 58), caused by heat production in skeletal muscle, due to excessive release of Ca\n2+ from the \nsarcoplasmic reticulum. The result is muscle contracture, \nacidosis, increased metabolism and an associated dramatic \nrise in body temperature that can be fatal unless treated promptly. Triggers include halogenated anaesthetics and \ndepolarising neuromuscular-blocking drugs (see Ch. 14). \nSusceptibility has a genetic basis, being associated with mutations in the gene encoding the ryanodine receptor, \nwhich controls Ca\n2+ release from the sarcoplasmic reticulum \n(Ch. 4). Malignant hyperthermia is treated with dantrolene , \na muscle relaxant drug that blocks these calcium-release \nchannels.\nINDIVIDUAL INHALATION ANAESTHETICS\nThe main inhalation anaesthetics currently used in devel -\noped countries are isoflurane , desflurane and sevoflurane , \nsometimes used in combination with nitrous oxide. Due to its relatively rapid onset of action and pleasant smell, sevoflurane is used, under some circumstances, on its own \nto induce anaesthesia, e.g. in paediatrics or in adults \nfrightened by the prospect of venous cannulation. Xenon, \nan inert gas shown many years ago to have anaesthetic \nproperties, is making something of a comeback in the clinic \nbecause \u2013 not surprisingly for an inert gas \u2013 it lacks toxicity, Pharmacokinetic properties of \ninhalation anaesthetics \n\u2022\tRapid\tinduction \tand \trecovery \tare \timportant \tproperties \t\nof an anaesthetic agent, allowing flexible control over \nthe depth of anaesthesia.\n\u2022\tSpeed\tof \tinduction \tand \trecovery \tare \tdetermined \tby \t\ntwo properties of the anaesthetic: solubility in blood (blood:gas partition coefficient) and solubility in fat (lipid solubility).\n\u2022\tAgents\twith \tlow \tblood:gas \tpartition \tcoefficients \t\nproduce rapid induction and recovery (e.g. nitrous \noxide, desflurane); agents with high blood:gas \npartition coefficients show slow induction and \nrecovery.\n\u2022\tAgents\twith \thigh \tlipid \tsolubility \taccumulate \tgradually \tin \t\nbody fat and may produce a prolonged \u2018hangover\u2019 if \nused for a long operation.\n\u2022\tSome\thalogenated \tanaesthetics \t(especially \thalothane \nand methoxyflurane) are metabolised. This is not \nvery important in determining their duration of action, \nbut contributes to toxicity (e.g. renal toxicity associated \nwith fluoride production with methoxyflurane \u2013 no \nlonger used).\n7The problem of toxicity of low concentrations of anaesthetics inhaled \nover long periods by operating theatre staff was at one time a cause for \nconcern. Strict measures are now used to minimise the escape of \nanaesthetics into the air of operating theatres.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3448, "end_char_idx": 6798, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "384da572-54ec-4b9a-8ec8-c598eeacf240": {"__data__": {"id_": "384da572-54ec-4b9a-8ec8-c598eeacf240", "embedding": null, "metadata": {"page_label": "546", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "85df7da8-5c73-45be-95d1-cee9bd5f9f6f", "node_type": null, "metadata": {"page_label": "546", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c9ac04e067b5766c1c65cf7437a2bbf16f97be891af6fbeff282eb213f2c039"}, "3": {"node_id": "31adc796-c59f-4e81-8e97-211e9c18012a", "node_type": null, "metadata": {"page_label": "546", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9ae524c9bd0c52cc3bdaa46290be8d4626f9c69fcf33af7a53d279ca684ed8cf"}}, "hash": "61b6cfd7ebdf58cae6846acceec22f27185ec506fd55d2434b3b0063867bc80d", "text": "42 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n540neuromuscular blockade (sugammadex, which binds and \ninactivates steroidal neuromuscular-blocking drugs, can \nalso be used for this purpose) and an analgesic for post -\noperative pain relief (e.g. an opioid such as morphine and/\nor a non-steroidal anti-inflammatory drug, see Ch. 43). Such Individual inhalation anaesthetics \n\u2022\tThe\tmain \tagents \tin \tcurrent \tuse \tin \tdeveloped \tcountries \t\nare isoflurane, desflurane and sevoflurane, \nsometimes supplemented with nitrous oxide.\n\u2022\tAs\ta\trare \tbut \tserious \thazard, \tinhalation \tanaesthetics \t\ncan cause malignant hyperthermia.\n\u2022\tNitrous oxide:\n\u2013 low potency, therefore must be combined with other \nagents\n\u2013 rapid induction and recovery\n\u2013 good analgesic properties\n\u2013 risk of bone marrow depression with prolonged \nadministration\n\u2013 accumulates in gaseous cavities\n\u2022\tIsoflurane:\n\u2013 similar to enflurane but lacks epileptogenic property\n\u2013 may precipitate myocardial ischaemia in patients \nwith coronary disease\n\u2013 irritant to respiratory tract\n\u2022\tDesflurane:\n\u2013 similar to isoflurane but with faster onset and \nrecovery\n\u2013 respiratory irritant, so liable to cause coughing and \nlaryngospasm\n\u2013 useful for day-case surgery\n\u2022\tSevoflurane:\n\u2013 similar to desflurane, with lack of respiratory \nirritation\nClinical uses of general \nanaesthetics \n\u2022\tIntravenous anaesthetics are used for:\n\u2013 induction of anaesthesia (e.g. propofol or \nthiopental);\n\u2013 maintenance of anaesthesia throughout surgery \n(\u2018total intravenous anaesthesia\u2019, e.g. propofol \nsometimes in combination with muscle relaxants \nand analgesics).\n\u2022\tInhalational anaesthetics (gases or volatile liquids) are used for maintenance of anaesthesia. Points to note are that:\n\u2013 volatile anaesthetics (e.g. isoflurane, sevoflurane) \nare delivered in air, oxygen or oxygen\u2013nitrous oxide mixtures as the carrier gas;\n\u2013 nitrous oxide must always be given with oxygen;\n\u2013 because of its potential for inducing hepatotoxicity, \nhalothane has largely been replaced by newer volatile anaesthetics such as isoflurane;\n\u2013 all inhalational anaesthetics can trigger malignant \nhyperthermia in susceptible individuals.diethyl-ether hexafluoroether, is a powerful convulsant \nagent, although the mechanism is not understood.\nHalothane was an important drug in the development \nof volatile inhalation anaesthetics, but its use has declined in favour of isoflurane due to the potential for accumulation \nof toxic metabolites. Halothane has a marked relaxant effect \non the uterus which can cause postpartum bleeding and limits its usefulness for obstetric purposes.\nNITROUS OXIDE\nNitrous oxide (N 2O, not to be confused with nitric oxide, \nNO) is an odourless gas with many advantageous features \nfor anaesthesia. It is rapid in onset of action because of its \nlow blood:gas partition coefficient (see Table 42.2), and is an effective analgesic in concentrations too low to cause \nunconsciousness. Its potency is low. It is used as a 50 : 50 \nmixture with O 2 to reduce pain during childbirth. It must \nnever be given as 100% of the inspired gas as patients do \nneed to breathe oxygen! Even at 80% in the inspired gas \nmixture, nitrous oxide does not produce surgical anaesthesia. It is not therefore used on its own as an anaesthetic, but is \nused (as", "start_char_idx": 0, "end_char_idx": 3258, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "31adc796-c59f-4e81-8e97-211e9c18012a": {"__data__": {"id_": "31adc796-c59f-4e81-8e97-211e9c18012a", "embedding": null, "metadata": {"page_label": "546", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "85df7da8-5c73-45be-95d1-cee9bd5f9f6f", "node_type": null, "metadata": {"page_label": "546", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c9ac04e067b5766c1c65cf7437a2bbf16f97be891af6fbeff282eb213f2c039"}, "2": {"node_id": "384da572-54ec-4b9a-8ec8-c598eeacf240", "node_type": null, "metadata": {"page_label": "546", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61b6cfd7ebdf58cae6846acceec22f27185ec506fd55d2434b3b0063867bc80d"}}, "hash": "9ae524c9bd0c52cc3bdaa46290be8d4626f9c69fcf33af7a53d279ca684ed8cf", "text": "It is not therefore used on its own as an anaesthetic, but is \nused (as 70% nitrous oxide in oxygen) as an adjunct to \nvolatile anaesthetics to speed up induction \u2013 see description of the second gas effect (p. 538). During recovery from \nnitrous oxide anaesthesia, the transfer of the gas from the \nblood into the alveoli can be sufficient to reduce, by dilution, the alveolar partial pressure of oxygen, producing transient hypoxia (known as diffusional hypoxia). This is important \nfor patients with respiratory disease.\nNitrous oxide tends to enter gaseous cavities in the body \ncausing them to expand. This can be dangerous if a pneu -\nmothorax or vascular air embolus is present, or if the \nintestine is obstructed.\nGiven for brief periods, nitrous oxide is devoid of any \nserious toxic effects, but prolonged exposure ( >\n6 h) causes \ninactivation of methionine synthase, an enzyme required for DNA and protein synthesis, resulting in bone marrow \ndepression that may cause anaemia and leukopenia, so its \nuse should be avoided in patients with anaemia related to vitamin B\n12 deficiency. Bone marrow depression does not \noccur with brief exposure to nitrous oxide, but prolonged \nor repeated use (for example, in intermittently painful \nconditions such as sickle cell anaemia) should be avoided. Nitrous oxide \u2018sniffers\u2019 are subject to this danger.\nBALANCED ANAESTHESIA\nOnly in simple, short surgical procedures would a single anaesthetic be used on its own. In complex surgery, an \narray of drugs will be given at various times throughout \nthe procedure. These may include a sedative or anxiolytic premedication (e.g. a benzodiazepine, see Ch. 45), an \nintravenous anaesthetic for rapid induction (e.g. propofol ), \na perioperative opioid analgesic (e.g. alfentanil or remifen -\ntanil, see Ch. 43), an inhalation anaesthetic to maintain anaesthesia during surgery (e.g. nitrous oxide and isoflu-\nrane), a neuromuscular-blocking agent to produce adequate muscle relaxation (e.g. vecuronium, see Ch. 14) for access \nto the abdominal cavity for example, an antiemetic agent \n(e.g. ondansetron , see Ch. 31) and a muscarinic antagonist \nto prevent or treat bradycardia or to reduce bronchial and \nsalivary secretions (e.g. atropine or glycopyrrolate, see Ch. \n14). Towards the end of the procedure, an anticholinesterase agent (e.g. neostigmine, see Ch. 14) to reverse the mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3187, "end_char_idx": 6046, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aca1da39-4c39-4ddd-bd91-7c24e1970a39": {"__data__": {"id_": "aca1da39-4c39-4ddd-bd91-7c24e1970a39", "embedding": null, "metadata": {"page_label": "547", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c4da2f44-fc58-4548-97fe-d29f07f3782a", "node_type": null, "metadata": {"page_label": "547", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9fa08221795207408176db72db800710d403159a8dbe99144bacb8903c3981e"}}, "hash": "d9fa08221795207408176db72db800710d403159a8dbe99144bacb8903c3981e", "text": "42 GENERal aNaESThETic aGENTS\n541Low doses of general anaesthetics may be used to \nprovide sedation where a local anaesthetic (Ch. 44), \nadministered intrathecally, is used to provide analgesia and \nrelaxation needed to perform surgery to the lower parts of \nthe body.combinations of drugs result in much faster induction and \nrecovery, avoiding long (and potentially hazardous) periods \nof semiconsciousness, good analgesia and muscle relaxation \nand it enables surgery to be carried out with less undesirable \ncardiorespiratory depression.\nREFERENCES AND FURTHER READING\nAitkenhead, A.R., Moppett, I., Thompson, J., 2013. Smith & \nAitkenhead\u2019s Textbook of Anaesthesia, sixth ed. Churchill \nLivingstone/Elsevier, Edinburgh. ( Major textbook of anaesthesia )\nAntkowiak, B., Rudolph, U., 2016. New insights in the systemic and \nmolecular underpinnings of general anesthetic actions mediated by \n\u03b3-aminobutyric acid A receptors. Cur. Opin. In: Anaesth, vol. 29. pp. \n447\u2013453. ( Useful update on the interaction of general anaesthetics with the \nGABA A receptor )\nBayliss, D.A., Barrett, P.Q., 2008. Emerging roles for two-pore-domain \npotassium channels and their potential therapeutic impact. Trends \nPharmacol. Sci. 29, 566\u2013575.Franks, N.P., 2008. General anaesthesia: from molecular targets to \nneuronal pathways of sleep and arousal. Nat. Rev. Neurosci. 9, \n370\u2013386. ( Detailed discussion of the sites of action of general anaesthetics on \nspecific ion channels )\nSch\u00fcttler, J., Schwilden, H., 2008. Modern anesthetics. Handb. Exp. \nPharmacol. 182. ( Entire volume given over to multiauthor reviews of the \nmechanisms of action of general anaesthetics )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2135, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c44a0b80-8344-4603-ae49-260fc7cdcab1": {"__data__": {"id_": "c44a0b80-8344-4603-ae49-260fc7cdcab1", "embedding": null, "metadata": {"page_label": "548", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d412401d-8aeb-4584-bd30-e03053010af5", "node_type": null, "metadata": {"page_label": "548", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "870f420fade546cacd6977a6ea35a172c854ae3d0ddc03d5ead041bb1156b2b7"}, "3": {"node_id": "8ac890d3-0ff1-4716-8b5b-6949aa65d659", "node_type": null, "metadata": {"page_label": "548", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a1bd5f73f72ca220ee9850cdc2cedfde727a3f02ca3e6b3de66e87312188e9dd"}}, "hash": "962c46a52b10e7943eba9c1884e53a74b63eae5dd6eb77d92d95d04abf16df3f", "text": "542\nOVERVIEW\nPain is a disabling accompaniment of many acute \nand chronic medical conditions, and pain control is \none of the most important therapeutic priorities.\nIn this chapter, we discuss the neural mechanisms \nresponsible for different types of pain, and the various drugs that are used to reduce it. The \u2018classic\u2019 \nanalgesic drugs, notably opioids and non-steroidal anti-inflammatory drugs (NSAIDs; described in Ch. 27 ), \nhave their origins in natural products that have been used for centuries. The original compounds, typified by morphine and aspirin, are still in widespread \nuse, but many synthetic compounds that act by the \nsame mechanisms have been developed. Opioid analgesics are described in detail in this chapter. \nWe also consider various other drug classes, such as \nantidepressants and antiepileptic drugs, which clinical experience has shown to be effective in certain types \nof pain.\nNEURAL MECHANISMS OF PAIN\nPain is a subjective experience, hard to define exactly, even \nthough we all know what we mean by it. Typically, it is a \ndirect response to an untoward event associated with tissue \ndamage, such as injury, inflammation or cancer, but severe pain can arise independently of any obvious predisposing \ncause (e.g. trigeminal neuralgia), or persist long after the \nprecipitating injury has healed (e.g. phantom limb pain). It can also occur as a consequence of brain or nerve injury \n(e.g. following a stroke or herpes infection, and as a con -\nsequence of diabetes or multiple sclerosis). Painful conditions \nof the latter kind, not directly linked to tissue injury, are often described as \u2018neuropathic pains\u2019. They are very \ncommon and a major cause of disability and distress. Their \ncause is often uncertain and in general they respond less well to conventional analgesic drugs. In these cases, we \nneed to think of pain in terms of disordered neural function \nrather than simply as a \u2018normal\u2019 response to tissue injury. The perception of noxious stimuli (termed nociception by \nSherrington) is not the same thing as pain, which is a subjective experience and includes a strong emotional (affective) component, especially in people suffering from \nchronic pain.\nThough clinical pain is broadly categorised as \u2018acute\u2019 \nand \u2018chronic\u2019, these terms are a bit misleading (e.g. the pain occurring with cancer, while described as acute, can \nbe experienced for some considerable time). The following mechanistic classification is more relevant when considering \nanalgesic drugs.\u2022\tPain\tassociated \twith \ttissue \tpathology \t(e.g. \ttrauma, \t\ninflammation, tumours).\n\u2022\tNeuropathic \tpain \tassociated \twith \tnervous \tsystem \t\npathology (e.g. herpes, diabetes, stroke).\n\u2022\tMusculo-skeletal \tpain \t(e.g. \tback \tpain) \tand \tpain \tof \t\nunknown cause assumed by default to be psychogenic \n(e.g. fibromyalgia).\nGood accounts of the neural basis of pain can be found in \nMcMahon \tet \tal. \t(2013).\nNOCICEPTIVE AFFERENT NEURONS\nUnder normal conditions, pain is associated with impulse activity in small-diameter (C and A \u03b4) primary afferent fibres \nof peripheral nerves. These nerves have sensory endings in peripheral tissues and are activated by stimuli of various kinds (mechanical, thermal, chemical). The majority of \nnon-myelinated (C) fibres are associated with polymodal \nnociceptive endings and convey a dull, diffuse burning pain, \nwhereas myelinated (A \u03b4) fibres convey a sensation of sharp, \nwell-localised pain. C and A \u03b4 fibres convey nociceptive \ninformation from muscle and viscera", "start_char_idx": 0, "end_char_idx": 3513, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ac890d3-0ff1-4716-8b5b-6949aa65d659": {"__data__": {"id_": "8ac890d3-0ff1-4716-8b5b-6949aa65d659", "embedding": null, "metadata": {"page_label": "548", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d412401d-8aeb-4584-bd30-e03053010af5", "node_type": null, "metadata": {"page_label": "548", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "870f420fade546cacd6977a6ea35a172c854ae3d0ddc03d5ead041bb1156b2b7"}, "2": {"node_id": "c44a0b80-8344-4603-ae49-260fc7cdcab1", "node_type": null, "metadata": {"page_label": "548", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "962c46a52b10e7943eba9c1884e53a74b63eae5dd6eb77d92d95d04abf16df3f"}}, "hash": "a1bd5f73f72ca220ee9850cdc2cedfde727a3f02ca3e6b3de66e87312188e9dd", "text": "\u03b4 fibres convey nociceptive \ninformation from muscle and viscera as well as from the \nskin.\nWith many pathological conditions, tissue injury is the \nimmediate cause of the pain and results in the local release of a variety of chemicals that act on the nerve terminals, either activating them directly or enhancing their sensitivity \nto\tother\tforms\tof\tstimulation \t(Fig.\t43.1).\tThe\tpharmacological \t\nproperties of nociceptive nerve terminals are discussed in more detail later.\nThe cell bodies of spinal nociceptive afferent fibres lie \nin dorsal root ganglia; fibres enter the spinal cord via the dorsal roots, ending in the grey matter of the dorsal horn \n(see\tFig.\t43.4). \tMost \tof \tthe \tnociceptive \tafferents \tterminate \t\nin the superficial region of the dorsal horn, the C fibres and some A\u03b4 fibres innervating cell bodies in laminae I \nand II (also known as the substantia gelatinosa [SG]), while \nother A fibres penetrate deeper into the dorsal horn (lamina \nV). The SG is rich in both endogenous opioid peptides and \nopioid receptors, and may be an important site of action \nfor morphine-like drugs. Cells in laminae I and V give rise to the main projection pathways from the dorsal horn to \nthe thalamus. For a more detailed account of dorsal horn \ncircuitry, \tsee \tTodd \tand \tKoerber \t(2013).\nThe nociceptive afferent neurons release glutamate and \npossibly ATP as the fast neurotransmitters at their central \nsynapses \tin \tthe \tdorsal \thorn. \tGlutamate \tacting \ton \tAMPA \t\nreceptors is responsible for fast synaptic transmission at \nthe first synapse in the dorsal horn. There is also a slower \nNMDA\treceptor-mediated \tresponse, \twhich \tis \timportant \t\nin\trelation \tto \tthe \tphenomenon \tof \t\u2018wind-up\u2019 \t(Fig. \t43.2). \t\nThe nociceptive afferent neurons also contain several Analgesic drugs43 NERVOUS SYSTEM SECTION 4 \nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3449, "end_char_idx": 5756, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e46239eb-961e-466b-afde-03ac58b81fa7": {"__data__": {"id_": "e46239eb-961e-466b-afde-03ac58b81fa7", "embedding": null, "metadata": {"page_label": "549", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "32a63977-f28c-4b87-a12d-aa5d8c6c34c0", "node_type": null, "metadata": {"page_label": "549", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e40f0c07b095862a780165a3bea66f044a0a9a33215fa8e5b64c43c34751e132"}, "3": {"node_id": "b1e4f62f-c200-4440-9960-30dd7b9f025a", "node_type": null, "metadata": {"page_label": "549", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7c04cab7296c75c6f4ae0f605196e2567d50eaf961262b279023b6ecd174f598"}}, "hash": "8cc36806ec04ea8b0df711fd0c96c62a0f4909d8b77c0a34dac17964a9aeff0f", "text": "43 ANAlgESic dRUgS\n543neuropeptides \t(see \tCh. \t19), \tparticularly \tsubstance \tP \tand \t\ncalcitonin gene-related peptide (CGRP). These are released \nas mediators at both the central and the peripheral terminals, \nand play an important role in the pathology of pain. In the \nperiphery, substance P and CGRP produce some of the features of neurogenic inflammation. CGRP antagonists \nhave\tpotential \tfor \tthe \ttreatment \tof \tmigraine \t(see \tCh. \t16) \t\nbut have not proved effective for other pain states. In animal models, substance P acting on NK\n1 receptors was \nshown to be involved in wind-up and central sensitisation \nin\tthe\tdorsal \thorn \t(see \tFig. \t43.2). \tSurprisingly, \thowever, \t\nantagonists of substance P at NK 1 receptors turned out to \nbe ineffective as analgesics in humans, although they do \nhave\tantiemetic \tactivity \t(Ch. \t31).\nMODULATION IN THE NOCICEPTIVE PATHWAY\nPain resulting from trauma, inflammation or cancer is generally well accounted for in terms of nociception \u2013 an \nexcessive noxious stimulus giving rise to an intense and \nunpleasant sensation. In contrast, neuropathic pain states are associated with aberrations of the normal physiological \npathway, giving rise to hyperalgesia (an increased amount \nof pain associated with a mild noxious stimulus) and \nallodynia (pain evoked by a non-noxious stimulus). Some \nof\tthe\tmain \tmechanisms \tare \tsummarised \tin \tFig. \t43.3.\nHYPERALGESIA AND ALLODYNIA\n\u25bc A nyone who has suffered a burn or sprained ankle has experienced \nhyperalgesia and allodynia. Hyperalgesia involves both sensitisation \nof peripheral nociceptive nerve terminals and central facilitation of \ntransmission at the level of the dorsal horn and thalamus. The \nperipheral component is due to the action of mediators such as bradykinin and prostaglandins acting on the nerve terminals. The \ncentral component reflects facilitation of synaptic transmission in the \ndorsal\thorn\tof\tthe\tspinal\tcord\t(see\tYaksh,\t1999).\tThe\tsynaptic\tresponses \t\nof dorsal horn neurons to nociceptive inputs display the phenomenon \nof \u2018wind-up\u2019 \u2013 i.e. the synaptic potentials steadily increase in amplitude Mast cell or neutrophil \nSubstance P\nHistamine Heat/\ncold/\npressure\nTissue\ninjury\nPeripheryNGF\nBradykinin\nProstaglandin5-HT\nATP\nBlood\nvesselCGRP\nSubstance PSpinal cordHigher centres\nDRG\ncell body \nH+\nFig. 43.1 Activation of nociceptive neurons. Various stimuli \n(physical and chemical), some shown here, can initiate or \nenhance the rate of action potential firing in nociceptive primary afferent neurons (i.e. induce pain). These afferent fibres project to the dorsal horn of the spinal cord where they synapse on neurons projecting to higher centres. 5-HT, 5-hydroxytryptamine; \nCGRP, calcitonin gene-related peptide; DRG, dorsal root \nganglion; NGF, nerve growth factor. (Adapted from Julius, D., \nBasbaum, A.I., 2001. Nature 413, 203\u2013210.)SINGLE STIMULUS\nControl\nControl\nControlControlNMDA receptor antagonist\nNMDA receptor antagonistSubstance P\nantagonist\nSubstance P\nantagonist0.5 mV\n1 mV1.0 s\n1.0 sREPETITIVE STIMULATIONA\nB\nFig. 43.2 Effect of glutamate and substance P antagonists \non", "start_char_idx": 0, "end_char_idx": 3117, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b1e4f62f-c200-4440-9960-30dd7b9f025a": {"__data__": {"id_": "b1e4f62f-c200-4440-9960-30dd7b9f025a", "embedding": null, "metadata": {"page_label": "549", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "32a63977-f28c-4b87-a12d-aa5d8c6c34c0", "node_type": null, "metadata": {"page_label": "549", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e40f0c07b095862a780165a3bea66f044a0a9a33215fa8e5b64c43c34751e132"}, "2": {"node_id": "e46239eb-961e-466b-afde-03ac58b81fa7", "node_type": null, "metadata": {"page_label": "549", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8cc36806ec04ea8b0df711fd0c96c62a0f4909d8b77c0a34dac17964a9aeff0f"}}, "hash": "7c04cab7296c75c6f4ae0f605196e2567d50eaf961262b279023b6ecd174f598", "text": "43.2 Effect of glutamate and substance P antagonists \non nociceptive transmission in the rat spinal cord. The rat \npaw was inflamed by ultraviolet irradiation 2 days before the experiment, a procedure that induces hyperalgesia and spinal cord facilitation. The synaptic response was recorded from the ventral root, in response to stimulation of C fibres in the dorsal root with (A) single stimuli or (B) repetitive stimuli. The effects of the NMDA receptor antagonist D-AP-5 (see Ch. 39) and the substance P antagonist RP 67580 (selective for neurokinin type 2, (NK\n2) receptors) are shown. The slow component of the \nsynaptic response is reduced by both antagonists (A), as is the \u2018wind-up\u2019 in response to repetitive stimulation (B). These effects are much less pronounced in the normal animal. Thus both glutamate, acting on NMDA receptors, and substance P, acting on NK\n2 receptors, are involved in nociceptive transmission, and \ntheir contribution increases as a result of inflammatory \nhyperalgesia. (Records kindly provided by L. Urban and S.W. \nThompson.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3060, "end_char_idx": 4603, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "05ba4948-24a5-462b-9a2e-65f651c1664c": {"__data__": {"id_": "05ba4948-24a5-462b-9a2e-65f651c1664c", "embedding": null, "metadata": {"page_label": "550", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7ce0fe0-fba0-4e19-afa4-700ab4d0b61a", "node_type": null, "metadata": {"page_label": "550", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2243b88894c6bb66dac38de9515268fc7878abcf82e3751b5772e3adbb211581"}, "3": {"node_id": "a39c7343-3a23-4f30-8513-9cb27ff27709", "node_type": null, "metadata": {"page_label": "550", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c83df421ea5d1e17230c6613281ba6d5b51a4f85d657af33f3040d0cde0f14e"}}, "hash": "8ef10e8741a17e5ee2e001de46f262812956ff5d8717c2331461cb92af1b59d4", "text": "43 SECTION 4 NERVOUS SYSTEM\n544NOXIOUS\nSTIMULUS C-FIBRE\nACTIVITYNO FORMATION5-HT, NA\nNEUROPEPTIDE\nRELEASE (SP, CGRP)NGF\nPRODUCTIONMEDIATOR\nRELEASE\n(BK, 5-HT, PGs,\nTNF-\u03b1 IL-1\u03b2, etc)ENKEPHALINS, GABA\nInflammationDESCENDING\nINHIBITORY\nPATHWAYSPAIN\nLocal\ninterneurons\nNSAIDS?NOCICEPTIVE\nPATHWAYOpioids\nOpioidsEXCITATION OF\nTRANSMISSION\nNEURON\nFig. 43.3 Summary of modulatory mechanisms in the nociceptive pathway. 5-HT, 5-hydroxytryptamine; BK, bradykinin; CGRP, \ncalcitonin gene-related peptide; IL-1\u03b2, interleukin; NA, noradrenaline; NGF, nerve growth factor; NO, nitric oxide; NSAID, non-steroidal \nanti-inflammatory drug; PG, prostaglandin; SP, substance P; TNF-\u03b1, tumour necrosis factor- \u03b1. \nwith each stimulus \u2013 when repeated stimuli are delivered at \nphysiological frequencies. This activity-dependent facilitation of \ntransmission has features in common with the phenomenon of long-\nterm\tpotentiation, \tdescribed \tin\tChapter\t39,\tand\tthe\tchemical \tmecha -\nnisms underlying it may also be similar. In the dorsal horn, the facilitation is blocked by antagonists and also in part by antagonists \nof substance P and by inhibitors of nitric oxide (NO) synthesis (see \nFigs\t43.2 \tand \t43.3).\nSubstance P and CGRP released from primary afferent neurons (see \nFig.\t43.1) \talso \tact \tin \tthe \tperiphery, \tpromoting \tinflammation \tby \ttheir \t\neffects\ton \tblood \tvessels \tand \tcells \tof \tthe \timmune \tsystem \t(Ch. \t19). \t\nThis mechanism, known as neurogenic inflammation, amplifies and \nsustains the inflammatory reaction and the accompanying activation \nof nociceptive afferent fibres.\nCentral facilitation is an important component of pathological \nhyperalgesia (e.g. that associated with inflammatory responses). The \nmediators responsible for central facilitation include substance P, CGRP, brain-derived neurotrophic factor (BDNF) and NO, as well \nas many others. For example, nerve growth factor (NGF), a cytokine-like \nmediator produced by peripheral tissues, particularly in inflammation, acts on a kinase-linked receptor (known as TrkA) on nociceptive \nafferent neurons, increasing their electrical excitability, chemosensitivity \nand peptide content, and also promoting the formation of synaptic contacts. Increased NGF production may be an important mechanism \nby which nociceptive transmission becomes facilitated by tissue \ndamage, \tleading \tto \thyperalgesia \t(see \tMantyh \tet \tal., \t2011). \tIncreased \t\ngene expression in sensory neurons is induced by NGF and other \ninflammatory mediators; the up-regulated genes include those for \nneuropeptides and neuromodulators (e.g. CGRP, substance P and BDNF)\tas\twell\tas\tfor\treceptors \t(e.g.\ttransient \treceptor\tpotential \tTRPV1\t\nand the ATP receptor P2X) and sodium channels, and have the overall \neffect of facilitating transmission at the first synaptic relay in the \ndorsal horn. BDNF released from primary afferent nerve terminals \nactivates the kinase-linked TrkB receptor on postsynaptic dorsal horn \nneurons\tleading \tto \tphosphorylation \tof \tthe \tNMDA \tsubunit \tGluN1 \t\nand thus sensitisation of these glutamate receptors,", "start_char_idx": 0, "end_char_idx": 3082, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a39c7343-3a23-4f30-8513-9cb27ff27709": {"__data__": {"id_": "a39c7343-3a23-4f30-8513-9cb27ff27709", "embedding": null, "metadata": {"page_label": "550", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7ce0fe0-fba0-4e19-afa4-700ab4d0b61a", "node_type": null, "metadata": {"page_label": "550", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2243b88894c6bb66dac38de9515268fc7878abcf82e3751b5772e3adbb211581"}, "2": {"node_id": "05ba4948-24a5-462b-9a2e-65f651c1664c", "node_type": null, "metadata": {"page_label": "550", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8ef10e8741a17e5ee2e001de46f262812956ff5d8717c2331461cb92af1b59d4"}}, "hash": "2c83df421ea5d1e17230c6613281ba6d5b51a4f85d657af33f3040d0cde0f14e", "text": "\t\nand thus sensitisation of these glutamate receptors, resulting in synaptic facilitation, in the dorsal horn.\nExcitation of nociceptive sensory neurons depends, as in other neurons \n(see Ch. 4), on voltage-gated sodium channels. Individuals who express \nnon-functional mutations of Na\nv1.7 are unable to experience pain. \nThe expression and/or activity of certain sodium-channel subtypes (e.g. Na\nv1.3,\tNa v1.7,\tNa v\t1.8\tand \tNa v1.9\tchannels) \tis \tincreased \tin \t\nsensory neurons in various pathological pain states and their enhanced \nactivity underlies the sensitisation to external stimuli that occurs in \ninflammatory pain and hyperalgesia (see Ch. 4 for more detail on \nvoltage-activated sodium channels). Consistent with this hypothesis is the fact that many antiepileptic and antidysrhythmic drugs, which \nact\tby\tblocking\tsodium\tchannels \t(see\tChs\t22\tand\t46),\talso\tfind\tclinical\t\napplication as analgesics.\nTRANSMISSION OF PAIN TO HIGHER CENTRES\nFrom the dorsal horn, ascending nerve axons travel in the \ncontralateral spinothalamic tracts, and synapse on neurons \nin the ventral and medial parts of the thalamus, from which \nthere are further projections to the somatosensory cortex. In the medial thalamus in particular, many cells respond \nspecifically to noxious stimuli in the periphery, and lesions mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3028, "end_char_idx": 4821, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2cc82c4b-d358-4c61-8c91-2566ac3b7c90": {"__data__": {"id_": "2cc82c4b-d358-4c61-8c91-2566ac3b7c90", "embedding": null, "metadata": {"page_label": "551", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "587adbd0-d69d-4773-ba35-91228ed49afd", "node_type": null, "metadata": {"page_label": "551", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6dcd4cc458b0eebd38c5194cb9e65701040a5c0637ad85cc06684650c7cba55c"}, "3": {"node_id": "0deeb299-3842-488a-bbf2-91f4e3004e62", "node_type": null, "metadata": {"page_label": "551", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "68965f5f8b9331a5d1ad5c486e2c9b597c423ce4ef5f76338094e68188b8a412"}}, "hash": "be368e0096c1b7dbc0450be571a78493099be9113206a8db7e46ea831c7e7202", "text": "43 ANAlgESic dRUgS\n545studies have revealed that the placebo response results \nfrom changes in neuronal activity in the prefrontal cortex \nand PAG, resulting in activation of descending inhibitory \npathways to the spinal cord to suppress the processing of pain information.\nExpectation can also modify the response when an \nanalgesic drug is given. Subjects receiving an intravenous infusion of remifentanil, an opioid analgesic, showed more \npain relief when they were told they were receiving the \ndrug than when the drug was administered without them in this area cause analgesia. Functional brain imaging studies in conscious subjects have been performed to localise regions involved in pain processing. These include sensory, dis -\ncriminatory areas such as primary and secondary soma-tosensory cortex, thalamus and posterior parts of insula as well as affective, cognitive areas such as the anterior parts \nof insula, anterior cingulate cortex and prefrontal cortex \n(see\tApkarian \tet \tal., \t2013).\nDESCENDING INHIBITORY CONTROLS\nDescending \tpathways \t(Fig.\t43.4)\tcontrol\timpulse\ttransmis -\nsion in the dorsal horn. A key part of this descending system is the periaqueductal grey (PAG) area of the midbrain, a \nsmall area of grey matter surrounding the central canal. \nIn\t1969,\tReynolds \tfound \tthat \telectrical \tstimulation \tof \tthis \t\nbrain area in the rat caused analgesia sufficiently intense \nthat abdominal surgery could be performed without \nanaesthesia and without eliciting any marked response. \nThe responses to non-painful stimuli were unaffected. The PAG receives inputs from many other brain regions, includ -\ning the hypothalamus, amygdala and cortex, and is the main pathway through which cortical and other inputs act to control the nociceptive \u2018gate\u2019 in the dorsal horn.\nThe PAG projects first to the rostroventral medulla \n(RVM)\tand \tthence \tvia \tthe \tdorsolateral \tfuniculus \tof \tthe \t\nspinal cord to the dorsal horn. Two important transmitters in this pathway are 5-hydroxytryptamine (5-HT; serotonin) \nand the enkephalins, which act directly or via interneurons \nto inhibit the discharge of spinothalamic neurons (see \nFig.\t43.4).\nThe descending inhibitory pathway is probably an \nimportant site of action for opioid analgesics. Both PAG \nand SG are particularly rich in enkephalin-containing \nneurons, and opioid antagonists such as naloxone (see p. \n549)\tcan\tprevent \tanalgesia \tinduced \tby \tPAG \tstimulation, \t\nwhich would suggest that endogenous opioid peptides may function as transmitters in this system. The physiological \nrole of opioid peptides in regulating pain transmission has \nbeen controversial, mainly because under normal conditions naloxone has relatively little effect on pain threshold. Under \npathological conditions, however, when stress is present, \nnaloxone causes hyperalgesia, implying that the opioid system is active.\nInterneurons in the dorsal horn release GABA (see Ch. \n39),\twhich\tinhibits\ttransmitter \trelease\tfrom\tprimary\tafferent\t\nterminals.\nThere is also a noradrenergic pathway from the locus \ncoeruleus \t(LC;\tsee \tCh. \t40), \twhich \thas \ta \tsimilar \tinhibitory \t\neffect on transmission in the dorsal horn. Surprisingly, opioids inhibit rather than activate this pathway. The use \nof\ttricyclic \tantidepressants \tto \tcontrol \tpain \t(see \tp. \t559) \t\nprobably depends on potentiating this pathway.\nIt is thought that descending inhibitory purinergic", "start_char_idx": 0, "end_char_idx": 3409, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0deeb299-3842-488a-bbf2-91f4e3004e62": {"__data__": {"id_": "0deeb299-3842-488a-bbf2-91f4e3004e62", "embedding": null, "metadata": {"page_label": "551", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "587adbd0-d69d-4773-ba35-91228ed49afd", "node_type": null, "metadata": {"page_label": "551", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6dcd4cc458b0eebd38c5194cb9e65701040a5c0637ad85cc06684650c7cba55c"}, "2": {"node_id": "2cc82c4b-d358-4c61-8c91-2566ac3b7c90", "node_type": null, "metadata": {"page_label": "551", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be368e0096c1b7dbc0450be571a78493099be9113206a8db7e46ea831c7e7202"}}, "hash": "68965f5f8b9331a5d1ad5c486e2c9b597c423ce4ef5f76338094e68188b8a412", "text": "potentiating this pathway.\nIt is thought that descending inhibitory purinergic \npathways may release adenosine on to A 1 receptors on \ndorsal horn neurons to produce analgesia.\nPLACEBO ANALGESIA\nPlacebo analgesia is the phenomenon of reduced sensation of pain when the subject believes that they have been given \na drug that will suppress pain, when in fact no drug has \nbeen administered at all. It is often a substantial effect that poses problems in clinical trials of analgesic drugs. \nPlacebo analgesia is reduced by administration of an opioid \nantagonist such as naloxone, indicating that it involves \nthe release of endogenous opioid peptides. Brain imaging Cortex\nPAGMidbrain\nMedulla\nSpinal\ncordRVMIC\nA\nH\nFig. 43.4 The descending pain control system and sites of \naction of opioids to relieve pain. Opioids induce analgesia \nwhen microinjected into the insular cortex (IC), amygdala (A), \nhypothalamus (H), periaqueductal grey (PAG) region and rostroventral medulla (RVM), as well as into the dorsal horn of the spinal cord. The PAG receives input from higher centres and is the main output centre of the limbic system. It projects to the RVM. From the RVM, descending inhibitory fibres, some of which contain 5-hydroxytryptamine, project to the dorsal horn of the spinal cord. Pink shaded areas indicate regions expressing \u00b5 \nopioid receptors. The pathways shown in this diagram represent a considerable oversimplification. (Adapted from Fields, H., 2001. Prog. Brain Res. 122, 245\u2013253. For a fuller account of the descending pain modulating pathways, see Todd & Koerber, \n2013.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3331, "end_char_idx": 5401, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aca09c6d-1324-49b3-916a-0eb26afcb97e": {"__data__": {"id_": "aca09c6d-1324-49b3-916a-0eb26afcb97e", "embedding": null, "metadata": {"page_label": "552", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "82310adc-795a-4750-ba7d-60f19fe23fb5", "node_type": null, "metadata": {"page_label": "552", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "580321679fdb73109907261c656ae792dd43c7f9fc1a715bc3802d1bbc0fad9c"}, "3": {"node_id": "98e07ab9-9e37-4a81-a52b-adb2cd50eab6", "node_type": null, "metadata": {"page_label": "552", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c1cad817a6b39a27216ac09f661c6340cdac7adb99f7ea5762b70cb1b84cf10"}}, "hash": "fc50b4ff210031856e90245636165c27e4eb56de9dec81075032b3f7aa9742d7", "text": "43 SECTION 4 NERVOUS SYSTEM\n546knowing \t(see \tBingel \tet \tal., \t2012). \tEven \tmore \tsurprising \t\nwas the observation that when the subjects received the \nsame dose of remifentanyl, but were told the infusion was \nof a substance that would exacerbate pain, they did not \nshow any analgesic response to the opioid.\nModulation of pain transmission \n\u2022\tDescending \tpathways \tfrom \tthe \tmidbrain \tand \tbrain \t\nstem exert a strong inhibitory effect on dorsal horn \ntransmission. Electrical stimulation of the midbrain periaqueductal grey area causes analgesia through this \nmechanism.\n\u2022\tThe\tdescending \tinhibition \tis \tmediated \tmainly \tby \t\nendogenous opioid peptides, 5-hydroxytryptamine \n(serotonin), noradrenaline and adenosine. Opioids cause analgesia partly by activating these descending \npathways, partly by inhibiting transmission in the dorsal \nhorn and partly by inhibiting excitation of sensory nerve terminals in the periphery.\n\u2022\tRepetitive \tC-fibre \tactivity \tfacilitates \ttransmission \t\nthrough the dorsal horn (\u2018wind-up\u2019) by mechanisms involving activation of NMDA and substance P receptors.\nNEUROPATHIC PAIN\nNeurological disease affecting the sensory pathway can \nproduce severe chronic pain \u2013 termed neuropathic pain \n\u2013 unrelated to any peripheral tissue injury. This occurs \nTRPV1\nB2 receptorTrkA\nIncreased\nexpressionP2X\nreceptorV-gated\nNa channel K channelsASIC\nProstanoid\nreceptorOther inhibitory\nGPCRsATP Protons\nEndovanilloidsCapsaicin\nNoxious\nheat\nBradykinin Prostaglandins NoradrenalineOpioids CannabinoidsPKA PKCDEPOLARISATION EXCITATIONNGF\nFig. 43.5 Channels, receptors and transduction mechanisms of nociceptive afferent terminals. Only the main channels and \nreceptors are shown. Ligand-gated channels include acid-sensitive ion channels (ASICs), ATP-sensitive channels (P2X receptors) and the \ncapsaicin-sensitive channel (TRPV1), which is also sensitive to protons and to temperature. Various facilitatory and inhibitory G protein\u2013coupled receptors (GPCRs) are shown, which regulate channel function through various second messenger systems. Growth factors such as nerve growth factor (NGF) act via kinase-linked receptors (TrkA) to control ion channel function and gene expression. B\n2 receptor, \nbradykinin type 2 receptor; PKA, protein kinase A; PKC, protein kinase C. with central nervous system (CNS) disorders such as stroke \nand multiple sclerosis, or with conditions associated with \nperipheral nerve damage, such as mechanical injury, \ndiabetic neuropathy or herpes zoster infection (shingles). The pathophysiological mechanisms underlying this kind \nof pain are poorly understood, although spontaneous \nactivity in damaged sensory neurons, due to overexpres -\nsion or redistribution of voltage-gated sodium channels, \nis thought to be a factor. In addition, central sensitisation \noccurs. The sympathetic nervous system also plays a part, because damaged sensory neurons can express \u03b1\n1 \nadrenoceptors and develop a sensitivity to noradrenaline \nthat they do not possess under normal conditions. Thus, \nphysiological stimuli that evoke sympathetic responses can produce severe pain, a phenomenon described clinically \nas sympathetically mediated pain. Neuropathic pain \nresponds poorly to conventional analgesic drugs but can be relieved by some antidepressant and antiepileptic agents ", "start_char_idx": 0, "end_char_idx": 3325, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "98e07ab9-9e37-4a81-a52b-adb2cd50eab6": {"__data__": {"id_": "98e07ab9-9e37-4a81-a52b-adb2cd50eab6", "embedding": null, "metadata": {"page_label": "552", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "82310adc-795a-4750-ba7d-60f19fe23fb5", "node_type": null, "metadata": {"page_label": "552", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "580321679fdb73109907261c656ae792dd43c7f9fc1a715bc3802d1bbc0fad9c"}, "2": {"node_id": "aca09c6d-1324-49b3-916a-0eb26afcb97e", "node_type": null, "metadata": {"page_label": "552", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc50b4ff210031856e90245636165c27e4eb56de9dec81075032b3f7aa9742d7"}}, "hash": "4c1cad817a6b39a27216ac09f661c6340cdac7adb99f7ea5762b70cb1b84cf10", "text": "drugs but can be relieved by some antidepressant and antiepileptic agents \n(see\tp.\t559).\nCHEMICAL SIGNALLING IN THE \nNOCICEPTIVE PATHWAY\nCHEMOSENSITIVITY OF NOCICEPTIVE NERVE ENDINGS\nIn most cases, stimulation of nociceptive endings in the \nperiphery is chemical in origin. Excessive mechanical or \nthermal stimuli can obviously cause acute pain, but the \npersistence of such pain after the stimulus has been removed, or the pain resulting from inflammatory or ischaemic \nchanges in tissues, generally reflects an altered chemical \nenvironment of the pain afferents. The current state of \nknowledge \tis \tsummarised \tin \tFig. \t43.5.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3251, "end_char_idx": 4363, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4f9055de-e048-4733-910b-0d4b82471c2e": {"__data__": {"id_": "4f9055de-e048-4733-910b-0d4b82471c2e", "embedding": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5ca8a155-befa-4cae-b61b-6187336c62a9", "node_type": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb5d1d5f21758de75aeb3c41c51e93ed9201e43c0444d45df7f9668a2a7103b0"}, "3": {"node_id": "35c13ad1-f310-4815-8dbb-b0a173237984", "node_type": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61fef3ff75f97e2946b3b137b6f25d68034b09c315dde3e9057296936e5a699b"}}, "hash": "a1ce9ae3224f2ea33c007c459a8b5ea0a9a02c853217c074c87af376a8612545", "text": "43 ANAlgESic dRUgS\n547TRPM8\tis\timportant \tin\tcold\thypersensitivity, \twhich\tis\toften\ta\tfeature\t\nof\tneuropathic \tpain.\tTRPA1\tis\tactivated \tin\tsome\texperimental \tsettings\t\nby noxious cold temperatures, calcium, pain-producing substances \nand inflammatory mediators; it can therefore also be considered to \nbe a polymodal sensor. It may be important for the analgesic and \nantipyretic \tactions \tof \tparacetamol \t(see \tp. \t559).\nKinins\nWhen applied to sensory nerve endings, bradykinin and \nkallidin\t( see\tCh . \t1 9) \ti nduce\ti ntense \tpa in.\tT hese\tt wo\tc losely \t\nrelated peptides are produced under conditions of tissue \ninjury by the proteolytic cleavage of the active kinins from \na precursor protein contained in the plasma. Bradykinin \nacts partly by release of prostaglandins, which strongly enhance the direct action of bradykinin on the nerve ter -\nminals\t(Fig. \t43.6). \tBradykinin \tacts \ton \tB2 receptors on \nnociceptive neurons. B 2 receptors are coupled to activation \nof a specific isoform of protein kinase C (PKC \u03b5), which \nphosphorylates \tT RPV1\ta nd\tf acilitates\to pening\to f\tt he\tT RPV1\t\nchannel.\n\u25bc Bradykinin is converted in tissues by removal of a terminal arginine \nresidue to des-Arg9 bradykinin , which acts selectively on B 1 receptors. \nB1 receptors are normally expressed at very low levels, but their \nexpression is strongly up-regulated in inflamed tissues. Transgenic \nknock-out animals lacking either type of receptor show reduced \ninflammatory hyperalgesia. Specific competitive antagonists for both TRP channels \u2013 thermal sensation and pain\nThe transient receptor potential (TRP) channel family com -\nprises some 27 or more structurally related ion channels \nthat serve a wide variety of physiological functions (see \nNilius\t& \tSzallasi, \t2014). \tWithin \tthis \tfamily \tare \ta \tgroup \tof \t\nchannels present on sensory neurons that are activated \nboth by thermal stimuli across a wide range of temperatures \nand\tby\tchemical \tagents \t(Table \t43.1). \tWith \trespect \tto \tpain, \t\nthe\tmost\timportant \tchannels \tare \tTRPV1, \tTRPM8 \tand \tTRPA1.\n\u25bc Capsaicin, the substance in chilli peppers that gives them their \npungency, selectively excites nociceptive nerve terminals, causing \nintense pain if injected into the skin or applied to sensitive structures \nsuch as the cornea.1\tIt\tproduces \tthis \teffect \tby \tactivating \tTRPV1.2 \nAgonists such as capsaicin open the channel, which is permeable to \nNa+, Ca2+ and other cations, causing depolarisation and initiation of \naction potentials. The large influx of Ca2+ into peripheral nerve ter-\nminals also results in peptide release (mainly substance P and CGRP), causing intense vascular and other physiological responses. The Ca\n2+ \ninflux\tmay\tbe\tenough\tto\tcause\tnerve\tdegeneration \t(see\tCh.\t41).\tApplied\t\ntopically, capsaicin reduces neuropathic and osteoarthritic pain by \nthis mechanism, but the initial strong irritant effect is a major \ndisadvantage.\nTRPV1\tresponds \tnot \tonly \tto \tcapsaicin-like \tagonists \tbut \talso \tto \tother \t\nstimuli\t(see \tTable \t43.1), \tincluding \ttemperatures \tin \texcess \tof \tabout", "start_char_idx": 0, "end_char_idx": 3078, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "35c13ad1-f310-4815-8dbb-b0a173237984": {"__data__": {"id_": "35c13ad1-f310-4815-8dbb-b0a173237984", "embedding": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5ca8a155-befa-4cae-b61b-6187336c62a9", "node_type": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb5d1d5f21758de75aeb3c41c51e93ed9201e43c0444d45df7f9668a2a7103b0"}, "2": {"node_id": "4f9055de-e048-4733-910b-0d4b82471c2e", "node_type": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a1ce9ae3224f2ea33c007c459a8b5ea0a9a02c853217c074c87af376a8612545"}, "3": {"node_id": "ded51adf-8de7-481c-b98e-4aae483fb294", "node_type": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f91746bb7301a32372b90f6565ffa43e351227ad93035df4302815a10d4a0b33"}}, "hash": "61fef3ff75f97e2946b3b137b6f25d68034b09c315dde3e9057296936e5a699b", "text": "\t43.1), \tincluding \ttemperatures \tin \texcess \tof \tabout \t\n42\u00b0C (the threshold for pain) and proton concentrations in the \nmicromolar range (pH 5.5 and below), which also cause pain. The \nreceptor thus has unusual \u2018polymodal\u2019 characteristics and is believed \nto\tplay\ta \tcentral \trole \tin \tnociception. \tTRPV1 \tis, \tlike \tmany \tother \t\nionotropic receptors, modulated by phosphorylation, and several of \nthe pain-producing substances that act through G protein\u2013coupled \nreceptors \t(e.g. \tbradykinin) \twork \tby \tsensitising \tTRPV1. \tA \tsearch \tfor \t\nendogenous \tligands \tfor \tTRPV1 \trevealed, \tsurprisingly, \tthat \tanandamide \n(a lipid mediator previously identified as an agonist at cannabinoid \nreceptors; \tsee \tCh. \t20) \tis \talso \ta \tTRPV1 \tagonist, \talthough \tless \tpotent \t\nthan\tcapsaicin. \tTRPV1\tknock-out \tmice\tshow\treduced\tresponsiveness \t\nto noxious heat and also fail to show thermal hyperalgesia in response \nto\tinflammation. \tThe\tlatter\tobservation \tis\tinteresting, \tbecause\tTRPV1\t\nexpression is known to be increased by inflammation and this may be a key mechanism by which hyperalgesia is produced. A number \nof\tpharmaceutical \tcompanies \tdeveloped \tTRPV1 \tagonists \t\u2013 \tto \tact \tas \t\ndesensitising agents \u2013 and antagonists as analgesic agents. However, \nTRPV1\tagonists \twere \tfound \tto \tinduce \thypothermia, \tassociated \twith \t\nactivation \tof \thypothalamic \tthermosensitive \tneurons, \tand \tTRPV1 \t\nantagonists were found to induce hyperthermia, consistent with a \nrole\tof\tTRPV1 \tin \tbody \ttemperature \tcontrol \tas \twell \tas \tnociception.\nTRPM8\tand\tTRPA1\trespond\tto\tcold\trather\tthan\theat\t(see\tTable\t43.1).\tTable 43.1 Thermosensitive TRP channels expressed on sensory neurons\nChannel type TRPA1 TRPM8 TRPV4 TRPV3 TRPV1 TRPV2\nActivation temperature (\u00b0C) <17 8\u201328 >27 >33 >43 >52\nChemical activatorsIcilin\nWintergreen oilMustard oilMentholIcilinEucalyptolGeraniol4\u03b1PDDCamphorMentholEugenolCapsaicinProtonsAnandamideCamphorResiniferatoxinEugenol\u0394\n9-THC\n4\u03b1PDD, 4 alpha-phorbol 12,13-didecanoate; \u03949-THC, \u03949-tetrahydrocannabinol; TRP, transient receptor protein.\n2 sImpulses/4 s\nBrad.\n26 \u00b5gBrad.\n26 \u00b5gPGE 2\n30 \u00b5g 5 min50 mV\n02040\nFig. 43.6 Response of a nociceptive afferent neuron to \nbradykinin and prostaglandin. Recordings were made from a \nnociceptive afferent fibre supplying a muscle, and drugs were \ninjected into the arterial supply. Upper records: single-fibre recordings showing discharge caused by bradykinin (Brad) alone (left), and by bradykinin following injection of prostaglandin (right). Lower trace: ratemeter recording of single-fibre discharge, showing long-lasting enhancement of response to bradykinin after an injection of prostaglandin E\n2 (PGE 2). \nProstaglandin itself did not evoke a discharge. (From Mense, S., \n1981. Brain Res. 225, 95.)\n1Anyone who has rubbed their eyes after cutting up chilli peppers will \nknow", "start_char_idx": 3030, "end_char_idx": 5882, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ded51adf-8de7-481c-b98e-4aae483fb294": {"__data__": {"id_": "ded51adf-8de7-481c-b98e-4aae483fb294", "embedding": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5ca8a155-befa-4cae-b61b-6187336c62a9", "node_type": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb5d1d5f21758de75aeb3c41c51e93ed9201e43c0444d45df7f9668a2a7103b0"}, "2": {"node_id": "35c13ad1-f310-4815-8dbb-b0a173237984", "node_type": null, "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61fef3ff75f97e2946b3b137b6f25d68034b09c315dde3e9057296936e5a699b"}}, "hash": "f91746bb7301a32372b90f6565ffa43e351227ad93035df4302815a10d4a0b33", "text": "who has rubbed their eyes after cutting up chilli peppers will \nknow this.\n2The receptor was originally known as the vanilloid receptor because \nmany capsaicin-like compounds are based on the structure of vanillic \nacid.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5863, "end_char_idx": 6562, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b4262e83-781f-422d-ad79-5d1894fcb87d": {"__data__": {"id_": "b4262e83-781f-422d-ad79-5d1894fcb87d", "embedding": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87bf152e-d191-42e3-ab76-e4c9f59d29c0", "node_type": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59536570acd823c85dd20033b64d54244b21ea22d8f79a0868accaba3a4f0a16"}, "3": {"node_id": "5dbd025a-22cf-4a06-874e-906d8cd2bb50", "node_type": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fffadc811746fe2f22fb34633a88438017ea550ab443cc910e7cbf475d7dc63b"}}, "hash": "0a2f59ea27311a32ad56d084a3be200770019b17d456bc5d7d718c330ebf0e7d", "text": "43 SECTION 4 NERVOUS SYSTEM\n548substances are released locally in inflammation (see Chs \n16\tand\t18).\nIn summary, nociceptive nerve endings can be activated \nor sensitised by a wide variety of endogenous mediators, \nthe receptors for which are often up- or down-regulated \nunder pathophysiological conditions.B1 and B 2 receptors have been developed, such as the B 2 antagonist \nicatibant, \tused\tin\tthe \ttreatment \tof \tangioedema \t(Ch. \t19), \tbut \tnone \t\nhave yet been developed as analgesic agents.\nProstaglandins\nProstaglandins do not themselves cause pain, but they strongly enhance the pain-producing effect of other agents \nsuch\tas\t5-HT \tor \tbradykinin \t(see \tFig. \t43.6). \tProstaglandins \t\nof\tthe\tE\tand \tF \tseries \tare \treleased \tin \tinflammation \t(Ch. \t18) \t\nand also during tissue ischaemia. Antagonists at EP 1 recep -\ntors decrease inflammatory hyperalgesia in animal models. \nProstaglandins sensitise nerve terminals to other agents, \npartly by inhibiting potassium channels and partly by facilitating \u2013 through second messenger-mediated phos-\nphorylation \treactions \t(see \tCh. \t3) \t\u2013 \tthe \tcation \tchannels \t\nopened by noxious agents. It is of interest that bradykinin itself causes prostaglandin release, and thus has a powerful \n\u2018self-sensitising\u2019 effect on nociceptive afferents. Other \neicosanoids, including prostacyclin, leukotrienes and the unstable hydroxyeicosatetraenoic acid (HETE) derivatives \n(Ch.\t18), \tmay \talso \tbe \timportant. \tThe \tanalgesic \teffects \tof \t\nNSAIDs (Ch. 27) result from inhibition of prostaglandin synthesis.\nOther peripheral mediators\nPro-inflammatory cytokines such as tumour necrosis factor- \u03b1 \n(TNF-\u03b1)\tand\tinterleukin-1 \u03b2\t(IL-1 \u03b2) (described in detail in \nCh. 27) are released from macrophages to activate and \nsensitise\tnociceptive \tneurons\t(see\tFig.\t43.3)\tand\tcontribute \t\nto persistent pain states.\nVarious metabolites and substances are released from \ndamaged or ischaemic cells, or inflamed tissues, including ATP, protons (produced by lactic acid), 5-HT, histamine and K\n+, many of which affect nociceptive nerve terminals.\nATP\texcites \tnociceptive \tnerve \tterminals \t(see \tFig. \t43.5) \t\nby acting on homomeric P2X 3 receptors or heteromeric \nP2X 2/P2X 3\treceptors \t(see\tCh.\t17),\tligand-gated \tion\tchannels \t\nthat are selectively expressed by these neurons. Down-regulation of P2X\n3 receptors, by antisense DNA, reduces \ninflammatory pain.3 Antagonists at this receptor were \ndeveloped as potential analgesic drugs. In a surprising \ndevelopment one such P2X 3 antagonist, gefapixant (formerly \nknown\tas\tAF-219),\thas\tbeen\tshown\tto\tbe\teffective\tin\ttreating\t\nrefractory \tcough \t(see \tCh. \t29). \tOther \tP2X \treceptors \t(P2X 4 \nand P2X 7) are expressed on microglia in the spinal cord; \nactivation results in the release of cytokines and chemokines that then act on neighbouring neurons to promote hyper -\nsensitivity. ATP and other purine mediators, such as \nadenosine, also play a role in the dorsal horn, and other \ntypes of purinoceptor may also be targeted by", "start_char_idx": 0, "end_char_idx": 3016, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5dbd025a-22cf-4a06-874e-906d8cd2bb50": {"__data__": {"id_": "5dbd025a-22cf-4a06-874e-906d8cd2bb50", "embedding": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87bf152e-d191-42e3-ab76-e4c9f59d29c0", "node_type": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59536570acd823c85dd20033b64d54244b21ea22d8f79a0868accaba3a4f0a16"}, "2": {"node_id": "b4262e83-781f-422d-ad79-5d1894fcb87d", "node_type": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a2f59ea27311a32ad56d084a3be200770019b17d456bc5d7d718c330ebf0e7d"}, "3": {"node_id": "958aa070-1ae9-462e-9414-00ea05ad8bf3", "node_type": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7cce7617eb9d1374c95bbfb13785a98b5b43a6d7503f8a055f6075741a63f180"}}, "hash": "fffadc811746fe2f22fb34633a88438017ea550ab443cc910e7cbf475d7dc63b", "text": "the dorsal horn, and other \ntypes of purinoceptor may also be targeted by analgesic \ndrugs in the future. In the periphery adenosine exerts dual effects \u2013 acting on A\n1 receptors it causes analgesia but on \nA2 receptors it does the opposite.\nLow pH excites nociceptive afferent neurons partly by \nopening proton-activated cation channels (acid-sensitive \nion\tchannels, \tASICs) \tand \tpartly \tby \tactivation \tof \tTRPV1 \t\n(see p. 547).\n5-HT causes excitation, but studies with antagonists \nsuggest that it plays at most a minor role. Histamine is also active but causes itching rather than pain. Both these \n3P2X3 knock-out mice are, in contrast, fairly normal in this respect, \npresumably because other mechanisms take over.Mechanisms of pain and \nnociception \n\u2022\tNociception \tis \tthe \tmechanism \twhereby \tnoxious \t\nperipheral stimuli are transmitted to the central nervous \nsystem. Pain is a subjective experience not always associated with nociception.\n\u2022\tPolymodal \tnociceptors \t(PMNs) \tare \tthe \tmain \ttype \tof \t\nperipheral sensory neuron that responds to noxious stimuli. The majority are non-myelinated C fibres whose endings respond to thermal, mechanical and \nchemical stimuli.\n\u2022\tChemical \tstimuli \tacting \ton \tPMNs \tto \tcause \tpain \tinclude \t\nbradykinin, protons, ATP and vanilloids (e.g. \ncapsaicin). PMNs are sensitised by prostaglandins, which explains the analgesic effect of aspirin-like \ndrugs, particularly in the presence of inflammation.\n\u2022\tThe\tTRPV1 \treceptor \tresponds \tto \tnoxious \theat \tas \twell \t\nas to capsaicin-like agonists.\n\u2022\tNociceptive \tfibres \tterminate \tin \tthe \tsuperficial \tlayers \tof \t\nthe dorsal horn, forming synaptic connections with transmission neurons running to the thalamus.\n\u2022\tPMN\tneurons \trelease \tglutamate \t(fast \ttransmitter) \tand \t\nvarious peptides that act as slow transmitters. Peptides are also released peripherally and contribute to neurogenic inflammation.\n\u2022\tNeuropathic \tpain, \tassociated \twith \tdamage \tto \tneurons \t\nof the nociceptive pathway rather than an excessive peripheral stimulus, is frequently a component of chronic pain states and may respond poorly to opioid \nanalgesics.\nANALGESIC DRUGS\nOPIOID DRUGS\nOpium is an extract of the juice of the poppy Papaver \nsomniferum that contains morphine, the prototypic opioid \nagonist, and other related alkaloids. It has been used for \nsocial and medicinal purposes for thousands of years as an agent to produce euphoria, analgesia and sleep, and to \nprevent diarrhoea. It was introduced in Britain at the end \nof\tthe\t17th \tcentury, \tusually \ttaken \torally \tas \t\u2018tincture \tof \t\nlaudanum\u2019, addiction to which acquired a certain social \ncachet\tduring \tthe \tnext \t200 \tyears. \tThe \tsituation \tchanged \t\nwhen the hypodermic syringe and needle were invented \nin\tthe\tmid-19th \tcentury, \tand \topioid \tdependence \tbegan \tto \t\ntake\ton\ta \tmore \tsinister \tsignificance \t(see \tCh. \t50).\nThe history of opioid research is reviewed by Corbett \net\tal.\t(2006).\nCHEMICAL ASPECTS\nThe\tstructure \tof \tmorphine \t(Fig. \t43.7) \twas \tdetermined \tin \t\n1902,\tand\tsince\tthen\tmany\tsemisynthetic", "start_char_idx": 2956, "end_char_idx": 6023, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "958aa070-1ae9-462e-9414-00ea05ad8bf3": {"__data__": {"id_": "958aa070-1ae9-462e-9414-00ea05ad8bf3", "embedding": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87bf152e-d191-42e3-ab76-e4c9f59d29c0", "node_type": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59536570acd823c85dd20033b64d54244b21ea22d8f79a0868accaba3a4f0a16"}, "2": {"node_id": "5dbd025a-22cf-4a06-874e-906d8cd2bb50", "node_type": null, "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fffadc811746fe2f22fb34633a88438017ea550ab443cc910e7cbf475d7dc63b"}}, "hash": "7cce7617eb9d1374c95bbfb13785a98b5b43a6d7503f8a055f6075741a63f180", "text": "\tin \t\n1902,\tand\tsince\tthen\tmany\tsemisynthetic \tcompounds \t(some\tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6039, "end_char_idx": 6582, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "18716294-2fd0-4d07-8124-08ad1eb853cf": {"__data__": {"id_": "18716294-2fd0-4d07-8124-08ad1eb853cf", "embedding": null, "metadata": {"page_label": "555", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b6e878e1-0466-424f-8b74-11d293349df3", "node_type": null, "metadata": {"page_label": "555", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b9d0429b099694e4966342be0bc9159e63b5281df00a57aa6148792160690301"}, "3": {"node_id": "a27fdab2-1406-4b49-8f34-0ac90f97ee50", "node_type": null, "metadata": {"page_label": "555", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d9b96827cacc6432863914c6e833766177c55027b4547d95d8fbe1beb49a1597"}}, "hash": "23b95f3b89e70c3b3cbca5b4dc975d8845be17266da42c39610c1db7fdd244fd", "text": "43 ANAlgESic dRUgS\n549binding (see Ch. 2) was used to demonstrate the presence \nof \u00b5 receptors in the brain.\nWhy are there specific receptors in the brain for morphine, \na drug that is present in the opium poppy? Hughes and Kosterlitz argued that there must be an endogenous sub -\nstance or substances in the brain that activated these receptors.\n6\tIn\t1975\tthey \treported \tthe \tisolation \tand \tcharac -\nterisation of the first endogenous ligands, the enkephalins. \nWe now know that the enkephalins are only two members of a larger family of endogenous opioid peptides known collectively as the endorphins , all of which possess a tyrosine \nresidue at their N-terminus. The chemical structure of tyrosine includes an amine group separated from a phenol ring by two carbon atoms. This same structure (phenol-2 \ncarbon atom chain-amine) is also contained within the produced by chemical modification of morphine) and fully \nsynthetic opioids have been developed in attempts to develop better analgesic drugs devoid of the unwanted side effects of morphine.\nMorphine \tis\ta\tphenanthrene \tderivative \twith\ttwo\tplanar\t\nrings and two aliphatic ring structures, which occupy a plane roughly at right-angles to the rest of the molecule \n(see\tFig.\t43.7). \tThe \tmost \timportant \tparts \tof \tthe \tmolecule \t\nfor opioid activity are the free hydroxyl on the benzene ring that is linked by two carbon atoms to a nitrogen atom. \nVariants of the morphine molecule have been produced by \nsubstitution at one or both of the hydroxyls (e.g. diamor-\nphine\n4\t3,6-diacetylmorphine, \tcodeine\t3-methoxymorphine \t\nand oxycodone). Pethidine and fentanyl represent more \ndramatic changes to the basic morphine structure whereas \nmethadone and the novel opioid analgesics, oliceridine \nand PZM21, bear little obvious chemical relationship \nto morphine. Substitution of a bulky substituent on the nitrogen atom of morphine introduces antagonist activity \nto the molecule (e.g. naloxone).\nOPIOID RECEPTORS\nThe proposal that opioids produce analgesia and their other effects by interacting with specific receptors first arose in \nthe\t1950s,\tbased\ton\tthe\tstrict\tstructural \tand\tstereochemical \t\nrequirements essential for activity. It was, however, only with the development of molecules with antagonist activity \n(e.g. naloxone) that the notion of a specific receptor became \naccepted. \tMartin \tand \tco-workers \tthen \tprovided \tpharm -\nacological evidence for multiple types of opioid receptors. They proposed three different types of receptor, called \u00b5, \n\u03ba and \u03c3.\n5\tSubsequently, \tin \tthe \tearly \t1970s, \tradioligand \tHeroinCH3CO OOO\nCC H3CH3\nON\nMorphineHO OHO36CH3\nN\nNaloxoneHOOH\nOONCH2CH CH2\nFig. 43.7 Chemical structures of morphine and related drugs. The shaded area indicates the part of the morphine molecule that is \nstructurally similar to tyrosine, the N-terminal amino acid in the endorphins. Carbon atoms 3 and 6 in the morphine structure are indicated. \nDiamorphine (heroin) is 3,6-diacetylmorphine, and morphine is metabolised by addition of a glucuronide moiety at either position 3 or position 6. \nOpioid analgesics \n\u2022\tTerminology:\n\u2013 opioid: any substance, whether endogenous or \nsynthetic, that produces morphine-like effects that \nare blocked by antagonists such as naloxone;\n\u2013", "start_char_idx": 0, "end_char_idx": 3265, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a27fdab2-1406-4b49-8f34-0ac90f97ee50": {"__data__": {"id_": "a27fdab2-1406-4b49-8f34-0ac90f97ee50", "embedding": null, "metadata": {"page_label": "555", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b6e878e1-0466-424f-8b74-11d293349df3", "node_type": null, "metadata": {"page_label": "555", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b9d0429b099694e4966342be0bc9159e63b5281df00a57aa6148792160690301"}, "2": {"node_id": "18716294-2fd0-4d07-8124-08ad1eb853cf", "node_type": null, "metadata": {"page_label": "555", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23b95f3b89e70c3b3cbca5b4dc975d8845be17266da42c39610c1db7fdd244fd"}}, "hash": "d9b96827cacc6432863914c6e833766177c55027b4547d95d8fbe1beb49a1597", "text": "effects that \nare blocked by antagonists such as naloxone;\n\u2013 opiate: compounds such as morphine and \ncodeine that are found in the opium poppy;\n\u2013 narcotic analgesic : old term for opioids; narcotic \nrefers to their ability to induce sleep. Unfortunately, the term narcotic has subsequently been hijacked \nand used inappropriately by some to refer \ngenerically to drugs of abuse (see Ch. 50).\n\u2022\tImportant \tstructurally \trelated \tagonists \tinclude \t\ndiamorphine, oxycodone and codeine.\n\u2022\tSynthetic \tanalogues \tinclude \tpethidine, fentanyl, \nmethadone, buprenorphine.\n\u2022\tOpioid\tanalgesics \tmay \tbe \tgiven \torally, \tby \tinjection \tor \t\nintrathecally to produce analgesia.\n4While \u2018diamorphine\u2019 is the recommended International Nonproprietary \nName (rINN), this drug is widely known as heroin.\n5The \u03c3 \u2018receptor\u2019 is no longer considered to be an opioid receptor. It \nwas originally postulated in order to account for the dysphoric effects \n(anxiety, hallucinations, bad dreams, etc.) produced by some opioids. It \nis now accepted that these effects result from drug-induced block of the \nNMDA\treceptor \tchannel \tpore, \tan \teffect \tthat \tis \talso \tproduced \tby \tagents \t\nsuch as ketamine (see Ch. 42). Novel \u03c3 receptors \u2013 \u03c3 1 and \u03c3 2 subtypes \n\u2013 have now been cloned and characterized. They are not structurally \nrelated to other receptor types and little is known about their \nphysiological role, but they have been suggested as novel drug targets for psychiatric disorders.6It may seem obvious today that if there is a receptor then there is likely \nalso to be an endogenous ligand for that receptor but it was the search \nfor, and subsequent discovery of, the enkephalins that gave credence to \nthis idea.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3205, "end_char_idx": 5383, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ac0c1610-74ce-4fba-a746-567fa4c30581": {"__data__": {"id_": "ac0c1610-74ce-4fba-a746-567fa4c30581", "embedding": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a0a5f33a-36aa-49df-b54c-a619f70412ad", "node_type": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2152735a52e1c67ff79585254eeb061f7f22750662bc62eb38be5e916195376"}, "3": {"node_id": "dc946f53-77e2-4de2-97dd-fed95ea4a770", "node_type": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc73b1b88058cb84aa7dd82ec96e280def8cf1e8fc52a11ea96c3339df7489d7"}}, "hash": "fb374eb6c5dada257041fe84e393e61f5592565b89519f003c07b8cf4adbbe17", "text": "43 SECTION 4 NERVOUS SYSTEM\n550morphine \tstructure \t(see\tFig.\t43.7).\tIt\tis\tprobably \tjust\tchance\t\n(good or bad luck depending on one\u2019s viewpoint) that the \nopium poppy synthesises a semi-rigid alkaloid molecule, \nmorphine, part of which structurally resembles the tyrosine \nresidue in the endogenous opioid peptides.\nFollowing on from the discovery of the enkephalins, \npharmacological and ligand-binding studies revealed another receptor, \u03b4, and the three recognised receptor types \n(\u00b5, \u03b4 and \u03ba) were cloned. Later, another opioid receptor \n(ORL\n1) that had a high a degree of amino acid sequence \nhomology (> 60%)\ttowards \tthe \t\u00b5, \u03b4 and \u03ba opioid receptors \nwas identified by cloning techniques, although the antago -\nnist, naloxone, did not bind to this new receptor. The terminology used for opioid receptors has over the years been through several revisions; in this chapter we shall \nuse the classical terminology. The four opioid receptors, \n\u00b5, \u03b4, \u03ba and NOP (originally referred to as opioid receptor \nlike\treceptor\t1\tor\tORL1) are all G protein\u2013coupled receptors \n(see\tCh.\t3).7 The main behavioural effects resulting from \ntheir\tactivation \tare\tsummarised \tin\tTable\t43.2.\tThe\tinteraction \t\nof various endogenous opioid peptides with the various \nreceptor\ttypes \tis \tsummarised \tin \tTable \t43.3. \tSome \tagents \t\nthat are used as experimental tools for distinguishing the different receptor types are also shown.\nThe development of transgenic mouse strains lacking \neach of the three main opioid receptor types has revealed that the major pharmacological effects of morphine, includ -\ning analgesia, are mediated by the \u00b5 receptor.\nAll four opioid receptors appear to form homomeric as \nwell\tas\theteromeric \treceptor\tcomplexes \t(see\tCh.\t3).\tOpioid\t\nreceptors are, in fact, quite promiscuous and can form heteromers with non-opioid receptors. Heteromerisation \nbetween opioid receptors has been shown to result in \npharmacological characteristics distinct from those observed with the monomeric receptors and may explain some of \nthe subtypes of each receptor that have been proposed (see \nFujita\tet\tal., \t 2014). \t Another \t level \t of \t complexity \t may \t reflect\t\n\u2018bias\u2019\t(see \tCh. \t3), \twhereby \tdifferent \tligands \tacting \ton \tthe \t\nsame opioid receptor can elicit different cellular responses \nand\tdifferential \treceptor \ttrafficking \t(see \tKelly, \t2013).8\nMECHANISM OF ACTION OF OPIOIDS\nThe opioids have probably been studied more intensively \nthan any other group of drugs in the effort to understand \ntheir powerful effects in molecular, cellular and physiological \nterms, and to use this understanding to develop new drugs as analgesics with significant advantages over morphine. \nEven so, morphine \u2013 described by Osler as \u2018God\u2019s own \nmedicine\u2019 \u2013 remains the standard against which any new analgesic is assessed.\n7The opioid receptors are unusual among G protein\u2013coupled receptors. \nFirst,\tin\tthat \tthere \tare \tmany \t(20 \tor \tmore) \topioid \tpeptides \tbut \tonly \tfour \t\nreceptors. In contrast, 5-hydroxytryptamine (5-HT), for example, is a \nsingle\tmediator \tinteracting \twith \tmany \t(about \t14) \treceptors, \twhich \tis \tthe \t\nmore common pattern. Second, all four receptors couple to the same \ntypes of G protein", "start_char_idx": 0, "end_char_idx": 3225, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dc946f53-77e2-4de2-97dd-fed95ea4a770": {"__data__": {"id_": "dc946f53-77e2-4de2-97dd-fed95ea4a770", "embedding": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a0a5f33a-36aa-49df-b54c-a619f70412ad", "node_type": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2152735a52e1c67ff79585254eeb061f7f22750662bc62eb38be5e916195376"}, "2": {"node_id": "ac0c1610-74ce-4fba-a746-567fa4c30581", "node_type": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb374eb6c5dada257041fe84e393e61f5592565b89519f003c07b8cf4adbbe17"}, "3": {"node_id": "c7ee4aa8-479b-4ef8-8934-8c8215e73ae7", "node_type": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ba7cb86b1e7fb6de27e5a5648f59ccd2c6a3c6988f8e24e6e59f45514bc087a3"}}, "hash": "fc73b1b88058cb84aa7dd82ec96e280def8cf1e8fc52a11ea96c3339df7489d7", "text": "common pattern. Second, all four receptors couple to the same \ntypes of G protein (G i/G o) and therefore activate the same spectrum of \ncellular effector mechanisms. In contrast, other receptor families (e.g. \nmuscarinic receptors) couple to different types of G proteins and \ntherefore \tgive \trise \tto \tdifferent \tcellular \tresponses \t(see \tCh. \t14).\n8Claims have been made recently that \u2018G protein biased\u2019 \u00b5 opioid \nreceptor ligands will show a reduced side-effect profile in comparison to morphine which is \u2018unbiased\u2019, but time will tell if this is indeed true.Table 43.2 Functional effects associated with the main \ntypes of opioid receptor\nReceptor \u00b5 \u03b4 \u03ba NOP\nAnalgesia\n Supraspinal +++ \u2014? \u2014 Anti-opioida\n Spinal ++ ++ + ++\n Peripheral ++ \u2014 ++ \u2014\nRespiratory \ndepression+++ ++ \u2014 \u2014\nPupil constriction ++ \u2014 + \u2014\nReduced gastrointestinal motility++ ++ + \u2014\nEuphoria +++ \u2014 \u2014 \u2014\nDysphoria and hallucinations\u2014 \u2014 +++ \u2014\nSedation ++ \u2014 ++ \u2014\nCatatonia \u2014 \u2014 \u2014 ++\nPhysical dependence+++ \u2014 \u2014 \u2014\naNOP receptor agonists were originally thought to produce \nnociception or hyperalgesia but it was later shown that they reverse the supraspinal analgesic effects of endogenous and exogenous \u00b5 receptor agonists.\nCellular actions\nAll four types of opioid receptor belong to the family \nof G i/G o protein\u2013coupled receptors. Opioids thus exert \npowerful effects on ion channels on neuronal membranes \nthrough a direct G protein coupling to the channel. Opioids \npromote the opening of potassium channels (see Ch. 4) and inhibit the opening of voltage-gated calcium channels. \nThese membrane effects decrease neuronal excitability \n(because the increased K\n+ conductance causes hyperpo-\nlarisation of the membrane making the cell less likely to \nfire action potentials) and reduce transmitter release (due \nto inhibition of Ca2+ entry). The overall effect is therefore \ninhibitory at the cellular level. Nonetheless, opioids do \nincrease activity in some neuronal pathways (see p. 545, \nFig.\t43.4). \tThey \tcause \texcitation \tof \tprojection \tneurons \t\nby suppressing the activity of inhibitory interneurons \nthat\ttonically \tinhibit \tthe \tprojection \tneurons \t(see \tCh. \t38, \t \nFig.\t38.2).\nAt the biochemical level, all four receptor types inhibit \nadenylyl \tcyclase \tand \tcause \tMAP \tkinase \t(ERK) \tactivation \t\n(see\tCh.\t3).\tThese\tcellular\tresponses \tare\tlikely\tto\tbe\timpor -\ntant in mediating the long-term adaptive changes that occur in response to prolonged receptor activation and which, \nfor \u00b5 receptor agonists, may underlie the phenomenon of \nphysical\tdependence \t(see \tCh. \t50).\nAt the cellular level, therefore, all four types of opioid \nreceptor mediate very similar effects. It is their heterogeneous \nanatomical distributions across the CNS that give rise to \nthe different behavioural responses seen with selective agonists for each type of receptor.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3158, "end_char_idx": 6460, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c7ee4aa8-479b-4ef8-8934-8c8215e73ae7": {"__data__": {"id_": "c7ee4aa8-479b-4ef8-8934-8c8215e73ae7", "embedding": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a0a5f33a-36aa-49df-b54c-a619f70412ad", "node_type": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2152735a52e1c67ff79585254eeb061f7f22750662bc62eb38be5e916195376"}, "2": {"node_id": "dc946f53-77e2-4de2-97dd-fed95ea4a770", "node_type": null, "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fc73b1b88058cb84aa7dd82ec96e280def8cf1e8fc52a11ea96c3339df7489d7"}}, "hash": "ba7cb86b1e7fb6de27e5a5648f59ccd2c6a3c6988f8e24e6e59f45514bc087a3", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6481, "end_char_idx": 6544, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9d58108d-e823-41eb-a57d-f85ed029a3f5": {"__data__": {"id_": "9d58108d-e823-41eb-a57d-f85ed029a3f5", "embedding": null, "metadata": {"page_label": "557", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b8d83a0c-2327-41aa-914d-db6c59ce53c8", "node_type": null, "metadata": {"page_label": "557", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4adda8fc6669ebd8bc3c67c07f65cdc71895cfd61ebb455de42e4e1ab466e6f"}, "3": {"node_id": "8cee13f3-b563-46c5-8bc3-126814b170fe", "node_type": null, "metadata": {"page_label": "557", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7b833ef263efe7a48a282518dbeda2aabcf0001fb94353514f795adb08b88ef6"}}, "hash": "186848e07618b20ea025e1b3cccb806dda44e61d3388a5dde411bb93149e08f9", "text": "43 ANAlgESic dRUgS\n551There\tis\talso \tevidence \t(see \tSawynok, \t2003) \tthat \topioids \t\ninhibit the discharge of nociceptive afferent terminals in \nthe periphery, particularly under conditions of inflammation, \nin which the expression of opioid receptors by sensory \nneurons is increased. Injection of morphine into the knee joint following surgery to the joint provides effective \nanalgesia, undermining the age-old belief that opioid \nanalgesia is exclusively a central phenomenon.\nPHARMACOLOGICAL ACTIONS\nMorphine \ti s \tt ypical\to f \tm any\to pioid\ta nalgesics \ta nd\tw ill\tb e \t\ntaken as the reference compound. Its effects are mediated predominately through \u00b5 receptors.\nThe most important effects of morphine are on the CNS \nand the gastrointestinal tract, although numerous effects of lesser significance on many other systems have been \ndescribed.\nEffects on the CNS\nAnalgesia\nMorphine \tand \tother \topioids \tare \thighly \teffective \tin \tmost \t\nkinds of acute pain as well as in \u2018end of life\u2019 pain resulting \nfrom cancer. They are less effective in treating neuropathic \nand other chronic pain states.\nHyperalgesia\nIn both animal studies and in patients receiving opioids \nfor pain relief, prolonged exposure to opioids may paradoxi -\ncally induce a state of hyperalgesia in which pain sensitisa -\ntion\tor\tallodynia \toccurs\t(see\tLee\tet\tal., \t 2011). \t This \t can \t appear\t\nas a reduced analgesic response to a given dose of opioid Sites of action of opioids to produce analgesia\nOpioid receptors are widely distributed in the brain and \nspinal cord. Opioids are effective as analgesics when injected in minute doses into a number of specific brain nuclei (such \nas the insular cortex, amygdala, hypothalamus, PAG region \nand\tRVM)\tas\twell\tas\tinto\tthe\tdorsal\thorn\tof\tthe\tspinal\tcord\t\n(see\tFig.\t43.4).\tThere\tis\tevidence \tto\tsuggest\tthat\tsupraspinal \t\nopioid analgesia involves endogenous opioid peptide release \nboth at supraspinal and spinal sites and that at the spinal \nlevel there is also a component of the analgesia that results \nfrom the release of serotonin (5-HT) from descending inhibitory fibres. Surgical interruption of the descending \npathway \tfrom\tthe\tRVM\tto\tthe\tspinal\tcord\treduces\tanalgesia \t\ninduced by morphine that has been given systemically or microinjected into supraspinal sites, implying that a com-\nbination of effects at supraspinal and spinal sites contribute \nto the analgesic response.\nAt the spinal level, morphine inhibits transmission \nof nociceptive impulses through the dorsal horn and suppresses nociceptive spinal reflexes, even in patients with spinal cord transection. It can act presynaptically to \ninhibit release of various neurotransmitters from primary \nafferent terminals in the dorsal horn as well as acting postsynaptically to reduce the excitability of dorsal horn \nneurons.Opioid receptors \n\u2022\t\u00b5 Receptors are responsible for most of the analgesic \neffects of opioids, and for some major unwanted effects (e.g. respiratory depression, constipation, \neuphoria, sedation and dependence).\n\u2022\t\u03b4 Receptor activation results in analgesia but also can \nbe proconvulsant.\n\u2022\t\u03ba Receptors contribute to analgesia at the spinal level \nand may elicit sedation, dysphoria and", "start_char_idx": 0, "end_char_idx": 3208, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8cee13f3-b563-46c5-8bc3-126814b170fe": {"__data__": {"id_": "8cee13f3-b563-46c5-8bc3-126814b170fe", "embedding": null, "metadata": {"page_label": "557", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b8d83a0c-2327-41aa-914d-db6c59ce53c8", "node_type": null, "metadata": {"page_label": "557", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4adda8fc6669ebd8bc3c67c07f65cdc71895cfd61ebb455de42e4e1ab466e6f"}, "2": {"node_id": "9d58108d-e823-41eb-a57d-f85ed029a3f5", "node_type": null, "metadata": {"page_label": "557", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "186848e07618b20ea025e1b3cccb806dda44e61d3388a5dde411bb93149e08f9"}}, "hash": "7b833ef263efe7a48a282518dbeda2aabcf0001fb94353514f795adb08b88ef6", "text": "at the spinal level \nand may elicit sedation, dysphoria and hallucinations. \nSome analgesics are mixed \u03ba agonists/ \u00b5 antagonists.\n\u2022\tNOP\treceptors \tare \talso \tmembers \tof \tthe \topioid-\nreceptor family. Activation results in an antiopioid effect (supraspinal), analgesia (spinal), immobility and impairment of learning.\n\u2022\t\u03c3 Receptors are not true opioid receptors but are the site of action of certain psychotomimetic drugs, with which some opioids also interact.\n\u2022\tAll\topioid \treceptors \tare \tlinked \tthrough \tGi/Go proteins \nand thus open potassium channels (causing hyperpolarisation) and inhibit the opening of calcium \nchannels (inhibiting transmitter release). In addition, \nthey inhibit adenylyl cyclase and activate the MAP kinase (ERK) pathway.\n\u2022\tFunctional \theteromers, \tformed \tby \tcombination \tof \t\ndifferent types of opioid receptor or with other types of G protein\u2013coupled receptor, may occur and give rise to further pharmacological diversity.Table 43.3 Endogenous opioid peptides and receptor-\nselective drugs\n\u00b5 \u03b4 \u03ba NOP\nEndogenous peptides\n\u03b2-Endorphin +++ +++ + \u2212\nLeu-enkephalin (++) +++ + \u2212\nMet-enkephalin ++ +++ + \u2212\nDynorphin + + +++ \u2212\nOrphanin FQ/nociceptina\u2212 \u2212 \u2212 +++\nResearch tools\nAGONISTS\nDAMGOb+++ \u2212 \u2212 \u2212\nDPDPEb\u2212 ++ \u2212 \u2212\nEnadoline \u2212 \u2212 +++ \u2212\nRo64-6198 \u2212 \u2212 \u2212 +++\nAntagonistsCTOP\nb+++ \u2212 \u2212 \u2212\nNaltrindole \u2212 +++ + \u2212\nNor-binaltorphimine + + +++ \u2212\nSB 612111 \u2212 \u2212 \u2212 +++\nNote: + symbols represent agonist or antagonist activity; partial \nagonists in parentheses; \u2212 symbols represent weak or no \nactivity.\naThe endogenous ligand for the NOP receptor is referred to in \nthe literature both as orphanin FQ and as nociceptin.\nbDAMGO, DPDPE and CTOP are synthetic peptides.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3149, "end_char_idx": 5305, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "453fed39-d183-4baa-981d-cf61a05b5fd5": {"__data__": {"id_": "453fed39-d183-4baa-981d-cf61a05b5fd5", "embedding": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6a62aeb6-3715-429b-b810-e369669062f7", "node_type": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42cc5ea5a832c46e6d5bb141b110cc50ea4c08da961eda936435316c1980db62"}, "3": {"node_id": "7fef0404-fc81-4e03-9f05-bd85749803d8", "node_type": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9fe5d977c0c391df4450fa80c2b0086ac5f3d74bb199a0794af85481c35071c8"}}, "hash": "8ed441b352b235691d324e87da20bd4aa9c359a78ae26296a8df8d6666728b42", "text": "43 SECTION 4 NERVOUS SYSTEM\n552cardiovascular function (in contrast to the action of general \nanaesthetics and other CNS depressants). This means that \nrespiratory depression produced by opioids is much better \ntolerated than a similar degree of depression caused by, say, a barbiturate. Nonetheless, respiratory depression is \na dangerous unwanted effect of these drugs and, unlike \nthat due to general CNS depressant drugs, it occurs at therapeutic doses. It is the commonest cause of death in \nacute opioid poisoning.\nDepression of cough reflex\nCough\tsuppression \t(antitussive \teffect; \tsee \talso \tCh. \t29), \t\nsurprisingly, does not correlate closely with the analgesic \nand respiratory depressant actions of opioids, and its \nmechanism at the receptor level is unclear. In general, \nincreasing substitution on the phenolic hydroxyl group of morphine increases antitussive relative to analgesic activity. \nCodeine and pholcodine suppress cough in subanalgesic \ndoses but they cause constipation as an unwanted effect.\n\u25bc Dextromethorphan, the dextro-isomer of the opioid analgesic \nlevorphanol, suppresses cough but has very low affinity for opioid \nreceptors and its cough suppressing action, unlike that of opioids, is \nnot\tantagonised \tby\tnaloxone. \tIt\tis\tan\tuncompetitive \tNMDA\treceptor\t\nantagonist \u2013 this might explain why at high doses it evokes CNS \neffects similar to ketamine and may be abused \u2013 and has putative \nactions at \u03c3 receptors. It is believed to work at various sites in the \nbrain stem and medulla to suppress cough. In addition to its antitussive \naction,\tdextromethorphan \tis\tneuroprotective \t(see\tCh.\t41)\tand\thas\tan\t\nanalgesic action in neuropathic pain.\nNausea and vomiting\nNausea\tand \tvomiting \toccur \tin \tup \tto \t40% \tof \tpatients \tto \t\nwhom morphine is given, and do not seem to be separable \nfrom the analgesic effect among a range of opioid analgesics. \nThe site of action is the area postrema (chemoreceptor trigger \nzone), a region of the medulla where chemical stimuli of \nmany\tkinds \tmay \tinitiate \tvomiting \t(see \tCh. \t31).9 Nausea \nand vomiting following morphine injection are usually transient and disappear with repeated administration, \nalthough in some individuals they persist and can limit patient compliance.\nPupillary constriction\nPupillary constriction is caused by \u00b5 and \u03ba receptor-\nmediated stimulation of the oculomotor nucleus. Pinpoint pupils are an important diagnostic feature in opioid poison -\ning,\n10 because most other causes of coma and respiratory \ndepression produce pupillary dilatation. Tolerance does \nnot develop to the pupillary constriction induced by \nopioids and therefore can be observed in opioid-dependent drug users who may have been taking opioids for a \nconsiderable time.\nEffects on the gastrointestinal tract\nOpioids increase tone and reduce motility in many parts of the gastrointestinal system, resulting in constipation, \nwhich may be severe and very troublesome to the patient.\n11 but should not be confused with tolerance, which is a \nreduced responsiveness due in large part to \u00b5 receptor \ndesensitisation \t(see \tp. \t553) \tand \toccurs \twith \tother \topioid-\ninduced effects such as euphoria and to a lesser extent respiratory depression. Hyperalgesia appears to have \nperipheral, spinal and supraspinal components. At the \nneuronal level, an array of mediators and mechanisms have been proposed to", "start_char_idx": 0, "end_char_idx": 3384, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7fef0404-fc81-4e03-9f05-bd85749803d8": {"__data__": {"id_": "7fef0404-fc81-4e03-9f05-bd85749803d8", "embedding": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6a62aeb6-3715-429b-b810-e369669062f7", "node_type": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42cc5ea5a832c46e6d5bb141b110cc50ea4c08da961eda936435316c1980db62"}, "2": {"node_id": "453fed39-d183-4baa-981d-cf61a05b5fd5", "node_type": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8ed441b352b235691d324e87da20bd4aa9c359a78ae26296a8df8d6666728b42"}, "3": {"node_id": "28d88afd-196e-4bd5-96e1-221041702a36", "node_type": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1db8634b5bc46a6af9b0688c1442580c561e79d7157e8864374324cedc29428c"}}, "hash": "9fe5d977c0c391df4450fa80c2b0086ac5f3d74bb199a0794af85481c35071c8", "text": "\nneuronal level, an array of mediators and mechanisms have been proposed to contribute to this phenomenon (Roeckel \net\tal.,\t2016). \tThese \tinclude \tNO, \tPKC \tand \tNMDA \treceptor \t\nactivation. In addition, P2X 4 receptor expression in microglia \nis up-regulated resulting in BDNF release, TrkB signalling \nand down-regulation of the K+/Cl\u2212 co-transporter KCC2. \nIn mice in which BDNF has been deleted from microglia, hyperalgesia to morphine does not occur, whereas antino -\nciception and tolerance are unaffected. Opioid-induced \nhyperalgesia \tcan \tbe \treduced \tby \tketamine \t(an \tNMDA \t\nantagonist), propofol (an intravenous anaesthetic), \u03b12-\nadrenoceptor agonists and COX-2 inhibitors. Switching to another opioid can also reduce hyperalgesia; in this regard, \nmethadone \tmay \tbe \ta \tgood \tchoice \tas \tit \tis \ta \tweak \tNMDA-\nreceptor antagonist.\nEuphoria\nMorphine \tcauses \ta \tpowerful \tsense \tof \tcontentment \tand \t\nwell-being \t(see \talso \tCh. \t50). \tThis \tmay \tcontribute \tto \tits \t\nanalgesic effect. If morphine or diamorphine (heroin) is given \nintravenously, the result is a sudden \u2018rush\u2019 likened to an \n\u2018abdominal orgasm\u2019. The euphoria produced by morphine \ndepends considerably on the circumstances. In patients who are distressed, it is pronounced, but in patients who become \naccustomed to chronic pain, morphine causes analgesia \nwith little or no euphoria. Some patients report restlessness rather than euphoria under these circumstances.\nEuphoria is mediated through \u00b5 receptors, whereas \u03ba \nreceptor activation produces dysphoria and hallucinations \n(see\tTable \t43.2). \tThus, \tdifferent \topioid \tdrugs \tvary \tgreatly \t\nin the amount of euphoria that they produce. It does not occur with codeine to any marked extent. There is evidence \nthat antagonists at the \u03ba receptor have antidepressant \nproperties which may indicate that release of endogenous \n\u03ba agonists may occur in depression.\nRespiratory depression\nRespiratory depression, resulting in increased arterial P\nCO 2, \noccurs with a normal analgesic dose of morphine or related \ncompounds, although in patients in severe pain the degree \nof respiratory depression produced may be less than anticipated. Respiratory depression is mediated by \u00b5 recep-\ntors. The depressant effect is associated with a decrease in the sensitivity of the respiratory centres to arterial P\nCO 2 \nand an inhibition of respiratory rhythm generation. Changes \nin PCO 2 are detected by chemosensitive neurons in a number \nof brain stem and medullary nuclei. Increased arterial CO 2 \n(hypercapnia) thus normally results in a compensatory increase in minute ventilation rate ( V\nE). In some of the \nchemosensitive regions, opioids exert a depressant effect on the hypercapnic response, making the increase in V\nE \ninsufficient to counteract the increased CO 2. Respiratory \nmovements originate from activity of a rhythm generator (the pre-B\u00f6tzinger complex) within the ventral respiratory \ncolumn of the medulla. \u00b5 opioid receptors are located in \nthis region, and local injection of opioid agonists decreases \nrespiratory frequency.\nRespiratory depression by opioids is not accompanied \nby depression of the medullary centres controlling 9The chemically related compound apomorphine is more strongly \nemetic than morphine, through its action as a dopamine agonist; despite \nits name, it is inactive on opioid receptors.\n10The exception is pethidine, which causes", "start_char_idx": 3321, "end_char_idx": 6726, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "28d88afd-196e-4bd5-96e1-221041702a36": {"__data__": {"id_": "28d88afd-196e-4bd5-96e1-221041702a36", "embedding": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6a62aeb6-3715-429b-b810-e369669062f7", "node_type": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42cc5ea5a832c46e6d5bb141b110cc50ea4c08da961eda936435316c1980db62"}, "2": {"node_id": "7fef0404-fc81-4e03-9f05-bd85749803d8", "node_type": null, "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9fe5d977c0c391df4450fa80c2b0086ac5f3d74bb199a0794af85481c35071c8"}}, "hash": "1db8634b5bc46a6af9b0688c1442580c561e79d7157e8864374324cedc29428c", "text": "opioid receptors.\n10The exception is pethidine, which causes pupillary dilatation because \nit blocks muscarinic receptors.\n11In treating pain, constipation is regarded as an undesirable side effect. \nHowever, opiates such as codeine and morphine can be used to treat diarrhoea.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6730, "end_char_idx": 7486, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9cf0e609-bf63-4f38-b58f-3b33b22a641e": {"__data__": {"id_": "9cf0e609-bf63-4f38-b58f-3b33b22a641e", "embedding": null, "metadata": {"page_label": "559", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "46918be8-509e-4e60-8e08-aec8235b451b", "node_type": null, "metadata": {"page_label": "559", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4adc6ef1d077e19aa44518be4dadcd81fd2622fdbf2821e2d9149abb0813b8aa"}, "3": {"node_id": "3c314be2-808c-4a58-b179-448bf5e6a392", "node_type": null, "metadata": {"page_label": "559", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fee02329932ec5e5f41ada1c2892b6d6ea44bdc6659dc0e9f5a4f8a4708dc0ff"}}, "hash": "fe1f2db462ff31950b042504f157990fce20cbe8b9dc277e0af123c6e39a4021", "text": "43 ANAlgESic dRUgS\n553opioids are administered for more than a few days. They \nmust\tnot\tbe\tconfused \twith\taddiction \t(see\tCh.\t50),\tin\twhich\t\nphysical dependence is much more pronounced and \npsychological dependence (or \u2018craving\u2019) is the main driving \nforce.\nTolerance\nIn animal experiments, tolerance can be detected even with \na single dose of morphine. Tolerance extends to most of \nthe pharmacological effects of morphine, including analgesia, \nemesis, euphoria and respiratory depression, but affects the constipating and pupil-constricting actions much less. \nTherefore, \taddicts\tmay\ttake\t50\ttimes\tthe\tnormal\tanalgesic \t\ndose of morphine with relatively little respiratory depression but marked constipation and pupillary constriction.\nThe cellular mechanisms responsible for tolerance are \ndiscussed in Chapter 2. Tolerance results in part from desensitisation of the \u00b5 receptors (i.e. at the level of the \ndrug target) as well as from long-term adaptive changes at the cellular, synaptic and network levels (see Williams \net\tal.,\t2013). \tTolerance \tis \ta \tgeneral \tphenomenon \tof \topioid \t\nreceptor ligands, irrespective of which type of receptor they act on. Cross-tolerance occurs between drugs acting \nat the same receptor, but not between opioids that act on \ndifferent receptors. In clinical settings, the opioid dose required for effective pain relief may increase as a result \nof developing tolerance, but it does not constitute a major \nproblem.\nPhysical dependence\nPhysical dependence is characterised by a clear-cut absti -\nnence syndrome. In experimental animals (e.g. rats), abrupt \nwithdrawal of morphine after repeated administration for \na few days, or the administration of an antagonist such as naloxone, causes an increased irritability, diarrhoea, loss \nof weight and a variety of abnormal behaviour patterns, \nsuch as body shakes, writhing, jumping and signs of aggres -\nsion. These reactions decrease after a few days, but abnormal \nirritability and aggression persist for many weeks. The signs The resulting delay in gastric emptying can considerably retard the absorption of other drugs. Pressure in the biliary \ntract increases because of contraction of the gall bladder and constriction of the biliary sphincter. Opioids should \nbe avoided in patients suffering from biliary colic due to \ngallstones, in whom pain may be increased rather than relieved. The rise in intrabiliary pressure can cause a \ntransient increase in the concentration of amylase and lipase \nin the plasma.\nThe action of morphine on visceral smooth muscle is \nprobably mediated mainly through the intramural nerve \nplexuses, because the increase in tone is reduced or abolished \nby atropine. It is also partly mediated by a central action, because intracerebroventricular injection of morphine \ninhibits propulsive gastrointestinal movements. Methylnal -\ntrexone bromide\n\t( see\ta lso \tC h. \t9 )\talvimopan and naloxegol \nare opioid antagonists that do not cross the blood\u2013brain barrier. They have been developed to reduce unwanted \nperipheral side effects of opioids, such as constipation, without significantly reducing analgesia or precipitating \nwithdrawal in dependent individuals.\nOther actions of opioids\nMorphine \treleases \thistamine \tfrom \tmast \tcells \tby \tan \taction \t\nunrelated to opioid receptors. Pethidine and fentanyl do \nnot produce this effect. The release of histamine can cause \nlocal effects, such as urticaria and itching at the site of the \ninjection, or systemic effects, namely bronchoconstriction and hypotension.\nHypotension and bradycardia", "start_char_idx": 0, "end_char_idx": 3569, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3c314be2-808c-4a58-b179-448bf5e6a392": {"__data__": {"id_": "3c314be2-808c-4a58-b179-448bf5e6a392", "embedding": null, "metadata": {"page_label": "559", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "46918be8-509e-4e60-8e08-aec8235b451b", "node_type": null, "metadata": {"page_label": "559", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4adc6ef1d077e19aa44518be4dadcd81fd2622fdbf2821e2d9149abb0813b8aa"}, "2": {"node_id": "9cf0e609-bf63-4f38-b58f-3b33b22a641e", "node_type": null, "metadata": {"page_label": "559", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe1f2db462ff31950b042504f157990fce20cbe8b9dc277e0af123c6e39a4021"}}, "hash": "fee02329932ec5e5f41ada1c2892b6d6ea44bdc6659dc0e9f5a4f8a4708dc0ff", "text": "bronchoconstriction and hypotension.\nHypotension and bradycardia occur with large doses of \nmost opioids, due to an action on the medulla. With morphine and similar drugs, histamine release may con -\ntribute to the hypotension.\nEffects on smooth muscle other than that of the \ngastrointestinal tract and bronchi are slight, although spasms of the ureters, bladder and uterus sometimes occur. Opioids \nalso exert complex immunosuppressant effects, which may \nbe important as a link between the nervous system and immune function. The pharmacological significance of this \nis not yet clear, but there is evidence in humans that the \nimmune system is depressed by long-term opioid use, and that in addicts suffering from AIDS the use of opioids may \nexacerbate the immune deficiency.\nTOLERANCE AND DEPENDENCE\nTolerance to many of the actions of opioids (i.e. an increase \nin the dose needed to produce a given pharmacological effect) develops within a few days during repeated admin -\nistration. There is some controversy over whether significant \ntolerance develops to the analgesic effects of morphine, \nespecially in palliative care patients with severe cancer pain \n(see\tMcQuay, \t1999;\tBallantyne \t&\tMao,\t2003).\tDrug\trotation\t\n(changing from one opioid to another) is frequently used \nclinically to overcome loss of effectiveness. As tolerance is \nlikely to depend upon the level of receptor occupancy, the \ndegree of tolerance observed may reflect the response being assessed (e.g. analgesia versus respiratory depression), the \nintrinsic efficacy of the drug and the dose being administered \n(see\tHayhurst \t& \tDurieaux, \t2016).\nPhysical dependence refers to a state in which withdrawal \nof the drug causes adverse physiological effects, i.e. the abstinence syndrome.\nDifferent adaptive cellular mechanisms underlie tolerance \nand\tdependence \t(see \tWilliams \tet \tal., \t2013; \tsee \talso \tChs \t2 \t\nand\t50).\tThese\tphenomena \toccur\tto\tsome\tdegree\twhenever \tActions of morphine \n\u2022\tThe\tmain \tpharmacological \teffects \tare:\n\u2013 analgesia\n\u2013 euphoria and sedation\n\u2013 respiratory depression\n\u2013 suppression of cough\n\u2013 nausea and vomiting\n\u2013 pupillary constriction\n\u2013 reduced gastrointestinal motility, causing \nconstipation\n\u2013 histamine release, causing itch, bronchoconstriction \nand hypotension\n\u2022\tThe\tmost \ttroublesome \tunwanted \teffects \tare \tnausea \t\nand vomiting, constipation and respiratory depression.\n\u2022\tAcute\toverdosage \twith \tmorphine produces coma and \nrespiratory depression.\n\u2022\tDiamorphine (heroin) is inactive at opioid receptors \nbut is rapidly cleaved in the brain to 6-acetylmorphine \nand morphine.\n\u2022\tCodeine is also converted to morphine but more \nslowly by liver metabolism.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3505, "end_char_idx": 6662, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "67e8fea8-f933-499e-88ad-6eb3299effd6": {"__data__": {"id_": "67e8fea8-f933-499e-88ad-6eb3299effd6", "embedding": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "658f80f4-c2bb-4d41-8c41-19bbe55ee16d", "node_type": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3bf3866da4ff56bf9d08dd1e332eb52b12d0e60f0a4267924c432e015f143e4"}, "3": {"node_id": "0bea631a-877a-4179-abbe-83e9f2689ffb", "node_type": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "453625fa69e3dbb844add662b6f4b23f85db93a2074a4f235856edca162d4790"}}, "hash": "f3f2837f87e233f9c19ebd019be60141b5380db849701e6b02f470db0eac0a47", "text": "43 SECTION 4 NERVOUS SYSTEM\n554The plasma half-life of most morphine analogues is \n3\u20136\th.\tHepatic \t metabolism \t is \t the \t main \t mode \t of \t inactivation, \t\nusually by conjugation with glucuronide. This occurs at \nthe\t3-\tand \t6-OH \tgroups \t(see \tFig. \t43.7), \tand \tthese \tglucuro -\nnides constitute a considerable fraction of the drug in the \nbloodstream. \tMorphine-6-glucuronide \tis \tmore \tactive \tas \t\nan analgesic than morphine itself, and contributes to the \npharmacological \teffect.\tMorphine-3-glucuronide \thas\t been \t\nclaimed to antagonise the analgesic effect of morphine, but \nthe significance of this experimental finding is uncertain, as \nthis metabolite has little or no affinity for opioid receptors. \nMorphine \tglucuronides \tare\texcreted\tin\tthe\turine,\tso\tthe\tdose\t\nneeds to be reduced in cases of renal failure. Glucuronides \nalso reach the gut via biliary excretion, where they are \nhydrolysed, most of the morphine being reabsorbed (entero -\nhepatic circulation). Because of low conjugating capacity in \nneonates, morphine-like drugs have a much longer duration \nof action; because even a small degree of respiratory depres -\nsion can be hazardous, morphine congeners should not be \nused in the neonatal period, nor used as analgesics during \nchildbirth. Pethidine (see p. 557) is a safer alternative for this \npurpose.\nAnalogues \tthat \thave \tno \tfree \thydroxyl \tgroup \tin \tthe \t3 \t\nposition (i.e. diamorphine, codeine) are converted to \nmorphine, which accounts for all or part of their pharm -\nacological activity. With heroin the conversion occurs rapidly in the brain but with codeine the effect is slower and occurs \nby\tmetabolism \tin\tthe\tliver. \t Morphine \tproduces \tvery \t effective\t\nanalgesia when administered intrathecally, and is used in this way by anaesthetists, the advantage being that the \nsedative and respiratory depressant effects are reduced, \nalthough not completely avoided. Remifentanil is rapidly \nhydrolysed \tand\teliminated \twith\ta\thalf-life\tof\t3\u20134\tmin. \t The\t\nadvantage of this is that when given by intravenous infusion during general anaesthesia, the level of the drug can be \nmanipulated \trapidly \twhen \trequired \t(see \tCh. \t11 \tfor \ta \t\ndescription of how, for intravenous infusion, both the rate of rise and the rate of decay of the plasma concentration \nare determined by the half-time of elimination).\nIn postoperative and cancer pain, opioids are often given \n\u2018on demand\u2019 (patient-controlled analgesia). The patients are provided with an infusion pump that they control, the \nmaximum possible rate of administration being limited to avoid acute toxicity. Patients show little tendency to use \nexcessively large doses and become dependent; instead, \nthe dose is adjusted to achieve analgesia without excessive sedation, and is reduced as the pain subsides. Being in control of their own analgesia, the patients\u2019 anxiety and \ndistress are reduced, and analgesic consumption actually \ntends to decrease. In chronic pain, patients often experience sudden, sharp increases in the level of pain they are \nexperiencing. This is referred to as breakthrough pain. To \ncombat this, there is a therapeutic need to be able to increase rapidly the amount of opioid being administered. This has \nled to the development of touch-sensitive transdermal \npatches containing potent opioids such as fentanyl that rapidly release", "start_char_idx": 0, "end_char_idx": 3364, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0bea631a-877a-4179-abbe-83e9f2689ffb": {"__data__": {"id_": "0bea631a-877a-4179-abbe-83e9f2689ffb", "embedding": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "658f80f4-c2bb-4d41-8c41-19bbe55ee16d", "node_type": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3bf3866da4ff56bf9d08dd1e332eb52b12d0e60f0a4267924c432e015f143e4"}, "2": {"node_id": "67e8fea8-f933-499e-88ad-6eb3299effd6", "node_type": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3f2837f87e233f9c19ebd019be60141b5380db849701e6b02f470db0eac0a47"}, "3": {"node_id": "0567c999-271e-418b-9378-bdaf5f481d37", "node_type": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca3a1201eb56314dd855ade49ad3ef881b54882631f7cb78e4aa8aae8ade6922"}}, "hash": "453625fa69e3dbb844add662b6f4b23f85db93a2074a4f235856edca162d4790", "text": "\npatches containing potent opioids such as fentanyl that rapidly release drug into the bloodstream. Fentanyl lozenges \nand lollipops, producing rapid absorption through the \nbuccal mucosa, are also used.\nThe opioid antagonist, naloxone, has a shorter biological \nhalf-life than most opioid agonists. In the treatment of opioid overdose, it must be given repeatedly to avoid the respira -\ntory depressant effect of the agonist reoccurring once the \nnaloxone has been eliminated. Naltrexone has a longer \nbiological half-life.of physical dependence are much less intense if the opioid is withdrawn gradually. Humans often experience an abstinence syndrome when opioids are withdrawn after \nbeing used for pain relief over days or weeks, with symp -\ntoms of restlessness, runny nose, diarrhoea, shivering and \npiloerection.\n12\nMany\tphysiological \tchanges \thave \tbeen \tdescribed \tin \t\nrelation to the abstinence syndrome. For example, spinal reflex hyperexcitability occurs in morphine-dependent \nanimals and can be produced by chronic intrathecal as well \nas systemic administration of morphine. The noradrenergic \npathways \temanating \tfrom \tthe \tLC \t(see \tCh. \t40) \tmay \talso \t\nplay an important role in causing the abstinence syndrome. The rate of firing of LC neurons is reduced by opioids and \nincreased during the abstinence syndrome. The \u03b1\n2-\nadrenoceptor agonist lofexidine \t(Ch.\t15) \tcan \tbe \tused \tto \t\nalleviate withdrawal symptoms. In animal models, and \nalso in humans, the abstinence syndrome can also be reduced \nby\tgiving \tNMDA \treceptor \tantagonists \t(e.g. \tketamine).\nTolerance and dependence \n\u2022\tTolerance \tdevelops \trapidly.\n\u2022\tThe\tmechanism \tof \ttolerance \tinvolves \treceptor \t\ndesensitisation. It is not pharmacokinetic in origin.\n\u2022\tDependence \tcomprises \ttwo \tcomponents:\n\u2013 physical dependence, associated with the \nwithdrawal syndrome and lasting for a few days;\n\u2013 psychological dependence, associated with craving \nand lasting for months or years; it rarely occurs in \npatients being given opioids as analgesics.\n\u2022\tPhysical \tdependence, \tcharacterised \tby \ta \twithdrawal \t\nsyndrome on cessation of drug administration, occurs with \u00b5 receptor agonists.\n\u2022\tThe\twithdrawal \tsyndrome \tis \tprecipitated \tby \t\u00b5 receptor \nantagonists.\n\u2022\tLong-acting \t\u00b5 receptor agonists such as methadone \nand buprenorphine may be used to relieve \nwithdrawal symptoms.\n\u2022\tCertain\topioid \tanalgesics, \tsuch \tas \tcodeine, \nbuprenorphine and tramadol, are much less likely to \ncause physical or psychological dependence.\n12Causing goose pimples. This is the origin of the phrase \u2018cold turkey\u2019 \nused to describe the effect of morphine withdrawal.PHARMACOKINETIC ASPECTS\nTable\t43.4 \tsummarises \tthe \tpharmacokinetic \tproperties \tof \t\nthe main opioid analgesics. The absorption of morphine \ncongeners \tby \tmouth \tis \tvariable. \tMorphine \titself \tis \tslowly \t\nand erratically absorbed, and is commonly given by \nintravenous injection to treat acute severe pain; oral mor -\nphine is, however, often used in treating chronic pain, and slow-release preparations are available to increase its duration of action. Oxycodone is also available as a slow-\nrelease oral preparation. Codeine is well absorbed and \nnormally \tgiven \tby \tmouth. \tMost \tmorphine-like \tdrugs \t\nundergo considerable first-pass", "start_char_idx": 3302, "end_char_idx": 6581, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0567c999-271e-418b-9378-bdaf5f481d37": {"__data__": {"id_": "0567c999-271e-418b-9378-bdaf5f481d37", "embedding": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "658f80f4-c2bb-4d41-8c41-19bbe55ee16d", "node_type": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3bf3866da4ff56bf9d08dd1e332eb52b12d0e60f0a4267924c432e015f143e4"}, "2": {"node_id": "0bea631a-877a-4179-abbe-83e9f2689ffb", "node_type": null, "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "453625fa69e3dbb844add662b6f4b23f85db93a2074a4f235856edca162d4790"}}, "hash": "ca3a1201eb56314dd855ade49ad3ef881b54882631f7cb78e4aa8aae8ade6922", "text": "\tMost \tmorphine-like \tdrugs \t\nundergo considerable first-pass metabolism, and are \ntherefore markedly less potent when taken orally than when \ninjected.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6583, "end_char_idx": 7214, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "541dbff1-8a78-4ac4-ab80-8c81b71bc9bd": {"__data__": {"id_": "541dbff1-8a78-4ac4-ab80-8c81b71bc9bd", "embedding": null, "metadata": {"page_label": "561", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "136b4853-e457-4f52-acf6-f9ff493b4f56", "node_type": null, "metadata": {"page_label": "561", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b97021e87a7ab6f07d58504a6868a408fd61a7cb35d081ef3ef5e6829e3e6b51"}}, "hash": "b97021e87a7ab6f07d58504a6868a408fd61a7cb35d081ef3ef5e6829e3e6b51", "text": "43 ANAlgESic dRUgS\n555Table 43.4 Characteristics of the main opioid analgesic drugs\nDrug Use(s)Route(s) of \nadministration Pharmacokinetic aspects Main adverse effects Notes\nMorphineWidely used \nfor acute and chronic painOral, including sustained-release formInjection\na\nIntrathecalHalf-life 3\u20134 h\nConverted to active metabolite (morphine-6-glucuronide)SedationRespiratory depressionConstipationNausea and vomitingItching (histamine release)Tolerance and dependenceEuphoriaTolerance and withdrawal effects not common when used for analgesia\nDiamorphine (heroin)Acute and chronic painOralInjectionActs more rapidly than morphine because of rapid brain penetration.As morphineNot available in all countriesMetabolised to morphine and other active metabolites\nHydromorphone Acute and chronic painOralInjection\nHalf-life 2\u20134 h\nNo active metabolitesAs morphine but allegedly less sedativeLevorphanol is similar, with longer duration of action\nOxycodoneAcute and chronic painOral, including sustained-release formInjection\nHalf-life 3\u20134.5 h As morphineHas become a major drug of abuseHydrocodone, used primarily in the United States, is similar\nMethadoneChronic painMaintenance of addictsOralInjectionLong half-life ( >\n24 h)\nSlow onsetAs morphine but less euphoric effectAccumulation may occurSlow recovery results in attenuated withdrawal syndrome because of long half-life\nPethidine Acute painOralIntramuscular injection\nHalf-life 2\u20134 h\nActive metabolite (norpethidine) may account for stimulant effectsAs morphineAnticholinergic effectsRisk of excitement and convulsionsKnown as meperidine in United StatesInteracts with monoamine oxidase inhibitors (Ch. 48)\nBuprenorphineAcute and chronic painMaintenance of addictsSublingualInjectionTransdermal patchIntrathecal\nHalf-life about 12 h\nSlow onsetInactive orally because of first-pass metabolismAs morphine but less pronouncedRespiratory depression not reversed by naloxone (therefore not suitable for obstetric use)May precipitate opioid withdrawal (partial agonist)Useful in chronic pain with patient-controlled injection systems\nContinued\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2573, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6a8eee5b-2a59-4c68-bd54-1d9cab1fbd46": {"__data__": {"id_": "6a8eee5b-2a59-4c68-bd54-1d9cab1fbd46", "embedding": null, "metadata": {"page_label": "562", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8d9b8fe9-8049-4b7e-a2d3-8f0327fc7c9a", "node_type": null, "metadata": {"page_label": "562", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "75106c0afd7817933b46c7f84289b8444cba22f4e4446fdfe05379a7495ae429"}}, "hash": "75106c0afd7817933b46c7f84289b8444cba22f4e4446fdfe05379a7495ae429", "text": "43 SECTION 4 NERVOUS SYSTEM\n556\nTable 43.4 Characteristics of the main opioid analgesic drugs\u2014cont\u2019d\nDrug Use(s)Route(s) of \nadministration Pharmacokinetic aspects Main adverse effects Notes\nDipipanoneModerate to \nsevere painOralHalf-life 3.5 h (although there \nare longer values quoted)In addition to effects similar to \nmorphine it produces psychosisMarketed in combination with \ncyclazine (Diconal) and became \na popular intravenous drug of \nabuse\nFentanylAcute pain\nAnaesthesiaIntravenous\nSublingual\nTransdermal \npatchHalf-life 1\u20132 h As morphineHigh potency allows transdermal \nadministration\nSufentanil is similar\nRemifentanil Anaesthesia Intravenous \ninfusionHalf-life 5 min Respiratory depression Very rapid onset and recovery\nCodeine Mild pain OralActs as prodrug\nMetabolised to morphine and \nother active metabolitesMainly constipation\nLow dependence liabilityEffective only in mild pain\nAlso used to suppress cough\nDihydrocodeine is similar\nDextropropoxyphene Mild pain Mainly oralHalf-life ~4 h\nActive metabolite \n(norpropoxyphene) with \nhalf-life ~24 hRespiratory depression\nMay cause convulsions (possibly \nby action of norpropoxyphene)Similar to codeine\nNo longer recommended\nTramadolAcute (mainly \npostoperative) \nand chronic \npainOral\nIntravenousWell absorbed\nHalf-life 4\u20136 hDizziness\nMay cause convulsions\nNo respiratory depressionMechanism of action uncertain\nWeak agonist at opioid receptors\nAlso inhibits monoamine uptake. \nTapentadol is similar\naInjections may be given intravenously, intramuscularly or subcutaneously for most drugs.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2037, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "642f2eef-4879-4840-bfee-7c0c25157463": {"__data__": {"id_": "642f2eef-4879-4840-bfee-7c0c25157463", "embedding": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "15813631-0973-46e1-93a0-8c0c3cf609f4", "node_type": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95115da055ebee49f0bbf269ba441726701b0fbdb614563e45547a4718fdae8f"}, "3": {"node_id": "813b64cd-44a1-4f4a-ba80-0e090af038e3", "node_type": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e28111f35e8c23c3ec3a76f59e34fe64b24ceeb7b7997ee989a08a6df741a90"}}, "hash": "f49fa2ace428fb0f094c524deac9855efbf5fc6afdef5b6983c980648b7a3daf", "text": "43 ANAlgESic dRUgS\n557on combined use of opioids and NSAIDs). In relation to \nits analgesic effect, codeine produces the same degree of \nrespiratory depression as morphine, but the limited \nresponse, even at high doses, means that it is seldom a problem in practice. It does, however, cause constipation. \nCodeine has marked antitussive activity and is often used \nin\tcough \tmixtures \t(see \tCh. \t29). \tDihydrocodeine is phar-\nmacologically very similar, having no substantial advantages or disadvantages over codeine.\nOxycodone is used in the treatment of acute and chronic \npain. The suggestion that it acts on a subtype of \u03ba opioid \nreceptor is not generally accepted. Claims that it has less \neuphoric effect and less abuse potential are unfounded. It is available as a slow-release oral preparation, as is hydroco -\ndone\n\twhich\tis \tsimilar \tin \taction. \tMisprescribing \tof \tthese \t\ndrugs has led to them becoming major drugs of abuse, \nespecially \tin \tNorth \tAmerica \t(see \tCh. \t50).\nFentanyl, alfentanil, sufentanil and remifentanil are \nhighly potent phenylpiperidine derivatives, with actions \nsimilar to those of morphine but with a more rapid onset \nand shorter duration of action, particularly remifentanil. They are used extensively in anaesthesia, and they may be \ngiven intrathecally. Carfentanil is a more potent analogue \nused to sedate large animals. Fentanyl, alfentanil and sufentanil are also used in patient-controlled infusion \nsystems and in severe chronic pain, when they are admin -\nistered via patches applied to the skin. The rapid onset is \nadvantageous in breakthrough pain. Fentanyl has minimal cardiovascular effects and does not release histamine. In \nrecent years, illegally produced fentanyl, carfentanil and \na range of other analogues have become major drugs of \nabuse,\tespecially \tin \tthe \tUnited \tStates \t(See \tCh. \t50). \tUnlike \t\nother opioids, they are easily synthesised, without the need to harvest poppies.\nMethadone is orally active and pharmacologically similar \nto morphine, the main difference being that its duration of action is considerably longer (plasma half-life >\n24 h). \nThe increased duration seems to occur because the drug is bound in the extravascular compartment and slowly \nreleased. On withdrawal, the physical abstinence syndrome \nis less acute than with morphine, although the psychological \ndependence \tis \tno \tless \tpronounced. \tMethadone \tis \twidely \t\nused\tas\ta \tmeans \tof \ttreating \theroin \taddiction \t(see \tCh. \t50). \t\nIt is possible to wean addicts from heroin by giving regular oral doses of methadone \u2013 an improvement, if not a cure.\n14 \nMethadone \thas\tactions\tat\tother\tsites\tin\tthe\tCNS,\tincluding \t\nblock\tof\tpotassium \tchannels, \tNMDA \treceptors \tand \t5-HT \t\nreceptors, that may explain its CNS side-effect profile. There is also interindividual variation in the response to metha -\ndone, probably due to genetic variability between individu -\nals in its metabolism.\nPethidine (meperidine) is very similar to morphine in \nits pharmacological effects, except that it tends to cause restlessness rather than sedation. It was originally inves -\ntigated as a new antimuscarinic agent but was found to \nhave opioid analgesic activity; its residual antimuscarinic \naction being responsible for its side effects of dry mouth and blurring of vision. It produces a very similar euphoric effect and is equally liable to cause dependence. Its duration \nof action is the same or slightly shorter than that of", "start_char_idx": 0, "end_char_idx": 3469, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "813b64cd-44a1-4f4a-ba80-0e090af038e3": {"__data__": {"id_": "813b64cd-44a1-4f4a-ba80-0e090af038e3", "embedding": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "15813631-0973-46e1-93a0-8c0c3cf609f4", "node_type": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95115da055ebee49f0bbf269ba441726701b0fbdb614563e45547a4718fdae8f"}, "2": {"node_id": "642f2eef-4879-4840-bfee-7c0c25157463", "node_type": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f49fa2ace428fb0f094c524deac9855efbf5fc6afdef5b6983c980648b7a3daf"}, "3": {"node_id": "3d9f1620-3155-4e43-8d73-18bf3d7d8e63", "node_type": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4cb273019bd73e678d68b9ca86515deb20ce43782fcd7abc5f66f7f4a91c7549"}}, "hash": "1e28111f35e8c23c3ec3a76f59e34fe64b24ceeb7b7997ee989a08a6df741a90", "text": "cause dependence. Its duration \nof action is the same or slightly shorter than that of UNWANTED EFFECTS\nThe main unwanted effects of morphine and related drugs \nare\tlisted \tin \tTable \t43.4.\nAcute overdosage with morphine results in coma and \nrespiratory depression, with characteristically constricted pupils. It is treated by giving naloxone intramuscularly or \nintravenously. This also serves as a diagnostic test, for failure to respond to naloxone suggests a cause other than opioid \npoisoning for the comatose state.\n13 There is a danger of \nprecipitating a severe withdrawal syndrome with naloxone, because opioid poisoning occurs mainly in addicts.\nIndividual variability\n\u25bc\tIndividuals \t vary \t by \t as \t much \t as \t 10-fold \t in \t their \t sensitivity \t to \t opioid\t\nanalgesics. This can be due to altered metabolism or altered sensitivity \nof\tthe\treceptors \t(for \textensive \treview, \tsee \tRollason \tet \tal., \t2008). \tFor \t\nmorphine, reduced responsiveness may result from mutations in a \nnumber of genes including that for the drug transporter, P-glycoprotein \n(see\tChs \t10 \tand \t12), \tfor \tglucuronyltransferase \tthat \tmetabolises \t\nmorphine and for the \u00b5\treceptor\titself.\tMutations \tof\tvarious\tcytochrome \t\nP450\t(CYP)\tenzymes \tinfluence \tthe\tmetabolism \tof\tcodeine,\toxycodone, \t\nmethadone, tramadol and dextromethorphan. Genotyping could in principle be used to identify opioid-resistant individuals, but first \nthe contribution of genotype to clinical outcome must be confirmed \nin the population at large.\nOTHER OPIOID ANALGESICS\nDiamorphine \t(heroin) \tis \t3,6-diacetylmorphine; \tit \tcan \tbe \t\nconsidered as a prodrug because its high analgesic potency \nis\tattributable \tto\trapid\tconversion \tto\t6-monoacetylmorphine \t\nand morphine. Its effects are indistinguishable from those of \nmorphine following oral administration. However, because \nof its greater lipid solubility, it crosses the blood\u2013brain \nbarrier more rapidly than morphine and gives a greater \u2018buzz\u2019 when injected intravenously. It is said to be less \nemetic than morphine, but the evidence for this is slight. It \nis still available in Britain for use as an analgesic, although it is banned in many countries. Its only advantage over \nmorphine is its greater solubility, which allows smaller \nvolumes to be given orally, subcutaneously or intrathe -\ncally. It exerts the same respiratory depressant effect as morphine and, if given intravenously, is more likely to cause \ndependence.\nCodeine\n\t(3-methoxymorphine) \tis \talso \ta \tprodrug \tbut, \t\nunlike\theroin, \t undergoes \t demethylation \t by \tCY P2D6\t in \tt he\t\nliver\tt o\tp roduce \tm orphine.\tI t\th as\t2 0%\to r\tl ess\to f\tt he\ta nalgesic\t\npotency of morphine, as a large proportion of the absorbed drug is not converted to morphine but instead undergoes \nhepatic glucuronidation and is then excreted. Its analgesic \neffect does not increase appreciably at higher dose levels, presumably because of limited conversion to morphine, \nand so it is sometimes referred to as a weak agonist. It is \nmore reliably absorbed by mouth than morphine and is therefore used mainly as an oral analgesic for mild types \nof\tpain\t(headache, \tbackache,", "start_char_idx": 3398, "end_char_idx": 6555, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3d9f1620-3155-4e43-8d73-18bf3d7d8e63": {"__data__": {"id_": "3d9f1620-3155-4e43-8d73-18bf3d7d8e63", "embedding": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "15813631-0973-46e1-93a0-8c0c3cf609f4", "node_type": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95115da055ebee49f0bbf269ba441726701b0fbdb614563e45547a4718fdae8f"}, "2": {"node_id": "813b64cd-44a1-4f4a-ba80-0e090af038e3", "node_type": null, "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e28111f35e8c23c3ec3a76f59e34fe64b24ceeb7b7997ee989a08a6df741a90"}}, "hash": "4cb273019bd73e678d68b9ca86515deb20ce43782fcd7abc5f66f7f4a91c7549", "text": "for mild types \nof\tpain\t(headache, \tbackache, \tetc.).\tAbout\t10%\tof\tthe\tpopula -\ntion is resistant to the analgesic effect of codeine, because \nthey lack the demethylating enzyme that converts it to \nmorphine. Unlike morphine, it causes little or no euphoria and is rarely addictive. It is often combined with paraceta-\nmol in proprietary analgesic preparations (see later section \n14The benefits come mainly from removing the risks of self-injection and \nthe need to finance the drug habit through crime.13Naloxone is less effective in reversing the effects of buprenorphine as \nthis agonist dissociates very slowly from the receptors.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6582, "end_char_idx": 7696, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3fb01ab8-f52a-4e92-8082-3e1349727369": {"__data__": {"id_": "3fb01ab8-f52a-4e92-8082-3e1349727369", "embedding": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7183eb36-1477-4313-a97d-d7387a47216c", "node_type": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f200ee22f7a89c5344bee76266ef8eab4bd9cf223102178ece32f513868a8f76"}, "3": {"node_id": "6fd4eb53-1091-44d2-9955-02913369a759", "node_type": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce3d9af0c223d0f14f2b615fa07ace86329e3e255f859b840789bc7608289806"}}, "hash": "24a65ad6699f4ef675c140a4ca8643262e6ed9795b6f06927dfbbc826bd7d7b8", "text": "43 SECTION 4 NERVOUS SYSTEM\n558psychiatric reactions have been reported. They are given \nby mouth or by intramuscular or intravenous injection for \nacute and chronic pain, including musculoskeletal pain and \nthe pain associated with diabetic neuropathy.\nNalbuphine is an analgesic that has activity at \u03ba, \u00b5, and \nto a lesser extent, \u03b4 receptors. It acts as an agonist at \u03ba \nreceptors and as a partial agonist at \u00b5 receptors. Pentazocine , \nrarely used clinically nowadays, also combines a degree \nof \u03ba agonist and \u00b5 antagonist (or weak partial agonist) \nactivity. These agents are thought to produce less euphoria \nthan \u00b5 receptor agonists. Cebranopadol, currently in late \nstages of clinical trials, is an agonist at all four opioid \nreceptors.\nLoperamide is a \u00b5 receptor agonist that is effectively \nextruded from the brain by P-glycoprotein and therefore \nlacks analgesic activity. It inhibits peristalsis, and is used \nto\tcontrol \tdiarrhoea \t(see \tCh. \t31).\nOPIOID ANTAGONISTS\nNaloxone was the first pure opioid antagonist, with affinity \nfor all three classic opioid receptors ( \u00b5 > \u03ba \u2265 \u03b4). It blocks \nthe actions of endogenous opioid peptides as well as those \nof morphine-like drugs and has been extensively used as an experimental tool to determine the physiological role \nof these peptides, particularly in pain transmission.\nGiven on its own, naloxone produces very little effect \nin normal subjects but produces a rapid reversal of the effects of morphine and other opioids. It has little effect \non pain threshold under normal conditions but causes hyperalgesia under conditions of stress or inflammation, when endogenous opioids are produced. This occurs, for \nexample, in patients undergoing dental surgery, or in \nanimals subjected to physical stress. Naloxone also inhibits acupuncture analgesia, which is known to be associated with \nthe release of endogenous opioid peptides, but does not \nreduce meditation-induced analgesia. Analgesia produced by PAG stimulation is also prevented by naloxone.\nThe main clinical uses of naloxone are to treat respiratory \ndepression \tcaused \tby \topioid \toverdosage \t(see \tCh. \t50), \tand \t\noccasionally to reverse the effect of opioid analgesics, used during labour, on the respiration of the newborn baby. It can \nbe administered nasally, intramuscularly or intravenously, \nand its effects are rapid in onset. It is rapidly metabolised by \nthe liver, and its effect lasts only 2\u20134 h, which is considerably \nshorter than that of most morphine-like drugs and therefore it may have to be given repeatedly.\nNaloxone has no important unwanted effects of its own \nbut precipitates withdrawal symptoms in addicts. It can be used to detect opioid addiction.\nNaltrexone is very similar to naloxone but with the \nadvantage of a much longer duration of action (half-life \nabout\t10 \th). \tIt \tmay \tbe \tof \tvalue \tin \taddicts \twho \thave \tbeen \t\n\u2018detoxified\u2019, because it nullifies the effect of a dose of opioid should the patient\u2019s resolve fail. For this purpose, it is \navailable in a slow-release subcutaneous implant formula -\ntion. It is also effective in reducing alcohol consumption \nin\theavy\tdrinkers\t(see\tCh.\t50),\tthe\trationale \tbeing\tthat\tpart\t\nof the high from alcohol comes from the release of endo -\ngenous opioid peptides. Nalmefene , another non-selective \nopioid antagonist, is also used to treat alcoholics.", "start_char_idx": 0, "end_char_idx": 3370, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6fd4eb53-1091-44d2-9955-02913369a759": {"__data__": {"id_": "6fd4eb53-1091-44d2-9955-02913369a759", "embedding": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7183eb36-1477-4313-a97d-d7387a47216c", "node_type": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f200ee22f7a89c5344bee76266ef8eab4bd9cf223102178ece32f513868a8f76"}, "2": {"node_id": "3fb01ab8-f52a-4e92-8082-3e1349727369", "node_type": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24a65ad6699f4ef675c140a4ca8643262e6ed9795b6f06927dfbbc826bd7d7b8"}, "3": {"node_id": "a7f9037d-1793-4661-ad0a-718f816dbea9", "node_type": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4841f3ddd60ff92c26110c54ea4f9187b503089341eddae7cd5a5aec35b83d44"}}, "hash": "ce3d9af0c223d0f14f2b615fa07ace86329e3e255f859b840789bc7608289806", "text": "non-selective \nopioid antagonist, is also used to treat alcoholics. Naltrexone \nmay also have beneficial effects in septic shock. It is effective in treating chronic itching (pruritus), as occurs in chronic \nliver disease. Again, this may indicate the involvement of \nendogenous opioid peptides in the pathophysiology of such itch conditions.morphine, but the route of metabolic degradation is dif-ferent. Pethidine is partly N-demethylated in the liver to \nnorpethidine, which has hallucinogenic and convulsant effects. These become significant with large oral doses of pethidine, producing an overdose syndrome rather different \nfrom that of morphine. Pethidine is preferred to morphine \nfor analgesia during labour, because it does not reduce the force of uterine contraction. Pethidine is only slowly \neliminated in the neonate, and naloxone may be needed \nto reverse respiratory depression in the newborn (morphine is even more problematic in this regard, because the conjuga -\ntion reactions on which the excretion of morphine, but not \nof pethidine, depends are deficient in the newborn). Severe \nreactions, consisting of excitement, hyperthermia and convulsions, have been reported when pethidine is given \nto patients receiving monoamine oxidase inhibitors. This \nseems to be due to inhibition of an alternative metabolic pathway, leading to increased norpethidine formation, but \nthe details are unclear.\nEtorphine is a morphine analogue with a potency more \nthan\t1000\ttimes\tthat\tof\tmorphine, \tbut\totherwise \tvery\tsimilar\t\nin its actions. Its high potency confers no particular human \nclinical advantage, but it is used in veterinary practice, \nespecially in large animals. It can be used in conjunction \nwith sedative agents (neuroleptanalgesia) to immobilise wild animals for trapping.\n15\nBuprenorphine is a partial agonist on \u00b5 receptors that \nproduces strong analgesia but there is a ceiling to its respira -\ntory depressant effect. Because of its antagonist actions, it can produce mild withdrawal symptoms in patients dependent on other opioids. It dissociates slowly from the \nreceptors and so has a long duration of action and can be \ndifficult to reverse with naloxone. It has abuse liability but, like methadone, it is also used in the treatment of heroin \naddiction. When heroin is injected \u2018on top\u2019 of buprenor -\nphine, less euphoria is obtained because buprenorphine is \na partial agonist. It is marketed as a sublingual preparation combined with naloxone for the management of opioid \ndependence; when administered as intended the naloxone \nis not absorbed and does not influence the effect of the buprenorphine, but if it is administered parenterally the \neffects of the buprenorphine are hopefully reduced by \nthe naloxone, discouraging such abuse. How effective this is in practice has been questioned.\nMeptazinol is an opioid of unusual chemical structure. \nIt can be given orally or by injection and has a duration of action shorter than that of morphine. It seems to be relatively \nfree of morphine-like side effects, causing neither euphoria \nnor dysphoria, nor severe respiratory depression. It does, however, produce nausea, sedation and dizziness, and has \natropine-like actions. Because of its short duration of action \nand lack of respiratory depression, it may have advantages for obstetric analgesia.\nTramadol and tapentadol are widely used as analgesics \nfor postoperative pain. Tramadol comprises two structural enantiomers \u2013 (+)-tramadol inhibits 5-HT reuptake and (\u2212)-tramadol inhibits", "start_char_idx": 3312, "end_char_idx": 6843, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a7f9037d-1793-4661-ad0a-718f816dbea9": {"__data__": {"id_": "a7f9037d-1793-4661-ad0a-718f816dbea9", "embedding": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7183eb36-1477-4313-a97d-d7387a47216c", "node_type": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f200ee22f7a89c5344bee76266ef8eab4bd9cf223102178ece32f513868a8f76"}, "2": {"node_id": "6fd4eb53-1091-44d2-9955-02913369a759", "node_type": null, "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce3d9af0c223d0f14f2b615fa07ace86329e3e255f859b840789bc7608289806"}}, "hash": "4841f3ddd60ff92c26110c54ea4f9187b503089341eddae7cd5a5aec35b83d44", "text": "inhibits 5-HT reuptake and (\u2212)-tramadol inhibits NA reuptake \u2013 and the major metabo -\nlite of (+)-tramadol, O-desmethyltramadol activates the \n\u00b5 \nreceptor. Tapentadol inhibits NA reuptake and activates \nthe \u00b5 receptor. They are effective analgesics and appear to \nhave a better side-effect profile than most opioids, although \n15The required dose of etorphine, even for an elephant, is small enough \nto be incorporated into a dart or pellet.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6854, "end_char_idx": 7774, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0ddc725c-3003-4099-88ea-9805b795cd23": {"__data__": {"id_": "0ddc725c-3003-4099-88ea-9805b795cd23", "embedding": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e6b994ce-063a-4e45-b7f1-752e0007227c", "node_type": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f598d4689ef4ab11e263b22e212367a3bf5e79ae53ac41524806bc4c0b8c8ec0"}, "3": {"node_id": "0535d8e7-c49f-4507-a886-42b4cd7b503f", "node_type": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "daaca0f285bb49f5898ad4e73837e677f78a0f5c3447e85731cb76f5a4ebea2c"}}, "hash": "aa702da9d8d3be0a34d7f9817120390bad878fe6354372a01fc59a90857811f1", "text": "43 ANAlgESic dRUgS\n559is\tcommonly \tfatal \t(see \tChs \t27 \tand \t58), \tand \tthe \tdrug \tis \t\noften used in attempted suicide.\nUSE OF OPIOIDS AND NSAIDS IN COMBINATION\nThe rationale behind co-administration of two drugs that \nproduce analgesia by different mechanisms is that, if the \neffects are additive, less of each drug can therefore be given \nbut the same degree of analgesia produced. This has the effect of reducing the intensity of the unwanted side effects \nproduced by each drug. In the case of opioids (e.g. codeine) \nin combination with paracetamol or aspirin, the combination appears to produce synergy rather than simple additivity. \nThe combination of dextropropoxyphene and paracetamol \nhas been withdrawn in the United Kingdom due to concerns about overdosing.\nTREATMENT OF CHRONIC PAIN\nChronic pain, that which persists beyond normal healing time and which includes pain of musculoskeletal or neu -\nropathic origin, involves not only the processing of nocicep -\ntive information but also comprises emotional and psychosocial components (e.g. mood, circumstance, stress, \nduration, meaning, acceptance, expectation and fear), more \nso\tthan\tacute \tor \tcancer-related \tpain \t(see \tStannard, \t2016). \t\nThese other components may render opioid drugs less \neffective in the long-term treatment of chronic pain (i.e. \ntreatment \tlasting\tmore\tthan\t12\tweeks)16.\tThe\tBritish\tMedical\t\nAssociation have concluded that \u2018There is a lack of good-quality evidence to support a strong clinical recommendation \nfor the long-term use of opioids for patients with chronic \npain\u2019\t(see \tBMA, \t2017).\nSeveral non-opioid drugs that are also used clinically \nfor effects other than analgesia have been found to be \neffective\tin\tneuropathic \tpain\t(see\tDworkin \tet\tal., \t 2010; \t BMA,\t\n2017),\tlargely\tas\ta\tresult\tof\tserendipitous \tobservations \trather\t\nthan a rational programme of drug discovery.\nTricyclic antidepressants, particularly amitriptyline, \nnortriptyline and desipramine \t(Ch.\t48) \tare \twidely \tused. \t\nThese drugs act centrally by inhibiting noradrenaline \nreuptake and are effective in relieving neuropathic pain in \nsome, but not all, cases. Their action is independent of their \nantidepressant effects. Drugs such as duloxetine and \nvenlafaxine, which inhibit serotonin and noradrenaline \nuptake, are also effective and have a different side-effect \nprofile, but selective serotonin reuptake inhibitors show little or no benefit.\nGabapentin and its congener, pregabalin , are antiepileptic \ndrugs\t(Ch. \t46) \tthat \tare \talso \teffective \tin \tthe \ttreatment \tof \t\nneuropathic pain. They reduce the expression of \u03b12\u03b4 subu -\nnits of voltage-activated calcium channels on the nerve \nmembrane (see Ch. 4) and reduce neurotransmitter release. \nThe \u03b12\u03b4 subunits are up-regulated in damaged sensory \nneurons, which may explain why these agents are more \neffective across a range of pain states associated with nerve \ndamage than in other forms of pain.\nCarbamazepine, another type of anti-epileptic drug, \nis effective in trigeminal neuralgia but evidence for effectiveness against other neuropathic pains is lacking. Carbamazepine blocks voltage-gated sodium channels Methylnaltrexone bromide, alvimopan and naloxegol \nare \u00b5 receptor antagonists that do not cross the blood\u2013brain \nbarrier. They can be used in combination with", "start_char_idx": 0, "end_char_idx": 3322, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0535d8e7-c49f-4507-a886-42b4cd7b503f": {"__data__": {"id_": "0535d8e7-c49f-4507-a886-42b4cd7b503f", "embedding": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e6b994ce-063a-4e45-b7f1-752e0007227c", "node_type": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f598d4689ef4ab11e263b22e212367a3bf5e79ae53ac41524806bc4c0b8c8ec0"}, "2": {"node_id": "0ddc725c-3003-4099-88ea-9805b795cd23", "node_type": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa702da9d8d3be0a34d7f9817120390bad878fe6354372a01fc59a90857811f1"}, "3": {"node_id": "df542374-a46e-45b2-89b7-8faa3e275934", "node_type": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8bcadbe64aeda459f66713b39865e908ce41983a8803566d33dc227b511ad37e"}}, "hash": "daaca0f285bb49f5898ad4e73837e677f78a0f5c3447e85731cb76f5a4ebea2c", "text": "that do not cross the blood\u2013brain \nbarrier. They can be used in combination with opioid \nagonists to block unwanted effects, most notably reduced \ngastrointestinal motility, nausea and vomiting.\nSpecific antagonists at \u00b5, \u03b4 and \u03ba receptors are available \nfor\texperimental \tuse\t(see\tTable\t43.3)\tbut\tthey\tare\tnot\tused\t\nclinically.\nOpioid antagonists \n\u2022\tPure\tantagonists \tinclude \tnaloxone (short acting) and \nnaltrexone (longer acting). They block \u00b5, \u03b4 and \u03ba \nreceptors. Selective antagonists are available as \nexperimental tools.\n\u2022\tAlvimopan and naloxegol are \u00b5 receptor antagonists \nthat do not cross the blood\u2013brain barrier. They block \nopioid-induced constipation, nausea and vomiting.\n\u2022\tNaloxone does not affect pain threshold normally but blocks stress-induced analgesia and can exacerbate clinical pain.\n\u2022\tNaloxone rapidly reverses opioid-induced analgesia and respiratory depression, and is used mainly to treat \nopioid overdose or to improve breathing in newborn \nbabies affected by opioids given to the mother.\n\u2022\tNaloxone precipitates withdrawal symptoms in morphine-dependent patients or animals. \nBuprenorphine (a partial agonist) can also precipitate \nwithdrawal due to its antagonist action against higher efficacy opioid agonists.\n16Over\tthe \tpast \t30 \tyears \tthere \thas \tbeen \twidespread \tlong-term \t\nprescribing of opioids for chronic pain in the developed world leading \nto an alarming increase in addiction to prescription opioids and to \noverdose \tdeaths \t(see \tCh \t50).PARACETAMOL\nNon-steroidal antiinflammatory drugs (NSAIDs, covered in \ndetail in Ch. 27) are widely used to treat painful inflamma -\ntory conditions and to reduce fever. Paracetamol (known \nas acetaminophen in the United States) deserves special \nmention here. It was first synthesised more than a century \nago,\tand\tsince\tthe\t1950s\thas\t(alongside \taspirin\tand\tibupro -\nfen) been the most widely used over-the-counter remedy \nfor minor aches and pains. Paracetamol differs from other \nNSAIDs in producing analgesic and antipyretic effects while lacking anti-inflammatory effects. It also lacks the tendency \nof other NSAIDs to cause gastric ulceration and bleeding. \nThe reason for the difference between paracetamol and other NSAIDs is unclear. Biochemical tests showed it to be \nonly a weak cyclo-oxygenase (COX) inhibitor, with some \nselectivity for brain COX, possibly because of the unique reducing environment in neurones (see Ch. 27). Interestingly, the antinociceptive and antipyretic effects of paracetamol \nare\tabsent \tin \tmice \tlacking \tthe \tTRPA1 \treceptor \t(see \tp. \t\n547). These effects appear to be mediated by a metabolite (N-acetyl- p-benzoquinoneimine), not by paracetamol itself. \nThis\tactivates \tTRPA1 \tand \tthus \treduces \tvoltage-gated \t\ncalcium and sodium currents in primary sensory neurons.\nParacetamol is well absorbed by mouth, and its plasma \nhalf-life\tis \tabout \t3 \th. \tIt \tis \tmetabolised \tby \thydroxylation, \t\nconjugated mainly as glucuronide, and excreted in the urine. In therapeutic doses, it has few adverse effects. However, \nin overdose, paracetamol causes severe liver damage, which mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3256, "end_char_idx": 6473, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "df542374-a46e-45b2-89b7-8faa3e275934": {"__data__": {"id_": "df542374-a46e-45b2-89b7-8faa3e275934", "embedding": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e6b994ce-063a-4e45-b7f1-752e0007227c", "node_type": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f598d4689ef4ab11e263b22e212367a3bf5e79ae53ac41524806bc4c0b8c8ec0"}, "2": {"node_id": "0535d8e7-c49f-4507-a886-42b4cd7b503f", "node_type": null, "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "daaca0f285bb49f5898ad4e73837e677f78a0f5c3447e85731cb76f5a4ebea2c"}}, "hash": "8bcadbe64aeda459f66713b39865e908ce41983a8803566d33dc227b511ad37e", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6493, "end_char_idx": 6908, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4de4e6b7-90cb-4982-b15c-83a567507296": {"__data__": {"id_": "4de4e6b7-90cb-4982-b15c-83a567507296", "embedding": null, "metadata": {"page_label": "566", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ea1a5971-3ca1-4667-928a-e163d8cab129", "node_type": null, "metadata": {"page_label": "566", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "350f800a5a343b1642f7c0ea3813c03b3e70a49440498e4191ceede1f2c6294e"}, "3": {"node_id": "8564f69e-1b21-48fa-a06e-49fa141b9699", "node_type": null, "metadata": {"page_label": "566", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f31fbd72168d0040924df6bbd45d7f1d901c5be082760dbef1494abffa478a5"}}, "hash": "4d3ce5342a04e4c963b3294a402499422d3e952038ced6f651ba88a3b71cdc63", "text": "43 SECTION 4 NERVOUS SYSTEM\n560avoided. It is used for acute pain relief rather than long-term \ntreatment.\nZiconotide , a synthetic analogue of the N-type calcium-\nchannel blocking peptide \u03c9-conotoxin \tMVIIA, \tis \teffective \t\nwhen administered by the intrathecal route. It is used in patients whose pain does not respond to other analgesic \nagents. Blockers of low voltage-activated T-type calcium \nchannels may also be effective analgesics in some pain states.\nCannabinoids \t(see \tCh. \t20) \tacting \tat \tCB1 receptors are \neffective pain-relieving agents in animal pain models, \nincluding models of acute, antinociceptive, inflammatory \nand neuropathic pain. There is also mounting evidence that these agents are effective in reducing pain in humans \n(see\tBarnes \t& \tBarnes, \t2016). \tThe \tstrongest \tevidence \tof \t\ntherapeutic benefit is for central neuropathic pain in multiple sclerosis. Effective cannabinoids include synthetic agents \nsuch as nabilone and dronabinol as well as natural can -\nnabinoids such as nabiximols (formerly known by its trade \nname Sativex). Nabiximols is an extract of the cannabis \nplant containing \u0394\n9-tetrahydrocannabinol (THC) and can-\nnabidiol that has been suggested to have improved thera -\npeutic efficacy. CB 2 receptor agonists may also be potential \nanalgesic agents.\nIn addition, cannabinoids and related drugs that lack \nagonist action at CB 1 receptors have been observed to induce \nanalgesia by potentiating the actions of the inhibitory amino \nacid\tglycine \tat \tthe \tionotropic \tglycine \treceptor \t(see \tCh. \t39) \t\nin the spinal cord. This may lead to the development of \nnew therapeutic agents lacking the unwanted effects of \nCB1 agonism.\nBotulinum toxin injections are effective in relieving back \npain and the pain associated with spasticity. This effect is \ndue\tmainly \tto \ta \trelief \tof \tmuscle \tspasm \t(Ch. \t14).\nRopinirole, pramipexole and rotigotine, dopamine-\nreceptor\ta gonists \t( see\tC h.\t4 0),\ta re\tu sed\tt o\tt reat\tr estless\tl eg \t\nsyndrome, which can be painful in some individuals.(see Ch. 4) being slightly more potent in blocking Na v1.8\t\nthan Na v1.7\tand\tNa v1.3\tchannels; \tall \tof \tthese \tchannel \t\nsubtypes are thought to be up-regulated by nerve damage \nand contribute to the sensation of pain. At higher con -\ncentrations, it inhibits voltage-activated calcium channels. Phenytoin administered intravenously is sometimes used in \na crisis.\nOther antiepileptic agents such as valproic acid, lamo-\ntrigine , oxcarbazepine , topiramate and levetiracetam may \nhave efficacy in some neuropathic pain states.\nLidocaine (lignocaine), a local anaesthetic drug (Ch. 44), \ncan be used topically to relieve neuropathic pain. It probably acts by blocking spontaneous discharges from damaged sensory nerve terminals. Some antidysrhythmic drugs (e.g. \nmexiletine, tocainide, flecainide; see Ch. 22) are effective \norally.\nThe abundance of drugs and mechanisms deployed to \nalleviate chronic pain reflects the current lack of drugs that \nwork effectively and reliably in this common and serious condition, the cause of which is often unclear. Psychological \ntreatments are often used in addition to drugs.\nDrugs used to treat neuropathic \npain \n\u2022\tVarious \tantidepressants \t(e.g. \tamitriptyline,", "start_char_idx": 0, "end_char_idx": 3257, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8564f69e-1b21-48fa-a06e-49fa141b9699": {"__data__": {"id_": "8564f69e-1b21-48fa-a06e-49fa141b9699", "embedding": null, "metadata": {"page_label": "566", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ea1a5971-3ca1-4667-928a-e163d8cab129", "node_type": null, "metadata": {"page_label": "566", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "350f800a5a343b1642f7c0ea3813c03b3e70a49440498e4191ceede1f2c6294e"}, "2": {"node_id": "4de4e6b7-90cb-4982-b15c-83a567507296", "node_type": null, "metadata": {"page_label": "566", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4d3ce5342a04e4c963b3294a402499422d3e952038ced6f651ba88a3b71cdc63"}}, "hash": "6f31fbd72168d0040924df6bbd45d7f1d901c5be082760dbef1494abffa478a5", "text": "\tantidepressants \t(e.g. \tamitriptyline, \nduloxetine) provide therapeutic benefit.\n\u2022\tGabapentin and pregabalin are now used more to \nrelieve neuropathic pain than as antiepileptic agents.\n\u2022\tCarbamazepine, as well as some other antiepileptic \nagents that block sodium channels, can be effective in treating trigeminal neuralgia.\n\u2022\tLidocaine may provide relief when applied topically.\nOther analgesic drugs \n\u2022\tParacetamol resembles non-steroidal anti-inflammatory drugs and is effective as an analgesic, but it lacks anti-inflammatory activity. It may act by \ninhibiting cyclo-oxygenase (COX)-3, a splice variant of \nCOX-1, but probably has other effects as well. In overdose, it causes hepatotoxicity.\n\u2022\tNefopam is an amine uptake inhibitor that can be \nused to treat opioid-resistant pain.\n\u2022\tThe\tNMDA \treceptor \tantagonist \tketamine is \noccasionally used as a short-term treatment.TREATMENT OF FIBROMYALGIA\nFibromyalgia is a chronic disorder characterised by wide-\nspread musculoskeletal pain, fatigue and insomnia. Its cause \nis unknown, with no obvious characteristic pathology being \napparent. It is associated with allodynia. Classical analgesics (i.e. NSAIDs and opioids), while bringing some relief, are \nnot very effective in treating this disorder. Various anti -\ndepressant drugs (e.g. amitriptyline, citalopram , milnacip -\nran\n,\tduloxetine, \tvenlafaxine; \tsee\tCh.\t48),\tantiepileptic \tagents\t\n(e.g.\tgabapentin, \tpregabalin; \tsee \tCh. \t46), \tbenzodiazepines \t\n(e.g. clonazepam , zopiclone ; see Ch. 45) are currently used \nfor this disorder \u2013 this long list reflecting their uncertain efficacy.\nOTHER PAIN-RELIEVING DRUGS\nNefopam, an inhibitor of amine uptake with some sodium \nchannel-blocking properties is used in the treatment of persistent pain unresponsive to opioid drugs. It does not \ndepress respiration but does produce sympathomimetic and antimuscarinic side effects.\nKetamine , a dissociative anaesthetic (Ch. 42), memantine \nand dextromethorphan\n\twork\tby\tblocking \tNMDA\treceptor\t\nchannels, and probably reduce the wind-up phenomenon \nin\tthe\tdorsal\thorn\t(see\tFig.\t43.2).\tGiven\tintrathecally, \tketa-\nmine\u2019s effects on memory and cognitive function are largely NEW APPROACHES\n\u25bc As in other fields of neuropharmacology, increasing knowledge \nof the various chemical mediators and signalling pathways responsible \nfor pain sensation suggests many new approaches to the control of \npain. Pain treatment is currently far from perfect, and a vast array \nof novel approaches, too numerous be covered in detail here, are \ncurrently \tbeing \texplored \t(see \tGilron \t& \tDickenson, \t2014; \tMcEntire \t\net\tal.,\t2016).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3218, "end_char_idx": 6321, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "adc1438e-1555-4ca1-9382-18c0bc78bdd9": {"__data__": {"id_": "adc1438e-1555-4ca1-9382-18c0bc78bdd9", "embedding": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b6f0e40f-c08e-4837-84ad-938b67cdadc8", "node_type": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1de53d5b632e2e1af9b3b483196e6d0ce44c8250fa68681883ed0750b1b10e07"}, "3": {"node_id": "b49f34e5-9064-493a-9796-9aebee3bc9ff", "node_type": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a1841a59e9ab853a7f87388cef96ec75a0b402de3acb3f98ad0064339a113c01"}}, "hash": "d968d66535b43bad438dcd554495caab9e572dd3dabd2d387b2360aa4e12f454", "text": "43 ANAlgESic dRUgS\n561Clinical uses of analgesic drugs (1) \n\u2022\tAnalgesics\t are\tused\tto\ttreat\tand\tprevent\tpain,\tfor\t\nexample:\n\u2013 pre- and postoperatively\n\u2013 common painful conditions including headache, \ndysmenorrhoea, labour, trauma and burns\n\u2013 many medical and surgical emergencies (e.g. \nmyocardial infarction and renal colic)\n\u2013 terminal disease (especially metastatic cancer)\n\u2022\tOpioid\tanalgesics\t are\tused\tin\tsome\tnon-painful\t\nconditions, for example acute heart failure (because of \ntheir haemodynamic effects) and terminal chronic heart \nfailure (to relieve distress).\n\u2022\tThe\tchoice\tand\troute\tof\tadministration\t of\tanalgesic\t\ndrugs depends on the nature and duration of the pain.\n\u2022\tA\tprogressive\t approach\t is\toften\tused,\tstarting\twith\t\nnon-steroidal anti-inflammatory drugs (NSAIDs), supplemented first by weak opioid analgesics and then \nby strong opioids.\n\u2022\tIn\tgeneral,\tsevere\tacute\tpain\tis\ttreated\twith\tstrong\t\nopioids (e.g. morphine , fentanyl ) given by injection. \nMild inflammatory pain (e.g. sprains, mild arthralgia) is \ntreated with NSAIDs (e.g. ibuprofen ) or by \nparacetamol supplemented by weak opioids (e.g. \ncodeine ). Severe pain (e.g. cancer pain) is treated with \nstrong opioids given orally, intrathecally, epidurally or by \nsubcutaneous injection. Patient-controlled infusion \nsystems are useful postoperatively.\n\u2022\tChronic\t neuropathic\t pain\tis\tless\tresponsive\t to\topioids\t\nand can be treated with tricyclic antidepressants (e.g. \namitriptyline ) or anticonvulsants (e.g. carbamazepine , \ngabapentin ).\nClinical uses of analgesic drugs (2) \n\u2022\tNon-steroidal\t anti-inflammatory\t drugs\t(see\tfirst\tclinical\t\nbox), including paracetamol , are useful for \nmusculoskeletal and dental pain and for dysmenorrhoea. \nThey reduce opioid requirements in acute (e.g. \npostoperative) and chronic (e.g. bone metastasis) pain.\n\u2022\tWeak\topioids\t(e.g.\t codeine ) combined with \nparacetamol are useful in moderately severe pain if \nnon-opioids are not sufficient. Tramadol and \ntapentadol (a weak opioid with additional action on \n5-hydroxytryptamine and noradrenaline uptake) are \nalternatives.\n\u2022\tStrong\t opioids\t(e.g.\t morphine ) are used for severe pain, \nparticularly of visceral origin.\n\u2022\tNote\tthat:\n\u2013 the intravenous route provides rapid relief from pain \nand distress;\n\u2013 the intravenous dose is much lower than the oral dose \nbecause of presystemic metabolism;\u2013 morphine is given orally as a solution or as \n\u2018immediate-release\u2019 tablets every 4 h;\n\u2013 dose is titrated; when the daily requirement is \napparent, the preparation is changed to a modified-\nrelease formulation to allow once- or twice-daily \ndosing;\n\u2013 morphine and oxycodone can be given orally in \nslow-release tablet form;\n\u2013 transdermal administration (e.g. patches of fentanyl ) is \nan alternative, rapid means of pain relief;\n\u2013 adverse effects (nausea, constipation) are anticipated \nand treated pre-emptively;\n\u2013 addiction is not an issue in the setting of terminal care.\n\u2022\tSubanaesthetic\t doses\tof\tnitrous oxide ", "start_char_idx": 0, "end_char_idx": 2990, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b49f34e5-9064-493a-9796-9aebee3bc9ff": {"__data__": {"id_": "b49f34e5-9064-493a-9796-9aebee3bc9ff", "embedding": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b6f0e40f-c08e-4837-84ad-938b67cdadc8", "node_type": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1de53d5b632e2e1af9b3b483196e6d0ce44c8250fa68681883ed0750b1b10e07"}, "2": {"node_id": "adc1438e-1555-4ca1-9382-18c0bc78bdd9", "node_type": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d968d66535b43bad438dcd554495caab9e572dd3dabd2d387b2360aa4e12f454"}, "3": {"node_id": "064152b4-0e4f-4f81-bba5-4ed3edc63692", "node_type": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3a5575494bfee3839e6e3ae2d5b85504d6036dea19e5721bab950034cd779523"}}, "hash": "a1841a59e9ab853a7f87388cef96ec75a0b402de3acb3f98ad0064339a113c01", "text": "terminal care.\n\u2022\tSubanaesthetic\t doses\tof\tnitrous oxide (Ch. 42) are \nanalgesic, and self-administration of a mixture of nitrous \noxide with oxygen is widely used during labour or for \npainful dressing changes.\nREFERENCES AND FURTHER READING\nGeneral\nApkarian,\t A.V.,\tBushnell,\t M.C.,\tSchweinhardt,\t P.,\t2013.\tRepresentation\t\nof\tpain\tin\tthe\tbrain.\tIn:\tMcMahon,\t S.B.,\tKoltzenburg,\t M.,\tTracey,\tI.,\t\nTurk,\tD.C.\t(Eds.),\tWall\t&\tMelzack\u2019s\t Textbook\t of\tPain,\tsixth\ted.\t\nElsevier,\t Philadelphia,\t pp.\t111\u2013128.\t (Detailed account of central pathways \nthat inhibit or enhance transmission in the dorsal horn )\nTodd,\tA.J.,\tKoerber,\t H.R.,\t2013.\tNeuroanatomical\t substrates\t of\tspinal\t\nnociception.\t In:\tMcMahon,\t S.B.,\tKoltzenburg,\t M.,\tTracey,\tI.,\tTurk,\t\nD.C.\t(Eds.),\tWall\t&\tMelzack\u2019s\t Textbook\t of\tPain,\tsixth\ted.\tElsevier,\t\nPhiladelphia,\t pp.\t77\u201393.\t(Detailed account of central pathways that inhibit \nor enhance transmission in the dorsal horn )\nMcMahon,\t S.B.,\tKoltzenburg,\t M.,\tTracey,\tI.,\tTurk,\tD.C.\t(Eds.),\t2013.\t\nWall\t&\tMelzack\u2019s\t Textbook\t of\tPain,\tsixth\ted.\tElsevier,\t Philadelphia.\t\n(Large multiauthor reference book )\nYaksh,\tT.L.,\t1999.\tSpinal\tsystems\t and\tpain\tprocessing:\t development\t of\t\nnovel analgesic drugs with mechanistically defined models. Trends \nPharmacol.\t Sci.\t20,\t329\u2013337.\t (Good general review article on spinal cord \nmechanisms \u2013 more general than its title suggests )TRP channels\nNilius,\tB.,\tSzallasi,\t A.,\t2014.\tTransient\t receptor\t potential\t channels\t as\t\ndrug targets: from the science of basic research to the art of medicine. \nPharmacol.\t Rev.\t66,\t676\u2013814.\t (Extensive review of the potential of TRP \nchannels for drug development )\nBDNF and TrkA\nMantyh,\t P.W.,\tKoltzenburg,\t M.,\tMendell,\t L.M.,\tTive,\tL.,\tShelton,\t D.L.,\t\n2011.\tAntagonism\t of\tnerve\tgrowth\tfactor-TrkA\t signaling\t and\tthe\t\nrelief\tof\tpain.\tAnesthesiology\t 115,\t189\u2013204.\nOpioids\nBallantyne,\t J.C.,\tMao,\tJ.,\t2003.\tOpioid\ttherapy\tfor\tchronic\tpain.\tN.\tEngl.\t\nJ.\tMed.\t349,\t1943\u20131953.\t (Considers whether or not tolerance is a problem \nwhen opioids are used to treat chronic pain )\nBingel,\tU.,\tTracey,\tI.,\tWiech,\tK.,\t2012.\tNeuroimaging\t as\ta\ttool\tto\t\ninvestigate how cognitive factors influence analgesic drug outcomes. \nNeurosci.\t Lett.\t520,\t149\u2013155.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2939, "end_char_idx": 5388, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "064152b4-0e4f-4f81-bba5-4ed3edc63692": {"__data__": {"id_": "064152b4-0e4f-4f81-bba5-4ed3edc63692", "embedding": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b6f0e40f-c08e-4837-84ad-938b67cdadc8", "node_type": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1de53d5b632e2e1af9b3b483196e6d0ce44c8250fa68681883ed0750b1b10e07"}, "2": {"node_id": "b49f34e5-9064-493a-9796-9aebee3bc9ff", "node_type": null, "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a1841a59e9ab853a7f87388cef96ec75a0b402de3acb3f98ad0064339a113c01"}}, "hash": "3a5575494bfee3839e6e3ae2d5b85504d6036dea19e5721bab950034cd779523", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5409, "end_char_idx": 5712, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "876b97ae-6834-46f9-b97f-98145d513934": {"__data__": {"id_": "876b97ae-6834-46f9-b97f-98145d513934", "embedding": null, "metadata": {"page_label": "568", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e86ddae-f9eb-4271-b073-3a7370738ab7", "node_type": null, "metadata": {"page_label": "568", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a4b87c8e51c87b7be76fe74e34b376db3fcb9c49c3cb844d857de840d96a234e"}, "3": {"node_id": "b9325247-4fb3-4cac-9f2f-6707de4b5bc0", "node_type": null, "metadata": {"page_label": "568", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59de2b7657d340d8759ec15f5de2619e37360c3658c37f951536db673e2ceb44"}}, "hash": "3014cb26e1b4ddbfc990594aad266cb25d878c60188ad90bc73d95e3b456848a", "text": "43 SECTION 4 NERVOUS SYSTEM\n562Stannard, \tC., \t2016. \tOpioids \tand \tchronic \tpain: \tusing \twhat \twe \tknow \tto \t\nchange\twhat \twe \tdo. \tCurr. \tOpin. \tSupport. \tPalliat. \tCare \t10, \t129\u2013136. \t\n(An interesting article that tries to explain why opioids are not very effective \nin the treatment of chronic pain)\nWilliams, \tJ.T., \tIngram, \tS.L., \tHenderson, \tG., \tet \tal., \t2013. \tRegulation \tof \t\n\u00b5-opioid receptors: desensitization, phosphorylation, internalization, \nand\ttolerance. \tPharmacol. \tRev. \t65, \t223\u2013254. \t(Very comprehensive review \nof the molecular and cellular mechanisms underlying opioid tolerance)\nNeuropathic pain and new drug targets\nBarnes,\tM.P., \tBarnes, \tJ.C., \t2016. \tCannabis: \tthe \tevidence \tfor \tmedical \tuse. \t\nAll Party Parliamentary Group on Drug Policy Reform report. \nAvailable \tat \thttps://drive.google.com/file/d/0B0\nc_8hkDJu0DUDZMUzhoY1RqMG8/view. \t(A very comprehensive review \nof clinical trials of natural and synthetic cannabinoids for a range of \ndisorders including pain)\nDworkin, \tR.H., \tO\u2019Connor, \tA.B., \tAudette, \tJ., \tet \tal., \t2010. \t\nRecommendations for the pharmacological management of \nneuropathic \tpain: \tan \toverview \tand \tliterature \tupdate. \tMayo \tClin. \tProc. \t\n85\t(3\tSuppl.), \tS3\u2013S14. \t(An evaluation of the clinical effectiveness of current \ndrugs used to treat neuropathic pain)\nGilron,\tI., \tDickenson, \tA.H., \t2014. \tEmerging \tdrugs \tfor \tneuropathic \tpain. \t\nExpert\tOpin. \tEmerg. \tDrugs \t19, \t329\u2013341. \t(Contains details on a range of \nnew drugs in development for the treatment of neuropathic pain)\nMcEntire, \tD.M., \tKirkpatrick, \tD.R., \tDueck, \tN.P., \tet \tal., \t2016. \tPain \t\ntransduction: a pharmacologic perspective. Expert Rev. Clin. \nPharmacol. \t9, \t1069\u20131080. \t(Reviews the development of analgesic drugs \ninteracting with TRP, ASIC and Na+ channels)BMA,\t2017. \tChronic \tpain: \tsupporting \tsafer \tprescribing \tof \tanalgesics. \t\nAvailable at https://www.bma.org.uk/collective-voice/policy-and- \nresearch/public-and-population-health/analgesics-use.\nCorbett,\tA.D., \tHenderson, \tG., \tMcKnight, \tA.T., \tet \tal., \t2006. \t75 \tyears \tof \t\nopioid research: the exciting but vain search for the holy grail. Br. J. \nPharmacol. \t147, \tS153\u2013S162. \t(Comprehensive historical review of opioid \nresearch)\nFujita,\tW., \tGomes, \tI., \tDevi, \tL.A., \t2014. \tRevolution \tin \tGPCR \tsignalling: \t\nopioid receptor heteromers as novel therapeutic targets: IUPHAR \nreview\t10. \tBr.", "start_char_idx": 0, "end_char_idx": 2418, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b9325247-4fb3-4cac-9f2f-6707de4b5bc0": {"__data__": {"id_": "b9325247-4fb3-4cac-9f2f-6707de4b5bc0", "embedding": null, "metadata": {"page_label": "568", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5e86ddae-f9eb-4271-b073-3a7370738ab7", "node_type": null, "metadata": {"page_label": "568", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a4b87c8e51c87b7be76fe74e34b376db3fcb9c49c3cb844d857de840d96a234e"}, "2": {"node_id": "876b97ae-6834-46f9-b97f-98145d513934", "node_type": null, "metadata": {"page_label": "568", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3014cb26e1b4ddbfc990594aad266cb25d878c60188ad90bc73d95e3b456848a"}}, "hash": "59de2b7657d340d8759ec15f5de2619e37360c3658c37f951536db673e2ceb44", "text": "\tJ. \tPharmacol. \t171, \t4155\u20134176.\nHayhurst, \tC.J., \tDurieux, \tM.E., \t2016. \tDifferential \topioid \ttolerance \tand \t\nopioid-induced \thyperalgesia: \ta \tclinical \treality. \tAnesthesiology \t124, \t\n483\u2013488.\t(Discusses the potential adverse consequences of tolerance \ndeveloping more to the analgesic that respiratory depressant effects of opioids)\nKelly,\tE., \t2013. \tEfficacy \tand \tligand \tbias \tat \tthe \t\u00b5-opioid receptor. Br. J. \nPharmacol. \t169, \t1430\u20131446. \t(Gentle introduction to the topic of ligand \nbias)\nLee,\tM.,\tSilverman, \tS.M., \tHansen, \tH., \tPatel, \tV.B., \tManchikanti, \tL., \t2011. \t\nA comprehensive review of opioid-induced hyperalgesia. Pain \nPhysician \t14, \t145\u2013161.\nMcQuay, \tH., \t1999. \tOpioids \tin \tpain \tmanagement. \tLancet \t353, \t2229\u20132232. \t\n(Discusses whether or not tolerance occurs to opioids in clinical situations )\nRoeckel,\tL.A., \tLe \tCoz, \tG.M., \tGav\u00e9riaux-Ruff, \tC., \tSimonin, \tF., \t2016. \t\nOpioid-induced hyperalgesia: cellular and molecular mechanisms. \nNeuroscience \t338, \t160\u2013182.\nRollason, \tV., \tSamer, \tC., \tPiquet, \tV., \tet \tal., \t2008. \tPharmacogenetics \tof \t\nanalgesics: towards the personalization of prescription. \nPharmacogenomics \t9, \t905\u2013933.\nSawynok, \tJ., \t2003. \tTopical \tand \tperipherally \tacting \tanalgesics. \t\nPharmacol. \tRev. \t55, \t1\u201320. \t(Review of the numerous mechanisms by which \ndrugs interfere with nociceptive mechanisms in the periphery)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2419, "end_char_idx": 4286, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5e936a17-dff7-4ef6-89e1-171634c7775d": {"__data__": {"id_": "5e936a17-dff7-4ef6-89e1-171634c7775d", "embedding": null, "metadata": {"page_label": "569", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "15a084ec-7d94-4458-bddb-f8e138b1ec71", "node_type": null, "metadata": {"page_label": "569", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f2b036d11e7a47743f4bd296f33302c881560ec9ea813a567017aa0200928d08"}, "3": {"node_id": "9798ef3f-9c00-486d-8855-7b76b26519db", "node_type": null, "metadata": {"page_label": "569", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e53fa5176880015e8a79c276cec1c6329bfd794151bf1098fca248a1479dd08d"}}, "hash": "20bbdc4d5f38944d163b086cf1a6b9ee7cded6a3e9a98aeaf664020ddd9a387e", "text": "563\nOVERVIEW\nAs described in Chapter 4, the property of electri-\ncal excitability is what enables the membranes of \nnerve and muscle cells to generate propagated action \npotentials, which are essential for communication in the nervous system and for the initiation of mechani -\ncal activity in striated muscle. Initiation of the action potential depends on voltage-gated sodium chan -\nnels, which open transiently when the membrane \nis depolarised. Here we discuss local anaesthetics, \nwhich act mainly by blocking sodium channels, and mention briefly other drugs that affect sodium-channel \nfunction.\nThere are, broadly speaking, two ways in which \nchannel function may be modified, namely block of \nthe channels and modification of gating behaviour. \nBlocking sodium channels reduces excitability. On the other hand, different types of drugs can \neither facilitate channel opening and thus increase \nexcitability, or inhibit channel opening and reduce \nexcitability.\nLOCAL ANAESTHETICS\nAlthough many drugs can, at high concentrations, block \nvoltage-sensitive sodium channels and inhibit the generation \nof the action potential, the only drugs used clinically for \nthis effect are the local anaesthetics, various antiepileptic and analgesic drugs (see Chs 43 and 46) and class I anti -\ndysrhythmic drugs (see Ch. 22).\nHISTORY\nCoca leaves have been chewed for their psychotropic effects for thousands of years (see Ch. 49) by South American \nIndians, who knew about the numbing effect they produced \non the mouth and tongue. Cocaine was isolated in 1860 \nand proposed as a local anaesthetic for surgical procedures. \nSigmund Freud, who tried unsuccessfully to make use of \nits \u2018psychic energising\u2019 power, gave some cocaine to his ophthalmologist friend in Vienna, Carl K\u00f6ller, who reported \nin 1884 that reversible corneal anaesthesia could be produced \nby dropping cocaine on to the eye. The idea was rapidly taken up, and within a few years cocaine anaesthesia was introduced into dentistry and general surgery. A synthetic \nsubstitute, procaine, was discovered in 1905, and many \nother useful compounds were later developed.\nCHEMICAL ASPECTS\nLocal anaesthetic molecules consist of an aromatic part \nlinked by an ester or amide bond to a basic side chain (Fig. 44.1). They are weak bases, with p Ka values mainly in the \nrange 8\u20139, so that they are mainly, but not completely, \nionised at physiological pH (see Ch. 9 for an explanation \nof how pH influences the ionisation of weak bases). This is important in relation to their ability to penetrate the \nnerve sheath and axon membrane; quaternary derivatives \nsuch as QX-314, which are fully ionised irrespective of pH, are ineffective as local anaesthetics but have important \nexperimental uses. Benzocaine , an atypical local anaesthetic, \nhas no basic group.\nThe presence of the ester or amide bond in local anaes -\nthetic molecules is important because of its susceptibility to metabolic hydrolysis. The ester-containing compounds \nare fairly rapidly inactivated in the plasma and tissues (mainly liver) by non-specific esterases. Amides are more \nstable, and these anaesthetics generally have longer plasma \nhalf-lives.\nMECHANISM OF ACTION\nLocal anaesthetics block the initiation and propagation of action potentials by preventing the voltage-dependent \nincrease in Na\n+ conductance (see Ch. 4 and Strichartz & \nRitchie, 1987; Hille, 2001). At low concentrations they decrease the rate of rise of the action potential, increasing \nits duration, and increase the refractory period thus reducing the firing rate. At higher concentrations they prevent action \npotential firing. Currently available local anaesthetic agents \ndo not, by", "start_char_idx": 0, "end_char_idx": 3692, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9798ef3f-9c00-486d-8855-7b76b26519db": {"__data__": {"id_": "9798ef3f-9c00-486d-8855-7b76b26519db", "embedding": null, "metadata": {"page_label": "569", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "15a084ec-7d94-4458-bddb-f8e138b1ec71", "node_type": null, "metadata": {"page_label": "569", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f2b036d11e7a47743f4bd296f33302c881560ec9ea813a567017aa0200928d08"}, "2": {"node_id": "5e936a17-dff7-4ef6-89e1-171634c7775d", "node_type": null, "metadata": {"page_label": "569", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20bbdc4d5f38944d163b086cf1a6b9ee7cded6a3e9a98aeaf664020ddd9a387e"}}, "hash": "e53fa5176880015e8a79c276cec1c6329bfd794151bf1098fca248a1479dd08d", "text": "prevent action \npotential firing. Currently available local anaesthetic agents \ndo not, by and large, distinguish between different sodium-channel subtypes, although their potencies vary (see Ch. \n4). They block sodium channels by physically plugging the \ntransmembrane pore, interacting with various amino acid residues of the S6 transmembrane helical domain of the channel protein (see Catterall & Swanson, 2015).\n\u25bc Local anaesthetic activity is strongly pH-dependent, being increased \nat alkaline extracellular pH (i.e. when the proportion of ionised \nmolecules is low) and reduced at acid pH. This is because the com-\npound needs to penetrate the nerve sheath and the axon membrane \nto reach the inner end of the sodium channel (where the local anaesthetic-binding site resides). Because the ionised form is not \nmembrane-permeant, penetration is very poor at acid pH. Once inside \nthe axon, it is primarily the ionised form of the local anaesthetic molecule that binds to the channel and blocks it (Fig. 44.2), the \nunionised form having only weak channel-blocking activity. This pH \ndependence can be clinically important, because the extracellular fluid \nof inflamed tissues is often relatively acidic and such tissues are thus \nsomewhat resistant to local anaesthetic agents.\nFurther analysis of local anaesthetic action (see Strichartz & Ritchie, \n1987) has shown that many drugs exhibit the property of \u2018use-dependent\u2019 \nblock of sodium channels, as well as affecting, to some extent, the \ngating of the channels. Use-dependence means that the more the \nchannels are opened, the greater the block becomes. It is a prominent \nfeature of the action of many class I antidysrhythmic drugs (Ch. 22) \nand antiepileptic drugs (Ch. 46), and occurs because the blocking Local anaesthetics and other drugs \naffecting sodium channels 44 NERVOUS SYSTEM SECTION 4\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3602, "end_char_idx": 5942, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5176d231-eade-4c4e-a089-bee948130310": {"__data__": {"id_": "5176d231-eade-4c4e-a089-bee948130310", "embedding": null, "metadata": {"page_label": "570", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "91cb7cc1-cd79-4b6c-9331-66471ae4f32d", "node_type": null, "metadata": {"page_label": "570", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "273d8993fc150a4881d5735d3c2c6828e2992834a59776813a3467548fdeccc9"}, "3": {"node_id": "ae4cd4b8-4de5-4da1-92af-ffce8b2f6399", "node_type": null, "metadata": {"page_label": "570", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a0760ccc88cd8d272ff8c315b7d706f5e2deba65ef884802c3cf409d6b9957e"}}, "hash": "5f0d55f1a2ae62499e3c38729f19df7e33fbdbeb8b4923f292388383a64dce93", "text": "44 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n564effect by reducing the number of channels available for opening, and \nby prolonging the refractory period following an action potential. \nThe passage of a train of action potentials, for example, in response \nto a painful stimulus, causes the channels to cycle through the open and inactivated states, both of which are more likely to bind local \nanaesthetic molecules than the resting state; thus both mechanisms \ncontribute to use dependence, which explains in part why pain transmission may be blocked more effectively than other sensory \nmodalities.\nQuaternary amine local anaesthetics only work when applied to the \ninside of the membrane and the channels must be cycled through \ntheir open state a few times before the blocking effect appears. With tertiary amine local anaesthetics, block can develop even if the channels \nare not open, and it is likely that the blocking molecule (uncharged) \ncan reach the channel either directly from the membrane phase through fenestrations in the channel protein that allow uncharged molecules \nto access the pore of the channel in the resting (closed) state or from \nthe intracellular side via the open gate (see Fig. 44.2). The relative \nimportance of these two blocking pathways \u2013 the hydrophobic pathway \nvia the membrane and the hydrophilic pathway via the inner mouth of the channel \u2013 varies according to the lipid solubility of the drug.\nIn general, local anaesthetics block conduction in small-diameter nerve \nfibres more readily than in large fibres. Because nociceptive impulses are carried by A\u03b4 and C fibres (Ch. 43), pain sensation is blocked \nmore readily than other sensory modalities (touch, proprioception, \netc.). Motor axons, being large in diameter, are also relatively resistant. \nThe differences in sensitivity among different nerve fibres, although \neasily measured experimentally, are not of much practical importance, and it is not possible to block pain sensation without affecting other \nsensory modalities.\nLocal anaesthetics, as their name implies, are mainly used \nto produce local nerve block. At low concentrations, they \nare also able to suppress the spontaneous action potential \ndischarge in sensory neurons that occurs in neuropathic pain. The properties of individual local anaesthetic drugs \nare summarised in Table 44.1.molecule enters the channel much more readily when the channel is \nopen than when it is closed. Furthermore, for local anaesthetics that \nrapidly dissociate from the channel, block only occurs at high frequen -\ncies of action potential firing when the time between action potentials \nis too short for drug dissociation from the channel to occur. The \nchannel can exist in three functional states: resting, open and inactivated \n(see Ch. 4). Many local anaesthetics bind most strongly to the inac-tivated state of the channel. Therefore, at any given membrane \npotential, the equilibrium between resting and inactivated channels \nwill, in the presence of a local anaesthetic, be shifted in favour of the \ninactivated state, and this factor contributes to the overall blocking BupivacainePrilocaineLidocaine\n(lignocaine)Cinchocaine\n(dibucaine)Tetracaine\n(amethocaine)CocaineProcaineBasic amine\nside-chainEster\nor\namide\nbondAromatic regionLocal anaesthetics\nH2NCH2CH3\nCH2CH3CH2CH2N\nCH2CH3\nCH2CH3\nCH2CH3\nCH2CH3OO\nC\nOO\nCCH2\nCH2NCH3COOCH3\nOO\nC NH\nO\nC N\nCH3\nCH3CH2NO\nC NH\nO\nC NH CH\nCH3NHCH2CH2CH3\nCH3\nCH3\nCH3O\nC NH", "start_char_idx": 0, "end_char_idx": 3445, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ae4cd4b8-4de5-4da1-92af-ffce8b2f6399": {"__data__": {"id_": "ae4cd4b8-4de5-4da1-92af-ffce8b2f6399", "embedding": null, "metadata": {"page_label": "570", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "91cb7cc1-cd79-4b6c-9331-66471ae4f32d", "node_type": null, "metadata": {"page_label": "570", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "273d8993fc150a4881d5735d3c2c6828e2992834a59776813a3467548fdeccc9"}, "2": {"node_id": "5176d231-eade-4c4e-a089-bee948130310", "node_type": null, "metadata": {"page_label": "570", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5f0d55f1a2ae62499e3c38729f19df7e33fbdbeb8b4923f292388383a64dce93"}}, "hash": "8a0760ccc88cd8d272ff8c315b7d706f5e2deba65ef884802c3cf409d6b9957e", "text": "NH CHCH3CH2CH2CH2\nCH3CH2CH2CH2OCH3\nCH3CH2CH2N\nNHCH2CH2N\nNCH2CH2CH2CH3\nBenzocaine\nQX-314OO\nC H2N CH2CH3\nOC H2CCH3\nC2H5\nC2H5\nC2H5\nCH3N+\nNHArticaineOO\nC\nCH3CH3\nCO NH CH NH C3H7\nCH3S\nFig. 44.1 Structures of local anaesthetics. The general \nstructure of local anaesthetic molecules consists of an aromatic \ngroup (left), ester or amide group (shaded blue) and amine \ngroup (right). B\nBB\nBB\nB\nChannel\nshutChannel\nopenExteriorAxonal\nmembrane Interior\nNa+\nH+\nNa+\nH+BH+ BH+\nBH+ BH+Hydrophobic\npathway\n(no use-\ndependence)Hydrophilic pathway\n(use-dependent)\nFig. 44.2 Interaction of local anaesthetics with sodium \nchannels. The blocking site within the channel can be reached \nvia the open channel gate on the inner surface of the membrane by the charged species BH\n+ (hydrophilic pathway), or directly \nfrom the membrane through fenestrations in the channel wall by the uncharged species B (hydrophilic pathway). mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3443, "end_char_idx": 4830, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "53ae1884-6536-4f2f-8031-64b71b80143e": {"__data__": {"id_": "53ae1884-6536-4f2f-8031-64b71b80143e", "embedding": null, "metadata": {"page_label": "571", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c5dd7e24-3968-43c2-888d-dba258dcaee0", "node_type": null, "metadata": {"page_label": "571", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29156c7c4b73619710034c3be639220f9a8b0b0d75712b05e557557c47549ba8"}}, "hash": "29156c7c4b73619710034c3be639220f9a8b0b0d75712b05e557557c47549ba8", "text": "44 LOcaL aNaESThETicS aNd OT h ER d RU g S aff E c T i N g SO di UM cha NNELS\n565the systemic circulation. They may also be injected into \nveins or arterioles in error.\nMost local anaesthetics produce a mixture of depressant \nand stimulant effects on the CNS. Depressant effects pre -\ndominate at low plasma concentrations, giving way to \nstimulation at higher concentrations, resulting in restless -\nness, tremor and sometimes convulsions, accompanied by \nsubjective effects ranging from confusion to extreme agita -\ntion. Further increasing the dose produces profound CNS UNWANTED \u2003EFFECTS\nWhen used clinically as local anaesthetics, the main unwanted effects involve the central nervous system (CNS) \nand the cardiovascular system (see Table 44.1). Their action \non the heart can also be of use in treating cardiac arrhythmias (see Ch. 22). Although local anaesthetics are usually \nadministered in such a way as to minimise their spread to \nother parts of the body, they are ultimately absorbed into Table 44.1 Properties of local anaesthetics\nDrug Onset DurationTissue \npenetrationPlasma half-life (h) Main unwanted effects Notes\nCocaine Medium Medium Good ~1Cardiovascular and CNS \neffects owing to block of \namine uptakeRarely used, only as spray for \nupper respiratory tract\nProcaine Medium Short Poor <1CNS: restlessness, shivering, \nanxiety, occasionally \nconvulsions followed by \nrespiratory depression\nCardiovascular system: \nbradycardia and decreased \ncardiac output; \nvasodilatation, which can \ncause cardiovascular \ncollapseThe first synthetic agentNo longer usedChloroprocaine is also short acting and is used to produce intrathecal anaesthesia\nLidocaine (lignocaine)Rapid Medium Good ~2As procaine but less \ntendency to cause CNS \neffectsWidely used for local anaesthesiaAlso used intravenously for treating ventricular dysrhythmias though no longer as first choice (Ch. 22)\nMepivacaine Rapid Medium Good ~2 As procaineLess vasodilatation (may be administered without a vasoconstrictor)\nTetracaine (amethocaine)Very slowLong Moderate ~1 As lidocaineUsed mainly for anaesthesia before venipuncture or venous cannulation\nBupivacaine Slow Long Moderate ~2As lidocaine but greater \ncardiotoxicityWidely used because of long duration of actionRopivacaine is similar, with less cardiotoxicityLevobupivacaine causes less cardiotoxicity and CNS depression than the racemate, bupivacaine\nPrilocaine Medium Medium Moderate ~2No vasodilator activity\nCan cause \nmethaemoglobinaemiaWidely used; not for obstetric analgesia because of risk of neonatal methaemoglobinaemia\nArticaine Rapid Short Good ~0.5 As lidocaineUsed in dentistryWhile its chemical structure contains an amide linkage it also has an ester group on a side chain (see Fig. 44.1). Hydrolysis of the side chain inactivates the drug\nCNS, central nervous system.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3311, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bdb5eb1b-ea37-427c-bfc5-072c06a3d8b4": {"__data__": {"id_": "bdb5eb1b-ea37-427c-bfc5-072c06a3d8b4", "embedding": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "13a69199-7d94-43f5-af01-6b3e7237a822", "node_type": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e41a34573f8f2c30a376006cba7bb202177f3396316d4219b08508de8afe9e7"}, "3": {"node_id": "050d053d-4109-48f7-bd57-2f8579c13ec4", "node_type": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0331d50c08b92beeb7235d254da3f93087dec004746021032053d05ef5cc7955"}}, "hash": "690a29d9b9ac25156bfbf8b034f5bd1a064b51daa5c5051eab0ed95bce7c4ef7", "text": "44 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n566cardiac output, vasoconstriction and increased arterial \npressure.\nHypersensitivity reactions sometimes occur with local \nanaesthetics, usually in the form of allergic dermatitis but \nrarely as an acute anaphylactic reaction. Other unwanted \neffects that are specific to particular drugs include mucosal \nirritation (cocaine) and methaemoglobinaemia (which occurs after large doses of prilocaine, because of the production \nof a toxic metabolite).\nPHARMACOKINETIC ASPECTS\nLocal anaesthetics vary a good deal in the rapidity with \nwhich they penetrate tissues, and this affects the rate at \nwhich they cause nerve block when injected into tissues, \nand the rate of onset of, and recovery from, anaesthesia (see Table 44.1; see Becker & Reed, 2012). It also affects \ntheir usefulness as surface anaesthetics for application to \nmucous membranes.\nMost of the ester-linked local anaesthetics (e.g. tetracaine ) \nare rapidly hydrolysed by plasma cholinesterase, so their plasma half-life is short. Procaine \u2013 now rarely used \u2013 is hydrolysed to p-aminobenzoic acid, a folate precursor that \ninterferes with the antibacterial effect of sulfonamides (see \nCh. 52). The amide-linked drugs (e.g. lidocaine and prilo-\ncaine) are metabolised mainly in the liver, usually by N-dealkylation rather than cleavage of the amide bond, \nand the metabolites are often pharmacologically active.\nBenzocaine is an unusual local anaesthetic of very low \nsolubility, which is used as a dry powder to dress painful skin ulcers, or as throat lozenges. The drug is slowly released \nand produces long-lasting surface anaesthesia.\n1\nThe routes of administration, uses and main adverse \neffects of local anaesthetics are summarised in Table 44.2.\nMost local anaesthetics have a direct vasodilator action, \nwhich increases the rate at which they are absorbed into the systemic circulation, thus increasing their potential \ntoxicity and reducing their local anaesthetic action. \nAdrenaline (epinephrine ), phenylephrine or felypressin , \na short-acting vasopressin analogue (see Ch. 34), may be \nadded to local anaesthetic solutions injected locally to \ncause vasoconstriction. Adrenaline and phenylephrine absorbed into the circulation may induce unwanted cardiovascular effects such as tachycardia and vasoconstric -\ntion, and felypressin may cause coronary artery constric-tion. Their use in patients with cardiovascular disease is \ncontraindicated.\nNEW APPROACHES\nBlocking specific sodium-channel subtypes is seen as a promising therapeutic strategy for a variety of clinical \nconditions, including epilepsy (see Ch. 46), neurodegenera -\ntive diseases and stroke (see Ch. 41), neuropathic pain (see \nCh. 43) and myopathies (see Ch. 22). As our understanding \nof the role of specific sodium-channel subtypes in different \npathophysiological situations increases, so too will be the likelihood that selective blocking agents can be developed \nfor use in different clinical situations.\n\u25bc Charged local anaesthetics do not cross the plasma membrane \nand thus when applied to the outside of nerves do not inhibit action \npotential firing. They can, however, enter cells via the pore of TRP \nchannels such as TRPV1 (see Ch. 43). As TRPV1 channels are primarily \nlocalised on sensory neurons carrying pain information, this raises depression and death due to respiratory depression. The \nonly local anaesthetic with markedly different CNS effects \nis cocaine (see Ch. 49), which produces euphoria at doses \nwell below those that cause other CNS effects.", "start_char_idx": 0, "end_char_idx": 3555, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "050d053d-4109-48f7-bd57-2f8579c13ec4": {"__data__": {"id_": "050d053d-4109-48f7-bd57-2f8579c13ec4", "embedding": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "13a69199-7d94-43f5-af01-6b3e7237a822", "node_type": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e41a34573f8f2c30a376006cba7bb202177f3396316d4219b08508de8afe9e7"}, "2": {"node_id": "bdb5eb1b-ea37-427c-bfc5-072c06a3d8b4", "node_type": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "690a29d9b9ac25156bfbf8b034f5bd1a064b51daa5c5051eab0ed95bce7c4ef7"}, "3": {"node_id": "976c8e0e-a268-4fee-937e-809807e7fa9c", "node_type": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6513a0980ecb7f689b2e5c5bbf8263ff94c9c606813564c61f46a8f0bc136c6b"}}, "hash": "0331d50c08b92beeb7235d254da3f93087dec004746021032053d05ef5cc7955", "text": "which produces euphoria at doses \nwell below those that cause other CNS effects. This relates \nto its specific effect to inhibit monoamine uptake, an effect \nnot shared by other local anaesthetics. Procaine is particu -\nlarly liable to produce unwanted central effects, and has \nbeen superseded in clinical use by agents such as lidocaine \nand prilocaine. Studies with bupivacaine, a widely used \nlong-acting local anaesthetic prepared as a racemic mixture of two optical isomers, suggested that its CNS and cardiac effects were mainly due to the S(+) isomer. The R(\u2212) isomer \n(levobupivacaine) has a better margin of safety.\nActions of local anaesthetics \n\u2022\tLocal\tanaesthetics \tblock \taction \tpotential \tgeneration \tby \t\nblocking sodium channels.\n\u2022\tLocal\tanaesthetics \tare \tamphiphilic \tmolecules \twith \ta \t\nhydrophobic aromatic group and a basic amine group.\n\u2022\tLocal\tanaesthetics \tare \tweak \tbases \tthat \tact \tin \ttheir \t\ncationic form but must reach their site of action by \npenetrating the nerve sheath and axonal membrane as un-ionised species.\n\u2022\tMany\tlocal \tanaesthetics \tshow \tuse-dependence \t(depth \t\nof block increases with action potential frequency). This arises:\n\u2013 because anaesthetic molecules gain access to the \nchannel more readily when the channel is open;\n\u2013 because anaesthetic molecules have higher affinity \nfor inactivated than for resting channels.\n\u2022\tUse-dependence \tis \tmainly \tof \timportance \tin \trelation \tto \t\nantidysrhythmic and antiepileptic effects of sodium-channel blockers.\n\u2022\tLocal\tanaesthetics \tblock \tconduction \tin \tperipheral \t\nnerves in the following order: small myelinated axons, non-myelinated axons, large myelinated axons. Nociceptive and sympathetic transmission is thus \nblocked first.\n\u2022\tSodium-channel \tblock \tin \tcardiac \tmuscle \tand \tin \tcentral \t\nnervous system neurons is exploited in the therapy of \ncardiac dysrhythmias (Ch. 22) and epilepsy (Ch. 46).\n1Benzocaine is also used in \u2018endurance\u2019 condoms to delay ejaculation.The adverse cardiovascular effects of local anaesthetics \nare due mainly to myocardial depression, conduction block \nand vasodilatation. Reduction of myocardial contractility \nprobably results indirectly from an inhibition of the Na+ \ncurrent in cardiac muscle (see Ch. 22). The resulting decrease \nof [Na+]i in turn reduces intracellular Ca2+ stores (see Ch. \n4), and this reduces the force of contraction. Interference with atrioventricular conduction can result in partial or \ncomplete heart block, as well as other types of dysrhythmia. Ropivacaine has less cardiotoxicity than bupivacaine.\nVasodilatation, mainly affecting arterioles, is due partly \nto a direct effect on vascular smooth muscle, and partly to inhibition of the sympathetic nervous system. This \nleads to a fall in blood pressure, which may be sudden \nand life-threatening. Cocaine is an exception in respect of its cardiovascular effects, because of its ability to inhibit noradrenaline reuptake (see Ch. 15). This enhances \nsympathetic activity, leading to tachycardia, increased mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3488, "end_char_idx": 6882, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "976c8e0e-a268-4fee-937e-809807e7fa9c": {"__data__": {"id_": "976c8e0e-a268-4fee-937e-809807e7fa9c", "embedding": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "13a69199-7d94-43f5-af01-6b3e7237a822", "node_type": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3e41a34573f8f2c30a376006cba7bb202177f3396316d4219b08508de8afe9e7"}, "2": {"node_id": "050d053d-4109-48f7-bd57-2f8579c13ec4", "node_type": null, "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0331d50c08b92beeb7235d254da3f93087dec004746021032053d05ef5cc7955"}}, "hash": "6513a0980ecb7f689b2e5c5bbf8263ff94c9c606813564c61f46a8f0bc136c6b", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6919, "end_char_idx": 7062, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a1f0717b-d0fe-41e9-9594-e8e996a1e19d": {"__data__": {"id_": "a1f0717b-d0fe-41e9-9594-e8e996a1e19d", "embedding": null, "metadata": {"page_label": "573", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd51dc01-54b4-4c49-aaa3-573b1d09a9dd", "node_type": null, "metadata": {"page_label": "573", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82638c2c1aa51b8bd795c7789139b3815a967e82df6dd7b5083e47c8cd8916dd"}, "3": {"node_id": "6b8a59e6-6e95-4d91-844c-45802303ffd3", "node_type": null, "metadata": {"page_label": "573", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "262efa9b945c34a1f6f240af0e821b94698f38d13e1f13f2956cc34bdb9817db"}}, "hash": "5de9973bff433abb0de21996bee0ce5ef1edef740f678e2710fed82bb4b14346", "text": "44 LOcaL aNaESThETicS aNd OT h ER d RU g S aff E c T i N g SO di UM cha NNELS\n567it in public restaurants, however, the chef must be registered as \nsufficiently skilled in removing the toxic organs (especially liver and \novaries) to make the flesh safe to eat. Accidental TTX poisoning is \nquite common, nonetheless. Historical records of long sea voyages often contained reference to attacks of severe weakness, progressing \nto complete paralysis and death, caused by eating puffer fish. It was \nsuggested that the powders used by voodoo practitioners to induce zombification may contain TTX but this is disputed.\nSaxitoxin (STX) is produced by a marine microorganism that sometimes \nproliferates in very large numbers and even colours the sea, giving \nthe red tide phenomenon. At such times, marine shellfish can accumulate \nthe toxin and become poisonous to humans.\nThese toxins, unlike conventional local anaesthetics, act exclusively \nfrom the outside of the membrane. Both are complex molecules, bearing a positively charged guanidinium moiety. The guanidinium \nion is able to permeate voltage-sensitive sodium channels, and this the possibility of applying a charged local anaesthetic such as QX-314 \nalong with a TRPV1 activator, thus allowing the local anaesthetic to \nenter and block sodium channels only on nociceptive neurons, resulting \nin the block of pain sensation without affecting motor, autonomic or \nother sensory nerves.\nOTHER DRUGS THAT AFFECT SODIUM \nCHANNELS\nTETRODOTOXIN AND SAXITOXIN\n\u25bc Tetrodotoxin (TTX) is produced by a marine bacterium and \naccumulates in the tissues of a poisonous Pacific fish, the puffer fish. \nThe puffer fish is regarded in Japan as a special delicacy, partly because \nof the mild tingling sensation that follows eating its flesh. To serve Table 44.2 Methods of administration, uses and adverse effects of local anaesthetics\nMethod Uses Drug(s) Notes and adverse effects\nSurface \nanaesthesiaNose, mouth, bronchial tree (usually in spray form), cornea, urinary tract, uterus (for hysteroscopy)Not very effective for skin\naLidocaine, tetracaine, (amethocaine), dibucaine, benzocaineRisk of systemic toxicity when high concentrations and large areas are involvedChloroethane (ethyl chloride) applied to the skin produces a mild chilling and local numbing. It can be used for minor surgical procedures\nInfiltration anaesthesiaDirect injection into tissues to reach nerve branches and terminalsUsed in minor surgeryMostAdrenaline (epinephrine) or felypressin often added as vasoconstrictors (not with fingers or toes, for fear of causing ischaemic tissue damage)Suitable for only small areas, otherwise serious risk of systemic toxicity\nIntravenous regional anaesthesiaLA injected intravenously distal to a pressure cuff to arrest blood flow; remains effective until the circulation is restoredUsed for limb surgeryMainly lidocaine, prilocaineRisk of systemic toxicity when cuff is released prematurely; risk is small if cuff remains inflated \nfor at least 20 min\nNerve block anaesthesiaLA is injected close to nerve trunks (e.g. brachial plexus, intercostal or dental nerves) to produce a loss of sensation peripherallyUsed for surgery, dentistry, analgesiaMostLess LA needed than for infiltration anaesthesiaAccurate placement of the needle is importantOnset of anaesthesia may be slowDuration of anaesthesia may be increased by addition of vasoconstrictor\nSpinal anaesthesia\nbLA injected into the subarachnoid or intrathecal space (containing cerebrospinal", "start_char_idx": 0, "end_char_idx": 3511, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6b8a59e6-6e95-4d91-844c-45802303ffd3": {"__data__": {"id_": "6b8a59e6-6e95-4d91-844c-45802303ffd3", "embedding": null, "metadata": {"page_label": "573", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd51dc01-54b4-4c49-aaa3-573b1d09a9dd", "node_type": null, "metadata": {"page_label": "573", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82638c2c1aa51b8bd795c7789139b3815a967e82df6dd7b5083e47c8cd8916dd"}, "2": {"node_id": "a1f0717b-d0fe-41e9-9594-e8e996a1e19d", "node_type": null, "metadata": {"page_label": "573", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5de9973bff433abb0de21996bee0ce5ef1edef740f678e2710fed82bb4b14346"}}, "hash": "262efa9b945c34a1f6f240af0e821b94698f38d13e1f13f2956cc34bdb9817db", "text": "into the subarachnoid or intrathecal space (containing cerebrospinal fluid) to act on spinal roots and spinal cordSometimes formulated with glucose (\u2018hyperbaricity\u2019) so that spread of LA can be controlled by tilting patientUsed for surgery to abdomen, pelvis or legLA can be used alone or in conjunction with a general anaesthetic to reduce stressProvides good postoperative pain reliefMainly lidocaineMain risks are bradycardia and hypotension (owing to sympathetic block), respiratory depression (owing to effects on phrenic nerve or respiratory centre); avoided by minimising cranial spreadPostoperative urinary retention (block of pelvic autonomic outflow) is common\nEpidural anaesthesia\ncLA injected into epidural space, blocking spinal rootsUses as for spinal anaesthesia; also for painless childbirthMainly lidocaine, bupivacaineUnwanted effects similar to those of spinal anaesthesia but less probable, because longitudinal spread of LA is reducedPostoperative urinary retention common\nLA,\tlocal\tanaesthetic.\naSurface\tanaesthesia \tdoes \tnot \twork \twell \ton \tthe \tskin, \talthough \ta \tnon-crystalline \tmixture \tof \tlidocaine \tand \tprilocaine \t(eutectic \tmixture \tof \tlocal \t\nanaesthetics \tor \tEMLA) \thas \tbeen \tdeveloped \tfor \tapplication \tto \tthe \tskin, \tproducing \tcomplete \tanaesthesia \tin \tabout \t1 \th. \tLidocaine \tis \tavailable \t\nin a patch preparation that can be applied to the skin to reduce pain in conditions such as post-herpetic neuralgia (shingles).\nbUse\tof\tspinal \tanaesthesia \tis \tdeclining \tin \tfavour \tof \tepidural \tadministration.\ncIntrathecal \tor \tepidural \tadministration \tof \tLA \tin \tcombination \twith \tan \topioid \t(see \tCh. \t43) \tproduces \tmore \teffective \tanalgesia \tthan \tcan \tbe \t\nachieved\twith \tthe \topioid \talone. \tOnly \ta \tsmall \tconcentration \tof \tLA \tis \tneeded, \tinsufficient \tto \tproduce \tappreciable \tloss \tof \tsensation \tor \tother \t\nside effects. The mechanism of this synergism is unknown, but the procedure has proved useful in pain treatment.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3443, "end_char_idx": 5907, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6051d786-2428-40e0-b853-fdbf0af907e9": {"__data__": {"id_": "6051d786-2428-40e0-b853-fdbf0af907e9", "embedding": null, "metadata": {"page_label": "574", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c88dd2e6-a699-49b4-bf59-3c0365771b14", "node_type": null, "metadata": {"page_label": "574", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f5888668f6f8ea7e437696b8085f0d391bf98ce2094b26ed55cd3d9e046ce93"}, "3": {"node_id": "e127933f-e806-4559-bfa1-85152bce5bbc", "node_type": null, "metadata": {"page_label": "574", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4958d43f1407863d1a4084498ea4316929167152208f49879140dab5ef737406"}}, "hash": "2512fad6f784e8b865ea4cd77021a1c120800b23d838ea7458308d8f9c9f59e8", "text": "44 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n568AGENTS THAT AFFECT SODIUM-CHANNEL \nGATING\n\u25bc Various substances modify sodium-channel gating in such a way \nas to increase the probability of opening of the channels (see Hille, \n2001). They include various toxins, mainly from frog skin (e.g. \nbatrachotoxin), scorpion or sea anemone venoms; plant alkaloids such \nas veratridine ; and insecticides such as DDT and the pyrethrins. They \nfacilitate sodium-channel activation so that sodium channels open at \nmore negative potentials close to the normal resting potential; they \nalso inhibit inactivation, so that the channels fail to close if the membrane remains depolarised. The membrane thus becomes hyper-\nexcitable, and the action potential is prolonged. Spontaneous discharges \noccur at first, but the cells eventually become permanently depolarised \nand inexcitable. All these substances affect the heart, producing \nextrasystoles and other dysrhythmias, culminating in fibrillation; they also cause spontaneous discharges in nerve and muscle, leading to \ntwitching and convulsions. The very high lipid solubility of substances \nlike DDT makes them effective as insecticides, for they are readily absorbed through the integument. Drugs in this class are useful as \nexperimental tools for studying sodium channels but have no clinical \nuses.\npart of the TTX or STX molecule lodges in the channel, while the rest of the molecule blocks its outer mouth. In the manner of its blockade of sodium channels, TTX can be likened to a champagne cork. In \ncontrast to the local anaesthetics, there is no interaction between the \ngating and blocking reactions with TTX or STX \u2013 their association and dissociation are independent of whether the channel is open or \nclosed. Some voltage-sensitive sodium channels expressed in cardiac \nmuscle or up-regulated in sensory neurons in neuropathic pain (i.e. Na\nV1.5, Na V1.8 and Na V1.9) are relatively insensitive to TTX (see \nCh. 43).\nBoth TTX and STX are unsuitable for clinical use as local anaesthetics, \nbeing expensive to obtain from their exotic sources and poor at \npenetrating tissues because of their very low lipid solubility. They \nhave, however, been important as experimental tools for the isolation and cloning of sodium channels (see Ch. 4).Unwanted effects and \npharmacokinetics of local \nanaesthetics \n\u2022\tLocal\tanaesthetics \tare \teither \testers \tor \tamides. \tEsters \t\nare rapidly hydrolysed by plasma and tissue esterases, \nand amides are metabolised in the liver. Plasma \nhalf-lives\tare \tgenerally \tshort, \tabout \t1\u20132 \th.\n\u2022\tUnwanted \teffects \tare \tdue \tmainly \tto \tescape \tof \tlocal \t\nanaesthetics into the systemic circulation.\n\u2022\tMain\tunwanted \teffects \tare:\n\u2013 central nervous system effects, namely agitation, \nconfusion, tremors progressing to convulsions and respiratory depression;\n\u2013 cardiovascular effects, namely myocardial \ndepression and vasodilatation, leading to fall in blood pressure;\n\u2013 occasional hypersensitivity reactions.\n\u2022\tLocal\tanaesthetics \tvary \tin \tthe \trapidity \twith \twhich \tthey \t\npenetrate tissues, and in their duration of action. Lidocaine (lignocaine) penetrates tissues readily and is suitable for surface application; bupivacaine has a \nparticularly long duration of action.\nClinical uses of local anaesthetics \n\u2022\tLocal\tanaesthetics \tmay \tbe \tinjected \tinto \tsoft \ttissue \t\n(e.g. of gums) or to block a nerve or nerve", "start_char_idx": 0, "end_char_idx": 3387, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e127933f-e806-4559-bfa1-85152bce5bbc": {"__data__": {"id_": "e127933f-e806-4559-bfa1-85152bce5bbc", "embedding": null, "metadata": {"page_label": "574", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c88dd2e6-a699-49b4-bf59-3c0365771b14", "node_type": null, "metadata": {"page_label": "574", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f5888668f6f8ea7e437696b8085f0d391bf98ce2094b26ed55cd3d9e046ce93"}, "2": {"node_id": "6051d786-2428-40e0-b853-fdbf0af907e9", "node_type": null, "metadata": {"page_label": "574", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2512fad6f784e8b865ea4cd77021a1c120800b23d838ea7458308d8f9c9f59e8"}}, "hash": "4958d43f1407863d1a4084498ea4316929167152208f49879140dab5ef737406", "text": "\t\n(e.g. of gums) or to block a nerve or nerve plexus.\n\u2022\tCo-administration \tof \ta \tvasoconstrictor \t(e.g. \t\nadrenaline) prolongs the local effect.\n\u2022\tLipid-soluble \tdrugs \t(e.g. \tlidocaine) are absorbed from \nmucous membranes and are used as surface anaesthetics.\n\u2022\tBupivacaine has a slow onset but long duration. It is often used for epidural blockade (e.g. to provide continuous epidural blockade during labour) and spinal anaesthesia. Its isomer levobupivacaine is less \ncardiotoxic if it is inadvertently administered into a blood vessel.\nREFERENCES AND FURTHER READING\nBecker, D.E., Reed, K.L., 2012. Local anesthetics: review of \npharmacological considerations. Anesth. Progr. 59, 90\u2013102. (Brief \nreview of local anaesthetic pharmacology from a dental perspective)\nCatterall, W.A., Swanson, T.M., 2015. Structural basis for pharmacology \nof voltage-gated sodium and calcium channels. Mol. Pharmacol. 88, 141\u2013150. (Reviews recent advances in our knowledge of the structure of \nsodium channels that explains how local anaesthetics enter and bind to the pore region of the channel)Hille, B., 2001. Ionic Channels of Excitable Membranes. Sinauer, \nSunderland. (Excellent, clearly written textbook. The information it \ncontains is still very relevant today)\nStrichartz, G.R., Ritchie, J.M., 1987. The action of local anaesthetics on \nion channels of excitable tissues. Handb. Exp. Pharmacol. 81, 21\u201352. (Excellent review of actions of local anaesthetics \u2013 other articles in the same \nvolume cover more clinical aspects)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3342, "end_char_idx": 5339, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2e404c37-b20e-472c-bf59-2c126e9b50f9": {"__data__": {"id_": "2e404c37-b20e-472c-bf59-2c126e9b50f9", "embedding": null, "metadata": {"page_label": "575", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1696d94e-8b2b-4f90-a0fc-6ee95980665d", "node_type": null, "metadata": {"page_label": "575", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "32dfc81d6480924f214a57444c84980ac36426f08a0bab69d83d7856a70760c9"}, "3": {"node_id": "9932f449-1d46-408c-bbb0-8e6c23c84dd6", "node_type": null, "metadata": {"page_label": "575", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c71289de4f3c5899b48f6ffa0941be6b56e08cb67f10886eca62a750419c3033"}}, "hash": "a4c478101f6bb246b0257a3d28bb041ee68012ff4a6c64af1f6d43e0296034a5", "text": "569\nOVERVIEW\nIn this chapter we discuss the nature of anxiety and \nthe drugs used to treat it (anxiolytic drugs), as well \nas drugs used to treat insomnia (hypnotic drugs). \nHistorically there was overlap between these two groups, reflecting the fact that older anxiolytic drugs \ncommonly caused a degree of sedation and drowsi -\nness. Newer anxiolytic drugs show much less sedative \neffect and other hypnotic drugs have been introduced \nthat lack specific anxiolytic effects. Many of the drugs \nnow used to treat anxiety were first developed, and are still used, to treat other disorders such as \ndepression (Ch. 48), epilepsy (Ch. 46) and schizo-\nphrenia (Ch. 47). Here we will focus on their use as \nanxiolytics.\nTHE NATURE OF ANXIETY AND ITS \nTREATMENT\nThe normal fear response to threatening stimuli comprises \nseveral components, including defensive behaviours, \nautonomic reflexes, arousal and alertness, corticosteroid \nsecretion and negative emotions. In anxiety states, these reactions occur in an anticipatory manner, often indepen -\ndently of external events. The distinction between a \u2018pathological\u2019 and a \u2018normal\u2019 state of anxiety is not clear-cut but represents the point at which the symptoms interfere \nwith normal productive activities. The term \u2018anxiety\u2019 is \napplied to several distinct disorders. A useful division of anxiety disorders that may help to explain why different types of anxiety respond differently to different drugs is \ninto (i) disorders that involve fear (panic attacks and phobias) \nand (ii) those that involve a more general feeling of anxiety \n(often categorised as general anxiety disorder).\nAnxiety disorders recognised clinically include the \nfollowing:\n\u2022\tgeneralised anxiety disorder (an ongoing state of \nexcessive anxiety lacking any clear reason or focus)\n\u2022\tsocial anxiety disorder (fear of being with and \ninteracting with other people)\n\u2022\tphobias (strong fears of specific objects or situations, \ne.g. snakes, open spaces, flying)\n\u2022\tpanic disorder (sudden attacks of overwhelming fear that occur in association with marked somatic symptoms, such as sweating, tachycardia, chest pains, \ntrembling and choking). Such attacks can be induced \neven in normal individuals by infusion of sodium lactate, and the condition appears to have a genetic component.Related disorders include:\n\u2022\tpost-traumatic stress disorder (PTSD; distress triggered \nby recall of past stressful experiences)\n\u2022\tobsessive\u2013compulsive disorder (compulsive ritualistic \nbehaviour driven by irrational anxiety, e.g. fear of \ncontamination).\nExtensive descriptions of anxiety disorders can be found in DSM-5.\n1\nIt should be stressed that the treatment of such disorders \ngenerally involves psychological approaches as well as drug treatment. Over the last decade, the drug treatment of \nanxiety has changed from using traditional anxiolytic/hypnotic agents (i.e. benzodiazepines and barbiturates) to \nusing a range of drugs that are also used to treat other \ncentral nervous system (CNS) disorders (e.g. antidepressant, antiepileptic and antipsychotic drugs) or 5-hydroxytryptamine \n(5-HT)\n1A-receptor agonists (e.g. buspirone) that have no \nhypnotic effect. Furthermore, benzodiazepines, while being effective anxiolytic drugs, have the disadvantages of produc -\ning unwanted side effects such as amnesia, and of inducing \ntolerance and physical dependence, as well as being drugs \nof abuse. They are also ineffective in treating any depression \nthat may occur along with anxiety. Unlike antidepressants and buspirone, which require treatment for three", "start_char_idx": 0, "end_char_idx": 3567, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9932f449-1d46-408c-bbb0-8e6c23c84dd6": {"__data__": {"id_": "9932f449-1d46-408c-bbb0-8e6c23c84dd6", "embedding": null, "metadata": {"page_label": "575", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1696d94e-8b2b-4f90-a0fc-6ee95980665d", "node_type": null, "metadata": {"page_label": "575", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "32dfc81d6480924f214a57444c84980ac36426f08a0bab69d83d7856a70760c9"}, "2": {"node_id": "2e404c37-b20e-472c-bf59-2c126e9b50f9", "node_type": null, "metadata": {"page_label": "575", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a4c478101f6bb246b0257a3d28bb041ee68012ff4a6c64af1f6d43e0296034a5"}}, "hash": "c71289de4f3c5899b48f6ffa0941be6b56e08cb67f10886eca62a750419c3033", "text": "along with anxiety. Unlike antidepressants and buspirone, which require treatment for three or more \nweeks to show any therapeutic effect, benzodiazepines act \nwithin 30 minutes, so they can be useful for patients who \nneed acute treatment, and can be taken on an \u2018as needed\u2019 \nbasis.\nIn recent years a number of over-the-counter \u2018relaxation\u2019 \ndrinks containing CNS neurotransmitters, their precursors or other hormones and amino acids have been marketed, \nwithout any evidence of efficacy.\n2\nMEASUREMENT OF ANXIOLYTIC \nACTIVITY\nANIMAL MODELS OF ANXIETY\nIn addition to the subjective (emotional) component of \nhuman anxiety, there are measurable behavioural and \nphysiological effects that also occur in experimental animals. \nIn biological terms, anxiety induces a particular form of behavioural inhibition that occurs in response to novel \nenvironmental events that are threatening or painful. In \nanimals, this behavioural inhibition may take the form of Anxiolytic and hypnotic drugs 45 NERVOUS SYSTEM SECTION 4\n1DSM-5: Diagnostic and Statistical Manual of Mental Disorders, 2013. \nfifth ed. American Psychiatric Association, Washington, DC.\n2Because \u2018relaxation\u2019 drinks are classified as dietary supplements they \nare not subject to the same efficacy and safety tests as drugs (see \nEditorial in Nature Neuroscience, 2012, vol. 15, p. 497).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3476, "end_char_idx": 5300, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "98fe7404-2a52-4115-b46f-05903de98fab": {"__data__": {"id_": "98fe7404-2a52-4115-b46f-05903de98fab", "embedding": null, "metadata": {"page_label": "576", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "910bc5dc-d7a0-4c3f-8100-64f1dae76f33", "node_type": null, "metadata": {"page_label": "576", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be5f9878c5dbc89095a93a273d39ef615dd3d46f3ca6a7b8d7be9ec7f97adfac"}, "3": {"node_id": "fa637b19-34c4-4983-a393-c915d2a755c9", "node_type": null, "metadata": {"page_label": "576", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43480013452cf3c7b6ea01e24f56ce55aed7a10c02fd93a49323cebe086c8c07"}}, "hash": "aa8c8745bc281bfdbe09db2b293f019a0aba341a1de6cd06ae5c718f9fa6c8d5", "text": "45 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n570pressing the bar (behavioural inhibition), and thus avoids \nthe shock, while the signal is sounding. The effect of an \nanxiolytic drug is to relieve this suppressive effect, so that \nthe rats continue bar pressing for reward despite the \u2018punishment\u2019. Other types of psychotropic drug are not \neffective, nor are analgesic drugs. Other evidence confirms \nthat anxiolytic drugs affect the level of behavioural inhibition produced by the \u2018conflict situation\u2019, rather than simply \nraising the pain threshold.\nSome of these anxiety models may measure fear rather \nthan general anxiety, which occurs in humans in the absence \nof specific stimuli. To develop new anxiolytic drugs, it is \nimportant to have animal tests that give a good guide to \nefficacy in humans, and much ingenuity has gone into developing and validating such tests (see Ramos, 2008; \nEnnaceur & Chazot, 2016).\nTESTS ON HUMANS\nVarious subjective anxiety scale tests have been devised based on standard patient questionnaires. Galvanic skin \nreactions \u2013 a measure of sweat secretion \u2013 are also used to \nmonitor anxiety. Neuropsychological tests have been immobility or suppression of a behavioural response, such \nas bar pressing to obtain food. A rat placed in an unfamiliar \nenvironment normally responds by remaining immobile although alert (behavioural suppression) for a time, which \nmay represent \u2018anxiety\u2019 produced by the strange environ -\nment. This immobility is reduced if anxiolytic drugs are \nadministered. The \u2018elevated cross maze\u2019 is a widely used \ntest model (Fig. 45.1). Two arms of the raised horizontal \ncross are closed in, and the others are open. Normally, rats spend most of their time in the closed arms and avoid the open arms (afraid, possibly, of falling off or being attacked). \nAdministration of anxiolytic drugs increases the time spent \nin the open arms and also increases the number of entries made into the open arm but without an increase in motor \nactivity.\nConflict tests can also be used. For example, a rat trained \nto press a bar repeatedly to obtain a food pellet normally achieves a high and consistent response rate. A conflict \nelement is then introduced: at intervals, indicated by an auditory signal, bar pressing results in an occasional \n\u2018punishment\u2019 in the form of an electric shock in addition \nto the reward of a food pellet. Normally, the rat ceases 0510152025300\n0 0.03 0.1 0.313102030405060708090\n0.001.002.003.004.00\nAir7.5% CO27.5% CO2\nAirChange in VAS anxiety scoresDose (mg/kg, PO)DiazepamTime spent in open arms (s)Mean salivary cortisol levels ng/mLAB\nCD\nFig. 45.1 Anxiety testing. (A) Illustration of the elevated plus maze with open and closed arms. (B) Effect of diazepam on time spent by \nrats in the open arms of the elevated plus maze. Each bar represents time spent with movement in the open arms during a 5-min test \nperiod. (C) and (D) Effect of a 7.5% CO 2 challenge for 20 minutes on anxiety, measured on a visual analogue scale (VAS), and salivary \ncortisol levels in human subjects. (Panel [B], data taken from Kapus et al., 2008. Psychopharmacology 198, 2231\u20132241; panels [C] and [D], \ndata taken from K. Seddon et al., 2011. J. Psychopharmacol. 25, 43\u201351.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3373, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fa637b19-34c4-4983-a393-c915d2a755c9": {"__data__": {"id_": "fa637b19-34c4-4983-a393-c915d2a755c9", "embedding": null, "metadata": {"page_label": "576", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "910bc5dc-d7a0-4c3f-8100-64f1dae76f33", "node_type": null, "metadata": {"page_label": "576", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "be5f9878c5dbc89095a93a273d39ef615dd3d46f3ca6a7b8d7be9ec7f97adfac"}, "2": {"node_id": "98fe7404-2a52-4115-b46f-05903de98fab", "node_type": null, "metadata": {"page_label": "576", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa8c8745bc281bfdbe09db2b293f019a0aba341a1de6cd06ae5c718f9fa6c8d5"}}, "hash": "43480013452cf3c7b6ea01e24f56ce55aed7a10c02fd93a49323cebe086c8c07", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3326, "end_char_idx": 3709, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5a461167-637e-4e8c-b80e-3a06ea634d50": {"__data__": {"id_": "5a461167-637e-4e8c-b80e-3a06ea634d50", "embedding": null, "metadata": {"page_label": "577", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ed137863-472d-414c-b5e7-59e8a8c664ca", "node_type": null, "metadata": {"page_label": "577", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a41d199d9b9cc4e620ec24b84592dd681af32ea22469af9aa2d4daefa5ec09a8"}, "3": {"node_id": "93a87c73-652d-4052-a286-843789bb65d4", "node_type": null, "metadata": {"page_label": "577", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d0b92ed4e68725fecdfeb1fee7741515aff8d3cb25665c933a389f611957c8a8"}}, "hash": "365b29ac0a1011f6c6505a566ea07b2f1ee4699f9b1a9a46e28459e75ab264fa", "text": "45 ANxiOlYTic AN d h Y p NOT ic d RU g S\n571effective, but a lower side-effect profile favours the \nuse of SSRIs. These agents have the additional \nadvantage of reducing depression, which is not \nuncommonly associated with anxiety.\n\u2022\tBenzodiazepines. Used to treat acute anxiety. Those \nused to treat anxiety have a long biological half-life \n(Table 45.1). They may be co-administered during stabilisation of a patient on an SSRI.\n\u2022\tGabapentin and pregabalin are used to treat general anxiety disorder, although trial data on gabapentin are limited. Other antiepileptic drugs such as tiagabine, valproate and levetiracetam (see Ch. 46), may also be \neffective in treating generalised anxiety disorder.\n\u2022\tBuspirone. This 5-HT\n1A receptor agonist is effective in \ngeneralised anxiety disorder but ineffective in the treatment of phobias or severe anxiety states.\n\u2022\tSome\tatypical \tantipsychotic \tagents \t(see \tCh. \t47) \tsuch \t\nas olanzapine, risperidone, quetiapine and \nziprasidone may be effective in generalised anxiety disorder and post-traumatic stress disorder.\n\u2022\t\u03b2-Adrenoceptor antagonists (e.g. propranolol; Ch. 15). \nThese are used to treat some forms of anxiety, \nparticularly where physical symptoms such as \nsweating, tremor and tachycardia are troublesome.\n3 \nTheir effectiveness depends on block of peripheral \nsympathetic responses rather than on any central \neffects.developed to investigate emotional and attentional biases associated with responses to emotive faces and words. An \nexperience akin to a panic attack can be induced in many \nsubjects by breathing an increased level of CO\n2, usually \nprolonged breathing of 7.5% CO 2 or a single inhalation of \n35% CO 2 (see Fig. 45.1). Such tests have confirmed the \nefficacy of many anxiolytic drugs, but placebo treatment \noften also produces highly significant responses.\nA human version of the conflict test described above \ninvolves the substitution of money for food pellets, and the use of graded electric shocks as punishment. As with \nrats, administration of diazepam increases the rate of button pressing for money during the periods when the punishment \nwas in operation, although the subjects reported no change \nin the painfulness of the electric shock.\nDRUGS USED TO TREAT ANXIETY\nThe main groups of drugs are as follows:\n\u2022\tAntidepressants \t(see \tCh. \t48 \tfor \tdetails). \tSelective \t\nserotonin (5-HT) reuptake inhibitors (SSRIs; e.g. escitalopram, sertraline and paroxetine) and \nserotonin/noradrenaline reuptake inhibitors (SNRIs; e.g. venlafaxine and duloxetine) are effective in the \ntreatment of generalised anxiety disorder, phobias, \nsocial anxiety disorder, post-traumatic stress disorder \nand obsessive\u2013compulsive disorder. Older antidepressants (tricyclic antidepressants and \nmonoamine oxidase inhibitors [MAOIs]) are also Table 45.1 Characteristics of benzodiazepines in humans\nDrug(s)Half-life of parent \ncompound (h)Active metaboliteHalf-life of metabolite (h)Overall duration of action Main use(s)\nMidazolama2\u20134Hydroxylated \nderivative2 Ultrashort (< 6 h)HypnoticMidazolam used as intravenous anaesthetic and anticonvulsant\nZolpidem\nb2 No \u2014 Ultrashort (~4 h) Hypnotic\nLorazepam, oxazepam, temazepam, lormetazepam8\u201312 No \u2014\nShort (12\u201318 h)Anxiolytic, hypnotic. Lorazepam used", "start_char_idx": 0, "end_char_idx": 3267, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "93a87c73-652d-4052-a286-843789bb65d4": {"__data__": {"id_": "93a87c73-652d-4052-a286-843789bb65d4", "embedding": null, "metadata": {"page_label": "577", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ed137863-472d-414c-b5e7-59e8a8c664ca", "node_type": null, "metadata": {"page_label": "577", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a41d199d9b9cc4e620ec24b84592dd681af32ea22469af9aa2d4daefa5ec09a8"}, "2": {"node_id": "5a461167-637e-4e8c-b80e-3a06ea634d50", "node_type": null, "metadata": {"page_label": "577", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "365b29ac0a1011f6c6505a566ea07b2f1ee4699f9b1a9a46e28459e75ab264fa"}}, "hash": "d0b92ed4e68725fecdfeb1fee7741515aff8d3cb25665c933a389f611957c8a8", "text": " h)Anxiolytic, hypnotic. Lorazepam used as anticonvulsant\nAlprazolam 6\u201312 Hydroxylated derivative6\nMedium (24 h) Anxiolytic, antidepressant\nNitrazepam 16\u201340 No \u2014 Medium Anxiolytic, hypnoticc\nDiazepam, chlordiazepoxide20\u201340 Nordazepam 60\nLong (24\u201348 h)Anxiolytic, muscle relaxantDiazepam used as anticonvulsant\nFlurazepam 1 Desmethyl-flurazepam60 Long Anxiolytic, hypnotic\nc\nClonazepam 50 No \u2014 Long Anticonvulsant, anxiolytic (especially mania)\naAnother short-acting benzodiazepine, triazolam, has been withdrawn from use in the United Kingdom on account of side effects.\nbZolpidem is not a benzodiazepine but acts in a similar manner. Zopiclone and zaleplon are similar.\ncDue to their long half-life, drowsiness is common on waking.\n3\u03b2-Blockers are sometimes used by actors and musicians to reduce the \nsymptoms of stage fright, but their use by snooker players to minimise \ntremor is banned as unsportsmanlike.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3228, "end_char_idx": 4620, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "74dfc485-5b34-4518-9994-b271a3c696f2": {"__data__": {"id_": "74dfc485-5b34-4518-9994-b271a3c696f2", "embedding": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "72e0fd58-cbb9-45f3-a217-9e41af532c88", "node_type": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4a4ab97ed2998faf43c4319a99f7eb452c73f629715e49a310a69c4f01cd044"}, "3": {"node_id": "c9bea34c-88e8-46d6-89a2-3efbfe1ed909", "node_type": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29078f7794c48abcf2dda17d4467816f84b37f24f9809ec72a3c35d67f3028f4"}}, "hash": "b55363470039b024fba897c28c3953fb301015ef599afb54da8a5e53221622b4", "text": "45 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n572autoreceptors \u2013 and thus swiftly enhance 5-HT release \u2013 \nmight be anxiolytic without delayed onset. Drugs with \ncombined 5-HT 1A antagonism and SSRI properties have \nbeen developed but have not been found to be effective in man, perhaps because they block both 5HT\n1A autoreceptors \nand postsynaptic receptors, the latter effect occluding the beneficial effect of the former. Elevated 5-HT levels may \nalso induce other postsynaptic adaptations. 5-HT\n2 receptors \nhave also been implicated, down-regulation of which may \nbe important for anxiolytic action. Drugs with 5-HT 2 and \n5-HT 3 receptor antagonist activity are in clinical trials for \ntreating anxiety.\nBuspirone inhibits the activity of noradrenergic locus \ncoeruleus neurons (Ch. 40) and thus interferes with arousal \nreactions. It has side effects quite different from those of \nbenzodiazepines. It does not cause sedation or motor \nincoordination, nor have tolerance or withdrawal effects been reported. Its main side effects are nausea, dizziness, \nheadache and restlessness, which generally seem to be less \ntroublesome than the side effects of benzodiazepines. Buspirone does not suppress the benzodiazepine withdrawal syndrome (see p. 576), presumably because it acts by a \ndifferent mechanism. Hence, when switching from benzo -\ndiazepine treatment to buspirone treatment, the benzodi -\nazepine dose still needs to be reduced gradually.Antidepressants (Ch. 48), antiepileptics (Ch. 46), anti -\npsychotics Ch. 47) and \u03b2-adrenoceptor antagonists (Ch. 15) \nare described in detail elsewhere in this book. Here we \nwill first focus on how SSRIs and buspirone exert their anxiolytic activity and then discuss in detail the benzo -\ndiazepines, the primary use of which is to treat anxiety.\nClasses of anxiolytic drugs \n\u2022\tAntidepressant \tdrugs \t(selective \tserotonin \treuptake \t\ninhibitors [SSRIs], serotonin/noradrenaline reuptake \ninhibitors [SNRIs], tricyclic antidepressants and monoamine oxidase inhibitors [MAOIs] \u2013 see Ch. 48) \nare effective anxiolytic agents.\n\u2022\tBenzodiazepines \tare \tused \tfor \ttreating \tacute \tanxiety \t\nand insomnia.\n\u2022\tGabapentin and pregabalin drugs have anxiolytic \nproperties.\n\u2022\tBuspirone is a 5-hydroxytryptamine (5-HT) 1A-receptor \nagonist with anxiolytic activity but little sedative effect.\n\u2022\tSome\tatypical \tantipsychotic \tagents \t(e.g. \tquetiapine) \ncan be useful to treat some forms of anxiety, but have \nsignificant unwanted effects.\n\u2022\t\u03b2-Adrenoceptor antagonists (e.g. propranolol) are used mainly to reduce physical symptoms of anxiety (tremor, palpitations, etc.); no effect on affective component.\nAntidepressants and 5-HT 1A \nagonists as anxiolytic drugs \n\u2022\tAnxiolytic \teffects \ttake \tdays \tor \tweeks \tto \tdevelop.\n\u2022\tAntidepressants \t(selective \tserotonin \treuptake \tinhibitors \t\n[SSRIs], serotonin/noradrenaline reuptake inhibitors [SNRIs], tricyclic antidepressants and monoamine oxidase inhibitors [MAOIs] \u2013 see Ch. 48):\n\u2013 effective treatments for generalised anxiety disorder, \nphobias, social anxiety disorder and post-traumatic stress disorder;\n\u2013 may also reduce depression associated with anxiety.\n\u2022\tBuspirone is a potent agonist at 5-hydroxytryptamine (5-HT)\n1A", "start_char_idx": 0, "end_char_idx": 3205, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c9bea34c-88e8-46d6-89a2-3efbfe1ed909": {"__data__": {"id_": "c9bea34c-88e8-46d6-89a2-3efbfe1ed909", "embedding": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "72e0fd58-cbb9-45f3-a217-9e41af532c88", "node_type": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4a4ab97ed2998faf43c4319a99f7eb452c73f629715e49a310a69c4f01cd044"}, "2": {"node_id": "74dfc485-5b34-4518-9994-b271a3c696f2", "node_type": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b55363470039b024fba897c28c3953fb301015ef599afb54da8a5e53221622b4"}, "3": {"node_id": "6e9e8c93-f501-4d5a-8388-3b826fda1563", "node_type": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "717f5867d6698b182044ebfc6716d8af096d4d48218ac16569c917619f41d337"}}, "hash": "29078f7794c48abcf2dda17d4467816f84b37f24f9809ec72a3c35d67f3028f4", "text": "a potent agonist at 5-hydroxytryptamine (5-HT)\n1A receptors:\n\u2013 it is an effective treatment for generalised anxiety \ndisorder but not phobias\n\u2013 side effects appear less troublesome than with \nbenzodiazepines; they include dizziness, nausea, headache, but not sedation or loss of coordination.DELAYED ANXIOLYTIC EFFECT OF SSRIs \nAND BUSPIRONE\nThe anxiolytic effects of SSRIs (e.g. escitalopram and \nsertraline) and buspirone are not immediate but take days \nor weeks to develop after commencing drug therapy, sug -\ngesting that adaptive responses to the initial effects of these \ndrugs that develop over time are important.\nBuspirone is a partial agonist at 5-HT 1A receptors (Ch. \n16) and also binds to dopamine receptors, but it is likely \nthat its 5-HT-related actions are important in relation to \nanxiety suppression, because related experimental com -\npounds (e.g. ipsapirone and gepirone), which are highly \nspecific for 5-HT 1A receptors, show similar anxiolytic activity \nin experimental animals.\n5-HT 1A receptors are expressed on the soma and dendrites \nof 5-HT-containing neurons, where they function as inhibi -\ntory autoreceptors, as well as being expressed on other \ntypes of neuron (e.g. noradrenergic locus coeruleus neurons) where, along with other types of 5-HT receptor (see Ch. \n40), they mediate the postsynaptic actions of 5-HT. Post -\nsynaptic 5-HT\n1A receptors are highly expressed within the \ncortico-limbic circuits implicated in emotional behaviour. One theory of how SSRIs and buspirone produce their \ndelayed anxiolytic effect is that over time they induce desensitisation of somatodendritic 5-HT\n1A autoreceptors, \nresulting in heightened excitation of serotonergic neurons \nand enhanced 5-HT release (Ch. 48, Fig. 48.3). This might \nalso explain why early in treatment, anxiety can be worsened by these drugs due to the initial activation of 5-HT\n1A \nautoreceptors and inhibition of 5-HT release. This receptor \ndesensitisation theory would predict that a 5-HT 1A antagonist \nthat would rapidly block the action of 5-HT at 5-HT 1A BENZODIAZEPINES AND RELATED DRUGS\n\u25bc The first benzodiazepine, chlordiazepoxide, was synthesised by \naccident in 1961, the unusual seven-membered ring having been \nproduced as a result of a reaction that went wrong in the laboratories \nof Hoffman\u2013La Roche. Its unexpected pharmacological activity was recognised in a routine screening procedure, and benzodiazepines \nquite soon became the most widely prescribed drugs in the \npharmacopoeia.\nThe basic chemical structure of benzodiazepines consists of a seven-\nmembered ring fused to an aromatic ring, with four main substituent groups that can be modified without loss of activity. Thousands of \ncompounds have been made and tested, and about 20 are available \nfor clinical use, the most important ones being listed in Table 45.1. They are basically similar in their pharmacological actions, although \nsome degree of selectivity has been reported. For example, some, \nsuch as clonazepam, show anticonvulsant activity with less marked mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3162, "end_char_idx": 6542, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6e9e8c93-f501-4d5a-8388-3b826fda1563": {"__data__": {"id_": "6e9e8c93-f501-4d5a-8388-3b826fda1563", "embedding": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "72e0fd58-cbb9-45f3-a217-9e41af532c88", "node_type": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4a4ab97ed2998faf43c4319a99f7eb452c73f629715e49a310a69c4f01cd044"}, "2": {"node_id": "c9bea34c-88e8-46d6-89a2-3efbfe1ed909", "node_type": null, "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29078f7794c48abcf2dda17d4467816f84b37f24f9809ec72a3c35d67f3028f4"}}, "hash": "717f5867d6698b182044ebfc6716d8af096d4d48218ac16569c917619f41d337", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6539, "end_char_idx": 6730, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5a15dffa-b5aa-43ac-a07f-082396ea11f4": {"__data__": {"id_": "5a15dffa-b5aa-43ac-a07f-082396ea11f4", "embedding": null, "metadata": {"page_label": "579", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e95d63a7-d868-4108-9fa6-8ccd568bed33", "node_type": null, "metadata": {"page_label": "579", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59010950cfa3e6fc10fdb2ff62c5e9bb8b0667aad8cb70b4aeb1511600fb9e1e"}, "3": {"node_id": "955d26aa-24d8-4788-83d3-38190eac383a", "node_type": null, "metadata": {"page_label": "579", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0991fa9d2ef0dfb85169ed37aafc8c9567bc8ef2ed9671c81778e45f8e141e41"}}, "hash": "35adbcb81fb4eac91a5e7cd697850a402ce45c3f82ae98ed50c0c5b4e9fde7ef", "text": "45 ANxiOlYTic AN d h Y p NOT ic d RU g S\n573\u25bc The GABA A receptor is a ligand-gated ion channel (see Ch. 3) \nconsisting of a pentameric assembly of different subunits, the main \nones being \u03b1, \u03b2 and \u03b3 (see Ch. 39). The GABA A receptor should actually \nbe thought of as a family of receptors as there are six different subtypes of \u03b1 subunit, three subtypes of \u03b2 and three subtypes of \u03b3. Although \nthe potential number of combinations is therefore large, certain \ncombinations predominate in the adult brain (see Ch. 39). The various \ncombinations occur in different parts of the brain, have different \nphysiological functions and have subtle differences in their pharm -\nacological properties.\nBenzodiazepines bind across the interface between the \u03b1 and \u03b3 subunits \nbut only to receptors that contain \u03b32 and \u03b11, \u03b12, \u03b13 or \u03b15 subunits. \nGenetic approaches have been used to study the roles of different \nsubunits in the different behavioural effects of benzodiazepines. Behavioural analysis of mice with various mutations of the GABA\n\u0391 \nreceptor subunit indicates that \u03b11-containing receptors mediate the \nanticonvulsant, sedative/hypnotic and addictive effects but not the \nanxiolytic effect of benzodiazepines, whereas \u03b12-containing receptors \nmediate the anxiolytic effect, \u03b12-, \u03b13- and \u03b15-containing receptors \nmediate muscle relaxation and \u03b11- and \u03b15-containing receptors mediate \nthe amnesic effects (Tan et al., 2011).\nThe obvious next step was to try to develop subunit-selective drugs. Unfortunately, this has proved difficult, due to the structural similarity \nbetween the benzodiazepine binding site on different \u03b1 subunits. \nThe \u03b1-subunit selectivity of some benzodiazepines is given in Table \n45.2. It was hoped that selective efficacy at \u03b12-containing receptors \nwould produce anxiolytic drugs lacking the unwanted effects of \nsedation and amnesia. However, such compounds have not yet translated into human therapeutic agents ( Skolnick, 2012 ). Pagoclone , \nreported to be a full agonist at \u03b13 with less efficacy at \u03b11, \u03b12 and \u03b15, \nhas little or no sedative/hypnotic or amnesic actions. Clinical trials \nof this drug as a treatment for stammering proved unsuccessful.\nPeripheral benzodiazepine-binding sites, not associated \nwith GABA receptors, are present in many tissues. The \ntarget is a protein known as translocator protein located \nprimarily on mitochondrial membranes.\nANTAGONISM \u2003AND \u2003NEGATIVE \u2003\u2003\nALLOSTERIC \u2003MODULATION\nFlumazenil is a benzodiazepine-like compound that com -\npetes with benzodiazepines at their binding site on GABA A \nreceptors and thus antagonises their effects. This compound was originally reported to lack effects on behaviour or on \ndrug-induced convulsions when given on its own, although it was later found to possess some \u2018anxiogenic\u2019 and procon -\nvulsant activity which may indicate that it possesses weak negative allosteric modulatory activity. Flumazenil can be used to reverse the effect of benzodiazepine overdosage sedative effects. From a clinical point of view, differences in phar -\nmacokinetic behaviour among different benzodiazepines (see Table \n45.1) are more important than differences in profile of activity. Drugs \nwith a similar structure have been discovered that reverse the effects of the benzodiazepines, for example, flumazenil (see later).\nThe term \u2018benzodiazepine\u2019 refers to a distinct chemical structure. \nAlso discussed here are \u2018Z-drugs\u2019 such as zaleplon, zolpidem and \nzopiclone\n4 as well as abecarnil \u2013 a \u03b2 -carboline (not licensed for clinical", "start_char_idx": 0, "end_char_idx": 3523, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "955d26aa-24d8-4788-83d3-38190eac383a": {"__data__": {"id_": "955d26aa-24d8-4788-83d3-38190eac383a", "embedding": null, "metadata": {"page_label": "579", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e95d63a7-d868-4108-9fa6-8ccd568bed33", "node_type": null, "metadata": {"page_label": "579", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59010950cfa3e6fc10fdb2ff62c5e9bb8b0667aad8cb70b4aeb1511600fb9e1e"}, "2": {"node_id": "5a15dffa-b5aa-43ac-a07f-082396ea11f4", "node_type": null, "metadata": {"page_label": "579", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "35adbcb81fb4eac91a5e7cd697850a402ce45c3f82ae98ed50c0c5b4e9fde7ef"}}, "hash": "0991fa9d2ef0dfb85169ed37aafc8c9567bc8ef2ed9671c81778e45f8e141e41", "text": "as well as abecarnil \u2013 a \u03b2 -carboline (not licensed for clinical \nuse) \u2013 which have different chemical structures, but bind to the same \nsites as the benzodiazepines.\nMECHANISM \u2003OF \u2003ACTION\nBenzodiazepines act selectively on GABA A receptors (Ch. \n39), which mediate inhibitory synaptic transmission \nthroughout the CNS. They act as positive allosteric modula -\ntors (see Ch. 2) to facilitate the opening of GABA-activated \nchloride channels thus enhancing the response to GABA \n(Ch. 39, Fig. 39.5). They bind specifically to a modulatory \nsite on the receptor, distinct from the GABA-binding sites (see Fig. 45.3), and act allosterically to increase the affinity \nof GABA for the receptor. Single-channel recordings show \nan increase in the frequency of channel opening by a given concentration of GABA, but no change in the conductance or mean open time, consistent with an effect on GABA \nbinding rather than the channel-gating mechanism. \nBenzodiazepines do not affect receptors for other amino acids, such as glycine or glutamate (Fig. 45.2).Chlordiazepoxide ControlGly GlyGlu Glu1 s10 mV\nCon Diazepam ConGABA\nGABA\nGABA GABAGABA\nFig. 45.2 Potentiating effect of benzodiazepines and \nchlordiazepoxide on the action of GABA. Drugs were applied \nby iontophoresis to mouse spinal cord neurons grown in tissue \nculture, from micropipettes placed close to the cells. The membrane was hyperpolarised to \u2212\n90 mV, and the cells were \nloaded with Cl\u2212 from the recording microelectrode, so inhibitory \namino acids (GABA and glycine [Gly]), as well as excitatory ones (glutamate [Glu]), caused depolarising responses. The potentiating effect of diazepam is restricted to GABA responses, glutamate and glycine responses being unaffected. Con, \nControl. \nTable 45.2 GABA A-receptor \u03b1-subunit selectivity of \nsome therapeutically used benzodiazepines\nDrug Subunit selectivity\nDiazepam \u03b11, \u03b12, \u03b13, \u03b14, \u03b15, \u03b16\nFlunitrazepam \u03b11, \u03b12, \u03b15\nMidazolam \u03b11, \u03b12, \u03b13, \u03b14, \u03b15, \u03b16\nZolpidem \u03b11\nFlumazenil Antagonist at \u03b11, \u03b12, \u03b13, \u03b14, \u03b15, \u03b16\n(Adapted from Tan, K.R., Rudolph, U., L\u00fcscher, C., 2011. Hooked on benzodiazepines: GABA\nA-receptor subtypes and \naddiction. Trends Neurosci. 34, 188\u2013197.)4Z-drugs are used primarily to induce sleep and so should perhaps be \ncalled \u2018Zzzzzz drugs\u2019.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3459, "end_char_idx": 6203, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0a61e912-c3d4-4fdc-897a-19c278da523c": {"__data__": {"id_": "0a61e912-c3d4-4fdc-897a-19c278da523c", "embedding": null, "metadata": {"page_label": "580", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "845c1790-78fd-4f32-ad27-f0b26131cb90", "node_type": null, "metadata": {"page_label": "580", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "72903fab1d493a0f662d35348680c59121c7d8863f91d7a6b225965ef5f70014"}, "3": {"node_id": "15c1ce16-505c-4a8d-b6d8-10b6358e8a05", "node_type": null, "metadata": {"page_label": "580", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0d03ac33ff219c3da0e1e31c2d743cb2209060858dc925cad42c03fca6cc8f5b"}}, "hash": "cd58ff3c52b732244023da51a2d19390cd8f12e79147a4fe002df1bfaadda443", "text": "45 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n574IS\u2003THERE \u2003AN \u2003ENDOGENOUS \u2003\u2003\nBENZODIAZEPINE-LIKE \u2003MEDIATOR?\n\u25bc Despite considerable scientific effort, the question of whether or \nnot there are endogenous ligands for the benzodiazepine site, whose \nfunction is to regulate the action of GABA, remains unanswered.\nThat flumazenil produces responses both in vivo and in vitro in \nthe absence of any exogenous benzodiazepines has been cited to \nsupport the view that there must be ongoing benzodiazepine-like \naction produced by endogenous ligand(s). However, it is possible that it has positive or negative modulatory activity at subtypes of \nGABA\nA receptor (depending on the \u03b1 subunit present), or in some \npathological conditions in which the GABA A receptors have become \nmodified.\nSeveral endogenous compounds that act at the benzodiazepine site \nhave been isolated, including \u03b2-carbolines (e.g. \u03b2CCE), structurally \nrelated to tryptophan, and diazepam-binding inhibitor , a 10-kDa peptide. \nWhether these molecules exist in the brain (i.e. are endogenous) or are generated during the processes involved in extracting them from \nthe tissue is an open issue. Interestingly, both \u03b2CCE and diazepam-\nbinding inhibitor have the opposite effect to benzodiazepines, i.e. \nthey are negative allosteric modulators and inhibit chloride channel \nopening by GABA and, in the whole animal, exert anxiogenic and \nproconvulsant effects. There was also a suggestion that benzodiazepines \nthemselves may occur naturally in the brain, but the origin of these compounds and how biosynthesis occurs is unclear. At present there \nis no general agreement on the identity and function of endogenous \nligands for the benzodiazepine site. Other possible endogenous \nmodulators of GABA\nA receptors include steroid metabolites, but they \nbind to a different site from benzodiazepines (see Ch. 39).\nPHARMACOLOGICAL \u2003EFFECTS \u2003AND \u2003USES\nThe main effects of benzodiazepines are:\n\u2022\treduction \tof \tanxiety \tand \taggression;\n\u2022\tinduction \tof \tsleep \t(see \tsection \ton \thypnotic \tdrugs, \t \np. 577);\n\u2022\treduction \tof \tmuscle \ttone;\n\u2022\tanticonvulsant \teffect;\n\u2022\tanterograde \tamnesia.\nReduction of anxiety and aggression\nBenzodiazepines show anxiolytic effects in animal tests, \nas described previously, and also exert a marked \u2018taming\u2019 \neffect, allowing animals to be handled more easily.5 With \nthe possible exception of alprazolam (see Table 45.1), benzodiazepines do not have antidepressant effects. \nBenzodiazepines may paradoxically produce an increase in irritability and aggression in some individuals. This appears \nto be particularly pronounced with the ultrashort-acting \ndrug triazolam (and led to its withdrawal in the United Kingdom and some other countries), and is generally \nmore common with short-acting compounds. It is prob-\nably a manifestation of the benzodiazepine withdrawal syndrome, which occurs with all these drugs (see p. 576) but is more acute with drugs whose action wears off \nrapidly.\nBenzodiazepines are now used mainly for treating acute \nanxiety states, behavioural emergencies and during pro -\ncedures such as endoscopy. They are also used as premedica -\ntion before surgery (both medical and dental). Under these circumstances their anxiolytic, sedative and amnesic (normally used only if respiration is severely depressed), or to reverse the effect of benzodiazepines such as midazolam used for minor surgical procedures. Flumazenil", "start_char_idx": 0, "end_char_idx": 3419, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "15c1ce16-505c-4a8d-b6d8-10b6358e8a05": {"__data__": {"id_": "15c1ce16-505c-4a8d-b6d8-10b6358e8a05", "embedding": null, "metadata": {"page_label": "580", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "845c1790-78fd-4f32-ad27-f0b26131cb90", "node_type": null, "metadata": {"page_label": "580", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "72903fab1d493a0f662d35348680c59121c7d8863f91d7a6b225965ef5f70014"}, "2": {"node_id": "0a61e912-c3d4-4fdc-897a-19c278da523c", "node_type": null, "metadata": {"page_label": "580", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cd58ff3c52b732244023da51a2d19390cd8f12e79147a4fe002df1bfaadda443"}}, "hash": "0d03ac33ff219c3da0e1e31c2d743cb2209060858dc925cad42c03fca6cc8f5b", "text": "as midazolam used for minor surgical procedures. Flumazenil acts quickly \nand effectively when given by injection, but its action \nlasts for only about 2 h, so drowsiness tends to return. \nConvulsions may occur in patients treated with flumazenil, \nand this is more common in patients receiving tricyclic \nantidepressants (Ch. 48). Reports that flumazenil improves \nthe mental state of patients with severe liver disease (hepatic encephalopathy) and alcohol intoxication have not been \nconfirmed in controlled trials.\n\u25bc Drugs that bind to the benzodiazepine site and exert the opposite \neffect to that of conventional benzodiazepines (negative allosteric \nmodulators, see Ch. 2), produce signs of increased anxiety and convul -\nsions. These include ethyl-\u03b2-carboline-3-carboxylate (\u03b2CCE) and diazepam-binding inhibitor (see later), as well as some benzodiazepine analogues. It is possible (Fig. 45.3) to explain these complexities in \nterms of the two-state model discussed in Chapter 2, by postulating \nthat the receptor exists in two distinct conformations, only one of which (A) can bind GABA molecules and open the chloride channel. \nThe other conformation (B) cannot bind GABA. Normally, with no \nbenzodiazepine ligand present, there is an equilibrium between these \ntwo conformations; sensitivity to GABA is present but submaximal. \nPositive allosteric modulators (e.g. diazepam) are postulated to bind preferentially to conformation (A), thus shifting the equilibrium in \nfavour of (A) and enhancing GABA sensitivity. Negative allosteric modulators bind selectively to (B) and have the opposite effect.\nConformational\nequilibri umBenzodiazepines\n(PAMs)GABA\n\u03b2-Carbolines\n(NAMs)Chlori de channel\nopen\nA\nB\nFig. 45.3 Model of benzodiazepine/GABA A-receptor \ninteraction. Benzodiazepines and related drugs bind to a \nmodulatory site on the GABA A receptor distinct from the \nGABA-binding site. This model envisages a conformational equilibrium between states in which the benzodiazepine site binds positive allosteric modulators (PAMs) (A) and negative allosteric modulators (NAMs) (B). In the latter state, the GABA\nA \nreceptor has a much reduced affinity for GABA; consequently, the chloride channel remains closed. 5This depends on the species. Cats actually become more excitable (and \nhungry), as a colleague of one of the authors discovered to his cost \nwhen attempting to sedate a tiger in the Baltimore zoo.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3360, "end_char_idx": 6259, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "65f11d47-4569-496d-a8cc-83114174e2d8": {"__data__": {"id_": "65f11d47-4569-496d-a8cc-83114174e2d8", "embedding": null, "metadata": {"page_label": "581", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f472d0ca-2bf5-444d-b5b4-0a7a0a83d985", "node_type": null, "metadata": {"page_label": "581", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc0b7ddcc3567b274f84e1226cbe0ed761082d1e00c0500a4b08fbd40dbd17ed"}, "3": {"node_id": "17ba6139-c9df-47d5-a8c2-d84de8a5c45a", "node_type": null, "metadata": {"page_label": "581", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8c2b5135af74912bd1b4086011a825fea5ace0ad702bc5477ad4f5dd45c16096"}}, "hash": "14bac6e6318315ecd1b6347be5f15e475647302055fff3f8946bb2dc1348ac5a", "text": "45 ANxiOlYTic AN d h Y p NOT ic d RU g S\n575phenotype. This raises the possibility that an \u03b15 subunit-\nselective negative allosteric modulator could be memory \nenhancing.\nPHARMACOKINETIC \u2003ASPECTS\nBenzodiazepines are well absorbed when given orally, \nusually giving a peak plasma concentration in about 1 h. \nSome (e.g. oxazepam, lorazepam) are absorbed more slowly. \nThey bind strongly to plasma protein, and their high lipid \nsolubility causes many of them to accumulate gradually \nin body fat. They are normally given by mouth but can be given intravenously (e.g. diazepam in status epilepticus, \nmidazolam in anaesthesia), buccally, or rectally. Intramus -\ncular injection often results in slow absorption.\nBenzodiazepines are all metabolised and eventually \nexcreted as glucuronide conjugates in the urine. They vary \ngreatly in duration of action and can be roughly divided into short-, medium- and long-acting compounds (see Table 45.1). Duration of action influences their use, short-\nacting compounds being useful hypnotics with reduced \nhangover effect on wakening, long-acting compounds being more useful for use as anxiolytic and anticonvulsant \ndrugs. Several are converted to active metabolites such as \nN-desmethyldiazepam (nordazepam), which has a half-\nlife of about 60 h, and which accounts for the tendency \nof many benzodiazepines to produce cumulative effects and long hangovers when they are given repeatedly. The \nshort-acting compounds are those that are metabolised \ndirectly by conjugation with glucuronide. Fig. 45.4 shows \nthe gradual build up and slow disappearance of nordazepam \nfrom the plasma of a human subject given diazepam daily \nfor 15 days.\n\u25bc Advancing age affects the rate of oxidative reactions more than \nthat of conjugation reactions. Thus the effect of the long-acting \nbenzodiazepines tends to increase with age, and it is common for \ndrowsiness and confusion to develop insidiously for this reason.6properties may be beneficial. Intravenous midazolam can \nbe used to induce anaesthesia (see Ch. 42).\nReduction of muscle tone\nBenzodiazepines reduce muscle tone by a central action on GABA\nA receptors, primarily in the spinal cord.\nIncreased muscle tone is a common feature of anxiety \nstates in humans and may contribute to the aches and pains, including headache, that often trouble anxious patients. The relaxant effect of benzodiazepines may therefore be \nclinically useful. A reduction of muscle tone appears to be \npossible without appreciable loss of coordination. However, with intravenous administration in anaesthesia and in \noverdose when these drugs are being abused, airway \nobstruction may occur. Other clinical uses of muscle relax -\nants are discussed in Chapter 14.\nAnticonvulsant effects\nAll the benzodiazepines have anticonvulsant activity in experimental animal tests. They are highly effective against \nchemically induced convulsions caused by pentylenetet-\nrazol, bicuculline and similar drugs that act by blocking \nGABA\nA receptors (see Chs 39 and 46) but less so against \nelectrically induced convulsions.\nClonazepam (see Table 45.1), diazepam, midazolam \nand lorazepam are used to treat epilepsy (Ch. 46). They \ncan be given intravenously to control life-threatening sei-\nzures in status epilepticus. Diazepam can be administered \nrectally to children to control acute seizures. Tolerance develops to the anticonvulsant actions of benzodiazepines \n(see p. 576).\nAnterograde amnesia\nBenzodiazepines prevent memory of events", "start_char_idx": 0, "end_char_idx": 3496, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "17ba6139-c9df-47d5-a8c2-d84de8a5c45a": {"__data__": {"id_": "17ba6139-c9df-47d5-a8c2-d84de8a5c45a", "embedding": null, "metadata": {"page_label": "581", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f472d0ca-2bf5-444d-b5b4-0a7a0a83d985", "node_type": null, "metadata": {"page_label": "581", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc0b7ddcc3567b274f84e1226cbe0ed761082d1e00c0500a4b08fbd40dbd17ed"}, "2": {"node_id": "65f11d47-4569-496d-a8cc-83114174e2d8", "node_type": null, "metadata": {"page_label": "581", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14bac6e6318315ecd1b6347be5f15e475647302055fff3f8946bb2dc1348ac5a"}}, "hash": "8c2b5135af74912bd1b4086011a825fea5ace0ad702bc5477ad4f5dd45c16096", "text": "576).\nAnterograde amnesia\nBenzodiazepines prevent memory of events experienced while under their influence, an effect not seen with other \nCNS depressants. Minor surgical or invasive procedures \ncan thus be performed without leaving unpleasant memo -\nries. Flunitrazepam (better known to the general public \nby one of its trade names, Rohypnol) is infamous as a date rape drug and victims frequently have difficulty in recalling exactly what took place during the attack.\nAmnesia is thought to be due to benzodiazepines \nbinding to GABA\nA receptors containing the \u03b15 subunit. \n\u03b15-Knock-out mice show an enhanced learning and memory A B\n0.0010.01\n0.010.11\n0.11\n48 30 25 20 15 10 5 0 24 20 16 12 8 4 0\nTime (hours) Time (days)Concentration (\u00b5mol/L)NordazepamDiazepam\nIntravenousOral\nNordazepam concentration (\u00b5mol/L)Diazepam 35 \u00b5mol/dayFig. 45.4 Pharmacokinetics of \ndiazepam in humans. (A) \nConcentrations of diazepam and \nnordazepam following a single oral or intravenous dose. Note the very slow disappearance of both substances \nafter the first 20 h. (B) Accumulation \nof nordazepam during 2 weeks\u2019 daily administration of diazepam, and slow decline (half-life about 3 days) after cessation of diazepam administration. \n(Data from Kaplan, S.A. et al., 1973. \nJ. Pharmacol. Sci. 62, 1789.)\n6At the age of 91 years, the grandmother of one of the authors was \ngrowing increasingly forgetful and mildly dotty, having been taking \nnitrazepam for insomnia regularly for years. To the author\u2019s lasting \nshame, it took a canny general practitioner to diagnose the problem. Cancellation of the nitrazepam prescription produced a dramatic \nimprovement.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3430, "end_char_idx": 5557, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "025ef01f-29d2-4352-aedd-3896af457063": {"__data__": {"id_": "025ef01f-29d2-4352-aedd-3896af457063", "embedding": null, "metadata": {"page_label": "582", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "865eb2a8-f914-4962-92b4-e85a08a97102", "node_type": null, "metadata": {"page_label": "582", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1836e2ccf804f2b257dd6a4ea9d543175d57cb7cfcd2d6e0056b21c10348f8bb"}, "3": {"node_id": "61cf5316-6784-42d7-b63b-2042b4ab4c06", "node_type": null, "metadata": {"page_label": "582", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d26ce9fea9346c7b5d45774b8969442d0ee645fbea3ed8ad137982de34c2df8"}}, "hash": "1921c399cbbb97074d992a76bf6562c43f64936031e94139264565d9a0275dcd", "text": "45 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n576enhanced REM sleep (see p. 578). It is recommended that \nbenzodiazepines be withdrawn gradually by stepwise \nlowering of the dose. Withdrawal after chronic administra -\ntion causes physical symptoms, namely nervousness, tremor, \nloss of appetite and sometimes convulsions.8 The withdrawal \nsyndrome, in both animals and humans, is slower in onset \nthan with opioids, probably because of the long plasma \nhalf-life of most benzodiazepines. With diazepam, the withdrawal symptoms may take up to 3 weeks to become \napparent. Short-acting benzodiazepines cause more abrupt \nwithdrawal effects.\nThe physical and psychological withdrawal symptoms \nmake it difficult for patients to give up taking benzo -\ndiazepines, but craving (i.e. severe psychological dependence that outlasts the physical withdrawal syndrome), which occurs with many drugs of abuse (Ch. 50), is not a major \nproblem.\nAbuse potential\nBenzodiazepines are widely abused drugs, often taken in \ncombination with other drugs such as opioids or alcohol \n(see Ch. 50). Most illicit use comes from diversion of \nprescribed benzodiazepines. They induce a feeling of calm and reduced anxiety, with users describing a dream \nstate where they are cushioned from reality. The risk of \noverdose is greatly increased when used in combination with alcohol. Tolerance and physical dependence occur as \ndescribed above.\nOTHER POTENTIAL ANXIOLYTIC DRUGS\nPost-traumatic stress disorder (PTSD) is caused by experiencing stressful, frightening or distressing events. \nSufferers often relive the traumatic events through night -\nmares and flashbacks, and may experience feelings of \nisolation, irritability and guilt. Symptoms include anxiety, \ndepression and insomnia. If treatment with psychological \ntherapies is unsuccessful then drug therapy with anxiolytic/antidepressant drugs (see Ch. 48) such as SSRIs (e.g. par-\noxetine , sertraline and mirtazapine) , a tricyclic antidepres -\nsant (amitriptyline) or a monoamine oxidase inhibitor (phenelzine) may be tried. In addition hypnotic agents (see later) may aid sleeping.\nA recent development has been the realisation that the \nunpleasant, negative memories that underlie fear are not necessarily permanent. When such memories are reactivated \n(recalled) they return transiently to a labile state that can \nbe disrupted. In humans, propranolol administered before memory reactivation may erase negative memories (see Lon -\nergan et al., 2013). Ketamine, psilocybin, lysergic acid dieth -\nylamide (LSD) and 3,4-methylenedioxymethamphetamine \n(MDMA or ecstasy) may have a similar effect. Disrupting \nunpleasant memories in this way may provide a new treatment for PSTD.\nBesides the GABA and 5-HT mechanisms discussed \nbefore, many other transmitters and hormones have been implicated in anxiety and panic disorders, particularly \nnoradrenaline, glutamate, melatonin, corticotrophin-releasing \nfactor, cholecystokinin (CCK), substance P, neuropeptide Y, galanin, orexins and neurosteroids. Anxiolytic drugs UNWANTED \u2003EFFECTS\nThese may be divided into:\n\u2022\ttoxic\teffects \tresulting \tfrom \tacute \toverdosage;\n\u2022\tunwanted \teffects \toccurring \tduring \tnormal \ttherapeutic \t\nuse;\n\u2022\ttolerance \tand \tdependence.\nAcute toxicity\nBenzodiazepines in acute overdose are considerably less dangerous than other anxiolytic/hypnotic drugs. Because \nsuch agents are often used", "start_char_idx": 0, "end_char_idx": 3387, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "61cf5316-6784-42d7-b63b-2042b4ab4c06": {"__data__": {"id_": "61cf5316-6784-42d7-b63b-2042b4ab4c06", "embedding": null, "metadata": {"page_label": "582", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "865eb2a8-f914-4962-92b4-e85a08a97102", "node_type": null, "metadata": {"page_label": "582", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1836e2ccf804f2b257dd6a4ea9d543175d57cb7cfcd2d6e0056b21c10348f8bb"}, "2": {"node_id": "025ef01f-29d2-4352-aedd-3896af457063", "node_type": null, "metadata": {"page_label": "582", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1921c399cbbb97074d992a76bf6562c43f64936031e94139264565d9a0275dcd"}}, "hash": "8d26ce9fea9346c7b5d45774b8969442d0ee645fbea3ed8ad137982de34c2df8", "text": "other anxiolytic/hypnotic drugs. Because \nsuch agents are often used in attempted suicide, this is an \nimportant advantage. In overdose, benzodiazepines cause prolonged sleep, without serious depression of respiration \nor cardiovascular function. However, in the presence of \nother CNS depressants, particularly alcohol, benzodiazepines can cause severe, even life-threatening, respiratory depres -\nsion. This is a frequent problem when benzodiazepines are abused (see Chs 50 and 59). The availability of an effective antagonist, flumazenil, means that the effects of an acute overdose can be counteracted,\n7 which is not possible for \nmost CNS depressants.\nSide effects during therapeutic use\nThe main side effects of benzodiazepines are drowsiness, confusion, amnesia and impaired coordination, which \nconsiderably impairs manual skills such as driving perfor -\nmance. Benzodiazepines enhance the depressant effect of \nother drugs, including alcohol, in a more than additive \nway. The long and unpredictable duration of action of many \nbenzodiazepines is important in relation to side effects. Long-acting drugs such as nitrazepam are rarely used as \nhypnotics, and even shorter-acting compounds such as \nlorazepam can produce a substantial day-after impairment of job performance and driving skill.\nTolerance and dependence\nTolerance (i.e. a gradual escalation of dose needed to produce the required effect) occurs with all benzodiazepines, \nas does dependence, which is their main drawback. They \nshare these properties with other sedatives. Tolerance appears to represent a change at the receptor level, but the \nmechanism is not well understood. There may be selective \nloss of membrane GABA\nA receptors containing the \u03b12 \nsubunit (Jacob et al., 2012).\nAt the receptor level, the degree of tolerance will be \ngoverned both by the number of sites occupied (i.e. the \ndose) and the duration of site occupancy (which may vary \naccording to the therapeutic use). Therefore marked toler -\nance develops when benzodiazepines are used continuously \nto treat epilepsy, whereas less tolerance occurs to the \nsleep-inducing effect of short-acting agents when the subject is relatively drug free during the day. It is not clear to what \ndegree tolerance develops to the anxiolytic effect.\nBenzodiazepines produce dependence, and this is a major \nproblem. In human subjects and patients, abrupt cessation \nof benzodiazepine treatment after weeks or months causes \na rebound heightened anxiety, together with tremor, diz -\nziness, tinnitus, weight loss and disturbed sleep due to \n7In practice, patients are usually left to sleep it off, because there is a \nrisk of seizures with flumazenil; however, flumazenil may be useful \ndiagnostically to rule out coma of other causes.8Withdrawal symptoms can be more severe. A relative of one of the \nauthors, advised to stop taking benzodiazepines after 20 years, suffered hallucinations and one day tore down all the curtains, convinced that \nthey were on fire.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3319, "end_char_idx": 6796, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7ff6bec9-cf17-45af-87ac-0530ea9faece": {"__data__": {"id_": "7ff6bec9-cf17-45af-87ac-0530ea9faece", "embedding": null, "metadata": {"page_label": "583", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5a20bf0e-e068-4714-b1b0-211e3cda595d", "node_type": null, "metadata": {"page_label": "583", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20317047403ceb91c335b872215d431aa792fa125db82aaa8792afedbb44f9f3"}, "3": {"node_id": "b13732f2-d306-4493-93fa-3e48eab23c05", "node_type": null, "metadata": {"page_label": "583", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e17b024cc1f9ee5404405e14840d248045d306f9589bd6aa8e1f2df08916b0e1"}}, "hash": "9f6acb48773d5d5085fecf6df55836bfdc253d8b89837b9be66780311f8fb4e2", "text": "45 ANxiOlYTic AN d h Y p NOT ic d RU g S\n577\u2022\tBenzodiazepines. \tShort-acting \tbenzodiazepines \t(e.g. \t\nlorazepam and temazepam) are used for treating \ninsomnia as they have little hangover effect. \nDiazepam, which is longer-acting, can be used to treat \ninsomnia associated with daytime anxiety.\n\u2022\tZ-drugs \t(e.g. \tzaleplon, zolpidem and zopiclone). \nAlthough chemically distinct, these short-acting \nhypnotics act at the benzodiazepine site on GABA A \nreceptors containing the \u03b11 subunit. They lack appreciable anxiolytic activity. Eszopiclone is the \nactive stereoisomer of zopiclone.\n\u2022\tClomethiazole. It acts as a positive allosteric \nmodulator of GABA\nA receptors acting at a site distinct \nfrom the benzodiazepines.\n\u2022\tMelatonin \treceptor \tagonists. \tMelatonin, ramelteon \nand tasimelteon are agonists at MT 1 and MT 2 \nreceptors (see Ch. 40). They are effective in treating insomnia in the elderly and autistic children as well as \nin totally blind individuals.\n\u2022\tOrexin \treceptor \tantagonist. \tSuvorexant is an \nantagonist of OX 1 and OX 2 receptors which mediate \nthe actions of the orexins, peptide transmitters in the \nCNS that are important in setting diurnal rhythm. \nOrexin levels are normally high in daylight and low at night, so the drug reduces wakefulness.\n\u2022\tAntihistamines\n9 (see Ch. 27; e.g. diphenhydramine \nand promethazine) can be used to induce sleep. They \nare included in various over-the-counter preparations. Doxepin is an SNRI antidepressant (see Ch. 48) with histamine H\n1- and H 2-receptor antagonist properties \nand quetiapine is an antipsychotic drug with a wide \nspectrum of activity (see Table 47.1) including H 1 \nantagonism; both are used to treat insomnia.\n\u2022\tMiscellaneous \tother \tdrugs \t(e.g. \tchloral hydrate and \nmeprobamate). They are no longer recommended, \nbut therapeutic habits die hard and they are \noccasionally used. Methaqualone, used as a hypnotic and once popular as a drug of abuse, has been \ndiscontinued.aimed at these targets are in development (see Murrough \net al., 2015). Some cannabinoids (see Ch. 20) may have \nanxiolytic properties.\nDRUGS USED TO TREAT INSOMNIA \n(HYPNOTIC DRUGS)\nInsomnia can be transient, in people who normally sleep \nwell but have to do shift work or have jet lag, short-term, \nusually due to illness or emotional upset, or chronic, where there is an underlying cause such as anxiety, depression, drug abuse, pain, pruritus or dyspnoea. While in anxiety \nand depression the underlying psychiatric condition \nshould be treated, improvement of sleep patterns can improve the underlying condition. The drugs used to treat \ninsomnia are:Benzodiazepines \n\u2022\tAct\tby\tbinding \tto \ta \tspecific \tallosteric \tmodulatory \tsite \t\non the GABA A receptor, thus enhancing the inhibitory \neffect of GABA. Subtypes of the GABA A receptor exist \nin different regions of the brain and differ in their \nfunctional effects.\n\u2022\tAnxiolytic \tbenzodiazepines \tare \tagonists \tat \tthis \t\nmodulatory site. Other benzodiazepines (e.g. flumazenil) are antagonists or weak negative allosteric modulators and prevent the actions of the anxiolytic \nbenzodiazepines. Strong negative allosteric modulators \n(not used clinically) are anxiogenic and", "start_char_idx": 0, "end_char_idx": 3191, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b13732f2-d306-4493-93fa-3e48eab23c05": {"__data__": {"id_": "b13732f2-d306-4493-93fa-3e48eab23c05", "embedding": null, "metadata": {"page_label": "583", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5a20bf0e-e068-4714-b1b0-211e3cda595d", "node_type": null, "metadata": {"page_label": "583", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20317047403ceb91c335b872215d431aa792fa125db82aaa8792afedbb44f9f3"}, "2": {"node_id": "7ff6bec9-cf17-45af-87ac-0530ea9faece", "node_type": null, "metadata": {"page_label": "583", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9f6acb48773d5d5085fecf6df55836bfdc253d8b89837b9be66780311f8fb4e2"}}, "hash": "e17b024cc1f9ee5404405e14840d248045d306f9589bd6aa8e1f2df08916b0e1", "text": "Strong negative allosteric modulators \n(not used clinically) are anxiogenic and proconvulsant.\n\u2022\tAnxiolytic \teffects \tare \tmediated \tby \tGABA A receptors \ncontaining the \u03b12 subunit, while sedation occurs through those with the \u03b11 subunit.\n\u2022\tBenzodiazepines \tcause:\n\u2013 reduction of anxiety and aggression\n\u2013 sedation, leading to improvement of insomnia\n\u2013 muscle relaxation and loss of motor coordination\n\u2013 suppression of convulsions (antiepileptic effect)\n\u2013 anterograde amnesia\n\u2022\tDifferences \tin \tthe \tpharmacological \tprofile \tof \tdifferent \t\nbenzodiazepines are minor; clonazepam appears to \nhave more anticonvulsant action in relation to its other effects.\n\u2022\tBenzodiazepines \tare \tactive \torally \tand \tdiffer \tmainly \tin \t\nrespect of their duration of action. Short-acting agents (e.g. lorazepam and temazepam\n, half-lives 8\u201312 h) \nare metabolised to inactive compounds and are used mainly as sleeping pills. Some long-acting agents (e.g. diazepam and chlordiazepoxide) are converted to a \nlong-lasting active metabolite ( nordazepam).\n\u2022\tSome\tare \tused \tintravenously, \tfor \texample, \tdiazepam \nand lorazepam in status epilepticus, midazolam in \nanaesthesia.\n\u2022\tBenzodiazepines \tare \trelatively \tsafe \tin \toverdose. \tTheir \t\nmain disadvantages are interaction with alcohol, long-lasting \u2018hangover\u2019 effects and the development of tolerance and physical dependence \u2013 characteristic \nwithdrawal syndrome on cessation of use.Clinical use of drugs as anxiolytics \n\u2022\tAntidepressants \t(selective \tserotonin \treuptake \tinhibitors \t\n[SSRIs] or serotonin/noradrenaline reuptake inhibitors \n[SNRIs]) are now the main drugs used to treat anxiety, especially when this is associated with depression. \nTheir effects are slow in onset ( >2 weeks).\n\u2022\tBenzodiazepines \tare \tnow \tconsidered \tonly \tas \ta \t\nshort-term measure, usually limited to acute relief of \nsevere and disabling anxiety.\n\u2022\tBuspirone (5-hydroxytryptamine [5-HT] 1A agonist) has \na different pattern of adverse effects from benzodiazepines and much lower abuse potential. Its \neffect is slow in onset ( >2 weeks). It is licensed for \nshort-term use, but specialists may use it for several \nmonths.\n9This is an interesting example of an initial unwanted side effect \n\u2013 sedation is undesired when treating hay fever \u2013 subsequently \nbecoming a therapeutic use.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3112, "end_char_idx": 5900, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f3ed670c-23df-47e2-b3a4-612233ed6648": {"__data__": {"id_": "f3ed670c-23df-47e2-b3a4-612233ed6648", "embedding": null, "metadata": {"page_label": "584", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b77f441f-6c18-4904-b14a-41d4fb97c0be", "node_type": null, "metadata": {"page_label": "584", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6413d50377f53c483e5727c0be4d6b6f2b4f45b30630772ddf8cd8dc70af154e"}, "3": {"node_id": "a761a3ef-8386-443a-9505-f0117182f81e", "node_type": null, "metadata": {"page_label": "584", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ff442d2fb0f122433fa4db9b42275fbb171c2dd1738ffae2a6c43c2819db44c1"}}, "hash": "e7693bbc961ea0a72c00a86ad2d82dae2a111a762003adc2ea6390f00d5994c5", "text": "45 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n578REFERENCES AND FURTHER READING\nEnnaceur, A., Chazot, P.L., 2016. Preclinical animal anxiety research \n\u2013 flaws and prejudices. Pharmacol. Res. Perspect. 4, e00223. (An \ninteresting critique of animal models of anxiety)Jacob, T.C., Michels, G., Silayeva, L., Haydonm, J., Succol, F., Moss, S.J., \n2012. Benzodiazepine treatment induces subtype-specific changes in GABA\nA receptor trafficking and decreases synaptic inhibition. Proc. INDUCTION OF SLEEP BY BENZODIAZEPINES\nBenzodiazepines decrease the time taken to get to sleep, \nand increase the total duration of sleep, although the \nlatter effect occurs only in subjects who normally sleep \nfor less than about 6 h each night. With agents that have \na short duration of action (e.g. zolpidem or temazepam), a \npronounced hangover effect on wakening can be avoided.\n\u25bc On the basis of electroencephalography measurements, several levels \nof sleep can be recognised. Of particular psychological importance are \nREM sleep, which is associated with dreaming, and slow-wave sleep, \nwhich corresponds to the deepest level of sleep when the metabolic \nrate and adrenal steroid secretion are at their lowest and the secretion of growth hormone is at its highest (see Ch. 34). Most hypnotic drugs \nreduce the proportion of REM sleep, although benzodiazepines affect \nit less than other hypnotics, and zolpidem least of all. Artificial inter -\nruption of REM sleep causes irritability and anxiety, even if the total \namount of sleep is not reduced, and the lost REM sleep is made up \nfor at the end of such an experiment by a rebound increase. The same \nrebound in REM sleep is seen at the end of a period of administration \nof benzodiazepines or other hypnotics. The proportion of slow-wave sleep is significantly reduced by benzodiazepines, although growth \nhormone secretion is unaffected.\nFig. 45.5 shows the improvement of subjective ratings \nof sleep quality produced by a benzodiazepine, and \nthe rebound decrease at the end of a 32-week period of \ndrug treatment. It is notable that, although tolerance to objective effects such as reduced sleep latency occurs \nSleep score\nTreatment (32 weeks)PlaceboNitrazepamLormetazepam\nFig. 45.5 Effects of long-term benzodiazepine treatment \non sleep quality. A group of 100 poor sleepers were given, \nunder double-blind conditions, lormetazepam 5 mg, nitrazepam \n2 mg or placebo nightly for 24 weeks, the test period being \npreceded and followed by 4 weeks of placebo treatment. They \nwere asked to assess, on a subjective rating scale, the quality of sleep during each night, and the results are expressed as a 5-day rolling average of these scores. The improvement in sleep quality was maintained during the 24-week test period, and \nwas followed by a \u2018rebound\u2019 worsening of sleep when the test \nperiod ended. (From Oswald, I. et al., 1982. Br. Med. J. 284, \n860\u2013864.)Hypnotic drugs \n\u2022\tDrugs\tthat \tpotentiate \tthe \taction \tof \tGABA \tat \tGABA A \nreceptors (e.g. benzodiazepines, zolpidem, \nzopiclone, zaleplon and clomethiazole) are used to \ninduce sleep.\n\u2022\tDrugs\twith \tshorter \thalf-lives \tin \tthe \tbody \treduce \tthe \t\nincidence of hangover the next morning.\n\u2022\tDrugs\twith \tH1-receptor antagonist properties induce \nsedation and sleep.\n\u2022\tDrugs\twith \tnovel \tmechanisms \tof \taction", "start_char_idx": 0, "end_char_idx": 3308, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a761a3ef-8386-443a-9505-f0117182f81e": {"__data__": {"id_": "a761a3ef-8386-443a-9505-f0117182f81e", "embedding": null, "metadata": {"page_label": "584", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b77f441f-6c18-4904-b14a-41d4fb97c0be", "node_type": null, "metadata": {"page_label": "584", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6413d50377f53c483e5727c0be4d6b6f2b4f45b30630772ddf8cd8dc70af154e"}, "2": {"node_id": "f3ed670c-23df-47e2-b3a4-612233ed6648", "node_type": null, "metadata": {"page_label": "584", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e7693bbc961ea0a72c00a86ad2d82dae2a111a762003adc2ea6390f00d5994c5"}}, "hash": "ff442d2fb0f122433fa4db9b42275fbb171c2dd1738ffae2a6c43c2819db44c1", "text": "sleep.\n\u2022\tDrugs\twith \tnovel \tmechanisms \tof \taction \thave \tbeen \t\ndeveloped, e.g. melatonin receptor agonists and orexin \nreceptor antagonists.\nClinical use of hypnotics (\u2018sleeping \ntablets\u2019) \n\u2022\tThe\tcause \tof \tinsomnia \tshould \tbe \testablished \tbefore \t\nadministering hypnotic drugs. Common causes include alcohol or other drug misuse (see Ch. 50) and physical or psychiatric disorders (especially depression).\n\u2022\tTricyclic \tantidepressants \t(Ch. \t48) \tcause \tdrowsiness, \t\nso can kill two birds with one stone if taken at night by depressed patients with sleep disturbance.\n\u2022\tOptimal \ttreatment \tof \tchronic \tinsomnia \tis \toften \tby \t\nchanging behaviour (e.g. increasing exercise, staying awake during the day) rather than with drugs.\n\u2022\tBenzodiazepines \tshould \tbe \tused \tonly \tfor \tshort \tperiods \t\n(<4 weeks) and for severe insomnia. They can be useful for a few nights when transient factors such as admission to hospital, jet lag or an impending \nprocedure cause insomnia.\n\u2022\tDrugs\tused \tto \ttreat \tinsomnia \tinclude:\n\u2013 benzodiazepines (e.g. temazepam) and related \ndrugs (e.g. zolpidem, zopiclone, which also act at \nthe benzodiazepine binding site);\n\u2013 chloral hydrate and triclofos, which were used \nformerly in children, but this is seldom justified;\n\u2013 sedating antihistamines (e.g. promethazine), which \ncause drowsiness (see Ch. 27) are less suitable for \ntreating insomnia. They can impair performance the \nnext day.within a few days, this is not obvious in the subjective \nratings.\nBenzodiazepines are now, however, only recommended \nfor short courses of treatment of insomnia. Tolerance \ndevelops over 1\u20132 weeks with continuous use, and on \ncessation rebound insomnia and withdrawal occurs.\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3258, "end_char_idx": 5439, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "39c29a5c-7882-40d0-9a01-adb3566abe62": {"__data__": {"id_": "39c29a5c-7882-40d0-9a01-adb3566abe62", "embedding": null, "metadata": {"page_label": "585", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "56594b9b-b903-4f5f-903b-aa7261fe37ee", "node_type": null, "metadata": {"page_label": "585", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aaf7aecfe6bf0de0d32a08ec988b85b8683cd1939ef15d32df7c785d95ac3967"}}, "hash": "aaf7aecfe6bf0de0d32a08ec988b85b8683cd1939ef15d32df7c785d95ac3967", "text": "45 ANxiOlYTic ANd hYpNOTic dRUgS\n579Natl. Acad. Sci. U. S. A. 109, 18595\u201318600. ( At last the mechanism of \nbenzodiazepine tolerance is beginning to be explained )\nLonergan, M.H., Olivera-Figueroa, L.A., Pitman, R.K., Brunet, A., 2013. \nPropranolol\u2019s effects on the consolidation and reconsolidation of \nlong-term emotional memory in healthy participants: a meta-analysis. \nJ. Psychiatry Neurosci. 38, 222\u2013231. ( A meta analysis of a number of trials \nexamining the ability of propranolol to disrupt negative memories )\nMurrough, J.W., Yaqubi, S., Sayed, S., Charney, D.S., 2015. Emerging \ndrugs for the treatment of anxiety. Expert Opin. Emerg. Drugs 20, \n393\u2013406. ( This review focuses on the potential for development of novel \ntreatments for anxiety )Ramos, A., 2008. Animal models of anxiety: do I need multiple tests? \nTrends Pharmacol. Sci. 29, 493\u2013498. ( Describes the need for animal models \nin the testing of anxiolytic drugs )\nSkolnick, P., 2012. Anxioselective anxiolytics: on a quest for the Holy \nGrail. Trends Pharmacol. Sci. 33, 611\u2013620.\nTan, K.R., Rudolph, U., L\u00fcscher, C., 2011. Hooked on benzodiazepines: \nGABA A receptor subtypes and addiction. Trends Neurosci. 34, \n188\u2013197. ( Don\u2019t be fooled by the title, this review also contains information \non how different GABA A-receptor subunits mediate the different effects of \nbenzodiazepines ) mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1840, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "612ce01a-76ca-4d21-9707-9f37f07e8465": {"__data__": {"id_": "612ce01a-76ca-4d21-9707-9f37f07e8465", "embedding": null, "metadata": {"page_label": "586", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3bbd682c-2cc0-49f6-aa9e-fb1841e0d27d", "node_type": null, "metadata": {"page_label": "586", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f0efcb3eab72bf1ac9dafe93589b239a5838cea87268dafe9045e9a9ef247ac"}, "3": {"node_id": "aa485f7e-deaa-4be1-829e-f7ed129efc99", "node_type": null, "metadata": {"page_label": "586", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "85bb40b9996b0313f085d93e77d8bdaf2263c15db4fee2452df079dc46ebcc30"}}, "hash": "cc08cf19193aeab6a054e22d0e192527e511f73ac7cca159db6376a0855b3374", "text": "580\nOVERVIEW\nIn this chapter we describe the nature of epilepsy, \nthe neurobiological mechanisms underlying it and \nthe animal models that can be used to study it. We \nthen proceed to describe the various classes of drugs that are used to treat it, the mechanisms by which \nthey work and their pharmacological characteristics.\nCentrally acting muscle relaxants are discussed \nbriefly at the end of the chapter.\nINTRODUCTION\nEpilepsy is a very common disorder, characterised by \nseizures , which take various forms and result from episodic \nneuronal discharges, the form of the seizure depending on the part of the brain affected. Epilepsy affects 0.5%\u20131% of the population, i.e. ~50 million people worldwide. It may \nbe genetic in origin (often referred to as idiopathic) or \ndevelop after brain damage, such as trauma, stroke, infection or tumour growth, or other kinds of neurological disease. \nIn some instances the cause is unknown. Epilepsy is treated \nmainly with drugs, although brain surgery may be used for suitable severe cases. Current antiepileptic drugs are effective in controlling seizures in about 70% of cases, but \ntheir use is often limited by side effects. In addition to their \nuse in patients with epilepsy, antiepileptic drugs are used to treat or prevent convulsions caused by other brain \ndisorders, for example trauma (including following neu -\nrosurgery), infection (as an adjunct to antibiotics), brain \ntumours and stroke. For this reason, they are sometimes \ntermed anticonvulsants rather than antiepileptics. Increas -\ningly, some antiepileptic drugs have been found to have \nbeneficial effects in non-convulsive disorders such as \nneuropathic pain (Ch. 43), bipolar depression (Ch. 48) and \nanxiety (Ch. 45). Many new antiepileptic drugs have been developed over the past 25 or so years in attempts to \nimprove their efficacy and side-effect profile, for example \nby modifying their pharmacokinetics. Improvements have been steady rather than spectacular, and epilepsy remains \na difficult problem, despite the fact that controlling rever -\nberative neuronal discharges would seem, on the face of \nit, to be a much simpler problem than controlling those aspects of brain function that determine emotions, mood \nand cognitive function.\nTHE NATURE OF EPILEPSY\nThe term \u2018epilepsy\u2019 is used to define a group of neurologi -\ncal disorders, all of which exhibit periodic seizures. For information on the underlying causes of epilepsy and \nfactors that precipitate periodic seizures see Browne and \nHolmes (2008). As explained later, not all seizures involve convulsions. Seizures are associated with episodic high-frequency discharge of impulses by a group of neurons (sometimes referred to as the focus ) in the brain. What starts \nas a local abnormal discharge may then spread to other areas of the brain. The site of the primary discharge and the extent of its spread determine the symptoms that are \nproduced, which range from a brief lapse of attention to \na full convulsive fit lasting for several minutes, as well as odd sensations or behaviours. The particular symptoms \nproduced depend on the function of the region of the brain \nthat is affected. Thus, involvement of the motor cortex causes convulsions, involvement of the hypothalamus causes \nperipheral autonomic discharge, and involvement of the \nreticular formation in the upper brain stem leads to loss of \nconsciousness.\nAbnormal electrical activity during and following a \nseizure can be detected by electroencephalography (EEG) recording from electrodes distributed over the surface of \nthe scalp. Various types of seizure can be recognised on \nthe basis of the nature and distribution of the abnormal discharge (Fig.", "start_char_idx": 0, "end_char_idx": 3712, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aa485f7e-deaa-4be1-829e-f7ed129efc99": {"__data__": {"id_": "aa485f7e-deaa-4be1-829e-f7ed129efc99", "embedding": null, "metadata": {"page_label": "586", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3bbd682c-2cc0-49f6-aa9e-fb1841e0d27d", "node_type": null, "metadata": {"page_label": "586", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f0efcb3eab72bf1ac9dafe93589b239a5838cea87268dafe9045e9a9ef247ac"}, "2": {"node_id": "612ce01a-76ca-4d21-9707-9f37f07e8465", "node_type": null, "metadata": {"page_label": "586", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cc08cf19193aeab6a054e22d0e192527e511f73ac7cca159db6376a0855b3374"}}, "hash": "85bb40b9996b0313f085d93e77d8bdaf2263c15db4fee2452df079dc46ebcc30", "text": "on \nthe basis of the nature and distribution of the abnormal discharge (Fig. 46.1). Modern brain imaging techniques, such as magnetic resonance imaging and positron emission \ntomography, are now routinely used in the evaluation of \npatients with epilepsy (Fig. 46.2) to identify structural abnormalities (e.g. ischaemic lesions, tumours; see Deblaere \n& Achten, 2008).\nTYPES OF EPILEPSY\nThe clinical classification of epilepsy is done on the basis of the characteristics of the seizure rather than on the cause \nor underlying pathology. There are two major seizure \ncategories, namely partial (localised to part of the brain) \nand generalised (involving the whole brain).\nPARTIAL SEIZURES\nPartial (focal) seizures are those in which the discharge begins locally and often remains localised. The symptoms \ndepend on the brain region or regions involved, and include \ninvoluntary muscle contractions, abnormal sensory experi -\nences or autonomic discharge, or effects on mood and \nbehaviour \u2013 often termed psychomotor epilepsy \u2013 which may \narise from a focus within a temporal lobe. The EEG discharge \nin this type of epilepsy is normally confined to one hemi -\nsphere (see Fig. 46.1D). Partial seizures can often be attributed to local cerebral lesions, and their incidence increases with age. In complex partial seizures, loss of consciousness may occur at the outset of the attack, or \nsomewhat later, when the discharge has spread from its \nsite of origin to regions of the brain stem reticular formation. In some individuals, a partial seizure can, during the seizure, Antiepileptic drugs46 NERVOUS SYSTEM SECTION 4\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3636, "end_char_idx": 5736, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "470c3dd2-db51-42a0-a2f9-ba997ae99658": {"__data__": {"id_": "470c3dd2-db51-42a0-a2f9-ba997ae99658", "embedding": null, "metadata": {"page_label": "587", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd85ddd7-7132-4c68-9bdd-f820ad8e8cf1", "node_type": null, "metadata": {"page_label": "587", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6af64bd19df759316ef7bebb3cb602ba1eea848803dadff4ac39f5414dd0d6c2"}, "3": {"node_id": "dd3f9c7f-e1d2-4dba-90be-adad213f2a9f", "node_type": null, "metadata": {"page_label": "587", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cac1625cad5819c60241d5f6023dc09ce3ff0035f0b3c72079441b8efed4db02"}}, "hash": "0398ebaae681d3bade1ee3f8d267cf2b76bd1331e546175d3442b3874692979d", "text": "46 ANTiEpilEpTic dRUgS\n581become generalised when the abnormal neuronal activity \nspreads across the whole brain.\nAn epileptic focus in the motor cortex results in attacks, \nsometimes called Jacksonian epilepsy ,1 consisting of repetitive \njerking of a particular muscle group, beginning on one side \nof the body, often in the thumb, big toe or angle of the \nmouth, which spreads and may involve much of the body \nwithin about 2 min before dying out. The patient loses \nvoluntary control of the affected parts of the body but does not necessarily lose consciousness. In psychomotor epilepsy \nthe attack may consist of stereotyped purposive movements such as rubbing or patting movements, or much more complex behaviour such as dressing, walking or hair \ncombing. The seizure usually lasts for a few minutes, after \nwhich the patient recovers with no recollection of the event. The behaviour during the seizure can be bizarre and \naccompanied by a strong emotional response.\nGENERALISED SEIZURES\nGeneralised seizures involve the whole brain, including \nthe reticular system, thus producing abnormal electrical \nactivity throughout both hemispheres. Immediate loss of \nconsciousness is characteristic of generalised seizures. There are a number of types of generalised seizure \u2013 two important \ncategories are tonic\u2013clonic seizures (formerly referred to as \ngrand mal, see Fig. 46.1B) and absence seizures (petit mal, \nsee Fig. 46.1C ); others include myoclonic, tonic, atonic and \nclonic seizures.\nA tonic\u2013clonic seizure consists of an initial strong contrac -\ntion of the whole musculature, causing a rigid extensor \nspasm and an involuntary cry. Respiration stops, and A B\nD COOTTF FNormal Generalised seizure (grand mal)\n\u2014 tonic\u2013clonic type\nGeneralised seizure (petit mal)\u2014 absence seizure typePartial seizureF\nT\nO4 3 2 1\n1sFig. 46.1 Electroencephalography \n(EEG) records in epilepsy. (A) Normal EEG \nrecorded from frontal (F), temporal (T) and \noccipital (O) sites on both sides, as shown \nin the inset diagram. The \u03b1 rhythm (10/s) \ncan be seen in the occipital region. \n(B) Sections of EEG recorded during a \ngeneralised tonic\u2013clonic (grand mal) seizure: 1, normal record; 2, onset of tonic phase; \n3, clonic phase; 4, postconvulsive coma. \n(C) Generalised absence seizure (petit mal) showing sudden brief episode of 3/s \u2018spike-and-wave\u2019 discharge. (D) Partial seizure with synchronous abnormal discharges in left frontal and temporal \nregions. (From Eliasson, S.G. et al., 1978. \nNeurological Pathophysiology, second ed. Oxford University Press, New York.)\nFig. 46.2 Positron emission tomography (PET) image \nusing [18F]-fluoro-2-deoxyglucose (FDG) of the brain of a \nfemale patient suffering from temporal lobe epilepsy. The \ninterictal area of hypometabolism in the left temporal lobe (indicated by the arrow) is suggestive of the site of the epileptic \nfocus. (Image kindly provided by Prof. John Duncan and Prof. Peter Ell, UCL Institute of Neurology, London.)\n1After Hughlings Jackson, a distinguished 19th-century Yorkshire \nneurologist who published his outstanding work in the Annals of the \nWest Riding Lunatic Asylum.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3285, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dd3f9c7f-e1d2-4dba-90be-adad213f2a9f": {"__data__": {"id_": "dd3f9c7f-e1d2-4dba-90be-adad213f2a9f", "embedding": null, "metadata": {"page_label": "587", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fd85ddd7-7132-4c68-9bdd-f820ad8e8cf1", "node_type": null, "metadata": {"page_label": "587", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6af64bd19df759316ef7bebb3cb602ba1eea848803dadff4ac39f5414dd0d6c2"}, "2": {"node_id": "470c3dd2-db51-42a0-a2f9-ba997ae99658", "node_type": null, "metadata": {"page_label": "587", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0398ebaae681d3bade1ee3f8d267cf2b76bd1331e546175d3442b3874692979d"}}, "hash": "cac1625cad5819c60241d5f6023dc09ce3ff0035f0b3c72079441b8efed4db02", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3238, "end_char_idx": 3621, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c0f9ceae-7a96-4f5d-99a3-91b444e4d107": {"__data__": {"id_": "c0f9ceae-7a96-4f5d-99a3-91b444e4d107", "embedding": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ae98dfd7-bd97-4b59-9673-f70ff15009e7", "node_type": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "83f17ff98ef075d8c18fbbdc7e6186edb705bb28f7745c79ec9b6e4f33a776ce"}, "3": {"node_id": "5e27f721-703c-4e45-83a0-bb8bca91f862", "node_type": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91188a9a7d38e3b2068984eb36b5257c9ad247ed72d13e38c15fa43c25ff99f0"}}, "hash": "aab65b35ae1238215aaaf7931e42986d87324412ddc372c9e323c49234fd5458", "text": "46 SECTION 4 NERVOUS SYSTEM\n582receptors (see Ch. 39) produces \u2018plateau-shaped\u2019 depolarising responses \nvery similar to the PDS.\nBecause detailed studies are difficult to carry out on epileptic patients, \nmany different animal models of epilepsy have been investigated \n(see Bialer & White, 2010; Grone & Baraban, 2015 ). Transgenic mouse \nstrains have been reported that show spontaneous seizures. They \ninclude knock-out mutations of various ion channels, receptors and \nother synaptic proteins. Local application of penicillin crystals to the \ncerebral cortex results in focal seizures, probably by interfering with inhibitory synaptic transmission. Convulsant drugs (e.g. pentylene-\ntetrazol [PTZ]) are often used, as are seizures caused by electrical stimulation of the whole brain. In the kainate model a single injection \nof the glutamate receptor agonist kainic acid into the amygdaloid \nnucleus of a rat can produce spontaneous seizures 2\u20134 weeks later \nthat continue indefinitely. This is believed to result from excitotoxic damage to inhibitory neurons.\nIn the kindling model , brief low-intensity electrical stimulation of certain \nregions of the limbic system, such as the amygdala, normally produces \nno seizure response but if repeated daily for several days the response \ngradually increases until very low levels of stimulation will evoke a full seizure, and eventually seizures occur spontaneously. This kindled \nstate can persist indefinitely but is prevented by NMDA receptor \nantagonists or deletion of the neurotrophin receptor, TrkB.\nIn human focal epilepsies, surgical removal of a damaged region of \ncortex may fail to cure the condition, as though the abnormal discharge from the region of primary damage had somehow produced a second -\nary hyperexcitability elsewhere in the brain. Furthermore, following severe head injury, prophylactic treatment with antiepileptic drugs reduces the incidence of post-traumatic epilepsy, which suggests that \na phenomenon similar to kindling may underlie this form of epilepsy.\nMost recently, zebrafish have been used to study epileptic phenotypes \nresulting from genetic manipulation, both gene knock-out and knock-in \nof specific mutations. There is promise for this approach in the screening of drugs with activity against specific forms of genetic \nepilepsies (Grone & Baraban, 2015)\nANTIEPILEPTIC DRUGS\nAntiepileptic (sometimes known as anticonvulsant) drugs \nare used to treat epilepsy as well as non-epileptic convulsive \ndisorders.defecation, micturition and salivation often occur. This tonic \nphase lasts for about 1 min, during which the face is suffused \nand becomes blue (an important clinical distinction from \nsyncope, the main disorder from which fits must be dis -\ntinguished, where the face is ashen pale), and is followed by a series of violent, synchronous jerks that gradually die \nout in 2\u20134 min. The patient stays unconscious for a few \nmore minutes and then gradually recovers, feeling ill and confused. Injury may occur during the convulsive episode. \nThe EEG shows generalised continuous high-frequency \nactivity in the tonic phase and an intermittent discharge in the clonic phase (see Fig. 46.1B).\nAbsence seizures occur in children; they are much less \ndramatic but may occur more frequently (many seizures each day) than tonic\u2013clonic seizures. The patient abruptly \nceases whatever he or she was doing, sometimes stopping \nspeaking in mid-sentence, and stares vacantly for a few seconds, with little or no motor disturbance. Patients are unaware of their surroundings and recover abruptly with \nno after effects. The EEG pattern shows", "start_char_idx": 0, "end_char_idx": 3632, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5e27f721-703c-4e45-83a0-bb8bca91f862": {"__data__": {"id_": "5e27f721-703c-4e45-83a0-bb8bca91f862", "embedding": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ae98dfd7-bd97-4b59-9673-f70ff15009e7", "node_type": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "83f17ff98ef075d8c18fbbdc7e6186edb705bb28f7745c79ec9b6e4f33a776ce"}, "2": {"node_id": "c0f9ceae-7a96-4f5d-99a3-91b444e4d107", "node_type": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aab65b35ae1238215aaaf7931e42986d87324412ddc372c9e323c49234fd5458"}, "3": {"node_id": "e217289f-adb9-4478-aeda-594fd76d0243", "node_type": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4445abecc4749dd1fa334d410ed1e092bd97bb8fb0a8822d46d5de792100429"}}, "hash": "91188a9a7d38e3b2068984eb36b5257c9ad247ed72d13e38c15fa43c25ff99f0", "text": "surroundings and recover abruptly with \nno after effects. The EEG pattern shows a characteristic \nrhythmic discharge during the period of the seizure (see Fig. 46.1C). The rhythmicity appears to be due to oscillatory \nfeedback between the cortex and the thalamus, the special \nproperties of the thalamic neurons being dependent on the T-type calcium channels that they express (see Shin, 2006). \nThe pattern differs from that of partial seizures, where a \nhigh-frequency asynchronous discharge spreads out from a local focus. Accordingly, the drugs used specifically to \ntreat absence seizures act mainly by blocking T-type calcium \nchannels, whereas drugs effective against other types of epilepsy act mainly by blocking sodium channels or enhanc -\ning GABA-mediated inhibition.\nA particularly severe kind of epilepsy, Lennox\u2013Gastaut \nsyndrome , occurs in children and is associated with progres -\nsive mental retardation, possibly a reflection of excitotoxic neurodegeneration (see Ch. 41).\nAbout one-third of cases of epilepsy are familial and \ninvolve genetic mutations. While some are due to a single \nmutation, most result from polygenetic mutations (see \nPandolfo, 2011). Most genes associated with familial epi -\nlepsies encode neuronal ion channels closely involved in \ncontrolling action potential generation (see Ch. 4), such as \nvoltage-gated sodium and potassium channels, GABA receptors and nicotinic acetylcholine receptors. Some other \ngenes encode proteins that interact with ion channels.\nStatus epilepticus refers to continuous uninterrupted \nseizures, requiring emergency medical treatment.\nNEURAL MECHANISMS AND ANIMAL MODELS \nOF EPILEPSY\n\u25bc The underlying neuronal abnormality in epilepsy is poorly \nunderstood. In general, excitation will naturally tend to spread \nthroughout a network of interconnected neurons but is normally \nprevented from doing so by inhibitory mechanisms. Thus epileptogenesis \ncan arise if excitatory transmission is facilitated or inhibitory transmis -\nsion is reduced (exemplified by GABA A receptor antagonists causing \nconvulsions; see Ch. 39). In certain respects, epileptogenesis resembles long-term potentiation (Ch. 39), and similar types of use-dependent \nsynaptic plasticity may be involved. Neurons from which the epileptic discharge originates display an unusual type of electrical behaviour, \ntermed the paroxysmal depolarising shift (PDS), during which the \nmembrane potential suddenly decreases by about 30 mV and remains \ndepolarised for up to a few seconds before returning to normal. A \nburst of action potentials often accompanies this depolarisation (Fig. \n46.3). This event probably results from the abnormally exaggerated and prolonged action of an excitatory transmitter. Activation of NMDA 1 s50 mV500 ms\nBA\nFig. 46.3 \u2018Paroxysmal depolarising shift\u2019 (PDS) compared \nwith experimental activation of glutamate receptors of the \nNMDA type. (A) PDS recorded with an intracellular microelectrode from cortical neurons of anaesthetised cats. Seizure activity was induced by topical application of penicillin. (B) Intracellular recording from the caudate nucleus of an anaesthetised cat. The glutamate analogue NMDA was applied by ionophoresis from a nearby micropipette. (Panel [A] from Matsumoto, H., Marsan, C.A., 1964. Exp. Neurol. 9, 286; panel \n[B] from Herrling, P.L. et al., 1983. J. Physiol. 339, 207.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3565, "end_char_idx": 7072, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e217289f-adb9-4478-aeda-594fd76d0243": {"__data__": {"id_": "e217289f-adb9-4478-aeda-594fd76d0243", "embedding": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ae98dfd7-bd97-4b59-9673-f70ff15009e7", "node_type": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "83f17ff98ef075d8c18fbbdc7e6186edb705bb28f7745c79ec9b6e4f33a776ce"}, "2": {"node_id": "5e27f721-703c-4e45-83a0-bb8bca91f862", "node_type": null, "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "91188a9a7d38e3b2068984eb36b5257c9ad247ed72d13e38c15fa43c25ff99f0"}}, "hash": "d4445abecc4749dd1fa334d410ed1e092bd97bb8fb0a8822d46d5de792100429", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7109, "end_char_idx": 7492, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2ab3b2fb-bc7d-4043-af72-c8de1aa0d204": {"__data__": {"id_": "2ab3b2fb-bc7d-4043-af72-c8de1aa0d204", "embedding": null, "metadata": {"page_label": "589", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d30d9ee7-c655-450b-b608-5879c7ab9d87", "node_type": null, "metadata": {"page_label": "589", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "88b7964194212da28adcf6994a8f14f83bd923000be7bd20e77890e988e8cb4a"}, "3": {"node_id": "514ecaf3-fc03-4697-9fe4-78622b29fe54", "node_type": null, "metadata": {"page_label": "589", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eb7a7b88832ee46ea538a187efadc22c5a3a6b65288f3524e342257f9a9a6ced"}}, "hash": "3f9f1a95d24822ccfbef3dc9662bf9deb79534d1606a1b7d3366f2c07f59948f", "text": "46 ANTiEpilEpTic dRUgS\n583Table 46.1. Newer drugs (see Table 46.2) with similar \nmechanisms of action to older drugs or novel mechanisms \nof action may offer advantages in terms of efficacy in \ndrug-resistant epilepsies, better pharmacokinetic profile, improved tolerability, lower potential for interaction with \nother drugs (see Ch. 58) and fewer adverse effects. The \nappropriate use of drugs from this large available menu \ndepends on many clinical factors (see Shih et al., 2017).\nMECHANISM OF ACTION\nAntiepileptic drugs aim to inhibit the abnormal neuronal discharge rather than to correct the underlying cause. Three \nmain mechanisms of action appear to be important:\n1. Enhancement of GABA action.\n2. Inhibition of sodium channel function.\n3. Inhibition of calcium channel function.\nMore recently, newer drugs with other, novel mechanisms \nof action have been developed.\nAntiepileptic drugs may exert more than one beneficial \naction, prime examples being valproate and topiramate (see Tables 46.1 and 46.2). The relative importance and \ncontribution of each of these actions to the therapeutic effect \nis somewhat uncertain.\nAs with drugs used to treat cardiac dysrhythmias (Ch. \n22), the aim is to prevent the paroxysmal discharge without affecting normal transmission. It is clear that properties such as use-dependence and voltage-dependence of channel-blocking drugs (see Ch. 4) are important in achieving this \nselectivity, but our understanding remains fragmentary.\nEnhancement of GABA action\nSeveral antiepileptic drugs (e.g. phenobarbital and \nbenzodiazepines ) enhance the activation of GABA A recep -\ntors, thus facilitating the GABA-mediated opening of chloride channels (see Chs 3 and 45).\n3 Vigabatrin acts by \nirreversibly inhibiting the enzyme GABA transaminase that is responsible for inactivating GABA (see Ch. 39) in astro -\ncytes and GABAergic nerve terminals. Tiagabine is an \ninhibitor of the \u2018neuronal\u2019 GABA transporter GAT1 that is expressed on GABAergic nerve terminals, and, to a lesser \nextent, on neighbouring astrocytes, thus inhibiting the removal of GABA from the synapse. It elevates the extracel -\nlular GABA concentration, as measured in microdialysis experiments, and also potentiates and prolongs GABA-mediated synaptic responses in the brain.\nInhibition of sodium channel function\nMany antiepileptic drugs (e.g. carbamazepine, phenytoin \nand lamotrigine ; see Tables 46.1 and 46.2) affect membrane \nexcitability by an action on voltage-dependent sodium channels (see Chs 4 and 44), which carry the inward membrane current necessary for the generation of an action \npotential. Their blocking action shows the property of \nuse-dependence; in other words, they block preferentially the excitation of cells that are firing repetitively, and the \nhigher the frequency of firing, the greater the block pro -\nduced. This characteristic, which is relevant to the ability \nof drugs to block the high-frequency discharge that occurs in an epileptic fit without unduly interfering with the With optimal drug therapy, epilepsy is controlled com -\npletely in about 75% of patients, but about 10% (50,000 in Britain) continue to have seizures at intervals of 1 month \nor less, which severely disrupts their life and work. There \nis therefore a need to improve the efficacy of therapy.\nPatients with epilepsy usually need to take drugs continu -\nously for many years, so avoidance of side effects is par -\nticularly important. Nevertheless, some drugs that have considerable adverse effects are still quite widely used even \nthough they are", "start_char_idx": 0, "end_char_idx": 3572, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "514ecaf3-fc03-4697-9fe4-78622b29fe54": {"__data__": {"id_": "514ecaf3-fc03-4697-9fe4-78622b29fe54", "embedding": null, "metadata": {"page_label": "589", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d30d9ee7-c655-450b-b608-5879c7ab9d87", "node_type": null, "metadata": {"page_label": "589", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "88b7964194212da28adcf6994a8f14f83bd923000be7bd20e77890e988e8cb4a"}, "2": {"node_id": "2ab3b2fb-bc7d-4043-af72-c8de1aa0d204", "node_type": null, "metadata": {"page_label": "589", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f9f1a95d24822ccfbef3dc9662bf9deb79534d1606a1b7d3366f2c07f59948f"}}, "hash": "eb7a7b88832ee46ea538a187efadc22c5a3a6b65288f3524e342257f9a9a6ced", "text": "drugs that have considerable adverse effects are still quite widely used even \nthough they are not drugs of choice for newly diagnosed \npatients.\n2 There is a need for more specific and effective \ndrugs, and a number of new drugs have recently been \nintroduced for clinical use or are in late stages of clinical \ntrials. Long-established antiepileptic drugs are listed in Nature of epilepsy \n\u2022\tEpilepsy \taffects \tabout \t0.5% \tof \tthe \tpopulation.\n\u2022\tThe\tcharacteristic \tevent \tis \tthe \tseizure, \twhich \tmay \tbe \t\nassociated with convulsions but may take other forms.\n\u2022\tThe\tseizure \tis \tcaused \tby \tan \tasynchronous \thigh-\nfrequency discharge of a group of neurons, starting \nlocally and spreading to a varying extent to affect other parts of the brain. In absence seizures, the discharge \nis regular and oscillatory.\n\u2022\tPartial\tseizures \taffect \tlocalised \tbrain \tregions, \tand \tthe \t\nattack may involve mainly motor, sensory or \nbehavioural phenomena. Unconsciousness occurs when the reticular formation is involved.\n\u2022\tGeneralised \tseizures \taffect \tthe \twhole \tbrain. \tTwo \t\ncommon forms of generalised seizure are the tonic\u2013clonic fit and the absence seizure. Status epilepticus is a life-threatening condition in which seizure activity is \nuninterrupted.\n\u2022\tPartial\tseizures \tcan \tbecome \tsecondarily \tgeneralised \tif \t\nthe localised abnormal neuronal activity subsequently \nspreads across the whole brain.\n\u2022\tMany\tanimal \tmodels \thave \tbeen \tdevised, \tincluding \t\nelectrically and chemically induced generalised seizures, production of local chemical damage and kindling. These provide good prediction of antiepileptic \ndrug effects in humans.\n\u2022\tThe\tneurochemical \tbasis \tof \tthe \tabnormal \tdischarge \tis \t\nnot well understood. It may be associated with \nenhanced excitatory amino acid transmission, impaired inhibitory transmission or abnormal electrical properties \nof the affected cells. Several susceptibility genes, \nmainly encoding neuronal ion channels, have been identified.\n\u2022\tRepeated \tepileptic \tdischarge \tcan \tcause \tneuronal \t\ndeath (excitotoxicity).\n\u2022\tCurrent \tdrug \ttherapy \tis \teffective \tin \t70%\u201380% \tof \t\npatients.\n2Bromide was the first antiepileptic agent. Its propensity to induce \nsedation and other unwanted side effects has resulted in it being largely \nwithdrawn from human medicine, although it is still approved for \nhuman use in some countries and may have uses in drug-resistant childhood epilepsies. It is still widely used in veterinary practice to treat \nepilepsy in dogs and cats.3Absence seizures, paradoxically, are often exacerbated by drugs that \nenhance GABA activity and better treated by drugs acting by different mechanisms such as T-type calcium-channel inhibition.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3478, "end_char_idx": 6665, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aeba0693-6d5c-4426-8c36-196787e98273": {"__data__": {"id_": "aeba0693-6d5c-4426-8c36-196787e98273", "embedding": null, "metadata": {"page_label": "590", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b75d166d-6fec-4370-befe-44087ce027ad", "node_type": null, "metadata": {"page_label": "590", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "296aa19c3cacdc46c3d88044decbad6a0691dcf7f99190e8baf7e6be9aed2dd8"}, "3": {"node_id": "226910e6-a2ea-490c-abce-615584118567", "node_type": null, "metadata": {"page_label": "590", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9706b57927df0eee92f9be5c6dcff2ac5cc60c3db2aed49dc268b4c958ecbba2"}}, "hash": "265a6614c220a25e262b61f92e1772d2f6756fe3c008e598bbac05483d5b6fca", "text": "46 SECTION 4 NERVOUS SYSTEM\n584available to generate subsequent action potentials. Lacosa -\nmide enhances sodium channel inactivation, but unlike \nother antiepileptic drugs it appears to affect slow rather \nthan rapid inactivation processes.\nInhibition of calcium channels\nDrugs that are used to treat absence seizures (e.g. etho-suximide and valproate) share the ability to block T-type \nlow-voltage-activated calcium channels. T-type channel low-frequency firing of neurons in the normal state, arises from the ability of blocking drugs to discriminate between \nsodium channels in their resting, open and inactivated states \n(see Chs 4 and 44). Depolarisation of a neuron (such as occurs in the PDS described previously) increases the \nproportion of the sodium channels in the inactivated state. \nAntiepileptic drugs bind preferentially to channels in this state, preventing them from returning to the resting state, \nand thus reducing the number of functional channels Table 46.1 Properties of long-established antiepileptic drugs\nDrugSite of action\nMain usesMain unwanted \neffect(s) PharmacokineticsSodium channelGABA\nA \nreceptorCalcium channel Other\nCarbamazepinea+ \u2014 \u2014 \u2014All types except \nabsence seizuresSedation, ataxia, blurred vision, water retention, hypersensitivity reactions, leukopenia, liver failure (rare)Half-life 12\u201318 h \n(longer initially)\nEspecially focal seizures such as temporal lobe epilepsyStrong induction of liver enzymes, so risk of drug interactions\nAlso trigeminal neuralgia\nPhenytoin\nb+ \u2014 \u2014 \u2014All types except absence seizuresAtaxia, vertigo, gum hypertrophy, hirsutism, megaloblastic anaemia, fetal malformation, hypersensitivity reactions Half-life ~24 h\nSaturation kinetics, therefore unpredictable plasma levelsPlasma monitoring often required\nValproate + ?+ +GABA transaminase inhibitionMost types, including absence seizuresGenerally less than with other drugs\nHalf-life 12\u201315 h Nausea, hair loss, weight gain, fetal malformations\nEthosuximide\nc\u2014 \u2014 + \u2014Absence seizures Nausea, anorexia, mood changes, headacheLong plasma \nhalf-life (~60 h)May exacerbate tonic\u2013clonic seizures\nPhenobarbital\nd?+ + \u2014 \u2014All types except absence seizuresSedation, depressionLong plasma half-life (>\n60 h)\nStrong induction of liver enzymes, so risk of drug interactions (e.g. with phenytoin)\nBenzodiazepines \n(e.g. clonazepam, clobazam, lorazepam, diazepam)\u2014 + \u2014 \u2014Lorazepam used intravenously to control status epilepticusSedation\nSee Ch. 45Withdrawal syndrome (see Ch. 45)\naOxcarbazepine and eslicarbazepine, recently introduced, are similar; claimed to have fewer side effects.\nbFosphenytoin is a water-soluble phenytoin prodrug that is safer than phenytoin when given by injection.\ncTrimethadione is similar to ethosuximide in that it acts selectively against absence seizures but has greater toxicity (especially the risk of \nsevere hypersensitivity reactions and teratogenicity).\ndPrimidone is pharmacologically similar to phenobarbital and is converted to phenobarbital in the body. It has no clear advantages and is \nmore liable to produce hypersensitivity reactions, so is now rarely used.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 0, "end_char_idx": 3294, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "226910e6-a2ea-490c-abce-615584118567": {"__data__": {"id_": "226910e6-a2ea-490c-abce-615584118567", "embedding": null, "metadata": {"page_label": "590", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b75d166d-6fec-4370-befe-44087ce027ad", "node_type": null, "metadata": {"page_label": "590", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "296aa19c3cacdc46c3d88044decbad6a0691dcf7f99190e8baf7e6be9aed2dd8"}, "2": {"node_id": "aeba0693-6d5c-4426-8c36-196787e98273", "node_type": null, "metadata": {"page_label": "590", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "265a6614c220a25e262b61f92e1772d2f6756fe3c008e598bbac05483d5b6fca"}}, "hash": "9706b57927df0eee92f9be5c6dcff2ac5cc60c3db2aed49dc268b4c958ecbba2", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3247, "end_char_idx": 3598, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d43e6ede-6000-4233-971c-2e723d0e9133": {"__data__": {"id_": "d43e6ede-6000-4233-971c-2e723d0e9133", "embedding": null, "metadata": {"page_label": "591", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8db06f35-b0dc-4488-ae1a-ecb47748b226", "node_type": null, "metadata": {"page_label": "591", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "186f4559b932a513c2822beb21c7649be83f0df897a2d3b1dae4c3f4458d2038"}}, "hash": "186f4559b932a513c2822beb21c7649be83f0df897a2d3b1dae4c3f4458d2038", "text": "46 ANTiEpilEpTic dRUgS\n585Table 46.2 Properties of newer antiepileptic drugsa\nDrugSite of action\nMain usesMain unwanted \neffect(s) PharmacokineticsSodium channelGABA\nA \nreceptorCalcium channel Other\nVigabatrin \u2014 \u2014 \u2014GABA \ntransaminase inhibitionAll typesAppears to be effective in patients resistant to other drugsSedation, behavioural and mood changes (occasionally psychosis)Visual field defectsShort plasma half-life, but enzyme inhibition is long-lasting\nLamotrigine + \u2014 ?+Inhibits glutamate releaseAll typesDizziness, sedation, rashesPlasma half-life \n24\u201336 h\nGabapentinPregabalin\u2014 \u2014 + \u2014 Partial seizures Few side effects, mainly sedationPlasma half-life \n6\u20139 h\nFelbamate + + ?+? NMDA receptor blockUsed mainly for severe epilepsy (Lennox\u2013Gastaut syndrome) because of risk of adverse reactionFew acute side effects but can cause aplastic anaemia and liver damage (rare but serious)Plasma half-life \n~20 h\nExcreted unchanged\nTiagabine \u2014 \u2014 \u2014Inhibits GABA uptake Partial seizuresSedationDizziness, lightheadednessPlasma half-life \n~7 h\nLiver metabolism\nTopiramate + ?+ ?+AMPA-receptor blockPartial and generalised tonic\u2013clonic seizures.Lennox\u2013Gastaut syndromeSedationFewer pharmacokinetic interactions than phenytoinFetal malformationPlasma half-life \n~20 h\nExcreted unchanged\nLevetiracetam\na\u2014 \u2014 \u2014Binds to SV2A proteinPartial and generalised tonic\u2013clonic seizuresSedation (slight)Plasma half-life \n~7 h\nExcreted unchanged\nZonisamide + ?+ + \u2014 Partial seizuresSedation (slight)Appetite suppression, weight lossPlasma half-life \n~70 h\nRufinamide + \u2014 \u2014 ?+ Inhibits GABA reuptakePartial seizures Headache, dizziness, fatiguePlasma half-life \n6\u201310 h\nLacosamide + \u2014 \u2014 \u2014 Partial seizuresNausea and vomiting dizziness, visual disturbances impaired coordination mood changesPlasma half-life \n13 h\nPerampanel \u2014 \u2014 \u2014Non-competitive AMPA antagonistPartial seizuresDizziness, weight gain, sedation impaired coordination changes in mood and behaviourPlasma half-life \n70\u2013100 h\naBrivaracetam is a structural analogue.\nSV2A, synaptic vesicle protein 2A.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2519, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3ee31c09-301d-44df-8702-76d5b874ab97": {"__data__": {"id_": "3ee31c09-301d-44df-8702-76d5b874ab97", "embedding": null, "metadata": {"page_label": "592", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ac0b7db0-e4ea-4680-a4d3-05b2eb89eeda", "node_type": null, "metadata": {"page_label": "592", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea2b848cb9542c3eae2c0e539ca066ba582a2eee8866444802ec944388d845e9"}, "3": {"node_id": "993ef7ae-b698-4e86-aeb0-fee379eb3c48", "node_type": null, "metadata": {"page_label": "592", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44b9db8f195f3d9c94c8946d59fb208ff40bef10292238b3a5145bd042f6cd64"}}, "hash": "89cbedab7a1914e5bd083d1a61b1e92ab87c01cbdb5c8d1e8b825e07a083d361", "text": "46 SECTION 4 NERVOUS SYSTEM\n586CARBAMAZEPINE\nCarbamazepine is chemically related to the tricyclic anti -\ndepressant drugs (see Ch. 48) and was found in a routine \nscreening test to inhibit electrically evoked seizures in mice. \nPharmacologically and clinically, its actions resemble those of phenytoin, although it appears to be particularly effective \nin treating certain partial seizures (e.g. psychomotor epi -\nlepsy). It is also used to treat other conditions, such as \nneuropathic pain (Ch. 43) and manic-depressive illness \n(Ch. 48).\nPharmacokinetic aspects\nCarbamazepine is slowly but well absorbed after oral \nadministration. Its plasma half-life is about 30 h when it \nis given as a single dose, but it is a strong inducer of hepatic \nenzymes, and the plasma half-life shortens to about 15 h \nwhen it is given repeatedly. Some of its metabolites have antiepileptic properties. A slow-release preparation is used \nfor patients who experience transient side effects coinciding \nwith plasma concentration peaks following oral dosing.\nUnwanted effects\nCarbamazepine produces a variety of unwanted effects ranging from drowsiness, dizziness and ataxia to more \nsevere mental and motor disturbances.\n4 It can also cause \nwater retention (and hence hyponatraemia; Ch. 30) and a variety of gastrointestinal and cardiovascular side effects. \nThe incidence and severity of these effects is relatively low, however, compared with other drugs. Treatment is usually \nstarted with a low dose, which is built up gradually to \navoid dose-related toxicity. Severe bone marrow depression, causing neutropenia, and other severe forms of hypersen -\nsitivity reaction can occur, especially in people of Asian origin (see Ch. 12).\nCarbamazepine is a powerful inducer of hepatic micro-\nsomal enzymes, and thus accelerates the metabolism of \nmany other drugs, such as phenytoin, oral contraceptives, \nwarfarin and corticosteroids, as well as of itself. When starting treatment, the opposite of a \u2018loading dose\u2019 strategy \nis employed: small initial doses are gradually increased, \nas when dosing is initiated, metabolising enzymes are not induced and so even low doses may give rise to adverse \neffects (notably ataxia); as enzyme induction occurs, increas -\ning doses are needed to maintain therapeutic plasma \nconcentrations. In general, it is inadvisable to combine it \nwith other antiepileptic drugs, and interactions with other \ndrugs (e.g. warfarin) metabolised by cytochrome P450 (CYP) enzymes are common and clinically important. Oxcarbaz -\nepine is a prodrug that is metabolised to a compound closely \nresembling carbamazepine, with similar actions but less tendency to induce drug-metabolising enzymes. Another \nstructurally related drug, eslicarbazepine may have less \neffect on metabolising enzymes.\nPHENYTOIN\nPhenytoin is the most important member of the hydantoin group of compounds, which are structurally related to the \nbarbiturates. It is highly effective in reducing the intensity activity is important in determining the rhythmic discharge of thalamic neurons associated with absence seizures \n(Khosravani et al., 2004).\nGabapentin, though designed as a simple analogue of \nGABA that would be sufficiently lipid soluble to penetrate the blood\u2013brain barrier, owes its antiepileptic effect mainly \nto an action on P/Q-type calcium channels. By binding to a particular channel subunit (\u03b12\u03b41), both gabapentin and \npregabalin (a related analogue) reduce the trafficking to \nthe plasma membrane of calcium", "start_char_idx": 0, "end_char_idx": 3512, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "993ef7ae-b698-4e86-aeb0-fee379eb3c48": {"__data__": {"id_": "993ef7ae-b698-4e86-aeb0-fee379eb3c48", "embedding": null, "metadata": {"page_label": "592", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ac0b7db0-e4ea-4680-a4d3-05b2eb89eeda", "node_type": null, "metadata": {"page_label": "592", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ea2b848cb9542c3eae2c0e539ca066ba582a2eee8866444802ec944388d845e9"}, "2": {"node_id": "3ee31c09-301d-44df-8702-76d5b874ab97", "node_type": null, "metadata": {"page_label": "592", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "89cbedab7a1914e5bd083d1a61b1e92ab87c01cbdb5c8d1e8b825e07a083d361"}}, "hash": "44b9db8f195f3d9c94c8946d59fb208ff40bef10292238b3a5145bd042f6cd64", "text": "analogue) reduce the trafficking to \nthe plasma membrane of calcium channels containing this subunit, thereby reducing calcium entry into the nerve \nterminals and reducing the release of various neurotransmit-\nters and modulators.\nOther mechanisms\nMany of the newer antiepileptic drugs were developed empirically on the basis of activity in animal models. Their \nmechanism of action at the cellular level is not fully \nunderstood.\nLevetiracetam is believed to interfere with neurotransmit -\nter release by binding to synaptic vesicle protein 2A (SV2A), which is involved in synaptic vesicle docking and fusion. Brivaracetam, a related antiepileptic agent, also binds to \nSV2A with 10-fold higher affinity.\nWhile a drug may appear to work by one of the major \nmechanisms described, close scrutiny often reveals other \nactions that may also be therapeutically relevant. For \nexample, phenytoin not only causes use-dependent block \nof sodium channels (see p. 583) but also affects other aspects \nof membrane function, including calcium channels and \npost-tetanic potentiation, as well as intracellular protein \nphosphorylation by calmodulin-activated kinases, which could also interfere with membrane excitability and synaptic \nfunction.\nAntagonism at ionotropic excitatory amino acid receptors \nhas been a major focus in the search for new antiepileptic drugs. Despite showing efficacy in animal models, by and \nlarge they did not prove useful in the clinic, because the margin between the desired anticonvulsant effect and \nunacceptable side effects, such as loss of motor coordination, \nwas too narrow. However, perampanel , a non-competitive \nAMPA-receptor antagonist, has been approved as an add \non treatment for partial seizures.\nMechanism of action of \nantiepileptic drugs \n\u2022\tThe\tmajor \tantiepileptic \tdrugs \tare \tthought \tto \tact \tby \t\nthree main mechanisms:\n\u2013 reducing electrical excitability of cell membranes, \nmainly through use-dependent block of sodium \nchannels;\n\u2013 enhancing GABA-mediated synaptic inhibition; this \nmay be achieved by an enhanced postsynaptic action of GABA, by inhibiting GABA transaminase or by inhibiting GABA uptake into neurons and glial \ncells;\n\u2013 inhibiting T-type calcium channels (important in \ncontrolling absence seizures).\n\u2022\tNewer\tdrugs \tact \tby \tother \tmechanisms, \tsome \tyet \tto \t\nbe elucidated.4One of the authors who was a keen hockey player played in a team \nwith a goalkeeper who sometimes made silly errors early in the match. \nIt turned out that he suffered from epilepsy and had taken his dose of \ncarbamazepine too close to the start of the match.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3445, "end_char_idx": 6523, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cd5f10d2-5483-49c0-a8bb-fab71341d723": {"__data__": {"id_": "cd5f10d2-5483-49c0-a8bb-fab71341d723", "embedding": null, "metadata": {"page_label": "593", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bf4d2666-79e3-4149-ad55-f289e88bf3c4", "node_type": null, "metadata": {"page_label": "593", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8f21ef08ba0326061aef0ee7cf1c66ac83321b8c8cf76c91875c8cb0a72789d"}, "3": {"node_id": "de887d18-d6f7-4a83-8451-e32457ff8a1c", "node_type": null, "metadata": {"page_label": "593", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f117e3696165fed4c59cf829eee900bd81e6d851711accf5d50e3e0d1f84bc1a"}}, "hash": "3ad18eb4e4d4bf98eb9661ffa6af1112443fc2aa4350bb9f329f6aaaff6d78bc", "text": "46 ANTiEpilEpTic dRUgS\n587The range of plasma concentration over which phenytoin \nis effective without causing excessive unwanted effects is \nquite narrow (approximately 40\u2013100 \u00b5mol/L). The very \nsteep relationship between dose and plasma concentration, \nand the many interacting factors, mean that there is consider -\nable individual variation in the plasma concentration \nachieved with a given dose. Regular monitoring of plasma \nconcentration has helped considerably in achieving an \noptimal therapeutic effect. The past tendency was to add further drugs in cases where a single drug failed to give \nadequate control. It is now recognised that much of the \nunpredictability can be ascribed to pharmacokinetic vari -\nability, and regular monitoring of plasma concentration has reduced the use of polypharmacy.\nUnwanted effects\nSide effects of phenytoin begin to appear at plasma con -\ncentrations exceeding 100 \u00b5mol/L and may be severe above \nabout 150 \u00b5mol/L. The milder side effects include vertigo, \nataxia, headache and nystagmus, but not sedation. At higher \nplasma concentrations, marked confusion with intellectual \ndeterioration occurs; a paradoxical increase in seizure frequency is a particular trap for the unwary prescriber. \nThese effects occur acutely and are quickly reversible. \nHyperplasia of the gums often develops gradually, as does hirsutism and coarsening of the features, which probably \nresult from increased androgen secretion. Megaloblastic \nanaemia, associated with a disorder of folate metabolism, sometimes occurs, and can be corrected by giving folic acid (Ch. 26). Hypersensitivity reactions, mainly rashes, are quite \ncommon. Phenytoin has also been implicated as a cause \nof the increased incidence of fetal malformations in children born to epileptic mothers, particularly the occurrence of \ncleft palate, associated with the formation of an epoxide \nmetabolite. Severe idiosyncratic reactions, including hepa -\ntitis, skin reactions and neoplastic lymphocyte disorders, \noccur in a small proportion of patients.\nVALPROATE\nValproate is a simple monocarboxylic acid usually admin -\nistered as the sodium salt. It is chemically unrelated to any other class of antiepileptic drug, and in 1963 it was dis -\ncovered quite accidentally to have anticonvulsant properties and duration of electrically induced convulsions in mice, \nalthough ineffective against PTZ-induced convulsions. Owing to its many side effects and unpredictable pharma -\ncokinetic behaviour, phenytoin usage is declining. Phenytoin is effective against various forms of partial and generalised seizures, although not against absence seizures, which it \nmay even worsen.\nPharmacokinetic aspects\nPhenytoin has certain pharmacokinetic peculiarities that \nneed to be taken into account when it is used clinically. It \nis well absorbed when given orally, and about 80%\u201390% \nof the plasma content is bound to albumin. Other drugs, such as salicylates, phenylbutazone and valproate, inhibit \nthis binding competitively (see Ch. 58). This increases the \nfree phenytoin concentration but also increases hepatic clearance of phenytoin, so may enhance or reduce the effect \nof the phenytoin in an unpredictable way. Phenytoin is \nmetabolised by the hepatic mixed function oxidase system and excreted mainly as glucuronide. It causes enzyme induction, and thus increases the rate of metabolism of \nother drugs (e.g. oral anticoagulants). The metabolism of \nphenytoin itself can be either enhanced or competitively inhibited by various other drugs that share the same hepatic \nenzymes. Phenobarbital produces both effects, and because \ncompetitive inhibition", "start_char_idx": 0, "end_char_idx": 3649, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "de887d18-d6f7-4a83-8451-e32457ff8a1c": {"__data__": {"id_": "de887d18-d6f7-4a83-8451-e32457ff8a1c", "embedding": null, "metadata": {"page_label": "593", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bf4d2666-79e3-4149-ad55-f289e88bf3c4", "node_type": null, "metadata": {"page_label": "593", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a8f21ef08ba0326061aef0ee7cf1c66ac83321b8c8cf76c91875c8cb0a72789d"}, "2": {"node_id": "cd5f10d2-5483-49c0-a8bb-fab71341d723", "node_type": null, "metadata": {"page_label": "593", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ad18eb4e4d4bf98eb9661ffa6af1112443fc2aa4350bb9f329f6aaaff6d78bc"}}, "hash": "f117e3696165fed4c59cf829eee900bd81e6d851711accf5d50e3e0d1f84bc1a", "text": "Phenobarbital produces both effects, and because \ncompetitive inhibition is immediate whereas induction takes \ntime, it initially enhances and later reduces the pharm -\nacological activity of phenytoin. Ethanol has a similar dual \neffect.\nThe metabolism of phenytoin shows the characteristic \nof saturation (see Ch. 11), which means that over the therapeutic plasma concentration range the rate of inactiva -\ntion does not increase in proportion to the plasma concentra -\ntion. The consequences of this are that:\n\u2022\tthe\tplasma \thalf-life \t(approximately \t20 \th) \tincreases \tas \t\nthe dose is increased\n\u2022\tthe\tsteady-state \tmean \tplasma \tconcentration, \tachieved \t\nwhen a patient is given a constant daily dose, varies disproportionately with the dose. Fig. 46.4 shows that, \nin one patient, increasing the dose by 50% caused the \nsteady-state plasma concentration to increase more than four-fold.\nTherapeutic\nrange\n050100150Plasma concentration (\u00b5mol/L)\nDaily dose (mmol)4 3 2 1 0Fig. 46.4 Non-linear relationship \nbetween daily dose of phenytoin and \nsteady-state plasma concentration in \nfive individual human subjects. The \ndaily dose required to achieve the \ntherapeutic range of plasma \nconcentrations (40\u2013100 \u00b5mol/L) varies \ngreatly between individuals, and for any one individual the dose has to be adjusted rather precisely to keep within the acceptable plasma concentration \nrange.\t(Redrawn \tfrom \tRichens, \tA., \t\nDunlop,\tA., \t1975. \tLancet \t2, \t247.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3576, "end_char_idx": 5517, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "af86ae83-26b3-4be9-aecb-4e097e188e31": {"__data__": {"id_": "af86ae83-26b3-4be9-aecb-4e097e188e31", "embedding": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bece3d50-eb40-481e-b025-57eb4b175b7e", "node_type": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10685a4ad4f54792f5856e04a6ca78c7b9a0e975c63e91faef6aa347b736ab9b"}, "3": {"node_id": "f11cc710-96ea-4f17-8adf-ccf174a7bb5b", "node_type": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7da6aaf0e14f5e1ff07221e96ea8158165202fdc858235e638533c4ac7aea4c4"}}, "hash": "a3d4315713b8e2b20c4d1243848845711642b909a10c7894afaaf29f2ee83a71", "text": "46 SECTION 4 NERVOUS SYSTEM\n588anorexia, sometimes lethargy and dizziness, and it is \nsaid to precipitate tonic\u2013clonic seizures in susceptible \npatients. Very rarely, it can cause severe hypersensitivity \nreactions.\nPHENOBARBITAL\n\u25bc Phenobarbital was one of the first barbiturates to be developed \nbut is rarely used nowadays. Its clinical effectiveness closely resembles \nthat of phenytoin; it affects the duration and intensity of artificially \ninduced seizures, rather than the seizure threshold, and is (like \nphenytoin) ineffective in treating absence seizures. Primidone, also \nnow rarely used, acts by being metabolised to phenobarbital. It often \ncauses hypersensitivity reactions. The clinical uses of phenobarbital \nare virtually the same as those of phenytoin, but it is seldom used now because it causes sedation. For some years, phenobarbital was \nwidely used in children, including as prophylaxis following febrile \nconvulsions in infancy, but it can cause behavioural disturbances and \nhyperkinesias. It is, however, widely used in veterinary practice.\nPharmacokinetic aspects\n\u25bc Phenobarbital is well absorbed, and about 50% of the drug in \nthe blood is bound to plasma albumin. It is eliminated slowly from \nthe plasma (half-life 50\u2013140 h). About 25% is excreted unchanged \nin the urine. Because phenobarbital is a weak acid, its ionisation and hence renal elimination are increased if the urine is made alkaline \n(see Ch. 10). The remaining 75% is metabolised, mainly by oxidation and conjugation, by hepatic microsomal enzymes. Phenobarbital \nis a powerful inducer of liver CYP enzymes, and it lowers the \nplasma concentration of several other drugs (e.g. steroids, oral contraceptives, warfarin, tricyclic antidepressants) to an extent that is \nclinically important.\nUnwanted effects\n\u25bc The main unwanted effect of phenobarbital is sedation, which \noften occurs at plasma concentrations within the therapeutic range for seizure control. This is a serious drawback, because the drug \nmay have to be used for years on end. Some degree of tolerance to \nthe sedative effect seems to occur, but objective tests of cognition and motor performance show impairment even during long-term \ntreatment. Other unwanted effects that may occur with clinical \ndosage include megaloblastic anaemia (similar to that caused by phenytoin), mild hypersensitivity reactions and osteomalacia. Like \nother barbiturates, it must not be given to patients with porphyria \n(see Ch. 12). In overdose, phenobarbital depresses brain stem func -\ntion, producing coma and respiratory and circulatory failure, as do \nall barbiturates.\nBENZODIAZEPINES\nBenzodiazepines can be used to treat both acute seizures, \nespecially in children \u2013 midazolam given buccally or \ndiazepam being administered rectally \u2013 and status epilep -\nticus (a life-threatening condition in which epileptic seizures \noccur almost without a break) for which agents such as \nlorazepam, diazepam, or clonazepam are administered \nintravenously. The advantage in status epilepticus is that they act very rapidly compared with other antiepileptic \ndrugs. With most benzodiazepines (see Ch. 45), the sedative \neffect is too pronounced for them to be used for maintenance therapy and tolerance develops over 1\u20136 months. Clonaz-\nepam is unique among the benzodiazepines in that in \naddition to acting at the GABA\nA receptor, it also inhibits \nT-type calcium channels. Both it and the", "start_char_idx": 0, "end_char_idx": 3437, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f11cc710-96ea-4f17-8adf-ccf174a7bb5b": {"__data__": {"id_": "f11cc710-96ea-4f17-8adf-ccf174a7bb5b", "embedding": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bece3d50-eb40-481e-b025-57eb4b175b7e", "node_type": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10685a4ad4f54792f5856e04a6ca78c7b9a0e975c63e91faef6aa347b736ab9b"}, "2": {"node_id": "af86ae83-26b3-4be9-aecb-4e097e188e31", "node_type": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a3d4315713b8e2b20c4d1243848845711642b909a10c7894afaaf29f2ee83a71"}, "3": {"node_id": "7d5de878-2047-403f-84f3-a7477bda590c", "node_type": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "47484c33341971c468b0268778819755038d650b35367dcf7e025138a12b0707"}}, "hash": "7da6aaf0e14f5e1ff07221e96ea8158165202fdc858235e638533c4ac7aea4c4", "text": "it also inhibits \nT-type calcium channels. Both it and the related compound clobazam are claimed to be relatively selective as antiepileptic \ndrugs. Sedation is the main side effect of these compounds, \nand an added problem may be the withdrawal syndrome, \nwhich results in an exacerbation of seizures if the drug is \nstopped abruptly.in mice. It inhibits most kinds of experimentally induced convulsions and is effective in many kinds of epilepsy, being particularly useful in certain types of infantile epilepsy, \nwhere its low toxicity and lack of sedative action are \nimportant, and in adolescents who exhibit both tonic\u2013clonic or myoclonic seizures as well as absence seizures, because \nvalproate (unlike most antiepileptic drugs) is effective \nagainst each. Like carbamazepine, valproate is also used in psychiatric conditions such as bipolar depressive illness \n(Ch. 48).\nValproate works by several mechanisms (see Table 46.1), \nthe relative importance of which remains to be clarified. It \ncauses a significant increase in the GABA content of the \nbrain and is a weak inhibitor of the enzyme system that \ninactivates GABA, namely GABA transaminase and succinic semialdehyde dehydrogenase (Ch. 39), but in vitro studies \nsuggest that these effects would be very slight at clinical \ndosage. Other more potent inhibitors of these enzymes (e.g. vigabatrin; see p. 589) also increase GABA content \nand have an anticonvulsant effect in experimental animals. There is some evidence that it enhances the action of GABA by a postsynaptic action, but no clear evidence that it affects \ninhibitory synaptic responses. It inhibits sodium channels, \nbut less so than phenytoin, and inhibits T-type calcium channels, which might explain why it is effective against \nabsence seizures.\nValproate is well absorbed orally and excreted, mainly \nas the glucuronide, in the urine, the plasma half-life being \nabout 15 h.\nUnwanted effects\nValproate is contra-indicated in women of childbearing \nage because it is a potent teratogen (even more so than \nother anticonvulsants that tend to share this secondary \npharmacology) (see p. 590), causing spina bifida and other neural tube defects.\nAnother serious but rare side effect is hepatotoxicity. An \nincrease in plasma glutamic oxaloacetic transaminase, which signals liver damage of some degree, commonly occurs, \nbut proven cases of valproate-induced hepatitis are rare. \nThe few cases of fatal hepatitis in valproate-treated patients may well have been caused by other factors. More com -\nmonly, valproate causes thinning and curling of the hair, \nin about 10% of patients. Analogues of valproate with \npotentially reduced side effects are in development.\nETHOSUXIMIDE\nEthosuximide is another drug developed empirically by modifying the barbituric acid ring structure. Pharmacologi -\ncally and clinically, however, it is different from the drugs so far discussed, in that it is active against PTZ-induced convulsions in animals and against absence seizures in \nhumans, with little or no effect on other types of epilepsy. \nIt supplanted trimethadione, the first drug found to be \neffective in absence seizures, which had major side effects. \nEthosuximide is used clinically for its selective effect on \nabsence seizures.\nEthosuximide and trimethadione, unlike other antiepileptic \ndrugs, act mainly by inhibition of T-type calcium channels, \nwhich play a role in generating the firing rhythm in thalamic \nrelay neurons that generates the 3/s spike-and-wave EEG pattern characteristic", "start_char_idx": 3389, "end_char_idx": 6912, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7d5de878-2047-403f-84f3-a7477bda590c": {"__data__": {"id_": "7d5de878-2047-403f-84f3-a7477bda590c", "embedding": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "bece3d50-eb40-481e-b025-57eb4b175b7e", "node_type": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "10685a4ad4f54792f5856e04a6ca78c7b9a0e975c63e91faef6aa347b736ab9b"}, "2": {"node_id": "f11cc710-96ea-4f17-8adf-ccf174a7bb5b", "node_type": null, "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7da6aaf0e14f5e1ff07221e96ea8158165202fdc858235e638533c4ac7aea4c4"}}, "hash": "47484c33341971c468b0268778819755038d650b35367dcf7e025138a12b0707", "text": "that generates the 3/s spike-and-wave EEG pattern characteristic of absence seizures.\nEthosuximide is well absorbed, and metabolised and \nexcreted much like phenobarbital, with a plasma half-\nlife of about 60 h. Its main side effects are nausea and mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6897, "end_char_idx": 7626, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7364b4be-e84c-403b-afdd-294c57e53e7e": {"__data__": {"id_": "7364b4be-e84c-403b-afdd-294c57e53e7e", "embedding": null, "metadata": {"page_label": "595", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "509f652a-353f-41a1-893e-8ca2be914814", "node_type": null, "metadata": {"page_label": "595", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07eba799a8c72ffac6e5ef022ee9b234ddf2fc45e58dad34abf60ac00d37c9ed"}, "3": {"node_id": "fd7cfb9c-05f9-403d-a453-4ba3135d479e", "node_type": null, "metadata": {"page_label": "595", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "154ab1125cff2eb3d256a51d28f14e62f528a1c88097464e1d3a695d498d2230"}}, "hash": "a069c6a132fc53e41ea9eb9150bf65569f42b1ae8c4815979912241f21db07fc", "text": "46 ANTiEpilEpTic dRUgS\n589As these drugs are excreted unchanged in the urine they \nmust be used with care in patients whose renal function \nis impaired. Both drugs are also used as analgesics to treat \nneuropathic pain (Ch. 43) and as anxiolytics in the treatment \nof general anxiety disorders (see Ch. 45). Recently they \nhave become drugs of abuse especially popular amongst \nheroin users and may contribute to opioid overdose deaths \n(see Ch. 50).\nTIAGABINE\nTiagabine is an analogue of GABA that is able to penetrate \nthe blood\u2013brain barrier. It has a short plasma half-life and \nis mainly used as an add-on therapy for partial seizures. \nIts main side effects are drowsiness and confusion, dizziness, \nfatigue, agitation and tremor.\nTOPIRAMATE\nTopiramate is a drug that appears to do a little of every -\nthing, blocking sodium and calcium channels, enhancing \nthe action of GABA, blocking AMPA receptors and, for \ngood measure, weakly inhibiting carbonic anhydrase. Its \nclinical effectiveness resembles that of phenytoin, and it \nis claimed to produce less severe side effects, as well as \nbeing devoid of the pharmacokinetic properties that cause \ntrouble with phenytoin. Currently, it is mainly used as \nadd-on therapy in refractory cases of partial and generalised \nseizures.\nLEVETIRACETAM\nLevetiracetam was developed as an analogue of piracetam , \na drug developed to improve cognitive function, and \ndiscovered by accident to have antiepileptic activity in \nanimal models. Unusually, it lacks activity in conventional \nmodels such as electroshock and PTZ tests, but is effective \nin the audiogenic and kindling models (see p. 582). Leveti -\nracetam is excreted unchanged in the urine. Common side \neffects include headaches, inflammation of the nose and \nthroat, sleepiness, vomiting and irritability. Brivaracetam \nis similar to levetiracetam.\nZONISAMIDE\nZonisamide is a sulfonamide compound originally intended \nas an antibacterial drug and found accidentally to have \nantiepileptic properties. It is mainly free of major unwanted \neffects, although it causes drowsiness, and of serious \ninteraction with other drugs. It tends to suppress appetite \nand cause weight loss, and is sometimes used for this \npurpose. Zonisamide has a long plasma half-life of 60\u201380 h, \nand is partly excreted unchanged and partly converted to \na glucuronide metabolite. It is licensed for use as an adjunct \ntreatment of partial and generalised seizures but may be \neffective as a monotherapy.\nRUFINAMIDE\nRufinamide is a triazole derivative structurally unrelated \nto other antiepileptic drugs. It is licensed for treating \nLennox\u2013Gastaut syndrome and may also be effective in \npartial seizures. It has low plasma protein binding and is \nnot metabolised by CYP enzymes.\nPERAMPANEL\nPerampanel is effective in refractory partial seizures. \nSide effects include dizziness, sedation, fatigue, irritabil -\nity, weight gain, and loss of motor coordination. There \nis a risk of serious psychiatric problems (violent, even NEWER ANTIEPILEPTIC DRUGS\nVIGABATRIN\nVigabatrin, the first \u2018designer drug\u2019 in the epilepsy field, \nis a vinyl-substituted analogue of GABA that was designed \nas an irreversible inhibitor of the GABA-metabolising \nenzyme GABA transaminase. In animal studies, vigabatrin \nincreases the GABA content of the brain and also increases \nthe stimulation-evoked release of GABA, implying that \nGABA transaminase", "start_char_idx": 0, "end_char_idx": 3413, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fd7cfb9c-05f9-403d-a453-4ba3135d479e": {"__data__": {"id_": "fd7cfb9c-05f9-403d-a453-4ba3135d479e", "embedding": null, "metadata": {"page_label": "595", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "509f652a-353f-41a1-893e-8ca2be914814", "node_type": null, "metadata": {"page_label": "595", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07eba799a8c72ffac6e5ef022ee9b234ddf2fc45e58dad34abf60ac00d37c9ed"}, "2": {"node_id": "7364b4be-e84c-403b-afdd-294c57e53e7e", "node_type": null, "metadata": {"page_label": "595", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a069c6a132fc53e41ea9eb9150bf65569f42b1ae8c4815979912241f21db07fc"}}, "hash": "154ab1125cff2eb3d256a51d28f14e62f528a1c88097464e1d3a695d498d2230", "text": "stimulation-evoked release of GABA, implying that \nGABA transaminase inhibition can increase the releasable \npool of GABA and effectively enhance inhibitory transmis -\nsion. In humans, vigabatrin increases the content of GABA \nin the cerebrospinal fluid. Although its plasma half-life is \nshort, it produces a long-lasting effect because the enzyme \nis blocked irreversibly, and the drug can be given by mouth \nonce daily.\nVigabatrin\u2019s licence is restricted to patients with resist -\nant epilepsy who have not responded or tolerated other \nappropriate drug combinations. A major drawback of \nvigabatrin is the development of irreversible peripheral \nvisual field defects in a proportion of patients on long-\nterm therapy, thus necessitating systematic screening \nexaminations of the visual fields at regular intervals. \nVigabatrin may cause depression, and occasionally psy -\nchotic disturbances and hallucinations, in a minority of \npatients.\nLAMOTRIGINE\nLamotrigine, although chemically unrelated, resembles \nphenytoin and carbamazepine in its pharmacological effects \nbut it appears that, despite its similar mechanism of action, \nlamotrigine has a broader therapeutic profile than the earlier \ndrugs, with significant efficacy against absence seizures (it \nis also used to treat unrelated psychiatric disorders). Its \nmain side effects are nausea, dizziness and ataxia, and \nhypersensitivity reactions (mainly mild rashes, but occasion -\nally more severe). Its plasma half-life is about 24 h, with \nno particular pharmacokinetic anomalies, and it is taken \norally.\nFELBAMATE\nFelbamate is an analogue of an obsolete anxiolytic drug, \nmeprobamate . It is active in many animal seizure models \nand has a broader clinical spectrum than earlier antiepileptic \ndrugs, but its mechanism of action at the cellular level is \nuncertain. Its acute side effects are mild, mainly nausea, \nirritability and insomnia, but it occasionally causes severe \nreactions resulting in aplastic anaemia or hepatitis. For this \nreason, its recommended use is limited to intractable \nepilepsy (e.g. in children with Lennox\u2013Gastaut syndrome) \nthat is unresponsive to other drugs. Its plasma half-life is \nabout 24 h, and it can enhance the plasma concentration \nof other antiepileptic drugs given concomitantly.\nGABAPENTIN AND PREGABALIN\nGabapentin and pregabalin are effective against partial \nseizures. Side effects (sleepiness, headache, fatigue, diz -\nziness and weight gain) are less severe than with many \nantiepileptic drugs. The absorption of gabapentin from \nthe intestine depends on the L-amino acid carrier system \nand shows the property of saturability, which means that \nincreasing the dose does not proportionately increase the \namount absorbed. Its plasma half-life is about 6 h, requiring \ndosing two to three times daily. Pregabalin is more readily \nabsorbed from the gut and has a longer half-life (6\u201312 h). mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3345, "end_char_idx": 6727, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "433417a6-7815-46a9-960a-f48303308a1c": {"__data__": {"id_": "433417a6-7815-46a9-960a-f48303308a1c", "embedding": null, "metadata": {"page_label": "596", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "afa32515-efdc-4c1c-b38b-71796b965215", "node_type": null, "metadata": {"page_label": "596", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4145d722dc9ee460326d826d6d5bbf49f1d824fe6ed33b0270c8e1c86751871b"}, "3": {"node_id": "7775c399-8965-45ed-9ec6-b2c6d5fbf888", "node_type": null, "metadata": {"page_label": "596", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6672c8acef135d0dad49d9bd706c54a3e4777d50311178e93db3f8cdadf289d"}}, "hash": "d671bd359e83eef1ab12913f067bde0656e48f3e96338660c5a0b1a849a1a3ec", "text": "46 SECTION 4 NERVOUS SYSTEM\n590ANTIEPILEPTIC DRUGS AND PREGNANCY\nThere are several important implications for women taking \nantiepileptic drugs. By inducing hepatic CYP3A4 enzymes, \nsome antiepileptic drugs may increase oral contraceptive \nmetabolism, thus reducing their effectiveness (see Ch. 36). Taken during pregnancy, drugs such as phenytoin, carba -\nmazepine, lamotrogine, topiramate and valproate are thought to have some risk of teratogenic effects, although the magnitude of risk appears greatest with valproate. It \nremains to be clarified if newer agents also have this \nproblem. Induction of CYP enzymes may result in vitamin K deficiency in the newborn (Ch. 26).homicidal, thoughts and threatening behaviour) in some \nindividuals.\nLACOSAMIDE\nLacosamide is used to treat partial seizures. Side effects include nausea, dizziness, sedation and fatigue. It produces \nrelief of pain due to diabetic neuropathy.\nSTIRIPENTOL\nStiripentol has some efficacy as an adjunctive therapy in \nchildren. It enhances GABA release and prolongs GABA-\nmediated synaptic events in a manner similar to pheno -\nbarbital. It also inhibits lactate dehydrogenase (LDH) which \nmay reduce the metabolic energy production required to \nmaintain seizures.\nNEW DRUGS\nThere are a number of new antiepileptic agents with novel \nmechanism of action approved or in late stages of clinical \ntrials.5 Ganaxolone, structurally resembling endogenous \nneurosteroids (see Ch. 39), is a positive allosteric modulator of GABA\nA receptors containing \u03b4 subunits that has recently \nbeen approved for the treatment of CDLK5 disorder, a rare form of genetic epilepsy predominantly affecting young \ngirls. Cannabidiol, the major non-psychoactive component of cannabis (see Ch. 20), has recently been approved in the \nUSA for the treatment of Dravet syndrome and Lennox\u2013\nGastaut syndrome. The mechanisms underlying its anti-epileptic efficacy are unclear as it has low affinity for CB\n1 \nand CB 2 cannabinoid receptors. Other phytocannabinoids \nare reported to have anticonvulsant properties \u2013 an area \nto watch. Everolimus, an inhibitor of mammalian target of \nrapamycin (mTOR, see Ch. 27) is in phase III clinical trial for partial seizures. Tonabersat is a novel neuronal gap \njunction inhibitor that shows early promise.\nThe identification of epileptogenic mutations of genes \nencoding specific ion channels and other functional proteins (see Weber & Lerche, 2008) has for some time been expected \nto lead to new drugs aimed at these potential targets, but we are still waiting.\nOTHER USES OF ANTIEPILEPTIC DRUGS\nAntiepileptic drugs have proved to have much wider clinical applications than was originally envisaged, and clinical \ntrials have shown many of them to be effective in the \nfollowing conditions:\n\u2022\tbipolar \tdisorder \t(valproate, carbamazepine, \noxcarbazepine, lamotrigine, topiramate; Ch. 48)\n\u2022\tmigraine \tprophylaxis \t(valproate, gabapentin, \ntopiramate; Ch. 16)\n\u2022\tanxiety \tdisorders \t(gabapentin, pregabalin; Ch. 45)\n\u2022\tneuropathic \tpain \t(gabapentin, pregabalin, \ncarbamazepine, lamotrigine; Ch. 43)\nThis surprising multiplicity of clinical indications may reflect the fact that similar neurobiological mechanisms, involving synaptic plasticity and increased excitability of \ninterconnected populations of neurons, underlie each of \nthese disorders.Clinical uses of", "start_char_idx": 0, "end_char_idx": 3348, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7775c399-8965-45ed-9ec6-b2c6d5fbf888": {"__data__": {"id_": "7775c399-8965-45ed-9ec6-b2c6d5fbf888", "embedding": null, "metadata": {"page_label": "596", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "afa32515-efdc-4c1c-b38b-71796b965215", "node_type": null, "metadata": {"page_label": "596", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4145d722dc9ee460326d826d6d5bbf49f1d824fe6ed33b0270c8e1c86751871b"}, "2": {"node_id": "433417a6-7815-46a9-960a-f48303308a1c", "node_type": null, "metadata": {"page_label": "596", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d671bd359e83eef1ab12913f067bde0656e48f3e96338660c5a0b1a849a1a3ec"}}, "hash": "d6672c8acef135d0dad49d9bd706c54a3e4777d50311178e93db3f8cdadf289d", "text": "populations of neurons, underlie each of \nthese disorders.Clinical uses of antiepileptic drugs \n\u2022\tGeneralised \ttonic\u2013clonic \tseizures:\n\u2013 valproate, lamotrigine or carbamazepine;\n\u2013 use of a single drug is preferred, when possible, to \navoid pharmacokinetic interactions;\n\u2013 newer agents include topiramate, levetiracetam.\n\u2022\tPartial\t(focal) \tseizures: \tcarbamazepine, or \nlamotrigine; alternatives include valproate, \nlevetiracetam, clobazam, gabapentin, topiramate, \nlevetiracetam.\n\u2022\tAbsence \tseizures: \tethosuximide, valproate\n\u2013 valproate is the first-choice drug when absence \nseizures coexist with tonic\u2013clonic seizures, because most other drugs used for tonic\u2013clonic seizures can \nworsen absence seizures.\n\u2022\tMyoclonic \tseizures: \tvalproate, topiramate, \nlevetiracetam\n\u2022\tStatus\tepilepticus: \tlorazepam intravenously or (in \nabsence of accessible veins, intramuscular or \noromucosal midazolam, or diazepam rectally).\n\u2022\tNeuropathic \tpain: \tfor \texample \tcarbamazepine, \ngabapentin (see Ch. 43).\n\u2022\tTo\tstabilise \tmood \tin \tmono- \tor \tbipolar \taffective \t\ndisorder (as an alternative to lithium): for example, \ncarbamazepine, valproate (see Ch. 48).\n5The Epilepsy Foundation website (http://www.epilepsy.com/\naccelerating-new-therapies/new-therapies-pipeline#drugs) gives details \nof the large number of drugs currently in development for the \ntreatment of epilepsies.MUSCLE SPASM AND MUSCLE \nRELAXANTS\nMany diseases of the brain and spinal cord produce an \nincrease in muscle tone, which can be painful and disabling. \nSpasticity resulting from birth injury or cerebral vascular \ndisease, and the paralysis produced by spinal cord lesions, are examples. Multiple sclerosis is a neurodegenerative \ndisease that is triggered by inflammatory attack on the \ncentral nervous system (see Ch. 41). When the disease has progressed for some years it can cause muscle stiffness \nand spasms, as well as other symptoms such as pain, fatigue, \ndifficulty passing urine and tremors. Local injury or inflam -\nmation, as in arthritis, can also cause muscle spasm, and chronic back pain is also often associated with local muscle \nspasm.\nCertain centrally acting drugs are available that have \nthe effect of reducing the background tone of the muscle without seriously affecting its ability to contract transiently mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3274, "end_char_idx": 6048, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a921653a-79fb-4e40-9e44-ee07af3eafcf": {"__data__": {"id_": "a921653a-79fb-4e40-9e44-ee07af3eafcf", "embedding": null, "metadata": {"page_label": "597", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a207c394-df9d-4414-8fb1-1774ec46f401", "node_type": null, "metadata": {"page_label": "597", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "303830e08c1c767a2481c770bb441c6df881e02e1e914430dd48fdf9e99dff76"}, "3": {"node_id": "2161e05e-ece4-459c-92f3-e590a2e4d83d", "node_type": null, "metadata": {"page_label": "597", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d06a0bcdcbb10421b7034b1346a423c85cd2402d845abfba5c429f9565a0c5a"}}, "hash": "12a2577aa58f2d36c50b9382c189a1de627a292ec395f44b2c889b6183789bad", "text": "46 ANTiEpilEpTic dRUgS\n591Benzodiazepines are discussed in detail in Chapter 45. \nThey produce muscle relaxation by an effect in the spinal \ncord. They are also anxiolytic.\nTizanidine is an \u03b12-adrenoceptor agonist that relieves \nspasticity associated with multiple sclerosis and spinal cord \ninjury.\nFor many years anecdotal evidence suggested that \nsmoking cannabis (Ch. 20) relieves the painful muscle \nspasms associated with multiple sclerosis. Sativex , a can -\nnabis extract containing \u03949-tetrahydrocannabinol (also \nknown as THC or dronabinol ; see Ch. 20) and cannabidiol, \nis licensed in some countries as a treatment for spasticity \nin multiple sclerosis. It also has pain-relieving properties \n(see Chs 20 and 43).\nMethocarbamol is used to treat muscle pain and stiffness. \nIts mechanism of action is unclear.\nDantrolene acts peripherally rather than centrally to \nproduce muscle relaxation (see Ch. 4).\nBotulinum toxin (see Ch. 14) injected into a muscle, \ninhibits acetylcholine release, causing long-lasting paralysis \nconfined to the site of injection; its use to treat local muscle \nspasm is increasing. Its non-medicinal use as a \u2018beauty\u2019 \ntreatment has become widespread.under voluntary control. The distinction between voluntary \nmovements and \u2018background tone\u2019 is not clear-cut, and the \nselectivity of those drugs is not complete. Postural control, \nfor example, is usually jeopardised by centrally acting \nmuscle relaxants. Furthermore, drugs that affect motor \ncontrol generally produce rather widespread effects on the \ncentral nervous system, and drowsiness and confusion turn \nout to be very common side effects of these agents.\nBaclofen (see Ch. 39) is a chlorophenyl derivative of \nGABA originally prepared as a lipophilic GABA-like \nagent in order to assist penetration of the blood\u2013brain \nbarrier, which is impermeable to GABA itself. Baclofen \nis a selective agonist at GABA B receptors (see Ch. 39). \nThe antispastic action of baclofen is exerted mainly on \nthe spinal cord, where it inhibits both monosynaptic and \npolysynaptic activation of motor neurons. It is effective \nwhen given by mouth, and is used in the treatment of \nspasticity associated with multiple sclerosis or spinal injury. \nHowever, it is ineffective in cerebral spasticity caused by \nbirth injury.\nBaclofen produces various unwanted effects, particularly \ndrowsiness, motor incoordination and nausea, and it may \nalso have behavioural effects. It is not useful in epilepsy.\nREFERENCES AND FURTHER READING\nGeneral\nBrowne, T.R., Holmes, G.L., 2008. Handbook of Epilepsy. Lippincott, \nWilliams & Wilkins, Philadelphia. ( A compact textbook covering most \nareas of epilepsy and its treatment )\nPathogenesis and types of epilepsy\nDeblaere, K., Achten, E., 2008. Structural magnetic resonance imaging in \nepilepsy. Eur. Radiol. 18, 119\u2013129. ( Describes the use of brain imaging in \nthe diagnosis of epilepsy )\nGrone, B.P., Baraban, S.C., 2015. Animal models in epilepsy research: \nlegacies and new directions. Nat. Neurosci. 18, 339\u2013343. ( Good \ndescription of older animal models of epilepsy and of the use of newer \ninvertebrate models to study genetic idiopathic epilepsies )\nKhosravani, H., Altier, C., Simms, B., et al., 2004. Gating effects of \nmutations in the Ca v3.2 T-type calcium channel associated with", "start_char_idx": 0, "end_char_idx": 3318, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2161e05e-ece4-459c-92f3-e590a2e4d83d": {"__data__": {"id_": "2161e05e-ece4-459c-92f3-e590a2e4d83d", "embedding": null, "metadata": {"page_label": "597", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a207c394-df9d-4414-8fb1-1774ec46f401", "node_type": null, "metadata": {"page_label": "597", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "303830e08c1c767a2481c770bb441c6df881e02e1e914430dd48fdf9e99dff76"}, "2": {"node_id": "a921653a-79fb-4e40-9e44-ee07af3eafcf", "node_type": null, "metadata": {"page_label": "597", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "12a2577aa58f2d36c50b9382c189a1de627a292ec395f44b2c889b6183789bad"}}, "hash": "9d06a0bcdcbb10421b7034b1346a423c85cd2402d845abfba5c429f9565a0c5a", "text": "effects of \nmutations in the Ca v3.2 T-type calcium channel associated with \nchildhood absence epilepsy. J. Biol. Chem. 279, 9681\u20139684. ( Study \nshowing that calcium channel mutations seen in childhood absence seizures \ncause abnormal neuronal discharges in transgenic mice )Pandolfo, M., 2011. Genetics of epilepsy. Semin. Neurol. 31, 506\u2013518.\nShin, H.S., 2006. T-type Ca2+ channels and absence epilepsy. Cell \nCalcium 40, 191\u2013196.\nWeber, Y.G., Lerche, H., 2008. Genetic mechanisms in idiopathic \nepilepsies. Dev. Med. Child Neurol. 50, 648\u2013654. ( Reviews how \nmutations in voltage- and ligand-gated ion channels are associated with \nidiopathic epilepsy syndromes )\nAntiepileptic drugs\nBialer, M., White, H.S., 2010. Key factors in the discovery and \ndevelopment of new antiepileptic drugs. Nat. Rev. Drug Discov. 9, \n68\u201382. ( Interesting account of avenues for antiepileptic drug discovery )\nShih, J.J., Whitlock, J.B., Chimato, N., Vargas, E., Karceski, S.C., Frank, \nR.D., 2017. Epilepsy treatment in adults and adolescents. Epilepsy \nBehav. 69, 186\u2013222. ( Brings together the views of a number of \nacknowledged experts in epilepsy treatment on current drug therapies for \ndifferent forms of epilepsy )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3243, "end_char_idx": 4928, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1af33916-9be3-4f94-aa69-968b3752c031": {"__data__": {"id_": "1af33916-9be3-4f94-aa69-968b3752c031", "embedding": null, "metadata": {"page_label": "598", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ba7e63b3-524a-4c9c-984e-4be98a558c04", "node_type": null, "metadata": {"page_label": "598", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6eb33f8bb082b77a14181bf655d13ab44147e713f6037499249f73d96ec55c75"}, "3": {"node_id": "b6a177fd-b637-4898-8b11-fd396edc867d", "node_type": null, "metadata": {"page_label": "598", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cf57364bf74acb31ddd0204e64ff154954e1f7b0578507a74c8186a351e5719e"}}, "hash": "7fb66533b93ddd616a4402b833000fefbf58d1640a4efc8c723285a282628d50", "text": "592\nOVERVIEW\nIn this chapter we focus on schizophrenia and the \ndrugs used to treat it. We start by describing the \nillness and what is known of its pathogenesis, includ -\ning the various neurochemical hypotheses and their \nrelation to the actions of the main types of antipsychotic \ndrugs that are in use or in development. Further \ninformation can be found in Gross and Geyer (2012) .\nINTRODUCTION\nPsychotic illnesses include various disorders, but the term \nantipsychotic drugs \u2013 previously known as neuroleptic drugs , \nantischizophrenic drugs or major tranquillisers \u2013 conventionally \nrefers to those used to treat schizophrenia, one of the most common and debilitating forms of mental illness. These \nsame drugs are also used to treat mania (Ch. 48) and other \nacute behavioural disturbances. Pharmacologically, most are dopamine receptor antagonists, although many of them \nalso act on other targets, particularly 5-hydroxytryptamine \n(5-HT) receptors, which may contribute to their clinical efficacy. Existing drugs have many drawbacks in terms of their efficacy and side effects. Gradual improvements have \nbeen achieved with newer drugs, but radical new approaches \nwill require a better understanding of the causes and underlying pathology of the disease, which are still poorly \nunderstood.\n1\nTHE NATURE OF SCHIZOPHRENIA\nSchizophrenia2 (see Stahl, 2008) affects about 1% of the \npopulation. It is one of the most important forms of psy -\nchiatric illness, because it affects young people, is often \nchronic and is usually highly disabling.3 There is a strong hereditary factor in its aetiology, and evidence suggestive \nof a fundamental biological disorder. The main clinical \nfeatures of the disease are as follows.\nPositive symptoms\n\u2022\tDelusions \t(often \tparanoid \tin \tnature).\n\u2022\tHallucinations \t(often \tin \tthe \tform \tof \tvoices, \twhich \tmay \t\nbe exhortatory in their message).\n\u2022\tThought \tdisorder \t(comprising \twild \ttrains \tof \tthought, \t\ndelusions of grandeur, garbled sentences and irrational conclusions).\n\u2022\tAbnormal, \tdisorganised \tbehaviour \t(such \tas \t\nstereotyped movements, disorientation and occasionally aggressive behaviours).\n\u2022\tCatatonia \t(can \tbe \tapparent \tas \timmobility \tor \t\npurposeless motor activity).\nNegative symptoms\n\u2022\tWithdrawal \tfrom \tsocial \tcontacts.\n\u2022\tFlattening \tof \temotional \tresponses.\n\u2022\tAnhedonia \t(an \tinability \tto \texperience \tpleasure).\n\u2022\tReluctance \tto \tperform \teveryday \ttasks.\nCognition\n\u2022\tDeficits \tin \tcognitive \tfunction \t(e.g. \tattention, \t \nmemory).\nIn addition, anxiety, guilt, depression and self-punishment are often present, leading to suicide attempts in up to 50% \nof cases, about 10% of which are successful. The clinical \nphenotype varies greatly, particularly with respect to the balance between positive and negative symptoms, and this \nmay have a bearing on the efficacy of antipsychotic drugs \nin individual cases. Schizophrenia can present dramatically, usually in young people, with predominantly positive features such as hallucinations, delusions and uncontrollable \nbehaviour, or more insidiously in older patients with \nnegative features such as flat mood and social withdrawal. The latter may be more debilitated than those with a florid \npresentation, and the prognosis is generally worse. Cognitive \nimpairment may be evident even before the onset of other symptoms. Schizophrenia can follow a relapsing and remit -\nting course, or be chronic and progressive, particularly in cases with a later onset. Chronic schizophrenia used to account for most of the patients in long-stay psychiatric \nhospitals; following", "start_char_idx": 0, "end_char_idx": 3595, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b6a177fd-b637-4898-8b11-fd396edc867d": {"__data__": {"id_": "b6a177fd-b637-4898-8b11-fd396edc867d", "embedding": null, "metadata": {"page_label": "598", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ba7e63b3-524a-4c9c-984e-4be98a558c04", "node_type": null, "metadata": {"page_label": "598", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6eb33f8bb082b77a14181bf655d13ab44147e713f6037499249f73d96ec55c75"}, "2": {"node_id": "1af33916-9be3-4f94-aa69-968b3752c031", "node_type": null, "metadata": {"page_label": "598", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7fb66533b93ddd616a4402b833000fefbf58d1640a4efc8c723285a282628d50"}}, "hash": "cf57364bf74acb31ddd0204e64ff154954e1f7b0578507a74c8186a351e5719e", "text": "account for most of the patients in long-stay psychiatric \nhospitals; following the closure of many of these in the \nUnited Kingdom, it now accounts for many of society\u2019s outcasts.\nA\tcharacteristic \tfeature \tof \tschizophrenia \tis \ta \tdefect \tin \t\n\u2018selective attention\u2019. Whereas a normal individual quickly accommodates to stimuli of a familiar or inconsequential \nnature, and responds only to stimuli that are unexpected \nor significant, the ability of schizophrenic patients to Antipsychotic drugs47 NERVOUS SYSTEM SECTION 4\n1In this respect, the study of schizophrenia lags some years behind that of \nAlzheimer\u2019s \tdisease \t(Ch. \t41), \twhere \tunderstanding \tof \tthe \tpathogenesis \t\nhas progressed rapidly to the point where promising drug targets have \nbeen identified. On the other hand, pragmatists can argue that drugs \nagainst\tAlzheimer\u2019s \tdisease \tare \tso \tfar \tonly \tmarginally \teffective, \twhereas\t\ncurrent antipsychotic drugs deliver great benefits even though we do not quite know how they work.\n2Schizophrenia is a condition where the patient exhibits symptoms of \npsychosis (e.g. delusions, hallucinations and disorganized behaviour). \nPsychotic episodes may also occur as a result of taking certain \nrecreational drugs (see Ch. 49); as an adverse effect of drug treatment, for example steroid-induced psychoses; or in disorders such as mania, \ndepression \t(see \tCh. \t48) \tand \tAlzheimer\u2019s \tdisease \t(see \tCh. \t41).\n3A\tcompelling \taccount \tof \twhat \tit \tis \tlike \tto \tsuffer \tfrom \tschizophrenia \tis \t\ncontained in Kean (2009) Schizophrenia Bulletin 35, 1034\u20131036. The author is a pharmacology graduate.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3516, "end_char_idx": 5610, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "553a4bc6-1cc0-411a-97de-37f706286d56": {"__data__": {"id_": "553a4bc6-1cc0-411a-97de-37f706286d56", "embedding": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "002f2c5e-4dd7-42a7-bef4-0d068e952e3c", "node_type": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b3a2a10276ecf2c46fbb1e6d26210962cb902fbc5c2fde1349ada4b58b1b75a"}, "3": {"node_id": "d03c13b8-c4c3-46c6-ac4c-7d1b3683c341", "node_type": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1f853854d3e1188e447b33ddfeadde47b8846e31470de699d09a188a2ddc5d4e"}}, "hash": "81f3a83d9bdf18e4263211f8cf051b7f290f5fc02b35835a18c4a2b2e0a5a8a0", "text": "47 ANTipSYchOTic dRUgS\n593cortical atrophy apparent in the early course of the disease which \nmay increase with time and correlate with the progression of the \ndisorder (van Haren et al., 2007). Studies of postmortem schizophrenic \nbrains show evidence of misplaced cortical neurons with abnormal morphology. Other environmental factors such as cannabis consump -\ntion in adolescence and early adulthood (see Chs 20 and 49) may also reveal schizophrenia.\nTHE NEUROANATOMICAL AND NEUROCHEMICAL \nBASIS OF SCHIZOPHRENIA\nDifferent \tsymptoms \tof\tschizophrenia \tappear\tto\tresult\tfrom\t\nmalfunctions in different neuronal circuits. Changes in the \nmesolimbic pathway (the neuronal projection from the \nventral\ttegmental \tarea \t(VTA) \tto \tthe \tnucleus \taccumbens, \t\namygdala and hippocampus) being associated with positive symptoms, whereas negative symptoms are associated with \nchanges in the prefrontal cortex which receives input from \nthe\tVTA\tvia\tthe\tmesocortical \tpathway \tand\twhich\tprojects\t\nto the nucleus accumbens and dorsal striatum.\nThe main neurotransmitters thought to be involved in \nthe pathogenesis of schizophrenia are dopamine and \nglutamate.\nDopamine\nThe original dopamine theory of schizophrenia was pro -\nposed by Carlson \u2013 awarded a Nobel Prize in 2000 \u2013 on \nthe basis of indirect pharmacological evidence in humans \nand experimental animals. Amphetamine releases dopamine \nin the brain and can produce in humans a behavioural \nsyndrome reminiscent of an acute schizophrenic episode. \nAlso,\thallucinations \tare \ta \tside \teffect \tof \tlevodopa \tand \t\ndopamine agonists used for Parkinson\u2019s disease (see Ch. \n41). In animals, dopamine release causes a specific pattern \nof stereotyped behaviour that resembles the repetitive \nbehaviours sometimes seen in schizophrenic patients. Potent D\n2 receptor agonists, such as bromocriptine, produce similar \neffects in animals, and these drugs, like amphetamine, \nexacerbate \tthe \tsymptoms \tof \tschizophrenic \tpatients. \tFur-\nthermore, dopamine antagonists and drugs that block \nneuronal dopamine storage (e.g. reserpine) are effective \nin controlling the positive symptoms of schizophrenia, and \nin preventing amphetamine-induced behavioural changes.\n\u25bc It is now believed that positive symptoms result from overactivity \nin\tthe\tmesolimbic \tdopaminergic \tpathway \tactivating \tD2 receptors (for \na more detailed description of the dopamine pathways in the brain, \nsee Ch. 40) whereas negative symptoms may result from a decreased \nactivity\tin\tthe\tmesocortical \tdopaminergic \tpathway \twhere\tD1 receptors \npredominate. Other dopaminergic pathways in the brain (i.e. nigros -\ntriatal and tuberoinfundibular; see Ch. 40) appear to function normally \nin schizophrenia.\nThere is a strong correlation between antipsychotic potency in reducing \npositive\tsymptoms \tand \tactivity \tin \tblocking \tD2\treceptors \t(Fig. \t47.1) \t\nand receptor imaging studies have shown that clinical efficacy of \nantipsychotic \tdrugs \tis \tconsistently \tachieved \twhen \tD2 receptor \noccupancy reaches about 80%.4\tFurthermore, \tbrain \timaging \tstudies \t\nhave revealed an increased dopamine synthesis and release in the \nstriatum of schizophrenic patients (Laruelle et a l., 1999). Similar changes \nhave also been reported in non-schizophrenic close relatives, indicating \nthat such changes may indicate predisposition to schizophrenia rather \nthan the exhibition of", "start_char_idx": 0, "end_char_idx": 3386, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d03c13b8-c4c3-46c6-ac4c-7d1b3683c341": {"__data__": {"id_": "d03c13b8-c4c3-46c6-ac4c-7d1b3683c341", "embedding": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "002f2c5e-4dd7-42a7-bef4-0d068e952e3c", "node_type": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b3a2a10276ecf2c46fbb1e6d26210962cb902fbc5c2fde1349ada4b58b1b75a"}, "2": {"node_id": "553a4bc6-1cc0-411a-97de-37f706286d56", "node_type": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "81f3a83d9bdf18e4263211f8cf051b7f290f5fc02b35835a18c4a2b2e0a5a8a0"}, "3": {"node_id": "5ff81ec4-4568-468a-8943-70e371a9a767", "node_type": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "21de6afae4fe46b80e39ffd2a173bcd5c460e7a7430dbc1feb076e52b844c0f2"}}, "hash": "1f853854d3e1188e447b33ddfeadde47b8846e31470de699d09a188a2ddc5d4e", "text": "such changes may indicate predisposition to schizophrenia rather \nthan the exhibition of symptoms. Injection of amphetamine caused \ndopamine release that was greater by a factor of two or more in discriminate between significant and insignificant stimuli \nseems to be impaired. Thus the ticking of a clock may \ncommand as much attention as the words of a companion; \na chance thought, which a normal person would dismiss as inconsequential, may become an irresistible imperative.\nAETIOLOGY AND PATHOGENESIS OF \nSCHIZOPHRENIA\nGENETIC AND ENVIRONMENTAL FACTORS\nThe causes of schizophrenia remain unclear but involve a \ncombination of genetic and environmental factors. Thus a \nperson may have a genetic makeup that predisposes them \nto schizophrenia, but exposure to environmental factors may be required for schizophrenia to develop. The different \nforms that gene\u2013environment interaction can take are \ndiscussed \tin \tdetail \tin \tAyhan \tet \tal. \t(2016).\nThe disease shows a strong, but incomplete, hereditary \ntendency. In first-degree relatives, the risk is about 10%, but even in monozygotic (identical) twins, one of whom \nhas schizophrenia, the probability of the other being affected is only about 50%, pointing towards the importance of \nenvironmental factors. Genetic linkage studies have identi -\nfied more than 100 genetic regions (loci) associated with a \nrisk\tof\tschizophrenia \t(see \tRipke \tet \tal., \t2014; \tSekar \tet \tal., \t\n2016). There are significant associations between polymor -\nphisms in individual genes and the likelihood of an indi -\nvidual developing schizophrenia but there appears to be \nno single gene that has an overriding influence. Some of the genes implicated in schizophrenia are also associated \nwith bipolar disorder (see Ch. 48).\n\u25bc The most robust associations are with genes that control neuronal \ndevelopment, synaptic connectivity and glutamatergic neurotransmis -\nsion. These include complement component 4A (C4A), neuregulin , dys-\nbindin, DISC-1, TCF4 and NOTCH4 .\tIncreases \tin\tC4A\texpression \tresult\t\nin increased synaptic pruning (the process of synapse elimination \nthat occurs between early childhood and the onset of puberty) and \nmay help explain the reduced numbers of synapses in the brains of \nschizophrenics. Transgenic mice that underexpress neuregulin-1, a protein involved in synaptic development and plasticity and which \ncontrols\tNMDA \treceptor \texpression, \tshow \ta \tphenotype \tresembling \t\nhuman\tschizophrenia \tin \tcertain \trespects. \tMalfunction \tof \tNMDA \t\nreceptors is further implicated by genetic association with the genes \nfor\tD-amino \tacid \toxidase \t(DAAO), \tthe \tenzyme \tresponsible \tfor \t\nmetabolising \tD-serine, \tan \tallosteric \tmodulator \tof \tNMDA \treceptors \t\n(see\tCh.\t39), \tand \tfor \tDAAO \tactivator \t(G72). \tDysbindin \tis \tlocated \tin \t\npostsynaptic density domains and may be involved in tethering \nreceptors \tincluding \tNMDA \treceptors. \tDISC-1 \t\u2013 \twhich \tstands \tfor \t\ndisrupted in schizophrenia-1 \u2013 is a protein that associates with \ncytoskeletal proteins and is involved with cell migration, neurite \noutgrowth and receptor trafficking. Population genetic studies have \nsuggested that NOTCH4, a developmentally expressed gene, and \nTCF-4,\ta \tgene \talso \tassociated \twith \tmental \tretardation, \tare \tstrongly \t\nassociated with susceptibility for schizophrenia but their precise roles", "start_char_idx": 3310, "end_char_idx": 6671, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5ff81ec4-4568-468a-8943-70e371a9a767": {"__data__": {"id_": "5ff81ec4-4568-468a-8943-70e371a9a767", "embedding": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "002f2c5e-4dd7-42a7-bef4-0d068e952e3c", "node_type": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b3a2a10276ecf2c46fbb1e6d26210962cb902fbc5c2fde1349ada4b58b1b75a"}, "2": {"node_id": "d03c13b8-c4c3-46c6-ac4c-7d1b3683c341", "node_type": null, "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1f853854d3e1188e447b33ddfeadde47b8846e31470de699d09a188a2ddc5d4e"}}, "hash": "21de6afae4fe46b80e39ffd2a173bcd5c460e7a7430dbc1feb076e52b844c0f2", "text": "\t\nassociated with susceptibility for schizophrenia but their precise roles \nin\tits\taetiology \tremain \tto \tbe \telucidated. \tAmong \tother \tsuggested \t\nsusceptibility genes, some (such as the genes for monoamine oxidase \nA\t[MAO-A], \ttyrosine \thydroxylase \tand \tthe \tD2 dopamine receptor) \nare involved in monoamine transmission in the central nervous system. \nHowever, the weight of current evidence seems to suggest that \nschizophrenia may result from abnormal glutamatergic transmission, \ninvolving \ta \tdecrease \tin \tNMDA \treceptor \tfunction \t(see \tp. \t594).\nSome environmental influences early in development have been identified as possible predisposing factors, particularly maternal virus \ninfections. This and other evidence suggests that schizophrenia is \nassociated with a neurodevelopmental disorder affecting mainly the cerebral cortex and occurring in the first few months of prenatal \ndevelopment. This view is supported by brain imaging studies showing 4There are, however, exceptions to this simple rule. Up to one-third of \nschizophrenic \tpatients \tfail \tto \trespond \teven \twhen \tD2 receptor blockade \nexceeds 90%, and clozapine (see Table 47.1 ) can be effective at much lower \nlevels of block.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6674, "end_char_idx": 8361, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7f263fe4-9409-4824-84fd-a7b9df35d5c0": {"__data__": {"id_": "7f263fe4-9409-4824-84fd-a7b9df35d5c0", "embedding": null, "metadata": {"page_label": "600", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43fd4ed7-1572-412f-a47f-356d2c67939f", "node_type": null, "metadata": {"page_label": "600", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c2e1cf3291436f1f74425010838712135551eed1c5530dddcf8a001dbb2a264"}, "3": {"node_id": "f53e5479-2729-4b38-b27c-e8af013e34ad", "node_type": null, "metadata": {"page_label": "600", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2cde25dd6bba5f67eee982b0d4e48648e12961f0a52d7e92af7de82c9d6eae5b"}}, "hash": "a0d2cd0a62d934bf74e7d1b9cedaa5529836aa533ec9121e138e031108734085", "text": "47 SECTION 4 NERVOUS SYSTEM\n594NMDA\treceptor \thypofunction \tin \tthe \tcortex \tmay \taffect \tGABAergic \t\ninterneurons and alter cortical processing, giving rise to cognitive \nimpairment. \tIn\taddition, \tNMDA\treceptor\thypofunction \ton\tGABAergic \t\nneurons would reduce inhibition of the excitatory cortical input to \nthe\tVTA \tand \tthus \tenhance activity in the mesolimbic dopaminergic \npathway. \tThus \tNMDA \treceptor \thypofunction \tcould \tgive \trise \tto \t\nenhanced dopamine release in limbic areas such as the nucleus \naccumbens, resulting in the production of positive symptoms.\nGiven the evidence that schizophrenic symptoms may be due to a \nreduction \tin \tNMDA \treceptor \tfunction, \tefforts \thave \tbeen \tmade \tto \t\ndevelop\tnew \tdrugs \tto \tenhance \tNMDA \treceptor \tfunction \tbut \tnot \tto \t\na level where it becomes neurotoxic (see Ch. 41), e.g. by activating \nthe\tfacilitatory \tglycine \tsite \ton \tthe \tNMDA \treceptor \t(see \tCh. \t39) \twith \t\nan agonist or by raising extracellular glycine levels by inhibiting the \nGlyT1 transporter. However, bitopertin, a GlyT1 inhibitor, failed as \nan antipsychotic drug in clinical trials.\nOther glutamate pathways thought to be involved in schizophrenia \nare the corticostriatal, thalamocortical, corticothalamic and cortico-\nbrain stem pathways. The thalamus normally functions as a sensory \nfilter\tto\tlimit \tunnecessary \tsensory \tinput \tto \tthe \tcortex. \tDisruption \tof \t\nthe normal inputs to the thalamus, for example from a reduction in \nglutamatergic \tor\tGABAergic \ttransmission, \tdisables\tthis\t\u2018sensory\tgate\u2019\t\nfunction, allowing uninhibited input to reach the cortex. The role of \nthe thalamus in schizophrenia is reviewed by Pergola et al. (2015).\nThe hope is that a fuller understanding of the altered function of glutamate transmission in schizophrenia will lead to the development \nof new, improved antipsychotic drugs.\nAnimal models\nThere is a need for the development of animal models of \nschizophrenia that simulate the positive, negative and \ncognitive deficit components of this disorder. Schizophrenia \npresents as a heterogeneous disorder with sufferers exhibit -\ning different combinations of symptoms that may result \nfrom different neuronal abnormalities. Traditional models \nby and large reflect behaviours resulting from heightened dopaminergic transmission in the brain. Thus they were schizophrenic subjects compared with control subjects. The effect \nwas greatest in schizophrenic individuals during acute attacks, and \nabsent during spontaneous remissions \u2013 clear evidence linking \ndopamine release to the symptomatology.\nAn\tincrease\tin\tdopamine \treceptor\tdensity\tin\tschizophrenia \thas\tbeen\t\nreported in some studies, but not consistently, and the interpretation is complicated by the fact that chronic antipsychotic drug treatment \nis known to increase dopamine receptor expression.\nThus, therapeutically it might be desirable to inhibit dopaminergic \ntransmission in the limbic system yet enhance dopaminergic transmis -\nsion in the prefrontal cortex (how this might be achieved is discussed \nlater).\nGlutamate\nIn\thumans, \tNMDA \treceptor \tantagonists \tsuch \tas \tphency-\nclidine, ketamine and dizocilpine (Ch. 39) can produce \npositive, negative and cognitive deficit symptoms \u2013 in \ncontrast to amphetamine, which produces only positive symptoms. In the brains from schizophrenic patients, \nexpression of the glutamate uptake transporter VGLUT1 \nis reduced, which may", "start_char_idx": 0, "end_char_idx": 3432, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f53e5479-2729-4b38-b27c-e8af013e34ad": {"__data__": {"id_": "f53e5479-2729-4b38-b27c-e8af013e34ad", "embedding": null, "metadata": {"page_label": "600", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "43fd4ed7-1572-412f-a47f-356d2c67939f", "node_type": null, "metadata": {"page_label": "600", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c2e1cf3291436f1f74425010838712135551eed1c5530dddcf8a001dbb2a264"}, "2": {"node_id": "7f263fe4-9409-4824-84fd-a7b9df35d5c0", "node_type": null, "metadata": {"page_label": "600", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a0d2cd0a62d934bf74e7d1b9cedaa5529836aa533ec9121e138e031108734085"}}, "hash": "2cde25dd6bba5f67eee982b0d4e48648e12961f0a52d7e92af7de82c9d6eae5b", "text": "of the glutamate uptake transporter VGLUT1 \nis reduced, which may indicate a disruption of glutamatergic nerve terminals. It has therefore been postulated that \nschizophrenia may result from disruption of glutamatergic \nneurotransmission, evident as a reduction in the function \nof\tNMDA\treceptors \t(the\tNMDA\thypofunction \thypothesis; \t\nsee Coyle 2017). Consistent with this hypothesis, transgenic \nmice\tin\twhich \tNMDA \treceptor \texpression \tis \treduced \t(not \t\nabolished, because this is fatal) show stereotypic behaviours and reduced social interaction that are features of human \nschizophrenia and that respond to antipsychotic drugs.\n\u25bc\tGlutamatergic \tneurons \tand \tGABAergic \tneurons \tplay \tcomplex \t\nroles in controlling the level of activity in neuronal pathways involved \nin\tschizophrenia. \tNMDA \treceptor \thypofunction \tis \tthought \tto \treduce \nthe level of activity in mesocortical dopaminergic neurons. This would \nresult in a decrease in dopamine release in the prefrontal cortex \nand could thus give rise to negative symptoms of schizophrenia. SpiroperidolBenperidolTrifluperidolPimozideFluphenazineDroperidolHaloperidolThiothixeneTrifluperazineMoperoneProchlorperazineMolindoneTrazodone\nThioridazineClozapineChlorpromazinePromazine\n1000 100 10 1 0.1\nAverage clinical dose (mg/day)10\u22127\n10\u22128\n10\u22129\n10\u221210IC50 (mol/L)\nFig. 47.1 Correlation between the \nclinical potency and affinity for \ndopamine D 2 receptors among \nantipsychotic drugs. Clinical potency is expressed as the daily dose used in treating schizophrenia, and binding activity is expressed as the concentration needed to produce 50% inhibition of haloperidol binding. (From \nSeeman, P. et al., 1976. Nature 361, \n717.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3367, "end_char_idx": 5537, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f3a18da5-0229-4907-b186-9403903b7c9d": {"__data__": {"id_": "f3a18da5-0229-4907-b186-9403903b7c9d", "embedding": null, "metadata": {"page_label": "601", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8cdf5ec7-244a-4e0b-9728-85fb0c88ab94", "node_type": null, "metadata": {"page_label": "601", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f20adb00546797b15afab6b41a9d279b5d42944e39ef17723ca3380058463586"}, "3": {"node_id": "085d7461-731d-4087-9b93-4d10f6e920b4", "node_type": null, "metadata": {"page_label": "601", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "78ff3b431201f717ffe57d5dc53d09d719a1de79b77155570f4c12f53b92aeb4"}}, "hash": "5aca0c9b7c3679cc43216644cb4b8adaae0f1bd7bc86a073e82e40f8eb93f847", "text": "47 ANTipSYchOTic dRUgS\n595very usefully \u2013 to distinguish the large group of similar first-generation \ndopamine antagonists from the more diverse group of later \ncompounds.\nThe therapeutic activity of the prototype drug, chlorpromazine, in \nschizophrenic patients was discovered through the acute observations \nof\ta\tFrench \tsurgeon, \tLaborit, \tin \t1947. \tHe \ttested \tvarious \tsubstances, \t\nincluding promethazine, for their ability to alleviate signs of stress \nin patients undergoing surgery, and concluded that promethazine had a calming effect that was different from mere sedation. Elaboration \nof the phenothiazine structure led to chlorpromazine, the antipsychotic effect of which was demonstrated in man, at Laborit\u2019s instigation, \nby\tDelay \tand \tDeniker \tin \t1953. \tThis \tdrug \twas \tunique \tin \tcontrolling \t\nthe symptoms of psychotic patients. The clinical efficacy of pheno -\nthiazines was discovered long before their mechanism was guessed \nat, let alone understood.\nPharmacological investigation showed that phenothiazines, the first-\ngeneration antipsychotic agents, block many different mediators, \nincluding histamine, catecholamines, acetylcholine and 5-HT, and this multiplicity of actions led to the trade name Largactil for chlor-\npromazine. \tIt\tis\tnow\tclear\t(see\tFig.\t47.1)\tthat\tantagonism \tof\tdopamine \t\nis the main determinant of antipsychotic action.likely to show positive results with drugs that have dopa -\nmine receptor-antagonist activity. Models based on inhibi -\ntion\tof\tNMDA\tfunction\tby\tphencyclidine (PCP) and related \ndrugs\thave \tbecome \tpopular \tin \trecent \tyears. \tAlso, \tvarious \t\ngenetic models are being examined. These have focused \non\tproteins \tsuch \tas \tDISC-1 \tthat \tare \timplicated \tin \tschizo -\nphrenia and on receptors and transporters for neurotransmit -\nters such as glutamate and dopamine. However, as described \nearlier, the genetic basis of schizophrenia is multifactorial and environmental factors are also important. Thus mutation \nof a single gene may provide only limited information. \nModels of cognitive deficits and negative symptoms are lacking. The development of such models is a major chal -\nlenge that requires a better understanding of the pathophysi -\nological\tprocesses \tthat \tunderlie \tdifferent \tsymptoms. \tFor \t\nfurther details on the development of new animal models \nof schizophrenia see Pratt et al. (2012) and Sigardsson (2015).\nThe nature of schizophrenia \n\u2022\tPsychotic \tillness \tcharacterised \tby \tdelusions, \t\nhallucinations and thought disorder (positive \nsymptoms), together with social withdrawal and flattening of emotional responses (negative symptoms), \nand cognitive impairment.\n\u2022\tAcute\tepisodes \t(mainly \tpositive \tsymptoms) \tfrequently \t\nrecur and may develop into chronic schizophrenia, \nwith predominantly negative symptoms.\n\u2022\tIncidence \tis \tabout \t1% \tof \tthe \tpopulation, \twith \ta \t\nsignificant hereditary component. Genetic linkage studies suggest involvement of multiple genes, but no single \u2018schizophrenia gene\u2019.\n\u2022\tPharmacological \tevidence \tis \tgenerally \tconsistent \twith \t\ndopamine dysregulation and glutamate underactivity hypotheses, supported by biochemical findings, clinical efficacy and imaging studies.\n5Wikipedia (https://en.wikipedia.org/wiki/List_of_antipsychotics) \nlists no fewer than 49 first-generation and 32 second-generation agents \napproved \tfor \tclinical \tuse. \tDespite \tthis \thuge \tinvestment \tby \tthe \t\npharmaceutical industry and plethora of me-too compounds, clinical \nbenefits have been", "start_char_idx": 0, "end_char_idx": 3504, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "085d7461-731d-4087-9b93-4d10f6e920b4": {"__data__": {"id_": "085d7461-731d-4087-9b93-4d10f6e920b4", "embedding": null, "metadata": {"page_label": "601", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8cdf5ec7-244a-4e0b-9728-85fb0c88ab94", "node_type": null, "metadata": {"page_label": "601", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f20adb00546797b15afab6b41a9d279b5d42944e39ef17723ca3380058463586"}, "2": {"node_id": "f3a18da5-0229-4907-b186-9403903b7c9d", "node_type": null, "metadata": {"page_label": "601", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5aca0c9b7c3679cc43216644cb4b8adaae0f1bd7bc86a073e82e40f8eb93f847"}}, "hash": "78ff3b431201f717ffe57d5dc53d09d719a1de79b77155570f4c12f53b92aeb4", "text": "industry and plethora of me-too compounds, clinical \nbenefits have been modest.ANTIPSYCHOTIC DRUGS\nCLASSIFICATION OF ANTIPSYCHOTIC DRUGS\nMore than 80 different antipsychotic drugs are available \nfor clinical use. These have been divided into two groups \n\u2013 those drugs that were originally developed (e.g. chlor-\npromazine, haloperidol and many similar compounds), \noften referred to as first-generation, typical or conventional \nantipsychotic drugs, and more recently developed agents \n(e.g. clozapine, risperidone), which are termed second-\ngeneration or atypical antipsychotic drugs. Table 47.1 sum-\nmarises the main drugs that are in clinical use.5\n\u25bc The term \u2018atypical\u2019 has been widely used but not clearly defined. \nIn effect, it refers to the diminished tendency of later compounds to \ncause unwanted motor side effects, but it is also used to describe \ncompounds with a different pharmacological profile from first-\ngeneration compounds. In practice, however, it often serves \u2013 not Classification of antipsychotic \ndrugs \n\u2022\tMain\tcategories \tare:\n\u2013 first-generation (\u2018typical\u2019, \u2018classical\u2019 or \u2018conventional\u2019) \nantipsychotics (e.g. chlorpromazine, haloperidol, \nfluphenazine, flupentixol, zuclopenthixol);\n\u2013 second-generation (\u2018atypical\u2019) antipsychotics (e.g. \nclozapine, risperidone, quetiapine, amisulpride, \naripiprazole, ziprasidone).\n\u2022\tDistinction \tbetween \tfirst- \tand \tsecond-generation \tdrugs \t\nis\tnot\tclearly \tdefined \tbut \trests \ton:\n\u2013 receptor profile;\n\u2013 incidence of extrapyramidal side effects (less in \nsecond-generation group);\n\u2013 efficacy (specifically of clozapine) in \u2018treatment-\nresistant\u2019 group of patients;\n\u2013 efficacy against negative symptoms.\nCLINICAL EFFICACY IN TREATMENT \nOF SCHIZOPHRENIA\nThe clinical efficacy of antipsychotic drugs in enabling \nschizophrenic patients to lead more normal lives has been \ndemonstrated in many controlled trials (see Leucht et al., \n2013). The inpatient population (mainly chronic schizo -\nphrenics) of mental hospitals declined sharply in the 1950s \nand 1960s. The introduction of antipsychotic drugs was a \nsignificant enabling factor, as well as the changing public and professional attitudes towards hospitalisation of the \nmentally ill.\nAntipsychotic \tdrugs\thave\tsevere\tdrawbacks \tthat\tinclude:\n\u2022\tNot\tall \tschizophrenic \tpatients \trespond \tto \tdrug \t\ntherapy. It is recommended to try clozapine in \npatients who are resistant to other antipsychotic \ndrugs. The 30% of patients who do not respond are \nclassed as \u2018treatment resistant\u2019 and present a major therapeutic problem. The reason for the difference \nbetween responsive and unresponsive patients is \nunknown at present, although there is some evidence mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3433, "end_char_idx": 6589, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f77f2a97-7648-433b-b19c-f051361579ab": {"__data__": {"id_": "f77f2a97-7648-433b-b19c-f051361579ab", "embedding": null, "metadata": {"page_label": "602", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "338ded58-3ef4-40b5-b531-502ca258b2a4", "node_type": null, "metadata": {"page_label": "602", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fd06dd3b18b50bbe027129ccd9e1108405be762b48559c3977a2be31d279fb22"}}, "hash": "fd06dd3b18b50bbe027129ccd9e1108405be762b48559c3977a2be31d279fb22", "text": "47 SECTION 4 NERVOUS SYSTEM\n596Table 47.1 Characteristics of some major antipsychotic drugs\nDrugReceptor affinity Main side effects\nNotes D1D2 \u03b11H1 mACh 5-HT 2AEPS Sed Hypo Other\nChlorpromazine ++++ ++++++++ +++ ++ +++++Increased \nprolactin \n(gynaecomastia)Phenothiazine class\nHypothermia\nPerphenazine and \nprochlorperazine are similar.\nFluphenazine, trifluoperazine are \nsimilar but:\n\u2022\tdo\tnot\tcause\tjaundice\n\u2022\tcause\t less\thypotension\n\u2022\tcause\t more\tEPSAnticholinergic \neffects\nHypersensitivity \nreactions\nObstructive \njaundice\nFluphenazine available as depot \npreparation\nPericyazine\t causes\tless\tEPS\t\nprobably due to its greater \nmuscarinic antagonist actions.\nPipotiazine has been withdrawn\nHaloperidol +++++ +++ \u2014 ++ +++\u2014 +As \nchlorpromazine \nbut does not \ncause\tjaundiceButyrophenone class\nFewer \nanticholinergic \nside effectsWidely used antipsychotic drug\nStrong\tEPS\ttendency\nAvailable as depot preparation\nFlupentixol ++++++ +++\u2014 + ++ + +Increased \nprolactin \n(gynaecomastia)Thioxanthine class\nRestlessness Zuclopenthixol is similar\nAvailable as depot preparation\nAmisulpride \u2014 ++ \u2014 \u2014 \u2014 \u2014 + + \u2014Increased \nprolactin \n(gynaecomastia)Benzamide class (includes \nsulpiride)\nSelective\t D2/D3 antagonist\nLess\tEPS\tthan\thaloperidol\t\n(reason for this unclear, but could \nresult\tfrom\taction\tat\tD3 or very \nweak\tpartial\tagonism\t at\tD2)\nIncreases alertness in apathetic \npatients\nPoorly absorbed\nAmisulpride and pimozide \n(long-acting) are similar\nClozapine + + +++++++++ +++ \u2014 ++ ++Risk of \nagranulocytosis \n(~1%): regular \nblood counts \nrequiredDibenzodiazepine\t class\nSeizuresNo\tEPS\t(first\tsecond-generation\t\nantipsychotic)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2102, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c87f70f4-7c5c-4c17-84f2-e339fb2626c7": {"__data__": {"id_": "c87f70f4-7c5c-4c17-84f2-e339fb2626c7", "embedding": null, "metadata": {"page_label": "603", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "57769d3a-6a56-4554-9cf7-58d387f248de", "node_type": null, "metadata": {"page_label": "603", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f440837a33623264a0d7f57dd3cdefe8d145a6b694488145f64b3b9bda6e7cc"}}, "hash": "3f440837a33623264a0d7f57dd3cdefe8d145a6b694488145f64b3b9bda6e7cc", "text": "47 ANTipSYchOTic dRUgS\n597Table 47.1 Characteristics of some major antipsychotic drugs\u2014cont\u2019d\nDrugReceptor affinity Main side effects\nNotes D1D2 \u03b11H1 mACh 5-HT 2AEPS Sed Hypo Other\nClozapine, \ncont\u2019dSalivationShows\tefficacy \tin \t\u2018treatment-\nresistant\u2019 patients and reduces incidence of suicide\nAnticholinergic side effects\nEffective \tagainst \tnegative \tand \t\npositive symptoms\nWeight gainOlanzapine is somewhat less sedative, without risk of agranulocytosis, but questionable \nefficacy\tin \ttreatment-resistant \t\npatients\nRisperidone + +++ +++ ++ \u2014++++ (IA?)+ ++ ++Weight gain\nSignificant \trisk \tof \tEPS\nEPS\tat\thigh \t\ndoses?\tEffective \tagainst \tnegative \t\nsymptoms\nHypotension Potent\ton \tD4 receptors\nAvailable as depot preparation\nPaliperidone is a metabolite of \nrisperidone\nIloperidone reported to have low \nincidence \tof \tEPS \tand \tweight \tgain\nQuetiapine + + +++ +++ + + \u2014 ++ ++Tachycardia Low\tincidence \tof \tEPS\nDrowsiness No increase in prolactin secretion\nDry\tmouth 5-HT 1A partial agonist\nConstipationShort-acting \t(plasma \thalf-life \t\n~6 h)\nWeight gain\nAripiprazole +++++ (PA)++ ++ \u2014 +++ \u2014 + \u2014 \u2014Long-acting (plasma half-life ~3 days)\nUnusual\tD2\tpartial\tagonist \tprofile \t\nmay account for paucity of side effects\nAlso a 5HT\n1A partial agonist\nNo effect on prolactin secretionNo weight gainAvailable as a depot preparationBrexpiprazole may also be useful \nin the treatment of depression\nZiprasidone ++ +++ +++ ++ \u2014 ++++ + \u2014 +Tiredness\nLow\tincidence \tof \tEPS\nNausea No weight gain\nLurasidone is similar\n?\tEffective \tagainst \tnegative \t\nsymptoms\nShort-acting \t(plasma \thalf-life \t\n~8 h) but a depot preparation is \navailable\n+, pKi 5\u20137; ++, pKi 7\u20138; +++, pKi 8\u20139; +++, pKi >9; 5-HT 1A, 5-HT 2A,\t5-hydroxytryptamine \ttypes \t1A \tand \t2A \treceptors; \t\u03b11, \u03b11 adrenoceptor; \nD1, D 2, D 3, D 4,\tdopamine \ttypes \t1, \t2, \t3 \tand \t4 \treceptor, \trespectively; \tECG, electrocardiograph; EPS, extrapyramidal side effects; H1, \nhistamine type 1 receptor; Hypo, hypotension; IA, inverse agonist; mACh, muscarinic acetylcholine receptor; PA, partial agonist; Sed, \nsedation.\n(Table\tbased \ton \tdata \tcontained \tin \tGuide \tto \tPharmacology \t(http://www.guidetopharmacology.org/) \tand \tNIMH \tPsychoactive \tDrug \tScreening \t\nProgram\tdatabase \t(http://pdsp.med.unc.edu/). \tWhere \tavailable, \tdata \tobtained \ton \thuman \treceptors \tare \tgiven.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2807, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2a11dbcc-ca59-4cff-832a-fbe928bbf0aa": {"__data__": {"id_": "2a11dbcc-ca59-4cff-832a-fbe928bbf0aa", "embedding": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "69b4d408-bc94-4ba6-a6ae-bc0d317331d7", "node_type": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8dcb920e08d48c748cdbcc56c8dbb646845ef4a08564e4b7106bffa546bcfa85"}, "3": {"node_id": "131a0e16-36da-4cbb-bdd2-e82e0d62753a", "node_type": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "257cbaf86f2b0e175ef1ac724ef9a6df436f3a692eb0d4ddd5bce55ad3d9534a"}}, "hash": "e753b3241960c9529f6e9d98c111da226dfd9eec76a0e795bc62fa9ebdda8007", "text": "47 SECTION 4 NERVOUS SYSTEM\n598block\to f\tD2 receptors. The first-generation compounds show \nsome\tpreference \tfor \tD2\tover\tD1 receptors, whereas some \nof the later agents (e.g. sulpiride , amisulpride ,) are highly \nselective \tfor \tD2\treceptors. \tD2 antagonists that dissociate \nrapidly from the receptor (e.g. quetiapine )\tand\tD2 partial \nagonists (e.g. aripiprazole ) were introduced in an attempt \nto reduce extrapyramidal motor side effects (see p. 599). \nCariprazine ,\ta\tnew\tantipsychotic \tdrug,\tis\ta\tD2\tand\tD3 partial \nagonist\twith \thigher \taffinity \tfor \tD3\tthan\tD2 receptors.\nIt\tis\tthe\tantagonism \tof \tD2 receptors in the mesolimbic \npathway that is believed to relieve the positive symptoms \nof schizophrenia. Unfortunately, systemically administered \nantipsychotic \tdrugs\tdo\tnot\tdiscriminate \tbetween\tD2 recep -\ntors\tin\tdistinct\tbrain\tregions\tand\tD2 receptors in other brain \npathways will also be blocked. Thus antipsychotic drugs \nproduce\tunwanted \tmotor \teffects \t(block \tof \tD2 receptors in \nthe nigrostriatal pathway), enhance prolactin secretion \n(block\tof\tD2 receptors in the tuberoinfundibular pathway), \nreduce\tpleasure \t(block \tof \tD2 receptors in the reward \ncomponent of the mesolimbic pathway) and perhaps even worsen the negative symptoms of schizophrenia (block of \nD\n2 receptors in the prefrontal cortex, although these are \nonly\texpressed \tat \ta \tlow \tdensity \t\u2013 \tD1 receptors being in \ngreater abundance). While all antipsychotic drugs block \nD2 receptors and should therefore in theory induce all of \nthese unwanted effects, some have additional pharm -\nacological \tactivity \t(e.g. \tmACh \treceptor \tantagonism \tand \t\n5-HT 2A receptor antagonism) that, to varying degrees, \nameliorate unwanted effects. 5-HT 2A antagonism may also \nhelp to alleviate the negative and cognitive impairments of schizophrenia.\nAntipsychotic \tdrugs \thave \tclassically \tbeen \tthought \tto \t\nhave a delayed onset to their therapeutic actions, even \nthough their dopamine receptor-blocking action is immedi -\nate. This view has, however, been called into question ( Kapur \net al., 2005; Leucht et al., 2005). In animal studies, chronic \nantipsychotic drug administration does produce compensa -\ntory changes in the brain, for example, a reduction in the \nactivity of dopaminergic neurons and proliferation of \ndopamine receptors, detectable as an increase in haloperidol binding, with a pharmacological supersensitivity to dopa -\nmine reminiscent of the phenomenon of denervation supersensitivity (Ch. 13). The mechanism(s) of these delayed effects are poorly understood. They are likely to contribute \nto the development of unwanted tardive dyskinesias . The \nsedating effect of antipsychotic drugs is immediate, allowing \nthem to be used in acute behavioural emergencies.(not conclusive) that polymorphisms within the family \nof dopamine and 5-HT receptors may be involved.\n\u2022\tWhile\tthey \tcontrol \tthe \tpositive \tsymptoms \t(thought \t\ndisorder, hallucinations, delusions, etc.) effectively, \nmost are ineffective in relieving the negative \nsymptoms (emotional flattening, social isolation) and \ncognitive impairment.\n\u2022\tThey\tinduce \ta \trange \tof", "start_char_idx": 0, "end_char_idx": 3151, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "131a0e16-36da-4cbb-bdd2-e82e0d62753a": {"__data__": {"id_": "131a0e16-36da-4cbb-bdd2-e82e0d62753a", "embedding": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "69b4d408-bc94-4ba6-a6ae-bc0d317331d7", "node_type": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8dcb920e08d48c748cdbcc56c8dbb646845ef4a08564e4b7106bffa546bcfa85"}, "2": {"node_id": "2a11dbcc-ca59-4cff-832a-fbe928bbf0aa", "node_type": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e753b3241960c9529f6e9d98c111da226dfd9eec76a0e795bc62fa9ebdda8007"}, "3": {"node_id": "2b32a601-335b-48b5-bd86-987a61ac54b4", "node_type": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3ec80fd2c1cacf1e19e4fb935adfebd6a00e81116122e7a78f4ff82926832f8"}}, "hash": "257cbaf86f2b0e175ef1ac724ef9a6df436f3a692eb0d4ddd5bce55ad3d9534a", "text": "\ncognitive impairment.\n\u2022\tThey\tinduce \ta \trange \tof \tside \teffects \tthat \tinclude \t\nextrapyramidal motor, endocrine and sedative effects (see Table 47.1) that can be severe and limit patient \ncompliance.\n\u2022\tThey\tmay \tproduce \tunwanted \tcardiac \t(pro-arrhythmic) \t\neffects (see Ch. 22).\nSecond-generation antipsychotic drugs were believed to \novercome these shortcomings to some degree. However, \na meta-analysis (Leucht et al., 2013) concluded that only \nsome of the second-generation antipsychotic drugs examined showed better overall efficacy. There is a definite need for \nthe development of new treatments.\nAbrupt\tcessation \tof \tantipsychotic \tdrug \tadministration \t\nmay lead to a rapid onset psychotic episode distinct from \nthe underlying illness.\nOTHER USES OF ANTIPSYCHOTIC DRUGS\nA\tcommon \temerging \ttheme \twith \tcentrally \tacting \tdrugs \tis \t\nthat while they were initially developed to treat one brain disorder they have been subsequently found to be effective \nin treating other disorders. This is also the case with \nantipsychotic drugs, which are now used to treat a range of disorders, including:\n\u2022\tbipolar \tdisorder, \tmania \tand \tdepression \t(see \tCh. \t48)\n\u2022\tpsychomotor \tagitation \tand \tsevere \tanxiety \t\n(chlorpromazine and haloperidol)\n\u2022\tagitation \tand \trestlessness \tin \tthe \telderly \t\n(risperidone), although this is highly questionable\n\u2022\tpsychosis \tassociated \twith \tParkinson\u2019s \tdisease \t\n(primavanserin) (see Ch. 41)\n\u2022\trestlessness \tand \tpain \tin \tpalliative \tcare \t\n(levomepromazine)\n\u2022\tnausea \tand \tvomiting \t(e.g. \tchlorpromazine and \nhaloperidol) reflecting antagonism at dopamine, \nmuscarinic, histamine and possibly 5-HT receptors\n\u2022\tmotor\ttics \tand \tintractable \thiccup \t(chlorpromazine \nand haloperidol)\n\u2022\tantisocial \tsexual \tbehaviour \t(benperidol)\n\u2022\tinvoluntary \tmovements \tcaused \tby \tHuntington\u2019s \t\ndisease (mainly haloperidol; see Ch. 41)\nPHARMACOLOGICAL PROPERTIES\nDOPAMINE RECEPTORS\nThe classification of dopamine receptors in the central \nnervous system is discussed in Chapter 40 (see Table 40.1). \nThere are five subtypes, which fall into two functional \nclasses:\tthe\tD1\ttype,\tcomprising \tD1\tand\tD5,\tand\tthe\tD2 type, \ncomprising \tD2,\tD3\tand\tD4.\tAntipsychotic \tdrugs \towe \ttheir \t\ntherapeutic \teffects\tmainly\tto\tblockade \tof\tD2 receptors.6\tAs\t\nstated previously, antipsychotic effects require about 80% \n6The\tD4 receptor attracted attention on account of the high degree of \ngenetic polymorphism that it shows in human subjects, and because \nsome of the newer antipsychotic drugs (e.g. clozapine) have a high \naffinity\tfor \tthis \treceptor \tsubtype. \tHowever, \ta \tspecific \tD4 receptor \nantagonist proved ineffective in clinical trials.Mechanism of action of \nantipsychotic drugs \n\u2022\tMost\tantipsychotic \tdrugs \tare \tantagonists \tor \tpartial \t\nagonists\tat \tD2 dopamine receptors, but they also \nblock a variety of other receptors.\n\u2022\tAntipsychotic \tpotency \tgenerally \truns \tparallel \tto \tactivity \t\non\tD2 receptors, but activities at other receptors (e.g.", "start_char_idx": 3106, "end_char_idx": 6095, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2b32a601-335b-48b5-bd86-987a61ac54b4": {"__data__": {"id_": "2b32a601-335b-48b5-bd86-987a61ac54b4", "embedding": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "69b4d408-bc94-4ba6-a6ae-bc0d317331d7", "node_type": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8dcb920e08d48c748cdbcc56c8dbb646845ef4a08564e4b7106bffa546bcfa85"}, "2": {"node_id": "131a0e16-36da-4cbb-bdd2-e82e0d62753a", "node_type": null, "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "257cbaf86f2b0e175ef1ac724ef9a6df436f3a692eb0d4ddd5bce55ad3d9534a"}}, "hash": "c3ec80fd2c1cacf1e19e4fb935adfebd6a00e81116122e7a78f4ff82926832f8", "text": "\n5-HT2A and muscarinic) may reduce extrapyramidal \nside effects.\n\u2022\tActivity\tat \tmuscarinic, \tH1 and \u03b1 receptors may \ndetermine unwanted side effect profile.\n\u2022\tImaging \tstudies \tsuggest \tthat \ttherapeutic \teffect \t\nrequires\tabout \t80% \toccupancy \tof \tD2 receptors.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6142, "end_char_idx": 6884, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "42cd00ad-1111-45d1-a48a-21e18ff8b20a": {"__data__": {"id_": "42cd00ad-1111-45d1-a48a-21e18ff8b20a", "embedding": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "312a2f71-a34a-4d6f-8308-3187507591fe", "node_type": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "22d0991e727e680052ba4e2110dd77b694c19d63e9ef188e59e7bfa92c04efd3"}, "3": {"node_id": "9321d863-a52a-48a9-992c-c408dfa4f38e", "node_type": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e3e1961de7d4c5fdd8082cca1873db40981403f5f7cdbf60ee0e00a43ebc56d"}}, "hash": "c9041b1c8314f1868746f9490b69ec2821374dbfa6a830cad1b8132bf0285d48", "text": "47 ANTipSYchOTic dRUgS\n599terminals are thought to innervate cholinergic interneurons \nthat\texpress\tinhibitory \tD2 receptors (Pisani et al., 2007 ). It \nis\tsuggested \tthat\tthere\tis\tnormally \ta\tbalance\tbetween\tD2 \nreceptor activation and muscarinic receptor activation. \nBlocking \tD2 receptors in the striatum with an antipsychotic \nagent will result in enhanced acetylcholine release on to \nmuscarinic receptors, thus producing extrapyramidal side \neffects,\twhich\tare\tcounteracted \tif\tthe\tD2 antagonist also \nhas muscarinic antagonist activity. Maintaining the dopamine/acetylcholine balance was also the rationale for the use of the muscarinic antagonist benztropine to reduce \nextrapyramidal effects of antipsychotic drugs. Muscarinic antagonist activity does, however, induce side effects such as constipation, dry mouth and blurred vision.\nUNWANTED EFFECTS\nEXTRAPYRAMIDAL MOTOR DISTURBANCES\nAntipsychotic \tdrugs\tproduce\ttwo\tmain\tkinds\tof\tmotor\t\ndisturbance in humans: acute dystonias and tardive dyskinesias , \ncollectively termed extrapyramidal side effects. These all result \ndirectly\tor\tindirectly \tfrom\tD2 receptor blockade in the \nnigrostriatal pathway. Extrapyramidal side effects constitute \none of the main disadvantages of first-generation anti -\npsychotic drugs. Second-generation drugs were thought to have less tendency to produce extrapyramidal side effects. However, a long-term study of olanzapine, risperidone, quetiapine and ziprasidone concluded that they too can induce extrapyramidal side effects (see Lieberman & Stroup, \n2011).\tEven\taripiprazole, \twhich\tis\ta\tD2 partial agonist, has \nbeen reported to produce this unwanted effect.\nAcute dystonias are involuntary movements (restlessness, \nmuscle spasms, protruding tongue, fixed upward gaze, neck muscle spasm), often accompanied by symptoms of Parkinson\u2019s disease (Ch. 41). They occur commonly in the first few weeks, often declining with time, and are reversible on stopping drug treatment. The timing is consistent with block of the dopaminergic nigrostriatal pathway. Concomi -\ntant block of muscarinic receptors and 5-HT\n2A receptors \nmitigates the motor effects of dopamine receptor antagonists (see earlier).\nTardive dyskinesia\n (see Klawans et al., 1988) develops \nafter months or years (hence \u2018tardive\u2019) in 20%\u201340% of patients treated with first-generation antipsychotic drugs, and is one of the main problems of antipsychotic therapy. Its seriousness lies in the fact that it is a disabling and often irreversible condition, which often gets worse when anti -\npsychotic therapy is stopped and is resistant to treatment. The syndrome consists of involuntary movements, often of the face and tongue, but also of the trunk and limbs, which can be severely disabling. It resembles that seen after prolonged treatment of Parkinson\u2019s disease with levodopa (see Ch. 41). The incidence depends greatly on drug, dose and age (being commonest in patients who are over 50 years of age).\n\u25bc There are several theories about the mechanism of tardive dyskinesia \n(see Casey, 1995). One is that it is associated with a gradual increase \nin\tthe\tnumber\tof\tD2 receptors in the striatum, which is less marked \nduring treatment with second-generation than with first-generation \nantipsychotic \tdrugs.\tAnother\tpossibility \tis\tthat\tchronic\tblock\tof\t\ninhibitory dopamine receptors", "start_char_idx": 0, "end_char_idx": 3348, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9321d863-a52a-48a9-992c-c408dfa4f38e": {"__data__": {"id_": "9321d863-a52a-48a9-992c-c408dfa4f38e", "embedding": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "312a2f71-a34a-4d6f-8308-3187507591fe", "node_type": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "22d0991e727e680052ba4e2110dd77b694c19d63e9ef188e59e7bfa92c04efd3"}, "2": {"node_id": "42cd00ad-1111-45d1-a48a-21e18ff8b20a", "node_type": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9041b1c8314f1868746f9490b69ec2821374dbfa6a830cad1b8132bf0285d48"}, "3": {"node_id": "7ddf767f-6f0b-4843-acf9-8d06d5ccce24", "node_type": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27ec41f3659e0cdbba4f8ac1a4934b452c593371e436a9d537082862a1bd1fca"}}, "hash": "9e3e1961de7d4c5fdd8082cca1873db40981403f5f7cdbf60ee0e00a43ebc56d", "text": "dopamine receptors enhances catecholamine and/or \nglutamate release in the striatum, leading to excitotoxic neurodegenera -\ntion (Ch. 41).\nDrugs\tthat\trapidly\tdissociate \tfrom\tD2 receptors (e.g. clozapine, \nolanzapine) \tinduce\tless\tsevere\textrapyramidal \tside\teffects.\tA\tpossible\t\nexplanation for this (see Kapur & Seeman, 2001) is that with a rapidly 5-HYDROXYTRYPTAMINE RECEPTORS\nThe idea that 5-HT dysfunction could be involved in \nschizophrenia has drifted in and out of favour many times. \nIt\twas\toriginally \tbased\ton\tthe\tfact\tthat\tLSD,\ta\tpartial\tagonist\t\nat 5-HT 2A receptors (see Chs 16 and 49), produces hallucina -\ntions. Conventional wisdom was that 5-HT is not directly involved in the pathogenesis of schizophrenia. Nevertheless, pharmacological manipulation of 5-HT receptor activity, \ncombined \twith\tD2 receptor antagonism, has resulted in \nnew drugs with improved therapeutic profiles (see Table 47.1).\n7 There is a plethora of 5-HT receptors (see Chs 16 \nand 40), with disparate functions in the body. It is the 5-HT\n2A receptor and, to a lesser extent, the 5-HT 1A receptor \nthat are important in the treatment of schizophrenia.\n5-HT 2A receptors are G i/G o-coupled receptors and their \nactivation produces neuronal inhibition (through decreased neuronal excitability at the soma and decreased transmitter release at the nerve terminals; see Ch. 40). In this way, in the nigrostriatal pathway, 5-HT\n2A receptors control the \nrelease\tof\tdopamine. \tDrugs\twith\t5-HT2A antagonist proper -\nties (e.g. olanzapine and risperidone) enhance dopamine release in the striatum by reducing the inhibitory effect of 5-HT. This will reduce extrapyramidal side effects (see later). In contrast, in the mesolimbic pathway, the combined \neffects\tof\tD2 and 5-HT 2A antagonism are thought to coun -\nteract the increased dopamine function that gives rise to \npositive\tsymptoms \tof\tschizophrenia. \tFurther,\tenhancing \t\nboth dopamine and glutamate release in the mesocortical circuit, 5-HT\n2A receptor antagonism may improve the \nnegative symptoms of schizophrenia (Stahl, 2008). P rima-\nvanserin, a drug recently introduced for the treatment of psychosis associated with Parkinson\u2019s disease (see Ch. 41) and which may be beneficial as an adjunct to other anti-psychotic drugs in the treatment of schizophrenia, is an inverse agonist at the 5-HT\n2A receptor and has no activity \nat dopaminergic receptors.\n5-HT 1A receptors are somatodendritic autoreceptors that \ninhibit\t5-HT\trelease\t(see\tCh.\t40).\tAntipsychotic \tdrugs\tthat\t\nare agonists or partial agonists at 5-HT 1A receptors (e.g. \nquetiapine; see Table 47.1) may work by decreasing 5-HT release, thus enhancing dopamine release in the striatum and prefrontal cortex.\nThe concept of 5-HT receptors as targets for novel \nantipsychotic drug development is discussed further at the end of this chapter.\nMUSCARINIC ACETYLCHOLINE RECEPTORS\nSome phenothiazine antipsychotic drugs (e.g. pericyazine ) \nhave been reported to produce fewer extrapyramidal side effects than others, and this was thought to correlate with \ntheir\tmuscarinic \tantagonist", "start_char_idx": 3332, "end_char_idx": 6421, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7ddf767f-6f0b-4843-acf9-8d06d5ccce24": {"__data__": {"id_": "7ddf767f-6f0b-4843-acf9-8d06d5ccce24", "embedding": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "312a2f71-a34a-4d6f-8308-3187507591fe", "node_type": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "22d0991e727e680052ba4e2110dd77b694c19d63e9ef188e59e7bfa92c04efd3"}, "2": {"node_id": "9321d863-a52a-48a9-992c-c408dfa4f38e", "node_type": null, "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e3e1961de7d4c5fdd8082cca1873db40981403f5f7cdbf60ee0e00a43ebc56d"}}, "hash": "27ec41f3659e0cdbba4f8ac1a4934b452c593371e436a9d537082862a1bd1fca", "text": "and this was thought to correlate with \ntheir\tmuscarinic \tantagonist \tactions.\tAlso,\tsome\tsecond-\ngeneration drugs possess muscarinic antagonist properties (e.g. olanzapine). In the striatum, dopaminergic nerve \n7Early antipsychotic drugs (e.g. chlorpromazine) had actions at various \nreceptors but also had unwanted side effects that resulted from activity \nat other receptors. Towards the end of the 20th century, drug development, not just of antipsychotic drugs, was focused largely on developing agents with a single action with the intention of reducing unwanted side effects. This philosophy drove the search for selective \nD\n4 receptor antagonists, which proved ineffective. What is now \napparent is that drugs with selected multiple actions (e.g. a combination \nof\tD2 antagonism and 5-HT 2A antagonism) may have a better \ntherapeutic profile.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6370, "end_char_idx": 7701, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ad9dc5b2-25f7-4602-aa62-6f242d560dea": {"__data__": {"id_": "ad9dc5b2-25f7-4602-aa62-6f242d560dea", "embedding": null, "metadata": {"page_label": "606", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2efe2c16-367f-43b5-9630-e6a39097e363", "node_type": null, "metadata": {"page_label": "606", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4371fcd41bc44902d3fb196377db6e4584e12290dcf85d71ef2091b065da4a03"}, "3": {"node_id": "3d29483e-98c6-4dd1-b4d0-47221ba4abef", "node_type": null, "metadata": {"page_label": "606", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51af46fdf351feb75399cb4986da79d8a886506223bef2b86e824c6c74747de2"}}, "hash": "dd1bac80fad6cb0cef0be07e4e81c8a6e1e47e72f47f0a6ca450801b323b7900", "text": "47 SECTION 4 NERVOUS SYSTEM\n600dissociating compound, a brief surge of dopamine can effectively \novercome the block by competition (see Ch. 2), whereas with a slowly \ndissociating compound, the level of block takes a long time to respond \nto the presence of endogenous dopamine, and is in practice non-\ncompetitive. \tAdverse \tmotor \teffects \tmay \tbe \tavoided \tif \tfractional \t\nreceptor occupation by the antagonist falls during physiological surges \nof\tdopamine. \tAn \textension \tof \tthis \tidea \tis \tthat \tperhaps \ta \tlittle \tD2 \nreceptor activation may be beneficial. This could be produced, for \nexample, \tby \tdrugs \tthat \tare \tD2 partial agonists (e.g. aripiprazole) in \ncontrast to simple antagonists. It is thought that partial agonists reduce \nD2 hyperactivation in the mesolimbic pathway, thus alleviating positive \nsymptoms \tof\tschizophrenia, \tbut\tprovide\tenough\tD2 receptor stimula -\ntion in the mesocortical pathway to prevent negative symptoms, and in the nigrostriatal pathway to lower the incidence of extrapyramidal \nside effects.\nAntipsychotic-induced motor \ndisturbances \n\u2022\tMajor\tproblem \tof \tantipsychotic \tdrug \ttreatment.\n\u2022\tTwo\tmain \ttypes \tof \tdisturbance \toccur:\n\u2013 acute, reversible dystonias and Parkinson-like \nsymptoms (indeed, antipsychotic drugs generally \nworsen Parkinson\u2019s disease and block the actions of drugs used to treat the disorder);\n\u2013 slowly developing tardive dyskinesia, often \nirreversible.\n\u2022\tAcute\tsymptoms \tcomprise \tinvoluntary \tmovements, \t\ntremor and rigidity, and are probably the direct \nconsequence \tof \tblock \tof \tnigrostriatal \tdopamine \t\nreceptors.\n\u2022\tTardive\tdyskinesia \tcomprises \tmainly \tinvoluntary \t\nmovements of the face and limbs, appearing after \nmonths\tor \tyears \tof \tantipsychotic \ttreatment. \tIt \tmay \tbe \t\nassociated with proliferation of dopamine receptors in the corpus striatum. Treatment is generally unsuccessful.\n\u2022\tIncidence \tof \tacute \tdystonias \tand \ttardive \tdyskinesia \tis \t\nless with newer, second-generation antipsychotics, and particularly low with clozapine, aripiprazole and \nzotepine.02000080160240320400Serum prolactin concentration\n(ng/mL)Chlorpromazine\n(mg/day)Injection of fluphenazine\ndecanoate (225 mg)\n180 150 120 90 60 30 0\nDays\nFig. 47.2 Effects of antipsychotic drugs on prolactin \nsecretion in a schizophrenic patient. \tWhen\tdaily \tdosage \twith \t\nchlorpromazine \twas \treplaced \twith \ta \tdepot \tinjection \tof \t\nfluphenazine, the plasma prolactin initally dropped, because of \nthe delay in absorption, and then returned to a high level. (From \nMeltzer,\tH.Y. \tet \tal., \t1978. \tIn: \tLipton \tet \tal. \t(Eds). \t\nPsychopharmacology: \tA \tGeneration \tin \tProgress. \tRaven \tPress, \t\nNew\tYork.)\nENDOCRINE EFFECTS\nDopamine, \treleased \tin \tthe \tmedian \teminence \tby \tneurons \t\nof the tuberohypophyseal pathway (see Chs 34 and 40), \nacts\tphysiologically \tvia \tD2 receptors to inhibit prolactin \nsecretion. \tBlocking \tD2 receptors by antipsychotic drugs", "start_char_idx": 0, "end_char_idx": 2929, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3d29483e-98c6-4dd1-b4d0-47221ba4abef": {"__data__": {"id_": "3d29483e-98c6-4dd1-b4d0-47221ba4abef", "embedding": null, "metadata": {"page_label": "606", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2efe2c16-367f-43b5-9630-e6a39097e363", "node_type": null, "metadata": {"page_label": "606", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4371fcd41bc44902d3fb196377db6e4584e12290dcf85d71ef2091b065da4a03"}, "2": {"node_id": "ad9dc5b2-25f7-4602-aa62-6f242d560dea", "node_type": null, "metadata": {"page_label": "606", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd1bac80fad6cb0cef0be07e4e81c8a6e1e47e72f47f0a6ca450801b323b7900"}}, "hash": "51af46fdf351feb75399cb4986da79d8a886506223bef2b86e824c6c74747de2", "text": "can \ntherefore \tincrease\tthe\tplasma\tprolactin \tconcentration \t(Fig.\t\n47.2), resulting in breast swelling, pain and lactation (known \nas \u2018galactorrhoea\u2019), which can occur in men as well as in \nwomen.\tAs \tcan \tbe \tseen \tfrom \tFig. \t47.2, \tthe \teffect \tis \tmain -\ntained during chronic antipsychotic administration, without \nany habituation. Other less pronounced endocrine changes \nhave also been reported, including a decrease of growth hormone secretion, but these, unlike the prolactin response, \nare believed to be relatively unimportant clinically. Because \nof\tits\tD2 receptor partial agonist action aripiprazole, unlike \nother antipsychotic drugs, reduces prolactin secretion.\nOTHER UNWANTED EFFECTS\nMost antipsychotic drugs block a variety of receptors, \nparticularly acetylcholine (muscarinic), histamine (H 1), noradrenaline (\u03b1 ) and 5-HT receptors (see Table 47.1). This \ngives rise to a wide range of side effects.\nThey can produce sexual dysfunction \u2013 decreased libido \nand decreased arousal as well as erection and ejaculation difficulties in men \u2013 through block of dopamine, muscarinic and \u03b1\n1 receptors.\nDrowsiness \tand \tsedation, \twhich \ttend \tto \tdecrease \twith \t\ncontinued use, occur with many antipsychotic drugs. \nAntihistamine \t(H 1) activity is a property of some pheno -\nthiazine antipsychotics (e.g. chlorpromazine and methotri -\nmeprazine ) and contributes to their sedative and antiemetic \nproperties (see Ch. 31), but not to their antipsychotic action.\nWhile block of muscarinic receptors produces a variety \nof peripheral effects, including blurring of vision and increased intraocular pressure, dry mouth and eyes, con-stipation and urinary retention (see Ch. 14), it may, however, \nalso be beneficial in relation to extrapyramidal side effects \n(see p. 599).\nBlocking \u03b1 adrenoceptors causes orthostatic hypotension \n(see Ch. 15) but does not seem to be important for their \nantipsychotic action.\nWeight gain is a common and troublesome side effect. \nIncreased risk of diabetes and cardiovascular disease occurs with several second-generation antipsychotic drugs. These \neffects are probably related to their antagonist actions at H\n1, 5-HT and muscarinic receptors.\nAntipsychotic \tdrugs \tcan \tprolong \tthe \tQT \tinterval \tin \tthe \t\nheart (see Ch. 22) giving rise to arrhythmia and risk of \nsudden\tdeath\t(Jolly\tet\tal., \t 2009). \t As \t such, \t a \t range \t of \t baseline\t\nmeasurements are usually recommended prior to starting mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2930, "end_char_idx": 5860, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "86d817f1-93ad-4c07-aa29-1a911daff4c5": {"__data__": {"id_": "86d817f1-93ad-4c07-aa29-1a911daff4c5", "embedding": null, "metadata": {"page_label": "607", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d99252a-62df-4cb3-b0f1-43ad935ac179", "node_type": null, "metadata": {"page_label": "607", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "712fc70558943ec6c824b3ac7d27368af886267095900b86cf6f7ae2954f2746"}, "3": {"node_id": "2afca5f0-da4a-4cc7-8644-18a89394b048", "node_type": null, "metadata": {"page_label": "607", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e99914aca0a58e9836d5e2f8573daf020ffd578ef8f738a27259c8c963fd2b53"}}, "hash": "49853fc975121e54f74fc7ff95f32e732a6f2de96e93e12290a921eabbe3393d", "text": "47 ANTipSYchOTic dRUgS\n601This is made even more difficult by the fact that at least \n40% of schizophrenic patients fail to take drugs as pre -\nscribed. It is remarkably fortunate that the acute toxicity of antipsychotic drugs is slight, given the unpredictability of the clinical response.\nThe plasma half-life of most antipsychotic drugs is 15\u201330 h, \nclearance depending entirely on hepatic transformation by a combination of oxidative and conjugative reactions.\nMost antipsychotic drugs can be given orally or in urgent \nsituations by intramuscular injection. Slow-release (depot) preparations of many are available, in which the active \ndrug is esterified with heptanoic or decanoic acid and \ndissolved in oil. Given as an intramuscular injection, the drug acts for 2\u20134 weeks, but initially may produce acute \nside effects. These preparations are widely used to minimise \ncompliance problems.\nFUTURE DEVELOPMENTS\nThe cognition enhancer modafinil (see Ch. 49) may be useful \nin treating the cognitive deficit in schizophrenia.\nPreclinical and clinical studies have provided encouraging \nevidence \tthat\torthosteric \tand\tallosteric \tagonists\tof\tmGluR 2 \nand\tmGluR 3 metabotropic glutamate receptors (see Ch. 39) \nare effective in the treatment of the positive symptoms of \nschizophrenia. \tParadoxically, \tactivating \tpresynaptic \tmGluR 2 \nand\tmGluR 3 autoreceptors reduces glutamate release but \nthis\tmay\tresult\tin\ta\tcompensatory \tup-regulation \tof\tNMDA\t\nreceptors \twhich\tmight\tbe\tbeneficial. \tmGluR 2 receptors form \nheteromers with 5-HT 2A receptors (see Ch. 3) with altered \nintracellular signalling properties and targeting the dimer \nmay\toffer \thope \tfor \tfuture \tdrug \tdevelopment. \tAgonists \tat \t\npostsynaptic \tmGluR 5 receptors may improve positive and \nnegative \tsymptoms \tas \twell \tas \tcognitive \tfunction. \tmGluR 5 \nreceptors \t are\t closely \tas sociated \t with \t NMDA \t receptors \t and\t\nactivation \tof\tmGluR 5\tmay\tenhance\tNMDA\treceptor\tfunction\t\nby\tincreasing \tNMDA \treceptor \tphosphorylation.\nA\tnumber \tof \tcurrent \tantipsychotic \tdrugs \thave, \tamong \t\ntheir myriad of actions, 5-HT 6 and 5-HT 7 receptor antagonist \nproperties; more specific antagonists at these receptors are antipsychotic drugs; these include weight, blood pressure, blood glucose, and electrocardiogram.\nVarious idiosyncratic and hypersensitivity reactions can \noccur, the most important being the following:\n\u2022\tJaundice, which occurs with older phenothiazines such \nas chlorpromazine. The jaundice is usually mild, associated with elevated serum alkaline phosphatase \nactivity (an \u2018obstructive\u2019 pattern), and disappears \nquickly when the drug is stopped or substituted by a chemically unrelated antipsychotic.\n\u2022\tLeukopenia and agranulocytosis are rare but potentially \nfatal, and occur in the first few weeks of treatment. \nThe incidence of leukopenia (usually reversible) is less than 1 in 10,000 for most antipsychotic drugs, but \nmuch higher (1%\u20132%) with clozapine, whose use \ntherefore requires regular monitoring of blood cell counts. Provided the drug is stopped at the first sign \nof leukopenia or anaemia, the effect is reversible. \nOlanzapine appears to be free of this disadvantage.\n\u2022\tUrticarial skin reactions are common but usually mild. \nExcessive sensitivity to ultraviolet light may also", "start_char_idx": 0, "end_char_idx": 3289, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2afca5f0-da4a-4cc7-8644-18a89394b048": {"__data__": {"id_": "2afca5f0-da4a-4cc7-8644-18a89394b048", "embedding": null, "metadata": {"page_label": "607", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d99252a-62df-4cb3-b0f1-43ad935ac179", "node_type": null, "metadata": {"page_label": "607", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "712fc70558943ec6c824b3ac7d27368af886267095900b86cf6f7ae2954f2746"}, "2": {"node_id": "86d817f1-93ad-4c07-aa29-1a911daff4c5", "node_type": null, "metadata": {"page_label": "607", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "49853fc975121e54f74fc7ff95f32e732a6f2de96e93e12290a921eabbe3393d"}}, "hash": "e99914aca0a58e9836d5e2f8573daf020ffd578ef8f738a27259c8c963fd2b53", "text": "reactions are common but usually mild. \nExcessive sensitivity to ultraviolet light may also occur.\n\u2022\tAntipsychotic malignant syndrome is a rare but serious \ncomplication similar to the malignant hyperthermia \nsyndrome seen with certain anaesthetics (see Ch. 42). \nMuscle rigidity is accompanied by a rapid rise in body temperature and mental confusion. It is usually \nreversible, but death from renal or cardiovascular \nfailure occurs in 10%\u201320% of cases.\nUnwanted effects of antipsychotic \ndrugs \n\u2022\tImportant \tside \teffects \tcommon \tto \tmany \tdrugs \tare:\n\u2013 motor disturbances (see Antipsychotic-induced \nmotor disturbances box);\n\u2013 endocrine disturbances (increased prolactin release);\n\u2013 these are secondary to dopamine receptor block.\n\u2022\tSedation, \thypotension \tand \tweight \tgain \tare \tcommon.\n\u2022\tObstructive \tjaundice \tsometimes \toccurs \twith \t\nphenothiazines.\n\u2022\tOther\tside \teffects \t(dry \tmouth, \tblurred \tvision, \t\nhypotension, etc.) are due to block of other receptors, \nparticularly muscarinic receptors and \u03b1 adrenoceptors.\n\u2022\tSome\tantipsychotic \tdrugs \tcause \tagranulocytosis \tas \ta\t\nrare\tand\tserious \tidiosyncratic \treaction. \tWith \tclozapine, \nleukopenia \tis \tcommon \tand \trequires \troutine \tmonitoring.\n\u2022\tAntipsychotic \tmalignant \tsyndrome \tis \ta \trare \tbut \t\npotentially dangerous idiosyncratic reaction.02004006008001000\n10 5\nDose (mg/kg twice daily)Peak plasma concentration (ng/mL)No responseSide\neffects\nFig. 47.3 Individual variation in the relation between dose \nand plasma concentration of chlorpromazine in a group of \nschizophrenic patients. \t(Data\tfrom \tCurry, \tS.H. \tet \tal., \t1970. \t\nArch.\tGen. \tPsychiatry \t22, \t289.)\nPHARMACOKINETIC ASPECTS\nChlorpromazine, in common with other phenothiazines, \nis\terratically \tabsorbed \tafter \toral \tadministration. \tFig. \t47.3 \t\nshows the wide range of variation of the peak plasma \nconcentration \t as\t a \tfu nction \t of \t dosage \tin\t 14 \tpat ients. \t Among\t\nfour patients treated at the high dosage level of 6\u20138 mg/\nkg, the variation in peak plasma concentration was nearly \n90-fold; two showed marked side effects, one was well \ncontrolled and one showed no clinical response.\nThe relationship between the plasma concentration and \nthe clinical effect of antipsychotic drugs is highly variable, and the dosage has to be adjusted on a trial-and-error basis. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3198, "end_char_idx": 5997, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5307a524-20e4-4bed-b02a-7b228230e4aa": {"__data__": {"id_": "5307a524-20e4-4bed-b02a-7b228230e4aa", "embedding": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2820bc6e-883e-4448-84da-9c2bcb123de1", "node_type": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d4a6f9d82fb1facb5a7c4c4393ac9dcbc60e5517169872f3930b6c1839638bf"}, "3": {"node_id": "3d6cc7f4-4031-4e79-b6af-02a8b7477ae3", "node_type": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3982226c3cbc58185c970af1794b49f01c68555ba7f6aa2fdea83c25b6e4960"}}, "hash": "b4d8d988f518f1f39befc3f90f46f263cda9744b8e1d2c0834a67cdd7e993558", "text": "47 SECTION 4 NERVOUS SYSTEM\n602being investigated; their ability to produce cognitive \nimprovement is controversial.\nAlso\tin\tvarious\tstages\tof\tdevelopment\t are\tinhibitors\t of\t\nphosphodiesterase\t(PDE10),\t \u03b17 nicotinic receptor agonists, \nhistamine H 3 antagonists and 5-HT 6 antagonists. Selective \nagonist action at M 1 muscarinic receptors (either orthosteric Clinical uses of antipsychotic drugs \n\u2022\tBehavioural emergencies (e.g. violent patients with a \nrange of psychopathologies including mania , toxic \ndelirium , schizophrenia \tand\tothers):\n\u2013\tAntipsychotic\t drugs\t(e.g.\t chlorpromazine , \nhaloperidol , olanzapine , risperidone ) can rapidly \ncontrol hyperactive psychotic states.\n\u2013 Note that the intramuscular dose is lower than the oral \ndose of the same drug because of presystemic \nmetabolism.\n\u2022\tSchizophrenia :\n\u2013\tMany\tchronic\tschizophrenic\t patients\tare\ttreated\twith\t\nfirst-generation\t antipsychotic\t drugs.\tDepot\tinjections\t\n(e.g. flupentixol decanoate ) may be useful for \nmaintenance treatment when compliance with oral \ntreatment is a problem\u2013 Flupentixol has antidepressant properties distinct \nfrom its antipsychotic action.\n\u2013 Newer antipsychotic drugs (e.g. amisulpride , \nolanzapine , risperidone ) are used if extrapyramidal \nsymptoms are troublesome or if symptom control is \ninadequate.\n\u2013 Clozapine can cause agranulocytosis but is \ndistinctively effective against \u2018negative\u2019 features of \nschizophrenia.\t It\tis\treserved\tfor\tpatients\twhose\t\ncondition\t remains\tinadequately\t controlled\t despite\t\nprevious use of two or more antipsychotic drugs, of \nwhich at least one is a second-generation drug. Blood \ncount is monitored weekly for the first 18 weeks, and \nless\tfrequently\t thereafter.\nor allosteric) has significant potential for cognition enhance -\nment\tin\tboth\tschizophrenia\t and\tAlzheimer\u2019s\t disease,\t but\t\nto date drug development has been hampered by a lack \nof selectivity across muscarinic receptor subtypes (e.g. \nxanomeline is an M 1 and M 4 agonist and M 5 antagonist) \nthat gives rise to significant unwanted effects.\nREFERENCES AND FURTHER READING\nGeneral reading\nGross,\tG.,\tGeyer,\tM.A.,\t2012.\tCurrent\t antipsychotics.\t Handb.\tExp.\t\nPharmacology 212, Springer Verlag. ( Multi-authored volume containing \nindividual chapters on current drugs )\nStahl,\tS.M.,\t2008.\tAntipsychotics\t and\tMood\tStabilizers,\t third\ted.\t\nCambridge University Press, New York. ( Highly readable, yet detailed, \ndescription of the biology of schizophrenia and of the mechanisms of action of \nthe drugs used to treat the disorder )\nPathogenesis of schizophrenia\nAyhan,\tY.,\tMcFarland,\t R.,\tPletnikov,\t M.V.,\t2016.\tAnimal\tmodels\tof\t\ngene-environment interaction in schizophrenia: a dimensional \nperspective. Prog. Neurobiol. 136, 1\u201327. ( Don\u2019t be deceived by the title, \nthis paper contains a wealth of information from human studies of \ngene-environment interactions in the development of schizophrenia )\nRipke,\tS.,\tNeale,\tB.M.,\tCorvin,\tA.,\tet\tal.,\t2014.\tBiological\t insights\t from\t\n108 schizophrenia-associated genetic loci. Nature 511, 421\u2013427. \n(Extensive study on the human genetic basis of schizophrenia", "start_char_idx": 0, "end_char_idx": 3120, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3d6cc7f4-4031-4e79-b6af-02a8b7477ae3": {"__data__": {"id_": "3d6cc7f4-4031-4e79-b6af-02a8b7477ae3", "embedding": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2820bc6e-883e-4448-84da-9c2bcb123de1", "node_type": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d4a6f9d82fb1facb5a7c4c4393ac9dcbc60e5517169872f3930b6c1839638bf"}, "2": {"node_id": "5307a524-20e4-4bed-b02a-7b228230e4aa", "node_type": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4d8d988f518f1f39befc3f90f46f263cda9744b8e1d2c0834a67cdd7e993558"}, "3": {"node_id": "b6de8128-51c0-4015-a9cf-cf9274120170", "node_type": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "544c0a416395fa54abc4f03409955c0d18e204fe7d602ef7c5d18aac9ff9fcce"}}, "hash": "b3982226c3cbc58185c970af1794b49f01c68555ba7f6aa2fdea83c25b6e4960", "text": "421\u2013427. \n(Extensive study on the human genetic basis of schizophrenia )\nSekar,\tA.,\tBialas,\tA.R.,\tde\tRivera,\tH.,\tet\tal.,\t2016.\tSchizophrenia\t risk\t\nfrom complex variation of complement component 4. Nature 530, \n177\u2013183. ( Major gene-wide association study (GWAS) demonstrating the \nimportance of compliment component 4 in schizophrenia )\nPergola, G., Selvaggi, P., Trizio, S., et al., 2015. The role of the thalamus \nin schizophrenia from a neuroimaging perspective. Neurosci. \nBiobehav.\t Rev.\t54,\t57\u201375.\nvan\tHaren,\tN.E.,\tHulshoff\t Pol,\tH.E.,\tSchnack,\t H.G.,\tet\tal.,\t2007.\tFocal\t\ngray matter changes in schizophrenia across the course of the illness: \na 5-year follow-up study. Neuropsychopharmacology 32, 2057\u20132066.\nDopamine, glutamate and 5-hydroxytryptamine\nCoyle,\tJ.T.,\t2017.\tSchizophrenia:\t basic\tand\tclinical.\tAdv.\tNeurobiol.\t 15,\t\n255\u2013280. ( Discusses the importance of NMDA receptor hypofunction in \nschizophrenia )\nLaruelle,\t M.,\tAbi-Dargham,\t A.,\tGil,\tR.,\tet\tal.,\t1999.\tIncreased\t dopamine\t\ntransmission in schizophrenia: relationship to illness phases. Biol. \nPsychiatry 46, 56\u201372. ( The first direct evidence for increased dopamine \nfunction as a cause of symptoms in schizophrenia )\nAnimal models\nPratt,\tJ.,\tWinchester,\t C.,\tDawson,\t N.,\tMorris,\tB.,\t2012.\t \nAdvancing\t schizophrenia\t drug\tdiscovery:\t optimizing\t rodent\t models\tto\tbridge\tthe\ttranslational\t gap.\tNat.\tRev.\tDrug\tDiscov.\t11,\t\n560\u2013579.\nSigurdsson, T., 2015. Neural circuit dysfunction in schizophrenia: \ninsights from animal models. Neuroscience 321, 42\u201365.\nAntipsychotic drugs\nJolly,\tK.,\tGammage,\t M.D.,\tCheng,\tK.K.,\tBradburn,\t P.,\tBanting,\t M.V.,\t\nLangman, M.J., 2009. Sudden death in patients receiving drugs \ntending\tto\tprolong\t the\tQT\tinterval.\t Br.\tJ.\tClin.\tPharmacol.\t 68,\t743\u2013751.\t\n(Compares the risk of sudden death in patients receiving various \nantipsychotic and antidepressant therapies )\nKapur,\tS.,\tSeeman,\t P.,\t2001.\tDoes\tfast\tdissociation\t from\tthe\tdopamine\t\nD2\treceptor\t explain\tthe\taction\tof\tatypical\t antipsychotics?\t A\tnew\t\nhypothesis.\t Am.\tJ.\tPsychiatry\t 158,\t360\u2013369.\t (Suggests that differences in \ndissociation rates, rather than receptor selectivity profiles, may account for \ndiffering tendency of drugs to cause motor side effects )\nKapur,\tS.,\tArenovich,\t T.,\tAgid,\tO.,\tet\tal.,\t2005.\tEvidence\t for\tonset\tof\t\nantipsychotic\t effects\twithin\tthe\tfirst\t24\thours\tof\ttreatment.\t Am.\tJ.\t\nPsychiatry 162, 939\u2013946.\nLeucht,\tS.,\tBusch,\tR.,\tHamann,\t J.,\tKissling,\t W.,\tKane,\tJ.M.,\t2005.\t\nEarly-onset hypothesis of antipsychotic drug action: a hypothesis \ntested,", "start_char_idx": 3060, "end_char_idx": 5613, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b6de8128-51c0-4015-a9cf-cf9274120170": {"__data__": {"id_": "b6de8128-51c0-4015-a9cf-cf9274120170", "embedding": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2820bc6e-883e-4448-84da-9c2bcb123de1", "node_type": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d4a6f9d82fb1facb5a7c4c4393ac9dcbc60e5517169872f3930b6c1839638bf"}, "2": {"node_id": "3d6cc7f4-4031-4e79-b6af-02a8b7477ae3", "node_type": null, "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3982226c3cbc58185c970af1794b49f01c68555ba7f6aa2fdea83c25b6e4960"}}, "hash": "544c0a416395fa54abc4f03409955c0d18e204fe7d602ef7c5d18aac9ff9fcce", "text": "hypothesis of antipsychotic drug action: a hypothesis \ntested, confirmed and extended. Biol. Psychiatry 57, 1543\u20131549.\nLeucht,\tS.,\tCipriani,\t A.,\tSpineli,\tL.,\tet\tal.,\t2013.\tComparative\t efficacy\t\nand tolerability of 15 antipsychotic drugs in schizophrenia: a \nmultiple-treatments meta-analysis. Lancet 382, 951\u2013962. ( Meta-analysis \nof major antipsychotic drugs examining their efficacy and side effects )\nExtrapyramidal side effects\nCasey,\tD.E.,\t1995.\tTardive\t dyskinesia:\t pathophysiology.\t In:\tBloom,\tF.E.,\t\nKupfer,\tD.J.\t(Eds.),\tPsychopharmacology:\t A\tFourth\tGeneration\t of\t\nProgress.\t Raven\tPress,\tNew\tYork.\nKlawans, H.L., Tanner, C.M., Goetz, C.G., 1988. Epidemiology \nand\tpathophysiology\t of\ttardive\tdyskinesias.\t Adv.\tNeurol.\t49,\t \n185\u2013197.\nLieberman,\t J.A.,\tStroup,\tT.S.,\t2011.\tThe\tNIMH-CATIE\t Schizophrenia\t\nStudy:\twhat\tdid\twe\tlearn?\tAm.\tJ.\tPsychiatry\t 68,\t770\u2013775.\t (A \ncomprehensive review of the effectiveness and side effect profiles of \nantipsychotic drugs )\nPisani,\tA.,\tBernardi,\t G.,\tDing,\tJ.,\tSurmeier,\t D.J.,\t2007.\tRe-emergence\t of\t\nstriatal cholinergic interneurons in movement disorders. Trends \nNeurosci. 30, 545\u2013553.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5612, "end_char_idx": 7230, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1cf3a3eb-7da6-4888-9be6-1e53416118ef": {"__data__": {"id_": "1cf3a3eb-7da6-4888-9be6-1e53416118ef", "embedding": null, "metadata": {"page_label": "609", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7f2566f8-5879-4729-8b8b-de2ca19f31b3", "node_type": null, "metadata": {"page_label": "609", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a015cc2efa5314e0659663333b2678f81f7e6792e4b6eb77a35bfa374de591f"}, "3": {"node_id": "fb6b9d1c-a0b1-41f6-9b1b-848d313ef342", "node_type": null, "metadata": {"page_label": "609", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a3764c481b5cf2ffa395e02e4d189eaa6b66b64c4a09f1b6109b5fa56e63b667"}}, "hash": "e7371a45ed8e968f3f0abb9912c4cbe39063d76d0e92ecdc944b77589a9d1ddc", "text": "603\nOVERVIEW\nDepression is an extremely common psychiatric condi -\ntion, about which a variety of neurochemical theories \nexist, and for which a corresponding variety of dif -\nferent types of drug are used in treatment. It is a \nfield in which therapeutic empiricism has led the way, \nwith mechanistic understanding tending to lag behind, \npart of the problem being that it has been difficult to develop animal models that replicate the charac -\nteristics that define the human condition. In this chapter, we discuss the current understanding of the nature of the disorder, and describe the major drugs \nthat are used to treat it.\nTHE NATURE OF DEPRESSION\nDepression is the most common of the affective disorders \n(defined as disorders of mood); it may range from a very \nmild condition, bordering on normality, to severe (psychotic) \ndepression accompanied by hallucinations and delusions. Worldwide, depression is a major cause of disability and \npremature death. In addition to the significant suicide risk, \ndepressed individuals are more likely to die from other causes, such as heart disease or cancer. Depression is a heterogeneous \ndisorder, with patients presenting with one or more core \nsymptoms, and depression is often associated with other psychiatric conditions, including anxiety, eating disorders, schizophrenia, Parkinson\u2019s disease and drug addiction.\nThe symptoms of depression include emotional and \nbiological components. Emotional symptoms include:\n\u2022\tlow\tmood, \texcessive \trumination \tof \tnegative \tthought, \t\nmisery, apathy and pessimism\n\u2022\tlow\tself-esteem: \tfeelings \tof \tguilt, \tinadequacy \tand \t\nugliness\n\u2022\tindecisiveness, \tloss \tof \tmotivation\n\u2022\tanhedonia, \tloss \tof \treward\nBiological symptoms include:\n\u2022\tretardation \tof \tthought \tand \taction\n\u2022\tloss\tof \tlibido\n\u2022\tsleep\tdisturbance \tand \tloss \tof \tappetite\nThere are two distinct types of depressive syndrome, namely unipolar depression, in which the mood changes are always \nin the same direction, and bipolar disorder , in which depres -\nsion alternates with mania. Mania is in most respects exactly \nthe opposite, with excessive exuberance, enthusiasm and \nself-confidence, accompanied by impulsive actions, these \nsigns often being combined with irritability, impatience and aggression, and sometimes with grandiose delusions \nof the Napoleonic kind. As with depression, the mood and \nactions are inappropriate to the circumstances.Unipolar depression is commonly (about 75% of cases) \nnon-familial, clearly associated with stressful life events, and \nusually accompanied by symptoms of anxiety and agitation; \nthis type is sometimes termed reactive depression . Other cases \n(about 25%, sometimes termed endogenous depression ) show \na familial pattern, unrelated to obvious external stresses and with a somewhat different symptomatology. This distinction is made clinically, but there is little evidence that antide -\npressant drugs show significant selectivity between these conditions. After an inauspicious start, population genetic studies have begun to identify novel genetic variations associated with depression (see Mullins & Lewis, 2017), but \ndepression is probably a polygenic disorder where a number \nof individual genetic variations as well as environmental factors contribute to the disorder.\nDepression cannot be attributed to altered neuronal \nactivity within a single brain region; rather, the circuitry linking different parts of the brain may be affected. Brain-\nimaging studies have indicated that the prefrontal cortex, \namygdala and hippocampus may all be involved in different components of these disorders.\nBipolar disorder, which usually appears in early adult \nlife, is less common and results in oscillating depression and mania over a period of a few weeks. It can be difficult to \ndifferentiate between mild bipolar disorder and unipolar \ndepression. Also, bipolar manic", "start_char_idx": 0, "end_char_idx": 3882, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fb6b9d1c-a0b1-41f6-9b1b-848d313ef342": {"__data__": {"id_": "fb6b9d1c-a0b1-41f6-9b1b-848d313ef342", "embedding": null, "metadata": {"page_label": "609", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7f2566f8-5879-4729-8b8b-de2ca19f31b3", "node_type": null, "metadata": {"page_label": "609", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a015cc2efa5314e0659663333b2678f81f7e6792e4b6eb77a35bfa374de591f"}, "2": {"node_id": "1cf3a3eb-7da6-4888-9be6-1e53416118ef", "node_type": null, "metadata": {"page_label": "609", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e7371a45ed8e968f3f0abb9912c4cbe39063d76d0e92ecdc944b77589a9d1ddc"}}, "hash": "a3764c481b5cf2ffa395e02e4d189eaa6b66b64c4a09f1b6109b5fa56e63b667", "text": "between mild bipolar disorder and unipolar \ndepression. Also, bipolar manic episodes can be confused with episodes of schizophrenic psychosis (see Ch. 47). There \nis a strong hereditary tendency, and gene-wide association \nstudies (GWAS) have identified a number of new susceptibil -\nity genes that may have an effect on the brain functions \naffected in bipolar disorder (Soronen et al., 2010) but to \ndate these have not impacted on drug therapy of the \ndisorder.\nTHEORIES OF DEPRESSION\nSeveral theories have been proposed to explain the causes \nof depression. None fully explain all of the observations \nand evidence of pathological changes that occur with \ndepression. Here we summarise the main theories as they relate to the mechanisms of action of current drug therapies. \nA more comprehensive review and analysis is provided \nby Harmer et al. (2017).\nTHE MONOAMINE THEORY\nThe monoamine theory of depression, first proposed by \nSchildkraut in 1965, states that depression is caused by a \nfunctional deficit of the monoamine transmitters, noradrena -\nline and 5-hydroxytryptamine (5-HT) at certain sites in the \nbrain, while mania results from a functional excess.\nThe monoamine hypothesis grew originally out of asso -\nciations between the clinical effects of various drugs that cause or alleviate symptoms of depression and their known \nneurochemical effects on monoaminergic transmission in the Antidepressant drugs 48 NERVOUS SYSTEM SECTION 4\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3807, "end_char_idx": 5742, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f5c04ba9-a958-403e-b267-5b813a9e8e75": {"__data__": {"id_": "f5c04ba9-a958-403e-b267-5b813a9e8e75", "embedding": null, "metadata": {"page_label": "610", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1d3c8648-f910-44ef-b8f3-2b919f7a297c", "node_type": null, "metadata": {"page_label": "610", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b30eb767af97255ac1e4bd12cf16ecb218cb18df6fabf1faec82df136cb34df4"}, "3": {"node_id": "c3ba185f-02ea-4e45-9089-4e0ec8b71f29", "node_type": null, "metadata": {"page_label": "610", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b653de96a68060910cd7b82ab9b2bf4fe6f31fead698aa52d8354ae6883ce39"}}, "hash": "3b9f7132b43b03e18289259e00e252f123348b61e2a3591778e6e7ec6780d6b7", "text": "48 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n604bias. Studies comparing healthy volunteers and depressed \npatients suggest that antidepressant drugs may indeed exert \nacute effects on the way information is processed (cognitive \nprocessing), leading to a positive effect on emotional behaviour. For example, when presented with a series of \npictures showing facial expression of different levels of \nhappiness or sadness, depressed patients consider fewer of the faces to be happy than do healthy volunteers pre -\nsented with the same faces (Fig. 48.1). But after a single dose of an antidepressant the depressed patients now consider more of the same faces to be happy (i.e. their perception of what is happy [positive] has changed). It is \nsuggested that depressed patients may not initially be \nconsciously aware of the effect the antidepressant drug has produced, but over time, and with prolonged drug \nadministration, they subconsciously recalibrate what they \nperceive to be happy and thus their mood improves.\nNEUROENDOCRINE MECHANISMS\nVarious attempts have been made to test for a functional deficit of monoamine pathways in depression. Hypothalamic \nneurons controlling pituitary function receive noradrenergic \nand 5-HT inputs, which control the discharge of these cells. Hypothalamic cells release corticotrophin-releasing factor \n(CRF; also known as corticotrophin-releasing hormone ), which \nstimulates pituitary cells to secrete adrenocorticotrophic \nhormone (ACTH), leading in turn to cortisol secretion (Ch. \n34). The plasma cortisol concentration is usually high in \ndepressed patients. Other hormones in plasma are also affected, for example, growth hormone concentration is reduced and prolactin is increased. While these changes \nare consistent with deficiencies in monoamine transmission, \nthey are not specific to depressive syndromes.\nCRF is widely distributed in the brain and has behavioural \neffects that are distinct from its endocrine functions. Injected into the brain of experimental animals, CRF mimics some aspects of depression in humans, such as diminished activity, \nloss of appetite and increased signs of anxiety. Furthermore, \nCRF concentrations in the brain and cerebrospinal fluid of depressed patients are increased. Therefore CRF hyperfunc -\ntion, as well as monoamine hypofunction, may be associated with depression. Raised CRF levels are associated with brain. This pharmacological evidence, which is summarised in Table 48.1, gives general support to the monoamine \nhypothesis, although there are several anomalies. Attempts \nto obtain more direct evidence, by studying monoamine metabolism in depressed patients or by measuring changes \nin the number of monoamine receptors in postmortem \nbrain\ttissue, \thave \ttended \tto \tgive \tinconsistent \tand \tequivo -\ncal results, and the interpretation of these studies is often problematic, because the changes described are not specific \nto depression. Similarly, investigation by functional tests of the activity of known monoaminergic pathways (e.g. \nthose controlling pituitary hormone release) in depressed \npatients\thave \talso \tgiven \tequivocal \tresults.\nThe pharmacological evidence does not enable a clear \ndistinction to be drawn between the noradrenaline and 5-HT theories of depression. Clinically, it seems that inhibi -\ntors of noradrenaline reuptake and of 5-HT reuptake are \nequally\teffective \tas \tantidepressants, \talthough \tindividual \t\npatients may respond better to one or the other.\nOther evidence in support of the monoamine theory is \nthat agents known to block noradrenaline or 5-HT synthesis \nconsistently lower mood and reverse the therapeutic effects of antidepressant drugs that act selectively on these two \ntransmitter systems (see Table 48.1).\nAny theory of depression has to take account of the fact \nthat the direct", "start_char_idx": 0, "end_char_idx": 3820, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c3ba185f-02ea-4e45-9089-4e0ec8b71f29": {"__data__": {"id_": "c3ba185f-02ea-4e45-9089-4e0ec8b71f29", "embedding": null, "metadata": {"page_label": "610", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1d3c8648-f910-44ef-b8f3-2b919f7a297c", "node_type": null, "metadata": {"page_label": "610", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b30eb767af97255ac1e4bd12cf16ecb218cb18df6fabf1faec82df136cb34df4"}, "2": {"node_id": "f5c04ba9-a958-403e-b267-5b813a9e8e75", "node_type": null, "metadata": {"page_label": "610", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3b9f7132b43b03e18289259e00e252f123348b61e2a3591778e6e7ec6780d6b7"}}, "hash": "4b653de96a68060910cd7b82ab9b2bf4fe6f31fead698aa52d8354ae6883ce39", "text": "theory of depression has to take account of the fact \nthat the direct neurochemical effects of most antidepressant drugs appear very rapidly (minutes to hours), whereas their \nantidepressant effects take weeks to develop. A similar situ -\nation exists in relation to antipsychotic drugs (Ch. 47) and some anxiolytic drugs (Ch. 45). To explain this phenomenon, \nproponents of the monoamine theory have suggested that \nsecondary, adaptive changes in the brain (see p. 611), rather than the primary drug effect, are responsible for the clinical \nimprovement and that the drug-induced effects on brain \nmonoamine systems result in longer-term trophic effects, the time course of which is paralleled by mood changes.\nNEGATIVE AFFECTIVE BIAS\nPeople suffering from depression tend to perceive events in a negative way, focus on negative information and recall \ninformation in a negative rather than positive manner \u2013 a \nbehaviour pattern that psychologists term negative affective Table 48.1 Pharmacological evidence supporting the monoamine hypothesis of depression\nDrug(s) Principal action Effect in depressed patients\nTricyclic antidepressants Block noradrenaline and 5-HT reuptake Mood \u2191\nMAO inhibitors Increase stores of noradrenaline and 5-HT Mood \u2191\nReserpine Inhibits noradrenaline and 5-HT storage Mood \u2193\n\u03b1-Methyltyrosine Inhibits noradrenaline synthesis Mood \u2193 (calming of manic patients)\nMethyldopa Inhibits noradrenaline synthesis Mood \u2193\nElectroconvulsive therapy? Increases central nervous system \nresponses to noradrenaline and 5-HTMood \u2191\nTryptophan (5-hydroxytryptophan)Increases 5-HT synthesis Mood ? \u2191 in some studies\nTryptophan depletion Decreases brain 5-HT synthesis Induces relapse in SSRI-treated patients\n5-HT, 5-hydroxytryptamine; MAO, monoamine oxidase; SSRI, selective serotonin reuptake inhibitor.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3751, "end_char_idx": 6047, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1c1e3e3a-f8b8-489b-962d-7d48823eadb2": {"__data__": {"id_": "1c1e3e3a-f8b8-489b-962d-7d48823eadb2", "embedding": null, "metadata": {"page_label": "611", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f5a0ce43-750b-4daf-abe4-3b94a7320f12", "node_type": null, "metadata": {"page_label": "611", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48dd0d2c7358ba2fe4bdc5cbcc35906cb5381fb5d05fdd829d9cd07e216774ff"}, "3": {"node_id": "947d176e-6d0c-4c55-b790-48f0bcedf665", "node_type": null, "metadata": {"page_label": "611", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "04e20e173a91225922a850e77fad46e043f9568a3ea09a8544c486a2ae3fd384"}}, "hash": "5e64039b96e15af85f18f04a2e63a82a77b4e584e0c8c2e762645e2087440565", "text": "48 ANTidEpRESSANT dRUgS\n605of different kinds act by inhibiting or actually reversing this \nloss by stimulating neurogenesis.1 This surprising idea is \nsupported by various lines of evidence:\n\u2022\tBrain\timaging \tand \tpostmortem \tstudies \tshow \t\nventricular enlargement as well as shrinkage of the hippocampus and prefrontal cortex of depressed \npatients, with loss of neurons and glia. Functional \nimaging reveals reduced neuronal activity in these regions.\n\u2022\tIn\tanimals, \tthe \tsame \teffect \tis \tproduced \tby \tchronic \t\nstress of various kinds, or by administration of glucocorticoids, mimicking the increased cortisol \nsecretion in human depression. Excessive \nglucocorticoid secretion in humans (Cushing\u2019s syndrome; see Ch. 34) often causes depression.\n\u2022\tIn\texperimental \tanimals, \tantidepressant \tdrugs, \tor \t\nother treatments such as electroconvulsions (see later section on Brain Stimulation Therapies), promote \nneurogenesis in these regions, and (as in humans) \nrestore functional activity. Preventing hippocampal neurogenesis prevents the behavioural effects of \nantidepressants in rats.stress and, in many cases, depression is preceded by periods \nof chronic stress. However, CRF\n1 receptor antagonists have \nso far not proven to be effective antidepressant drugs.\nTROPHIC EFFECTS AND NEUROPLASTICITY\nIt has been suggested that lowered levels of brain-derived neurotrophic factor (BDNF) or malfunction of its receptor, \nTrkB, plays a significant role in the pathology of depression. \nDepressive behaviour is often associated with a reduction in BDNF expression and treatment with antidepressants \nelevates BDNF levels. Glycogen synthase kinase 3 (GSK3 \u03b2) \nhas been implicated in the pathogenesis of depression \nfollowing its identification as a target of the mood stabiliser \nlithium (see p. 620).\nChanges in glutamatergic neurotransmission may also \nbe involved in depression. Sufferers from depression have \nbeen shown to have elevated cortical levels of glutamate. \nAntidepressant treatment may reduce glutamate release \nand depress NMDA receptor function. Indeed ketamine, an NMDA antagonist, has antidepressant activity (see p. \n618). The effects of antidepressants on activity-induced \nlong-term potentiation (LTP; see Ch. 39) at hippocampal glutamatergic synapses is complex \u2013 both depression and \nfacilitation have been observed and may occur rapidly after \nantidepressant administration.\nAnother view (see Racagni & Popoli, 2008) is that major \ndepression is associated with neuronal loss in the hippocam -\npus and prefrontal cortex, and that antidepressant therapies B\n50\n45\n40\n35\n30Depressed patients,\nplaceboDepressed patients,\nplaceboControl subjects,\nplacebo\nRecognition of happinessRecognition of happiness\nDepressed patients,\nreboxetine50\n45\n40\n35\n30\nA\nFig. 48.1 Recognition of happy facial expressions by depressed patients. (A) An illustrative sample of sad and happy facial \nexpressions. (B) When presented with an array of faces, such as those in (A), depressed patients considered fewer faces to be happy than \ndid control subjects. After an acute dose of reboxetine, depressed patients considered more of the facial expressions to be happy. (Faces in panel [A] are reprinted from the P1vital Oxford Emotional Test Battery, P1vital Products Ltd. Data in panel [B] are adapted from Harmer \net al., 2009. Am. J. Psychiatry. 166:1178\u20131184.)\n1Neurogenesis (see Ch. 41) \u2013 the formation of new", "start_char_idx": 0, "end_char_idx": 3417, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "947d176e-6d0c-4c55-b790-48f0bcedf665": {"__data__": {"id_": "947d176e-6d0c-4c55-b790-48f0bcedf665", "embedding": null, "metadata": {"page_label": "611", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f5a0ce43-750b-4daf-abe4-3b94a7320f12", "node_type": null, "metadata": {"page_label": "611", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48dd0d2c7358ba2fe4bdc5cbcc35906cb5381fb5d05fdd829d9cd07e216774ff"}, "2": {"node_id": "1c1e3e3a-f8b8-489b-962d-7d48823eadb2", "node_type": null, "metadata": {"page_label": "611", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e64039b96e15af85f18f04a2e63a82a77b4e584e0c8c2e762645e2087440565"}}, "hash": "04e20e173a91225922a850e77fad46e043f9568a3ea09a8544c486a2ae3fd384", "text": "(see Ch. 41) \u2013 the formation of new neurons from stem \ncell precursors \u2013 occurs to a significant degree in the adult \nhippocampus, and possibly elsewhere in the brain, contradicting the old \ndogma that it occurs only during brain development.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3382, "end_char_idx": 4103, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "03375adb-39cd-449c-b601-a5c4b1e5b6d7": {"__data__": {"id_": "03375adb-39cd-449c-b601-a5c4b1e5b6d7", "embedding": null, "metadata": {"page_label": "612", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a7d782e9-35d0-4e51-bdfa-82fc22962e26", "node_type": null, "metadata": {"page_label": "612", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6345cad2eed9247f9b058673ac57665a1a1090ba1dfeafc71f6b6c5b78fd3d21"}, "3": {"node_id": "bcc12182-6b8b-4ae8-956b-e8f653e4a651", "node_type": null, "metadata": {"page_label": "612", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d2b767ea4525fc7e81e5fd1c2ee9ef2267d1f2449084a56f319a21c3660c5e11"}}, "hash": "e0fda51bd38ed856b62e67af44989a135acfb77b2e5900b5c206e0ba6b049761", "text": "48 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n606ANTIDEPRESSANT DRUGS\nTYPES OF ANTIDEPRESSANT DRUG\nAntidepressant drugs fall into the following categories.\nInhibitors of monoamine uptake\n\u2022\tSelective \tserotonin \t(5-HT) \treuptake \tinhibitors \t \n(SSRIs) (e.g. fluoxetine, fluvoxamine, \nparoxetine, sertraline, citalopram, escitalopram, \nvilazodone).\n\u2022\tClassic \ttricyclic \tantidepressants \t(TCAs) \t(e.g. \t\nimipramine, desipramine, amitriptyline, \nnortriptyline, clomipramine). These vary in their \nactivity and selectivity with respect to inhibition of \nnoradrenaline and 5-HT reuptake.\n\u2022\tNewer, \tmixed \t5-HT \tand \tnoradrenaline \treuptake \t\ninhibitors (e.g. venlafaxine [somewhat selective for 5-HT, although less so than SSRIs], desvenlafaxine, \nduloxetine).\n\u2022\tNoradrenaline \treuptake \tinhibitors \t(e.g. \treboxetine, \natomoxetine, bupropion).\n\u2022\tThe\therbal \tpreparation \tSt \tJohn\u2019s \twort, \tthe \tmain \tactive \t\ningredient of which is hyperforin: it has similar \nclinical efficacy to most of the prescribed \u2022\t5-HT\tand \tnoradrenaline, \twhose \tactions \tare \tenhanced \t\nby many antidepressants, promote neurogenesis, probably through activation of 5-HT\n1A receptors and \n\u03b12 adrenoceptors, respectively. This effect may be \nmediated by BDNF.\n\u2022\tExercise \thas \tbeen \tshown \tto \tpromote \tneurogenesis \tin \t\nanimals and to be effective in some patients with mild to moderate depression.\nFig. 48.2 summarises the possible mechanisms involved. It should be stressed that these hypotheses are far from \nproven, but the diagram emphasises the way in which the \nfield has moved on since the formulation of the monoamine hypothesis, suggesting a range of possible targets for the next generation of antidepressant drugs.\n2DEPRESSIVE\nSYMPTOMSSTRESS\nCRF\nreleaseHypothalamus\nACTH\nreleasePituitary\nCortisol\nreleaseAdrenal cortex\nHippocampus\nPrefrontal cortexDetrimental gene\ntranscription responseBeneficial gene\ntranscription responseNMDA\nreceptorsGlutamate\nNeural apoptosis Neurogenesis\u03b1 2\nreceptorsNA 5-HT\n TrkB\nreceptorsBDNF\n5HT1A\nreceptors\nSIGNAL TRANSDUCTION PATHWAYS\nFig. 48.2 Simplified diagram showing mechanisms believed to be involved in the pathophysiology of depression. The \nmain prodepressive pathways involve the hypothalamic\u2013pituitary\u2013adrenal axis, which is activated by stress and in turn enhances \nthe excitotoxic action of glutamate, mediated by NMDA receptors (see Ch. 39), and switches on the expression of genes that promote \nneural apoptosis in the hippocampus and prefrontal cortex. The antidepressive pathways involve the monoamines noradrenaline (NA) \nand 5-hydroxytryptamine (5-HT), which act on G protein\u2013coupled receptors, and the brain-derived neurotrophic factor (BDNF), which \nacts on a kinase-linked receptor (TrkB), switching on genes that protect neurons against apoptosis and also promote neurogenesis. \nACTH, adrenocorticotrophic hormone; CRF, corticotrophin-releasing factor. (For further detail, see Charney & Manji (2004) Science STKE \n2004, re5.)\n2Cynics may feel that", "start_char_idx": 0, "end_char_idx": 2979, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bcc12182-6b8b-4ae8-956b-e8f653e4a651": {"__data__": {"id_": "bcc12182-6b8b-4ae8-956b-e8f653e4a651", "embedding": null, "metadata": {"page_label": "612", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a7d782e9-35d0-4e51-bdfa-82fc22962e26", "node_type": null, "metadata": {"page_label": "612", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6345cad2eed9247f9b058673ac57665a1a1090ba1dfeafc71f6b6c5b78fd3d21"}, "2": {"node_id": "03375adb-39cd-449c-b601-a5c4b1e5b6d7", "node_type": null, "metadata": {"page_label": "612", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e0fda51bd38ed856b62e67af44989a135acfb77b2e5900b5c206e0ba6b049761"}}, "hash": "d2b767ea4525fc7e81e5fd1c2ee9ef2267d1f2449084a56f319a21c3660c5e11", "text": "(2004) Science STKE \n2004, re5.)\n2Cynics may feel that these mechanisms, in which glutamate, \nneurotrophic factors, monoamines and steroids all interact to control \nneuronal death, survival and plasticity, are being invoked just as \nenthusiastically to account for almost every neurological and psychiatric disorder that you can think of, from stroke and Parkinson\u2019s disease to \nschizophrenia. \u2018Are we missing something,\u2019 they may feel, \u2018or are all \nthese diseases basically the same? If so, why are their effects so different? Is this just a scientific bandwagon, or does this mechanistic convergence \npoint to some fundamental principles of neural organisation?\u2019 We do not \nhave the answers, of course, but it is a field worth watching.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2925, "end_char_idx": 4142, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8748c053-0b80-4fcf-894f-edad10851b33": {"__data__": {"id_": "8748c053-0b80-4fcf-894f-edad10851b33", "embedding": null, "metadata": {"page_label": "613", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5a136616-d1d9-4e89-a6ec-7713242f1fb5", "node_type": null, "metadata": {"page_label": "613", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "357e4be7ed5eb5658654ba300f54739b9b7311ef8b9f5da2273a404ef312e2b8"}, "3": {"node_id": "a30cee4b-a964-4792-9078-11de0a260c56", "node_type": null, "metadata": {"page_label": "613", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dc50a5bb714a239bf291b1e53e9d74f120c548f654a7bbcf183bcffccf7e0db0"}}, "hash": "4f96d1841c4787a73a2e60c6e633eebf87ac2f9000927740d00aba69a0bb3d25", "text": "48 ANTidEpRESSANT dRUgS\n607Miscellaneous agents\n\u2022\tKetamine is a non-competitive NMDA channel \nblocker.\nTable 48.2 summarises the main features of these types of \ndrug. Mention should also be made of electroconvulsive \ntherapy (ECT), electromagnetic therapy, deep brain stimula -\ntion and vagus stimulation, which are effective and usually \nact more rapidly than antidepressant drugs (see p. 619).\nTo some extent, the term \u2018antidepressant drug\u2019 is mislead -\ning, as many of these drugs are now also used to treat disorders other than depression. These include:\n\u2022\tneuropathic \tpain \t(e.g. \tamitriptyline, \tnortriptyline, \t\nduloxetine; Ch. 43)\n\u2022\tanxiety \tdisorders \t(e.g. \tSSRIs, \tvenlafaxine, \tduloxetine; \t\nCh. 45)\n\u2022\tfibromyalgia \t(e.g. \tduloxetine, \tvenlafaxine, \tSSRIs, \t\nTCAs; Ch. 43)\n\u2022\tbipolar \tdisorder \t(e.g. \tfluoxetine \tin \tconjunction \twith \t\nolanzapine; see later)\n\u2022\tsmoking \tcessation \t(e.g. \tbupropion; \tCh. \t50)\n\u2022\tattention \tdeficit/hyperactivity \tdisorder \t(e.g. \t\natomoxetine; Ch. 49)\nantidepressants. It is a weak monoamine uptake inhibitor but also has other actions.\n3\nMonoamine receptor antagonists\n\u2022\tDrugs \tsuch \tas \tmirtazapine, trazodone, mianserin are \nnon-selective and inhibit a range of amine receptors \nincluding \u03b12 adrenoceptors and 5-HT 2 receptors. They \nmay also have weak effects on monoamine uptake.\nMonoamine oxidase inhibitors (MAOIs)\n\u2022\tIrreversible, \tnon-competitive \tinhibitors \t(e.g. \t\nphenelzine, tranylcypromine), which are \nnon-selective with respect to the MAO-A and -B subtypes.\n\u2022\tReversible, \tMAO-A-selective \tinhibitors \t(e.g. \t\nmoclobemide).\nMelatonin receptor agonist\n\u2022\tAgomelatine is an agonist at MT 1 and MT 2 melatonin \nreceptors, and a weak 5-HT 2C antagonist.Theories of depression \n\u2022\tThe\tmonoamine \ttheory, \tfirst \tproposed \tin \t1965, \t\nsuggests that depression results from functionally \ndeficient\tmonoaminergic \t(noradrenaline \tand/or \t\n5-hydroxytryptamine) transmission in the central \nnervous system.\n\u2022\tThe\ttheory \tis \tbased \ton \tthe \tability \tof \tmost \t\nantidepressant drugs (tricyclic antidepressants and monoamine oxidase inhibitors) to facilitate monoaminergic transmission, and of drugs such as \nreserpine to cause depression.\n\u2022\tBiochemical \tstudies \ton \tdepressed \tpatients \tdo \tnot \t\nclearly support the monoamine hypothesis in its simple \nform.\n\u2022\tAlthough \tthe \tmonoamine \thypothesis \tin \tits \tsimple \tform \t\nis\tinsufficient \tas \tan \texplanation \tof \tdepression, \t\npharmacological manipulation of monoamine transmission remains the most successful therapeutic approach.\n\u2022\tThe\tnegative affective bias theory of depression \nsuggests that drugs may produce immediate behavioural changes but patients receiving the drugs \nneed time to become aware of the improvements in \ntheir mood.\n\u2022\tRecent\tevidence \tsuggests \tthat \tdepression \tmay \tbe \t\nassociated with neurodegeneration and reduced neurogenesis in the hippocampus.\n\u2022\tCurrent \tapproaches \tfocus \ton \tother", "start_char_idx": 0, "end_char_idx": 2922, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a30cee4b-a964-4792-9078-11de0a260c56": {"__data__": {"id_": "a30cee4b-a964-4792-9078-11de0a260c56", "embedding": null, "metadata": {"page_label": "613", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5a136616-d1d9-4e89-a6ec-7713242f1fb5", "node_type": null, "metadata": {"page_label": "613", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "357e4be7ed5eb5658654ba300f54739b9b7311ef8b9f5da2273a404ef312e2b8"}, "2": {"node_id": "8748c053-0b80-4fcf-894f-edad10851b33", "node_type": null, "metadata": {"page_label": "613", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f96d1841c4787a73a2e60c6e633eebf87ac2f9000927740d00aba69a0bb3d25"}}, "hash": "dc50a5bb714a239bf291b1e53e9d74f120c548f654a7bbcf183bcffccf7e0db0", "text": "in the hippocampus.\n\u2022\tCurrent \tapproaches \tfocus \ton \tother \tmediators, \tsignal \t\ntransduction pathways, growth factors, etc., but theories remain imprecise.\n3Although relatively free of acute side effects, hyperforin activates \ncytochrome P450, resulting in loss of efficacy (Ch. 10), with serious \nconsequences, \tof \tseveral \timportant \tdrugs, \tincluding \tciclosporine, \toral \t\ncontraceptives, some anti-HIV and anticancer drugs, and oral \nanticoagulants \u2013 underlining the principle that herbal remedies are not \ninherently safe, and must be used with the same degree of informed \ncaution as any other drug.Types of antidepressant drugs \n\u2022\tMain\ttypes \tare:\n\u2013 monoamine uptake inhibitors (tricyclic \nantidepressants, selective serotonin reuptake \ninhibitors, newer inhibitors of noradrenaline and 5-HT reuptake);\n\u2013 monoamine receptor antagonists;\n\u2013 monoamine oxidase (MAO) inhibitors.\n\u2022\tMonoamine \tuptake \tinhibitors \tact \tby \tinhibiting \tuptake \t\nof\tnoradrenaline \tand/or \t5-HT \tby \tmonoaminergic \tnerve \t\nterminals.\n\u2022\t\u03b12-Adrenoceptor antagonists can indirectly elevate \n5-HT release.\n\u2022\tMAO\tinhibitors \tinhibit \tone \tor \tboth \tforms \tof \tbrain \tMAO, \t\nthus increasing the cytosolic stores of noradrenaline and 5-HT in nerve terminals. Inhibition of type A MAO correlates with antidepressant activity. Most are \nnon-selective; moclobemide\n\tis\tspecific \tfor \tMAO-A.\n\u2022\tMost\tantidepressant \tdrugs \tappear \tto \ttake \tat \tleast \t2 \t\nweeks\tto\tproduce \tany \tperceived \tbeneficial \teffects.\n\u2022\tKetamine \t(not \tyet \tapproved \tas \tan \tantidepressant), \t\ngiven as a single intravenous dose, is reported to \nproduce a rapid response lasting for several days\nTESTING OF ANTIDEPRESSANT DRUGS\nANIMAL \u2003MODELS\nProgress in unravelling the neurochemical mechanisms is, \nas in so many areas of psychopharmacology, limited by \nthe lack of good animal models of the clinical condition. \nThere is no known animal condition corresponding to the inherited form of depression in humans. Procedures involv -\ning mild stress (e.g. the forced swim test, inescapable foot shock) produce behavioural states in animals (withdrawal from social interaction, loss of appetite, reduced motor \nactivity, etc.) that mimic aspects of human depression (see \nO\u2019Leary & Cryan, 2013). In such tests, current antidepressant mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2863, "end_char_idx": 5622, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f10b5deb-7587-4b20-af67-a60bf2bcbb02": {"__data__": {"id_": "f10b5deb-7587-4b20-af67-a60bf2bcbb02", "embedding": null, "metadata": {"page_label": "614", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4cdf9854-fb5e-4ec0-9bd1-752d12ec6643", "node_type": null, "metadata": {"page_label": "614", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a760dfba2c2a94c235ab4f973506d7e9e1d8006017a0c6d0e7a79ef60474c9d2"}}, "hash": "a760dfba2c2a94c235ab4f973506d7e9e1d8006017a0c6d0e7a79ef60474c9d2", "text": "48 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n608Table 48.2 Types of antidepressant drugs and their characteristics\nType and \nexamples Action(s) Unwanted effectsRisk of overdose Pharmacokinetics Notes\nMonoamine uptake inhibitors\n(1) SSRIsAll highly selective \nfor 5-HTNausea, diarrhoea, agitation, insomnia, anorgasmiaInhibit metabolism of other drugs, so risk of interactionsLow risk in overdose but must not be used in combination with MAO inhibitors\u2014 \u2014\nFluoxetine As above As above As above Long t\n1/2 (24\u201396 h) \u2014\nFluvoxamine As above As above As above t1/2 18\u201324 hLess nausea than with other SSRIs\nParoxetine As above As above As above t\n1/218\u201324 h Withdrawal reaction\nCitalopram As above As above As above t1/2 24\u201336 h \u2014\nEscitalopram As above As above As above t1/2 24\u201336 hActive S isomer of \ncitalopramFewer side effects\nSertraline As above As above As above t\n1/2 24\u201336 h \u2014\nVilazodoneAs above. Also has 5-HT\n1A receptor \npartial agonist activityAs above As above t\n1/2 25 h \u2014\nVortioxetineAs above. Also has partial agonist activity at 5-HT\n1A \nand 5-HT 1B \nreceptors and antagonist activity at 5-HT\n3A \nreceptors.As above As above t1/2 >60 h \u2014\n(2) Classical TCA group\naInhibition of NA and 5-HT reuptakeSedationAnticholinergic effects (dry mouth, constipation, blurred vision, urinary retention, etc.)Postural hypotensionSeizuresImpotenceInteraction with CNS depressants (especially alcohol, MAO inhibitors)Ventricular dysrhythmiasHigh risk in combination with CNS depressants\u2014\u2018First-generation\u2019 antidepressants, still very widely used, although newer compounds generally have fewer side effects and lower risk with overdose\nImipramineNon-selectiveConverted to desipramineAs above As above t\n1/2 4\u201318 h \u2014\nDesipramine NA selective As above As above t1/2 12\u201324 h \u2014\nAmitriptyline Non-selective As above As abovet1/2 12\u201324 h; \nconverted to nortriptylineWidely used, also for neuropathic pain (Ch. 43)\nNortriptyline NA selective (slight) As above As above Long t\n1/2 (24\u201396 h)Long duration, less sedative\nClomipramine Non-selective As above As above t\n1/2 18\u201324 hAlso used for anxiety disorders\naOther TCAs include dosulepin, doxepin, lofepramine, trimipramine.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2639, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "433a1465-f8a9-42b9-918f-fa18c8b0be46": {"__data__": {"id_": "433a1465-f8a9-42b9-918f-fa18c8b0be46", "embedding": null, "metadata": {"page_label": "615", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "df2004c2-5f6e-452b-ba4b-9b9103450cb5", "node_type": null, "metadata": {"page_label": "615", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0631ca65a4e7da5406500169c2a7f07631797659a6ce5bc6f749c833c9067b70"}, "3": {"node_id": "eecb9424-6a07-4c77-866e-f68c000a6880", "node_type": null, "metadata": {"page_label": "615", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61e9399ea0c596744941db0f3c5b8900687a30a13dbcab228c31f7d5635f2c40"}}, "hash": "f480b8c20c747ea66d79c50757974b7f66bd49e11c1df4e6bc22a5a27a11d532", "text": "48 ANTidEpRESSANT dRUgS\n609Table 48.2 Types of antidepressant drugs and their characteristics\u2014cont\u2019d\nType and \nexamples Action(s) Unwanted effectsRisk of overdose Pharmacokinetics Notes\n(3) Other 5-HT/NA uptake inhibitorsb\nVenlafaxineWeak non-selective \nNA/5-HT uptake inhibitorAlso, non-selective receptor-blocking effectsAs SSRIsWithdrawal effects common and troublesome if doses are missedSafe in overdoseShort t\n1/2 (~5 h)\nConverted to desvenlafaxine which inhibits NA uptakeClaimed to act more rapidly than other antidepressants, and to work better in \u2018treatment-resistant\u2019 patientsUsually classed as non-selective NA/5-HT uptake blocker, although in vitro data show selectivity for 5-HT\nDuloxetinePotent non-selective NA/5-HT uptake inhibitorNo action on monoamine receptorsFewer side effects than venlafaxineSedation, dizziness, nauseaSexual dysfunctionSee SSRIs above t\n1/2 ~14 hAlso used to treat urinary incontinence (see Ch. 30) and for anxiety disorders\nSt John\u2019s wort (active principle: hyperforin)Weak non-selective NA/5-HT uptake inhibitorAlso, non-selective receptor-blocking effectsFew side effects reportedRisk of drug interactions due to enhanced drug metabolism (e.g. loss of efficacy of ciclosporin, antidiabetic drugs, etc.)\u2014 t\n1/2 ~12 hFreely available as crude herbal preparationSimilar efficacy to other antidepressants, with fewer acute side effects but risk of serious drug interactions\n(4) NA-selective inhibitors\nBupropionSelective inhibitor \nof NA over 5-HT uptake but also inhibits dopamine uptakeConverted to active metabolites (e.g. radafaxine)Headache, dry mouth, agitation, insomniaSeizures at high dosest\n1/2 ~12 h\nPlasma half-life \n~20 hUsed in depression associated with anxietySlow-release formulation used to treat nicotine dependence (Ch. 50)\nReboxetineSelective NA uptake inhibitorDizzinessInsomniaAnticholinergic effectsSafe in overdose (low risk of cardiac dysrhythmia)t\n1/2 ~12 hLess effective than TCAsThe related drug atomoxetine now used mainly to treat ADHD (Ch. 49)\nMaprotilineSelective NA uptake inhibitorAs TCAs; no significant advantagesAs TCAs Long t\n1/2 ~40 hNo significant advantages over TCAs\nMonoamine receptor antagonists\nMirtazapineBlocks \u03b1\n2, 5-HT 2C \nand 5-HT 3 \nreceptorsDry mouth\nSedationWeight gainNo serious drug interactionst\n1/2 20\u201340 hClaimed to have faster onset of action than other antidepressants\nTrazodoneBlocks 5-HT\n2A and \n5-HT 2C receptors as \nwell as H 1 receptors\nWeak 5-HT uptake inhibitor (enhances NA/5-HT release)SedationHypotensionCardiac dysrhythmiasSafe in overdose t\n1/2 6\u201312 h Nefazodone is similar\nContinuedbOther\t5-HT/NA \tuptake \tinhibitors \tinclude \tmilnacipran \tand \tlevomilnacipran.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3062, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "eecb9424-6a07-4c77-866e-f68c000a6880": {"__data__": {"id_": "eecb9424-6a07-4c77-866e-f68c000a6880", "embedding": null, "metadata": {"page_label": "615", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "df2004c2-5f6e-452b-ba4b-9b9103450cb5", "node_type": null, "metadata": {"page_label": "615", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0631ca65a4e7da5406500169c2a7f07631797659a6ce5bc6f749c833c9067b70"}, "2": {"node_id": "433a1465-f8a9-42b9-918f-fa18c8b0be46", "node_type": null, "metadata": {"page_label": "615", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f480b8c20c747ea66d79c50757974b7f66bd49e11c1df4e6bc22a5a27a11d532"}}, "hash": "61e9399ea0c596744941db0f3c5b8900687a30a13dbcab228c31f7d5635f2c40", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3015, "end_char_idx": 3158, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ae34076b-a2ff-430a-8c8a-2761a624256d": {"__data__": {"id_": "ae34076b-a2ff-430a-8c8a-2761a624256d", "embedding": null, "metadata": {"page_label": "616", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7901cacf-47ed-4568-9920-9f3dfbe92689", "node_type": null, "metadata": {"page_label": "616", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e0984acac26c434ab555f11355795f2ead8dc12bc42ad9d98effaef6bfb65405"}}, "hash": "e0984acac26c434ab555f11355795f2ead8dc12bc42ad9d98effaef6bfb65405", "text": "48 SECTION 4 \u2003\u2003NERVOUS SYSTEM\n610Table 48.2 Types of antidepressant drugs and their characteristics\u2014cont\u2019d\nType and \nexamples Action(s) Unwanted effectsRisk of \noverdose Pharmacokinetics Notes\nMianserinBlocks \u03b11, \u03b12, \n5-HT 2A and H 1 \nreceptorsMilder \nantimuscarinic and \ncardiovascular \neffects than TCAs\nAgranulocytosis, \naplastic anaemia\u2014 t1/2 10\u201335 hBlood count advised in \nearly stages of use\nMAO inhibitorsInhibit MAO-A and/\nor MAO-B\nEarlier compounds \nhave long duration \nof action due to \ncovalent binding to \nenzyme\nPhenelzine Non-selective\u2018Cheese reaction\u2019 to \ntyramine-containing \nfoods (see text)\nAnticholinergic side \neffects\nHypotension\nInsomnia\nWeight gain\nLiver damage (rare)Many interactions \n(TCAs, opioids, \nsympathomimetic \ndrugs) \u2013 risk of \nsevere \nhypertension due \nto \u2018cheese \nreaction\u2019t1/2 1\u20132 h\nLong duration of \naction due to \nirreversible binding\u2014\nTranylcypromine Non-selective As phenelzine As phenelzinet1/2 1\u20132 h\nLong duration of \naction due to \nirreversible binding\u2014\nIsocarboxazid Non-selective As phenelzine As phenelzine Long t 1/2 ~36 h \u2014\nMoclobemideMAO-A selective\nShort actingNausea, insomnia, \nagitationInteractions less \nsevere than with \nother MAO \ninhibitors; no \n\u2018cheese reactions\u2019 \nreportedt1/2 1\u20132 hSafer alternative to \nearlier MAO inhibitors\nMelatonin agonist\nAgomelatineMT 1 and MT 2 \nreceptor agonist. \nWeak 5-HT 2C \nantagonistHeadache, dizziness, \ndrowsiness, fatigue, \nsleep disturbance, \nanxiety, nausea, GI \ndisturbances, \nsweatingLimited data \navailable at \npresentt1/2 1\u20132 hShould not be \ncombined with ethanol\nUsually taken once \ndaily before bed\nNMDA antagonist\nKetamineNMDA-channel \nblockerPsychotomimetic at \nhigher doses (see \nCh. 49)\nProlonged use of \nhigh doses can \ncause cystitisDeaths from \noverdose are raret1/2 2\u20134 h\nGiven \nintravenously.Rapid onset \nantidepressant action \nlasting for a few days \nafter single i.v. dose\nEffective in patients \nresistant to other \nantidepressants\nPotentially metabolites \nof ketamine are \nresponsible for the \nantidepressant effects\n5-HT, 5-hydroxytryptamine; ADHD,\tattention\tdeficit/hyperactivity\t disorder;\t CNS, central nervous system; GI, gastrointestinal; i.v., \nintravenous; MAO, monoamine oxidase; NA, noradrenaline; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2783, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "391b0fb3-949e-47f6-8ccd-3e4dee663829": {"__data__": {"id_": "391b0fb3-949e-47f6-8ccd-3e4dee663829", "embedding": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1e120836-3fed-48fd-bf36-e585e563e7ce", "node_type": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d169403bdf958961a09c9480b04fc0a7b8f60010a8a6ed491258952ed3a1def9"}, "3": {"node_id": "7bdcb91a-5f2a-4b7a-bd7e-b92c08e13259", "node_type": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d09f29214cd1375197ccdc68ce193d17a48033cb773738931a4942e4cf72204a"}}, "hash": "1e42ff646fea6c4b15fa00a091aae519f6b0bbf49d1b14c94646c49a2f3ed8d6", "text": "48 ANTidEpRESSANT dRUgS\n611(CNS) will reduce the negative feedback from released \nnoradrenaline and thus enhance further noradrenaline \nrelease (see Chs 15 and 38). In addition, \u03b12-adrenoceptor \nantagonists can indirectly enhance 5-HT release.\nThe effect of \u03b1 2-adrenoceptor antagonists on synaptic \nnoradrenaline and 5-HT levels would be rapid in onset and so these changes must somehow induce other, slower \nadaptive responses that give rise to the slowly developing antidepressant effects.\nGENE \u2003EXPRESSION \u2003AND \u2003NEUROGENESIS\nMore recently, interest has centred on intracellular signalling pathways, changes in gene expression and neurogenesis. \nMuch attention has been focused on how antidepressants \nmay activate the transcription factor, CREB, a cAMP response element-binding protein. The role of other transcription \nfactors, such as those of the Fos family and NF- \u03baB, have \nbeen less extensively studied. As described earlier, several \nantidepressant drugs appear to promote neurogenesis in the \nhippocampus, a mechanism that could account for the slow \ndevelopment of the therapeutic effect. The role of raised synaptic noradrenaline and 5-HT levels in inducing changes in gene expression and neurogenesis, and the mechanisms \ninvolved, await further elucidation.\nMONOAMINE UPTAKE INHIBITORS\nSELECTIVE \u20035-HYDROXYTRYPTAMINE \u2003UPTAKE \u2003INHIBITORS\nThese are the most commonly prescribed group of anti -\ndepressants. Examples include fluoxetine, fluvoxamine, \nparoxetine, citalopram, escitalopram and sertraline (see \nTable 48.2). As well as showing selectivity with respect to \n5-HT over noradrenaline uptake (Fig. 48.4), they are less \nlikely than TCAs to cause anticholinergic side effects and \nare less dangerous in overdose. In contrast to MAOIs, they do not cause \u2018cheese reactions\u2019. They are also used to treat \nanxiety disorders (see Ch. 45) and premature ejaculation. \nVortioxetine is a novel SSRI that also has partial agonist activity at 5-HT\n1A and 5-HT 1B receptors and is an antagonist \nat other 5-HT receptors including 5-HT 3A receptors.\nIndividual patients may respond more favourably to one \nSSRI than another. This may reflect other pharmacological properties of each individual drug as none is devoid of other actions. Fluoxetine has 5-HT\n2C antagonist activity, a \nproperty it shares with other non-SSRI antidepressants such \nas mirtazapine. Sertraline is a weak inhibitor of dopamine \nuptake. Escitalopram is the S isomer of racemic citalopram. \nIt lacks the antihistamine and CYP2D6 inhibitory properties of the R isomer.\nPharmacokinetic aspects\nThe SSRIs are well absorbed when given orally, and most \nhave plasma half-lives of 18\u201324 h (fluoxetine is longer \nacting: 24\u201396 h). Paroxetine and fluoxetine are not used in \ncombination with TCAs, whose hepatic metabolism they \ninhibit through an interaction with CYP2D6, for fear of \nincreasing TCA toxicity.\nUnwanted effects\nCommon side effects include nausea, anorexia, insomnia, \nloss of libido and failure of orgasm.4 Some of these unwanted drugs reverse the symptoms of depression. However, we \nneed new drugs to treat forms of depression that are resistant \nto\tcurrent\tdrugs\tand\tthus\tnew\tanimal\tmodels\tare\trequired. \t\nGenetically modified mice (e.g. knock-down of 5-HT, \nnoradrenaline and glutamate transporters, mutations or \nknock-down of 5-HT", "start_char_idx": 0, "end_char_idx": 3330, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7bdcb91a-5f2a-4b7a-bd7e-b92c08e13259": {"__data__": {"id_": "7bdcb91a-5f2a-4b7a-bd7e-b92c08e13259", "embedding": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1e120836-3fed-48fd-bf36-e585e563e7ce", "node_type": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d169403bdf958961a09c9480b04fc0a7b8f60010a8a6ed491258952ed3a1def9"}, "2": {"node_id": "391b0fb3-949e-47f6-8ccd-3e4dee663829", "node_type": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e42ff646fea6c4b15fa00a091aae519f6b0bbf49d1b14c94646c49a2f3ed8d6"}, "3": {"node_id": "49ada95d-aaed-4313-a2e3-8db3d0977f06", "node_type": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "397237c1c6631a701902b4857eafbbf512f301f614ecd1d679baf26a770c292a"}}, "hash": "d09f29214cd1375197ccdc68ce193d17a48033cb773738931a4942e4cf72204a", "text": "and glutamate transporters, mutations or \nknock-down of 5-HT receptors, etc.) have been extensively \nstudied to mimic various aspects of the disorder. However, a good animal model of drug-resistant depression has still \nto be developed (Willner & Belzung, 2015).\nTESTS \u2003ON \u2003HUMANS\nClinically, the effect of antidepressant drugs is usually \nmeasured by a subjective rating scale such as the Hamilton \nRating Scale or the Beck Depression Inventory. Clinical \ndepression takes many forms, and the symptoms vary between patients and over time. Quantitation is therefore \ndifficult, and the many clinical trials of antidepressants \nhave generally shown rather weak effects, after allowance \nfor\tquite\tlarge\tplacebo\tresponses. \tThere\tis\talso\ta\thigh\tdegree\t\nof individual variation, with 30%\u201340% of patients failing to show any improvement, possibly due to genetic factors \n(see later section on Clinical Effectiveness).\nMECHANISM OF ACTION OF \nANTIDEPRESSANT DRUGS\nCHRONIC \u2003ADAPTIVE \u2003CHANGES\nGiven the discrepancy between the fast onset of the neu -\nrochemical effects of most antidepressant drugs and the slow onset of their antidepressant effects, efforts have been \nmade to determine whether the therapeutic benefits arise from slow adaptive changes induced by chronic exposure \nto these drugs (Racagni & Popoli, 2008).\nThis approach led to the discovery that certain monoamine \nreceptors, in particular \u03b2\n1 and \u03b12 adrenoceptors, are con -\nsistently down-regulated following chronic antidepressant treatment and, in some cases, by ECT too. This can be \ndemonstrated in experimental animals as a reduction in the number of binding sites, as well as by a reduction in the \nfunctional response to agonists (e.g. stimulation of cAMP \nformation by \u03b2-adrenoceptor agonists). Receptor down-regulation probably also occurs in humans, because endo -\ncrine responses to clonidine , an \u03b1\n2-adrenoceptor agonist, are \nreduced by long-term antidepressant treatment. However, \nthe relevance of these findings to the antidepressant response \nis unclear. Loss of \u03b2 adrenoceptors as a factor in alleviating \ndepression does not fit comfortably with theory, because \n\u03b2-adrenoceptor antagonists are not antidepressant.\nOn acute administration, one would expect inhibition \nof 5-HT uptake (e.g. by SSRIs) to increase the level of 5-HT at the synapse by inhibiting reuptake into the nerve ter -\nminals. However, the increase in synaptic 5-HT levels has \nbeen observed to be less than expected. This is because increased activation of 5-HT\n1A receptors on the soma and \ndendrites of 5-HT-containing raphe neurons (Fig. 48.3A) \ninhibits these neurons and thus reduces 5-HT release, thus \ncancelling out to some extent the effect of inhibiting reuptake into the terminals. On prolonged drug treatment, the \nelevated level of 5-HT in the somatodendritic region \ndesensitises the 5-HT\n1A receptors, reducing their inhibitory \neffect on 5-HT release from the nerve terminals.\nNORADRENERGIC \u2003CONTROL \u2003OF \u20035-HT \u2003RELEASE\nBlock of presynaptic \u03b12 autoreceptors on noradrenergic \nnerve terminals throughout the central nervous system 4Thus, conversely, SSRIs can be used to treat premature ejaculation. \nDapoxetine has a short half-life and is taken 1\u20133 hours before sex.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3278, "end_char_idx": 6705, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "49ada95d-aaed-4313-a2e3-8db3d0977f06": {"__data__": {"id_": "49ada95d-aaed-4313-a2e3-8db3d0977f06", "embedding": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1e120836-3fed-48fd-bf36-e585e563e7ce", "node_type": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d169403bdf958961a09c9480b04fc0a7b8f60010a8a6ed491258952ed3a1def9"}, "2": {"node_id": "7bdcb91a-5f2a-4b7a-bd7e-b92c08e13259", "node_type": null, "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d09f29214cd1375197ccdc68ce193d17a48033cb773738931a4942e4cf72204a"}}, "hash": "397237c1c6631a701902b4857eafbbf512f301f614ecd1d679baf26a770c292a", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6711, "end_char_idx": 7046, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dfeb2f71-c017-4b57-8772-c8365f1c34b7": {"__data__": {"id_": "dfeb2f71-c017-4b57-8772-c8365f1c34b7", "embedding": null, "metadata": {"page_label": "618", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ad1eb29b-7bf6-4638-93de-c1bd04d73140", "node_type": null, "metadata": {"page_label": "618", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6325e22cb757ecabb983327ef4ed4df1aac67a663b7c5793d30276e63de5e1f4"}}, "hash": "6325e22cb757ecabb983327ef4ed4df1aac67a663b7c5793d30276e63de5e1f4", "text": "48 SECTION 4 \u2003\u2003NERVOUS SYSTEM\n612reflexes, hyperthermia and cardiovascular collapse, from \nwhich deaths have occurred.\nThere have been reports of increased aggression, and \noccasionally violence, in patients treated with fluoxetine, \nbut these have not been confirmed by controlled studies. \nThe use of SSRIs is not recommended for treating depression \nin children under 18, in whom efficacy is doubtful and \nadverse effects, including excitement, insomnia and aggres -\nsion in the first few weeks of treatment, may occur. The \npossibility of increased suicidal ideation is a concern in \nthis age group (see p. 619).effects result from the enhanced stimulation of postsynaptic \n5-HT receptors as a result of the drugs increasing the levels \nof extracellular 5-HT. This can be either stimulation of the \nwrong type of 5-HT receptor (e.g. 5-HT 2, 5-HT 3 and 5-HT 4 \nreceptors) or stimulation of the same receptor that gives \ntherapeutic benefit (e.g. postsynaptic 5-HT 1A receptors) but \nin the wrong brain region (i.e. enhanced stimulation of \n5-HT receptors can result in both therapeutic and adverse \nresponses).\nIn combination with MAOIs, SSRIs can cause a \u2018serotonin \nsyndrome\u2019 characterised by tremor, agitation, increased \nAbsence\nAcute 5-HT reuptake inhibition5-HT\n5-HTPostsynaptic\n5-HT receptors5-HT\n5-HT\n5-HT\n5-HT5-HT\n5-HT\nChronic 5-HT reuptake inhibition\n5-HT\n5-HT5-HT\n5-HT\n5-HT1A receptor\ndesensitised 5-HT1A receptor\n5-HT1B/D receptorA\nFig. 48.3 Control of 5-hydroxytryptamine (5-HT) release. (A) 5-HT release is controlled by the inhibitory action of 5-HT on \nsomatodendritic 5-HT 1A receptors. Acute inhibition of 5-HT reuptake results in increased extracellular levels of 5-HT but this increases \nsomatodendritic 5-HT 1A receptor-mediated inhibition, hence synaptic 5-HT levels do not rise as much as expected. 5-HT 1A receptors \neventually desensitise, resulting in reduced inhibition and thus greater 5-HT release. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2412, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9c2f936a-8b0c-4202-b1a2-47f099701f50": {"__data__": {"id_": "9c2f936a-8b0c-4202-b1a2-47f099701f50", "embedding": null, "metadata": {"page_label": "619", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7652755-7ba9-442d-bb56-d595adf3c0f3", "node_type": null, "metadata": {"page_label": "619", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "af363e2b362ba5df4b223863776adda8fb20d29a671c976753483ee3bc244942"}, "3": {"node_id": "e34cc61d-5d71-43b9-8ce8-cfbe98c45ecd", "node_type": null, "metadata": {"page_label": "619", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb9f039019238b82b13594aa587897df499aed10aaea8eb5b8553ebd3eefc554"}}, "hash": "365d72fbb59fc7c24bb7ded4ceb9c7188a949343947bd4f96b9a1637e227add6", "text": "48 ANTidEpRESSANT dRUgS\n613Despite the apparent advantages of 5-HT uptake inhibitors \nover TCAs in terms of side effects, the combined results \nof many trials show little overall difference in terms of \npatient acceptability (Cipriani et al., 2009).\nThey are relatively safe in overdose, compared with TCAs \n(see p. 619) but can prolong the cardiac QT interval, giving rise to ventricular arrhythmias (see Ch. 22) and risk of \nsudden\tdeath \t(Jolly \tet \tal., \t2009).\n5-HT uptake inhibitors are used in a variety of other \npsychiatric disorders, as well as in depression, including anxiety disorders and obsessive\u2013compulsive disorder (see \nCh. 45).\nTRICYCLIC \u2003ANTIDEPRESSANT \u2003DRUGS\nTCAs (imipramine, desipramine, amitriptyline, nortrip-\ntyline, clomipramine) are still widely used. They are, \nhowever, far from ideal in practice, and it was the need \nfor\tdrugs\tthat\tact\tmore\tquickly\tand\treliably,\tproduce\tfewer\t\nside effects and are less hazardous in overdose that led to the introduction of newer 5-HT reuptake inhibitors and \nother antidepressants.\nTCAs are closely related in structure to the phenothiazines \n(Ch. 47) and were initially synthesised (in 1949) as potential Absence\nNA\n5-HTNA\nNANA\nIn presence of \u03b12-adrenoceptor antagonist\nNA\n5-HTPostsynaptic\n5-HT receptorsNA\nNANA\n\u03b11 adrenoceptor\npresynaptic \u03b12 adrenoceptor\nantagonist bound \u03b12 adrenoceptorB\n(B) 5-HT release is controlled by both an excitatory action of noradrenaline (NA) on somatodendritic \u03b11 adrenoceptors \nand an inhibitory action on \u03b12 adrenoceptors on serotonergic nerve terminals. Block of \u03b12 adrenoceptors located on noradrenergic neurons \n(not shown) enhances noradrenaline release resulting in further excitation of serotonergic neurons, while block of \u03b12 adrenoceptors on \nserotonergic neurons removes presynaptic inhibition and thus 5-HT release is enhanced. Fig. 48.3, cont\u2019d\nSelective serotonin reuptake \ninhibitors (SSRIs) \n\u2022\tExamples \tinclude \tfluoxetine, fluvoxamine, \nparoxetine, sertraline, citalopram, escitalopram.\n\u2022\tAntidepressant \tactions \tare \tsimilar \tin \tefficacy \tand \ttime \t\ncourse to tricyclic antidepressants (TCAs).\n\u2022\tAcute\ttoxicity \t(especially \tcardiotoxicity) \tis \tless \tthan \tthat \t\nof monoamine oxidase inhibitors (MAOIs) or TCAs, so \noverdose risk is reduced.\n\u2022\tSide\teffects \tinclude \tnausea, \tinsomnia \tand \tsexual \t\ndysfunction. \tSSRIs \tare \tless \tsedating \tand \thave \tfewer \t\nantimuscarinic side effects than the older TCAs.\n\u2022\tNo\tfood \treactions, \tbut \tdangerous \t\u2018serotonin \treaction\u2019 \t\n(hyperthermia, muscle rigidity, cardiovascular collapse) can occur if given with MAOIs.\n\u2022\tThere\tis \tconcern \tabout \tthe \tuse \tof \tSSRIs \tin \tchildren \t\nand adolescents, due to reports of an increase in suicidal thoughts on starting treatment.\n\u2022\tAlso\tused \tfor \tsome \tother \tpsychiatric \tindications \t(e.g. \t\nanxiety and obsessive\u2013compulsive disorder).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2991, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e34cc61d-5d71-43b9-8ce8-cfbe98c45ecd": {"__data__": {"id_": "e34cc61d-5d71-43b9-8ce8-cfbe98c45ecd", "embedding": null, "metadata": {"page_label": "619", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7652755-7ba9-442d-bb56-d595adf3c0f3", "node_type": null, "metadata": {"page_label": "619", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "af363e2b362ba5df4b223863776adda8fb20d29a671c976753483ee3bc244942"}, "2": {"node_id": "9c2f936a-8b0c-4202-b1a2-47f099701f50", "node_type": null, "metadata": {"page_label": "619", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "365d72fbb59fc7c24bb7ded4ceb9c7188a949343947bd4f96b9a1637e227add6"}}, "hash": "fb9f039019238b82b13594aa587897df499aed10aaea8eb5b8553ebd3eefc554", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2944, "end_char_idx": 3327, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a4f93db8-1df1-49b5-aff9-e8e897dfcdd8": {"__data__": {"id_": "a4f93db8-1df1-49b5-aff9-e8e897dfcdd8", "embedding": null, "metadata": {"page_label": "620", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5f69c01-59be-41a8-a41a-3883ac1c321e", "node_type": null, "metadata": {"page_label": "620", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4eef3c7afe0d46ef1b73ae6e229a204903be2069759418d7e983c6733451e7bc"}, "3": {"node_id": "6946f9ff-8135-4fa6-98dc-4c5074f062c2", "node_type": null, "metadata": {"page_label": "620", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "76ae9d6ce350d24755708db5a33ceb0f4c38221cabe3db6c9b5644848f3053f0"}}, "hash": "f305e92450b317e655fd3b346bc51c3096d9366a1e35f83dcb264385d9a9153c", "text": "48 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n614also in depressed patients in the first few days of treatment, \nbut tend to wear off in 1\u20132 weeks as the antidepressant \neffect develops.\nTCAs produce a number of troublesome side effects, \nmainly due to interference with autonomic control.\nAnti-muscarinic effects include dry mouth, blurred vision, \nconstipation and urinary retention. These effects are strong \nwith amitriptyline and much weaker with desipramine. \nPostural hypotension occurs with TCAs. This may seem \nanomalous for drugs that enhance noradrenergic transmis -\nsion, and possibly results from an effect on adrenergic transmission in the medullary vasomotor centre. The other \ncommon side effect is sedation, and the long duration of \naction means that daytime performance is often affected by drowsiness and difficulty in concentrating.\nTCAs, particularly in overdose, may cause ventricular \ndysrhythmias associated with prolongation of the QT interval (see Ch. 22). Usual therapeutic doses of TCAs increase, \nslightly, but significantly, the risk of sudden cardiac death.\nInteractions with other drugs\nTCAs are particularly likely to cause adverse effects when \ngiven in conjunction with other drugs (see Ch. 58). They \nrely on hepatic metabolism by microsomal cytochrome P450 \n(CYP) enzymes for elimination, and this may be inhibited by competing drugs (e.g. antipsychotic drugs and some \nsteroids).\nTCAs potentiate the effects of alcohol and anaesthetic \nagents, for reasons that are not well understood, and deaths have occurred as a result of this, when severe respiratory \ndepression has followed a bout of drinking. TCAs also interfere with the action of various antihypertensive drugs \n(see\tCh.\t23), \twith \tpotentially \tdangerous \tconsequences, \tso \t\ntheir\tuse\tin\thypertensive \tpatients\trequires\tclose\tmonitoring.\nAcute toxicity\nTCAs are dangerous in overdose, and were at one time commonly used for suicide attempts, which was an impor -\ntant factor prompting the introduction of safer antidepres -\nsants. The main effects are on the CNS and the heart. The initial effect of TCA overdosage is to cause excitement and \ndelirium, which may be accompanied by convulsions. This \nis followed by coma and respiratory depression lasting for antipsychotic drugs. Several are tertiary amines and are \nquite\trapidly \tdemethylated \tin \tvivo \t(Fig. \t48.5) \tto \tthe \tcor-\nresponding secondary amines (e.g. imipramine to desip -\nramine, amitriptyline to nortriptyline), which are themselves active and may be administered as drugs in their own right. Other tricyclic derivatives with slightly modified \nbridge structures include doxepin. The pharmacological \ndifferences between these drugs are not very great and \nrelate mainly to their side effects, which are discussed later.\nSome TCAs are also used to treat neuropathic pain (see \nCh. 43).\nMechanism of action\nAs discussed previously, the main immediate effect of TCAs is to block the uptake of amines by nerve terminals, by com -\npetition for the binding site of the amine transporter (Ch. 15). Most TCAs inhibit noradrenaline and 5-HT uptake (see Fig. \n48.4) but have much less effect on dopamine uptake. It has \nbeen suggested that improvement of emotional symptoms \nreflects mainly an enhancement of 5-HT-mediated transmis -\nsion, whereas relief of biological symptoms results from \nfacilitation of noradrenergic transmission. Interpretation \nis made difficult by the fact that the major metabolites of TCAs have considerable pharmacological activity (in some cases greater than that of the parent drug) and often differ", "start_char_idx": 0, "end_char_idx": 3576, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6946f9ff-8135-4fa6-98dc-4c5074f062c2": {"__data__": {"id_": "6946f9ff-8135-4fa6-98dc-4c5074f062c2", "embedding": null, "metadata": {"page_label": "620", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5f69c01-59be-41a8-a41a-3883ac1c321e", "node_type": null, "metadata": {"page_label": "620", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4eef3c7afe0d46ef1b73ae6e229a204903be2069759418d7e983c6733451e7bc"}, "2": {"node_id": "a4f93db8-1df1-49b5-aff9-e8e897dfcdd8", "node_type": null, "metadata": {"page_label": "620", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f305e92450b317e655fd3b346bc51c3096d9366a1e35f83dcb264385d9a9153c"}}, "hash": "76ae9d6ce350d24755708db5a33ceb0f4c38221cabe3db6c9b5644848f3053f0", "text": "activity (in some cases greater than that of the parent drug) and often differ \nfrom\tthe\tparent\tdrug\tin\trespect\tof\ttheir\tnoradrenaline/5-HT \t\nselectivity (Table 48.3).\nIn addition to their effects on amine uptake, most TCAs \naffect other receptors, including muscarinic acetylcholine receptors, histamine receptors and 5-HT receptors. The antimuscarinic effects of TCAs are responsible for various \nside effects (see next section).\nUnwanted effects\nIn non-depressed human subjects, TCAs cause sedation, \nconfusion and motor incoordination. These effects occur 0.0010.010.11101001000\nCitalopramParoxetine\nFluvoxamineSertralineVenlafaxine\nFluoxetineClomipramineAmitriptylineMilnacipram\nImipramine\nDuloxetineNortriptylineProtriptylineDesipramine\nReboxetineMaprotiline\n5-HT selectiveNon-selectiveNA-selectiveRatio NA 5-HT uptake inhibition\nFig. 48.4 Selectivity of inhibition of noradrenaline (NA) and \n5-hydroxytryptamine (5-HT) uptake by various \nantidepressants. Table 48.3 Inhibition of neuronal noradrenaline (NA) \nand 5-hydroxytryptamine (5-HT) uptake by tricyclic antidepressants and their metabolites\nDrug/metaboliteNA \nuptake5-HT uptake\nImipramine +++ ++\nDesmethylimipramine (DMI)\n(also known as desipramine)++++ +\nHydroxy-DMI +++ \u2014\nClomipramine (CMI) ++ +++\nDesmethyl-CMI +++ +\nAmitriptyline (AMI) ++ ++\nNortriptyline (desmethyl-AMI) +++ ++\nHydroxynortriptyline ++ ++mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3498, "end_char_idx": 5353, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e8b777a0-8cf5-4894-8377-dfae081dcb31": {"__data__": {"id_": "e8b777a0-8cf5-4894-8377-dfae081dcb31", "embedding": null, "metadata": {"page_label": "621", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ecfd36e2-0e35-4c3a-8249-c02786406561", "node_type": null, "metadata": {"page_label": "621", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c712d6f0163613eb81ea0655daab483da72aba85a1ddc0f6e7b4b22f9b07ec2"}, "3": {"node_id": "6fa5609f-13d2-4abd-a46b-7d5645c95ce4", "node_type": null, "metadata": {"page_label": "621", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e42e5a0d62a6de0f9984ec094138163845231c8b6f5844f3b2cef32a22254030"}}, "hash": "d37f738ba92f544c85a5a64f709fd93be2a6544b66353d2933ae4ddb88319468", "text": "48 ANTidEpRESSANT dRUgS\n615some days. Atropine-like effects are pronounced, including \ndry mouth and skin, mydriasis and inhibition of gut and \nbladder. Anticholinesterase drugs have been used to counter \natropine-like effects but are no longer recommended. Cardiac dysrhythmias are common, and sudden death (rare) may \noccur from ventricular fibrillation.\nPharmacokinetic aspects\nTCAs are all rapidly absorbed when given orally and bind \nstrongly to plasma albumin, most being 90%\u201395% bound \nat therapeutic plasma concentrations. They also bind to \nextravascular tissues, which accounts for their generally \nvery\tlarge \tdistribution \tvolumes \t(usually \t10\u201350 \tL/kg; \tsee \t\nCh.\t9)\tand\tlow\trates\tof\telimination. \tExtravascular \tsequestra -\ntion, together with strong binding to plasma albumin, means \nthat haemodialysis is ineffective as a means of increasing \ndrug elimination.\nTCAs are metabolised in the liver by two main routes, \nN-demethylation and ring hydroxylation (see Fig. 48.5). Both the desmethyl and the hydroxylated metabolites commonly retain biological activity (Table 48.4). During \nprolonged treatment with TCAs, the plasma concentration \nof these metabolites is usually comparable to that of the parent drug, although there is wide variation between individuals. Inactivation of the drugs occurs by glucuronide \nconjugation of the hydroxylated metabolites, the glucuro -\nnides being excreted in the urine.\nThe overall half-times for elimination of TCAs are gener -\nally long, ranging from 10 to 20 h for imipramine and \ndesipramine to about 80 h for protriptyline . They are even N\nNN\nNNN\nNH\nH\nO\nOH OH OH\nGlucuronide Glucuronide2-Hydroxydesmethylimipramine 2-Hydroxyimipramine 2-Hydroxyiminodibenzyl\n*Hydroxylation catalysed by CYP2D6DesmethylimipramineImramine N-oxide Imipramine Iminodibenzyl\nCH2CH2CH2N(CH3)2CH3\nCH3 Demethylation\nHydroxylation*\nConjugationCH2CH2CH2N\nCH2CH2CH2NHCH3\nCH2CH2CH2N(CH3)2 CH2CH2CH2NHCH3Fig. 48.5 Metabolism of \nimipramine, which is typical of that \nof other tricyclic antidepressants. \n*The hydroxylating enzyme CYP2D6 is subject to genetic polymorphism, which may account for individual variation in response to tricyclic antidepressants (see Ch. 12). \nTable 48.4 Substrates and inhibitors for type A and type \nB monoamine oxidase\nType A Type B\nPreferred substratesNoradrenaline\n5-HydroxytryptaminePhenylethylamineBenzylamine\nNon-specific substratesDopamine\nTyramineDopamineTyramine\nSpecific inhibitorsClorgyline\nMoclobemideSelegiline\nNon-specific inhibitorsPargyline\nTranylcypromine\nIsocarboxazidPargylineTranylcypromineIsocarboxazid\nlonger in elderly patients. Therefore gradual accumulation \nis possible, leading to slowly developing side effects.\nSEROTONIN \u2003AND \u2003NORADRENALINE \u2003UPTAKE \u2003\nINHIBITORS \u2003(SNRIS)\nThese drugs are relatively non-selective for 5-HT and noradrenaline uptake. They include venlafaxine, desven-\nlafaxine and duloxetine (see Table 48.2).\nAs the dose of venlafaxine is increased, its efficacy also \nincreases, which", "start_char_idx": 0, "end_char_idx": 2994, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6fa5609f-13d2-4abd-a46b-7d5645c95ce4": {"__data__": {"id_": "6fa5609f-13d2-4abd-a46b-7d5645c95ce4", "embedding": null, "metadata": {"page_label": "621", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ecfd36e2-0e35-4c3a-8249-c02786406561", "node_type": null, "metadata": {"page_label": "621", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2c712d6f0163613eb81ea0655daab483da72aba85a1ddc0f6e7b4b22f9b07ec2"}, "2": {"node_id": "e8b777a0-8cf5-4894-8377-dfae081dcb31", "node_type": null, "metadata": {"page_label": "621", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d37f738ba92f544c85a5a64f709fd93be2a6544b66353d2933ae4ddb88319468"}}, "hash": "e42e5a0d62a6de0f9984ec094138163845231c8b6f5844f3b2cef32a22254030", "text": "dose of venlafaxine is increased, its efficacy also \nincreases, which has been interpreted as demonstrating that \nits weak action to inhibit noradrenaline reuptake may add mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2925, "end_char_idx": 3576, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "07c858f0-4a89-4b45-ab01-9d85da770778": {"__data__": {"id_": "07c858f0-4a89-4b45-ab01-9d85da770778", "embedding": null, "metadata": {"page_label": "622", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9d0495d1-80f5-4d6e-bd59-9b420170953c", "node_type": null, "metadata": {"page_label": "622", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ed65a1532226021f7d15ee543e6b7078710985a1262c7eacd660f359e601063"}, "3": {"node_id": "db8e1154-a5c3-4cdc-91bf-2f58ef938362", "node_type": null, "metadata": {"page_label": "622", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "90c71fd2ef78ded4ffedff9162ad2022cf29b05e0b732549f1c2f4a977ce1ed3"}}, "hash": "3ee221d693914606f4bbb6dde96d030569728d20ac8d9883546e4966778ea14c", "text": "48 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n616it will reduce unwanted effects mediated through these \nreceptors (e.g. sexual dysfunction and nausea) but leave \nintact stimulation of postsynaptic 5-HT 1A receptors. It also \nblocks histamine H 1 receptors, which may cause sedation. \nTrazodone combines 5-HT 2A and 5-HT 2C receptor antagonism \nwith 5-HT reuptake inhibition.\nMianserin , another \u03b12-adrenoceptor antagonist that also \nblocks H 1, 5-HT 2A and \u03b1 1 adrenoreceptors, can cause bone \nmarrow\tdepression, \trequiring \tregular \tblood \tcounts, \tso \tits \t\nuse has declined in recent years.\nMONOAMINE OXIDASE INHIBITORS\nMAOIs were among the first drugs to be introduced \nclinically as antidepressants but were largely superseded to its 5-HT uptake inhibition that occurs at lower doses, the combination providing additional therapeutic benefit. They \nare all active orally; slow-release formulations are available \nthat reduce the incidence of nausea. Venlafaxine, desvenla -\nfaxine and duloxetine are effective in some anxiety disorders \n(see Ch. 45). Desvenlafaxine may be useful in treating some \nperimenopausal symptoms such as hot flushes and insomnia. Duloxetine is also used in the treatment of neuropathic pain \nand fibromyalgia (see Ch. 43) and urinary incontinence.\nVenlafaxine and duloxetine are metabolised by CYP2D6. \nVenlafaxine is converted to desvenlafaxine, which shows \ngreater inhibition of noradrenaline reuptake. Unwanted \neffects of these drugs \u2013 largely due to enhanced activation \nof adrenoceptors \u2013 include headache, insomnia, sexual dysfunction, dry mouth, dizziness, sweating and decreased \nappetite. The most common symptoms in overdose are \nCNS depression, serotonin toxicity, seizure and cardiac conduction abnormalities. Duloxetine has been reported \nto cause hepatotoxicity and is contraindicated for patients \nwith hepatic impairment.\nOTHER \u2003NORADRENALINE \u2003UPTAKE \u2003INHIBITORS\nBupropion inhibits both noradrenaline and dopamine (but not 5-HT) uptake but, unlike cocaine and amphetamine (see \nCh. 49), does not induce euphoria and has so far not been \nobserved to have abuse potential. It is metabolised to active metabolites. It is also used to treat nicotine dependence (see \nCh. 50). At high doses it may induce seizures. Reboxetine \nand atomoxetine are highly selective inhibitors of noradrena -\nline uptake but their efficacy in depression is less than that of TCAs. Atomoxetine is approved for the treatment of \nattention \tdeficit/hyperactivity \tdisorder \t(see \tCh. \t49).\nMONOAMINE RECEPTOR ANTAGONISTS\nMirtazapine blocks not only \u03b12 adrenoreceptors but also \nother receptors, including 5-HT 2C receptors, which may \ncontribute to its antidepressant actions. Block of \u03b12 adreno -\nceptors will not only increase noradrenaline release but will also enhance 5-HT release (see Fig. 48.3B); however, \nby simultaneously blocking 5-HT\n2A and 5-HT 3 receptors, Other monoamine uptake \ninhibitors \n\u2022\tVenlafaxine is a 5-HT uptake inhibitor, but less \nselective\tfor \t5-HT \tversus \tnoradrenaline \tthan \tSSRIs. \tIt \t\nis metabolised to desvenlafaxine, which is also \nantidepressant.\n\u2022\tDuloxetine inhibits noradrenaline and 5-HT", "start_char_idx": 0, "end_char_idx": 3142, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "db8e1154-a5c3-4cdc-91bf-2f58ef938362": {"__data__": {"id_": "db8e1154-a5c3-4cdc-91bf-2f58ef938362", "embedding": null, "metadata": {"page_label": "622", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9d0495d1-80f5-4d6e-bd59-9b420170953c", "node_type": null, "metadata": {"page_label": "622", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ed65a1532226021f7d15ee543e6b7078710985a1262c7eacd660f359e601063"}, "2": {"node_id": "07c858f0-4a89-4b45-ab01-9d85da770778", "node_type": null, "metadata": {"page_label": "622", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3ee221d693914606f4bbb6dde96d030569728d20ac8d9883546e4966778ea14c"}}, "hash": "90c71fd2ef78ded4ffedff9162ad2022cf29b05e0b732549f1c2f4a977ce1ed3", "text": "inhibits noradrenaline and 5-HT uptake.\n\u2022\tBupropion is a noradrenaline and dopamine uptake \ninhibitor.\n\u2022\tGenerally \tsimilar \tto \ttricyclic \tantidepressants \tbut \tlack \t\nmajor receptor-blocking actions, so fewer side effects.\n\u2022\tLess\trisk \tof \tcardiac \teffects, \tso \tsafer \tin \toverdose \tthan \t\ntricyclic antidepressants.\n\u2022\tCan\tbe \tused \tto \ttreat \tother \tdisorders:\n\u2013 venlafaxine, desvenlafaxine and duloxetine \n\u2013 anxiety disorders\n\u2013 duloxetine \t\u2013\tneuropathic \tpain \tand \tfibromyalgia\n\u2013 duloxetine \u2013 urinary incontinence\n\u2013 bupropion \u2013 nicotine dependence \nMonoamine receptor antagonist \nantidepressant drugs \n\u2022\tMirtazapine blocks \u03b12 adrenoceptors and 5-HT 2C \nreceptors, enhancing noradrenaline and 5-HT release.\n\u2022\tMirtazapine may act more rapidly than other \nantidepressants, and causes less nausea and sexual \ndysfunction \tthan \tSSRIs.\n\u2022\tTrazodone blocks 5-HT 2A and 5-HT 2C receptors and \nblocks 5-HT reuptake.\n\u2022\tMianserin is an antagonist at multiple 5-HT receptors (including 5-HT\n2A) as well as at \u03b11 and \u03b12 receptors. It \nis also an inverse agonist at H 1 receptors. Use is \ndeclining because of risk of bone marrow depression. \nRegular\tblood \tcounts \tare \tadvisable.\n\u2022\tCardiovascular \tside \teffects \tof \tthese \tdrugs \tare \tfewer \t\nthan those of tricyclic antidepressants.\n\u2022\tVortioxetine has both 5-HT uptake inhibition and \nmultiple 5-HT receptor partial agonist or antagonist \nactions.Tricyclic antidepressants \n\u2022\tTricyclic \tantidepressants \tare \tchemically \trelated \tto \t\nphenothiazine antipsychotic drugs (Ch. 47), and some \nhave similar non-selective receptor-blocking actions.\n\u2022\tImportant \texamples \tare \timipramine, amitriptyline \nand clomipramine.\n\u2022\tMost\tare \tlong \tacting, \tand \tthey \tare \toften \tconverted \tto \t\nactive metabolites.\n\u2022\tImportant \tside \teffects: \tsedation \t(H1 block); postural \nhypotension (\u03b1-adrenoceptor block); dry mouth, blurred vision, constipation (muscarinic block); \noccasionally \tmania \tand \tconvulsions. \tRisk \tof \tventricular \t\ndysrhythmias.\n\u2022\tDangerous \tin \tacute \toverdose: \tconfusion \tand \tmania, \t\ncardiac dysrhythmias.\n\u2022\tLiable\tto \tinteract \twith \tother \tdrugs \t(e.g. \talcohol, \t\nanaesthetics, hypotensive drugs and non-steroidal anti-inflammatory drugs; should not be given with monoamine oxidase inhibitors).\n\u2022\tAlso\tused \tto \ttreat \tneuropathic \tpain.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3111, "end_char_idx": 5890, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "93fd3e61-a306-4da2-a662-1f288a4777b6": {"__data__": {"id_": "93fd3e61-a306-4da2-a662-1f288a4777b6", "embedding": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "78eddb40-33d6-43e4-af90-987363f1d25c", "node_type": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e125f925b0e6a78cbe4f6fa4ead34981bb05d6ff78dffe238623cb3ce27aeea"}, "3": {"node_id": "9b8ecf75-bdbc-4d6c-8e48-2cb578bdcb9e", "node_type": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a386f498e87ede2d92c1fc3d71d96d3c8f02446b6b0864b0a719a75e3b71910b"}}, "hash": "e131fccc7b8fae2493e8b9c0c8bde78c3f1f4187542eaa7170c123ee2b9c83c5", "text": "48 ANTidEpRESSANT dRUgS\n617MAOIs do not increase the response of peripheral organs, \nsuch as the heart and blood vessels, to sympathetic nerve \nstimulation. The main effect of MAOIs is to increase the \ncytoplasmic concentration of monoamines in nerve termi -\nnals, without greatly affecting the vesicular stores that are \nreleasable by nerve stimulation. The increased cytoplasmic \npool results in an increased rate of spontaneous leakage of monoamines, and also an increased release by indirectly \nacting sympathomimetic amines such as amphetamine and \ntyramine (see Ch. 15 and Fig. 15.7). Tyramine thus causes a much greater rise in blood pressure in MAOI-treated animals than in controls. This mechanism is important in \nrelation to the \u2018cheese reaction\u2019 produced by MAOIs in \nhumans (see later).\nIn normal human subjects, MAOIs cause an immediate \nincrease in motor activity; euphoria and excitement develop over the course of a few days. This is in contrast to TCAs, which cause only sedation and confusion when given to \nnon-depressed subjects. The effects of MAOIs on amine \nmetabolism develop rapidly, and the effect of a single dose lasts for several days. There is a clear discrepancy, as with \nSSRIs and TCAs, between the rapid biochemical response \nand the delayed antidepressant effect.\nUnwanted effects and toxicity\nMany of the unwanted effects of MAOIs result directly from MAO inhibition, but some are produced by other \nmechanisms.\nHypotension is a common side effect; indeed, pargyline \nwas at one time used as an antihypertensive drug. One possible explanation for this effect \u2013 the opposite of what \nmight have been expected \u2013 is that amines such as dopamine or octopamine accumulate within peripheral sympathetic \nnerve terminals and displace noradrenaline from the storage \nvesicles, thus reducing noradrenaline release associated with sympathetic activity.\nExcessive central stimulation may cause tremors, excite -\nment, insomnia and, in overdose, convulsions.\nIncreased appetite, leading to weight gain, can be so \nextreme\tas \tto \trequire \tthe \tdrug \tto \tbe \tdiscontinued.\nAtropine-like side effects (dry mouth, blurred vision, \nurinary retention, etc.) are common with MAOIs, although \nthey are less of a problem than with TCAs.\nMAOIs of the hydrazine type (e.g. phenelzine and \niproniazid) produce, very rarely (less than 1 in 10,000), severe hepatotoxicity, which seems to be due to the hydra -\nzine moiety of the molecule. Their use in patients with \nliver disease is therefore unwise.\nInteraction with other drugs and foods\nInteraction with other drugs and foods is the most serious problem with MAOIs and is the main factor that caused \ntheir clinical use to decline. The special advantage claimed \nfor the new reversible MAOIs, such as moclobemide, is that these interactions are reduced.\nThe\t\u2018cheese \treaction\u2019 \tis \ta \tdirect \tconsequence \tof \tMAO \t\ninhibition and occurs when normally innocuous amines (mainly tyramine) produced during fermentation are \ningested. Tyramine is normally metabolised by MAO in \nthe gut wall and liver, and little dietary tyramine reaches the systemic circulation. MAO inhibition allows tyramine \nto be absorbed, and also enhances its sympathomimetic \neffect, as discussed earlier. The result is acute hypertension, giving rise to a severe throbbing headache and occasionally \neven to intracranial haemorrhage. Although many foods \ncontain some tyramine, it appears that at least 10 mg of by other types of antidepressants, whose clinical efficacies \nwere considered better and whose", "start_char_idx": 0, "end_char_idx": 3547, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9b8ecf75-bdbc-4d6c-8e48-2cb578bdcb9e": {"__data__": {"id_": "9b8ecf75-bdbc-4d6c-8e48-2cb578bdcb9e", "embedding": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "78eddb40-33d6-43e4-af90-987363f1d25c", "node_type": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e125f925b0e6a78cbe4f6fa4ead34981bb05d6ff78dffe238623cb3ce27aeea"}, "2": {"node_id": "93fd3e61-a306-4da2-a662-1f288a4777b6", "node_type": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e131fccc7b8fae2493e8b9c0c8bde78c3f1f4187542eaa7170c123ee2b9c83c5"}, "3": {"node_id": "743bc24e-4d19-4763-89f5-3896eb213b24", "node_type": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "955f22246951221fcd2a7e13d5bc1432442fb43ab35970ad71159898a71d9642"}}, "hash": "a386f498e87ede2d92c1fc3d71d96d3c8f02446b6b0864b0a719a75e3b71910b", "text": "of by other types of antidepressants, whose clinical efficacies \nwere considered better and whose side effects are generally \nless than those of MAOIs. The main examples are phen-\nelzine, tranylcypromine and iproniazid. These drugs cause \nirreversible inhibition of the enzyme and do not distinguish between the two main isozymes (see later). The discovery \nof reversible inhibitors that show isozyme selectivity has rekindled interest in this class of drug. Although several \nstudies have shown a reduction in platelet MAO activity \nin certain groups of depressed patients, there is no clear evidence that abnormal MAO activity is involved in the pathogenesis of depression.\nMonoamine oxidase (see Ch. 15) is found in nearly all \ntissues, and exists in two similar molecular forms coded by separate genes (see Table 48.4). MAO-A has a substrate \npreference for 5-HT and noradrenaline, and is the main \ntarget for the antidepressant MAOIs. MAO-B has a substrate preference for phenylethylamine and dopamine. Type B \nis selectively inhibited by selegiline, which is used in the \ntreatment of Parkinson\u2019s disease (see Ch. 41). Disruption of \nthe MAO-A gene in mice causes increased brain accumula -\ntion of 5-HT and, to a lesser extent, noradrenaline, along with aggressive behaviour. A family has been reported with an inherited mutation leading to loss of MAO-A activity, \nwhose members showed mental retardation and violent \nbehaviour patterns. Most antidepressant MAOIs act on both forms of MAO, but clinical studies with subtype-specific \ninhibitors have shown clearly that antidepressant activity, \nas well as the main side effects of MAOIs, is associated with MAO-A inhibition. MAO is located intracellularly, mostly associated with mitochondria, and has two main functions:\n1. Within nerve terminals, MAO regulates the free \nintraneuronal concentration of noradrenaline or 5-HT. It is not involved in the inactivation of released \ntransmitter.\n2. MAO in the gut wall is important in the inactivation \nof endogenous and ingested amines such as tyramine \nthat would otherwise produce unwanted effects.\nChemical aspects\nMAOIs are substrate analogues with a phenylethylamine-like structure, and most contain a reactive group (e.g. \nhydrazine, propargylamine, cyclopropylamine) that enables \nthe inhibitor to bind covalently to the enzyme, resulting in a non-competitive and long-lasting inhibition. Recovery \nof MAO activity after inhibition takes several weeks with \nmost\tdrugs, \tbut \tis \tquicker \tafter \ttranylcypromine, which \nforms a less stable bond with the enzyme. Moclobemide \nacts as a reversible competitive inhibitor.\nMAOIs are not specific in their actions, and inhibit a \nvariety of other enzymes as well as MAO, including many enzymes involved in the metabolism of other drugs. This \nis responsible for some of the many clinically important drug interactions associated with MAOIs.\nPharmacological effects\nMonoamine oxidase inhibitors cause a rapid and sustained increase in the 5-HT, noradrenaline and dopamine content \nof the brain, 5-HT being affected most and dopamine least. \nSimilar changes occur in peripheral tissues such as heart, liver and intestine, and increases in the plasma concentrations of \nthese amines are also detectable. Although these increases \nin tissue amine content are largely due to accumulation within neurons, transmitter release in response to nerve \nactivity is not increased. In contrast to the effect of TCAs, mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3464, "end_char_idx": 7099, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "743bc24e-4d19-4763-89f5-3896eb213b24": {"__data__": {"id_": "743bc24e-4d19-4763-89f5-3896eb213b24", "embedding": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "78eddb40-33d6-43e4-af90-987363f1d25c", "node_type": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e125f925b0e6a78cbe4f6fa4ead34981bb05d6ff78dffe238623cb3ce27aeea"}, "2": {"node_id": "9b8ecf75-bdbc-4d6c-8e48-2cb578bdcb9e", "node_type": null, "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a386f498e87ede2d92c1fc3d71d96d3c8f02446b6b0864b0a719a75e3b71910b"}}, "hash": "955f22246951221fcd2a7e13d5bc1432442fb43ab35970ad71159898a71d9642", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7136, "end_char_idx": 7487, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2a81eb0c-90a2-4403-a16f-15345f94069a": {"__data__": {"id_": "2a81eb0c-90a2-4403-a16f-15345f94069a", "embedding": null, "metadata": {"page_label": "624", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a54dc9d5-fd9a-4943-bbb5-c1568dc70c0b", "node_type": null, "metadata": {"page_label": "624", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f31f64defcd057caf1e6ae4307ef4e255e3273bdfd8af1a69ac0afd176ccecf7"}, "3": {"node_id": "45b9431e-21d4-452f-9adf-f4d1130877b1", "node_type": null, "metadata": {"page_label": "624", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9b84e138b58ec23072dc3fd70e3e51a9bc155e5bc35e9dc8622a8abd9271c681"}}, "hash": "16e312f6b28a103465df8fc99e8af0406115646a3c690ce0053a985d78d79c00", "text": "48 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n618tyramine needs to be ingested to produce such a response, \nand the main danger is from ripe cheeses and from con -\ncentrated yeast products such as Marmite. Administration of indirectly acting sympathomimetic amines (e.g. ephedrine \n\u2013 a nasal decongestant \u2013 or amphetamine \u2013 a drug of abuse) \nalso causes severe hypertension in patients receiving MAOIs; \ndirectly acting agents such as noradrenaline (used, for example, in conjunction with local anaesthetics; see Ch. \n44) are not hazardous. Moclobemide, a specific MAO-A \ninhibitor, does not cause the \u2018cheese reaction\u2019, probably because tyramine can still be metabolised by MAO-B.\nHypertensive episodes have been reported in patients \ngiven TCAs and MAOIs simultaneously. The probable explanation is that inhibition of noradrenaline reuptake further enhances the cardiovascular response to dietary \ntyramine, thus accentuating the \u2018cheese reaction\u2019. This \ncombination of drugs can also produce excitement and hyperactivity.\nMonoamine oxidase inhibitors can interact with pethidine \n(see Ch. 43) to cause severe hyperpyrexia, with restlessness, coma and hypotension. The mechanism is uncertain, but \nit is likely that an abnormal pethidine metabolite is produced \nbecause of inhibition of demethylation.\nMELATONIN AGONIST\nAgomelatine is a potent agonist at MT 1 and MT 2 receptors \n(see Ch. 40) with weak antagonist activity at 5-HT 2A,2B,2C \nreceptors (almost 1000-fold lower potency). It has a short \nbiological half-life and does not give rise to the side effects \nassociated with other antidepressant drugs. Used to treat severe depression, it is usually taken once daily before bed \nand may work by correcting disturbances in circadian \nrhythms often associated with depression. There are reports of hepatotoxicity in a few patients, and it should not be \nused in patients with liver disease.\nKETAMINE\nSmall clinical trials suggest that a single, intravenous, \nsub-anaesthetic dose of ketamine may produce a rapid but \nshort-lasting decrease in depressive symptoms lasting from a few hours up to 14 days, without the 3- to 4-week delay in onset of action seen with other antidepressant drugs \n(see Malhi et al., 2016). Though not approved for use in \nthis indication, ketamine is claimed to improve mood in patients suffering from depression resistant to other forms \nof antidepressant therapy. Clinical trials of intranasal \nesketamine, the S isomer of ketamine, are underway, as are larger, longer-term studies of ketamine itself. The \nmuscarinic antagonist, scopolamine (see Ch. 14), may also \nhave rapid onset antidepressant effects but further, large \nclinical\ttrials \tare \trequired \tto \tsubstantiate \tthis \tclaim.\nKetamine is a non-competitive NMDA channel blocker \n(see Ch. 42), however, memantine, which also blocks NMDA receptors has not been shown to be antidepressant. There is \ncontroversy surrounding whether the putative antidepressant effect is produced by ketamine itself or by its metabolite, \nR,R-hydroxynorketamine. Hydroxynorketamine would have \nthe added advantage that, unlike ketamine, it may not produce psychotomimetic effects as it has low affinity for the NMDA \nreceptor, and thus would be unlikely to be abused (see Ch. 50).\nOTHER ANTIDEPRESSANT APPROACHES\nMethylfolate, given as a dietary supplement, may be \neffective in depressed individuals who have lowered folate \nlevels.Monoamine oxidase inhibitors \n(MAOIs) \n\u2022\tMain\texamples \tare \tphenelzine,", "start_char_idx": 0, "end_char_idx": 3474, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "45b9431e-21d4-452f-9adf-f4d1130877b1": {"__data__": {"id_": "45b9431e-21d4-452f-9adf-f4d1130877b1", "embedding": null, "metadata": {"page_label": "624", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a54dc9d5-fd9a-4943-bbb5-c1568dc70c0b", "node_type": null, "metadata": {"page_label": "624", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f31f64defcd057caf1e6ae4307ef4e255e3273bdfd8af1a69ac0afd176ccecf7"}, "2": {"node_id": "2a81eb0c-90a2-4403-a16f-15345f94069a", "node_type": null, "metadata": {"page_label": "624", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16e312f6b28a103465df8fc99e8af0406115646a3c690ce0053a985d78d79c00"}}, "hash": "9b84e138b58ec23072dc3fd70e3e51a9bc155e5bc35e9dc8622a8abd9271c681", "text": "\n\u2022\tMain\texamples \tare \tphenelzine, tranylcypromine, \nisocarboxazid (irreversible, long-acting, non-selective \nbetween MAO-A and -B) and moclobemide \n(reversible, short-acting, MAO-A selective).\n\u2022\tLong-acting \tMAOIs:\n\u2013 main side effects: postural hypotension (sympathetic \nblock); atropine-like effects (as with tricyclic antidepressants [TCAs]); weight gain; central nervous system (CNS) stimulation, causing \nrestlessness, insomnia; hepatotoxicity and \nneurotoxicity (rare);\n\u2013 acute overdose causes CNS stimulation, sometimes \nconvulsions;\n\u2013\t\u2018cheese \treaction\u2019, \ti.e. \tsevere \thypertensive \tresponse \t\nto tyramine-containing foods (e.g. cheese, beer, wine, well-hung game, yeast or soy extracts); such reactions can occur up to 2 weeks after treatment is \ndiscontinued.\n\u2022\tInteraction \twith \tother \tamines \t(e.g. \tephedrine in \nover-the-counter decongestants, clomipramine and \nother TCAs) and some other drugs (e.g. pethidine) \nare also potentially lethal.\n\u2022\tMoclobemide is used for major depression and social \nphobia.\t\u2018Cheese \treaction\u2019 \tand \tother \tdrug \tinteractions \t\nare less severe and shorter lasting than with \nirreversible MAOIs.\n\u2022\tMAOIs\tare \tused \tmuch \tless \tthan \tother \tantidepressants \t\nbecause of their adverse effects and serious interactions. They are indicated for major depression in patients who have not responded to other drugs.\nOestrogen , which is known to elevate mood in peri -\nmenopausal women, may also be of value for the treatment \nof postnatal depression. Its effectiveness in treating other \nforms of depression is unclear. In addition to its well-documented hormonal actions in the body (see Ch. 36), it \nalso has actions on monoaminergic, GABAergic and glu -\ntamatergic systems in the brain (see Chs 39 and 40).\nNovel-acting antidepressants \n\u2022\tAgomelatine is an agonist at MT 1 and MT 2 melatonin \nreceptors that improves mood, probably by improving \nsleep patterns.\n\u2022\tKetamine, an NMDA receptor channel blocker, produces rapid onset antidepressant effects in patients resistant to other therapies.\nCLINICAL EFFECTIVENESS OF \nANTIDEPRESSANT TREATMENTS\nThe overall clinical efficacy of antidepressants is generally \naccepted for severe depression, though there is concern that mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3440, "end_char_idx": 6131, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e93b4355-1890-4f3f-92e3-494d89d287ef": {"__data__": {"id_": "e93b4355-1890-4f3f-92e3-494d89d287ef", "embedding": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2113f332-9cbd-439f-ac53-98bbd9ec1a6f", "node_type": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95b9ad4d2a8883b4eb3e7f69797f633f96a24702cf45b7d83af1c1fab357fc54"}, "3": {"node_id": "1cb50598-8efd-40b2-bab2-48a5c4491a79", "node_type": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb18578ebb12e2a76a42c570eff2dacdde405bdd881b5a6e6a68025e610b142e"}}, "hash": "90a4b7df1f08ce0926c968766377c4d3dcae83b8f9252dd1cf7bad73cfedf310", "text": "48 ANTidEpRESSANT dRUgS\n619BRAIN STIMULATION THERAPIES\nA\tnumber \tof \tbrain \tstimulation \ttechniques \tare \tnow \tbeing \t\nused or developed to treat depression. Bright light stimula -\ntion has been proposed as a treatment for seasonal affective \ndisorder. \tThe\tmost\testablished \tbrain\tstimulation \ttechniques \t\nare electroconvulsive therapy (ECT) and repetitive tran -\nscranial magnetic stimulation (TMS). Brain stimulation \ntreatments are often used as the therapeutic approach of \nlast resort for patients who have not responded to antide -\npressant drugs.\nECT involves stimulation through electrodes placed on \neither side of the head, with the patient lightly anaesthetised, paralysed with a short-acting neuromuscular-blocking drug \n(e.g. suxamethonium ; Ch. 14) to avoid physical injury, and \nartificially ventilated. Controlled trials have shown ECT \nto be at least as effective as antidepressant drugs, with response rates ranging between 60% and 80%; it appears \nto be an effective treatment for severe suicidal depression \nand has the advantage of producing a fast-onset response. The main disadvantage of ECT is that it often causes confu -\nsion and memory loss lasting for days or weeks. TMS gives electrical stimulation without anaesthesia or convulsion and does not produce cognitive impairment, but compara -\ntive studies suggest that its antidepressant efficacy is less than that of conventional ECT.Clinical uses of drugs in \ndepression \n\u2022\tMild\tdepression \tis \toften \tbest \ttreated \tinitially \twith \t\nnon-drug measures (such as cognitive behavioural \ntherapy), with antidepressant drugs being used in addition if the response is poor.\n\u2022\tThe\tuse \tof \tantidepressant \tdrugs \tis \tadvisable \tin \tthe \t\ntreatment of moderate to severe depression.\n\u2022\tThe\tclinical \tefficacy \tof \tantidepressant \tdrugs \tis \tlimited, \t\nand varies between individuals. Clinical trials have produced inconsistent results, because of placebo responses and spontaneous fluctuations in the level of \ndepression.\n\u2022\tDifferent \tclasses \tof \tantidepressant \tdrugs \thave \tsimilar \t\nefficacy\tbut \tdifferent \tside \teffects.\n\u2022\tChoice\tof \tdrug \tis \tbased \ton \tindividual \taspects \t\nincluding concomitant disease treatment, suicide risk \nand previous response to treatment. Other things \nbeing\tequal, \ta \tSSRI \tis \tpreferred \tas \tthese \tare \tusually \t\nbetter tolerated and are less dangerous in overdose.\n\u2022\tAntidepressant \tdrugs \ttake \tseveral \tweeks \tbefore \ttaking \t\neffect, so decisions on dose increment or switching to another class should not be made precipitately. Use of MAOIs is managed by specialists.\n\u2022\tAn\teffective \tregimen \tshould \tbe \tcontinued \tfor \tat \tleast \t2 \t\nyears.\n\u2022\tIn\turgent \tsituations, \tspecialist \tconsideration \tshould \tbe \t\ngiven to possible use of electroconvulsive therapy.\n\u2022\tAnxiolytic \t(e.g. \tbenzodiazepine, \tCh. \t45), \tor \t\nantipsychotic drugs (Ch. 47) are useful adjuncts in some patients.the published clinical trials evidence may be misleading, \nbecause many negative trials have gone unreported. However, \n30%\u201340% of depressed patients fail to show improvement, \nand those that do may only show partial improvement, re-inforcing the need for new drugs with novel mechanisms \nof action. Clear evidence of benefit from current antidepres -\nsant drugs in mild to moderate depression is lacking. \nInterpretation of trials data is complicated by a high placebo \nresponse, and spontaneous recovery independent of any \ntreatment. Clinical trial data do not suggest that drugs cur -\nrently in use differ in terms of", "start_char_idx": 0, "end_char_idx": 3520, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1cb50598-8efd-40b2-bab2-48a5c4491a79": {"__data__": {"id_": "1cb50598-8efd-40b2-bab2-48a5c4491a79", "embedding": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2113f332-9cbd-439f-ac53-98bbd9ec1a6f", "node_type": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95b9ad4d2a8883b4eb3e7f69797f633f96a24702cf45b7d83af1c1fab357fc54"}, "2": {"node_id": "e93b4355-1890-4f3f-92e3-494d89d287ef", "node_type": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "90a4b7df1f08ce0926c968766377c4d3dcae83b8f9252dd1cf7bad73cfedf310"}, "3": {"node_id": "430aea8c-5fb0-47a0-b38f-649d2503e5e3", "node_type": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "339fae1c4c8e7368e37e8d3b5ca0ea9445b74c17b57639c6e8f27025ea11b5a6"}}, "hash": "fb18578ebb12e2a76a42c570eff2dacdde405bdd881b5a6e6a68025e610b142e", "text": "trial data do not suggest that drugs cur -\nrently in use differ in terms of efficacy. Nevertheless, clinical experience suggests that individual patients may, for \nunknown reasons, respond better to one drug than another. \nCurrent treatment guidelines recommend evidence-based psychological procedures as first-line treatments in most \ncases, before antidepressant drugs.\nPharmacogenetic factors\n\u25bc The individual variation in response to antidepressants and the \nincidence of adverse effects may be partly due to genetic factors \n(Crisafulli et al., 2014). Two genetic factors have received particular \nattention, namely:\n\u2022\tpolymorphism \tof \tcytochrome \tP450 \tgenes, \tespecially \tCYP2D6 \nand CYP2C19, which are responsible for hydroxylation and \ndemethylation of TCAs and SSRIs;\n\u2022\tpolymorphism \tof \tserotonin \tand \tnoradrenaline \ttransporter \tgenes.\nUp to 10% of Caucasians possess a dysfunctional CYP2D6 gene, and \nconsequently \tmay\tbe\tsusceptible \tto\tside\teffects\tof\tantidepressants \tand\t\nvarious other drugs (see Ch. 12) that are metabolised by this route. The opposite effect, caused by duplication of the gene, is common in Eastern \nEuropean and East African populations, and may account for a lack of \nclinical efficacy in some individuals. There is some evidence to suggest that responsiveness to SSRIs and SNRIs is related to polymorphism \nof the serotonin and noradrenaline transporter genes.\nAlthough genotyping may prove to be a useful approach in the future \nto individualising antidepressant therapy, its practical realisation is \nstill some way off.\nSuicide and antidepressants\n\u25bc SSRI and SNRI antidepressants can increase the risk of \u2018suicidality\u2019 \nand increase aggression in children, adolescents and young adults \n(see Sharma et al., 2016). The term suicidality encompasses suicidal \nthoughts and planning as well as unsuccessful attempts; actual suicide, \nalthough one of the major causes of death in young people, is much \nrarer than suicidality. The risk is less in older age groups. However, the risk has to be balanced against the beneficial effects of these drugs, \nnot only on depression but also on anxiety, panic and obsessive\u2013\ncompulsive disorders (see Ch. 45).\nFUTURE ANTIDEPRESSANT DRUGS\nConsiderable effort is being made to develop drugs that \ncombine a number of pharmacological effects thought to \ncontribute towards antidepressant actions in one chemical \nentity (e.g. drugs inhibiting 5-HT, noradrenaline and dopa -\nmine uptake as well as having one or more of the following \nproperties: \u03b23 adrenoreceptor agonism, D 2 dopamine receptor \nagonism or antagonism, 5-HT 1A receptor agonism or partial \nagonism and 5-HT 2A receptor antagonism).\nInterest in developing drugs acting as antagonists at \ndifferent subtypes of NMDA receptor (Ch. 39) has been \nstimulated by reports that ketamine rapidly alleviates depression. The drive is to find a drug devoid of ketamine\u2019s \nunwanted psychotomimetic effects.\nDrugs acting at these and other novel targets are discussed \nin detail by Ionescu and Papakostas (2017).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3460, "end_char_idx": 6964, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "430aea8c-5fb0-47a0-b38f-649d2503e5e3": {"__data__": {"id_": "430aea8c-5fb0-47a0-b38f-649d2503e5e3", "embedding": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2113f332-9cbd-439f-ac53-98bbd9ec1a6f", "node_type": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "95b9ad4d2a8883b4eb3e7f69797f633f96a24702cf45b7d83af1c1fab357fc54"}, "2": {"node_id": "1cb50598-8efd-40b2-bab2-48a5c4491a79", "node_type": null, "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb18578ebb12e2a76a42c570eff2dacdde405bdd881b5a6e6a68025e610b142e"}}, "hash": "339fae1c4c8e7368e37e8d3b5ca0ea9445b74c17b57639c6e8f27025ea11b5a6", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6978, "end_char_idx": 7041, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6cab7286-34e7-40d5-be18-85c4ade5c9a5": {"__data__": {"id_": "6cab7286-34e7-40d5-be18-85c4ade5c9a5", "embedding": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1a8ee66-1f5b-4847-96e7-09398b7db6b1", "node_type": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c2dc5cde7f71ba3c12de2f7c17d227b6a1e630dd5456d481a5ad61a6958c07e"}, "3": {"node_id": "bf41a9a7-cd62-4686-b73d-66176c7eb2d3", "node_type": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "573f67c782b18fe8025db0e43957a984e44e8113abc61b3a21466d9c7966add4"}}, "hash": "e893a3561fe0413e1ac5d100db761387783cc799a74a87ee624dc9d0703d8ac9", "text": "48 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n620manic\u2013depressive illness. The use of lithium is declining.5 \nIt is relatively difficult to use, as plasma concentration \nmonitoring \tis \trequired, \tand \tthere \tis \tthe \tpotential \tfor \t\nproblems in patients with renal impairment and for drug \ninteractions, for example with diuretics (see Ch. 58). Lithium \nmay have beneficial effects in neurodegenerative diseases \nsuch as Alzheimer\u2019s disease (see Ch. 41).\nPharmacological effects and mechanism of action\nLithium is clinically effective at a plasma concentration of \n0.5\u20131\tmmol/L, \t and \t above \t 1.5 \tmmol/L \t it \t produces \t a \t variety\t\nof toxic effects, so the therapeutic window is narrow. In \nnormal\tsubjects, \t1 \tmmol/L \tlithium \tin \tplasma \thas \tno \t\nappreciable psychotropic effects. It does, however, produce many detectable biochemical changes, and it is still unclear \nhow these may be related to its therapeutic effect.\nLithium is a monovalent cation that can mimic the role \nof Na\n+ in excitable tissues, being able to permeate the \nvoltage-gated Na+ channels that are responsible for action \npotential generation (see Ch. 4). It is, however, not pumped out by the Na\n+-K+-ATPase, and therefore tends to accumulate \ninside excitable cells, leading to a partial loss of intracellular K\n+, and depolarisation of the cell.\nThe biochemical effects of lithium are complex, and it \ninhibits many enzymes that participate in signal transduction \npathways. Those that are thought to be relevant to its therapeutic actions are as follows:\n\u2022\tInhibition \tof \tinositol \tmonophosphatase, \twhich \tblocks \t\nthe phosphatidylinositol (PI) pathway (see Ch. 3) at the point where inositol phosphate is hydrolysed to \nfree inositol, resulting in depletion of PI. This prevents \nagonist-stimulated inositol trisphosphate formation through various PI-linked receptors, and therefore \nblocks many receptor-mediated effects.\n\u2022\tInhibition \tof \tglycogen \tsynthase \tkinase \t3 \t(GSK3) \t\nisoforms, possibly by competing with magnesium for \nits association with these kinases. GSK3 isoforms \nphosphorylate a number of key enzymes involved in \npathways leading to apoptosis and amyloid formation (see Phiel & Klein, 2001). Lithium can also affect GSK3 \nisoforms indirectly by interfering with their regulation \nby\tAkt,\ta \tclosely \trelated \tserine/threonine \tkinase \t\nregulated through PI-mediated signalling and by \narrestins (see Ch. 3; Beaulieu et al., 2009).\nLithium inhibits G protein function, thus reducing K+ channel \nactivation and hormone-induced cAMP production. It also blocks other cellular responses (e.g. the response of renal \ntubular cells to antidiuretic hormone, and of the thyroid to thyroid-stimulating hormone; see Chs 30 and 35, respectively). \nThis is not, however, a pronounced effect in the brain.\nThe cellular selectivity of lithium appears to depend on \nits selective uptake, reflecting the activity of sodium channels in different cells. This could explain its relatively selective \naction in the brain and kidney, even though many other tissues use the same second messengers. Notwithstanding such insights, our ignorance of the nature of the disturbance \nunderlying the mood swings in bipolar disorder leaves us \ngroping for links between the biochemical and prophylactic effects of lithium.The effect of ECT on experimental animals has been \ncarefully analysed to see if it provides clues as to the mode \nof", "start_char_idx": 0, "end_char_idx": 3407, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bf41a9a7-cd62-4686-b73d-66176c7eb2d3": {"__data__": {"id_": "bf41a9a7-cd62-4686-b73d-66176c7eb2d3", "embedding": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1a8ee66-1f5b-4847-96e7-09398b7db6b1", "node_type": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c2dc5cde7f71ba3c12de2f7c17d227b6a1e630dd5456d481a5ad61a6958c07e"}, "2": {"node_id": "6cab7286-34e7-40d5-be18-85c4ade5c9a5", "node_type": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e893a3561fe0413e1ac5d100db761387783cc799a74a87ee624dc9d0703d8ac9"}, "3": {"node_id": "569e94be-18c5-4ce8-993b-65587b88d6a5", "node_type": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6ad2b1463df8e78bdcc95671049ba043a8d263b9caa67dce76a16172b95fb0c7"}}, "hash": "573f67c782b18fe8025db0e43957a984e44e8113abc61b3a21466d9c7966add4", "text": "been \ncarefully analysed to see if it provides clues as to the mode \nof action of antidepressant drugs, but the clues it gives are \nenigmatic. 5-HT synthesis and uptake are unaltered, and noradrenaline uptake is somewhat increased (in contrast \nto the effect of TCAs). Decreased \u03b2 adrenoceptor responsive -\nness, both biochemical and behavioural, occurs with both \nECT and long-term administration of antidepressant drugs, \nbut changes in 5-HT-mediated responses tend to go in \nopposite directions.\nThere have been reports that deep brain stimulation, \nwhich has also been used in the treatment of Parkinson\u2019s \ndisease (see Ch. 41), in which stimulation is delivered in \na specific brain region through surgically implanted elec -\ntrodes, is effective in patients not responding to other \ntreatments (see Mayberg et al., 2005). The effectiveness of \nanother\ttechnique, \tvagal \tstimulation, \tin \tproducing \tlong-term \t\nbenefit in depression is still unclear.\nDRUG TREATMENT OF BIPOLAR \nDISORDER\nA range of drugs are now used to control the mood swings \ncharacteristic of manic\u2013depressive (bipolar) illness. The \nmajor drugs are:\n\u2022\tlithium;\n\u2022\tseveral \tantiepileptic \tdrugs, \te.g. \tcarbamazepine, \nvalproate, lamotrigine;\n\u2022\tsome\tantipsychotic \tdrugs, \te.g. \tolanzapine, \nrisperidone, quetiapine, aripiprazole, brexpiprazole, \ncariprazine.\nWhen used to treat bipolar disorder, lithium and anti-\nepileptic agents are often referred to as mood-stabilising \ndrugs.\nOther agents that may have some beneficial effects in \nthe treatment of bipolar disorder are benzodiazepines (to \ncalm, induce sleep and reduce anxiety), memantine, \namantadine and ketamine . The use of antidepressant drugs \nin bipolar disorder is somewhat controversial. It is recom -\nmended that they are given in combination with an anti -\nmanic agent because, in some patients, they may induce \nor enhance mania.\nUsed prophylactically in bipolar disorder, drugs prevent \nthe swings of mood and thus can reduce both the depressive and the manic phases of the illness. They are given over \nlong periods, and their beneficial effects take 3\u20134 weeks to \ndevelop. Given in an acute attack, they are effective only in reducing mania, but not the depressive phase (although lithium is sometimes used as an adjunct to antidepressants \nin severe cases of unipolar depression).\nLITHIUM\nThe psychotropic effect of lithium was discovered in 1949 \nby Cade, who had predicted that urate salts should prevent \nthe induction by uraemia of a hyperexcitability state in \nguinea pigs. He found lithium urate to produce an effect, \nquickly\tdiscovered \tthat \tit \twas \tdue \tto \tlithium \trather \tthan \t\nurate, and went on to show that lithium produced a rapid improvement in a group of manic patients.\nAnti-epileptic and atypical antipsychotic drugs (see later) \nare\tequally\teffective\tin\ttreating\tacute\tmania;\tthey\tact\tmore\t\nquickly\tand \tare \tconsiderably \tsafer, \tso \tthe \tclinical \tuse \tof \t\nlithium is mainly confined to prophylactic control of 5The decline in lithium use may have been influenced by the imbalance \nin the marketing of this simple inorganic ion versus more profitable \npharmacological agents.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3350, "end_char_idx": 6694, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "569e94be-18c5-4ce8-993b-65587b88d6a5": {"__data__": {"id_": "569e94be-18c5-4ce8-993b-65587b88d6a5", "embedding": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f1a8ee66-1f5b-4847-96e7-09398b7db6b1", "node_type": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c2dc5cde7f71ba3c12de2f7c17d227b6a1e630dd5456d481a5ad61a6958c07e"}, "2": {"node_id": "bf41a9a7-cd62-4686-b73d-66176c7eb2d3", "node_type": null, "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "573f67c782b18fe8025db0e43957a984e44e8113abc61b3a21466d9c7966add4"}}, "hash": "6ad2b1463df8e78bdcc95671049ba043a8d263b9caa67dce76a16172b95fb0c7", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6705, "end_char_idx": 7040, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "32062168-3e7b-46c4-8b02-e224ae8c6da4": {"__data__": {"id_": "32062168-3e7b-46c4-8b02-e224ae8c6da4", "embedding": null, "metadata": {"page_label": "627", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f559645a-5b6c-4280-8910-6640170daa3c", "node_type": null, "metadata": {"page_label": "627", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "df2599e97aa8a3d4738cbe3d05184044998acfcfa8ae20086545ccaa88f1d8e9"}, "3": {"node_id": "e7c1d774-5e0d-4fa0-9b37-d18387efdb36", "node_type": null, "metadata": {"page_label": "627", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c354783bb373b92f525fa9c45ab3920c0ec7677e5f75375f123bc772d295ab7c"}}, "hash": "a0f8c50ef815fc72b149c957818260e15bdd8c3df295a4e56aedacc471c55563", "text": "48 ANTidEpRESSANT dRUgS\n621Pharmacokinetic aspects and toxicity\nLithium is given by mouth as the carbonate salt and is \nexcreted by the kidney. About half of an oral dose is excreted \nwithin about 12 h \u2013 the remainder, which presumably \nrepresents lithium taken up by cells, is excreted over the \nnext 1\u20132 weeks. This very slow phase means that, with \nregular dosage, lithium accumulates slowly over 2 weeks \nor more before a steady state is reached. The narrow \ntherapeutic window means that monitoring of the plasma \nconcentration is essential. Na+ depletion reduces the rate \nof excretion by increasing the reabsorption of lithium by \nthe proximal tubule, and thus increases the likelihood of \ntoxicity. Diuretics that act distal to the proximal tubule \n(Ch. 30) also have this effect, and renal disease also pre -\ndisposes to lithium toxicity.\nThe main toxic effects that may occur during treatment \nare as follows:\n\u2022\tnausea,\t vomiting\t and\tdiarrhoea;\n\u2022\ttremor;\n\u2022\trenal\teffects:\tpolyuria\t (with\tresulting\t thirst)\tresulting\t\nfrom inhibition of the action of antidiuretic hormone. \nAt the same time, there is some Na+ retention \nassociated with increased aldosterone secretion. With \nprolonged treatment, serious renal tubular damage \nmay occur, making it essential to monitor renal \nfunction regularly in lithium-treated patients;\n\u2022\tthyroid\t enlargement,\t sometimes\t associated\t with\t\nhypothyroidism;\n\u2022\tweight\t gain;\n\u2022\thair\tloss.\nAcute lithium toxicity results in various neurological effects, \nprogressing from confusion and motor impairment to coma, \nconvulsions and death if the plasma concentration reaches \n3\u20135\tmmol/L.\nANTIEPILEPTIC DRUGS\nCarbamazepine , valproate and lamotrigine (see Ch. 46) \nhave fewer side effects than lithium and have proved \nefficacious in the treatment of bipolar disorder.\nIt is assumed that the mechanisms of action of anticon -\nvulsant drugs in reducing bipolar disorder are related to \ntheir anticonvulsant activity. While each drug has multiple \nactions (see Table 46.1), the antiepileptic drugs effective \nin bipolar disorder share the property of sodium-channel \nblockade, although there are subtle differences in their \neffectiveness against the different phases of bipolar disor -\nder. Valproate and carbamazepine are effective in treating \nacute attacks of mania and in the long-term treatment of the \ndisorder, although carbamazepine may not be as effective \nin treating the depression phase. Valproate is sometimes \ngiven along with other drugs such as lithium. Lamotrigine \nis effective in preventing the recurrence of both mania and \ndepression.\nSECOND-GENERATION ANTIPSYCHOTIC DRUGS\nAn ever-increasing number of second-generation anti -\npsychotic drugs (e.g. olanzapine , risperidone , quetiapine , \naripiprazole, cariprazine, brexpiprazole, asenapine ), (see \nCh. 47), are proving effective in the treatment of bipolar \ndepression. These agents have D 2-dopamine and 5-HT 2A \nreceptor antagonist properties as well as actions on other \nreceptors and amine transporters that may contribute to \ntheir effectiveness. All appear to be effective against mania \nwhile some may also be effective against bipolar depression. Treatment of bipolar disorder \n\u2022\tLithium , an inorganic ion, taken orally as lithium \ncarbonate.\n\u2022\tMechanism\t of\taction\tis\tnot\tunderstood.\t The\tmain\t\nbiochemical possibilities are:\n\u2013 interference with inositol trisphosphate", "start_char_idx": 0, "end_char_idx": 3394, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e7c1d774-5e0d-4fa0-9b37-d18387efdb36": {"__data__": {"id_": "e7c1d774-5e0d-4fa0-9b37-d18387efdb36", "embedding": null, "metadata": {"page_label": "627", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f559645a-5b6c-4280-8910-6640170daa3c", "node_type": null, "metadata": {"page_label": "627", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "df2599e97aa8a3d4738cbe3d05184044998acfcfa8ae20086545ccaa88f1d8e9"}, "2": {"node_id": "32062168-3e7b-46c4-8b02-e224ae8c6da4", "node_type": null, "metadata": {"page_label": "627", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a0f8c50ef815fc72b149c957818260e15bdd8c3df295a4e56aedacc471c55563"}}, "hash": "c354783bb373b92f525fa9c45ab3920c0ec7677e5f75375f123bc772d295ab7c", "text": "possibilities are:\n\u2013 interference with inositol trisphosphate formation\n\u2013 inhibition of kinases\n\u2022\tAntiepileptic\t drugs\t(e.g.\t carbamazepine , valproate , \nlamotrigine ):\n\u2013\tbetter\tside\teffect\tand\tsafety\tprofile.\n\u2022\tAtypical\t antipsychotic\t drugs\t(e.g.\t olanzapine , \nrisperidone , quetiapine , aripiprazole ) and also \nhaloperidol .\nClinical uses of mood-stabilising \ndrugs \n\u2022\tLithium (as the carbonate) is the classical drug. It is \nused:\n\u2013 in prophylaxis and treatment of mania , and in the \nprophylaxis of bipolar or unipolar disorder (manic \ndepression or recurrent depression).\n\u2022\tPoints\tto\tnote\tinclude\tthe\tfollowing:\n\u2013 there is a narrow therapeutic window and long \nduration of action;\n\u2013 acute toxic effects include cerebellar effects, \nnephrogenic diabetes insipidus (see Ch. 30) and \nrenal failure;\n\u2013 dose must be adjusted according to the plasma \nconcentration;\n\u2013 elimination is via the kidney and is reduced by \nproximal tubular reabsorption. Diuretics increase the \nactivity of the reabsorptive mechanism and hence \ncan precipitate lithium toxicity;\n\u2013 thyroid disorders and mild cognitive impairment \noccur during chronic use.\n\u2022\tCarbamazepine valproate and lamotrigine \n(sodium-channel blockers with antiepileptic actions; \nCh. 46) are used for:\n\u2013 the prophylaxis and treatment of manic episodes in \npatients with bipolar disorder ;\n\u2013 the treatment of bipolar disorder (valproate , \nlamotrigine ).\n\u2022\tOlanzapine , risperidone , quetiapine , aripiprazole \n(atypical antipsychotic drugs) are primarily used to \ntreat mania .In bipolar depression, they are often used in combination \nwith lithium or valproate. Olanzapine is given in combina -\ntion with the antidepressant fluoxetine. Haloperidol, a \nfirst-generation antipsychotic drug is also sometimes used \nto treat bipolar depression.\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3333, "end_char_idx": 5617, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "516970e4-2f4f-4431-8ef0-156a834b44fd": {"__data__": {"id_": "516970e4-2f4f-4431-8ef0-156a834b44fd", "embedding": null, "metadata": {"page_label": "628", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2e86c0b2-bd7c-45f4-ba93-e4fb7d65f5f5", "node_type": null, "metadata": {"page_label": "628", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b97d07e30e75010742ef9cdbbbd6f645af4e5cec7341bd4e9649d3ea49fb8e6"}, "3": {"node_id": "8b5a1da4-3c7d-4806-bf40-b20ba0ed6a0a", "node_type": null, "metadata": {"page_label": "628", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a0f31be0f165b14743290d884da063f4969cc87c7dccb3ac2d350299ab209dc"}}, "hash": "66102378e4ed1f60606e780e722db440798f7f0522f64e2a6ed64cbe380eda08", "text": "48 SECTION 4 \u2003\u2003NERVOUS SYSTEM\n622REFERENCES AND FURTHER READING\nPathogenesis of depressive illness\nHarmer,\t C.J.,\tDuman,\t R.S.,\tCowen,\tP.J.,\t2017.\tHow\tdo\tantidepressants\t\nwork? New perspectives for refining future treatment approaches. \nLancet Psychiatry 4, 409\u2013418. ( Reviews the various theories of how \nantidepressant drugs produce their effects )\nIonescu, D.F., Papakostas, G.I., 2017. Experimental medication treatment \napproaches for depression. Transl. Psychiatry. 7, e1068. ( Describes new \ntargets for antidepressant drugs )\nMullins, N., Lewis, C.M., 2017. Genetics of depression: progress at last. \nCurr. Psychiatry Rep. 19, 43. ( Describes recent developments in \ndetermining the genetic causes of depression )\nO\u2019Leary,\t O.F.,\tCryan,\tJ.F.,\t2013.\tTowards\t translational\t rodent\tmodels\tof\t\ndepression. Cell Tissue Res. 354, 141\u2013153. ( Describes current animal \nmodels for depression )\nSoronen, P., Ollila, H.M., Antila, M., et al., 2010. Replication of GWAS \nof bipolar disorder: association of SNPs near CDH7 with bipolar \ndisorder and visual processing. Mol. Psychiatry 15, 4\u20136. ( A major study \nof potential genetic influences on depression )\nWillner, P., Belzung, C., 2015. Treatment-resistant depression: are \nanimal models of depression fit for purpose? Psychopharmacology \n(Berl) 232, 3473\u20133495. ( Detailed discussion of animal models of depression )\nAntidepressant treatments\nCipriani, A., Santilli, C., Furukawa, T.A., et al., 2009. Escitalopram \nversus other antidepressive agents for depression. Cochrane Database \nSyst.\tRev.\t(2),\tArt.\tNo.:\tCD006532,\t doi:10.1002/14651858.CD006532.\npub2. \nCrisafulli, C., Drago, A., Calabro, M., et al., 2014. Pharmacogenetics \nof antidepressant drugs: an update. Hospital Pharmacology 1, 33\u201351.Jolly,\tK.,\tGammage,\t M.D.,\tCheng,\tK.K.,\tBradburn,\t P.,\tBanting,\t M.V.,\t\nLangman,\t M.J.,\t2009.\tSudden\tdeath\tin\tpatients\t receiving\t drugs\t\ntending\tto\tprolong\t the\tQT\tinterval.\t Br.\tJ.\tClin.\tPharmacol.\t 68,\t743\u2013751.\t\n(Compares the risk of sudden death in patients receiving various \nantipsychotic and antidepressant therapies )\nMalhi, G.S., Byrow, Y., Cassidy, F., et al., 2016. Ketamine: stimulating \nantidepressant\t treatment?\t Brit\tJ.\tPsychiatry\t Open\t2,\te5\u2013e9.\t(Brings \ntogether the views of a wide range of experts on the effectiveness of ketamine \nas an antidepressant )\nMayberg, H.S., Lozano, A.M., Voon, V., et al., 2005. Deep brain \nstimulation for treatment-resistant depression. Neuron 45, 651\u2013660.\nRacagni, G., Popoli, M., 2008. Cellular and molecular mechanisms in the \nlong-term action of antidepressants. Dialogues Clin. Neurosci. 10, \n385\u2013400. ( An extensive review of long-term changes induced in the brain by \nantidepressant drugs that may be responsible for producing the therapeutic \nbenefit )\nSharma, T., Guski, L.S., Freund, N.,", "start_char_idx": 0, "end_char_idx": 2799, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8b5a1da4-3c7d-4806-bf40-b20ba0ed6a0a": {"__data__": {"id_": "8b5a1da4-3c7d-4806-bf40-b20ba0ed6a0a", "embedding": null, "metadata": {"page_label": "628", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2e86c0b2-bd7c-45f4-ba93-e4fb7d65f5f5", "node_type": null, "metadata": {"page_label": "628", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4b97d07e30e75010742ef9cdbbbd6f645af4e5cec7341bd4e9649d3ea49fb8e6"}, "2": {"node_id": "516970e4-2f4f-4431-8ef0-156a834b44fd", "node_type": null, "metadata": {"page_label": "628", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "66102378e4ed1f60606e780e722db440798f7f0522f64e2a6ed64cbe380eda08"}}, "hash": "8a0f31be0f165b14743290d884da063f4969cc87c7dccb3ac2d350299ab209dc", "text": ")\nSharma, T., Guski, L.S., Freund, N., G\u00f8tzsche, P.C., 2016. Suicidality and \naggression during antidepressant treatment: systematic review and \nmeta-analyses\t based\ton\tclinical\tstudy\treports.\tBrit.\tMed.\tJ.\t352,\ti65.\t\n(Detailed analysis of published papers that concludes SSRI and NRI can \ninduce suicidality and aggression in younger people )\nLithium\nBeaulieu,\t J.M.,\tGainetdinov,\t R.R.,\tCaron,\tM.G.,\t2009.\tAkt/GSK3\t\nsignaling in the action of psychotropic drugs. Annu. Rev. Pharmacol. \nToxicol. 49, 327\u2013347.\nPhiel,\tC.J.,\tKlein,\tP.S.,\t2001.\tMolecular\t targets\tof\tlithium\taction.\tAnnu.\t\nRev. Pharmacol. Toxicol. 41, 789\u2013813. ( Review of a topic that is still little \nunderstood )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2761, "end_char_idx": 3919, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "95b8a40d-e800-4917-b8c3-1396616df9be": {"__data__": {"id_": "95b8a40d-e800-4917-b8c3-1396616df9be", "embedding": null, "metadata": {"page_label": "629", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dd3b0751-225b-4d31-bbe3-ec2b4eab3a1a", "node_type": null, "metadata": {"page_label": "629", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e6164ca4c4c57be0e5cf835835d310755b3b8cdaff3ba6d893265fbc2f122ae8"}, "3": {"node_id": "07edd5b6-0501-4400-8e19-c30c8f229b3d", "node_type": null, "metadata": {"page_label": "629", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "965121c5f330c3a9ba9889f6ce600ddbb1a97114f13369e408c7ed550236cb18"}}, "hash": "f4dffa58763a6dfe6ac0ce2c12dc581aff80ee0a132912ef5db190a875d2e4ff", "text": "623\nOVERVIEW\nIn its broadest sense, the term \u2018psychoactive drug\u2019 \nwould cover all drugs that act on the brain to produce \nchanges in perception, mood, consciousness and \nbehaviour, and would thus include anaesthetic, anxiolytic, antipsychotic and antidepressant drugs, \nwhich are described elsewhere in this book. Here we \ndescribe psychoactive drugs that are not covered in detail elsewhere. Some of these drugs have proven \ntherapeutic usefulness in the treatment of behavioural \ndisorders such as attention deficit/hyperactive disorder and narcolepsy. Others may prove to have clinical \npotential as cognition enhancers.\nMany psychoactive drugs described in this chapter \nare used to alter mood and perception, or to satisfy addiction, and are drugs of abuse. This aspect is also \ndiscussed in Chapters 50 and 59.\nFurther information on psychoactive drugs is con -\ntained in Miller (2015).\nINTRODUCTION\nAttempting to classify psychoactive drugs according to \ntheir pharmacological mechanisms of action and their \nbehavioural effects is a challenging task. Several of the \ndrugs exert more than one important pharmacological action, drugs with apparently similar pharmacological \nactivity can induce different subjective experiences (e.g. \namphetamine and MDMA) and for a single drug the behavioural response may change with dose (e.g. ethanol \ninduces excitement at low doses but is depressant at higher \ndoses). Here, for convenience, we have grouped psychoac-tive drugs as\n\u2022\tPsychomotor \tstimulants\n\u2022\tPsychedelics\n\u2022\tKetamine \tand \trelated \tdrugs\n\u2022\tDepressants\n\u2022\tSynthetic \tcannabinoids\nThe 21st century has seen an explosion in the availability \nof\tnovel\tpsychoactive \tsubstances \t(NPS).\tBy\tand\tlarge,\tthese\t\nhave been developed to circumvent legal restrictions on more established drugs (e.g. amphetamines, cocaine, MDMA \nand cannabinoids) and were for a time referred to as \u2018legal \nhighs\u2019. This has led to changes in the law in the United \nKingdom \tto \tmake \tany \tNPS \tillegal. \tNPS \tare \tappearing \tso \t\nrapidly \u2013 over 600 were recorded between 2008 and 2015 \u2013 that any catalogue of them would likely be out of date \nby the time it had been compiled. In this chapter we \nconcentrate on psychoactive drugs for which good evidence of their behavioural effects and mechanisms of action are available.\nPSYCHOMOTOR STIMULANTS\nTable 49.1 lists the major psychomotor stimulants, their mechanisms of action and clinical uses.\nAMPHETAMINES1\nDL-amphetamine (speed or billy whizz), its active dextroi-\nsomer dextroamphetamine (dexies ), and methamphetamine \n(crystal meth or ice) have very similar chemical and \npharmacological properties (Fig. 49.1).\nPharmacological effects\nThe amphetamines act by releasing monoamines, primarily dopamine and noradrenaline, from nerve terminals in the \nbrain. They do this in a number of ways. They are substrates \nfor the neuronal plasma membrane monoamine uptake transporters DAT and NET but not SERT (see Chs 15, 16 \nand 40), and thus act as competitive inhibitors, reducing \nthe reuptake of dopamine and noradrenaline. In addition, they enter nerve terminals via the uptake processes or by \ndiffusion and interact with the vesicular monoamine pump \nVMAT-2 to inhibit the uptake into synaptic vesicles of cytoplasmic dopamine and noradrenaline. The ampheta -\nmines are taken up into the storage vesicles by VMAT-2 \nand displace the endogenous monoamines from the vesicles \ninto the cytoplasm. At high concentrations, amphetamines can inhibit monoamine oxidase, which otherwise would \nbreak down", "start_char_idx": 0, "end_char_idx": 3532, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "07edd5b6-0501-4400-8e19-c30c8f229b3d": {"__data__": {"id_": "07edd5b6-0501-4400-8e19-c30c8f229b3d", "embedding": null, "metadata": {"page_label": "629", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dd3b0751-225b-4d31-bbe3-ec2b4eab3a1a", "node_type": null, "metadata": {"page_label": "629", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e6164ca4c4c57be0e5cf835835d310755b3b8cdaff3ba6d893265fbc2f122ae8"}, "2": {"node_id": "95b8a40d-e800-4917-b8c3-1396616df9be", "node_type": null, "metadata": {"page_label": "629", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4dffa58763a6dfe6ac0ce2c12dc581aff80ee0a132912ef5db190a875d2e4ff"}}, "hash": "965121c5f330c3a9ba9889f6ce600ddbb1a97114f13369e408c7ed550236cb18", "text": "amphetamines can inhibit monoamine oxidase, which otherwise would \nbreak down cytoplasmic monoamines, and monoamine \noxidase inhibitors (see Ch. 48) potentiate the effects of amphetamine. The cytoplasmic monoamines can then be \ntransported out of the nerve endings via the plasma \nmembrane DAT and NET transporters working in reverse, a process that is thought to be facilitated by amphetamine \nbinding to these transporters. All of the above will combine \nto increase the concentration of extracellular dopamine and noradrenaline in the vicinity of the synapse (see Chs 15 \nand 40).\nIn animals, prolonged administration results in degenera -\ntion of monoamine-containing nerve terminals and eventu -\nally cell death. This effect is observed with toxic doses and \nis probably due to the accumulation of reactive metabolites of the parent compounds within the nerve terminals. In human brain-imaging studies a reduction in the levels of Psychoactive drugs 49 NERVOUS SYSTEM SECTION 4\n1As\tdiscussed \tin \tthe \tPreface \tto \tthis \tbook, \tin \tChapters \t49 \tand \t50, \twhere \t\nmainly illicit drug use is being described, we use common drug names \nand spellings (e.g. amphetamine and heroin) rather than their \nrecommended international non-proprietary names (amfetamine and \n3,6-diacetyl morphine).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3455, "end_char_idx": 5224, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9ec8c017-27ec-4435-91bb-da363cd05d96": {"__data__": {"id_": "9ec8c017-27ec-4435-91bb-da363cd05d96", "embedding": null, "metadata": {"page_label": "630", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2d76ece2-3022-4022-a259-989bfd5da8d6", "node_type": null, "metadata": {"page_label": "630", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad1e3aa955a4d51b6088cce6fa8e9d3cd9bbaab08bb74c7f9d67202e5c5acdf5"}}, "hash": "ad1e3aa955a4d51b6088cce6fa8e9d3cd9bbaab08bb74c7f9d67202e5c5acdf5", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n624Table 49.1 Major central nervous system psychomotor stimulants\nDrugs Mode(s) of action Clinical significance Notes\nAmphetamine and related \ncompounds (e.g. dexamphetamine, methamphetamine)Release of DA and NAInhibition of DA and NA uptakeDexamphetamine used to treat ADHD in children; otherwise very limited clinical useSome use to treat narcolepsyRisk of dependence, sympathomimetic side effects and pulmonary hypertensionMainly important as drugs of abuseFenethylline is a prodrug that is broken down to release both amphetamine and theophylline. It is a popular drug of abuse in Arab countries\nMethylphenidateInhibition of DA and NA uptakeUsed to treat ADHD in children.Structurally related to amphetamines (see Fig. 49.1)Ethylphenidate has similar actions\nModafinil Inhibition of DA reuptakeMay have use to reduce fatigue and enhance cognition\u2014\nCocaineInhibition of DA, 5-HT and NA uptakeLocal anaestheticRisk of fetal damageOccasionally used for nasopharyngeal and ophthalmic anaesthesia (see Ch. 44)Major drug of abuse\nMDMA (ecstasy)Releases 5-HT and inhibits uptakeMay have potential in the treatment of post-traumatic stress disorderOther related drugs are 3,4-methylenedioxyamphetamine (MDA), 4-bromo-2,5-\ndimethoxyphenethylamine (2CB) and 4-methylthioamphetamine \n(4-MTA)\nParamethoxyamphetamine (PMA)Releases 5-HT and blocks uptake\u2014Often added to, or sold as, MDMA,paramethoxymethamphetamine (PMMA) is similar but less potent\nMethyloneInhibits NA, DA and 5-HT uptake\u2014Cathinone derivative containing the dioxy ring of MDMAEthylone and butylone are similar\nBenzofuran derivativesReleases 5-HT and NA and inhibit uptake\u2014Have both MDMA and amphetamine-like propertiesExamples include 1-(benzofuran-\n5-yl)-propan-2-amine (5APB) and 1-(benzofuran-6-yl)-propan-2-amine (6APB)\nMephedroneInhibition of DA and 5-HT uptake\u2014Drug of abuseDerived from cathinoneMethedrone and mexedrone are \nsimilar\nBenzylpiperazine (BZP)Inhibition of DA, NA and 5-HT uptake\u03b1\n2-adrenoceptor agonist, \n5-HT 2A agonist\u2014 Drug of abuse\nMethylxanthines (e.g. caffeine, theophylline)Inhibition of phosphodiesteraseAntagonism of adenosine A\n2 \nreceptorsTheophylline used for action on \ncardiac and bronchial muscle \n(see Chs 22 and 29)Caffeine is a constituent of \nbeverages and tonics. It is also \navailable in tablet form\nNicotineStimulates and desensitises nicotinic receptors (see Chs 14 and 40)\u2014 \u2014\nArecoline Muscarinic agonist \u2014Mild stimulant contained in betel nut. Use is widespread in India, Thailand, Indonesia and other Asian countries\nADHD, attention deficit/hyperactivity disorder; DA, dopamine; 5-HT, 5-hydroxytryptamine; NA, noradrenaline.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3139, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f36ab8bc-71a5-4dc5-a0e2-5ac5c71005ea": {"__data__": {"id_": "f36ab8bc-71a5-4dc5-a0e2-5ac5c71005ea", "embedding": null, "metadata": {"page_label": "631", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d587c035-8386-43dc-b3b0-c7c6e58ef870", "node_type": null, "metadata": {"page_label": "631", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dc736bd8254b12a61170ae219ad22de9a20ea0a57ea7a36954f68958023cf348"}, "3": {"node_id": "e519616a-8e39-4172-a6c7-16fbe874a111", "node_type": null, "metadata": {"page_label": "631", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51bdbdfae1eafb763a6a0923a54f9bf1aa0a03573bbe887ac3350350cee20bc3"}}, "hash": "67ed94c0fed81faf2ca2bc33bb7ba6d8e2331288327fe4aa69e9661b8402aef0", "text": "49 PSYchOacTiVE dRUgS\n625an acute schizophrenic attack (see Ch. 47), with hallucina -\ntions, paranoia and aggressive behaviour. At the same time, \nrepetitive stereotyped behaviour may develop. The close \nsimilarity of this condition to schizophrenia, and the effectiveness of antipsychotic drugs in controlling it, is \nconsistent with the dopamine theory of schizophrenia (see \nCh. 47).\nTolerance develops rapidly to euphoric and anorexic \neffects of amphetamines, but more slowly to the other effects. \nPresumably \ttolerance \tis \tdue \tto \tdepletion \tof \tdopamine \tin \t\nnerve terminals.\nPsychological \tdependence \ton \tamphetamines, \ta \tconse -\nquence of the insistent memory of euphoria, is very strong \n(see Ch. 50). When drug taking is stopped there is usually \na period of deep sleep, and on awakening the subject feels lethargic, depressed, anxious, irritable (sometimes \neven suicidal) and hungry. These after effects may be \nthe result of depletion of the normal stores of dopamine and noradrenaline. It is estimated that about 10%\u201315% \nof users progress to full dependence, the usual pattern \nbeing that the dose is increased as tolerance develops, and then uncontrolled \u2018binges\u2019 occur in which the user takes the drug repeatedly over a period of a day or more, \nremaining continuously intoxicated. Large doses may \nbe consumed in such binges, with a high risk of acute toxicity, and the demand for the drug displaces all other \nconsiderations.\nExperimental animals, given unlimited access to \namphetamine, take it in such large amounts that they die \nfrom the cardiovascular effects within a few days. Given \nlimited amounts, they too develop a binge pattern of \ndependence.\nPharmacokinetic aspects\nAmphetamines are readily absorbed from the gastrointestinal tract, but to increase the intensity of the hit the drugs can \nbe snorted or injected. In crystal form, the free base of \nmethamphetamine can be ignited and smoked in a manner similar to crack cocaine (see p. 627). Amphetamines freely \npenetrate the blood\u2013brain barrier. They do this more readily \nthan other indirectly acting sympathomimetic amines such as ephedrine or tyramine (Ch. 15), which probably explains \nwhy they produce more marked central effects than those drugs. Amphetamines are mainly excreted unchanged in the urine, and the rate of excretion is increased when the urine is made more acidic (see Fig. 10.6).\nMETHYLPHENIDATE\nMethylphenidate (Ritalin) inhibits the NET and DAT transporters on the neuronal plasma membrane. Unlike \nthe amphetamines, methylphenidate is not a substrate \nfor these transporters and thus does not enter the nerve terminals to facilitate noradrenaline (NA) and dopamine \n(DA) release (Heal et al., 2009). It nevertheless produces \na profound and sustained elevation of extracellular NA \nand DA.\nMethylphenidate is orally active, being absorbed from \nthe intestine, but it undergoes presystemic metabolism such that only ~20% enters the systemic circulation. Absorption \nis slow following oral administration \u2013 T\nmax ~2 hours \u2013 which \nmay limit the intensity of any euphoric response to the drug. It is metabolised by carboxylesterase and has a half-life \nof ~2\u20134 h . It is used therapeutically to treat attention deficit/\nhyperactivity disorder (ADHD; see p. 626) and may also \nhave cognition-enhancing effects (see p. 633).DAT and D 2 receptors has been observed in the brains of \namphetamine users. It is unclear, however, whether this \nis due to long-term exposure to the drug inducing nerve \ndamage or is an", "start_char_idx": 0, "end_char_idx": 3529, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e519616a-8e39-4172-a6c7-16fbe874a111": {"__data__": {"id_": "e519616a-8e39-4172-a6c7-16fbe874a111", "embedding": null, "metadata": {"page_label": "631", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d587c035-8386-43dc-b3b0-c7c6e58ef870", "node_type": null, "metadata": {"page_label": "631", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dc736bd8254b12a61170ae219ad22de9a20ea0a57ea7a36954f68958023cf348"}, "2": {"node_id": "f36ab8bc-71a5-4dc5-a0e2-5ac5c71005ea", "node_type": null, "metadata": {"page_label": "631", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "67ed94c0fed81faf2ca2bc33bb7ba6d8e2331288327fe4aa69e9661b8402aef0"}}, "hash": "51bdbdfae1eafb763a6a0923a54f9bf1aa0a03573bbe887ac3350350cee20bc3", "text": "\nis due to long-term exposure to the drug inducing nerve \ndamage or is an underlying pathology that was responsible for drug-seeking in the first instance.\nThe main central effects of amphetamine-like drugs are:\n\u2022\tlocomotor \tstimulation\n\u2022\teuphoria \tand \texcitement\n\u2022\tinsomnia\n\u2022\tincreased \tstamina\n\u2022\tanorexia\n\u2022\tlong-term \tpsychological \teffects: \tpsychotic \tsymptoms, \t\nanxiety, depression and cognitive impairment\nIn addition, amphetamines have peripheral sympathomi-\nmetic actions (Ch. 15), producing a rise in blood pressure \nand inhibition of gastrointestinal motility.\nIn humans, amphetamines cause euphoria; with intra -\nvenous injection, this can be so intense as to be described as \u2018orgasmic\u2019. Rats quickly learn to press a lever in order to obtain a dose of amphetamine \u2013 an indication that the \ndrug is rewarding. Humans become confident, hyperactive \nand talkative, and sex drive is said to be enhanced. Fatigue, both physical and mental, is reduced. Amphetamines (and \nsimilar drugs such as dexfenfluramine and sibutramine) \ncause marked anorexia, but with continued administration \nthis effect wears off and food intake returns to normal. \nThey are no longer used clinically for weight reduction \n(Ch. 33). They are ineffective in producing maintained weight loss, and their central nervous system (CNS) and \ncardiovascular effects are harmful.\nAdverse effects of amphetamines include feelings of \nanxiety, irritability and restlessness. High doses may induce \npanic and paranoia.\nThe locomotor and rewarding effects of amphetamine are \ndue mainly to release of dopamine rather than noradrena -\nline, since destruction of the dopamine-containing nucleus \naccumbens (see Ch. 40) or administration of D\n2-receptor \nantagonists (see Ch. 47) inhibit these responses, which are absent in mice genetically engineered to lack DAT.\nChronic use, tolerance and dependence\nIf amphetamines are taken repeatedly over a few days, a \nstate of \u2018amphetamine psychosis\u2019 can develop, resembling AmphetamineCH2CHNH2CH3\nMethamphetamineCH2CHNHCH3CH3\nO\nO\nMethylenedioxymethamphetamine\n(MDMA, \u2018ecstasy\u2019)CH2CHNHCH3CH3\nMethylphenidateN\nHCCOOCH3\nFig. 49.1 Structures of amphetamine, MDMA and related \ndrugs. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3456, "end_char_idx": 6129, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "17ec8187-c9bd-4923-b31b-71360471fcb6": {"__data__": {"id_": "17ec8187-c9bd-4923-b31b-71360471fcb6", "embedding": null, "metadata": {"page_label": "632", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ead50f6-ec16-457d-8cf7-e29e6f9209fb", "node_type": null, "metadata": {"page_label": "632", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe2c192f94fe1edd0e813cf8ac6da5ba7b2acf04f298afdef015cd664d36753b"}, "3": {"node_id": "c48be504-0ab3-4d25-9333-51bae94645a0", "node_type": null, "metadata": {"page_label": "632", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4576fe20758ede092ecf1f7f6118eabc037b3016383c38341bcbcb3ddd82867"}}, "hash": "ad50394b264793b8e8e3c6a690cad1526142e4e697d44365c3b582b89d266fc5", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n626sometimes continued into adolescence and beyond. Drug \ntreatment should be part of a programme that includes \npsychological intervention if available, and is started after \nthe diagnosis has been confirmed by an expert. Disorders of noradrenaline and dopamine pathways in the frontal \ncortex and basal ganglia are thought to underlie ADHD \nsymptomatology, but there is still controversy over the relative importance of each monoamine and the specific \nbrain regions involved in the actions of drugs used to \nalleviate the symptoms of ADHD.\nSlow-release formulations of amphetamine and methyl -\nphenidate have been developed to deliver more stable \nconcentrations of drug, lower than that required to produce \neuphoria. D-amphetamine conjugated to lysine ( lisdexa-\nmphetamine) is an inactive prodrug that, following oral \nadministration, is cleaved enzymatically to release D-amphetamine, resulting in a slower onset of action and potentially a reduced abuse potential.\n\u25bc Other drug treatments for ADHD include the noradrenaline reuptake \ninhibitor atomoxetine (Ch. 48), and \u03b12-adrenoceptor agonists such \nas clonidine and guanfacine. The monoamine uptake inhibitor \nmodafinil is not approved for paediatric use but may be effective in \nadult ADHD, as is bupropion. Melatonin (Ch. 40) improves sleep \npatterns in ADHD sufferers. The pharmacology of drugs used to \ntreat ADHD is reviewed by Heal et al. (2009).\nNarcolepsy\nThis is a rare, disabling sleep disturbance in which the \npatient suddenly and unpredictably falls asleep at frequent \nintervals during the day, while suffering nocturnal insom -\nnia. Amphetamine is helpful but not completely effective. \nModafinil is also effective in reducing attacks. Narcolepsy \nis often accompanied by cataplexy (abrupt onset of paralysis \nof variable extent often triggered by emotion, sometimes \nwith \u2018frozen\u2019 posture). Treatment is usually with fluoxetine , \na selective 5-HT reuptake inhibitor or venlafaxine, a 5-HT \nand norepinephrine reuptake inhibitor (see Ch. 48). Sodium \noxybate , the sodium salt of \u03b3-hydroxybutyrate (also known \nas\tGHB\tand\tfrequently \tabused,\tsee\tCh.\t39),\tis\ta\tCNS\tdepres -\nsant that paradoxically is used to prevent cataplexy.MODAFINIL\nModafinil is the primary metabolite of adrafinil, a drug \nthat was introduced as a treatment for narcolepsy in the \n1980s. Since 1994, modafinil has been available as a drug \nin its own right. It inhibits dopamine reuptake by binding to DAT but with low potency. In the human brain, modafinil \nblocks DAT and increases extracellular dopamine levels \nin the caudate, putamen and nucleus accumbens. It also produces a number of other effects including \u03b1\n1-drenoceptor \nactivation, enhanced release of 5-hydroxytryptamine (5-HT), \nglutamate \tand\thistamine, \tand\tinhibition \tof\tGABA\trelease,\t\nas well as enhanced electrotonic coupling between neurons. The contribution of each action to the behavioural effects \nof modafinil remains to be clarified. Modafinil enhances \nsome aspects of cognitive performance (see p. 633), and has gained popularity as a \u2018lifestyle drug\u2019 (see Ch. 59) for \nthis reason.\nModafinil is well absorbed from the gut, metabolised in \nthe liver and has a half-life of 10\u201314 h. While reported to \n\u2018brighten mood\u2019 there is little evidence that modafinil \nproduces significant levels of euphoria when administered \nby mouth, but", "start_char_idx": 0, "end_char_idx": 3391, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c48be504-0ab3-4d25-9333-51bae94645a0": {"__data__": {"id_": "c48be504-0ab3-4d25-9333-51bae94645a0", "embedding": null, "metadata": {"page_label": "632", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4ead50f6-ec16-457d-8cf7-e29e6f9209fb", "node_type": null, "metadata": {"page_label": "632", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fe2c192f94fe1edd0e813cf8ac6da5ba7b2acf04f298afdef015cd664d36753b"}, "2": {"node_id": "17ec8187-c9bd-4923-b31b-71360471fcb6", "node_type": null, "metadata": {"page_label": "632", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad50394b264793b8e8e3c6a690cad1526142e4e697d44365c3b582b89d266fc5"}}, "hash": "b4576fe20758ede092ecf1f7f6118eabc037b3016383c38341bcbcb3ddd82867", "text": "\nproduces significant levels of euphoria when administered \nby mouth, but tablets can be crushed and snorted to obtain \na quicker onset of effect. Modafinil is too insoluble for intravenous injection to be practical.\nCLINICAL \u2003USE \u2003OF \u2003STIMULANTS\nAttention deficit/hyperactivity disorder (ADHD)The main use of amphetamines and methylphenidate is in \nthe treatment of ADHD, a common and increasingly \ndiagnosed condition, estimated as occurring in up to 9% of children whose overactivity and limited attention span \ndisrupt their education and social development. The efficacy \nof drug treatment (e.g. with methylphenidate) has been confirmed in controlled trials, but there is concern as to \npossible long-term adverse effects since treatment is Amphetamines \n\u2022\tThe\tmain \teffects \tare:\n\u2013 increased motor activity\n\u2013 euphoria and excitement\n\u2013 insomnia\n\u2013 anorexia\n\u2013 with prolonged administration, stereotyped and \npsychotic behaviour\n\u2022\tEffects\tare \tdue \tmainly \tto \trelease \tof \tcatecholamines, \t\nespecially dopamine and noradrenaline.\n\u2022\tStimulant \teffect \tlasts \tfor \ta \tfew \thours \tand \tis \tfollowed \t\nby depression and anxiety.\n\u2022\tTolerance \tto \tthe \tstimulant \teffects \tdevelops \trapidly, \t\nalthough\tperipheral \tsympathomimetic \teffects \tmay \t\npersist.\n\u2022\tAmphetamines \tinduce \tstrong \tpsychological \t\ndependence.\n\u2022\tAmphetamine \tpsychosis, \twhich \tclosely \tresembles \t\nschizophrenia, \tcan \tdevelop \tafter \tprolonged \tuse.\n\u2022\tAmphetamines \tmay \tbe \tuseful \tin \ttreating \tnarcolepsy, \t\nand also (paradoxically) to control hyperkinetic \nchildren.\tThey \tare \tno \tlonger \tprescribed \tas \tappetite \t\nsuppressants.\n\u2022\tTheir\tmain \timportance \tis \tin \tdrug \tabuse.\nClinical uses of CNS stimulants \n\u2022\tCentral\tnervous \tsystem \t(CNS) \tstimulants \thave \tfew \t\nlegitimate therapeutic indications. Where appropriate \nthey are usually initiated by experts.\n\u2022\tAttention \tdeficit/hyperactivity \tdisorder \t(ADHD): \t\nmethylphenidate, atomoxetine \t(see\tCh.\t48). \t\nDexamphetamine is an alternative in children who do not respond.\n\u2022\tNarcolepsy: \tmodafinil \tfor\tthe\texcessive \tsleepiness; \t\noxybate to reduce cataplexy (which can be associated with narcolepsy).\n\u2022\tApnoea \tof \tprematurity: \txanthine alkaloids (under expert \nsupervision \tin \thospital) \tare \teffective; \tcaffeine is \npreferred\tto \ttheophylline.\nCOCAINE\nCocaine is found in the leaves of the South American shrub \ncoca. These leaves are used for their stimulant properties by \nnatives of South America, particularly those in mountainous mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3318, "end_char_idx": 6273, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ac3749f-eceb-4bbf-8912-e28edbdac033": {"__data__": {"id_": "8ac3749f-eceb-4bbf-8912-e28edbdac033", "embedding": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8703b11f-dc88-4e11-850d-8402c234356f", "node_type": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0a6bdc81af5ab227854fe2b8797c37f59f3273da763cd78e07d8ee860280f49"}, "3": {"node_id": "ad4cc372-698b-45d5-be2c-a91578887da6", "node_type": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2885b687302015155a9598c9e79954d0e9c5a23848d0de8907e0d847695577c8"}}, "hash": "7fdc4cbe175032296850eca37b1c7f7cfd4ef0a1795ec4e473876dde71beb66a", "text": "49 PSYchOacTiVE dRUgS\n627psychological dependence where users crave the drug\u2019s \neuphoric and stimulatory effects. The cellular mechanisms \nunderlying craving, and pharmacological approaches to \nreduce craving, are discussed in Chapter 50. The pattern of dependence, evolving from occasional use through \nescalating dosage to compulsive binges, is similar to that \nseen with amphetamines.\nPharmacokinetic aspects\nCocaine is readily absorbed by many routes. For many years illicit supplies have consisted of the hydrochloride \nsalt, which could be taken by nasal inhalation or intra-\nvenously. The latter route produces an intense and immedi -\nate euphoria, whereas nasal inhalation produces a less \ndramatic sensation and also tends to cause atrophy and \nnecrosis of the nasal mucosa and septum.\nCocaine use increased dramatically when the free-base \nform (\u2018crack\u2019) became available as a street drug. When an aqueous solution of cocaine hydrochloride is heated with sodium bicarbonate, free-base cocaine, water, CO\n2 and NaCl \nare produced. The free-base cocaine is insoluble in water, \nprecipitates out and can then be rolled into \u2018rocks\u2019 of crack. \nFree-base cocaine vaporises at around 90\u00b0C, much lower than the melting point of cocaine hydrochloride (190\u00b0C), \nwhich burns rather than vaporises. Thus crack can be \nsmoked, with the uncharged free base being rapidly absorbed across the large surface area of the alveolae, giving \nrise to a greater CNS effect than that obtained by snorting \ncocaine. Indeed, the effect is nearly as rapid as that of intravenous administration. The social, economic and even political consequences of this small change in formulation \nhave been far-reaching.\nThe duration of its stimulant effect, about 30 min, is much \nshorter than that of amphetamine. It is rapidly metabolised \nin the liver. Heroin users may inject cocaine and heroin \ntogether intravenously (known as speedballing) to obtain \nthe rapid effect of cocaine before the prolonged effect of \nheroin kicks in.\nA cocaine metabolite is deposited in hair, and analysis \nof its content along the hair shaft allows the pattern of cocaine consumption to be monitored, a technique that has \nrevealed a much higher incidence of cocaine use than was \nvoluntarily reported. Cocaine exposure in utero can be estimated from analysis of the hair of neonates.\nCocaine is still occasionally used topically as a local \nanaesthetic, mainly in ophthalmology and minor nose and throat surgery, where its local vasoconstrictor action is an advantage, but has no other clinical uses.\nAdverse effects\nToxic effects occur commonly in cocaine abusers. The main acute dangers are serious cardiovascular events (cardiac \ndysrhythmias, aortic dissection, and myocardial or cerebral \ninfarction \tor\thaemorrhage). \tProgressive \tmyocardial \tdamage\t\ncan lead to heart failure, even in the absence of a history \nof acute cardiac effects.\nCocaine can severely impair brain development in utero. \nThe brain size is significantly reduced in babies exposed to cocaine in pregnancy, and neurological and limb mal -\nformations are increased. The incidence of ischaemic and haemorrhagic brain lesions, and of sudden infant death, is also higher in cocaine-exposed babies. Interpretation of \nthe data is difficult because many cocaine abusers also take \nother illicit drugs that may affect fetal development, but the probability is that cocaine is highly detrimental.areas, who use it to reduce fatigue during work at high altitude.\nConsiderable mystical significance", "start_char_idx": 0, "end_char_idx": 3527, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ad4cc372-698b-45d5-be2c-a91578887da6": {"__data__": {"id_": "ad4cc372-698b-45d5-be2c-a91578887da6", "embedding": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8703b11f-dc88-4e11-850d-8402c234356f", "node_type": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0a6bdc81af5ab227854fe2b8797c37f59f3273da763cd78e07d8ee860280f49"}, "2": {"node_id": "8ac3749f-eceb-4bbf-8912-e28edbdac033", "node_type": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7fdc4cbe175032296850eca37b1c7f7cfd4ef0a1795ec4e473876dde71beb66a"}, "3": {"node_id": "abd72f2f-6891-4008-8ca8-c4cc40cff131", "node_type": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7e0edd7c9e8e1cb278ab0f0371a8ed8b34484a77afc6bc743303bf0038b1aa53"}}, "hash": "2885b687302015155a9598c9e79954d0e9c5a23848d0de8907e0d847695577c8", "text": "reduce fatigue during work at high altitude.\nConsiderable mystical significance was attached to the \npowers of cocaine to boost the flagging human spirit, and Freud tested it extensively on his patients and his family, \npublishing an influential monograph in 1884 advocating \nits use as a psychostimulant.\n2 Freud\u2019s ophthalmologist \ncolleague, \tK\u00f6ller, \tobtained \tsupplies \tof \tthe \tdrug \tand \tdis-\ncovered its local anaesthetic action (Ch. 44), but the psy -\nchostimulant effects of cocaine have not proved to be clinically useful. On the other hand, they led to it becoming a widespread drug of abuse in Western countries. The \nmechanisms and treatment of cocaine abuse are discussed \nin Chapter 50.\nPharmacological effects\nCocaine binds to and inhibits the transporters NET, DAT and SERT (see Chs 15, 16 and 40), thereby producing a \nmarked psychomotor stimulant effect, and enhancing the \nperipheral effects of sympathetic nerve activity.\nIn humans, cocaine produces euphoria, garrulousness, \nincreased motor activity and a magnification of pleasure. Users feel alert, energetic and physically strong and believe they have enhanced mental capabilities. Its effects resemble \nthose of amphetamines, although it has less tendency to \nproduce stereotyped behaviour, delusions, hallucinations and paranoia. Evidence from transgenic knock-out mice indicates that the euphoric effects of cocaine involve inhibi -\ntion of both dopamine and 5-HT reuptake. The peripheral sympathomimetic actions lead to tachycardia, vasoconstric -\ntion\tand\tan \tincrease \tin \tblood \tpressure. \tBody \ttemperature \t\nmay increase, owing to the increased motor activity coupled with reduced heat loss. With excessive dosage, tremors \nand convulsions, followed by respiratory and vasomotor \ndepression, may occur.\nExperimental animals rapidly learn to press a lever to \nself-administer cocaine and will consume toxic amounts of the drug if access is not limited. In transgenic mice lacking the D\n2 receptor, the enhanced locomotor effects of \ncocaine are reduced, but surprisingly self-administration \nof cocaine is increased, in contrast to what is found \nwith other self-administered drugs such as ethanol and \nmorphine.\nChronic use, dependence and tolerance\nCocaine undoubtedly causes strong psychological depend -\nence (see Ch. 50), but there is some debate about whether \nor not its continued use induces tolerance and physical \ndependence. Users may increase their intake of the drug but this may reflect a desire for an increased effect rather \nthan the development of tolerance. In experimental animals, \nsensitisation (the opposite of tolerance) can be observed but the relevance of this to the situation in humans is unclear. \nCocaine does not produce a clear-cut withdrawal syndrome \nbut depression, dysphoria and fatigue may be experienced following the initial stimulant effect. Cocaine induces \n2In the 1860s a Corsican pharmacist, Mariani, devised cocaine-\ncontaining beverages, Vin Mariani and Th\u00e9 Mariani, which were sold \nvery successfully as tonics. Imitators soon moved in, and Th\u00e9 Mariani \nbecame the forerunner of Coca-Cola. In 1903, cocaine was removed from Coca-Cola because of its growing association with addiction and \ncriminality.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3457, "end_char_idx": 6976, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "abd72f2f-6891-4008-8ca8-c4cc40cff131": {"__data__": {"id_": "abd72f2f-6891-4008-8ca8-c4cc40cff131", "embedding": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "8703b11f-dc88-4e11-850d-8402c234356f", "node_type": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f0a6bdc81af5ab227854fe2b8797c37f59f3273da763cd78e07d8ee860280f49"}, "2": {"node_id": "ad4cc372-698b-45d5-be2c-a91578887da6", "node_type": null, "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2885b687302015155a9598c9e79954d0e9c5a23848d0de8907e0d847695577c8"}}, "hash": "7e0edd7c9e8e1cb278ab0f0371a8ed8b34484a77afc6bc743303bf0038b1aa53", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7016, "end_char_idx": 7239, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ab92eae8-620f-46d6-bfa3-c6699396b557": {"__data__": {"id_": "ab92eae8-620f-46d6-bfa3-c6699396b557", "embedding": null, "metadata": {"page_label": "634", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3d7f5e90-b5b5-4f5c-8e92-f1938d552974", "node_type": null, "metadata": {"page_label": "634", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6291e5973b5600261c6b0edd6e634e6abdd64f6f3c339a82ab53ba83c95b42cb"}, "3": {"node_id": "f5b0d324-b66e-40b3-94a1-863dc313e122", "node_type": null, "metadata": {"page_label": "634", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ccb48d6d73469155b7ff050bba00f3a6166f5808dba567c1e7369805234c9bdc"}}, "hash": "6938faac7a97d7cb0bdf2cb922a52cb23fca400b83b8e67100d70fd2f1b9b117", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n628addition, MDMA causes inappropriate secretion of \nantidiuretic hormone (see Ch. 34). This can lead to \noverhydration and hyponatraemia (\u2018water \nintoxication\u2019). Symptoms include dizziness and disorientation, leading to collapse into coma.\n\u2022\tHeart\tfailure \tin \tindividuals \twith \tan \tundiagnosed \t\nheart condition.\nThe after effects of MDMA persist for a few days and \ncomprise depression, anxiety, irritability and increased \naggression \u2013 the \u2018mid-week blues\u2019. There is also evidence of long-term deleterious effects on memory and cognitive function in heavy MDMA users. In animal studies, MDMA \ncan cause degeneration of 5-HT and dopamine neurons, \nbut whether this occurs in humans is uncertain (see Green \net al., 2012).Dependence, the main psychological adverse effect of \namphetamines and cocaine, has potentially severe effects \non quality of life (Ch. 50).\nCocaine \n\u2022\tCocaine acts by inhibiting catecholamine uptake \n(especially dopamine) by nerve terminals.\n\u2022\tBehavioural \teffects \tof \tcocaine \tare \tvery \tsimilar \tto \tthose \t\nof\tamphetamines, \talthough \tpsychotomimetic \teffects \t\nare\trarer.\tDuration \tof \taction \tis \tshorter.\n\u2022\tCocaine\tused\tin\tpregnancy \timpairs \tfetal \tdevelopment \t\nand\tmay\tproduce \tfetal \tmalformations.\n\u2022\tCocaine produces strong psychological dependence.Time (h)41\n37383940Rectal temp. (oC)\n-1 012345\nMDMA 15 mg/kg MDMA 4 mg/kgMDMA 10 mg/kg Saline\nFig. 49.2 A single injection of MDMA causes a dose-\nrelated increase in body temperature in rats. \tDrug\t\nadministered \tat \ttime \tzero. \t(Reproduced \twith \tpermission \tfrom \t\nGreen\tet\tal., \t2004. \tEur. \tJ. \tPharmacol. \t500, \t3\u201313.)\nMDMA (ecstasy) \n\u2022\tMDMA\tis\tan\tamphetamine \tanalogue \tthat \thas \tpowerful \t\npsychostimulant as well as mild psychotomimetic \neffects.\n\u2022\tMDMA inhibits monoamine transporters, principally \nthe\t5-hydroxytryptamine \t(5-HT) \ttransporter, \tand \t\nreleases\t5-HT.\n\u2022\tMDMA can cause an acute hyperthermic reaction as well as overhydration and hyponatraemia, sometimes fatal.\n\u2022\tMDMA does not cause physical dependence.MDMA\nMDMA (3,4-methylenedioxymethamphetamine, \u2018ecstasy\u2019 \nor \u2018molly\u2019) and related drugs are widely used as \u2018party \ndrugs\u2019 because of the feelings of empathy and euphoria, and \nthe loss of inhibitions, heightened sensations and energy surge, that they produce. They are sometimes referred to \nas \u2018empathogens\u2019 or \u2018enactogens\u2019. They also have mild \nhallucinogenic effects. Common examples are listed in Table 49.1. In conjunction with psychotherapy, MDMA is in phase III clinical trials for the treatment of post-traumatic \nstress disorder.\nPharmacological effects\nAlthough an amphetamine derivative (see Fig. 49.1), MDMA \naffects monoamine function in a different manner from the \namphetamines. It inhibits monoamine transporters, prin -\ncipally the 5-HT transporter, and also releases 5-HT, the \nnet effect being a large increase in free 5-HT in certain \nbrain regions, followed by depletion. Similar but smaller \nchanges occur in relation to dopamine and noradrenaline release. Simplistically, the effects on 5-HT function determine \nthe psychotomimetic effects, while dopamine and", "start_char_idx": 0, "end_char_idx": 3130, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f5b0d324-b66e-40b3-94a1-863dc313e122": {"__data__": {"id_": "f5b0d324-b66e-40b3-94a1-863dc313e122", "embedding": null, "metadata": {"page_label": "634", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3d7f5e90-b5b5-4f5c-8e92-f1938d552974", "node_type": null, "metadata": {"page_label": "634", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6291e5973b5600261c6b0edd6e634e6abdd64f6f3c339a82ab53ba83c95b42cb"}, "2": {"node_id": "ab92eae8-620f-46d6-bfa3-c6699396b557", "node_type": null, "metadata": {"page_label": "634", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6938faac7a97d7cb0bdf2cb922a52cb23fca400b83b8e67100d70fd2f1b9b117"}}, "hash": "ccb48d6d73469155b7ff050bba00f3a6166f5808dba567c1e7369805234c9bdc", "text": "5-HT function determine \nthe psychotomimetic effects, while dopamine and noradrena -\nline changes account for the initial euphoria and later \nrebound dysphoria. MDMA does not induce psychological or physical dependence but its use carries serious risks. \nUnintentional consumption of high doses may occur if pills \nhave a higher than expected MDMA content or when MDMA is taken in powdered form. Also, illicit MDMA \ntablets or powders may be contaminated with or entirely \nsubstituted with para -methoxyamphetamine\n\t(PMA)\ta\tmore\t\ndangerous psychoactive agent.\nCommon adverse effects of MDMA ingestion are:\n\u2022\tAcute\thyperthermia \t(Fig. \t49.2), \tresulting \tin \tdamage \tto \t\nskeletal muscle and consequent renal failure. It is still unclear how hyperthermia is produced in humans. It \nmay be mediated centrally through release of 5-HT, \ndopamine and noradrenaline acting on various receptors for these monoamines (Docherty & Green, \n2010). It could also reflect an action of MDMA on \nmitochondrial function. It is exacerbated by energetic dancing and high ambient temperature and certain \nindividuals may be particularly susceptible to this \ndanger.\n\u2022\tExcess \twater \tintake \tand \twater \tretention. \tUsers \tmay \t\nconsume large amounts of water as a result of increased physical activity and feeling hot. In CATHINONES\nCathinone and cathine are the active ingredients in the khat shrub. Chewing the leaves is popular in parts of Africa, \nsuch as Ethiopia and Somalia, and its use is spreading \nthrough immigrant populations in Western countries.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3058, "end_char_idx": 5076, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6be165eb-c820-497a-a223-7d02bace9369": {"__data__": {"id_": "6be165eb-c820-497a-a223-7d02bace9369", "embedding": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "874b9f4e-e762-491e-a533-a181f375a3fd", "node_type": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19f36ac35a8c097c1a86936f8d024a7fd9cf0f08e8c2d2adfbb1e3ab029fde2c"}, "3": {"node_id": "da7077c6-2ce5-4b8e-8def-ec1d4a757d0a", "node_type": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "190a1eede6ad13599d110b7fdd713c85ed2c0a712691b4b415dc8d520ee8eeba"}}, "hash": "f6fd103a57f2908780355c982bc8add8cf17f22a4c8df51d61bfb6a48df8138c", "text": "49 PSYchOacTiVE dRUgS\n629stereotyped behaviour patterns or a psychotic state, but \ntheir effects on fatigue and mental function are similar.\nTolerance and habituation develop to a small extent, but \nmuch less than with amphetamines; withdrawal effects are modest but can be troublesome.\n3 Caffeine is not self-\nadministered by animals, and it cannot be classified as a \ndependence-producing drug.\nClinical use and unwanted effects\nThere are few clinical uses for caffeine. It is included with \naspirin in some preparations for treating headaches and \nother aches and pains, and with ergotamine in some \nantimigraine preparations, the objective being to produce a mildly agreeable sense of alertness. Methylxanthines are \neffective respiratory stimulants in the treatment of apnoea \nof prematurity (a developmental disorder caused by immaturity of central respiratory control), for which indica -\ntion caffeine is preferred to theophylline because of its long half-life and safety. Theophylline (formulated as aminophyl -\nline) is used mainly as a bronchodilator in treating severe asthmatic attacks (see Ch. 29). In vitro tests show that it \nhas mutagenic activity, and large doses are teratogenic in \nanimals. However, epidemiological studies have shown no evidence of carcinogenic or teratogenic effects of tea or \ncoffee drinking in humans.Synthetic cathinone derivatives have become popular \nstreet drugs as they produce feelings of elevated mood and improved mental function. Mephedrone elevates \nextracellular levels of both dopamine and 5-HT, possibly by inhibiting reuptake and enhancing release.\nMETHYLXANTHINES\nVarious beverages, particularly tea, coffee and cocoa, contain methylxanthines, to which they owe their mild central \nstimulant effects. The main compounds responsible are \ncaffeine and theophylline. The nuts of the cola plant also contain caffeine, which is present in cola-flavoured soft \ndrinks. However, the most important sources, by far, are \ncoffee and tea, which account for more than 90% of caffeine consumption. Further information on the pharmacology \nand toxicology of caffeine is presented by Fredholm et al. \n(1999).\nPharmacological effects\nMethylxanthines have the following major pharmacological actions:\n\u2022\tCNS\tstimulation\n\u2022\tmild\tdiuresis, \tnot \tclinically \tsignificant\n\u2022\tstimulation \tof \tcardiac \tmuscle \t(see \tCh. \t22)\n\u2022\trelaxation \tof \tsmooth \tmuscle, \tespecially \tbronchial \t\nmuscle (see Ch. 29)\nThe latter two effects resemble those of \u03b2-adrenoceptor \nstimulation (see Chs 15, 22 and 29). This is thought to be \nbecause methylxanthines (especially theophylline ) inhibit \nphosphodiesterase, which is responsible for the intracellular \nmetabolism \tof\tcAMP\t(Ch.\t3).\tThey\tthus\tincrease\tintracellular \t\ncAMP\tand \tproduce \teffects \tthat \tmimic \tthose \tof \tmediators \t\nthat stimulate adenylyl cyclase. Methylxanthines also antagonise many of the effects of adenosine, acting on \nboth A\n1 and A 2 receptors (see Ch. 17). Transgenic mice \nlacking functional A 2 receptors are abnormally active and \naggressive, and fail to show increased motor activity in response to caffeine, suggesting that antagonism at A\n2 \nreceptors accounts for part, at least, of its CNS stimulant action. Caffeine also sensitises ryanodine receptors (see \nCh. 4) but this effect occurs at higher concentrations (>\n10 mmol/L) than those achieved by recreational intake \nof caffeine. The concentration of", "start_char_idx": 0, "end_char_idx": 3413, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "da7077c6-2ce5-4b8e-8def-ec1d4a757d0a": {"__data__": {"id_": "da7077c6-2ce5-4b8e-8def-ec1d4a757d0a", "embedding": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "874b9f4e-e762-491e-a533-a181f375a3fd", "node_type": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19f36ac35a8c097c1a86936f8d024a7fd9cf0f08e8c2d2adfbb1e3ab029fde2c"}, "2": {"node_id": "6be165eb-c820-497a-a223-7d02bace9369", "node_type": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f6fd103a57f2908780355c982bc8add8cf17f22a4c8df51d61bfb6a48df8138c"}, "3": {"node_id": "09bcd39e-0fa7-4867-aa66-56d5a9d268fd", "node_type": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "073776c751b04d0d460ec7e5a9b34c4f01b725c6a113f29bcb7db3f78b024aff"}}, "hash": "190a1eede6ad13599d110b7fdd713c85ed2c0a712691b4b415dc8d520ee8eeba", "text": "those achieved by recreational intake \nof caffeine. The concentration of caffeine reached in plasma and brain after two or three cups of strong coffee \u2013 about \n100 \u00b5mol/L \u2013 is sufficient to produce appreciable adenosine \nreceptor block and a small degree of phosphodiesterase \ninhibition. Adenosine receptor block probably causes the \ndiuretic effect by reducing proximal tubular reabsorption \nof sodium.\nCaffeine and theophylline have very similar stimulant \neffects on the CNS. Human subjects experience a reduction of fatigue, with improved concentration and a clearer flow \nof thought. This is confirmed by objective studies, which \nhave shown that caffeine reduces reaction time and produces an increase in the speed at which simple calculations can be performed (although without much improvement in \naccuracy). \tPerformance \tat\tmotor\ttasks,\tsuch\tas\ttyping\tand\t\nsimulated driving, is also improved, particularly in fatigued subjects. Mental tasks, such as syllable learning, association \ntests and so on, are also facilitated by moderate doses (up \nto about 200 mg of caffeine, or about two cups of coffee) \nbut\timpaired \tby \tlarger \tdoses. \tInsomnia \tis \tcommon. \tBy \t\ncomparison with amphetamines, methylxanthines produce \nless locomotor stimulation and do not induce euphoria, Methylxanthines \n\u2022\tCaffeine and theophylline produce psychomotor \nstimulant\teffects.\n\u2022\tAverage \tcaffeine\tconsumption \tfrom \tbeverages \tis \t\nabout 200 mg/day.\n\u2022\tMain\tpsychological \teffects \tare \treduced \tfatigue \tand \t\nimproved\tmental \tperformance, \twithout \teuphoria. \tEven \t\nlarge doses do not cause stereotyped behaviour or \npsychotomimetic \teffects.\n\u2022\tMethylxanthines \tact \tmainly \tby \tantagonism \tat \tA2 purine \nreceptors, and partly by inhibiting phosphodiesterase.\n\u2022\tPeripheral \tactions \tare \texerted \tmainly \ton \theart, \tsmooth \t\nmuscle and kidney.\n\u2022\tTheophylline is used clinically as a bronchodilator; \ncaffeine\tis\tused\tas \ta \trespiratory \tstimulant \tfor \tapnoea \t\nof\tprematurity \tand \tas \tan \tadditive \tin \tmany \tbeverages \t\nand over-the-counter analgesics.\n3Caffeine withdrawal symptoms are a well-recognised cause of adverse \nevents (headache, irritability) in residential phase I clinical trial units \nwhere caffeine-containing beverages are routinely prohibited.\n4From the plant Nicotiana, named after Jean Nicot, French ambassador \nto\tPortugal, \twho \tpresented \tseeds \tto \tthe \tFrench \tking \tin \t1560, \thaving \t\nbeen persuaded by natives of South America of the medical value of \nsmoking tobacco leaves. Smoking was believed to protect against \nillness, particularly the plague.NICOTINE\nNicotine4 is the psychoactive ingredient in tobacco.\nTobacco growing, chewing and smoking was indigenous \nthroughout the American subcontinent and Australia at \nthe time that European explorers first visited these places. Smoking spread through Europe during the 16th century, mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3351, "end_char_idx": 6650, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "09bcd39e-0fa7-4867-aa66-56d5a9d268fd": {"__data__": {"id_": "09bcd39e-0fa7-4867-aa66-56d5a9d268fd", "embedding": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "874b9f4e-e762-491e-a533-a181f375a3fd", "node_type": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19f36ac35a8c097c1a86936f8d024a7fd9cf0f08e8c2d2adfbb1e3ab029fde2c"}, "2": {"node_id": "da7077c6-2ce5-4b8e-8def-ec1d4a757d0a", "node_type": null, "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "190a1eede6ad13599d110b7fdd713c85ed2c0a712691b4b415dc8d520ee8eeba"}}, "hash": "073776c751b04d0d460ec7e5a9b34c4f01b725c6a113f29bcb7db3f78b024aff", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6666, "end_char_idx": 6761, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "322b9ddd-4f10-475e-b6d8-f124be0ad7d3": {"__data__": {"id_": "322b9ddd-4f10-475e-b6d8-f124be0ad7d3", "embedding": null, "metadata": {"page_label": "636", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4b3fcb1a-c638-4a31-a7d8-273fa736b792", "node_type": null, "metadata": {"page_label": "636", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e01e06eeb19ce75fd01909b5e4b95f04769a25d4246ed39bc85d9b1fb692b18"}, "3": {"node_id": "c2bca4ce-6c98-43d4-83ae-36f6874e1609", "node_type": null, "metadata": {"page_label": "636", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "42737cea02f4669861520eac539d411e2f9f5bded792c97c97d6230e4db74435"}}, "hash": "20045c7cdf429cc89e6a3deb21eba10124a620cfb731900746e97c33a60409e2", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n630in rats. Nicotine and other nicotinic agonists such as epi-\nbatidine (Ch. 43) have significant analgesic activity in animal \nmodels, but, taken in the form of tobacco smoke or admin -\nistered by other delivery systems such as patch or nasal \nspray, has only a weak analgesic effect in man.\nPeripheral effects\nThe peripheral effects of small doses of nicotine result from stimulation of autonomic ganglia (see Ch. 14) and of \nperipheral sensory receptors, mainly in the heart and lungs. \nStimulation of these receptors produces tachycardia, increased cardiac output and arterial pressure, sweating, \nand a reduction of gastrointestinal motility. When people \ntake nicotine for the first time, they usually experience nausea and sometimes vomit, probably because of stimula -\ntion of sensory receptors in the stomach. All these effects decline with repeated dosage, although the central effects remain. Secretion of adrenaline and noradrenaline from the adrenal medulla contributes to the cardiovascular effects, coming to England mainly as a result of its enthusiastic \nespousal by Walter Raleigh at the court of Elizabeth I. James \nI strongly disapproved of both Raleigh and tobacco, and in the early 17th century initiated the first antismoking \ncampaign, \twith\tthe\tsupport\tof\tthe\tRoyal\tCollege\tof\tPhysi -\ncians.\tP arliament \tr esponded \tb y\ti mposing \ta\ts ubstantial \td uty\t\non tobacco, thereby giving the state an economic interest in the continuation of smoking at the same time that its \nofficial expert advisers were issuing emphatic warnings \nabout its dangers.\nUntil the latter half of the 19th century, tobacco was \nsmoked in pipes, and primarily by men. Cigarette manu-facture began at the end of the 19th century. Filter cigarettes (which give a lower delivery of carcinogenic tars and nicotine \nthan standard cigarettes) and \u2018low-tar\u2019 cigarettes (which \nare also low in nicotine) became available in the 1950s and were thought to be less harmful.\n5 More recently, the use \nof electronic cigarettes (e-cigarettes) to deliver nicotine, \nwithout the carcinogenic tars of cigarette smoke, has become \npopular. Laws banning smoking in public places and the increased use of e-cigarettes has led to a reduction in ciga -\nrette\tconsumption \tin \tthe \tUnited \tKingdom.\nPHARMACOLOGICAL EFFECTS OF NICOTINE\nEFFECTS \u2003ON \u2003THE \u2003CNS\nAt the neuronal level, nicotine acts on nicotinic acetylcholine receptors (nAChRs) (see Ch. 40), which are widely expressed \nin the brain, particularly in the cortex and hippocampus, \nand are believed to play a role in cognitive function, as well as in the ventral tegmental area (VTA), from which dopa -\nminergic neurons project to the nucleus accumbens (the reward pathway, Fig. 40.3). nAChRs are ligand-gated cation channels located both pre- and postsynaptically, causing, \nrespectively, enhanced transmitter release and neuronal \nexcitation (see Wonnacott et al., 2005). Nicotine increases \nthe firing rate and phasic activity of VTA dopaminergic \nneurons (see Fig. 49.3). Of the various subtypes of nAChR \n(see Table 40.2), the \u03b14\u03b22, \u03b16\u03b22 and \u03b17 subtypes have received \nmost attention, but other subtypes may also be involved in \nthe rewarding effects of nicotine. As well as activating the \nreceptors, nicotine also causes desensitisation, so the effects \nof a dose of nicotine are diminished in animals after sustained exposure to the drug. Chronic nicotine administration leads \nto", "start_char_idx": 0, "end_char_idx": 3457, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c2bca4ce-6c98-43d4-83ae-36f6874e1609": {"__data__": {"id_": "c2bca4ce-6c98-43d4-83ae-36f6874e1609", "embedding": null, "metadata": {"page_label": "636", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4b3fcb1a-c638-4a31-a7d8-273fa736b792", "node_type": null, "metadata": {"page_label": "636", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e01e06eeb19ce75fd01909b5e4b95f04769a25d4246ed39bc85d9b1fb692b18"}, "2": {"node_id": "322b9ddd-4f10-475e-b6d8-f124be0ad7d3", "node_type": null, "metadata": {"page_label": "636", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20045c7cdf429cc89e6a3deb21eba10124a620cfb731900746e97c33a60409e2"}}, "hash": "42737cea02f4669861520eac539d411e2f9f5bded792c97c97d6230e4db74435", "text": "after sustained exposure to the drug. Chronic nicotine administration leads \nto a substantial increase in the number of nAChRs (an effect \nopposite to that produced by sustained administration of most receptor agonists), which may represent an adaptive response to prolonged receptor desensitisation. It is likely \nthat the overall effect of nicotine reflects a balance between \nactivation of nAChRs, causing neuronal excitation, and desensitisation, causing synaptic block.\nThe higher level functioning of the brain, as reflected in \nthe subjective sense of alertness or by the electroencepha -\nlography (EEG) pattern, can be affected in either direction \nby nicotine, according to dose and circumstances. Nicotine \nwakes people up when they are drowsy and calms them down when they are tense, and EEG recordings broadly \nbear this out. It also seems that small doses of nicotine tend \nto cause arousal, whereas large doses do the reverse. Tests of motor and sensory performance (e.g. reaction time \nmeasurements or vigilance tests) in humans generally show \nimprovement with nicotine, and nicotine enhances learning 2\n1\n0\n0 30 60Relative firing rate\nTIme (min)Nicotine\nControl\nNicotine\nPhasic\nburstsA\nB\nFig. 49.3 Nicotine alters action potential firing \ncharacteristics of VTA dopaminergic neurons in freely \nmoving rats. \t(A)\tNeuronal \tfiring \trate \tincreases \tafter \tnicotine \t\ninjection\ti.p. \t(B) \tAction \tpotential \tfiring \tis \tphasic \tafter \tnicotine \t\ninjection.\t(Adapted \tfrom \tDe \tBiasi \tet \tal., \t2011.)\n5Smokers, however, adapt by smoking more low-tar cigarettes and \ninhaling more deeply to maintain their nicotine consumption.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3378, "end_char_idx": 5498, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5be1fffd-6ab7-41e5-8e6b-321628302807": {"__data__": {"id_": "5be1fffd-6ab7-41e5-8e6b-321628302807", "embedding": null, "metadata": {"page_label": "637", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3eef0e8f-fdfb-4d56-aa44-4637b95e1723", "node_type": null, "metadata": {"page_label": "637", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a129a093674e1faa9f9a31714ca9b282c4fe923d5a41b4ea1fc369e7bdcacda"}, "3": {"node_id": "3e4810a7-c9c0-449d-9a0e-4c59eb46e2f5", "node_type": null, "metadata": {"page_label": "637", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86637180c453daae5bc5f109b665d1fc921022a1c9bac67440afb6d9285c0131"}}, "hash": "ec532b95287dab900e4139953511b44e0e86e78b992cf3c9ff95c26cd0a7b787", "text": "49 PSYchOacTiVE dRUgS\n631new-generation devices have been developed that deliver \nmore nicotine more rapidly, but as yet, not quite as fast as \na traditional cigarette (see Fig. 49.4).\nOther routes of nicotine administration that provide a more sustained delivery are used by smokers trying to quit. A \ntransdermal nicotine patch applied for 24 h causes the \nplasma concentration of nicotine to rise to 75\u2013150 nmol/L \nover 6 h and to remain fairly constant for about 20 h. \nAdministration by nasal spray or chewing gum results in a time course intermediate between that of smoking and \nthe nicotine patch.\nTOLERANCE AND DEPENDENCE\nAs with other dependence-producing drugs, three separate \nprocesses \u2013 psychological dependence, physical dependence \nand tolerance \u2013 contribute to the overall state of dependence, \nin which taking the drug becomes compulsive. For reviews \non\tnicotine \tand \taddiction \tsee \tDe \tBiasi \tet \tal. \t(2011) \tand \t\nLeslie et al. (2013).\nThe effects of nicotine associated with peripheral gan -\nglionic stimulation show rapid tolerance, perhaps as a result \nof desensitisation of nAChRs. With large doses of nicotine, \nthis desensitisation produces a block of ganglionic transmis -\nsion (see Ch. 14). Tolerance to the central effects of nicotine \n(e.g. in the arousal response) is much less than in the \nperiphery. The increase in the number of nAChRs in the brain produced by chronic nicotine administration in animals \nalso\toccurs \tin \theavy \tsmokers. \tBecause \tthe \tcellular \teffects \t\nof nicotine are diminished, it is possible that the additional binding sites represent desensitised rather than functional \nreceptors.\nThe addictiveness of nicotine is due to the effects of the \ndrug combined with the ritual of taking it (see Le Foll & \nGoldberg, 2005). Rats choose to drink dilute nicotine solution \nin preference to water if given a choice, and in a situation in which lever pressing causes an injection of nicotine to \nbe delivered \u2013 admittedly at high doses \u2013 they quickly \nlearn to self-administer it. Similarly, monkeys who have been trained to smoke, by providing a reward in response to smoking behaviour, will continue to do so spontaneously \n(i.e. unrewarded) if the smoking medium contains nicotine, \nbut not if nicotine-free tobacco is offered instead. Humans, however, are unlikely to become addicted to nicotine \ndelivered from patches, suggesting that other factors are \nalso involved, such as the controlled pulsatile delivery associated with smoking and vaping.\nLike other addictive drugs, nicotine causes excitation of \nthe mesolimbic reward pathway and increased dopamine release in the nucleus accumbens. Transgenic mice lacking \nthe \u03b22 subunit of the nAChR lose the rewarding effect of \nnicotine and its dopamine-releasing effect, confirming the \nimportance of the \u03b22-containing nAChR subtypes and \nmesolimbic dopamine release in the response to nicotine. In contrast to normal mice, the mutant mice could not be induced to self-administer nicotine, even though they did \nso with cocaine.\nIn contrast to euphoria, induction of physical dependence \ninvolves nicotinic receptors containing \u03b15 and \u03b24 subunits \nin the medial habenula\u2013interpeduncular nucleus pathway. A physical withdrawal syndrome occurs in humans on \ncessation of smoking. Its main features are increased irritabil -\nity, impaired performance of psychomotor tasks, aggres -\nsiveness and sleep disturbance. The withdrawal syndrome is much less severe than that produced by opioids, and can be alleviated by replacement nicotine. It lasts for 2\u20133 and release of", "start_char_idx": 0, "end_char_idx": 3578, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3e4810a7-c9c0-449d-9a0e-4c59eb46e2f5": {"__data__": {"id_": "3e4810a7-c9c0-449d-9a0e-4c59eb46e2f5", "embedding": null, "metadata": {"page_label": "637", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3eef0e8f-fdfb-4d56-aa44-4637b95e1723", "node_type": null, "metadata": {"page_label": "637", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a129a093674e1faa9f9a31714ca9b282c4fe923d5a41b4ea1fc369e7bdcacda"}, "2": {"node_id": "5be1fffd-6ab7-41e5-8e6b-321628302807", "node_type": null, "metadata": {"page_label": "637", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ec532b95287dab900e4139953511b44e0e86e78b992cf3c9ff95c26cd0a7b787"}}, "hash": "86637180c453daae5bc5f109b665d1fc921022a1c9bac67440afb6d9285c0131", "text": "be alleviated by replacement nicotine. It lasts for 2\u20133 and release of antidiuretic hormone from the posterior pituitary causes a decrease in urine flow.\n6 The plasma \nconcentration of free fatty acids is increased, probably owing \nto sympathetic stimulation and adrenaline secretion.\nSmokers weigh, on average, about 4 kg less than non-\nsmokers, mainly because of reduced food intake; giving \nup smoking usually causes weight gain associated with \nincreased food intake.\nPHARMACOKINETIC ASPECTS\nNicotine is rapidly absorbed from the lungs but less readily \nfrom the mouth and nasopharynx.7 Therefore inhalation is \nrequired to give appreciable absorption of nicotine, each puff \ndelivering a distinct bolus of drug to the CNS. The amount \nof nicotine absorbed varies greatly with the habits of the user and the way in which nicotine is self-administered.\nAn average cigarette, smoked over 10 min, causes the \nplasma nicotine concentration to rise to 15\u201330 ng/mL \n(100\u2013200 nmol/L), falling to about half within 10 min and \nthen more slowly over the next 1\u20132 h (Fig. 49.4). The rapid \ndecline results mainly from redistribution between the blood and other tissues; the slower decline is due to hepatic \nmetabolism, mainly by oxidation to an inactive ketone \nmetabolite, cotinine. This has a long plasma half-life, and \nmeasurement of urinary cotinine provides a useful indication \nof nicotine consumption.\nE-cigarettes work by heating a liquid (usually propylene \nglycol and glycerin) to generate a vapour containing nicotine which is then inhaled (a process commonly referred to as \nvaping). Vaping avoids inhalation of the toxic chemicals present in tobacco smoke. Early e-cigarette devices were found to deliver only minimal amounts of nicotine to the \nuser. However, the technology has advanced rapidly and Minutes after commencing inhalationCigarette\nVaping200\n150\n100\n50\n0\n01 02 03 04 05 0Plasma nicotine concentration (nmol/L)\nFig. 49.4 Nicotine concentration in plasma during \nsmoking or vaping. \tThe\tsubjects \twere \thabitual \tusers \twho \t\ninhaled\tfrom \ta \ttraditional \tcigarette \tor \tan \te-cigarette \taccording \tto \t\ntheir\tusual \thabit. \t(Data \tfrom \tBowman, \tW.C., \tRand, \tM., \t1980. \t\nChapter\t4. \tIn: \tTextbook \tof \tPharmacology. \tBlackwell, \tOxford \tand \t\nFarsalinos \tet \tal., \t2015. \tSci. \tRep. \t5, \t11269.)\n6This may explain why, in years gone by, men smoked cigars while \nchatting over drinks after dinner.\n7Nicotine absorbed from cigar smoke is via the buccal mucosa but \ncigars deliver a much higher dose per puff than cigarettes, so a \nsubstantial amount gets in despite a low fraction absorbed.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3508, "end_char_idx": 6607, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "67e56903-fefd-495c-8ee1-71c381d988a3": {"__data__": {"id_": "67e56903-fefd-495c-8ee1-71c381d988a3", "embedding": null, "metadata": {"page_label": "638", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0cff3a89-49c9-4dba-a3b0-16640524b0a2", "node_type": null, "metadata": {"page_label": "638", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "52a34b1a76095f599fbe909d5d9410120fa816fe9ccdf2f0cef25ac4a367ce28"}, "3": {"node_id": "6f87ace5-de7e-4683-be00-fd172654f5cd", "node_type": null, "metadata": {"page_label": "638", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8f1910d48112494cf4a915b4b784d1e3a235ae271dc820e9d0ba46ed31f07701"}}, "hash": "4a5af2448390507fda8fba7eaeeeb97a470f43ae674b5c0cdb58e45b74b69ceb", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n632lung cancer although the mechanisms behind this \nassociation are unclear (see Hung et al., 2008).\n\u2022\tCoronary heart disease and other forms of peripheral \nvascular disease. The mortality among men aged 55\u201364 \nfrom coronary thrombosis is about 60% greater in men \nwho smoke 20 cigarettes per day than in non-smokers. Although the increase in risk is less than it is for lung \ncancer, the actual number of excess deaths associated \nwith smoking is larger, because coronary heart disease is so common. Other kinds of vascular disease (e.g. \nstroke, intermittent claudication and diabetic \ngangrene) are also strongly smoking related. E-cigarettes and nicotine preparations, used to help smokers give up cigarettes, are not thought to carry a \nserious risk. Carbon monoxide (see later) could be a \nfactor. However, there is no clear increase in ischaemic heart disease in pipe and cigar smokers, even though \nsimilar blood nicotine and carboxyhaemoglobin \nconcentrations are reached, suggesting that other factors may be responsible for the risk associated with \ncigarettes.\n\u2022\tChronic obstructive pulmonary disease\n\t(COPD; \tsee \tCh. \t\n29) is a major global health problem. Cigarette \nsmoking is the main cause. Stopping smoking slows \nthe\tprogression \tof \tthe \tdisease. \tBronchitis, \t\ninflammation of the mucous membranes of the bronchi, is much more common in smokers than in \nnon-smokers. These effects are probably due to tar \nand other irritants rather than nicotine.\n\u2022\tHarmful effects in pregnancy. Smoking, particularly \nduring the latter half of pregnancy, significantly \nreduces birth weight (by about 8% in women who smoke 25 or more cigarettes per day during \npregnancy) and increases perinatal mortality (by an \nestimated 28% in babies born to mothers who smoke in the last half of pregnancy). There is evidence that children born to smoking mothers remain behind, in \nboth physical and mental development, for at least 7 \nyears.\tBy \t11 \tyears \tof \tage, \tthe \tdifference \tis \tno \tlonger \t\nsignificant. These effects of smoking, although \nmeasurable, are much smaller than the effects of other \nfactors, such as social class and birth order. Various \nother complications of pregnancy are also more common in women who smoke, including \nspontaneous abortion (increased 30%\u201370% by \nsmoking), premature delivery (increased about 40%) and placenta praevia (where the placenta obstructs \nnormal vaginal delivery, increased 25%\u201390%). \nNicotine is excreted in breast milk in sufficient amounts to cause tachycardia in the infant.\nThe agents probably responsible for the harmful effects are as follows:\n\u2022\tTar\tand \tirritants, \tsuch \tas \tnitrogen \tdioxide \tand \t\nformaldehyde. Cigarette smoke tar contains many known carcinogenic hydrocarbons, as well as tumour \npromoters, which together account for the high cancer \nrisk. It is likely that the various irritant substances are also responsible for the increase in bronchitis and \nemphysema.\n\u2022\tNicotine \tprobably \taccounts \tfor \tretarded \tfetal \t\ndevelopment because of its vasoconstrictor properties.\n\u2022\tCarbon \tmonoxide. \tCigarette \tsmoke \tcontains \tabout \t3% \t\ncarbon monoxide. Carbon monoxide has a high weeks, although the craving for cigarettes persists for much \nlonger than this; relapses during attempts to quit occur most commonly at a time when the physical withdrawal \nsyndrome has long since subsided.\nPharmacology of nicotine \n\u2022\tAt\tthe\tcellular \tlevel, \tnicotine acts on nicotinic \nacetylcholine \treceptors \t(nAChRs) \tto \tenhance \t\nneurotransmitter release and increase", "start_char_idx": 0, "end_char_idx": 3562, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6f87ace5-de7e-4683-be00-fd172654f5cd": {"__data__": {"id_": "6f87ace5-de7e-4683-be00-fd172654f5cd", "embedding": null, "metadata": {"page_label": "638", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0cff3a89-49c9-4dba-a3b0-16640524b0a2", "node_type": null, "metadata": {"page_label": "638", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "52a34b1a76095f599fbe909d5d9410120fa816fe9ccdf2f0cef25ac4a367ce28"}, "2": {"node_id": "67e56903-fefd-495c-8ee1-71c381d988a3", "node_type": null, "metadata": {"page_label": "638", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4a5af2448390507fda8fba7eaeeeb97a470f43ae674b5c0cdb58e45b74b69ceb"}}, "hash": "8f1910d48112494cf4a915b4b784d1e3a235ae271dc820e9d0ba46ed31f07701", "text": "\tto \tenhance \t\nneurotransmitter release and increase neuronal \nexcitation. \tIts \tcentral \teffects \tare \tblocked \tby \treceptor \t\nantagonists such as mecamylamine.\n\u2022\tAt\tthe\tbehavioural \tlevel, \tnicotine \tproduces \ta \tmixture \tof \t\ninhibitory\tand \texcitatory \teffects.\n\u2022\tNicotine\tshows\treinforcing \tproperties, \tassociated \twith \t\nincreased activity in the mesolimbic dopaminergic \npathway,\tand \tself-administration \tcan \tbe \telicited \tin \t\nanimal studies.\n\u2022\tElectroencephalography \tchanges \tshow \tan \tarousal \t\nresponse, and subjects report increased alertness \naccompanied \tby \ta \treduction \tof \tanxiety \tand \ttension.\n\u2022\tLearning, \tparticularly \tunder \tstress, \tis \tfacilitated \tby \t\nnicotine.\n\u2022\tPeripheral \teffects \tof \tnicotine are due mainly to \nganglionic \tstimulation: \ttachycardia, \tincreased \tblood \t\npressure and reduced gastrointestinal motility. \nTolerance \tdevelops \trapidly \tto \tthese \teffects.\n\u2022\tNicotine is metabolised to cotinine, mainly in the liver, \nwithin\t1\u20132 \th.\n\u2022\tNicotine gives rise to tolerance, physical dependence \nand\tpsychological \tdependence \t(craving). \tAttempts \tat \t\nlong-term\tcessation \tsucceed \tin \tonly \tabout \t20% \tof \t\ncases.\n\u2022\tNicotine replacement therapy (e-cigarettes, chewing \ngum or skin patch preparations) improves the chances \nof\tgiving\tup \tsmoking \twhen \tcombined \twith \tactive \t\ncounselling.\nHARMFUL EFFECTS OF TOBACCO SMOKING\nThe life expectancy of smokers is shorter than that of non-\nsmokers. Smoking causes almost 90% of deaths from lung \ncancer, about 80% of deaths from bronchitis and emphysema, \nand 17% of deaths from heart disease. The increased use of e-cigarettes should reduce the number of such deaths. \nAbout one-third of all cancer deaths can be attributed to \nsmoking. Smoking is, by a large margin, the biggest prevent -\nable cause of death, responsible for about 1 in 10 adult \ndeaths worldwide. Despite the introduction of e-cigarettes, \ndeaths from smoking worldwide are continuing to rise. In 2015, it was estimated that smoking was responsible for some 6.4 million deaths (and approximately 800,000 addi -\ntional deaths of non-smokers from involuntary secondary inhalation).\nThe main health risks are as follows:\n\u2022\tCancer, particularly of the lung and upper respiratory tract but also of the oesophagus, pancreas and bladder. Smoking \n20 cigarettes per day is estimated to increase the risk \nof lung cancer about 10-fold. Tar, rather than nicotine, is responsible for the cancer risk. Genetic variants of \nnicotinic-receptor subunits have been associated with mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3510, "end_char_idx": 6516, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a11d45fd-32b1-4b35-87ec-e3c6ce9f183c": {"__data__": {"id_": "a11d45fd-32b1-4b35-87ec-e3c6ce9f183c", "embedding": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7c3c77b5-3567-4f39-a560-42492e688f10", "node_type": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cbb0d22c0bd9d1813c4bc37984eaa0b875b306d480878a82cf2102c9817d1330"}, "3": {"node_id": "c1231d56-1997-4a9d-939c-172b99643883", "node_type": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9caa8188894d0f01242ed08a5c11d342bda212013eb2a0a598e386c5a3113bbf"}}, "hash": "040b7af731c197b907f15774203eaf1effddf02099b4ee4627794ae9de2058f1", "text": "49 PSYchOacTiVE dRUgS\n633Drugs currently available have been shown to:\n\u2022\talter\tmemory \tprocessing \t(i.e. \tenhance \tmemory);\n\u2022\treduce \tfatigue \t(stimulants), \tthus \tpermitting \tthe \tuser \tto \t\nfunction for longer (i.e. perform complex tasks, study \nfor examinations, overcome jet lag);\n\u2022\tincrease \tmotivation, \tenergy, \tconfidence \tand \t\nconcentration.\nThey are also referred to as \u2018smart drugs\u2019 or \u2018nootropics\u2019\nDrugs reported to enhance cognitive performance are \ncaffeine, amphetamines, methylphenidate, modafinil, arecoline, donepezil, vortioxetine and piracetam but the \nclinical efficacy of these drugs is limited, and development of more effective cognition enhancers could have significant benefits for many patient groups.\nCognition-enhancing drugs are also used by healthy \nindividuals aiming to enhance their performance e.g. in \nrevising for and taking examinations (d\u2019Angelo et al., 2017) \nor in demanding professional roles. The use of drugs by healthy individuals to enhance academic performance does \nraise ethical issues in relation to fairness, academic pressure \nand fears of coercion by \u2018pushy\u2019 parents. There are also safety issues. Although many of the drugs taken are available \nas medicines (i.e. have gone through standard drug safety \ntesting) there is still a lack of information on their acute and long-term effects in children and adolescents whose \nbrains are still in development. In healthy individuals, \ncognitive performance can be enhanced by improved sleep and mood as well as reduced anxiety. It would seem more appropriate to achieve this by lifestyle changes and behav -\nioural therapy rather than resorting to the use of drugs.\n8\nEFFECTIVENESS\nWhile the effectiveness of cognition enhancers on healthy individuals is often trumpeted by individuals who use them \nand in the media, their actual effectiveness as assessed in \nscientific studies is somewhat inconclusive and ambiguous. Also, drugs may affect different forms of memory differently \n(d\u2019Angelo et al ., 2017). It is important to distinguish between \ndrugs that only improve a subject\u2019s abilities when they are fatigued and those that might improve cognitive ability in \nnon-fatigued individuals.\nMany studies have shown that amphetamines improve \nmental performance in fatigued subjects. Mental perfor -\nmance is improved for simple tedious tasks much more \nthan for difficult tasks. Amphetamines are thought to increase ability to focus and maintain self-control. In addition \nto reducing fatigue, methylphenidate has a positive effect \non long-term memory consolidation. Amphetamines and modafinil have been used to improve the performance of soldiers, military pilots and others who need to remain \nalert under extremely fatiguing conditions. Modafinil \nappears to enhance cognition in non-fatigued individuals \n(Battleday \t&\tBrem,\t2015)\twhile\talso\timproving \twakefulness, \t\nmemory and executive functions in sleep-deprived individu -\nals. Evidence for efficacy in patients with chronic cognitive \nimpairment is controversial.affinity for haemoglobin, and the average \ncarboxyhaemoglobin content in the blood of cigarette smokers is about 2.5% (compared with 0.4% for \nnon-smoking urban dwellers). In very heavy smokers, \nup to 15% of haemoglobin may be carboxylated, a level that affects fetal development in rats. Fetal \nhaemoglobin has a higher affinity for carbon \nmonoxide than adult haemoglobin, and the proportion of carboxyhaemoglobin is higher in fetal than in \nmaternal blood.\n\u2022\tIncreased \toxidative \tstress \tmay \tcontribute \tto \t\natherogenesis \t(Ch. \t24) \tand \tCOPD \t(Ch. \t29).\nOTHER \u2003EFFECTS", "start_char_idx": 0, "end_char_idx": 3607, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c1231d56-1997-4a9d-939c-172b99643883": {"__data__": {"id_": "c1231d56-1997-4a9d-939c-172b99643883", "embedding": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7c3c77b5-3567-4f39-a560-42492e688f10", "node_type": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cbb0d22c0bd9d1813c4bc37984eaa0b875b306d480878a82cf2102c9817d1330"}, "2": {"node_id": "a11d45fd-32b1-4b35-87ec-e3c6ce9f183c", "node_type": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "040b7af731c197b907f15774203eaf1effddf02099b4ee4627794ae9de2058f1"}, "3": {"node_id": "fafeb35d-6cd7-4f40-aead-ca1dcb0f3993", "node_type": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7ed8e3b04e19c920e93714cfb30af566c60c1f2c3b4583deac47dd39eeb349d8"}}, "hash": "9caa8188894d0f01242ed08a5c11d342bda212013eb2a0a598e386c5a3113bbf", "text": "\tand \tCOPD \t(Ch. \t29).\nOTHER \u2003EFFECTS \u2003OF \u2003TOBACCO \u2003SMOKING\nParkinson\u2019s \tdisease \tis \tapproximately \ttwice \tas \tcommon \tin \t\nnon-smokers as in smokers. It is possible that this reflects \na protective effect of nicotine. Ulcerative colitis appears to \nbe a disease of non-smokers. Former smokers are at high \nrisk for developing ulcerative colitis, while current smokers have the least risk. This tendency indicates that smoking \ncigarettes may prevent the onset of ulcerative colitis. In \ncontrast, smoking tends to worsen the effects of Crohn\u2019s disease (another type of inflammatory bowel disease). Earlier \nreports that Alzheimer\u2019s disease is less common in smokers \nhave not been confirmed; indeed there is evidence that smoking may increase the occurrence of Alzheimer\u2019s disease in some genetic groups.\nEffects of tobacco smoking \n\u2022\tSmoking \taccounts \tfor \tmore \tthan \t10% \tof \tdeaths \t\nworldwide, \tmainly \tdue \tto:\n\u2013\tcancer, \tespecially \tlung \tcancer, \tof \twhich \tabout \t90% \t\nof\tcases\tare \tsmoking \trelated; \tcarcinogenic \ttars \tare \t\nresponsible;\n\u2013 chronic bronchitis; tars are mainly responsible.\n\u2022\tSmoking \tin \tpregnancy \treduces \tbirth \tweight \tand \t\nretards\tchildhood \tdevelopment. \tIt \talso \tincreases \t\nabortion rate and perinatal mortality. Nicotine and \npossibly carbon monoxide are responsible.\n\u2022\tUse\tof\te-cigarettes \t(vaping) \tavoids \tthe \tinhalation \tof \ttar \t\nand carbon monoxide that occurs with smoking.\n\u2022\tThe\tincidence \tof \tParkinson\u2019s \tdisease \tis \tlower \tin \t\nsmokers than in non-smokers.\n8A new phenomenon is \u2018microdosing\u2019 with very small quantities of \npsychedelic drugs such as LSD, psilocybin or mescaline (see p. 634) \nevery few days with the aim of improving concentration, creativity and \nproblem solving. At such low doses users do not experience psychedelic \neffects.\tProperly \tcontrolled \tscientific \tstudies \tare \trequired \tto \tdetermine \t\nwhether this form of drug taking really is effective.COGNITION-ENHANCING DRUGS\n\u2018Cognition\u2019 embraces many aspects of mental function, \nincluding memory, reasoning and problem-solving skills, \nsituational judgements, decision-making and executive \nfunction. A variety of different test batteries have been designed to measure these functions in humans (e.g. \nCambridge \tNeuropsychological \tTest \tAutomated \tBattery, \t\nCANTAB) \tand \ttest \tthe \teffects \tof \tdrugs. \tMany \tclinical \t\ndisorders, such as Alzheimer\u2019s disease (Ch. 41), schizo -\nphrenia (Ch. 47), depression (Ch. 48) and drug addiction \n(Ch. 50) impair these functions, and the hope is to develop \ncognition-enhancing \tdrugs \tto \trestore \tthem. \tProgress \thas \t\nbeen limited, though much hyped, as much with the \nquestionable aim of \u2018improving\u2019 mental function in healthy \nhumans, as in alleviating deficits in the sick.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3575, "end_char_idx": 6711, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fafeb35d-6cd7-4f40-aead-ca1dcb0f3993": {"__data__": {"id_": "fafeb35d-6cd7-4f40-aead-ca1dcb0f3993", "embedding": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "7c3c77b5-3567-4f39-a560-42492e688f10", "node_type": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cbb0d22c0bd9d1813c4bc37984eaa0b875b306d480878a82cf2102c9817d1330"}, "2": {"node_id": "c1231d56-1997-4a9d-939c-172b99643883", "node_type": null, "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9caa8188894d0f01242ed08a5c11d342bda212013eb2a0a598e386c5a3113bbf"}}, "hash": "7ed8e3b04e19c920e93714cfb30af566c60c1f2c3b4583deac47dd39eeb349d8", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6697, "end_char_idx": 6840, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a6f0f1b3-9e51-4091-940e-22f0adbd828a": {"__data__": {"id_": "a6f0f1b3-9e51-4091-940e-22f0adbd828a", "embedding": null, "metadata": {"page_label": "640", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c3648494-4412-4b52-ad27-3d72dc418a7d", "node_type": null, "metadata": {"page_label": "640", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f867177e219803d6534d3c1d5b9ea52a4f5b660d6d99df66fdf59d78a57d3f10"}, "3": {"node_id": "764b4dfd-5959-42a8-8fcf-9e76a73ed7f5", "node_type": null, "metadata": {"page_label": "640", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c33db4a4c50df231345280456715b74f001e4ab166b4b8e9d0f31b0b3123bcea"}}, "hash": "48a913cbeab06c8495d08c70fa51269080596534914601f3dbe2fa2bce02dd21", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n634in humans in doses less than 1 \u00b5g/kg. It is a chemical \nderivative of lysergic acid, which occurs in the cereal fungus \nergot (see Ch. 16).\n\u25bc LSD was first synthesised by Hoffman in 1943. Hoffman deliberately \nswallowed about 250 \u00b5g of LSD (the threshold dose is now known \nto be around 20 \u00b5g) and wrote 30 years later of the experience: \u2018the \nfaces of those around me appeared as grotesque coloured masks \u2026 \nmarked motoric unrest, alternating with paralysis \u2026 heavy feeling \nin the head, limbs and entire body, as if they were filled with lead \u2026 clear recognition of my condition, in which state I sometimes \nobserved, in the manner of an independent observer, that I shouted \nhalf insanely.\u2019 These effects lasted for a few hours, after which Hoffman fell asleep, \u2018and awoke next morning feeling perfectly well.\u2019 Apart \nfrom these dramatic psychological effects, LSD has few physiological \neffects in humans at doses that cause hallucinations.\nMescaline, which is derived from the Mexican peyote cactus \nand has been known as a hallucinogenic agent for many \ncenturies, was made famous by Aldous Huxley in The Doors \nof Perception.\nPsilocybin \tis\tobtained \tfrom\tfungi\t(\u2018magic\tmushrooms\u2019). \t\nIt is rapidly dephosphorylated to psilocin, the active moiety. \nIts effects are similar to those experienced with LSD. The \npotential of psilocybin as a treatment for depression and \nsome forms of anxiety is debated in Carhart-Harris and Gregory (2017).\nPharmacological effects\nThe main effects of these drugs are on mental function, most notably an alteration of perception in such a way that \nsights and sounds appear distorted and fantastic. Hallucina -\ntions \u2013 visual, auditory, tactile or olfactory \u2013 also occur, \nand sensory modalities may become confused, so that \nsounds are perceived as visions. Thought processes tend \nto become illogical and disconnected, but subjects retain insight into the fact that their disturbance is drug-induced, \nand generally find the experience exhilarating. Occasionally, \nespecially if the user is already anxious, LSD produces a syndrome that is extremely disturbing (the \u2018bad trip\u2019), in which the hallucinatory experience takes on a menacing \nquality and may be accompanied by paranoid delusions. \n\u2018Flashbacks\u2019 of the hallucinatory experience have been reported weeks or months later.\nLSD acts on various 5-HT-receptor subtypes (see Chs 16 \nand 40); its psychotomimetic effects are thought to be mediated mainly by its 5-HT\n2A-receptor agonist actions (see \nNichols, 2004). It inhibits the firing of 5-HT-containing \nneurons in the raphe nuclei (see Ch. 40), apparently by \nacting as an agonist on the inhibitory somatodendritic 5-HT 1A \nreceptors on these cells. The significance of this response \nto\tits\tpsychotomimetic \teffects \tis \tunclear. \tPsilocybin \tis \t\ndephosphorylated to psilocin, which is a weak agonist at several 5-HT receptors including the 5-HT\n2A receptor. The \nmechanism of action of mescaline is less well defined. There \nare contradictory reports about its activity at 5-HT 2A recep -\ntors. It has also been reported to act as an inhibitor of monoamine transport.\nDependence and adverse effects\nLSD, psilocybin and mescaline are seldom self-administered \nby experimental animals. Indeed, in contrast to most of \nthe drugs that are widely abused by humans, they have \naversive rather than reinforcing properties in behavioural tests.", "start_char_idx": 0, "end_char_idx": 3425, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "764b4dfd-5959-42a8-8fcf-9e76a73ed7f5": {"__data__": {"id_": "764b4dfd-5959-42a8-8fcf-9e76a73ed7f5", "embedding": null, "metadata": {"page_label": "640", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c3648494-4412-4b52-ad27-3d72dc418a7d", "node_type": null, "metadata": {"page_label": "640", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f867177e219803d6534d3c1d5b9ea52a4f5b660d6d99df66fdf59d78a57d3f10"}, "2": {"node_id": "a6f0f1b3-9e51-4091-940e-22f0adbd828a", "node_type": null, "metadata": {"page_label": "640", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "48a913cbeab06c8495d08c70fa51269080596534914601f3dbe2fa2bce02dd21"}}, "hash": "c33db4a4c50df231345280456715b74f001e4ab166b4b8e9d0f31b0b3123bcea", "text": "by humans, they have \naversive rather than reinforcing properties in behavioural tests. Tolerance to their effects develops quite quickly, but \nthere is no physical withdrawal syndrome in animals or \nhumans.NON-STIMULANT \u2003DRUGS\nThe novel antidepressant, vortioxetine (see Ch. 48), improves cognitive dysfunction in patients suffering from major \ndepression.\nPiracetam, which is a positive allosteric modulator at \nAMPA\treceptors \t(see \tCh. \t39), \tenhances \tmemory \tin \tnon-\nfatigued adults, and there is limited clinical evidence of \nreading improvement in dyslexic children. Phenylpiracetam \nis said to be more potent and may also have nicotinic antagonist properties. As with many CNS disorders, the possible importance of glutamate and its receptors is widely \nspeculated on, but new, effective drugs acting on the \nglutamatergic system are still awaited (see, for example, \nCollingridge et al., 2013; Harms et al., 2013).\nPSYCHEDELIC DRUGS\nPsychedelic \tdrugs \t(also \tsometimes \treferred \tto \tas \thalluci-\nnogenic or psychotomimetic drugs) affect thought, perception \nand mood, without causing marked psychomotor stimula -\ntion or depression (see Nichols, 2004 ). Thoughts and percep -\ntions tend to become distorted and dream-like, rather than \nbeing merely sharpened or dulled, and the change in mood \nis likewise more complex than a simple shift in the direction of euphoria or depression. Importantly, psychedelic drugs \ndo not cause dependence. Common psychedelic drugs are \nlisted in Table 49.2.\nLSD, PSILOCYBIN AND MESCALINE\nLysergic acid diethylamide (LSD) is an exceptionally potent psychotomimetic drug capable of producing strong effects \nTable 49.2 Major psychedelic drugs\nDrugs Mode(s) of action Notes\nLSDInteracts with 5-HT \nand DA receptorsPsychedelic effects are thought to be mainly through 5-HT\n2A receptor \nactivationNo current clinical use\nMescalineAgonist at 5-HT 2A \nand other 5-HT receptorsChemically related to amphetamineNo current clinical useFound in Peyote cactus plant\nPsilocybinRapidly metabolised to psilocin, a partial agonist at 5-HT\n2A \nreceptorsChemically related to 5-HTNo current clinical use\nMay have potential for \nthe treatment of \ndepression and some \nforms of anxiety\nSalvinorin A\u03ba Opioid receptor agonist (see Ch. 43)No clinical use\nFound in Salvia \ndivinorum (plant)\n5-HT, 5-hydroxytryptamine; DA, dopamine; LSD, lysergic acid \ndiethylamide.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3338, "end_char_idx": 6211, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9eeb51b3-85dd-42ba-96c2-0b0ec62ef93e": {"__data__": {"id_": "9eeb51b3-85dd-42ba-96c2-0b0ec62ef93e", "embedding": null, "metadata": {"page_label": "641", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "58e3bf08-ed16-4fb0-b826-41a45f86ba50", "node_type": null, "metadata": {"page_label": "641", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a04e3230359284db5afe8d50e86107717641484fda02716a566e4221eb70250"}, "3": {"node_id": "6ca8bd3a-03a8-46d0-9344-20f40d61f284", "node_type": null, "metadata": {"page_label": "641", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dfbe9d8ec24a95257ec0eaf07e2fb023810ab6f6e8c58129d58f8d30dfb7d653"}}, "hash": "9ccf42d902527dbdc562a680a2834f9065dbb9a6d16857a977c7be230dc12105", "text": "49 PSYchOacTiVE dRUgS\n635to cause psychotic episodes and is used in experimental \nanimals to produce a model of schizophrenia (see Ch. 47 \nand Morris et al., 2005).\nPharmacological effects\nTheir main pharmacological effect is non-competitive block of the NMDA-receptor channel (see Ch. 39). Methoxetamine , \na chemical derivative of ketamine, is an NMDA antagonist as well as an inhibitor of 5-HT reuptake, which may contribute to its CNS effects.\nAdverse effects\nTolerance develops with repeated use of ketamine, resulting in higher doses being taken to achieve the same effect. \nRepeated use is associated with serious and persistent toxic \neffects, including abdominal pain, ulcerative cystitis (with associated severe bladder pain), liver damage and cognitive \nimpairment (Morgan & Curran, 2012). Combination of \nketamine with depressant drugs such as alcohol, barbitu-\nrates and heroin can result in dangerous overdose.\nNitrous oxide is a weak general anaesthetic that acts as \nan antagonist at NMDA receptors (see Ch. 42). At low doses it produces feelings of euphoria \u2013 it is often referred to as \u2018laughing gas\u2019 \u2013 relaxation and dissociation.\nDEPRESSANTS\nMany CNS depressant drugs ( Table 49.3) that are used for \ntheir psychoactive effects also have important therapeutic \nuses that are described in detail elsewhere in this book. \nHere we will concentrate on ethanol, which has little or The main effects of these psychedelic drugs are subjective, \nso it is not surprising that animal tests that reliably predict \npsychedelic activity in humans have not been devised.9.\nOTHER PSYCHEDELIC DRUGS\nSalvinorin A is a hallucinogenic agent contained in the \nAmerican sage plant Salvia divinorum, a member of the \nmint family. It was originally used by the Mazatecs in Mexico; in recent years its use has spread and it has become known as herbal ecstasy. It is a \u03ba opioid receptor agonist \n(see Ch. 43).\n10 It also produces dissociative effects (see later) \nand at high doses, delirium.\nOther hallucinogens include \u03b1\u2212MT (methyltryptamine) \nand DMT (dimethyltryptamine), which are naturally \noccurring, and DPT (dipropyltryptamine) and DOM \n(2,5-dimethoxy-4-methylamphetamine).\nMuscarinic receptor antagonists (see Chs 14 and 40), hyos -\ncine, hyoscyamine and atropine are contained in various \nplants, including henbane and mandrake. Consumption can cause hallucinations, drowsiness and disorientation.\nIbogaine is contained in the root bark of iboga shrubs \nin Africa, South America and Australia. At high doses, it \nis hallucinogenic. Users have reported experiencing a \nreduced desire to take other drugs such as cocaine and heroin, leading to ibogaine being investigated as a potential \ntreatment for drug craving (see Ch. 50).\nPsychedelic drugs \n\u2022\tThe\tmain \ttypes \tare \tlysergic \tacid \tdiethylamide \t(LSD), \t\npsilocybin and mescaline.\n\u2022\tThey\tact \tas \t5-hydroxytryptamine \t(5-HT) 2A receptor \nagonists.\n\u2022\tThey\tcause \tsensory \tdistortion \tand \thallucinatory \t\nexperiences.\n\u2022\tLSD is exceptionally potent, producing a long-lasting \nsense\tof\tdissociation \tand \tdisordered \tthought. \t\nHallucinatory \tepisodes \tcan \trecur \tafter \ta \tlong \tinterval.\n\u2022\tIn\tanimal \tbehavioural \ttests, \tthey \texhibit \taversive \trather \t\nthan rewarding properties.\n\u2022\tSalvinorin A is a \u03ba opioid receptor agonist that \ncauses\thallucinatory \tand \tdissociative \teffects.\n9One of", "start_char_idx": 0, "end_char_idx": 3353, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6ca8bd3a-03a8-46d0-9344-20f40d61f284": {"__data__": {"id_": "6ca8bd3a-03a8-46d0-9344-20f40d61f284", "embedding": null, "metadata": {"page_label": "641", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "58e3bf08-ed16-4fb0-b826-41a45f86ba50", "node_type": null, "metadata": {"page_label": "641", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a04e3230359284db5afe8d50e86107717641484fda02716a566e4221eb70250"}, "2": {"node_id": "9eeb51b3-85dd-42ba-96c2-0b0ec62ef93e", "node_type": null, "metadata": {"page_label": "641", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9ccf42d902527dbdc562a680a2834f9065dbb9a6d16857a977c7be230dc12105"}}, "hash": "dfbe9d8ec24a95257ec0eaf07e2fb023810ab6f6e8c58129d58f8d30dfb7d653", "text": "\tand \tdissociative \teffects.\n9One of the more bizarre attempts involves spiders, whose normal \nelegantly symmetrical webs become jumbled and erratic if the animals \nare treated with LSD. Search the web (worldwide rather than arachnid) \nfor \u2018spiders LSD\u2019 to see images.\n10In phase I clinical trials of synthetic \u03ba-opioid-receptor agonists as \npotential analgesic agents, the drugs were reported to induce a feeling \nof\tdysphoria. \tPerhaps \tthe \t\u2018normal\u2019 \tvolunteers \tin \tthose \ttrials \twere \t\ndisturbed by the hallucinations they probably experienced. Interesting then that a naturally occurring \u03ba agonist has now become a drug of \nabuse.KETAMINE AND RELATED DRUGS\nKetamine \t(\u2018Special\tK\u2019 ),\t a\t dissociative \t anaesthetic \t(C h.\t 42), \t\nis also used for its psychoactive properties (see Morgan & \nCurran, 2012). Its fore-runner phencyclidine \t(PCP,\t\u2018angel \t\ndust\u2019), was a popular hallucinogen in the 1970s but its use has declined. These drugs produce a feeling of euphoria. \nAt higher doses they cause hallucinations and feelings of \ndetachment, \tdisorientation \tand \tnumbness. \tPCP \twas \treported\tTable 49.3 Depressant drugs\nDrugsDescribed \nin detail in Chapter Notes\nBenzodiazepines\n(diazepam, temazepam, diclazepam)45Etizolam and pyrazolam are derived from benzodiazepines and act similarly\nZopiclone and other Z drugs45Short acting but similar effects to benzodiazepines\nGabapentin and pregabalin46Often taken in high doses to induce a feeling of drunkenness and stuporMay enhance likelihood of overdose in opioid users\n\u03b3-Hydroxybutyric acid (GHB)39\u03b3-Butyrolactone (GBL) and 1,4-butanediol (BD) are broken down to GHB in the body\nEthanol This chapter\nPropofol 42Sub-anaesthetic doses induce a general feeling of well-being, euphoria, and sexual disinhibitionmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3317, "end_char_idx": 5559, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4fb27e9d-2386-4ac3-acc0-c04888f15d54": {"__data__": {"id_": "4fb27e9d-2386-4ac3-acc0-c04888f15d54", "embedding": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b5c4ccdc-4114-4b4d-af9d-cc4d4b31388a", "node_type": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a24e08f170cd0c61960a83142aa9e9b865fc1850ba68fc82e7efeba3c6d9973b"}, "3": {"node_id": "40c6360b-b674-4039-ac99-b012a0958161", "node_type": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1dbedd992d82e15dad69d89bf999e905705995029e4532bd087233a732914093"}}, "hash": "ec920c1f84036d2f4dab7a4a7478357616b84390c6e72b3f983a6e00c2f4489e", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n636\u2022\tinhibition \tof \tionotropic \tglutamate \treceptor \tfunction\n\u2022\tinhibition \tof \tadenosine \ttransport\nFor review, see Harris et al. (2008).\nEthanol\tenhances \tthe \taction \tof \tGABA \ton \tGABA A receptors \nin a similar way to benzodiazepines (see Ch. 45). Its effect \nis, however, smaller and less consistent than that of \nbenzodiazepines, and no clear effect on inhibitory synaptic transmission in the CNS has been demonstrated for ethanol. \nThis may be because the effect of ethanol is seen only on \nsome\tsubtypes \tof \tGABA A receptor (see Ch. 39) e.g. the \nextrasynaptic \u03b16\u03b23\u03b4\tGABA A receptor subtype has been \nreported to be sensitive to ethanol. Ethanol may also act \npresynaptically \tto \tenhance \tGABA \trelease.\nEthanol enhances glycine receptor function, due both to \na direct interaction with the \u03b11 subunit of the glycine \nreceptor and to indirect effects mediated through protein \nkinase\tC\t(PKC)\tactivation. \tEthanol\tcan\talso\tenhance\tglycine\t\nrelease from nerve terminals.\nEthanol reduces transmitter release in response to nerve \nterminal depolarisation by inhibiting the opening of voltage-\ngated calcium channels in neurons. It also reduces neuronal excitability by activating G protein-activated inwardly \nrectifying \tK+\t(GIRK)\tchannels \tas \twell \tas \tpotentiating \t\ncalcium-activated \tpotassium \t(BK) \tchannel \tactivity.\nThe excitatory effects of glutamate are inhibited by ethanol \nat concentrations that produce CNS depressant effects in \nvivo. NMDA receptor activation is inhibited at lower ethanol \nconcentrations \tthan\tare\trequired \tto\taffect\tAMPA\treceptors \t\n(see Ch. 39). Other effects produced by ethanol include an \nenhancement of the excitatory effects produced by activation \nof nAChRs and 5-HT 3 receptors. The relative importance \nof these various effects in the overall effects of ethanol on CNS function is not clear.\nThe depressant effects of ethanol on neuronal function \nresemble those of adenosine acting on A\n1 receptors (see \nCh. 17). Ethanol in cell culture systems increases extracellular adenosine by inhibiting adenosine uptake, and there is some \nevidence that inhibition of the adenosine transporter may account for some of its CNS effects.\nEndogenous opioids also play a role in the CNS effects \nof ethanol, because both human and animal studies show that the opioid receptor antagonist naltrexone reduces the \nreward associated with ethanol.\nBehavioural effects\nThe effects of acute ethanol intoxication in humans are well known and include slurred speech, motor incoordina -\ntion, increased self-confidence and euphoria. The effect on mood varies among individuals, most becoming louder and more outgoing, but some becoming morose and \nwithdrawn. At higher levels of intoxication, the mood tends \nto become highly labile, with euphoria and melancholy, aggression and submission, often occurring successively. \nThe association between alcohol consumption and violence \nis well documented.\nIntellectual and motor performance and sensory discrimi -\nnation are impaired by ethanol, but subjects are generally \nunable to judge this for themselves.\n12 Much effort has gone no therapeutic value but is widely used in many countries \nfor its psychoactive properties.\nETHANOL\nIt may at first seem strange to categorise ethanol as a depressant drug\n11 given that its consumption in alcoholic \nbeverages can make people excited, garrulous and violent. \nHowever, as with general anaesthetics (see Ch. 42), at low \nconcentrations ethanol", "start_char_idx": 0, "end_char_idx": 3499, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "40c6360b-b674-4039-ac99-b012a0958161": {"__data__": {"id_": "40c6360b-b674-4039-ac99-b012a0958161", "embedding": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b5c4ccdc-4114-4b4d-af9d-cc4d4b31388a", "node_type": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a24e08f170cd0c61960a83142aa9e9b865fc1850ba68fc82e7efeba3c6d9973b"}, "2": {"node_id": "4fb27e9d-2386-4ac3-acc0-c04888f15d54", "node_type": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ec920c1f84036d2f4dab7a4a7478357616b84390c6e72b3f983a6e00c2f4489e"}, "3": {"node_id": "a78b79b3-0ce7-43cf-af7f-7968c3f7dfbc", "node_type": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c676ea743d9686e4570bf26bb75d653c427c1edf3beccb378e24efecffc62abf"}}, "hash": "1dbedd992d82e15dad69d89bf999e905705995029e4532bd087233a732914093", "text": "as with general anaesthetics (see Ch. 42), at low \nconcentrations ethanol depresses inhibitions resulting in apparent behavioural stimulation whereas at higher con -\ncentrations all brain functions are depressed.\nJudged on a molar basis, the consumption of ethanol far \nexceeds that of any other drug. The ethanol content of \nvarious drinks ranges from about 2.5% (weak beer) to about \n55% (strong spirits), and the size of the normal measure is \nsuch that a single drink usually contains about 8\u201312 g \n(0.17\u20130.26 mol) of ethanol. Its low pharmacological potency \nis reflected in the range of plasma concentrations needed to produce pharmacological effects: minimal effects occur \nat about 10 mmol/L (46 mg/100 mL), and 10 times this \nconcentration may be lethal. The average per capita con-\nsumption \tof \tethanol \tin \tthe \tUnited \tKingdom \tdoubled \t\nbetween 1970 and 2007, but has fallen slightly since then. There has been an increase in non-drinkers, mainly amongst \nyoung people. Amongst those who do drink, the main \nchanges have been a growing consumption of wine in preference to beer among adults, greater consumption in \nthe home and an increasing tendency for binge drinking, \nespecially among young people.\nFor practical purposes, ethanol intake is often expressed \nin terms of units. One unit is equal to 8 g (10 mL) of ethanol, \nand is the amount contained in half a pint of normal strength beer, one measure of spirits or one small glass of wine. \nThe\tc urrent \tUK\t government\u2019s \t guidelines \t state\t that \t for\t both\t\nmen and women it is safest not to drink regularly more than 14 units per week, and that if as much as 14 units per \nweek are drunk, it is best to spread this evenly over 3 days \nor\tmore.\tIt\tis\testimated \tthat\tin\tthe\tUnited\tKingdom, \tabout\t\n31% of men and 16% of women exceed these levels. Govern -\nments in most developed countries are attempting to curb alcohol consumption.\nAn excellent detailed review of all aspects of alcohol and \nalcoholism is provided by Spanagel (2009).\nPHARMACOLOGICAL EFFECTS OF ETHANOL\nEffects on CNS neurons\nThe main effects of ethanol are on the CNS, where its \ndepressant actions resemble those of volatile anaesthetics \n(Ch. 42). At a neuronal level, the effect of ethanol is depres -\nsant, although it increases neuronal activity \u2013 presumably \nby disinhibition \u2013 in some parts of the CNS, notably in the \nmesolimbic dopaminergic pathway that is involved in \nreward. The main acute cellular effects of ethanol that occur \nat concentrations (5\u2013100 mmol/L) relevant to alcohol \nconsumption by humans are:\n\u2022\tenhancement \tof \tboth \tGABA- \tand \tglycine-mediated \t\ninhibition\n\u2022\tinhibition \tof \tCa2+ entry through voltage-gated calcium \nchannels\n\u2022\tactivation \tof \tcertain \ttypes \tof \tK+ channel\n12Bus\tdrivers \twere \tasked \tto \tdrive \tthrough \ta \tgap \tthat \tthey \tselected \tas \t\nthe minimum for their bus to pass through; ethanol caused them not \nonly to hit the barriers more often at any given gap setting, but also to \nset the gap to a narrower dimension, often narrower than the bus.11In some countries ethanol is classed as a food, not a drug! This reflects \nthe lobbying power of the alcohol industry. Ethanol meets the criteria for \u2018What is a drug?\u2019 given in Chapter 1.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3437, "end_char_idx": 6855, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a78b79b3-0ce7-43cf-af7f-7968c3f7dfbc": {"__data__": {"id_": "a78b79b3-0ce7-43cf-af7f-7968c3f7dfbc", "embedding": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b5c4ccdc-4114-4b4d-af9d-cc4d4b31388a", "node_type": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a24e08f170cd0c61960a83142aa9e9b865fc1850ba68fc82e7efeba3c6d9973b"}, "2": {"node_id": "40c6360b-b674-4039-ac99-b012a0958161", "node_type": null, "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1dbedd992d82e15dad69d89bf999e905705995029e4532bd087233a732914093"}}, "hash": "c676ea743d9686e4570bf26bb75d653c427c1edf3beccb378e24efecffc62abf", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6871, "end_char_idx": 7222, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0aef7c24-9306-4859-b62a-3cba9149a3bb": {"__data__": {"id_": "0aef7c24-9306-4859-b62a-3cba9149a3bb", "embedding": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1a46f68e-529f-43ea-a038-4d6f63034c9c", "node_type": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84b42ed92772e30d69361d863595f53239cf9d05337e209daa4f252240619a0b"}, "3": {"node_id": "531760e5-cdec-43b8-8619-16584da826a8", "node_type": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e957b1a2314c3ed4290fc7bd680df026d7b3aea4fd44d3ae9a5c9cf773129f1"}}, "hash": "6e0dc8b8a90b20cffde9a450b41a2372a6f8290e6eaf54b0fa91be2255830929", "text": "49 PSYchOacTiVE dRUgS\n637artery disease has come in for criticism in recent years. \nModerate ethanol consumption may protect against ischae -\nmic heart disease, especially in older people, perhaps partly by inhibiting platelet aggregation. This effect occurs at ethanol concentrations in the range achieved by moderate \ndrinking (10\u201320 mmol/L) and probably results from inhibi -\ntion of arachidonic acid formation from phospholipid. \nHowever, chronic or intermittent drinking of excessive \namounts of ethanol causes raised blood pressure, which is one of the most important risk factors for having a heart \nattack or a stroke.\nDiuresis is a familiar effect of ethanol. It is caused by \ninhibition of antidiuretic hormone secretion, and tolerance develops rapidly, so that the diuresis is not sustained. There \nis a similar inhibition of oxytocin secretion, which can delay parturition.\nEthanol increases salivary and gastric secretion, perhaps \na reason in some cultures for the popularity of a glass of sherry before dinner. However, heavy consumption of spirits causes damage directly to the gastric mucosa, causing \nchronic\tg astritis. \tB oth\tt his\ta nd\tt he\ti ncreased \ta cid\ts ecretion\t\nare factors in the high incidence of gastric bleeding in alcoholics. CNS depression predisposes to aspiration \npneumonia and lung abscess formation. Acute pancreatitis \nmay become chronic with pseudocyst formation (collections of fluid in the peritoneal sac), fat malabsorption and ulti -\nmately\tloss \tof \tB-cell \tfunction, \tand \tinsulin-dependent \t\ndiabetes mellitus.\nEthanol produces a variety of endocrine effects. In particular, \nit increases the output of adrenal steroid hormones by stimulat -\ning the anterior pituitary gland to secrete adrenocorticotrophic hormone. However, the increase in plasma hydrocortisone \nusually seen in alcoholics (producing a \u2018pseudo-Cushing\u2019s \nsyndrome\u2019 [Ch. 34]) is due partly to inhibition by ethanol of hydrocortisone metabolism in the liver.\nAcute toxic effects on muscle are exacerbated by seizures \nand prolonged immobility; severe myositis (\u2018rhabdomy -\nolysis\u2019) with myoglobinuria can cause acute renal failure. Chronic toxicity affects particularly cardiac muscle, giving \nrise to alcoholic cardiomyopathy and chronic heart failure.\nChronic ethanol consumption may also result in immuno -\nsuppression, leading to increased incidence of infections such as pneumonia (immunisation with pneumococcal vaccine \nis important in chronic alcoholics); and increased cancer risk, particularly of the mouth, larynx and oesophagus.\nMale alcoholics are often impotent and show signs of \nfeminisation. This is associated with impaired testicular steroid synthesis, but induction of hepatic microsomal \nenzymes by ethanol, and hence an increased rate of tes -\ntosterone inactivation, also contributes.\nEffects of ethanol on the liver\nTogether with brain damage, liver damage is the most \ncommon serious long-term consequence of excessive ethanol \nconsumption (see Lieber, 1995). Ethanol increases fat \naccumulation in the liver even after a single dose. Increased fat accumulation (fatty liver) progresses to hepatitis (i.e. \ninflammation of the liver) and eventually to irreversible \nhepatic necrosis and fibrosis. Cirrhosis is an end stage, with extensive fibrosis and foci of regenerating hepatocytes \nthat are not correctly \u2018plumbed in\u2019 to the blood and biliary \nsystems. Diversion of portal blood flow around the cirrhotic liver often causes portal hypertension and", "start_char_idx": 0, "end_char_idx": 3493, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "531760e5-cdec-43b8-8619-16584da826a8": {"__data__": {"id_": "531760e5-cdec-43b8-8619-16584da826a8", "embedding": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1a46f68e-529f-43ea-a038-4d6f63034c9c", "node_type": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84b42ed92772e30d69361d863595f53239cf9d05337e209daa4f252240619a0b"}, "2": {"node_id": "0aef7c24-9306-4859-b62a-3cba9149a3bb", "node_type": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6e0dc8b8a90b20cffde9a450b41a2372a6f8290e6eaf54b0fa91be2255830929"}, "3": {"node_id": "07957c2c-e6db-4cec-b16d-8ca6010f2022", "node_type": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4d52520887f74c9f406ac77a68382b7a7fd05db522533e5b9c6cb101824a5d5"}}, "hash": "5e957b1a2314c3ed4290fc7bd680df026d7b3aea4fd44d3ae9a5c9cf773129f1", "text": "blood flow around the cirrhotic liver often causes portal hypertension and the development of oesophageal varices, which can bleed suddenly and \ncatastrophically.into measuring the effect of ethanol on driving performance \nin real life, as opposed to artificial tests under experimental conditions. In a US study of city drivers, it was found that \nthe probability of being involved in an accident was unaf -\nfected at blood ethanol concentrations up to 50 mg/100 mL \n(10.9 mmol/L); by 80 mg/100 mL (17.4 mmol/L) the \nprobability was increased about four-fold, and by \n150 mg/100 mL (32.6 mmol/L) about 25-fold. In Scotland, \ndriving with a blood ethanol concentration greater than \n50 mg/100 mL is illegal whereas in the rest of the United \nKingdom \tthe \tlegal \tlimit \tis \t80 \tmg/100 \tmL.\nThe relationship between plasma ethanol concentration \nand effect is highly variable. A given concentration produces a larger effect when the concentration is rising than when \nit is steady or falling. A substantial degree of cellular toler -\nance develops in habitual drinkers, with the result that a \nhigher plasma ethanol concentration is needed to produce \na given effect. In one study, \u2018gross intoxication\u2019 (assessed by a battery of tests that measured speech, gait and so on) \noccurred in 30% of subjects between 50 and 100 mg/100 mL \nand in 90% of subjects with more than 150 mg/100 mL. \nComa generally occurs at about 400 m g/100 m L, and death \nfrom respiratory failure is likely at levels exceeding \n500 mg/100 mL.\nEthanol significantly enhances \u2013 sometimes to a dangerous \nextent \u2013 the CNS depressant effects of many other drugs, \nincluding benzodiazepines, antidepressants, antipsychotic \ndrugs and opioids.\nNeurotoxicity\nIn addition to the acute effects of ethanol on the nervous system, chronic administration also causes irreversible \nneurological damage (see Harper & Matsumoto, 2005). This \nmay be due to ethanol itself, or to metabolites such as acetaldehyde or fatty acid esters, or to dietary deficiencies \n(e.g.\tof\tthiamine) \tthat \tare \tcommon \tin \talcoholics. \tBinge \t\ndrinking is thought to produce greater damage; probably due to the high brain concentrations of ethanol achieved \nand to repeated phases of withdrawal between binges. \nHeavy drinkers often exhibit convulsions and may develop irreversible dementia and motor impairment associated \nwith thinning of the cerebral cortex (apparent as ventricular \nenlargement) detectable by brain-imaging techniques. Degeneration of the cerebellar vermis, the mammillary \nbodies and other specific brain regions can also occur, as \nwell as peripheral neuropathy.\nEffects on other systems\nThe main acute cardiovascular effect of ethanol is to produce cutaneous vasodilatation, central in origin, which causes \na warm feeling but actually increases heat loss.\n13 It has \nbeen proposed that mild consumption of ethanol reduces the incidence of coronary heart disease, by increasing \ncirculating levels of high-density lipoproteins (HDL) thus reducing the incidence of atherosclerosis (see Ch. 24). The \nmuch hyped notion that a glass of red wine each day (red \nwine contains the antioxidant, resveratrol) reduces coronary \n13The\timage \tof \ta \tlarge \tSt \tBernard \tdog \tcarrying \ta \tsmall \tkeg \tof \tbrandy \t\naround its neck to revive avalanche victims is an apocryphal one \ncreated by the English painter Edwin Landseer, who in 1820 produced \na painting called \u2018Alpine Mastiffs Reanimating", "start_char_idx": 3430, "end_char_idx": 6893, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "07957c2c-e6db-4cec-b16d-8ca6010f2022": {"__data__": {"id_": "07957c2c-e6db-4cec-b16d-8ca6010f2022", "embedding": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1a46f68e-529f-43ea-a038-4d6f63034c9c", "node_type": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84b42ed92772e30d69361d863595f53239cf9d05337e209daa4f252240619a0b"}, "2": {"node_id": "531760e5-cdec-43b8-8619-16584da826a8", "node_type": null, "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e957b1a2314c3ed4290fc7bd680df026d7b3aea4fd44d3ae9a5c9cf773129f1"}}, "hash": "b4d52520887f74c9f406ac77a68382b7a7fd05db522533e5b9c6cb101824a5d5", "text": "who in 1820 produced \na painting called \u2018Alpine Mastiffs Reanimating a Distressed Traveller\u2019. \nWith their keen sense of smell, such dogs were useful in searching for people buried in the snow, but taking a tot of brandy would only have \nenhanced the victim\u2019s heat loss.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6889, "end_char_idx": 7637, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bcd9764b-ab66-4b7d-98f2-40c8ed1760c3": {"__data__": {"id_": "bcd9764b-ab66-4b7d-98f2-40c8ed1760c3", "embedding": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b9cbf605-93df-4549-bd99-1271cf0dab9d", "node_type": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87917cc3d94514a3e9b705b7ea7aeb3256e43df0804d61bd9c540dc9d5c46b86"}, "3": {"node_id": "2c33f4a8-8e05-4e46-a4c9-c0c699d8c7f9", "node_type": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ca4f774213e161f496b0e7e5bf03c4edd79631ec5e9d59eedcac5f741f3e072"}}, "hash": "85c7cdd28cab43a7cce018a432f2aabd474c2227b4db385197e0d43dc7f64cad", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n638ethanol shows saturation kinetics (see Chs 10 and 11) at \nquite low ethanol concentrations, so the fraction of ethanol \nremoved decreases as the concentration reaching the liver \nincreases. Thus, if ethanol absorption is rapid and portal vein concentration is high, most of the ethanol escapes into the \nsystemic circulation, whereas with slow absorption more is \nremoved by first-pass metabolism. This is one reason why drinking ethanol on an empty stomach produces a much \ngreater pharmacological effect. Ethanol is quickly distributed \nthroughout the body water, the rate of its redistribution depending mainly on the blood flow to individual tissues, as with volatile anaesthetics (see Ch. 42).\nEthanol is about 90% metabolised, 5%\u201310% being excreted \nunchanged in expired air and in urine. This fraction is not pharmacokinetically significant but provides the basis for \nestimating blood ethanol concentration from measurements \non breath or urine. The ratio of ethanol concentrations in blood and alveolar air, measured at the end of deep expira -\ntion, is relatively constant, 80 mg/100 mL of ethanol in \nblood producing 35 \u00b5g/100 mL in expired air; this being \nthe basis of the breathalyser test. The concentration in urine is more variable and provides a less accurate measure of \nblood concentration.\nEthanol metabolism occurs almost entirely in the liver, \nand mainly by a pathway involving successive oxidations, first to acetaldehyde and then to acetic acid (Fig. 49.5). \nSince ethanol is often consumed in large quantities (com-\npared with most drugs), 1\u20132 mol daily being by no means \nunusual, it constitutes a substantial load on the hepatic \noxidative systems. The oxidation of 2 mol of ethanol \nconsumes about 1.5 kg of the co-factor nicotinamide adenine \ndinucleotide (NAD+). Availability of NAD+ limits the rate \nof ethanol oxidation to about 8 g/h in a normal adult, With chronic ethanol consumption, many other factors \ncontribute to the liver damage. One is malnutrition, for \nalcoholic individuals may satisfy much of their calorie \nrequirement from ethanol itself. Three hundred grams of ethanol (equivalent to one bottle of whisky) provides about \n2000 kcal but, unlike a normal diet, it provides no vitamins, \namino acids or fatty acids. Thiamine deficiency is an important factor in causing chronic neurological damage. \nFolate deficiency (Ch. 26) is also common in alcoholics, \noften associated with macrocytosis of red blood cells.\nThe overall incidence of chronic liver disease is a function \nof cumulative ethanol consumption over many years. An increase in the plasma concentration of the liver enzyme \u03b3\n-glutamyl \ttranspeptidase \t(a \tmarker \tof \tcytochrome \tP450 \t\ninduction, Ch. 10) often raises the suspicion of ethanol-related liver damage, although not specific to ethanol.\nThe effect of ethanol on fetal development\nDrinking alcohol, especially in the first 3 months of preg-nancy, increases the risk of miscarriage, premature birth \nand low birth weight. The adverse effect of heavier ethanol \nconsumption during pregnancy on fetal development was demonstrated in the early 1970s, when the term fetal alcohol \nsyndrome (FAS) was coined.\nThe features of full FAS include:\n\u2022\tabnormal \tfacial \tdevelopment, \twith \twide-set \teyes, \t\nshort palpebral fissures and small cheekbones;\n\u2022\treduced \tcranial \tcircumference;\n\u2022\tretarded \tgrowth;\n\u2022\tmental \tretardation \tand \tbehavioural \tabnormalities, \t\noften taking", "start_char_idx": 0, "end_char_idx": 3486, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2c33f4a8-8e05-4e46-a4c9-c0c699d8c7f9": {"__data__": {"id_": "2c33f4a8-8e05-4e46-a4c9-c0c699d8c7f9", "embedding": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b9cbf605-93df-4549-bd99-1271cf0dab9d", "node_type": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87917cc3d94514a3e9b705b7ea7aeb3256e43df0804d61bd9c540dc9d5c46b86"}, "2": {"node_id": "bcd9764b-ab66-4b7d-98f2-40c8ed1760c3", "node_type": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "85c7cdd28cab43a7cce018a432f2aabd474c2227b4db385197e0d43dc7f64cad"}, "3": {"node_id": "dcf98b54-e459-4c88-9f87-847e43c8e5bc", "node_type": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19136298a64f47218c66a1904ec963139b0501efe7a26275d27222abd5608ca9"}}, "hash": "4ca4f774213e161f496b0e7e5bf03c4edd79631ec5e9d59eedcac5f741f3e072", "text": "\tretardation \tand \tbehavioural \tabnormalities, \t\noften taking the form of hyperactivity and difficulty with social integration;\n\u2022\tother\tanatomical \tabnormalities, \twhich \tmay \tbe \tmajor \t\nor minor (e.g. congenital cardiac abnormalities, malformation of the eyes and ears).\nA lesser degree of impairment, termed alcohol-related neuro -\ndevelopmental disorder (ARND), results in behavioural problems, and cognitive and motor deficits, often associated \nwith reduced brain size. Full FAS occurs in about 3 per \n1000 live births and affects about 30% of children born to alcoholic mothers. It is rare with mothers who drink less \nthan about 5 units/day, and most common in binge drinkers \nwho sporadically consume much larger amounts, resulting in high peak levels of ethanol. ARND is about three times \nas common. Although there is no clearly defined safe \nthreshold, there is no evidence that amounts less than about 2 units/day are harmful. There is no critical period during \npregnancy when ethanol consumption is likely to lead to \nFAS, although one study suggests that FAS incidence correlates most strongly with ethanol consumption very \nearly in pregnancy, even before pregnancy is recognised, \nimplying that not only pregnant women, but also women who are likely to become pregnant, should be advised not to drink heavily. Experiments on rats and mice suggest \nthat the effect on facial development may be produced \nvery early in pregnancy (up to 4 weeks in humans), while the effect on brain development is produced rather later \n(up to 10 weeks).\nPHARMACOKINETIC ASPECTS\nMetabolism of ethanol\nEthanol is rapidly absorbed, an appreciable amount being \nabsorbed from the stomach. A substantial fraction is cleared \nby first-pass hepatic metabolism. Hepatic metabolism of Effects of ethanol \n\u2022\tEthanol acts as a general central nervous system \ndepressant, similar to volatile anaesthetic agents, \nproducing \tthe \tfamiliar \teffects \tof \tacute \tintoxication.\n\u2022\tSeveral\tcellular \tmechanisms \tare \tpostulated: \t\nenhancement \tof \tGABA \tand \tglycine \taction, \tinhibition \tof \t\ncalcium\tchannel \topening, \tactivation \tof \tpotassium \t\nchannels\tand \tinhibition \tat \tNMDA \treceptors.\n\u2022\tEffective \tplasma \tconcentrations:\n\u2013\tthreshold \teffects: \tabout \t20 \tmg/100 \tmL \t(5 \tmmol/L)\n\u2013\tsevere\tintoxication: \tabout \t150 \tmg/100 \tmL\n\u2013\tdeath\tfrom \trespiratory \tfailure: \tabout \t500 \tmg/100 \tmL\n\u2022\tMain\tperipheral \teffects \tare \tself-limiting \tdiuresis \t\n(reduced antidiuretic hormone secretion), and cutaneous vasodilatation.\n\u2022\tNeurological \tdegeneration \toccurs \twith \theavy \tand \tbinge\t\ndrinking, causing dementia and peripheral neuropathies.\n\u2022\tLong-term \tethanol \tconsumption \tcauses \tliver \tdisease, \t\nprogressing \tto \tcirrhosis \tand \tliver \tfailure.\n\u2022\tExcessive \tconsumption \tin \tpregnancy \tcauses \timpaired \t\nfetal\tdevelopment, \tassociated \twith \tsmall \tsize, \t\nabnormal\tfacial \tdevelopment \tand \tother \tphysical \t\nabnormalities, and mental retardation.\n\u2022\tPsychological \tdependence, \tphysical \tdependence \tand \t\ntolerance all occur with ethanol.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3431, "end_char_idx": 6721, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dcf98b54-e459-4c88-9f87-847e43c8e5bc": {"__data__": {"id_": "dcf98b54-e459-4c88-9f87-847e43c8e5bc", "embedding": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b9cbf605-93df-4549-bd99-1271cf0dab9d", "node_type": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87917cc3d94514a3e9b705b7ea7aeb3256e43df0804d61bd9c540dc9d5c46b86"}, "2": {"node_id": "2c33f4a8-8e05-4e46-a4c9-c0c699d8c7f9", "node_type": null, "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ca4f774213e161f496b0e7e5bf03c4edd79631ec5e9d59eedcac5f741f3e072"}}, "hash": "19136298a64f47218c66a1904ec963139b0501efe7a26275d27222abd5608ca9", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6730, "end_char_idx": 7001, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b24314a7-6d54-43a2-a0d6-8b3803dce7e0": {"__data__": {"id_": "b24314a7-6d54-43a2-a0d6-8b3803dce7e0", "embedding": null, "metadata": {"page_label": "645", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e59a8298-de9b-4d00-b1f4-08d427547d48", "node_type": null, "metadata": {"page_label": "645", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0ba2b9fa5b20b3cfd7905ed7a360be7821222a7178606bae4c5d4a86f75aec14"}, "3": {"node_id": "682c95f4-597f-4c32-82d4-21c11ad6e50f", "node_type": null, "metadata": {"page_label": "645", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3a331d83d778df3f55993ed8c438df000049bf21063ec1cf3787325c1c15a1d7"}}, "hash": "ac69a9f270f4cf1ff83a730a64a36d0ec74b161dd4104ac795e4322bbcdd055f", "text": "49 PSYchOacTiVE dRUgS\n639with various fatty acids also occurs in the tissues, and these \nesters may also contribute to long-term toxicity.\nAlcohol dehydrogenase is a soluble cytoplasmic enzyme, \nconfined mainly to liver cells, which oxidises ethanol at the same time as reducing NAD\n+ to NADH (see Fig. 49.5). \nEthanol metabolism causes the ratio of NAD+ to NADH \nto fall, and this has other metabolic consequences (e.g. \nincreased \tlactate \tand \tslowing \tdown \tof \tthe \tKrebs \tcycle). \t\nThe limitation on ethanol metabolism imposed by the limited rate of NAD\n+ regeneration has led to attempts to find a \n\u2018sobering up\u2019 agent that works by regenerating NAD+ from \nNADH. One such agent is fructose, which is reduced by \nan NADH-requiring enzyme. In large doses, it causes a \nmeasurable increase in the rate of ethanol metabolism, but not enough to have a useful effect on the rate of return to \nsobriety.\nNormally, only a small amount of ethanol is metabolised \nby the microsomal mixed function oxidase system (see Ch. 10), but induction of this system occurs in alcoholics. Ethanol \ncan affect the metabolism of other drugs that are metabolised by the mixed function oxidase system (e.g. phenobarbital , \nwarfarin and steroids), with an initial inhibitory effect \nproduced by competition, followed by enhancement due \nto enzyme induction.\nNearly all the acetaldehyde produced is converted \nto acetate in the liver by aldehyde dehydrogenase (see Fig. \n49.5). Normally, only a little acetaldehyde escapes from the liver, giving a blood acetaldehyde concentration of \n20\u201350 \u00b5mol/L after an intoxicating dose of ethanol in \nhumans. The circulating acetaldehyde usually has little or \nno effect, but the concentration may become much larger \nunder certain circumstances and produce toxic effects. This occurs if aldehyde dehydrogenase is inhibited by drugs \nsuch as disulfiram. In the presence of disulfiram, which \nproduces no marked effect when given alone, ethanol consumption is followed by a severe reaction comprising \nflushing, tachycardia, hyperventilation and considerable \npanic and distress, which is due to excessive acetaldehyde accumulation in the bloodstream. This reaction is extremely independently of ethanol concentration (Fig. 49.6), causing the process to show saturating kinetics (Ch. 11). It also \nleads to competition between the ethanol and other meta-\nbolic substrates for the available NAD\n+ supplies, which \nmay be a factor in ethanol-induced liver damage (see Ch. \n58). The intermediate metabolite, acetaldehyde, is a reactive \nand toxic compound, and this may also contribute to the hepatotoxicity. A small degree of esterification of ethanol MAINLY EXTRA-HEPATIC\nDISULFIRAMAldehyde oxidaseMixed function oxidaseO2\nO225%\n25%75%\n75%Alcohol dehydrogenase\nAldehyde dehydrogenaseNADH\nNAD+NAD+\nNADHLIVER\nAcetic acid\nCH3COOHAcetaldehyde\nCH3CHOEthanol\nCH3CH2OH\nFig. 49.5 Metabolism of ethanol. \nNAD, nicotinamide adenine \ndinucleotide. \n050100\n16 12 8 4 0Blood ethanol concentration (mmol/L)\nHours\nFig. 49.6 Zero-order kinetics of ethanol elimination in rats. \nRats\twere \tgiven \tethanol \torally \t(104 \tmmol/kg) \teither \tas \ta \tsingle \t\ndose\tor\tas \tfour \tdivided \tdoses. \tThe \tsingle \tdose \tresults \tin \ta \t\nmuch higher and more", "start_char_idx": 0, "end_char_idx": 3250, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "682c95f4-597f-4c32-82d4-21c11ad6e50f": {"__data__": {"id_": "682c95f4-597f-4c32-82d4-21c11ad6e50f", "embedding": null, "metadata": {"page_label": "645", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e59a8298-de9b-4d00-b1f4-08d427547d48", "node_type": null, "metadata": {"page_label": "645", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0ba2b9fa5b20b3cfd7905ed7a360be7821222a7178606bae4c5d4a86f75aec14"}, "2": {"node_id": "b24314a7-6d54-43a2-a0d6-8b3803dce7e0", "node_type": null, "metadata": {"page_label": "645", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ac69a9f270f4cf1ff83a730a64a36d0ec74b161dd4104ac795e4322bbcdd055f"}}, "hash": "3a331d83d778df3f55993ed8c438df000049bf21063ec1cf3787325c1c15a1d7", "text": "\tThe \tsingle \tdose \tresults \tin \ta \t\nmuch higher and more sustained blood ethanol concentration \nthan\tthe\tsame \tquantity \tgiven \tas \tdivided \tdoses. \tNote \tthat, \tafter \t\nthe single dose, ethanol concentration declines linearly, the rate \nof\tdecline \tbeing \tsimilar \tafter \ta \tsmall \tor \tlarge \tdose, \tbecause \tof \t\nthe\tsaturation \tphenomenon. \t(From \tKalant, \tH. \tet \tal., \t1975. \t\nBiochem.\tPharmacol. \t24, \t431.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3193, "end_char_idx": 4086, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "604b214e-51ad-4d0c-961c-430d576cdff8": {"__data__": {"id_": "604b214e-51ad-4d0c-961c-430d576cdff8", "embedding": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f9b72da7-a4e5-4e89-b678-9f094ec7b82f", "node_type": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f4ca92124f61b4810babbfa50eedec70c97415a90444ec33e6a7517c555cea9"}, "3": {"node_id": "5060825b-63d7-456d-9ddf-84dd3d76b032", "node_type": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "386dc3472dde2443b8fa3edb11d461109e17797cfd5ac9d85e040b721f686a3e"}}, "hash": "a5e4db1abed5819c226eb1df327261ffdcb2d67f2c641c6d6143adb958cdf139", "text": "49 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n640synaptosomes) as well as in vivo. The mechanism of this \ntolerance is not known for certain. Ethanol tolerance is \nassociated with tolerance to many anaesthetic agents, and \nalcoholics are often difficult to anaesthetise.\nChronic ethanol administration produces various changes \nin CNS neurons, which tend to oppose the acute cellular effects that it produces. There is a small reduction in the \ndensity\to f \tG ABA A receptors, and a proliferation of voltage-\ngated calcium channels and NMDA receptors.\nA well-defined physical abstinence syndrome develops \nin response to ethanol withdrawal. As with most other dependence-producing drugs, this is probably important \nas a short-term factor in sustaining the drug habit, but \nother (mainly psychological) factors are more important in the longer term (see Ch. 50). The physical abstinence \nsyndrome usually subsides in a few days, but the craving \nfor ethanol and the tendency to relapse last for very much longer. Treatment of alcohol dependence is described in Chapter 50.\nThe physical abstinence syndrome in humans, in severe \nform, develops after about 8 h. In the first stage, the main \nsymptoms are tremor, nausea, sweating, fever and some -\ntimes hallucinations. These last for about 24 h. This phase \nmay be followed by seizures (\u2018rum fits\u2019). Over the next few days, the condition of \u2018delirium tremens\u2019 develops, in which \nthe patient becomes confused, agitated and often aggressive, \nand may suffer much more severe hallucinations. Treatment of this medical emergency is by sedation with large doses \nof a benzodiazepine such as chlordiazepoxide (Ch. 45) \ntogether with large doses of thiamine.\nSYNTHETIC CANNABINOIDS\nThe endogenous cannabinoid system and cannabinoids \ncontained in the Cannabis sativa plant (phytocannabinoids) \nare described in detail in Chapter 20. Here we will focus on synthetic cannabinoids, which have names such as Spice, unpleasant but not usually harmful, at least in otherwise relatively healthy drinkers, and disulfiram can be used as \naversion therapy to discourage people from taking ethanol. \nSome other drugs (e.g. metronidazole ; see Ch. 52) produce \nsimilar reactions to ethanol. Interestingly, a Chinese herbal \nmedicine used traditionally to cure alcoholics contains \ndaidzin, a specific inhibitor of aldehyde dehydrogenase.\n14\nGenetic factors\nIn 50% of Asian people, an inactive genetic variant of one of the aldehyde dehydrogenase isoforms (ALDH-2) is \nexpressed; these individuals experience a disulfiram-like \nreaction after alcohol, and the incidence of alcoholism in this group is extremely low (see Tyndale, 2003).\nMetabolism and toxicity of methanol and \nethylene glycol\n\u25bc Methanol is metabolised in the same way as ethanol but produces \nformaldehyde instead of acetaldehyde from the first oxidation step. \nFormaldehyde is more reactive than acetaldehyde and reacts rapidly \nwith proteins, causing the inactivation of enzymes involved in the tricarboxylic acid cycle. It is converted to another toxic metabolite, \nformic acid. This, unlike acetic acid, cannot be utilised in the tricar -\nboxylic acid cycle and is liable to cause tissue damage. Conversion \nof alcohols to aldehydes occurs not only in the liver but also in the \nretina, catalysed by the dehydrogenase responsible for retinol\u2013retinal \nconversion. Formation of formaldehyde in the retina accounts for \none of the main toxic effects of methanol, namely blindness, which \ncan occur after ingestion of as little as 10 g. Formic acid production \nand derangement of the tricarboxylic", "start_char_idx": 0, "end_char_idx": 3584, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5060825b-63d7-456d-9ddf-84dd3d76b032": {"__data__": {"id_": "5060825b-63d7-456d-9ddf-84dd3d76b032", "embedding": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f9b72da7-a4e5-4e89-b678-9f094ec7b82f", "node_type": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f4ca92124f61b4810babbfa50eedec70c97415a90444ec33e6a7517c555cea9"}, "2": {"node_id": "604b214e-51ad-4d0c-961c-430d576cdff8", "node_type": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a5e4db1abed5819c226eb1df327261ffdcb2d67f2c641c6d6143adb958cdf139"}, "3": {"node_id": "a9f69881-2563-40c3-a5cd-846013a8a3b5", "node_type": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2305d044fec04c8c7577951c6240da382b2027afe778bae29126afa2cdfde43"}}, "hash": "386dc3472dde2443b8fa3edb11d461109e17797cfd5ac9d85e040b721f686a3e", "text": " g. Formic acid production \nand derangement of the tricarboxylic acid cycle also produce severe \nacidosis.\nMethanol is used as an industrial solvent and also to adulterate \nindustrial ethanol in order to make it unfit to drink. Methanol poisoning \nis quite common, and used to be treated by administration of large \ndoses of ethanol, which acts to retard methanol metabolism by competition for alcohol dehydrogenase. Fomepizole inhibits alcohol \ndehydrogenase and is now preferred, if available. Such treatment may be in conjunction with haemodialysis to remove unchanged methanol, which has a small volume of distribution.\nPoisoning \twith \tethylene \tglycol, \tused \tin \tautomobile \tantifreeze \tand \t\nbrake fluid, is a medical emergency. It is rapidly absorbed from the gut and metabolised to glycolate and then more slowly to oxalate. \nGlycolate interferes with metabolic processes and produces metabolic \nacidosis. It affects the brain, heart and kidneys. Treatment is with \nfomepizole or, with caution, ethanol,\n15 and haemodialysis.\nTOLERANCE AND DEPENDENCE\nTolerance to the effects of ethanol can be demonstrated in \nboth humans and experimental animals, to the extent of a \ntwo- to three-fold reduction in potency occurring over 1\u20133 \nweeks of continuing ethanol administration. A small component of this is due to the more rapid elimination of \nethanol. The major component is cellular tolerance, which \naccounts for a roughly two-fold decrease in potency and which can be observed in vitro (e.g. by measuring the \ninhibitory effect of ethanol on transmitter release from Metabolism of ethanol \n\u2022\tEthanol is metabolised mainly by the liver, first by \nalcohol dehydrogenase to acetaldehyde, then by \naldehyde\tdehydrogenase \tto \tacetate. \tAbout \t25% \tof \tthe \t\nacetaldehyde is metabolised extrahepatically.\n\u2022\tSmall\tamounts \tof \tethanol are excreted in urine and \nexpired air.\n\u2022\tHepatic \tmetabolism \tshows \tsaturation \tkinetics, \tmainly \t\nbecause\tof \tlimited \tavailability \tof \tnicotinamide \tadenine \t\ndinucleotide \t(NAD+).\tMaximal \trate \tof \tethanol \nmetabolism \tis \tabout \t10 \tmL/h. \tThus \tplasma \t\nconcentration \tfalls \tlinearly \trather \tthan \texponentially.\n\u2022\tAcetaldehyde \tmay \tproduce \ttoxic \teffects. \tInhibition \tof \t\naldehyde dehydrogenase by disulfiram accentuates \nnausea, etc., caused by acetaldehyde, and can be used in aversion therapy.\n\u2022\tMethanol\n\tis\tsimilarly \tmetabolised \tto \tformic \tacid, \t\nwhich is toxic, especially to the retina.\n\u2022\tAsian\tpeople \tshow \ta \thigh \trate \tof \tgenetic \t\npolymorphism \tof \talcohol \tand \taldehyde \t\ndehydrogenase, associated with alcoholism and alcohol intolerance, respectively.\n15When presented with a late evening emergency poisoning of a dog \nwith ethylene glycol, a veterinarian colleague of one of the authors ran \nto the local supermarket and purchased a bottle of vodka \u2013 the dog \nsurvived!14In hamsters (which spontaneously consume alcohol in amounts that \nwould defeat even the hardest two-legged drinker, while remaining, as \nfar as one can tell in a hamster, completely sober), daidzin markedly \ninhibits alcohol consumption.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3530, "end_char_idx": 6840, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a9f69881-2563-40c3-a5cd-846013a8a3b5": {"__data__": {"id_": "a9f69881-2563-40c3-a5cd-846013a8a3b5", "embedding": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f9b72da7-a4e5-4e89-b678-9f094ec7b82f", "node_type": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f4ca92124f61b4810babbfa50eedec70c97415a90444ec33e6a7517c555cea9"}, "2": {"node_id": "5060825b-63d7-456d-9ddf-84dd3d76b032", "node_type": null, "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "386dc3472dde2443b8fa3edb11d461109e17797cfd5ac9d85e040b721f686a3e"}}, "hash": "e2305d044fec04c8c7577951c6240da382b2027afe778bae29126afa2cdfde43", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6848, "end_char_idx": 7151, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a504cc21-d0f0-49c0-81ac-47871e3036ee": {"__data__": {"id_": "a504cc21-d0f0-49c0-81ac-47871e3036ee", "embedding": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c7f74e43-8e7d-4d08-89f1-bbaab2c6496a", "node_type": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20295aa3b53f52c0599ed423a44fa74128d366b55d186867868aa2a78b403d3a"}, "3": {"node_id": "81221f02-a342-470e-876b-569fc414769e", "node_type": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f30a95779bc03856472db1e6e1639414ee15687cf7951722431e388d2393709a"}}, "hash": "e25b2b4625f4db4f9c3d753f8716bdded6ed38e21041fea31dbcc0d59ea13227", "text": "49 PSYchOacTiVE dRUgS\n641cataleptic. This may explain their popularity amongst the \nhomeless and prisoners in jail, allowing them a period of \nescape from their daily lives.\nUnlike cannabis itself, synthetic cannabinoids are quite \nharmful and can induce hallucinations, psychotic episodes, seizures and death. The precise reasons for these toxic effects \nare not known. They may have \u2018off-target\u2019 effects unrelated \nto\ttheir\tactions \ton \tCB 1 receptors. Furthermore, when \nsmoked, the parent compounds are subject to pyrolysis \ngiving rise to unexpected derivatives, which may be \nresponsible for some of the damaging effects. Quality control is not a priority for the producers of these agents and so \nthere may be toxic contaminants in occasional batches of \nchemicals.K2 or Black Mamba. The chemical structures of synthetic cannabinoids are diverse, with over 10 chemical families \nhaving been described (see Davidson et al., 2017). Some \noriginated from legitimate attempts by pharmaceutical companies to develop new analgesic compounds but \nmore recently others have been developed purely for \nnon-medicinal purposes. Synthetic cannabinoids are com -\nmonly sprayed on herbal material and smoked but are also \navailable in crystal and powder form. They are agonists \nat\tthe\tCB 1 cannabinoid receptor, the target through which \n\u03949-tetrahydrocannabinol (THC), the major psychoactive \ningredient in cannabis, has its effects. Synthetic cannabi -\nnoids are said to exert a \u2018more forceful\u2019 activation of the \nCB 1 receptor, in that users often become \u2018zombie-like\u2019 or \nREFERENCES AND FURTHER READING\nGeneral reference\nMiller,\tR.J., \t2015. \tDrugged: \tThe \tScience \tand \tCulture \tBehind \t\nPsychotropic \tDrugs. \tOxford \tUniversity \tPress. \t(A lively account of \npsychoactive drug use)\nStimulants\nDocherty, J.R., Green, A.R., 2010. The role of monoamines in the changes in \nbody temperature induced by 3,4-methylene-dioxymethamphetamine \n(MDMA, \tecstasy) \tand \tits \tderivatives. \tBr. \tJ. \tPharmacol. \t160, \t1029\u20131044.\nFredholm, \tB.B., \tBattig, \tK., \tHolmes, \tJ., \tet \tal., \t1999. \tActions \tof \tcaffeine \tin \t\nthe brain with special reference to factors that contribute to its \nwidespread \tuse. \tPharmacol. \tRev. \t51, \t83\u2013133. \t(Comprehensive review \narticle covering pharmacological, behavioural and social aspects)\nGreen,\tA.R., \tKing, \tM.V., \tShortall, \tS.E., \tFone, \tK.C., \t2012. \tLost \tin \ttranslation: \t\npreclinical studies on 3,4-methylenedioxy-methamphetamine provide \ninformation on mechanisms of action, but do not allow accurate \nprediction \tof \tadverse \tevents \tin \thumans. \tBr. \tJ. \tPharmacol. \t166, \t1523\u20131536.\nHeal, D.J., Cheetham, S.C., Smith, S.L., 2009. The neuropharmacology of \nADHD drugs in vivo: insights on efficacy and safety. \nNeuropharmacology 57, 608\u2013618. (Reviews various aspects of the \npharmacology of drugs used to treat ADHD)\nNicotine\nDe\tBiasi, \tM., \tDani, \tJ.A., \t2011. \tReward, \taddiction, \twithdrawal \tto \t\nnicotine. Annu. Rev. Neurosci. 34, 105\u2013130.\nHung,\tR.J., \tMcKay, \tJ.D., \tGaborieau, \tV., \tet \tal., \t2008. \tA \tsusceptibility", "start_char_idx": 0, "end_char_idx": 3061, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "81221f02-a342-470e-876b-569fc414769e": {"__data__": {"id_": "81221f02-a342-470e-876b-569fc414769e", "embedding": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c7f74e43-8e7d-4d08-89f1-bbaab2c6496a", "node_type": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20295aa3b53f52c0599ed423a44fa74128d366b55d186867868aa2a78b403d3a"}, "2": {"node_id": "a504cc21-d0f0-49c0-81ac-47871e3036ee", "node_type": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e25b2b4625f4db4f9c3d753f8716bdded6ed38e21041fea31dbcc0d59ea13227"}, "3": {"node_id": "01fc53ae-48ed-430f-ad3c-2b789efd5a56", "node_type": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "138e161b3e8c89f859671b4c9788bb6b9069186ab5cb04ba8d705f0c061b3214"}}, "hash": "f30a95779bc03856472db1e6e1639414ee15687cf7951722431e388d2393709a", "text": "\tV., \tet \tal., \t2008. \tA \tsusceptibility \t\nlocus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452, 633\u2013637. (Original paper showing a genetic \nlink between cancer and single nucleotide polymorphisms in the nicotinic \nreceptor)\nLe\tFoll,\tB., \tGoldberg, \tS.R., \t2005. \tControl \tof \tthe \treinforcing \teffects \tof \t\nnicotine by associated environmental stimuli in animals and humans. \nTrends\tPharmacol. \tSci. \t26, \t287\u2013293.\nLeslie, F.M., Mojica, C.Y., Reynaga, D.D., 2013. Nicotinic receptors in \naddiction \tpathways. \tMol. \tPharmacol. \t83, \t753\u2013758.\nWonnacott, \tS., \tSidhpura, \tN., \tBalfour, \tD.J.K., \t2005. \tNicotine: \tfrom \t\nmolecular \tmechanisms \tto \tbehaviour. \tCurr. \tOpin. \tPharmacol. \t5, \t53\u201359. \t\n(Useful review on the acute and long-term CNS effects of nicotine)\nCognition enhancers\nBattleday, \tR.M., \tBrem, \tA.K., \t2015. \tModafinil \tfor \tcognitive \t\nneuroenhancement in healthy non-sleep-deprived subjects: a systematic review. Eur. Neuropsychopharmacol. 25, 1865\u20131881. (A \nsystematic review of published research papers evaluating the effect of \nmodafinil in non-fatigued individuals)\nCollingridge, \tG.L., \tVolianskis, \tA., \tBannister, \tN., \tet \tal., \t2013. \tThe \tNMDA \t\nreceptor as a target for cognitive enhancement. Neuropharmacology 64, 13\u201326.\nDe\tMei,\tC., \tRamos, \tM., \tLitaka, \tC., \tBorrelli, \tE., \t2009. \tGetting \tspecialized: \t\npresynaptic and postsynaptic dopamine D 2 receptors. Curr. Opin. \nPharmacol. \t9, \t53\u201358.\nD\u2019Angelo, \tL.S.C., \tSavulich, \tD., \tSahakian, \tB.J., \t2017. \tLifestyle \tuse \tof \t\ndrugs by healthy people for enhancing cognition, creativity, \nmotivation \tand \tpleasure. \tBr. \tJ. \tPharmacol. \t174, \t3257\u20133267.Harms,\tJ.E., \tBenveniste, \tM., \tMaclean, \tJ.K., \tPartin, \tK.M., \tJamieson, \tC., \t\n2013. Functional analysis of a novel positive allosteric modulator of \nAMPA\treceptors \tderived \tfrom \ta \tstructure-based \tdrug \tdesign \tstrategy. \t\nNeuropharmacology 64, 45\u201352.\nPsychedelics\nCarhart-Harris, R.L., Goodwin, G.M., 2017. The therapeutic potential of \npsychedelic drugs: past, present, and future. Neuropsychopharmacol. \n42, 2105\u20132113. (An interesting discussion between two leading scientists \nwith differing views on the topic)\nNichols,\tD.E., \t2004. \tHallucinogens. \tPharmacol. \tTher. \t101, \t131\u2013181. \t\n(Comprehensive review article focusing on 5-HT 2A receptors as the target of \npsychotomimetic drugs)\nEthanol\nGarbutt, J.C., 2009. The state of pharmacotherapy for the treatment of \nalcohol dependence. J. Subst. Abuse Treat. 36, S15\u2013S21. (Reviews \ncurrent treatments and potential new", "start_char_idx": 3027, "end_char_idx": 5591, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "01fc53ae-48ed-430f-ad3c-2b789efd5a56": {"__data__": {"id_": "01fc53ae-48ed-430f-ad3c-2b789efd5a56", "embedding": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c7f74e43-8e7d-4d08-89f1-bbaab2c6496a", "node_type": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20295aa3b53f52c0599ed423a44fa74128d366b55d186867868aa2a78b403d3a"}, "2": {"node_id": "81221f02-a342-470e-876b-569fc414769e", "node_type": null, "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f30a95779bc03856472db1e6e1639414ee15687cf7951722431e388d2393709a"}}, "hash": "138e161b3e8c89f859671b4c9788bb6b9069186ab5cb04ba8d705f0c061b3214", "text": "approaches)\nHarper, C., Matsumoto, I., 2005. Ethanol and brain damage. Curr. Opin. \nPharmacol. \t5, \t73\u201378. \t(Describes deleterious effects of long-term alcohol \nabuse on brain function)\nHarris, R.A., Trudell, J.R., Mihic, S.J., 2008. Ethanol\u2019s molecular targets. \nSci. Signal. 1, re7. (Short review of potential molecular actions of alcohol \nrelevant to its effects on the brain)\nLieber, C.S., 1995. Medical disorders of alcoholism. N. Engl. J. Med. 333, \n1058\u20131065. (Review focusing on ethanol-induced liver damage in relation to ethanol metabolism)\nSpanagel, R., 2009. Alcoholism: a systems approach from molecular \nphysiology \tto \taddictive \tbehaviour. \tPhysiol. \tRev. \t89, \t649\u2013705. \t\n(Comprehensive review article, very useful for reference)\nTyndale, R.F., 2003. Genetics of alcohol and tobacco use in humans. \nAnn. Med. 35, 94\u2013121. (Detailed review of the many genetic factors implicated in alcohol and nicotine consumption habits)\nDissociative drugs\nMorgan, \tC.J., \tCurran, \tH.V., \t2012. \tKetamine \tuse: \ta \treview. \tAddiction \t\n107, 27\u201338. (Extensive review of current use of ketamine and the harms associated with its use)\nMorris,\tB.J., \tCochran, \tS.M., \tPratt, \tJ.A., \t2005. \tPCP: \tfrom \tpharmacology \tto \t\nmodelling \tschizophrenia. \tCurr. \tOpin. \tPharmacol. \t5, \t101\u2013106. \t(Review \narguing that NMDA channel block by phencyclidine closely models human \nschizophrenia)\nSynthetic cannabinoids\nDavidson, C., Opacka-Juffry, J., Arevalo-Martin, A., Garcia-Ovejero, D., \nMolina-Holgado, E., Molina-Holgado, F., 2017. Spicing up pharmacology: a review of synthetic cannabinoids from structure to \nadverse\tevents. \tAdv. \tPharmacol. \t80, \t135\u2013168. \t(Gives details of the \nchemical structures of synthetic cannabinoids and describes their adverse effects)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5627, "end_char_idx": 7862, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f692a058-a0f2-4b40-8b21-9598299fd033": {"__data__": {"id_": "f692a058-a0f2-4b40-8b21-9598299fd033", "embedding": null, "metadata": {"page_label": "648", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6bc5877c-5e02-4e2a-b9f2-d6120adaf5b4", "node_type": null, "metadata": {"page_label": "648", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ae6ca8307fe0f604606e4c425a0eed78768d4d6e8569a8a258c9e609f4c720c3"}, "3": {"node_id": "f3b0c188-e64f-4925-b7d9-fe533b64e7ca", "node_type": null, "metadata": {"page_label": "648", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "27ba635772a6c26de52ce23a87b008be51a836b3b0a21e887a2a763bfd3cc587"}}, "hash": "b39e3df723e0770e399691dc82058d1ad579ad1e90d2d6dce09274d39ef711ea", "text": "642\nOVERVIEW\nIn other chapters, we have considered how drugs \nthat are taken (abused) because they are pleasurable \n(hedonic) exert their profound effects. In this chapter, \nwe now focus on factors that relate specifically to drug abuse (e.g. routes of administration, harms \ninvolved in drug taking) and on why some drugs of \nabuse produce dependence (addiction). Finally, pharmacological treatments for drug dependence are \ndescribed. The use of drugs in sport and bodybuilding \nis discussed in Chapter 59.\nThe reasons why the use of a particular drug is \nviewed as a problem to society \u2013 and hence may be considered \u2018drug abuse\u2019 \u2013 are complex and largely outside the scope of this book. The drug and its \npharmacological activity are only the starting point. \nFor many, but not all, drugs of abuse, continued use leads to dependence (addiction).\nDRUG USE AND ABUSE\nA number of terms are used, sometimes interchangeably \nand sometimes incorrectly, to describe drug use and the \nconsequences of self-administration of drugs. Terms that \nare best avoided are listed in Table 50.1. Other, more useful, terms are defined in the text.\nA vast and ever-increasing array of drugs is used to alter \nmood and perception.\n1 These include drugs that are also \nused as medicines, e.g. anxiolytics (Ch. 45), opioids (Ch. \n43) and general anaesthetics (Ch. 42), as well as cannabinoids \n(Ch. 20) and the range of non-medicinal drugs described in Chapter 49. Volatile organic solvents (present in glues \nand aerosols), taken by inhalation, also feature as abused \ndrugs. The popularity of each varies between different societies across the world, and within societies popularity \ndiffers among different groups of individuals.\n2 Frequently, \nusers will take more than one drug concomitantly (e.g. heroin users will inject cocaine and heroin together, an \nactivity known as speedballing) or sequentially. Sequential \nuse is often intended to reduce adverse effects when coming \ndown off the first drug (e.g. use of benzodiazepines when \ncoming down from stimulants). Polydrug use is a very under-researched area in regard to why it is done, how different drugs may interact and the potential harm that may arise from such practices. For example, ethanol alters \ncocaine metabolism, resulting in the production of cocaeth-\nylene , which is more potent than cocaine and has potentially \ngreater cardiovascular toxicity.\nDrugs of abuse are an extremely heterogeneous pharm -\nacological group; we can find little in common at the \nmolecular and cellular level between say, morphine , cocaine \nand LSD (lysergic acid diethylamide). What links them \nis that people find their effects pleasurable (hedonic) and tend to want to repeat the experience. The drug experience \nmay take the form of intense euphoria, mood elevation, \nhallucinations, stimulation, sedation or calming, depending upon the specific drug taken. In this regard, drug use can be \ndescribed as thrill seeking. Many drug users, however, have \nexisting mental health problems and for them drug taking is a means of escaping reality and this can be described as self-medicating.\nThe popularity and availability of drugs change with \ntime. For example, over the last 20 years the opioid epidemic in the United States has been fuelled first by the ease of \nobtaining prescription opioids such as oxycodone, and more \nrecently by the availability of illicitly produced fentanyls, \nsuch that in 2016 in the United States, of over 50,000 deaths \ndue to opioid overdose, some 38% were due to fentanyl \nand related drugs, 27% to prescription opioids and only 29% to heroin (official name diamorphine). The situation \nis different in other countries such as the United Kingdom, where", "start_char_idx": 0, "end_char_idx": 3720, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f3b0c188-e64f-4925-b7d9-fe533b64e7ca": {"__data__": {"id_": "f3b0c188-e64f-4925-b7d9-fe533b64e7ca", "embedding": null, "metadata": {"page_label": "648", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6bc5877c-5e02-4e2a-b9f2-d6120adaf5b4", "node_type": null, "metadata": {"page_label": "648", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ae6ca8307fe0f604606e4c425a0eed78768d4d6e8569a8a258c9e609f4c720c3"}, "2": {"node_id": "f692a058-a0f2-4b40-8b21-9598299fd033", "node_type": null, "metadata": {"page_label": "648", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b39e3df723e0770e399691dc82058d1ad579ad1e90d2d6dce09274d39ef711ea"}}, "hash": "27ba635772a6c26de52ce23a87b008be51a836b3b0a21e887a2a763bfd3cc587", "text": "The situation \nis different in other countries such as the United Kingdom, where oxycodone and fentanyl abuse is still fairly uncommon.\nDrug use involves effects on the brain that can be both \nacute and chronic (Fig. 50.1). The immediate, acute effect on mood is the reason the drug is taken. For some drugs \n(e.g. amphetamines, Ch. 49), this may be followed by a \nrebound negative or depressed phase. Persistent use of a \ndrug may lead to compulsive drug use (addiction \u2013 a complex state that involves both psychological and \nphysiological dependence) and to the development of \ntolerance. Psychological dependence can give rise to intense craving for the drug even when the user has been drug-free \nfor months or years.\nDRUG ADMINISTRATION\nFor drugs that induce strong feelings of euphoria, there are \ntwo components to the experience: an initial rapid effect (the \nrush or buzz ) and a more prolonged pleasurable effect (the \nhigh) that may for some drugs (e.g. gabapentin/pregabalin or \nopioids) be accompanied by a period of sedation ( gouching ). \nThe intensity of the initial effect is determined by how fast \nthe drug enters the brain and activates its effector mecha -\nnism. For many casual drug users, ease of administration \ndefines how the drug is taken (e.g. smoking, swallowing \nor snorting a drug is relatively easy). However, for other Drug abuse and dependence50 NERVOUS SYSTEM SECTION 4\n1Most are illegal in many countries, though there are strong lobbies to \nlegalise some that are considered less harmful.\n2A survey in one UK city showed that among Friday-night clubbers, the \nchoice of drug was associated with the type of music the clubs played \n(Measham & Moore, 2009).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3640, "end_char_idx": 5812, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d48528ea-29d1-4ebc-afdc-a6783df6b96f": {"__data__": {"id_": "d48528ea-29d1-4ebc-afdc-a6783df6b96f", "embedding": null, "metadata": {"page_label": "649", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2148cb08-62c0-4401-b896-597578c7c06f", "node_type": null, "metadata": {"page_label": "649", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d028e68d7bf9fea6a9d374e2360cd4fd33b75635159e94a1a885f5719ecbbeb"}, "3": {"node_id": "23833d5b-42b3-4a9a-bcf2-f8a85b026908", "node_type": null, "metadata": {"page_label": "649", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "20f4de0d9769e45b827d0845d929e516fc8e8444dc9a4b1d4411d5f805468843"}}, "hash": "84fabf45a171e7c2c1600f68549431ecdf4fef59a72e9080644a8dda1326ea30", "text": "50 DRUg ab USE aND DE p ENDEN c E\n643date-rape drugs). Many major harms relate to the ability \nof some drugs to induce dependence (e.g. psychostimulants, \nopioids, ethanol and tobacco) or to reveal a susceptibility \nto psychotic illness in some individuals (e.g. amphetamines and cannabis).\nAn attempt to produce a rational scale of harm, based \non assessment by an expert panel of physical risk, depend -\nence liability and social cost, was reported by Nutt et al. \n(2010), who have argued that such ratings should influence how governments police and punish people for supplying \nand using particular drugs. As might be expected, ethanol, \nheroin and cocaine were judged to be the most harmful, with cannabis, LSD and ecstasy ( MDMA , see Ch. 49) much \nless so \u2013 an order that is not reflected in the classification of these drugs under UK law.\n3\nDRUG DEPENDENCE\nDrug dependence (addiction) describes the human condition in which:\n\u2022\tdrug\ttaking \tbecomes \tcompulsive, \ttaking \tprecedence \t\nover other needs;\n\u2022\tthere\tis \ta \tloss \tof \tcontrol \tof \tthe \tamount \tof \tdrug \t\ntaken;\n\u2022\tphysical \tand \tpsychological \tchanges \toccur \twhen \t\naccess to drug is denied.\nDependence thus involves both psychological and \nphysiological components and can be considered as a \nthree-stage process around which dependent individuals recycle (see Fig. 50.1). The neurobiology of drug dependence \nis described in detail by Koob and Volkow (2016).\nDependence becomes a problem when the want becomes \nso insistent that it dominates the lifestyle of the individual and damages his or her quality of life, and the habit itself \ncauses actual harm to the individual or the community. Examples of the latter are the mental incapacity and liver \ndamage caused by ethanol, the many diseases associated drug users chasing a more intense experience, the route of administration and the choice of individual drug become \nimportant. Intravenous injection or smoking results in faster absorption of a drug than when it is taken orally. Heroin, cocaine, amphetamines, tobacco and cannabis are \nall taken by one or other of these routes. Heroin is more \npopular as a drug of abuse than morphine. This is because it enters the brain more rapidly than morphine. However, \nheroin itself does not interact with opioid receptors but is \nrapidly deacetylated to 6-acetylmorphine and morphine, \u00b5 opioid\u2013receptor agonists (see Ch. 43).\nDRUG HARM\nAll drugs of abuse are harmful to a varying extent. Adverse effects can be the result of drug overdose (e.g. respiratory \ndepression produced by opioids), of effects on tissues other \nthan the brain (e.g. necrosis of the nasal septum resulting from chronic cocaine use), of the route of administration \n(e.g. HIV and other infections in drug users who share \nneedles), of effects unrelated to the specific actions of the drug (e.g. carcinogenicity of tobacco smoke, severe bladder \npain in regular ketamine users) or of use for illegal purposes \n(e.g. flunitrazepam or \u03b3-hydroxybutyrate [GHB] as Table 50.1 Glossary of frequently used and \u2018abused\u2019 terms\nAddictPerson for whom the desire to experience a drug\u2019s effects overrides any consideration for the serious \nphysical, social or psychological problems that the drug may cause to the individual or others. Often used in non-scientific circles to convey criminal intent and so has fallen out of favour with those involved in treating people with drug problems\nDrug misuseNon-medicinal drug use (although some would not consider taking drugs to alter mood/induce hallucinations as \u2018misuse\u2019 or", "start_char_idx": 0, "end_char_idx": 3550, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "23833d5b-42b3-4a9a-bcf2-f8a85b026908": {"__data__": {"id_": "23833d5b-42b3-4a9a-bcf2-f8a85b026908", "embedding": null, "metadata": {"page_label": "649", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2148cb08-62c0-4401-b896-597578c7c06f", "node_type": null, "metadata": {"page_label": "649", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d028e68d7bf9fea6a9d374e2360cd4fd33b75635159e94a1a885f5719ecbbeb"}, "2": {"node_id": "d48528ea-29d1-4ebc-afdc-a6783df6b96f", "node_type": null, "metadata": {"page_label": "649", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84fabf45a171e7c2c1600f68549431ecdf4fef59a72e9080644a8dda1326ea30"}}, "hash": "20f4de0d9769e45b827d0845d929e516fc8e8444dc9a4b1d4411d5f805468843", "text": "drugs to alter mood/induce hallucinations as \u2018misuse\u2019 or \u2018abuse\u2019)\nJunkie Pejorative term for someone who is dependent upon a drug\nNarcoticsOriginally used as a term to describe opioids as they induce sleep (narcosis). Subsequently this term has been used by non-scientists to describe a wide range of drugs of abuse (including cocaine, which is a stimulant!)\nRecreational drug useOriginally used to describe all drug abuse, it is now sometimes used to describe drug use in the bar/club/dance scene\nSubstance useSome governments do not consider ethanol or chemical solvents to be drugs, hence \u2018substance use\u2019 (or \u2018substance abuse\u2019) is used to include these agents\nFrequent\ndrug taking\nAbstinence Relapse\nCRAVINGRewarding\nexperienceAcute (physical\nwithdrawal syndrome)\nProlonged (lowered,\nblunted mood, anxiety)\nCue-induced\nStress-inducedWITHDRAWAL\nDRUG TAKINGDependence\nFig. 50.1 A simplified scheme of the recurring cycle of drug \ndependence. \n3In determining society\u2019s attitude towards drugs, the media play an \ninfluential role. In the United Kingdom, deaths following consumption \nof ecstasy (63 in 2016) are often widely reported in the press and on \ntelevision, but deaths due to heroin overdose, which are much more prevalent (1209 in 2016), are largely ignored unless the victim is \nfamous.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3494, "end_char_idx": 5271, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "46452a1f-b27b-4240-87fa-a58466163bcc": {"__data__": {"id_": "46452a1f-b27b-4240-87fa-a58466163bcc", "embedding": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2fe47891-bc43-44c1-94ac-b4b2db97a144", "node_type": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "90e7fd1cc28326b002e14e59c1b248384957046177a5279b8a469cf2e51bb801"}, "3": {"node_id": "77dd74b2-7517-47e3-964e-1bc3a9007fdf", "node_type": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "09b81afc1b36fda90e8dafdec3d5ce12a923344d5da79a8ca6498afc93977a5f"}}, "hash": "30ba75df90158577e614587e5d64ade0eef7cb6ec7587f5f593bcf402eb7860e", "text": "50 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n644extracellular level of dopamine in the nucleus accumbens, as shown \nby microdialysis in animals and in vivo brain-imaging techniques in \nhumans. Opioids enhance the firing of VTA dopaminergic neurons \nby reducing the level of GABAergic inhibition (disinhibition) within the VTA, whereas amphetamine and cocaine act on dopaminergic \nnerve terminals in the nucleus accumbens to release dopamine or \nprevent its reuptake (see Ch. 15). Given that dopamine release in the nucleus accumbens is also enhanced by naturally rewarding stimuli, \nsuch as food, water, sex and nurturing, it would appear that drugs \nare simply activating, or overactivating, the body\u2019s own pleasure \nsystem. In experienced drug users the anticipation of the effect may \nbecome sufficient to elicit the release of dopamine. Paradoxically, brain-imaging studies have revealed that in chronic users the increase \nin dopamine may be less than expected when compared with what \nis seen in na\u00efve individuals, even though the subjective high is still intense. This may reflect some degree of sensitisation, but the mecha -\nnism is not well understood.\nChemical or surgical interruption of the VTA\u2013accumbens dopaminergic \npathway impairs drug-seeking behaviours in many experimental \nsituations. Deletion of D\n2 receptors in a transgenic mouse strain was \nshown to eliminate the rewarding properties of morphine administra -\ntion without reducing other opioid effects, and it did not prevent the occurrence of physical withdrawal symptoms in morphine-dependent \nanimals (Maldonado et al., 1997), suggesting that the dopaminergic \npathway is responsible for the positive reward but not for the negative withdrawal effects. However, D\n2-receptor antagonists (antipsychotic \ndrugs; see Ch. 47) have not been successful in treating addiction, and \nmore recent evidence suggests that D 1 receptors activated by steep \nincreases in dopamine release and possibly also D 3 receptors play \nimportant roles. The development of D 3-receptor antagonists or partial \nagonists as potential treatments for drug abuse is ongoing (see Maramai \net al., 2016).\nPHYSICAL \u2003DEPENDENCE\nThis is characterised by a withdrawal or abstinence syndrome \nwhereby on cessation of drug administration or on admin -\nistering an antagonist, adverse physiological effects are \nexperienced. On prolonged cessation of drug administration the withdrawal effects can persist for a period of days or \nweeks, the precise withdrawal responses being characteristic \nof the type of drug taken. The intensity of the withdrawal syndrome also varies between drugs of the same type \naccording to their pharmacokinetic characteristics. The \ndesire to avoid or suppress the withdrawal syndrome increases the drive to retake the drug. In individuals undergoing treatment for drug dependence (detox) \npharmacological intervention can be used to reduce the \nintensity of drug withdrawal (Table 50.2).\n\u25bc The mechanisms responsible for the withdrawal syndrome have \nbeen most fully characterised for opioid dependence but similar \nmechanisms may apply to cocaine and ethanol withdrawal. At the \ncellular level, opioids inhibit cAMP formation, and withdrawal results \nin a rebound increase as a result of \u2018superactivation\u2019 of adenylyl cyclase, as well as up-regulation of the amount of this enzyme. This \nresults in activation of protein kinase A (PKA), in an increase in \nadenosine as a consequence of the conversion of cAMP to adenosine, and in activation of a transcription factor \u2013 cAMP response element \nbinding protein (CREB). The rise in PKA activity increases the \nexcitability of nerve terminals by phosphorylating neurotransmitter \ntransporters to increase their ionic conductance (see", "start_char_idx": 0, "end_char_idx": 3739, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "77dd74b2-7517-47e3-964e-1bc3a9007fdf": {"__data__": {"id_": "77dd74b2-7517-47e3-964e-1bc3a9007fdf", "embedding": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2fe47891-bc43-44c1-94ac-b4b2db97a144", "node_type": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "90e7fd1cc28326b002e14e59c1b248384957046177a5279b8a469cf2e51bb801"}, "2": {"node_id": "46452a1f-b27b-4240-87fa-a58466163bcc", "node_type": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "30ba75df90158577e614587e5d64ade0eef7cb6ec7587f5f593bcf402eb7860e"}, "3": {"node_id": "11dddb05-a649-4cf7-95b9-bb1d0e6ba079", "node_type": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "844767cad2d96fc89d8103c040a4a5c2f2869c6e1d10b38517e610e6d780b0e2"}}, "hash": "09b81afc1b36fda90e8dafdec3d5ce12a923344d5da79a8ca6498afc93977a5f", "text": "neurotransmitter \ntransporters to increase their ionic conductance (see Bagley et al., \n2005), as well as increasing neurotransmitter release by a direct action \non the secretory process (Williams et al., 2001). Withdrawal results \nin enhanced GABA release in various parts of the brain, probably \nthrough the mechanisms described above (see Bagley et al., 2011). \nThe release of other neurotransmitters is also likely to be enhanced. On the other hand, the enhanced extracellular levels of adenosine, \nacting on presynaptic A\n1 receptors (see Ch. 17), inhibits glutamate \nrelease at excitatory synapses, and thus counteracts the neuronal hyperexcitability that occurs during drug withdrawal, suggesting with smoking tobacco, the high risk of infection when \ninjecting intravenously (especially HIV and hepatitis C), \nthe serious risk of overdose with most opioids and the \ncriminal behaviour resorted to when drug users need to finance their drug taking.\nNot all psychoactive drugs induce severe dependence. \nMajor dependence-inducing drugs are nicotine, ethanol, opioids, cocaine, amphetamine and benzodiazepines. Can -\nnabis, MDMA and psychedelic drugs are less dependence inducing.\nNot everyone who takes a drug progresses to become \ndependent upon it. Family studies show clearly that sus -\nceptibility to dependence is an inherited characteristic. Around 50% of the risk of becoming dependent is genetic, with the remainder being developmental (adolescents are \nmore at risk than adults) and environmental, e.g. stress, \nsocial pressures and drug availability. Variants of many different genes may each make a small contribution to the \noverall susceptibility of an individual to addiction \u2013 a \nfamiliar scenario that provides few pointers for therapeutic intervention. Polymorphisms in ethanol-metabolising genes \n(see Ch. 49) are the best example of genes that directly \naffect the tendency to abuse a drug.\nDRUG-INDUCED \u2003REWARD\nThe common feature of the various types of psychoactive drugs that are addictive is that all produce a rewarding \nexperience (e.g. an elevation of mood or a feeling of euphoria or calmness).\nIn animal studies, where the state of mood cannot be \ninferred directly, reward is manifest as positive reinforcement , \ni.e. an increase in the probability of occurrence of any behaviour that is associated with the drug experience. In \nconditioned place preference studies, animals receive a drug \nor placebo and are then placed in different environments. \nSubsequently, when tested in a drug-free state, they will spend more time in the environment associated with a \nprevious rewarding drug experience. Another way of \ndetermining if a drug is rewarding is to test whether or not animals will self-administer the drug by pressing a \nlever to obtain it. All dependence-producing drugs are \nself-administered by experimental animals. Psychedelic drugs are not, however, normally self-administered by \nexperimental animals, which may indicate that, unlike \nhumans, they find the experience non-rewarding.\nHumans have a choice as to whether or not they wish \nto experiment with and continue taking drugs \u2013 there may therefore be an element of risk-taking when experimenting with drugs. In behavioural tests, some rats are observed \nto be much more impulsive than others (Jupp et al., 2013). \nThese impulsive rats show a higher rate of cocaine, nicotine, alcohol and methylphenidate self-administration and have \na lower level of expression of D\n2 and D 3 dopamine receptors \nin the nucleus accumbens (see later for the importance of this brain region in drug use). Impulsive rats are not, \nhowever, more prone to self-administering opioids.\nREWARD \u2003PATHWAYS\n\u25bc Virtually all of the major dependence-producing drugs so far tested, ", "start_char_idx": 3676, "end_char_idx": 7437, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "11dddb05-a649-4cf7-95b9-bb1d0e6ba079": {"__data__": {"id_": "11dddb05-a649-4cf7-95b9-bb1d0e6ba079", "embedding": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2fe47891-bc43-44c1-94ac-b4b2db97a144", "node_type": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "90e7fd1cc28326b002e14e59c1b248384957046177a5279b8a469cf2e51bb801"}, "2": {"node_id": "77dd74b2-7517-47e3-964e-1bc3a9007fdf", "node_type": null, "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "09b81afc1b36fda90e8dafdec3d5ce12a923344d5da79a8ca6498afc93977a5f"}}, "hash": "844767cad2d96fc89d8103c040a4a5c2f2869c6e1d10b38517e610e6d780b0e2", "text": "Virtually all of the major dependence-producing drugs so far tested, \nincluding opioids, nicotine, amphetamines, ethanol and cocaine, \nactivate the reward pathway \u2013 the mesolimbic dopaminergic pathway \n(see Ch. 40), that runs, via the medial forebrain bundle, from the ventral tegmental area (VTA) of the midbrain to the nucleus accumbens and limbic region. Even though for some of these drugs their primary \nsites of action may be elsewhere in the brain, they all increase the mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7432, "end_char_idx": 8391, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0213c980-b226-4d91-b759-adc93579fa37": {"__data__": {"id_": "0213c980-b226-4d91-b759-adc93579fa37", "embedding": null, "metadata": {"page_label": "651", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c983fe62-8971-4ff7-8e50-86850bdfa874", "node_type": null, "metadata": {"page_label": "651", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b893b478f34ac7958e66e907545f277c01590d0c2462c6d87196d45480962d0"}, "3": {"node_id": "b818b4a3-960a-4e9f-a81b-5bf1d7ba7b3e", "node_type": null, "metadata": {"page_label": "651", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "865fdb456805ed244123ea66dc5446d4e2143b84dd34a414c99d68a1c4af38cf"}}, "hash": "b0e01747f2609597dab8412bd440dbca292cb40c17cfb9f58bcc8d7a3c979f35", "text": "50 DRUg ab USE aND DE p ENDEN c E\n645contribute to the drive to retake the drug to escape from \nwhat is a negative emotional state (negative affect).\nThe memory of previous drug-induced experiences can \nbe very intense and long lasting, giving rise to craving; it \nmay drive an individual to take the drug again \u2013 referred \nto as relapse \u2013 even after a prolonged period of abstinence \n(see Weiss, 2005). Craving may be triggered by stress or by cues, such as experiencing the environment that a person \nassociates with previously taking the drug or the sight of \ndrug administration paraphernalia e.g. a crack pipe or syringe. This suggests that associative learning may be an important factor in psychological dependence (Robbins \net al., 2008). It has been suggested that drugs alter memory \nformation to enhance the recollection of previous drug experience. In this regard, it is of interest that several drugs \nproduce changes in synaptic plasticity, a cellular correlate \nof memory formation (see Ch. 39). While cocaine, morphine, nicotine and ethanol enhance long-term potentiation (LTP) \nin the VTA by increasing the expression of AMPA receptors \non the plasma membrane, cocaine also increases long-term the possibility \u2013 not yet clinically proven \u2013 that adenosine agonists \nmight prove useful in treating drug dependence. CREB, which is \nup-regulated in the nucleus accumbens by prolonged administra -\ntion of opioids or cocaine, plays a key role in regulating various \ncomponents of cAMP signalling pathways, and transgenic animals \nlacking CREB show reduced withdrawal symptoms (see Chao & \nNestler, 2004).\nSeveral types of therapeutic drug, including antidepressant and \nantipsychotic agents, also produce withdrawal symptoms on cessation of administration, but it is important to distinguish this type of \ncommonly observed \u2018rebound\u2019 phenomenon from the physical \ndependence associated with drugs of abuse. A degree of physical dependence is common when patients receive opioid analgesics in \nhospital for several days, but this rarely leads to addiction.\nPSYCHOLOGICAL \u2003DEPENDENCE\nDuring periods of drug withdrawal, individuals experience \nirritability, stress, anxiety, low mood and blunted responses \nto experiences that would normally be pleasurable. These \naversive behavioural changes can be long lasting and Table 50.2 Pharmacological approaches to treating drug dependence\nMechanism Example(s)\nSubstitution therapies\u2022\tMethadone \t(orally \tactive \topioid \tagonist \twith \tlong \tbiological \thalf-life) \tand \tbuprenorphine \t\n(sublingually absorbed opioid partial agonist) or legal heroin to maintain opioid-dependent patients\n\u2022\tNicotine \tpatches \tor \tchewing \tgum \tto \talleviate \tnicotine \twithdrawal \tsymptoms\nBlocking pleasurable \nresponse\u2022\tNaltrexone \t(non-selective \topioid \tantagonist) \tto \tblock \topioid \teffects \tin \tdrug-withdrawn \tpatients\n\u2022\tNaltrexone \tand \tnalmefene \t(non-selective \topioid \tagonist/weak \tpartial \tagonist) \tto \treduce \tethanol \t\nuse (presumably by blocking the effects of endogenous opioids released by ethanol in the brain)\n\u2022\tMecamylamine \t(nicotinic \tantagonist) \tto \tblock \tnicotine \teffects\n\u2022\tImmunisation \tagainst \tnicotine, \tcocaine \tand \theroin \tto \tproduce \tcirculating \tantibodies \t(still \tbeing \t\ndeveloped)\nAversive therapies \u2022\tDisulfiram \t(aldehyde \tdehydrogenase \tinhibitor) \tto \tinduce \tunpleasant \tresponse \tto \tethanol\nTo alleviate withdrawal symptoms\u2022\tMethadone \tor \tbuprenorphine \tused", "start_char_idx": 0, "end_char_idx": 3450, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b818b4a3-960a-4e9f-a81b-5bf1d7ba7b3e": {"__data__": {"id_": "b818b4a3-960a-4e9f-a81b-5bf1d7ba7b3e", "embedding": null, "metadata": {"page_label": "651", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c983fe62-8971-4ff7-8e50-86850bdfa874", "node_type": null, "metadata": {"page_label": "651", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b893b478f34ac7958e66e907545f277c01590d0c2462c6d87196d45480962d0"}, "2": {"node_id": "0213c980-b226-4d91-b759-adc93579fa37", "node_type": null, "metadata": {"page_label": "651", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b0e01747f2609597dab8412bd440dbca292cb40c17cfb9f58bcc8d7a3c979f35"}}, "hash": "865fdb456805ed244123ea66dc5446d4e2143b84dd34a414c99d68a1c4af38cf", "text": "symptoms\u2022\tMethadone \tor \tbuprenorphine \tused \tshort \tterm \tto \tblunt \topioid \twithdrawal\n\u2022\tIbogaine \t(a \tnaturally \toccurring \tpsychoactive \tagent) \tused \tby \tsome \tto \treduce \topioid \twithdrawal \t\nsymptoms\n\u2022\t\u03b12-Adrenoceptor agonists (e.g. clonidine, lofexidine) to diminish opioid, alcohol and nicotine \nwithdrawal symptoms\n\u2022\t\u03b2-Adrenoceptor antagonists (e.g. propranolol) to diminish excessive peripheral sympathetic activity\n\u2022\tVarenicline \t(\u03b14\u03b22 nicotinic receptor partial agonist) to alleviate nicotine withdrawal symptoms. \nTreatment can be continued in abstinent individuals to reduce risk of relapse\n\u2022\tBenzodiazepines \t(e.g. \tchlordiazepoxide), \tclomethiazole, \ttopiramate \tand \tGHB \tto \tblunt \talcohol \t\nwithdrawal symptoms\nReducing continued drug use (may act by reducing craving)\u2022\tBupropion \t(antidepressant \twith \tsome \tnicotinic \treceptor \tantagonist \tactivity) \tand \tnortriptyline \t\n(noradrenaline reuptake inhibiting antidepressant) to reduce tobacco use\n\u2022\tClonidine \t(\u03b12-adrenoceptor agonist) to reduce craving for nicotinea\n\u2022\tAcamprosate \t(NMDA \treceptor \tantagonist) \tto \ttreat \talcoholisma\n\u2022\tTopiramate \tand \tlamotrigine \t(antiepileptic \tagents) \tto \ttreat \talcoholism \tand \tcocaine \tusea\n\u2022\tGHB\treported \tto \treduce \tcraving \tfor \talcohol \tand \tcocainea\n\u2022\tBaclofen \t(GABA B receptor agonist) reported to reduce opioid, alcohol and stimulant usea\n\u2022\tModafinil \t(dopamine \treuptake \tinhibitor) \tto \treduce \tcocaine \tusea\n\u2022\tIbogaine \t(natural \tproduct \thallucinogen) \treported \tto \treduce \tcraving \tfor \tstimulants \tand \topioidsa\naThe effectiveness of these agents at reducing the continued use of other drugs of abuse over and above the ones listed remains to be \ndetermined.Notes: Antidepressant, mood stabilising, anxiolytic and antipsychotic medications are useful when treating patients who, in addition to their drug use, also suffer from other mental disorders. The cannabinoid CB\n1-receptor antagonist rimonabant, in addition to its antiobesity \neffects, also reduces nicotine, ethanol, stimulant and opioid consumption. However, it also induces depression and its use has been discontinued.GHB, \u03b3-hydroxybutyric acid.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3406, "end_char_idx": 6024, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2029ef8e-ba17-462e-a505-460983e18d50": {"__data__": {"id_": "2029ef8e-ba17-462e-a505-460983e18d50", "embedding": null, "metadata": {"page_label": "652", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "69bd3a26-e6d9-4729-8f4d-376bcc555e30", "node_type": null, "metadata": {"page_label": "652", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "361404c0f11e1c38adb828a2ded7798e26d9bc1ba3c307bf319efbbe5b0bcf07"}, "3": {"node_id": "58662f01-c9f7-453f-bf89-728c26533199", "node_type": null, "metadata": {"page_label": "652", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bcbb1665d779eb5915b418be918eda4c41df8e996fa8c677c31b72cadd61eb62"}}, "hash": "e3f32679b28807f5505fa5fd8301611edb6e5847686cede601b9b8f7385a7dda", "text": "50 SECTION 4\u2003\u2003 NERVOUS SYSTEM\n646TOLERANCE\nTolerance (see Ch. 2) describes the decrease in pharm-\nacological effect on repeated administration of a drug \u2013 it \ndevelops over time, as does the state of dependence. It \ndoes not occur with all drugs of abuse. Contrary to earlier thinking, physical dependence and tolerance are now \nthought to involve different mechanisms (see Bailey & \nConnor, 2005).\n\u25bc For drugs such as opioids that are agonists at specific receptors \n(see Ch. 43), cellular tolerance results in part from desensitisation of \nthe receptors. On prolonged activation by an agonist, the \u00b5 receptor \nis phosphorylated by various intracellular kinases (Williams et al., \n2013) \u2013 which either directly desensitises the receptor or causes the binding to the receptor of other proteins, such as arrestins, that \nuncouple the receptor from its G protein (see Ch. 3). In the intact \nanimal, inhibition or knock-out of these kinases reduces the level of \ntolerance.).\nPHARMACOLOGICAL APPROACHES TO \nTREATING DRUG DEPENDENCE\nThere are a number of different approaches taken to treat \ndrug dependence. Specific examples of the drugs used in \neach are given in Table 50.2.\n\u2022\tSubstitution \ttherapy, \tin \twhich \ta \treplacement \t\nmedicinal grade drug (e.g. methadone or \nbuprenorphine for opioid users) is provided \nlong term to \u2018maintain\u2019 the individual, preventing \nthem from going into withdrawal and reducing the need/drive to take illicit drug(s). This form of \ntreatment has been shown to reduce illegal activities \nto fund illicit drug purchase and to reduce associated health hazards such as HIV and hepatitis C infection.\n\u2022\tFacilitating \tdrug \twithdrawal \t(detox) \tby \teither \t\nsubstituting a drug in the same class from which subsequent withdrawal is less intense or by depression (LTD) in the nucleus accumbens (Hyman et al., \n2006).\nThe psychological factors in drug dependence are dis -\ncussed in detail by Koob and Volkow (2016) and summarised in Fig. 50.2.\nNegative\nreinforcementNegative conditioningDrug withdrawalCues associated with drug withdrawal\nsocial situation\nnon-availability of drug etc.Cues associated with drug taking\nsocial situation\npurchase of drug\npreparation of drug etc.\nDrug administration\nPositive\nreinforcementPositive conditioning\nREWARD\u2022 Immediate\n\u2022 Brief (hours)\n\u2022 Decreases \nwith repetitionABSTINENCE\nSYNDROME \u2022 Delayed\n\u2022 Long-Iasting (days)\n\u2022 Increases with repetitionAgonistsAntagonists\nResponse modifiers\nFig. 50.2 A simplified scheme of some of the psychological factors involved in drug dependence. Drug dependence \n\u2022\tDependence \toccurs \twhen, \tas \ta \tresult \tof \trepeated \t\nadministration of the drug, the desire to experience the \neffects of a drug again becomes compulsive.\n\u2022\tDependence \toccurs \twith \ta \twide \trange \tof \tpsychotropic \t\ndrugs, acting by many different mechanisms.\n\u2022\tThe\tcommon \tfeature \tof \tthe \tmajor \tdependence-\ninducing drugs is that they have a positive reinforcing action (\u2018reward\u2019) associated with activation of the mesolimbic dopaminergic pathway.\n\u2022\tDependence \tcan \tbe \tsubdivided \tinto \tphysical \tand \t\npsychological components.\n\u2022\tPhysical \tdependence \tis \tcharacterised \tby \ta \twithdrawal \t\nsyndrome, which varies in type and intensity for different classes of drug.\n\u2022\tPsychological \tdependence \tcomprises \tboth \tmood \t\nchanges \u2013 irritability, stress, anxiety, and blunted responses to normally rewarding experiences \u2013 and", "start_char_idx": 0, "end_char_idx": 3404, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "58662f01-c9f7-453f-bf89-728c26533199": {"__data__": {"id_": "58662f01-c9f7-453f-bf89-728c26533199", "embedding": null, "metadata": {"page_label": "652", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "69bd3a26-e6d9-4729-8f4d-376bcc555e30", "node_type": null, "metadata": {"page_label": "652", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "361404c0f11e1c38adb828a2ded7798e26d9bc1ba3c307bf319efbbe5b0bcf07"}, "2": {"node_id": "2029ef8e-ba17-462e-a505-460983e18d50", "node_type": null, "metadata": {"page_label": "652", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e3f32679b28807f5505fa5fd8301611edb6e5847686cede601b9b8f7385a7dda"}}, "hash": "bcbb1665d779eb5915b418be918eda4c41df8e996fa8c677c31b72cadd61eb62", "text": "anxiety, and blunted responses to normally rewarding experiences \u2013 and craving.\n\u2022\tCraving \tcan \tbe \ttriggered \tby \tstress \tor \tcues \trelating \tto \t\nprevious drug experience and may occur in individuals who have been drug free for some considerable time.\n\u2022\tOn\trepeated \tadministration, \ttolerance \tmay \toccur \tto \t\nthe effects of the drug.\n\u2022\tAlthough \tgenetic \tfactors \tcontribute \tto \tdrug-seeking \t\nbehaviour, no specific genes have yet been identified.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3334, "end_char_idx": 4267, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d8db13fe-c627-4faa-89fe-9eaa6a9697da": {"__data__": {"id_": "d8db13fe-c627-4faa-89fe-9eaa6a9697da", "embedding": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dcab43cf-2ff9-4d1e-b988-b9759eadfbe4", "node_type": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "47f06d5a44831f43a289b297c5e12dbb632210d5a790f1d72cd86b3d67bc6111"}, "3": {"node_id": "240a91f6-9cbd-4e53-ac5c-5b71ae959686", "node_type": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8fcc0208990c0c3e47d433f9a11b6c4eff683c2092363d42f54b27f984f77315"}}, "hash": "93e6f75fca3a7e14a9e3b068cc02816424cf5c0af77952f4eac79ff4641cd773", "text": "50 DRUg ab USE aND DE p ENDEN c E\n647administration of other drugs during the withdrawal \nprocess that reduce the intensity of the withdrawal \nsymptoms.\n\u2022\tBlocking \tthe \teffects \tof \tan \tabused \tdrug \tby \tprior \t\nadministration of an antagonist so that if the \nindividual has detoxed but relapses and retakes the \ndrug again they will not experience the pleasurable \neffects of the drug. For this to be successful, the antagonist has to be long lasting or administered in \nthe form of an implant that releases the antagonist \nover a prolonged period.\n\u2022\tBlocking \tthe \teffects \tof \tan \tabused \tdrug \tby \t\nimmunisation to produce circulating antibodies. Vaccines against nicotine, heroin or cocaine, to \ninduce antibody formation that would mop up these drugs when they enter the blood stream are in early clinical development, although progress has been \nslow.\n\u2022\tMaking \tthe \tdrug \texperience \tunpleasant. \tThe \tbest \t\nexample of this approach is for ethanol which is \nrapidly metabolised to acetic acid by a two-step \nprocess (see Ch. 49, Fig. 49.5). Disulfiram, an \naldehyde dehydrogenase inhibitor, inhibits the second step, resulting in the build-up of acetaldehyde which \nelicits an unpleasant response when ethanol is \nconsumed.\n\u2022\tReducing \tcraving \tfor \ta \tdrug. \tA \trange \tof \tdrugs \thave \t\nbeen suggested to reduce craving for various drugs. Their effectiveness is an ongoing area of debate and \nresearch.\nFor intravenous drug users, the provision of sterile needles \nreduces needle sharing and the spread of blood-borne diseases such as HIV and hepatitis C. Opioid overdose results in severe respiratory depression that can lead \nto death. Opioid-induced respiratory depression is \nrapidly reversed by intramuscular injection of the opioid antagonist, naloxone. Supervised injection rooms and \nthe distribution of naloxone injection kits within the drug using community are ways to reduce opioid overdose \ndeaths.\nDrug abuse involves many psychosocial and some genetic \nfactors, as well as neuropharmacological mechanisms, and so while pharmacological approaches to drug treatment \nare important, they are only one component of the thera-\npeutic approaches that are used. For information on other approaches to the treatment of drug addiction, readers are \nadvised to consult the National Institute on Drug Abuse \n(NIDA) website at http://www.nida.nih.gov/.Clinical use of drugs in substance \ndependence \nTobacco dependence\n\u2022\tShort-term \tnicotine\tis\tan\tadjunct \tto \tbehavioural \t\ntherapy\tin \tsmokers \tcommitted \tto \tgiving \tup; \t\nvarenicline \tis\talso\tused \tas \tan \tadjunct \tbut \thas \tbeen \t\nlinked\tto\tsuicidal \tideation.\n\u2022\tBupropion is also effective but lowers seizure \nthreshold, \tso \tis \tcontraindicated \tin \tpeople \twith \trisk \t\nfactors for seizures (and also if there is a history of \neating disorder).\nAlcohol dependence\n\u2022\tLong-acting \tbenzodiazepines \t(e.g. \tchlordiazepoxide) \ncan be used to reduce withdrawal symptoms and the \nrisk\tof\tseizures; \tthey \tshould \tbe \ttapered \tover \t1\u20132 \t\nweeks\tand \tthen \tdiscontinued \tbecause \tof \ttheir \tabuse \t\npotential.\n\u2022\tDisulfiram \tis\tused\tas \tan \tadjunct \tto \tbehavioural \t\ntherapy in suitably motivated alcoholics after \ndetoxification; \tit \tis \tcontraindicated \tfor \tpatients \tin \twhom \t\nhypotension would be dangerous (e.g. those with coronary or cerebral", "start_char_idx": 0, "end_char_idx": 3318, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "240a91f6-9cbd-4e53-ac5c-5b71ae959686": {"__data__": {"id_": "240a91f6-9cbd-4e53-ac5c-5b71ae959686", "embedding": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dcab43cf-2ff9-4d1e-b988-b9759eadfbe4", "node_type": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "47f06d5a44831f43a289b297c5e12dbb632210d5a790f1d72cd86b3d67bc6111"}, "2": {"node_id": "d8db13fe-c627-4faa-89fe-9eaa6a9697da", "node_type": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "93e6f75fca3a7e14a9e3b068cc02816424cf5c0af77952f4eac79ff4641cd773"}, "3": {"node_id": "ce6d8334-9fa7-41e1-97f9-6e5cc4f8b472", "node_type": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb30313dd7d12a60aa2b05cae395e820869d6e3062c3583a3c6880d69aa62be1"}}, "hash": "8fcc0208990c0c3e47d433f9a11b6c4eff683c2092363d42f54b27f984f77315", "text": "would be dangerous (e.g. those with coronary or cerebral vascular disease).\n\u2022\tAcamprosate\n\tcan\thelp\tto \tmaintain \tabstinence; \tit \tis \t\nstarted as soon as abstinence has been achieved and maintained if relapse occurs, and it is continued for 1 year.\nOpioid dependence\n\u2022\tNaloxone, a competitive opioid antagonist, has become available for use in community settings to reverse respiratory depression from opioid overdose. It \ncan be administered as a nasal spray or by \nintramuscular \tinjection.\n\u2022\tOpioid\tagonists \tor \tpartial \tagonists \t(e.g., \trespectively, \t\nmethadone or buprenorphine) administered orally or \nsublingually \tmay \tbe \tsubstituted \tfor \tinjectable \tnarcotics, \t\nmany of whose harmful effects are attributable to the \nroute of administration.\n\u2022\tNaltrexone, a long-acting opioid antagonist, is used \nas\tan\tadjunct \tto \thelp \tprevent \trelapse \tin \tdetoxified \t\naddicts\t(opioid \tfree \tfor \tat \tleast \t1 \tweek).\n\u2022\tLofexidine, an \u03b12 agonist (cf. clonidine ;\tCh.\t15),\tis \t\nused short term (usually up to 10 days) to ameliorate symptoms of opioid withdrawal, and is then tapered \nover\ta\tfurther \t2\u20134 \tdays.\nREFERENCES AND FURTHER READING\nGeneral\nChao, J., Nestler, E.J., 2004. Molecular neurobiology of addiction. Annu. \nRev. Med. 55, 113\u2013132. (Useful review article by leading scientists in \naddiction research)\nKoob, G.F., Volkow, N.D., 2016. Neurobiology of addiction: a \nneurocircuitry analysis. Lancet Psychiatry 3, 760\u2013773. (Describes in detail the components of drug dependence as well as the neuronal pathways \nand neurotransmitters involved)\nMeasham, F., Moore, K., 2009. Repertoires of distinction. Exploring \npatterns of weekend polydrug use within local leisure scenes across the English night time economy. Criminol. Crim. Justice. 9, 437\u2013464.\nNutt, D., King, L.A., Phillips, L.D., 2010. Drug harms in the UK: a \nmulticriteria decision analysis. Lancet 376, 558\u2013565.Reward\nHyman, S.E., Malenka, R.C., Nestler, E.J., 2006. Neural mechanisms of \naddiction: the role of reward-related learning and memory. Annu. \nRev. Neurosci. 29, 565\u2013598. (Extensive review on how drugs of abuse can \nalter memory and learning processes)\nJupp, B., Caprioli, D., Dalley, J.W., 2013. Highly impulsive rats: modelling \nan endophenotype to determine the neurobiological, genetic and environmental mechanisms of addiction. Dis. Model. Mech. 6, 302\u2013311 (An extensive review of impulsivity and how it relates to drug seeking )\nMaldonado, R., Saiardi, A., Valverde, O., et al., 1997. Absence of opiate \nrewarding effects in mice lacking dopamine D 2 receptors. Nature 388, \n586\u2013589. (Use of transgenic animals to demonstrate role of dopamine \nreceptors in reward properties of opiates)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3271, "end_char_idx": 6287, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ce6d8334-9fa7-41e1-97f9-6e5cc4f8b472": {"__data__": {"id_": "ce6d8334-9fa7-41e1-97f9-6e5cc4f8b472", "embedding": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dcab43cf-2ff9-4d1e-b988-b9759eadfbe4", "node_type": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "47f06d5a44831f43a289b297c5e12dbb632210d5a790f1d72cd86b3d67bc6111"}, "2": {"node_id": "240a91f6-9cbd-4e53-ac5c-5b71ae959686", "node_type": null, "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8fcc0208990c0c3e47d433f9a11b6c4eff683c2092363d42f54b27f984f77315"}}, "hash": "fb30313dd7d12a60aa2b05cae395e820869d6e3062c3583a3c6880d69aa62be1", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6288, "end_char_idx": 6479, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6e55a8a4-20dc-488f-a9c3-61ad0e77fb04": {"__data__": {"id_": "6e55a8a4-20dc-488f-a9c3-61ad0e77fb04", "embedding": null, "metadata": {"page_label": "654", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f785b104-64fc-49a4-b797-9161997b8c43", "node_type": null, "metadata": {"page_label": "654", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9e5eeb66b830edc6886a620a87327bb5ae231f7e6b1dc0d8e7de4520cb612c88"}}, "hash": "9e5eeb66b830edc6886a620a87327bb5ae231f7e6b1dc0d8e7de4520cb612c88", "text": "50 SECTION 4 \u2003\u2003NERVOUS SYSTEM\n648Bailey, C.P., Connor, M., 2005. Opioids: cellular mechanisms of \ntolerance and physical dependence. Curr. Opin. Pharmacol. 5, 60\u201368.\nRobbins, T.W., Ersche, K.D., Everitt, B.J., 2008. Drug addiction and the \nmemory systems of the brain. Ann. N. Y. Acad. Sci. 1141, 1\u201321. \n(Review of how different forms of memory play important roles in drug \ndependence )\nWeiss, F., 2005. Neurobiology of craving, conditioned reward and \nrelapse. Curr. Opin. Pharmacol. 5, 9\u201319. ( Review of recent studies on the \nneurobiology of addiction, focusing mainly on animal models )\nWilliams, J.T., Christie, M.J., Manzoni, O., 2001. Cellular and synaptic \nadaptations mediating opioid dependence. Physiol. Rev. 81, 299\u2013343.\nWilliams, J.T., Ingram, S.L., Henderson, G., et al., 2013. Regulation of \n\u00b5-opioid receptors: desensitization, phosphorylation, internalization, \nand tolerance. Pharmacol. Rev. 65, 223\u2013254.Maramai, S., Gemma, S., Brogi, S., et al., 2016. Dopamine D3 \nreceptor antagonists as potential therapeutics for the treatment of \nneurological diseases. Front. Neurosci. 10, 451. ( Discusses the \ndevelopment and potential uses of selective D 3 antagonists in the treatment \nof drug abuse )\nDependence and tolerance\nBagley, E.E., Gerke, M.B., Vaughan, C.W., et al., 2005. GABA transporter \ncurrents activated by protein kinase A excite midbrain neurons during \nopioid withdrawal. Neuron 45, 433\u2013445.\nBagley, E.E., Hacker, J., Chefer, V.I., et al., 2011. Drug-induced GABA \ntransporter currents enhance GABA release to induce opioid \nwithdrawal behaviors. Nat. Neurosci. 14, 1548\u20131554. ( Describes the \ncellular mechanism underlying the opioid withdrawal response )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2167, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "24dc8f21-0e3f-4ac2-a965-2b00c544b25b": {"__data__": {"id_": "24dc8f21-0e3f-4ac2-a965-2b00c544b25b", "embedding": null, "metadata": {"page_label": "655", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "908c8163-8e30-4dd5-ad96-449b5afc9c46", "node_type": null, "metadata": {"page_label": "655", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc7b226bebab7623479ae14cf29df9e0415e6150f3f4223bbc3fcf266117f0f9"}, "3": {"node_id": "701e9792-594f-4c5e-8252-f8646d095a24", "node_type": null, "metadata": {"page_label": "655", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fcdd3dc9dd2a5c90e7137f851552a02d57ea6f4967dd164fe8c26cbf19f772eb"}}, "hash": "5607ba01293f7ede3863f16d1c1c19b09a00a65bb76e192ae6700d215990a375", "text": "649\nOVERVIEW\nThe term chemotherapy was originally used to \ndescribe the use of drugs that were \u2018selectively toxic\u2019 \nto pathogens (including bacteria, viruses, protozoa, \nfungi and helminths) while having minimal effects on the host. It also refers to the use of drugs to treat \ntumours and, in the public mind at least, is usually \nassociated with those cytotoxic anticancer drugs that cause distressing and unwanted effects such as loss of \nhair, nausea and vomiting. In this chapter, we focus \non antimicrobial chemotherapy: anticancer drugs are covered in Chapter 57 . The feasibility of the selective \ntoxicity strategy depends on the ability to exploit such biochemical differences as may exist between the infecting organism and the host. While the bulk \nof this section of the book describes the drugs used to \ncombat such infections, in this introductory chapter we consider the nature of these biochemical differences, \noutline the molecular targets of drug action and discuss \nthe grave problem of antibiotic resistance.\nBACKGROUND\nAll living organisms are vulnerable to infection. Humans, \nbeing no exception, are susceptible to diseases caused by \ncertain viruses, bacteria, protozoa, fungi and helminths \n(collectively referred to as pathogens). The use of chemo -\ntherapeutic agents dates back to the work of Ehrlich and \nothers and to the development of selectively toxic arsenical \ndrugs such as salvarsan for the treatment of syphilis.1 Indeed, \nit was Ehrlich himself who coined the term chemotherapy \nto describe the use of synthetic chemicals to destroy such pathogens. In recent years the definition of the term has been broadened to include antibiotics \u2013 strictly speaking, \nsubstances produced by microorganisms (although latterly \nby pharmaceutical chemists as well) that kill or inhibit the growth of other microorganisms. The successful develop -\nment of such agents during the past 80 years, particularly during the \u2018golden age\u2019 of antibiotic research (1940s\u20131970s), constitutes one of the most important therapeutic advances in the history of medicine.\nUnhappily, our success in developing drugs to neutralise \nthese invaders has been paralleled by their own success in counteracting their effects, resulting in the emergence of drug resistance. And at present, the invaders \u2013 particularly some bacteria \u2013 seem close to getting the upper hand. This \nis a very important problem, and so we will devote some \nspace to the mechanisms of resistance and the means by which it is spread.\nTHE MOLECULAR BASIS OF \nCHEMOTHERAPY\nChemotherapeutic agents, then, are chemicals intended to \nbe toxic to the pathogenic organism but innocuous to the \nhost. It is important to remember that many microorganisms \nshare our body spaces (e.g. the gut2) without causing disease \n(these are called commensals), although they may become \npathogenic under adverse circumstances (i.e. if the host is immunocompromised or if barrier breakdown results in them setting up shop in an inappropriate location elsewhere \nin our bodies).\nAll living organisms can be classified as either prokaryotes , \ncells without nuclei (e.g. bacteria), or eukaryotes, cells with \nnuclei (e.g. protozoa, fungi, helminths). In a separate cat -\negory are the viruses, which need to utilise the metabolic \nmachinery of the host cell to replicate, and they thus present a particular kind of problem for chemotherapeutic attack. \nLurking in the taxonomic shadows, there remain those \nmysterious proteinaceous agents, prions (see Ch. 40), which \ncause disease but resist all attempts at classification and \ntreatment.\nVirtually all creatures, host and parasite alike, have the \nsame basic DNA blueprint (an exception being the RNA viruses), so many biochemical processes are common to \nmost, if not", "start_char_idx": 0, "end_char_idx": 3775, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "701e9792-594f-4c5e-8252-f8646d095a24": {"__data__": {"id_": "701e9792-594f-4c5e-8252-f8646d095a24", "embedding": null, "metadata": {"page_label": "655", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "908c8163-8e30-4dd5-ad96-449b5afc9c46", "node_type": null, "metadata": {"page_label": "655", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc7b226bebab7623479ae14cf29df9e0415e6150f3f4223bbc3fcf266117f0f9"}, "2": {"node_id": "24dc8f21-0e3f-4ac2-a965-2b00c544b25b", "node_type": null, "metadata": {"page_label": "655", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5607ba01293f7ede3863f16d1c1c19b09a00a65bb76e192ae6700d215990a375"}}, "hash": "fcdd3dc9dd2a5c90e7137f851552a02d57ea6f4967dd164fe8c26cbf19f772eb", "text": "being the RNA viruses), so many biochemical processes are common to \nmost, if not all, organisms. Finding agents that affect pathogens but not other human cells necessitates finding \neither qualitative or quantitative biochemical differences \nbetween them.\nBACTERIA\nBacteria are a common cause both of mild and severe infectious disease, and Fig. 51.1 shows, in simplified dia -\ngrammatic form, the main components of a notional bacterial cell and their functions. Surrounding the bacterium is the cell wall, which characteristically contains peptidoglycan \n(except in Mycoplasma ). Peptidoglycan is unique to prokary -\notic cells and has no counterpart in eukaryotes. Within the cell wall is the plasma membrane , which, like that of eukaryotic \ncells, consists of a phospholipid bilayer and proteins. It Basic principles of \nantimicrobial chemotherapy 51 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER SECTION 5\n1Mercury-containing compounds were also once commonly used for \ntreating syphilis. \u2018One night with Venus, a lifetime with Mercury\u2019 was a \nsaying prior to the advent of the antibiotic era.2Humans harbour about 2 kg of bacteria in the gut, comprising a large \n\u2018forgotten organ\u2019 in the body which has important metabolic functions \nand which, together with the commensals living on our skin and other \norgans, are collectively known as the microbiome.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3694, "end_char_idx": 5543, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "23dabe2e-906a-4568-9a21-9f62330158fc": {"__data__": {"id_": "23dabe2e-906a-4568-9a21-9f62330158fc", "embedding": null, "metadata": {"page_label": "656", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "27a2a753-e2e2-4f71-9464-eaa2536dc508", "node_type": null, "metadata": {"page_label": "656", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f40be2e537cad46d499b2282a739d7a6ebd6cfb9eeb2306b56a02698182cc68"}, "3": {"node_id": "75fa331e-8517-47b9-b405-889b999b5edb", "node_type": null, "metadata": {"page_label": "656", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0cd326d0f109315a4de0db37417cc3bd591de2a006479cee8f94d53900debbe7"}}, "hash": "97bb44d6b8fee1e8d3b4818eebc7993536f55c8870fe3bf1f6ae835a1f40bad7", "text": "51 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n650\u2022\tClass II: synthetic pathways which utilise these \nprecursors in an energy-dependent synthesis of all the \namino acids, nucleotides, phospholipids, amino \nsugars, carbohydrates and growth factors required by the cell for survival and growth.\n\u2022\tClass III: anabolic reactions which assemble these small molecules into macromolecules \u2013 proteins, RNA, DNA, polysaccharides and peptidoglycan.\nOther potential drug targets include formed structures, for \nexample, the cell membrane, the microtubules in fungi or \nmuscle tissue in helminths. In considering these targets, emphasis will be placed on bacteria, but reference will also be made to protozoa, helminths, fungi and viruses. The \nclassification that follows is not rigid; a drug may affect \nmore than one class of reactions or more than one subgroup of reactions within a class.\nfunctions as a selectively permeable membrane with specific transport mechanisms for various nutrients. However, in \nbacteria the plasma membrane does not contain any sterols \n(e.g. cholesterol), and this may alter the penetration of some \nchemicals.\nThe cell wall supports the underlying plasma membrane, \nwhich is subject to an internal osmotic pressure of about 5 atmospheres in gram-negative organisms, and about 20 \natmospheres in gram-positive organisms (see Ch. 52 for a \nfull explanation of Gram staining). The plasma membrane \nand cell wall together comprise the bacterial envelope.\nAs in eukaryotic cells, the plasma membrane surrounds \nthe cytoplasm and cellular organelles. Bacterial cells have \nno nucleus or mitochondria. Instead, the genetic material, in the form of a single chromosome containing all the genetic \ninformation, lies in the cytoplasm with no surrounding nuclear membrane and cellular energy is generated by enzyme systems located in the plasma membrane rather \nthan dedicated organelles.\nBiochemical reactions that are potential targets for \nantibacterial drugs are shown in Fig. 51.1. These can be classified into three groups:\n\u2022\tClass I: those catabolic reactions involved in the \nutilisation of glucose, or some alternative carbon \nsource, for the generation of energy (ATP) and synthesis of simple carbon compounds used as precursors in the next class of reactions.Ribosomes\nCell wall\nGlucosePO43\u2212\nNH4+SO42-Hexosamines\nAmino\nacids\nNucleotidesPeptidoglycan\nProteinsRNADNAPrecursor\nmolecules\n& ATPCell membrane DNA (chromosome)Class I reactions\nClass II reactions\nClass III reactionsA\nB\nFig. 51.1 Diagram of the structure and metabolism of a \n\u2018typical\u2019 bacterial cell. (A) Schematic representation of a \nbacterial cell. (B) Flow diagram showing the synthesis of the main types of macromolecule of a bacterial cell. Class I reactions result in the synthesis of the precursor molecules necessary for class II reactions, which result in the synthesis of the constituent molecules; these are then assembled into macromolecules by class III reactions. (Modified from Mandelstam, J., McQuillen, K., Dawes, I. (Eds). 1982. Biochemistry of Bacterial growth. Blackwell Scientific, Oxford.)The molecular basis of \nantibacterial chemotherapy \n\u2022\tChemotherapeutic \tdrugs \tshould \tbe \ttoxic \tto \tinvading \t\norganisms \tand \tinnocuous \tto \tthe \thost. \tSuch \tselective \t\ntoxicity depends on the identification of biochemical \ndifferences between the pathogen and the host that can be appropriately exploited.\n\u2022\tThree\tgeneral", "start_char_idx": 0, "end_char_idx": 3451, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "75fa331e-8517-47b9-b405-889b999b5edb": {"__data__": {"id_": "75fa331e-8517-47b9-b405-889b999b5edb", "embedding": null, "metadata": {"page_label": "656", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "27a2a753-e2e2-4f71-9464-eaa2536dc508", "node_type": null, "metadata": {"page_label": "656", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f40be2e537cad46d499b2282a739d7a6ebd6cfb9eeb2306b56a02698182cc68"}, "2": {"node_id": "23dabe2e-906a-4568-9a21-9f62330158fc", "node_type": null, "metadata": {"page_label": "656", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "97bb44d6b8fee1e8d3b4818eebc7993536f55c8870fe3bf1f6ae835a1f40bad7"}}, "hash": "0cd326d0f109315a4de0db37417cc3bd591de2a006479cee8f94d53900debbe7", "text": "the pathogen and the host that can be appropriately exploited.\n\u2022\tThree\tgeneral \tclasses \tof \tbiochemical \treaction \tare \t\npotential targets for chemotherapy of bacteria:\n\u2013 class I: biochemical reactions that utilise glucose \nand\tother \tcarbon \tsources \tto \tproduce \tATP \tand \t\nsimple carbon compounds\n\u2013 class II : metabolic pathways utilising energy and \nclass I compounds to make small molecules (e.g. amino acids and nucleotides)\n\u2013 class III:\tanabolic \tpathways \tthat \tconvert \tsmall \t\nmolecules into macromolecules such as proteins, nucleic acids and peptidoglycan\nBIOCHEMICAL REACTIONS AS \nPOTENTIAL TARGETS\nCLASS \u2003I \u2003REACTIONS\nClass I reactions are not promising targets for two reasons. \nFirst, bacterial and human cells use similar mechanisms to \nobtain energy from glucose (the Embden\u2013Meyerhof pathway \nand the tricarboxylic acid cycle). Second, even if glucose \noxidation is blocked, many other compounds (amino acids, \nlactate, etc.) can be utilised by bacteria as an alternative \nenergy source.\nCLASS \u2003II \u2003REACTIONS\nClass II reactions are better targets because some pathways exist in pathogens, but not in human cells. There are several \nexamples, with one of the most significant being the folate \nbiosynthesis pathway.\nFolate biosynthesis and utilisation\nFolate is required for DNA synthesis in both bacteria and in humans (see Chs 26 and 52) but in humans, which \nhave no biosynthetic pathway, it must be obtained from \nthe diet and concentrated in cells by specific uptake mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3373, "end_char_idx": 5343, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cc75090a-ace5-4557-a639-c08cb2c9cb87": {"__data__": {"id_": "cc75090a-ace5-4557-a639-c08cb2c9cb87", "embedding": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c335243-72be-4536-8b34-045896734771", "node_type": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eb062c43576980d283b6d1f74e7b2ad5d5f292eaee895b605bcbfce36245890e"}, "3": {"node_id": "6667803d-4b94-418d-9db4-532c84c3d53b", "node_type": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "264480db2d50b6f5babc0ad185995394140e958ff9edb267fa30e0cac4dab0c5"}}, "hash": "f431a5562c111f0b1649175cbef8513358907d2996772e6e055fe2e145dffdb7", "text": "51 BASIC pRINCI plES OF ANTIMICROBIA l CHEMOTHERA py\n651The synthesis of peptidoglycan\nThe cell wall of bacteria contains peptidoglycan , a substance \nthat does not occur in eukaryotes and which contains \nD-amino acids and unusual sugars. It is the equivalent of \na non-stretchable string bag enclosing the whole bacterium. In gram-negative bacteria, this bag consists of a single \nthickness, but in gram-positive bacteria there may be as \nmany as 40 layers of peptidoglycan. Each layer consists of multiple backbones of amino sugars \u2013 alternating \nN-acetylglucosamine and N-acetylmuramic acid residues \n(Fig. 51.2) \u2013 the latter having short peptide side-chains that \nare cross-linked to form a polymeric lattice, which may constitute up to 10%\u201315% of the dry weight of the cell and \nis strong enough to resist the high internal osmotic pressure. \nThe cross-links differ in different species. In staphylococci, for example, they consist of five glycine residues.\n\u25bc To build up this very large insoluble peptidoglycan layer on the \noutside of the cell membrane, the bacterial cell has the problem of \nhow to transport the hydrophilic cytoplasmic \u2018building blocks\u2019 through \nthe hydrophobic cell membrane structure. This is accomplished by \nlinking them to a very large lipid carrier, containing 55 carbon atoms, which \u2018tows\u2019 them across the membrane. The process of peptidoglycan \nsynthesis is outlined in Fig. 51.3. First, N-acetylmuramic acid, attached \nto uridine diphosphate (UDP) and a pentapeptide, is transferred to \nthe C\n55 lipid carrier in the membrane, with the release of uridine \nmonophosphate. This is followed by a reaction with UDP\u2013N-acetyl-\nglucosamine, resulting in the formation of a disaccharide\u2013pentapeptide \ncomplex attached to the carrier. This complex is the basic building block of the peptidoglycan. In Staphylococcus aureus, the five glycine \nresidues are attached to the peptide chain at this stage. The building \nblock is now transported out of the cell and added to the growing end of the peptidoglycan, the \u2018acceptor\u2019, with the release of the C\n55 \nlipid, which still has two phosphates attached. The lipid carrier then \nloses one phosphate group and thus becomes available for another mechanisms. By contrast, most species of bacteria, as \nwell as the asexual forms of malarial protozoa, lack these \ntransport mechanisms. Therefore they cannot make use \nof preformed folate but must synthesise this de novo. Sulfonamides contain the sulfanilamide moiety \u2013 a struc-\ntural analogue of p-aminobenzoic acid (PABA), which is \nessential in bacterial synthesis of folate (see Ch. 52, Fig. \n52.1). Sulfonamides therefore compete with PABA, and thus \ninhibit bacterial growth without impairing mammalian cell \nfunction.\nThe intracellular utilisation of folate, in the form of \ntetrahydrofolate, as a co-factor in thymidylate synthesis is a good example of a pathway where human and bacterial \nenzymes exhibit a differential sensitivity to chemicals (Table \n51.1; see Volpato & Pelletier, 2009). Although the pathway \nis virtually identical in microorganisms and humans, one \nof the key enzymes, dihydrofolate reductase, which reduces \ndihydrofolate to tetrahydrofolate (Ch. 52, Fig. 52.2), is \nmany times more sensitive to the inhibitor trimethoprim \nin bacteria than in humans. In some", "start_char_idx": 0, "end_char_idx": 3311, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6667803d-4b94-418d-9db4-532c84c3d53b": {"__data__": {"id_": "6667803d-4b94-418d-9db4-532c84c3d53b", "embedding": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c335243-72be-4536-8b34-045896734771", "node_type": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eb062c43576980d283b6d1f74e7b2ad5d5f292eaee895b605bcbfce36245890e"}, "2": {"node_id": "cc75090a-ace5-4557-a639-c08cb2c9cb87", "node_type": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f431a5562c111f0b1649175cbef8513358907d2996772e6e055fe2e145dffdb7"}, "3": {"node_id": "b73569e5-6d0a-4ab4-9abe-567afd2eae4c", "node_type": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8094a238f7c894290dba81cf857d659ebc601d6467af4d8e8596f226fc7bb910"}}, "hash": "264480db2d50b6f5babc0ad185995394140e958ff9edb267fa30e0cac4dab0c5", "text": "to the inhibitor trimethoprim \nin bacteria than in humans. In some malarial protozoa, this \nenzyme is somewhat less sensitive than the bacterial enzyme \nto trimethoprim but more sensitive to pyrimethamine and \nproguanil, which are used as antimalarial agents (Ch. 55). \nThe relative IC\n50 values (the concentration causing 50% \ninhibition) for bacterial, malarial, protozoal and mammalian \nenzymes are given in Table 51.1. The human enzyme, by \ncomparison, is very sensitive to the effect of the folate analogue methotrexate, which is used to treat inflamma-\ntory arthritis (Ch. 27), severe psoriasis (Ch. 28) and cancer \n(Ch. 57).\n\u25bc The use of sequential blockade with a combination of two drugs \nthat affect the same pathway at different points, for example sulfona -\nmides and the folate antagonists, may be more successful than the \nuse of either alone. Thus, pyrimethamine and a sulfonamide ( sulf-\nadoxine) are used to treat falciparum malaria (Ch. 55). Co-trimoxazole \nis an antibacterial formulation that contains both a sulfonamide and trimethoprim. Once widely used, this combination has become less \npopular for treating bacterial infections because trimethoprim alone is similarly effective and does not cause sulfonamide-specific adverse \neffects; its use is now mainly restricted to treatment of Pneumocystis \njirovecii, for which high doses are required (Ch. 55).\nCLASS \u2003III \u2003REACTIONS\nAs pathogen cells cannot take up their own unique mac -\nromolecules, class III reactions are particularly good targets \nfor selective toxicity, and there are distinct differences \nbetween mammalian cells and parasitic cells in this respect. Once again, there are several examples.Table 51.1 Specificity of inhibitors of dihydrofolate \nreductase\nInhibitorIC50 (\u00b5mol/L) for \ndihydrofolate reductase\nHuman Protozoal Bacterial\nTrimethoprim 260 0.07 0.005\nPyrimethamine 0.7 0.0005 2.5\nMethotrexate 0.001 ~0.1aInactive\naTested\ton \tPlasmodium berghei, a rodent malaria. Tetrapeptide\nside-chain\nPeptide cross-links\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013NAMA\u2013NAG\u2013\n\u03b2-Lactams prevent the \ncross-linking peptides \nfrom binding to the \ntetrapeptide \nside-chains\nFig. 51.2 Schematic diagram of a single layer of \npeptidoglycan from a bacterial cell (e.g. Staphylococcus \naureus), showing the site of action of the \u03b2-lactam \nantibiotics. In S. aureus\tthe\tpeptide \tcross-links \tconsist \tof \tfive \t\nglycine\tresidues. \tGram-positive \tbacteria \thave \tseveral \tlayers \tof \t\npeptidoglycan. More detail in Fig. 51.3. NAG, \nN-acetylglucosamine; NAMA, N-acetylmuramic acid. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3256, "end_char_idx": 6228, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b73569e5-6d0a-4ab4-9abe-567afd2eae4c": {"__data__": {"id_": "b73569e5-6d0a-4ab4-9abe-567afd2eae4c", "embedding": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9c335243-72be-4536-8b34-045896734771", "node_type": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eb062c43576980d283b6d1f74e7b2ad5d5f292eaee895b605bcbfce36245890e"}, "2": {"node_id": "6667803d-4b94-418d-9db4-532c84c3d53b", "node_type": null, "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "264480db2d50b6f5babc0ad185995394140e958ff9edb267fa30e0cac4dab0c5"}}, "hash": "8094a238f7c894290dba81cf857d659ebc601d6467af4d8e8596f226fc7bb910", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6237, "end_char_idx": 6412, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c652cc54-db1c-43c8-952b-91ace1a0273c": {"__data__": {"id_": "c652cc54-db1c-43c8-952b-91ace1a0273c", "embedding": null, "metadata": {"page_label": "658", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "07dae539-6535-4c86-bb80-37aefc86baf5", "node_type": null, "metadata": {"page_label": "658", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "949acd86e44ac1196f38c88005a100321b1f70a12dbd140ea59eba69823ff7e2"}, "3": {"node_id": "888485b7-b1b5-4ee6-a13a-45270a9763f8", "node_type": null, "metadata": {"page_label": "658", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "436b650573f07e1dee0a94b2f65006e295b62e3617b3d3dd1cdb7cb832103ebc"}}, "hash": "2e34676ef024059c6a56a6e6a41004266be144f9394f6b7a4923cac0569be81b", "text": "51 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n65251.4), whereas in the mammalian ribosome the subunits \nare 60S and 40S. The other elements involved in peptide \nsynthesis are messenger RNA (mRNA), which forms the \ntemplate for protein synthesis, and transfer RNA (tRNA), which specifically transfers the individual amino acids to \nthe ribosome. The ribosome has three binding sites for \ntRNA, termed the A, P and E sites.\nA simplified version of protein synthesis in bacteria is \nshown in Fig. 51.4. To initiate translation, mRNA, transcribed from the DNA template, is attached to the 30S subunit of the ribosome. The 50S subunit then binds to the 30S subunit to form a 70S subunit,\n3 which moves along the mRNA such \nthat successive codons of the messenger pass along the \nribosome from the A position to the P position. Antibiotics \nmay affect protein synthesis at any one of these stages (see Fig. 51.4 and Ch. 52).cycle. Cross-linking between the peptide side-chains of the sugar \nresidues in the peptidoglycan layer then occurs, the hydrolytic removal \nof the terminal alanine supplying the requisite energy.\nThis synthesis of peptidoglycan is a vulnerable step and can be \nblocked at several points by antibiotics (see Fig. 51.3 and Ch. 52). \nCycloserine, which is a structural analogue of D-alanine, prevents the addition of the two terminal alanine residues to the initial trip -\neptide side-chain on N-acetylmuramic acid by competitive inhibition. \nVancomycin inhibits the release of the building block unit from the carrier, thus preventing its addition to the growing end of the \npeptidoglycan. Bacitracin interferes with the regeneration of the lipid \ncarrier by blocking its dephosphorylation. Penicillins , cephalosporins \nand other \u03b2-lactams inhibit the final transpeptidation by forming \ncovalent bonds with penicillin-binding proteins that have transpeptidase \nand carboxypeptidase activities, thus preventing formation of the \ncross-links.\nProtein synthesis\nAnother class III target is protein synthesis. This takes place \non the ribosomes but eukaryotic and prokaryotic ribosomes \nare different, and this provides the basis for the selective \nantimicrobial action of some antibiotics. The bacterial ribosome consists of a 50S subunit and a 30S subunit (Fig. G UDP UDP\nCELL MEMBRANE(Gly)5M UDP\nM UDP UMP\nM PC55 lipid G PP C55 lipid M PP C55 lipid GM PP C55 lipid\nPP C55 lipid PP C55 lipidCycloserine\nPi\n(The acceptor)OutsideInsideGlycine (gly) residues\nAmino acids of the peptide \nside-chain on muramic acid\n\u03b2-Lactam antibiotics, e.g.\npenicillins\ncephalosporins\nmonobactams\ncarbapenemsVancomycin Bacitracin\nFig. 51.3 Schematic diagram of the biosynthesis of peptidoglycan in a bacterial cell (e.g. Staphylococcus aureus), with the sites \nof action of various antibiotics. \tThe\thydrophilic \tdisaccharide\u2013pentapeptide \tis \ttransferred \tacross \tthe \tlipid \tcell \tmembrane \tattached \tto \ta \t\nlarge lipid (C 55\tlipid)\tby\ta \tpyrophosphate \tbridge \t(\u2013P\u2013P\u2013). \tOn \tthe \toutside, \tit \tis \tenzymically \tattached \tto \tthe \t\u2018acceptor\u2019 \t(the \tgrowing \t\npeptidoglycan \tlayer). \tThe", "start_char_idx": 0, "end_char_idx": 3116, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "888485b7-b1b5-4ee6-a13a-45270a9763f8": {"__data__": {"id_": "888485b7-b1b5-4ee6-a13a-45270a9763f8", "embedding": null, "metadata": {"page_label": "658", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "07dae539-6535-4c86-bb80-37aefc86baf5", "node_type": null, "metadata": {"page_label": "658", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "949acd86e44ac1196f38c88005a100321b1f70a12dbd140ea59eba69823ff7e2"}, "2": {"node_id": "c652cc54-db1c-43c8-952b-91ace1a0273c", "node_type": null, "metadata": {"page_label": "658", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2e34676ef024059c6a56a6e6a41004266be144f9394f6b7a4923cac0569be81b"}}, "hash": "436b650573f07e1dee0a94b2f65006e295b62e3617b3d3dd1cdb7cb832103ebc", "text": "\t(the \tgrowing \t\npeptidoglycan \tlayer). \tThe \tfinal \treaction \tis \ta \ttranspeptidation, \tin \twhich \tthe \tloose \tend \tof \tthe \t(Gly) \t5 \tchain \tis \tattached \tto \ta \tpeptide \tside-chain \t\nof\tan\tM\tin \tthe \tacceptor \tand \tduring \twhich \tthe \tterminal \tamino \tacid \t(alanine) \tis \tlost. \tThe \tlipid \tis \tregenerated \tby \tloss \tof \ta \tphosphate \tgroup \t\n(Pi)\tbefore \tfunctioning \tagain \tas \ta \tcarrier. \tG, N-acetylglucosamine; M, N-acetylmuramic acid; UDP, uridine diphosphate; UMP, uridine \nmonophosphate. \n3You query whether 30S + 50S = 70S? Yes it does, because we are \ntalking about Svedberg units, which measure sedimentation rate, which \nis only partly dependent on mass.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3072, "end_char_idx": 4223, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b0a97c8b-351a-4be9-9757-8297899ca902": {"__data__": {"id_": "b0a97c8b-351a-4be9-9757-8297899ca902", "embedding": null, "metadata": {"page_label": "659", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6b26feae-519d-4f6d-96a5-99f38d5772d1", "node_type": null, "metadata": {"page_label": "659", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d548656d8489a0fb1f1dded3c56d1ef599a5b0f92377994e8bc3cdc61da2689"}, "3": {"node_id": "cdf86a22-f0a2-42a2-9ab1-ca49de88370b", "node_type": null, "metadata": {"page_label": "659", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "244bacd963dc4f4c3b3c78676597d5219097f78a89c83c369ca7d5ce94939950"}}, "hash": "19e3bfa7be95d66b3d238f640dc7061f6c29011e251876392fb04a9fd1cb2dea", "text": "51 BASIC pRINCIplES OF ANTIMICROBIAl CHEMOTHERApy\n653\u2022\tby\tinhibiting\t the\tsynthesis\t of\tthe\tnucleotides;\n\u2022\tby\taltering\tthe\tbase-pairing\t properties\t of\tthe\tDNA\t\ntemplate;\n\u2022\tby\tinhibiting\t either\tDNA\tor\tRNA\tpolymerase;\n\u2022\tby\tinhibiting\t DNA\tgyrase,\twhich\tuncoils\tsupercoiled\t\nDNA to allow transcription;Nucleic acid synthesis\nGene expression and cell division also require nucleic \nacid synthesis, and this class III reaction is an important \nsite of action of many chemotherapeutic drugs. It is \npossible to interfere with nucleic acid synthesis in five \ndifferent ways:V TLM\nThe incoming tRNA binds to the A site by \ncomplementary base-pairing.\nTLM\nV Transpeptidation occurs, i.e. the peptide chain on the tRNA in the P site is transferred to the \ntRNA on the A site. The peptide chain \nattached to the tRNA in the A site now \nconsists of Met\u2013Leu\u2013Trp\u2013Val (MLTV). The \ntRNA in the P site has been \u2018discharged\u2019, i.e. \nhas lost its peptide.\nThe discharged tRNA is now transferred \nfrom the P site to the E site; the tRNA with \nthe growing peptide chain is translocated from the A site to the P site and the \nribosome moves on one codon, relative to \nthe messenger.TLM\nV\nThe tRNA from which the peptide chain \nhas been removed is ejected. A new \ntRNA, with amino acid (M) attached and with the relevant anticodon, now moves \ninto the A site, and the whole process is \nrepeated.M\nTLM\nVThe elements involved in protein synthesis are \nshown: a ribosome (with 3 binding sites for \ntransfer RNA [tRNA]: the P, A and E sites), \nmessenger RNA (mRNA) and tRNA. The \ndifferent mRNA codons (triplets of 3 nucleotides \nwhich code for specific amino acids) are \nrepresented by dots, dashes and straight or \nwavy lines and are shown in different colours. A tRNA with the growing peptide chain (consisting \nso far of Met\u2013Leu\u2013Trp: MLT) is in the P site, \nbound by codon:anticodon recognition (i.e. by complementary base-pairing). The incoming \ntRNA carries valine (V), covalently linked.Anticodon\ntRNAV\nTLM\nAPE\nCodons\nCodon:anticodon\nrecognition50S subunit\nof ribosome\n30S subunitCompetition with tRNA \nfor the A site, e.g. \ntetracyclines; selectivity \nlargely through selective \nuptake by active transport \ninto prokaryotic cells\nAbnormal \ncodon:anticodon leads to \nmisreading of the \nmessage, e.g. \naminoglycosides, \ngentamicin, amikacin, etc.\nInhibition of \ntranspeptidation, e.g. \nchloramphenicol\nInhibition of \ntranslocation,\ne.g. erythromycin\n(also spectinomycin, \nfusidic acid)Premature termination of \npeptide chain, e.g. \npuromycin, which \nresembles the amino acid \nend of tRNA (it also affects \nmammalian cells; used as \nan experimental tool)A\nB\nC\nD\nE\nFig. 51.4 Schematic diagram of bacterial protein synthesis, indicating the points at which antibiotics inhibit the process. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 0, "end_char_idx": 3026, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cdf86a22-f0a2-42a2-9ab1-ca49de88370b": {"__data__": {"id_": "cdf86a22-f0a2-42a2-9ab1-ca49de88370b", "embedding": null, "metadata": {"page_label": "659", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6b26feae-519d-4f6d-96a5-99f38d5772d1", "node_type": null, "metadata": {"page_label": "659", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d548656d8489a0fb1f1dded3c56d1ef599a5b0f92377994e8bc3cdc61da2689"}, "2": {"node_id": "b0a97c8b-351a-4be9-9757-8297899ca902", "node_type": null, "metadata": {"page_label": "659", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "19e3bfa7be95d66b3d238f640dc7061f6c29011e251876392fb04a9fd1cb2dea"}}, "hash": "244bacd963dc4f4c3b3c78676597d5219097f78a89c83c369ca7d5ce94939950", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2979, "end_char_idx": 3250, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2e4c9fc5-5ab4-4fe9-8305-3e74faf43613": {"__data__": {"id_": "2e4c9fc5-5ab4-4fe9-8305-3e74faf43613", "embedding": null, "metadata": {"page_label": "660", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2504e7f-e8e1-4ca5-81e2-e0c03cace9f3", "node_type": null, "metadata": {"page_label": "660", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5d6ceedbea5d734f8cd237abcfb4f64c458f85e0cf0f763152b84b0e649c264"}, "3": {"node_id": "be6bb892-1b6a-4aee-9c84-3b07c3735cd0", "node_type": null, "metadata": {"page_label": "660", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d71236937e9dcc2c88892fa0c1b40af4895b583daac1a995ac9fc33774d92304"}}, "hash": "a2326b820e89792215098a77675f8eb6650d280f8525523d7382c074cc481034", "text": "51 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n654Inhibition of DNA gyrase\nFig. 51.6 is a simplified scheme showing the action of \nDNA gyrase. The fluoroquinolones ( cinoxacin, ciprofloxacin, \nnalidixic acid and norfloxacin) act by inhibiting DNA \ngyrase, and these chemotherapeutic agents are particu-larly useful for treating infections with gram-negative \norganisms (Ch. 52). They are selective for the bacterial \nenzyme.\nTHE FORMED STRUCTURES OF THE CELL AS \nPOTENTIAL TARGETS\nTHE\u2003MEMBRANE\nThe plasma membrane of bacterial cells is similar to \nthat in mammalian cells in that it consists of a phos-\npholipid bilayer in which proteins are embedded, but \nit can be more easily disrupted in certain bacteria and \nfungi.\nPolymixins are cationic peptide antibiotics, containing \nboth hydrophilic and lipophilic groups, which have a selective effect on bacterial cell membranes. They act as \ndetergents, disrupting the phospholipid components of the \nmembrane structure, thus killing the cell.\nUnlike mammalian and bacterial cells, fungal cell mem -\nbranes contain large amounts of ergosterol. This facilitates \nthe attachment of polyene antibiotics (e.g. nystatin and \namphotericin; Ch. 54), which act as ionophores and cause leakage of cations from the cytoplasm.\nAzoles such as itraconazole kill fungal cells by inhibiting \nergosterol synthesis, thereby disrupting the function of membrane-associated enzymes. The azoles also affect \ngram-positive bacteria, their selectivity being associated \nwith the presence of high levels of free fatty acids in the membrane of susceptible organisms (Ch. 54).\u2022\tby\ta\tdirect \teffect \ton \tDNA \titself. \tSome \tanticancer \t\ndrugs, but no antimicrobial drugs, work in this way.\nInhibition of the synthesis of nucleotides\nThis can be accomplished by an effect on the metabolic \npathways that generate nucleotide precursors. Examples \nof agents that have such an effect have been described under class II reactions.\nAlteration of the base-pairing properties of the template\nAgents that intercalate in the DNA have this effect. Examples include acridines (proflavine and acriflavine), which are \nused topically as antiseptics. The acridines double the \ndistance between adjacent base pairs and cause a frameshift \nmutation , whereas some purine and pyrimidine analogues \ncause base mispairing.\nInhibition of either DNA or RNA polymerase\nSpecific inhibitors of bacterial RNA polymerase that act by \nbinding to this enzyme in prokaryotic, but not in eukaryotic, cells include rifamycin and rifampicin , which are particu -\nlarly useful for treating tuberculosis (see Ch. 52). Aciclovir \n(an analogue of guanine) is phosphorylated in cells infected with herpes virus, the initial phosphorylation being by a \nvirus-specific kinase to give the aciclovir trisphosphate, \nwhich has an inhibitory action on the DNA polymerase of the herpes virus (Ch. 53; Fig. 51.5).\nRNA retroviruses have a reverse transcriptase (viral RNA-\ndependent DNA polymerase) that copies the viral RNA into DNA that integrates into the host cell genome as a provirus. Various agents ( zidovudine , didanosine ) are phosphorylated \nby cellular enzymes to the trisphosphate forms, which compete with the host cell precursors essential for the forma -\ntion by the viral reverse transcriptase of proviral DNA.\nDNA polymerase\nPPS SP S P S", "start_char_idx": 0, "end_char_idx": 3361, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "be6bb892-1b6a-4aee-9c84-3b07c3735cd0": {"__data__": {"id_": "be6bb892-1b6a-4aee-9c84-3b07c3735cd0", "embedding": null, "metadata": {"page_label": "660", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2504e7f-e8e1-4ca5-81e2-e0c03cace9f3", "node_type": null, "metadata": {"page_label": "660", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5d6ceedbea5d734f8cd237abcfb4f64c458f85e0cf0f763152b84b0e649c264"}, "2": {"node_id": "2e4c9fc5-5ab4-4fe9-8305-3e74faf43613", "node_type": null, "metadata": {"page_label": "660", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a2326b820e89792215098a77675f8eb6650d280f8525523d7382c074cc481034"}}, "hash": "d71236937e9dcc2c88892fa0c1b40af4895b583daac1a995ac9fc33774d92304", "text": "transcriptase of proviral DNA.\nDNA polymerase\nPPS SP S P S P S PCTGA\nGA TSS P\nSS P S P S PCTGA\nGASS P\nCS PP PP S\nCIncoming \ndeoxyribonucleoside \ntrisphosphate\nTemplate\nRifampicin and \nrifamycin inhibit the \nbacterial enzyme;\naciclovir inhibits the \nherpes virus enzyme;\ncytarabine inhibits the \nhuman enzymeFig. 51.5 Schematic diagram of \nDNA replication, showing some \nantibiotics that inhibit it by acting on DNA polymerase. Nucleotides are \nadded, one at a time, by base pairing to an exposed template strand, and are \nthen\tcovalently \tjoined \ttogether \tin \ta \t\nreaction catalysed by DNA polymerase. \nThe\tunits\tthat \tpair \twith \tthe \t\ncomplementary residues in the template consist of a base linked to a sugar and three phosphate groups. Condensation occurs with the \nelimination \tof \ttwo \tphosphates. \tThe \t\nelements added to the template are shown in darker colours and bold type. \nA, adenine; C, cytosine; G, guanine; P, \nphosphate; S, sugar; T, thymine. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3303, "end_char_idx": 4746, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cc4787c9-c5f3-432c-a2d3-05b8215abae3": {"__data__": {"id_": "cc4787c9-c5f3-432c-a2d3-05b8215abae3", "embedding": null, "metadata": {"page_label": "661", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ff195ec-4f7f-4708-aa6b-e83508881e7e", "node_type": null, "metadata": {"page_label": "661", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "75abf64acbf1983c5448b25ebba1a47bd73cd05882094f69ec8db4ffb5c4ee58"}, "3": {"node_id": "94fbeca4-c332-4571-98cb-3934fa60cf58", "node_type": null, "metadata": {"page_label": "661", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5845a168d7c2a003c22a572b0d1298c7facdaeedd2642b0870853e0b2d3b22a"}}, "hash": "d80e409cd38252af7cc2349b775079f7ed8d35c8212045fc96a64f5572f64a00", "text": "51 BASIC pRINCI plES OF ANTIMICROBIA l CHEMOTHERA py\n655Muscle fibres\nSome antihelminthic drugs have a selective action on \nhelminth muscle cells (Ch. 56). Piperazine acts as an \nagonist on parasite-specific chloride channels gated by GABA in nematode muscle, hyperpolarising the muscle fibre membrane and paralysing the worm; avermectins \nincrease Cl\n\u2212 permeability in helminth muscle \u2013 possibly \nby a similar mechanism. Pyrantel and levamisole are \nagonists at nematode acetylcholine nicotinic receptors \non muscle, causing contraction followed by paralysis \n(Ch. 56).\nINTRACELLULAR \u2003ORGANELLES4\nMicrotubules and/or microfilaments\nThe benzimidazoles (e.g. albendazole) exert their antihel-minthic action by binding selectively to parasite tubulin \nand preventing microtubule formation (Ch. 56).\nFood vacuoles\nThe erythrocytic form of the malaria plasmodium feeds on \nhost haemoglobin, which is digested by proteases in the \nparasite food vacuole, the final product, haem, being \ndetoxified by polymerisation. Chloroquine and several \nother antimalarials exert their antimalarial actions by \ninhibiting plasmodial haem polymerase (Ch. 55).DNA gyraseCore\nCoreCell wall\nFolded\nchromosome\nSupercoiled \nfolded chromosome. \n \nEach loop is independently supercoiledQuinolonesChromosome A\nB\nC\nFig. 51.6 Schematic diagram of the action of DNA gyrase: \nthe site of action for quinolone antibacterials. (A) \nConventional \tdiagram \tused \tto \tdepict \ta \tbacterial \tcell \tand \t\nchromosome (e.g. Escherichia coli). Note that the E. coli \nchromosome is 1300 mm long and is contained in a cell \nenvelope\tof \t2 \t\u00b5m \u00d7 1 \u00b5m;\tthis\tis\tapproximately \tequivalent \tto \ta \t\n50 m length of cotton folded into a matchbox. (B) Chromosome \nfolded around RNA core, and then (C), supercoiled by DNA \ngyrase (topoisomerase II). Quinolone antibacterials interfere with \nthe\taction \tof \tthis \tenzyme. \t(Modified \tfrom \tSmith, \tJ.T., \t1985. \tIn: \t\nGreenwood, \tD., \tO\u2019Grady., \tF. \t(Eds). \tScientific \tBasis \tof \t\nAntimicrobial \tTherapy. \tCambridge \tUniversity \tPress, \tCambridge, \t\np. 69.)Biochemical reactions as potential \ntargets for chemotherapy \n\u2022\tClass\tI\treactions \tare \tpoor \ttargets.\n\u2022\tClass\tII\treactions \tare \tbetter \ttargets:\n\u2013 folate synthesis in bacteria is inhibited by \nsulphonamides;\n\u2013 folate utilisation is inhibited by folate antagonists, for \nexample trimethoprim (bacteria), pyrimethamine \n(malarial parasite).\n\u2022\tClass\tIII \treactions \tare \timportant \ttargets:\n\u2013 peptidoglycan synthesis in bacteria can be \nselectively \tinhibited \tby \t\u03b2-lactam antibiotics (e.g. \npenicillin);\n\u2013 bacterial protein synthesis \tcan\tbe\tselectively \t\ninhibited\tby \tantibiotics \tthat \tprevent \tbinding \tof \ttRNA \t\n(e.g. tetracyclines), promote misreading of mRNA \n(e.g. aminoglycosides), inhibit transpeptidation (e.g. chloramphenicol) or inhibit translocation of tRNA \n(e.g. erythromycin);\n\u2013 nucleic acid synthesis can be inhibited", "start_char_idx": 0, "end_char_idx": 2899, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "94fbeca4-c332-4571-98cb-3934fa60cf58": {"__data__": {"id_": "94fbeca4-c332-4571-98cb-3934fa60cf58", "embedding": null, "metadata": {"page_label": "661", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ff195ec-4f7f-4708-aa6b-e83508881e7e", "node_type": null, "metadata": {"page_label": "661", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "75abf64acbf1983c5448b25ebba1a47bd73cd05882094f69ec8db4ffb5c4ee58"}, "2": {"node_id": "cc4787c9-c5f3-432c-a2d3-05b8215abae3", "node_type": null, "metadata": {"page_label": "661", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d80e409cd38252af7cc2349b775079f7ed8d35c8212045fc96a64f5572f64a00"}}, "hash": "f5845a168d7c2a003c22a572b0d1298c7facdaeedd2642b0870853e0b2d3b22a", "text": "erythromycin);\n\u2013 nucleic acid synthesis can be inhibited by altering \nbase\tpairing \tof \tDNA \ttemplate \t(e.g. \tthe \tantiviral \t\nvidarabine), by inhibiting DNA polymerase (e.g. the \nantivirals\taciclovir and foscarnet) or by inhibiting \nDNA gyrase (e.g. the antibacterial ciprofloxacin).\nFormed structures of the cell that \nare targets for chemotherapy \n\u2022\tThe\tbacterial \tcell \twall \tmay \tbe \taffected \tby \tseveral \t\nclasses of antibiotics, such as the \u03b2-lactams.\n\u2022\tThe\tplasma \tmembrane \tis \taffected \tby:\n\u2013 amphotericin, which acts as an ionophore in fungal \ncells\n\u2013\tazoles,\twhich \tinhibit \tfungal \tmembrane \tergosterol \t\nsynthesis\n\u2022\tMicrotubule \tfunction \tis \tdisrupted \tby:\n\u2013\tbenzimidazoles \t(antihelminthics)\n\u2022\tMuscle\tfibres \tare \taffected \tby:\n\u2013\tavermectins \t(antihelminthics), \twhich \tincrease \t\nCl\u2212 permeability\n\u2013 pyrantel (antihelminthic), which stimulates nematode \nnicotinic\treceptors, \teventually \tcausing \tmuscle \t\nparalysis by depolarising neuromuscular block4Bacteria do not contain mitochondria so drugs such as atovaquine (see \nCh. 55) that target these organelles in parasites are ineffective in \nbacteria. However, they can damage the host mitochondria (which \noriginated from bacteria during eukaryote evolution) and contribute to the toxicity encountered during their use.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2843, "end_char_idx": 4610, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5de7d517-8dff-438a-93b6-d3e4ba9d4b0f": {"__data__": {"id_": "5de7d517-8dff-438a-93b6-d3e4ba9d4b0f", "embedding": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5c62a78-452e-43ec-aa98-6aa25c64d62f", "node_type": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b352d1164d34de8d439ef01c8eb1dc74d3c2b3e030292e6d9d03428f8f328a7d"}, "3": {"node_id": "29eb1067-6172-41ca-b929-1a1113e1bbd4", "node_type": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1a66fc0d93ae37bfc80571b514232dd6b3de7060dd31799227bffb54c515cac8"}}, "hash": "aadf11d263f12220e0e19eccd1add46fa96f9d0f2ed5cac01cd0f8c3f46f0d5c", "text": "51 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n656or as part of bacterial \u2018quorum sensing\u2019 mechanisms.5 Many \nof the resistance genes are located on mobile elements of \nDNA and transfer between organisms in the soil is by \nhorizontal gene transfer (as opposed to the vertical gene transfer \nthat occurs during reproduction). This in part explains why \nthe incidence of resistance is high in sites where bacteria \nproliferate and antibiotic usage is high, such as in agriculture or in hospitals.\nThe impact of the intense clinical usage of antibiotics \nhas been the stimulus for the accumulation of multiple resistance elements in pathogens under the \u2018selection pres -\nsure\u2019 of drug usage. This obviously imposes serious con-\nstraints on the options available for the medical treatment \nof many bacterial infections. Whilst resistance to chemo -\ntherapeutic agents can also develop in protozoa and \nmulticellular parasites (and in populations of malignant \ncells; see Ch. 57), we will confine our discussion here mainly to the mechanisms of resistance in bacteria.\nTHE SPREAD OF ANTIBIOTIC RESISTANCE\nAntibiotic resistance may be innate \u2013 pre-existing in a \nparticular strain \u2013 or acquired in some way from other \nbacterial cells. In either case, natural selection works to favour \nresistant strains when the antibiotic is prevalent in the environment. Fundamental to the whole issue is how \nbacterial resistance genes are moved around between \nchromosomal DNA and mobile elements both within and \nbetween bacteria.\nSeveral basic mechanisms have been identified:\n1. By transfer of resistance genes between genetic \nelements within bacteria, on transposons.\n2. By transfer of resistance genes between bacteria by \nmobile elements (such as plasmids).\n3. By transfer of resistant bacteria between people or \nanimals.\nAn understanding of these mechanisms is crucial for the \nsensible clinical use of existing medicines (\u2018antibiotic \nstewardship\u2019) as well as in the design of new antibacterial drugs. We look first at the mechanisms whereby genetic \ninformation can be exchanged and then at how these \ntransferred genes undermine the activity of antibiotics.\nMOVEMENT \u2003OF \u2003GENETIC \u2003INFORMATION\nPlasmids and mobile elements\n\u25bc In addition to the chromosome itself, many species of bacteria \ncontain extrachromosomal genetic elements called plasmids that exist \nfree in the cytoplasm. These are also genetic elements that can replicate \nindependently. Structurally, they are closed loops of DNA that may \ncomprise a single gene or as many as 500 or even more. Only a few plasmid copies may exist in the cell but often multiple copies are \npresent, and there may also be more than one type of plasmid in \neach bacterial cell. Plasmids that carry genes for resistance to antibiotics (r genes) are referred to as R plasmids. Much of the drug resistance \nencountered in clinical medicine is plasmid-determined.\nThe whole process can occur with frightening speed. Staphylococcus \naureus , for example, is a past master of the art of antibiotic resistance. \nHaving become completely resistant to penicillin through plasmid-\nmediated mechanisms, this organism, within only 1\u20132 years, was \nable to acquire resistance to its \u03b2-lactamase-resistant (see later) \ndescendant, meticillin\n (de Lencastre et al., 2007).RESISTANCE TO ANTIBACTERIAL DRUGS\nSince the 1940s, the development of effective and safe drugs \nto deal with bacterial and other infections has revolutionised \nmedical treatment, and the morbidity and mortality associ -\nated with these diseases have been dramatically reduced. \nUnfortunately, the development of effective antibacterial \ndrugs has been accompanied by the emergence of", "start_char_idx": 0, "end_char_idx": 3707, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "29eb1067-6172-41ca-b929-1a1113e1bbd4": {"__data__": {"id_": "29eb1067-6172-41ca-b929-1a1113e1bbd4", "embedding": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5c62a78-452e-43ec-aa98-6aa25c64d62f", "node_type": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b352d1164d34de8d439ef01c8eb1dc74d3c2b3e030292e6d9d03428f8f328a7d"}, "2": {"node_id": "5de7d517-8dff-438a-93b6-d3e4ba9d4b0f", "node_type": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aadf11d263f12220e0e19eccd1add46fa96f9d0f2ed5cac01cd0f8c3f46f0d5c"}, "3": {"node_id": "2d50d67c-f648-4468-aa3e-d35d1b350bb5", "node_type": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6d0b66cb196394f8f7c4c79b2ca589fb7b9c1b127a2a5675b6bd396284ce54b3"}}, "hash": "1a66fc0d93ae37bfc80571b514232dd6b3de7060dd31799227bffb54c515cac8", "text": "the development of effective antibacterial \ndrugs has been accompanied by the emergence of drug-\nresistant organisms.\nThe growing concern about antibiotic resistance has \nprompted several supra-national and domestic political responses. In addition to the WHO, which has formulated a Global Action Plan on Antibiotic Resistance and regularly \nissues updated fact sheets on the problem, other organisa -\ntions such as the Global Antibiotic Resistance Partnership \n(GARP) have been monitoring the emergence of resistant strains around the world since 2009 and advising on local \ntreatment strategies. There have been domestic initiatives \ntoo: in the United States, a national action plan was announced in 2015 and many other countries have intro -\nduced similar, if less formal, strategies to implement the advice arising from the WHO, GARP and other organisa -\ntions. Developing countries often struggle to introduce such \nmeasures and, because they are often burdened with large \nnumbers of immunocompromised patients, lack of access to drugs, poor hygiene and infection control, are faring \nless well.\n\u25bc So what is the cause of this problem? The prevailing view used \nto be that antibiotic resistance was a phenomenon unique to our age \nand which arose largely through human mismanagement of antibiotic \nresources. This \u2018anthropogenic\u2019 view seemed to be supported by the \nrelative absence of resistance elements in samples of bacteria taken from remote uninhabited islands (such as some of the Galapagos \nislands) or from ancient samples that predated the antibiotic era. On \nthe other hand, sequencing of recovered DNA from Pleistocene fossils (around 30,000 years old) suggested that at least some of the antibiotic \nresistance elements had a very ancient origin (see Bhullar et al., 2012). \nThis presumption was dramatically confirmed by (amongst others) the discovery, in New Mexico, of multidrug resistant bacteria in a \ndeep cave system, which had been isolated from human and animal \ncontact for 4\u20137 million years (Bhullar et al., 2012). A detailed analysis \nof one of the species recovered, Paenibacillus, which is resistant to \nmost clinically used antibiotics, found that these resistance genes in this bacterium had evidently been conserved for millions of years \n\u2013 and incidentally uncovered several hitherto-unknown resistance \nmechanisms (Pawlowski et al., 2016). Interestingly, whilst resistance \nto naturally occurring antibiotics (e.g. penicillin) was extensive, little resistance to synthetic drugs such as linezolid was observed. None \nof these genes were expressed in samples of this bacterium collected \nfrom the nearby cave surface, suggesting that the organisms in \nthe cave expressed these under some selection pressure. Findings \nsuch as these have led to a reappraisal of the origin and role of the \nbacterial \u2018resistome\u2019 and the issue of antibiotic resistance in general. \nIt is now clear that we have to take a more nuanced view of the \nproblem.\nMany clinically used antibiotics are complex, naturally \noccurring chemicals derived from soil-dwelling bacteria \nor fungi. These are released as part of a defensive strategy \nby these organisms. Obviously, organisms which release antibiotics must protect themselves against the effects of \nthese substances perhaps explaining, at least in part, why \nthe resistome \u2013 the pool of genes involved in antibiotic resistance \u2013 is so significant in soil-dwelling organisms. In \naddition, it is now thought that these endogenous antibiotics \nmay also have a more \u2018physiological\u2019 role: perhaps regulat -\ning metabolic pathways, acting as communication molecules 5Quorum sensing is a mechanism by which bacterial colonies can \nregulate their gene expression (and other metabolic activity) according \nto the population density.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3630, "end_char_idx": 7523, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2d50d67c-f648-4468-aa3e-d35d1b350bb5": {"__data__": {"id_": "2d50d67c-f648-4468-aa3e-d35d1b350bb5", "embedding": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d5c62a78-452e-43ec-aa98-6aa25c64d62f", "node_type": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b352d1164d34de8d439ef01c8eb1dc74d3c2b3e030292e6d9d03428f8f328a7d"}, "2": {"node_id": "29eb1067-6172-41ca-b929-1a1113e1bbd4", "node_type": null, "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1a66fc0d93ae37bfc80571b514232dd6b3de7060dd31799227bffb54c515cac8"}}, "hash": "6d0b66cb196394f8f7c4c79b2ca589fb7b9c1b127a2a5675b6bd396284ce54b3", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7554, "end_char_idx": 7985, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "779a348b-cb57-4041-ac88-749b9b5bcdce": {"__data__": {"id_": "779a348b-cb57-4041-ac88-749b9b5bcdce", "embedding": null, "metadata": {"page_label": "663", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9e1f1e74-9622-4e9c-b7eb-9e74a85ba5f9", "node_type": null, "metadata": {"page_label": "663", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "845625949c954975f946f0e5c1cd8a87db20aa485ba6bff221d4601181d190f8"}, "3": {"node_id": "b162d4e8-64c6-46da-8dd3-817aec41e5f2", "node_type": null, "metadata": {"page_label": "663", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c859e02d893fbedaa155a6b3b83e991ebf5be5ad875f0a2200a0f1c72ca2bd66"}}, "hash": "3df2f9ba0be9ab89bb175d8b84bfd697f2528db6d2669d9d11438b032c9e9e6e", "text": "51 BASIC pRINCI plES OF ANTIMICROBIA l CHEMOTHERA py\n657Conjugation\n\u25bc C onjugation involves cell-to-cell contact during which chromosomal \nor extrachromosomal DNA is transferred from one bacterium to \nanother, and is the main mechanism for the spread of resistance. The \nability to conjugate is encoded in conjugative plasmids : these are plasmids \nthat contain transfer genes that, in (for example) coliform bacteria, \ncode for the production by the host bacterium of proteinaceous surface \ntubules termed sex pili, which connect the two cells. The conjugative \nplasmid then passes across from one bacterial cell to another (generally \nof the same species).\nMany gram-negative and some gram-positive bacteria can conjugate. \nSome promiscuous plasmids can cross the species barrier, adopting \none host as readily as another. Many R plasmids are conjugative. \nNon-conjugative plasmids, if they co-exist in a \u2018donor\u2019 cell with conjugative plasmids, can hitch-hike from one bacterium to the other \nwith the conjugative plasmids. The transfer of resistance by conjugation \nis particularly significant in populations of bacteria that are normally found at high densities, as in the gut.\nTransduction\n\u25bc Transduction is a process by which plasmid DNA is enclosed in a \nvirus that infects bacteria (termed a phage ) and transferred to another \nbacterium of the same species. It is a relatively ineffective means of transfer of genetic material but is clinically important in the transmis -\nsion of resistance genes between strains of staphylococci and of \nstreptococci.\nTransformation\n\u25bc A few species of bacteria can, under natural conditions, undergo \ntransformation by taking up DNA from the environment and \nincorporating it into the genome by normal homologous recom -\nbination. However, this mechanism is probably not of importance \nclinically.\nThere are several other mechanisms through which resistance genes \ncan arise.\nCHROMOSOMAL \u2003MUTATIONS\nThe spontaneous mutation rate in bacterial populations \nfor any particular gene is very low, and the probability is \nthat approximately only one cell in 10 million will, on \ndivision, give rise to a daughter cell containing a mutation in that gene. However, as there are likely to be very many \nmore cells than this over the course of an infection, the \nprobability of a mutation causing a change from drug sensitivity to drug resistance can be quite high. Fortunately, \nthe presence of a few mutants is not generally sufficient \nto produce resistance: despite the selective advantage that the resistant mutants possess, the drastic reduction of the population by the antibiotic usually enables the host\u2019s \nnatural defences (see Ch. 7) to prevail at least in acute, if \nnot chronic, infections. However, the outcome may not be quite so happy if the primary infection is caused by a \ndrug-resistant strain.\nGENE \u2003AMPLIFICATION\n\u25bc Gene duplication and amplification are important mechanisms for \nresistance in some organisms (Sandegren & Andersson, 2009). Accord -\ning to this idea, treatment with antibiotics can induce an increased \nnumber of copies for pre-existing resistance genes such as antibiotic-destroying enzymes and efflux pumps.\nBIOCHEMICAL MECHANISMS OF RESISTANCE \nTO ANTIBIOTICS\nResistance genes are translated into proteins that subvert \nthe action of antibiotics in several ways. Here we discuss \nseveral of these, but new mechanisms are still being \nuncovered (Pawlowski et al., 2016).Transposons\n\u25bc Some stretches of DNA are readily transferred (transposed) from \none plasmid to another and also from plasmid to chromosome or \nvice versa.6 This is because integration of these", "start_char_idx": 0, "end_char_idx": 3640, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b162d4e8-64c6-46da-8dd3-817aec41e5f2": {"__data__": {"id_": "b162d4e8-64c6-46da-8dd3-817aec41e5f2", "embedding": null, "metadata": {"page_label": "663", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9e1f1e74-9622-4e9c-b7eb-9e74a85ba5f9", "node_type": null, "metadata": {"page_label": "663", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "845625949c954975f946f0e5c1cd8a87db20aa485ba6bff221d4601181d190f8"}, "2": {"node_id": "779a348b-cb57-4041-ac88-749b9b5bcdce", "node_type": null, "metadata": {"page_label": "663", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3df2f9ba0be9ab89bb175d8b84bfd697f2528db6d2669d9d11438b032c9e9e6e"}}, "hash": "c859e02d893fbedaa155a6b3b83e991ebf5be5ad875f0a2200a0f1c72ca2bd66", "text": "to chromosome or \nvice versa.6 This is because integration of these segments of DNA, \nwhich are called transposons, into the acceptor DNA can occur \nindependently of the normal mechanism of homologous genetic \nrecombination. Unlike plasmids, transposons are not able to replicate independently, although some may replicate during the process of \nintegration (Fig. 51.7), resulting in a copy in both the donor and the \nacceptor DNA molecules. Transposons may carry one or more resist -\nance genes and can \u2018hitch-hike\u2019 on a plasmid to a new species of \nbacterium. Even if the plasmid is unable to replicate in the new host, \nthe transposon may integrate into its chromosome or into its indigenous \nplasmids. This probably accounts for the widespread distribution of \ncertain of the resistance genes on different R plasmids and among unrelated bacteria.\nGene cassettes and integrons\n\u25bc Plasmids and transposons do not complete the tally of mechanisms \nthat natural selection has provided to confound the hopes of the microbiologist/chemotherapist. Resistance \u2013 in fact, multidrug \nresistance \u2013 can also be spread by another mobile element, the \ngene cassette, which consists of a resistance gene attached to a small recognition site. Several cassettes may be packaged together in a \nmulticassette array, which can, in turn, be integrated into a larger \nmobile DNA unit termed an integron. The integron (which may be \nlocated on a transposon) contains a gene for an enzyme, integrase \n(recombinase), which inserts the cassette(s) at unique sites into the \nhost DNA. This system \u2013 transposon/integron/multiresistance cassette \narray \u2013 allows particularly rapid and efficient transfer of multidrug \nresistance between genetic elements both within and between \nbacteria.\nTHE\u2003TRANSFER \u2003OF \u2003RESISTANCE \u2003GENES \u2003\u2003\nBETWEEN \u2003BACTERIA\n\u25bc Horizontal gene transfer between bacteria of the same, or indeed \nof different, species is considered the most significant mechanism whereby antibiotic resistance is spread. There are several important \nmechanisms including conjugation, transduction and transformation \nwith the former being the most significant.b\nTransposon\ndonora\nb\nPlasmid\ncointegratea\nba\nbaA B CD\nFig. 51.7 An example of the transfer and replication of a \ntransposon (which may carry genes coding for resistance to \nantibiotics). \t(A)\tTwo\tplasmids, \ta and b, with plasmid b \ncontaining a transposon (shown in brown) .\t(B)\tAn\tenzyme \t\nencoded by the transposon cuts DNA of both donor plasmid and target plasmid a to form a cointegrate. During this process, \nthe\ttransposon \treplicates. \t(C) \tAn \tenzyme \tencoded \tby \tthe \t\ntransposon \tresolves \tthe \tcointegrate. \t(D) \tBoth \tplasmids \tnow \t\ncontain the transposon DNA. \n6According to one school of thought, viruses may have arisen as transposons \nthat escaped from cells and continued to ply their trade independently.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3573, "end_char_idx": 6915, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7d21e192-b249-478e-8a4e-2350f88f8683": {"__data__": {"id_": "7d21e192-b249-478e-8a4e-2350f88f8683", "embedding": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1cc2fdc4-a2a1-4ca7-a8d6-9a9098d4b04a", "node_type": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f20800344f884c34994f267b970e2b83c3ee409abecedd3da64b104fa1bdca8"}, "3": {"node_id": "f4cece87-7184-4aa7-a8fd-594f85bcb543", "node_type": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "469c6f9f29cfcbda4957c8640a326b818a7030c600e8603180ed980b63d3ec74"}}, "hash": "9fa20962ca18f4d8b354ad8fb27d740e0d4cec078aff893081d03621058a1205", "text": "51 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n658susceptible to \u03b2-lactamase, some strains of S. aureus have \neven become resistant to some antibiotics that are not \nsignificantly inactivated by \u03b2-lactamase (e.g. meticillin), \nbecause they express an additional \u03b2-lactam-binding protein \ncoded for by a mutated chromosomal gene. See Lambert (2005) for other examples of this type of action.\n\u25bc Gram-negative organisms can also produce \u03b2-lactamases, and this \nis a significant factor in their resistance to the semisynthetic broad-\nspectrum \u03b2-lactam antibiotics. In these organisms, the enzymes may \nbe coded by either chromosomal or plasmid genes. In the former \ncase, the enzymes may be inducible, but in the latter they are produced \nconstitutively. When this occurs, the enzyme does not inactivate the \ndrug in the surrounding medium but instead remains attached to the cell wall, preventing access of the drug to membrane-associated \ntarget sites. Many of these \u03b2-lactamases are encoded by transposons, \nsome of which may also carry resistance determinants to several other antibiotics.\nInactivation of chloramphenicol\nChloramphenicol is inactivated by chloramphenicol acetyl-\ntransferase , an enzyme produced by resistant strains of both \ngram-positive and gram-negative organisms, the resistance gene being plasmid borne. In gram-negative bacteria, the enzyme is produced constitutively, resulting in levels of \nresistance five-fold higher than in gram-positive bacteria, \nin which the enzyme is inducible.\nInactivation of aminoglycosides\nAminoglycosides are inactivated by phosphorylation, adenylation or acetylation, and the requisite enzymes are \nfound in both gram-negative and gram-positive organisms. \nThe resistance genes are carried on plasmids, and several are found on transposons. Many other examples of this \nkind are given by Wright (2005) and Giedraitiene et al. \n(2011).\nALTERATION \u2003OF \u2003DRUG-BINDING \u2003SITE\nThe aminoglycoside-binding site on the 30S subunit of the ribosome may be altered by chromosomal mutation. A \nplasmid-mediated alteration of the binding site protein on \nthe 50S subunit also underlies resistance to erythromycin , \nand decreased binding of fluoroquinolones because of a \npoint mutation in DNA gyrase A has also been described. \nAn altered DNA-dependent RNA polymerase determined by a chromosomal mutation is reported to be the basis for \nrifampicin resistance.\nDECREASED \u2003ACCUMULATION \u2003OF \u2003DRUGS \u2003BY \u2003BACTERIA\nAn important example of decreased drug accumulation is \nthe plasmid-mediated resistance to tetracyclines encoun-\ntered in both gram-positive and gram-negative bacteria. In this case, resistance genes in the plasmid code for inducible proteins in the bacterial membrane, which promote \nenergy-dependent efflux of the tetracyclines, and hence \nresistance. This type of resistance is common and has greatly reduced the therapeutic value of the tetracyclines in human \nand veterinary medicine. Resistance of S. aureus to eryth-\nromycin and the other macrolides, and to fluoroquinolones, is also brought about by energy-dependent efflux. Inhibitors of such pumps may be useful adjuncts to antibiotics (Van \nBambeke et al., 2006).\nThere is also recent evidence of plasmid-determined \ninhibition of porin synthesis, which could affect those \nhydrophilic antibiotics that enter the bacterium through these water-filled channels in the outer membrane. Altered THE\u2003PRODUCTION \u2003OF \u2003ENZYMES", "start_char_idx": 0, "end_char_idx": 3458, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f4cece87-7184-4aa7-a8fd-594f85bcb543": {"__data__": {"id_": "f4cece87-7184-4aa7-a8fd-594f85bcb543", "embedding": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1cc2fdc4-a2a1-4ca7-a8d6-9a9098d4b04a", "node_type": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f20800344f884c34994f267b970e2b83c3ee409abecedd3da64b104fa1bdca8"}, "2": {"node_id": "7d21e192-b249-478e-8a4e-2350f88f8683", "node_type": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9fa20962ca18f4d8b354ad8fb27d740e0d4cec078aff893081d03621058a1205"}, "3": {"node_id": "8cc9d1a2-a412-4d05-96eb-1a409f2fabb9", "node_type": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e668fa96b7606af9978e4ca315384dcc79f12d38c2b09d8e78838f76200ed22"}}, "hash": "469c6f9f29cfcbda4957c8640a326b818a7030c600e8603180ed980b63d3ec74", "text": "Altered THE\u2003PRODUCTION \u2003OF \u2003ENZYMES \u2003THAT \u2003\u2003\nINACTIVATE \u2003DRUGS\nInactivation of \u03b2-lactam antibiotics\nPerhaps the most important example of resistance caused by inactivation is that of the \u03b2-lactam antibiotics . The enzymes \nconcerned are \u03b2-lactamases , which cleave the \u03b2-lactam ring \nof penicillins and cephalosporins (see Ch. 52). Cross-\nresistance between the two classes of antibiotic is not \ncomplete, because some \u03b2-lactamases have a preference \nfor penicillins and some for cephalosporins.\nStaphylococci are the principal bacterial species producing \n\u03b2-lactamase, and the genes coding for the enzymes are on plasmids that can be transferred by transduction. In staphylococci, the enzyme is inducible (i.e. it is not expressed in the absence of the drug) and minute, sub-inhibitory, \nconcentrations of antibiotics de-repress the gene and result \nin a 50- to 80-fold increase in expression. The enzyme passes through the bacterial envelope and inactivates antibiotic \nmolecules in the surrounding medium. The grave clinical \nproblem posed by resistant staphylococci secreting \u03b2-lactamase was tackled by developing semisynthetic \npenicillins (such as meticillin) and new \u03b2-lactam antibiotics \n(the monobactams and carbapenems ), and cephalosporins \n(such as cefamandole ), that are less susceptible to inactiva -\ntion. In addition to acquiring resistance to \u03b2-lactams Resistance to antibiotics \n\u2022\tAntibiotic \tresistance \tis \ta \tnaturally \toccurring \t\nphenomenon which plays a role in the normal bacterial \necology.\n\u2022\tIn\tmany \tbacterial \tspecies, \tresistance \tgenes \t(r \tgenes) \t\nare of ancient origin and are expressed in the presence of the antibiotic.\n\u2022\tR\tgenes \tmay \tbe \tmoved \taround \tbetween \tgenetic \t\nelements\twithin \tindividual \tbacteria. \tThere \tare \tseveral \t\nmechanisms:\n\u2013\tPlasmids \tare \textrachromosomal \tgenetic \telements \t\nthat can replicate independently and can carry genes coding for resistance to antibiotics (r genes).\n\u2013\tTransposons \tare \tstretches \tof \tDNA \tthat \tcan \tbe \t\ntransposed from one plasmid to another, from a \nplasmid\tto \ta \tchromosome \tor \tvice \tversa. \tA \tplasmid \t\ncontaining an r gene-bearing transposon may code \nfor\tenzymes \tthat \tcause \tthe \tplasmid \tto \tbe \tintegrated \t\nwith another. Following their separation, this transposon replicates so that both plasmids then contain the r gene.\n\u2022\tR\tgenes, \tincluding \tmulticassette arrays of drug \nresistance genes can also be transferred to other \nbacteria\tof \tthe \tsame, \tor \tdifferent, \tspecies. \tThere \tare \t\nseveral\tmechanisms:\n\u2013\tThe\tmain \tmethod \tof \ttransfer \tof \tr \tgenes \tfrom \tone \t\nbacterium \tto \tanother \tis \tby \tconjugative \tplasmids. \t\nThe\tbacterium \tforms \ta \tconnecting \ttube \twith \tother \t\nbacteria through which the plasmids pass.\n\u2013 A less common method of transfer is by \ntransduction, i.e. the transmission by a bacterial \nvirus\t(phage) \tof \ta \tplasmid \tbearing \tan \tr \tgene \tinto \t\nanother bacterium.mebooksfree.net", "start_char_idx": 3427, "end_char_idx": 6350, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8cc9d1a2-a412-4d05-96eb-1a409f2fabb9": {"__data__": {"id_": "8cc9d1a2-a412-4d05-96eb-1a409f2fabb9", "embedding": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1cc2fdc4-a2a1-4ca7-a8d6-9a9098d4b04a", "node_type": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6f20800344f884c34994f267b970e2b83c3ee409abecedd3da64b104fa1bdca8"}, "2": {"node_id": "f4cece87-7184-4aa7-a8fd-594f85bcb543", "node_type": null, "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "469c6f9f29cfcbda4957c8640a326b818a7030c600e8603180ed980b63d3ec74"}}, "hash": "5e668fa96b7606af9978e4ca315384dcc79f12d38c2b09d8e78838f76200ed22", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6383, "end_char_idx": 6846, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0f7b7808-aed9-427a-8fc7-33ee99afa9ac": {"__data__": {"id_": "0f7b7808-aed9-427a-8fc7-33ee99afa9ac", "embedding": null, "metadata": {"page_label": "665", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4c556122-bffe-4865-8fa1-530a8e5b00f6", "node_type": null, "metadata": {"page_label": "665", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "60ed55e4aeeb99b9b2387e4855d9f28682a8dbf3589d612e26a5b2fb14eac820"}, "3": {"node_id": "9bd9db61-eedf-4289-b996-18787e21cc6a", "node_type": null, "metadata": {"page_label": "665", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2535f3b0b1aaa322fc838690e5464f67c85b0bf10333485f6adfe35b3d9a6d92"}}, "hash": "bf8260ee30ecd0118325525ecd2bffbf09bb61e0fa2d300c3db6e879f3d4405d", "text": "51 BASIC pRINCI plES OF ANTIMICROBIA l CHEMOTHERA py\n659\u2022\tNeisseria gonorrhoea. Is now resistant to \n\u2018last resort\u2019 cephalosporin antibiotics in some \n10 countries.\n\u2022\tStaphylococcus aureus. There is now widespread \nresistance to first line drugs and patients with \nmethicillin-resistant staphylococcus aureus (MRSA) \nare more than twice as likely to die following \ninfection. Death rates are declining in the North \nAmerica and Europe but increasing in developing \ncountries.\n\u2022\tEnterbacteriaceae spp. These organisms can cause life threatening infections and recently resistance to the \n\u2018last resort\u2019 drug colistin has been reported.\n\u2022\tMycobacterium tuberculosis. Multidrug resistant \nstrains (MDR-TB) and extensively multidrug resistant \nstrains (XMDR-TB) are increasing and mortality \nfrom this hitherto treatable disease is on the increase.\nSo what is the way forward? Some authors (e.g. Chaudhary, \n2016) have advocated tackling the problem at the point of diagnosis and prescription suggesting that bacterial susceptibility testing should be mandatory before the \ndrug is dispensed. Unnecessary prescribing (e.g. for viral \ninfections), inadequate dosing, or inappropriate duration of treatment (which often leads to resistance) should all be scrupulously avoided and more rigorous adherence by \npatients to antibiotic regimes would help. Therapy using \nmultiple antibiotics acting through different mechanisms can be a useful strategy in some cases. Public health \nmeasures such as infection control procedures also play a \nkey role.\nPrescribers and consumers must also bear a responsibility \nfor the burgeoning problem of resistance. Indiscriminate \nuse of antibiotics in agriculture, human and veterinary medicine, and their use in animal foodstuffs, has undoubt -\nedly encouraged the spread of resistant strains. Most members of the general public have only a vague notion of the causes of the problem, its likely implications and \ntheir role in its development (McCullough et al., 2016). \nMore worryingly, many clinicians, whilst realising the scope of the problem also seem unaware of their crucial role in \nits spread (McCullough et al., 2015). Some governmental \nand regulatory bodies (e.g. the European Union) have devised political and social measures to curb such excesses, \nand these have been at least partly successful. Let us hope \nthat they continue to be so.permeability as a result of chromosomal mutations involving \nthe polysaccharide components of the outer membrane of \ngram-negative organisms may confer enhanced resistance to ampicillin. Mutations affecting envelope components \nhave been reported to affect the accumulation of amino -\nglycosides, \u03b2-lactams, chloramphenicol, peptide antibiotics \nand tetracycline.\nALTERATION \u2003OF \u2003ENZYME \u2003SELECTIVITY\nResistance to trimethoprim is the result of plasmid-directed synthesis of a dihydrofolate reductase with low or zero affinity \nfor trimethoprim. It is transferred by transduction and may be spread by transposons.\nSulfonamide resistance in many bacteria is plasmid-\nmediated and results from the production of a form of dihydropteroate synthetase with a low affinity for sulfonamides \nbut no change in affinity for PABA. Bacteria causing serious \ninfections and carrying plasmids with resistance genes to \nboth sulfonamides and trimethoprim have been reported.\nBiochemical mechanisms of \nresistance to antibiotics \nThe\tprincipal \tmechanisms \tare \tas \tfollows:\n\u2022\tProduction of enzymes that inactivate the drug : for \nexample, \u03b2-lactamases, \twhich", "start_char_idx": 0, "end_char_idx": 3537, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9bd9db61-eedf-4289-b996-18787e21cc6a": {"__data__": {"id_": "9bd9db61-eedf-4289-b996-18787e21cc6a", "embedding": null, "metadata": {"page_label": "665", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4c556122-bffe-4865-8fa1-530a8e5b00f6", "node_type": null, "metadata": {"page_label": "665", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "60ed55e4aeeb99b9b2387e4855d9f28682a8dbf3589d612e26a5b2fb14eac820"}, "2": {"node_id": "0f7b7808-aed9-427a-8fc7-33ee99afa9ac", "node_type": null, "metadata": {"page_label": "665", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bf8260ee30ecd0118325525ecd2bffbf09bb61e0fa2d300c3db6e879f3d4405d"}}, "hash": "2535f3b0b1aaa322fc838690e5464f67c85b0bf10333485f6adfe35b3d9a6d92", "text": "that inactivate the drug : for \nexample, \u03b2-lactamases, \twhich \tinactivate \tpenicillin; \nacetyltransferases, \twhich \tinactivate \tchloramphenicol; \nkinases\tand \tother \tenzymes, \twhich \tinactivate \t\naminoglycosides.\n\u2022\tAlteration of the drug-binding sites : this occurs with \naminoglycosides, erythromycin, penicillin.\n\u2022\tReduction of drug uptake by the bacterium : for \nexample, tetracyclines.\n\u2022\tAlteration of enzyme sensitivity : for example, \ndihydrofolate \treductase \tbecomes \tinsensitive \tto \t\ntrimethoprim.\nMultidrug resistance \nSome\tpathogenic \tbacteria \thave \tdeveloped \tresistance \tto \t\nmany or most commonly used antibiotics. Examples \ninclude the following:\n\u2022\tSome\tstrains \tof \tstaphylococci \tand \tenterococci \tthat \t\nare\tresistant \tto \tvirtually \tall \tcurrent \tantibiotics, \tthe \t\nresistance being transferred by transposons and/or plasmids; such organisms can cause serious and \nvirtually\tuntreatable \thospital-acquired \t(so-called \t\nnosocomial) infections.\n\u2022\tSome\tstrains \tof \tMycobacterium tuberculosis \tthat\thave \t\nbecome resistant to most antituberculosis agents.CURRENT STATUS OF ANTIBIOTIC \nRESISTANCE IN BACTERIA\nThe latest WHO assessment (2016) stresses that antibiotic \nresistance is now found in every country. Without effective \nantibiotics, many routine surgical procedures and other \nmedical interventions are impossible. Taking the United Kingdom and the United States together, deaths from \ninfection by resistant strains are in the region of 23,000\u201325,000 \nper annum, but in developing countries the mortality figures are at least double those numbers.\nIt also highlights the following cases as being of special \nsignificance:\n\u2022\tKlebsiella pneumoniae. Resistance of this organism to \n\u2018last resort\u2019 antibiotics such as carbapenem drugs has \nspread around the world and in many countries, treatment fails in about half of all cases.\n\u2022\tEscherichia coli. In many countries this organism has become resistant to fluoroquinolone antibiotics and again, treatment fails in about half of the patients in \nsome parts of the world.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3476, "end_char_idx": 5999, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "edd2db17-e93c-4430-9af2-7419ff9a22f1": {"__data__": {"id_": "edd2db17-e93c-4430-9af2-7419ff9a22f1", "embedding": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73d5a33c-cb52-45b9-aed5-d8aae20d0605", "node_type": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80dbdd460634ada22976233224fbcc65eb5c3cfdd2f3ce315d1b067d0eb24b0d"}, "3": {"node_id": "deba97d4-3a01-453b-a622-bc523ee0e4a8", "node_type": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4d0095bd4d338fd70aa008c0da1fec664d005136d24cab4d5402ae5e2c165c8"}}, "hash": "3422e55979feef6780a11fb059a769780b92f2a91fe7f6f0ddc4caef18185048", "text": "51 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n660REFERENCES AND FURTHER READING\nAmyes, S.G.B., 2001. Magic Bullets, Lost Horizons: The Rise and Fall of \nAntibiotics. Taylor & Francis, London. (Thought-provoking book by a \nbacteriologist with wide experience in bacterial resistance and genetics; he \nopines that unless the problem of antibiotic resistance is solved within 5 years, \u2018we are going to slip further into the abyss of uncontrollable infection\u2019 )\nArias, C.A., Murray, B.E., 2012. The rise of the Enterococcus: beyond \nvancomycin resistance. Nat. Rev. Microbiol. 10, 266\u2013278. (A comprehensive review dealing with many aspects of vancomycin resistance in \nenterococci and other species. Highly recommended)\nBarrett, C.T., Barrett, J.F., 2003. Antibacterials: are the new entries \nenough to deal with the emerging resistance problem? Curr. Opin. Biotechnol. 14, 621\u2013626. (Good general review with some compelling \nexamples and a round-up of new drug candidates)\nBax, R., Mullan, N., Verhoef, J., 2000. The millennium bugs \u2013 the need \nfor and development of new antibacterials. Int. J. Antimicrob. Agents 16, 51\u201359. (Excellent review of the problem of resistance and some potential new antibiotics)\nBhullar, K., Waglechner, N., Pawlowski, A., et al., 2012. Antibiotic \nresistance is prevalent in an isolated cave microbiome. PLoS ONE 7, e34953. (The extraordinary discovery of antibiotic resistant bacteria in caves \nwhich had been isolated since before hominids walked the earth has changed \nour understanding of the nature of this important mechanism. See also \nPawlowski et al. below )\nChaudhary, A.S., 2016. A review of global initiatives to fight antibiotic \nresistance and recent antibiotics discovery. Acta. Pharm. Sin. B 6, 552\u2013556. (Short but succinct account of the fight back against antibiotic resistance. Easy to read)\nCox, G., Wright, G.D., 2013. Intrinsic antibiotic resistance: mechanisms, \norigins, challenges and solutions. Int. J. Med. Microbiol. 303, 287\u2013292. (This paper reviews general mechanisms of bacterial resistance based upon \nthe notion that resistance is a naturally occurring defence in bacteria. \nRecommended)\nde Lencastre, H., Oliveira, D., Tomasz, A., 2007. Antibiotic resistant \nStaphylococcus aureus: a paradigm of adaptive power. Curr. Opin. Microbiol. 10, 428\u2013435. (A little specialised, but worth reading. It details the extraordinary ability of this organism to survive attack by virtually all \nthe drugs in our antibiotic arsenal)\nGiedraitiene, A., Vitkauskiene, A., Naginiene, R., Pavilonis, A., 2011. \nAntibiotic resistance mechanisms of clinically important bacteria. Medicina 47, 137\u2013146. (Good review of resistance mechanisms)\nHawkey, P.M., 1998. The origins and molecular basis of antibiotic \nresistance. Br. Med. J. 7159, 657\u2013659. (Succinct overview of resistance; useful, simple diagrams; this is one of 12 papers on resistance in this issue of \nthe journal)\nKnodler, L.A., Celli, J., Finlay, B.B., 2001. Pathogenic trickery: deception \nof host cell processes. Mol. Cell. Biol. 2, 578\u2013588. (Discusses bacterial ploys to subvert or block normal host cellular processes: mimicking the", "start_char_idx": 0, "end_char_idx": 3167, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "deba97d4-3a01-453b-a622-bc523ee0e4a8": {"__data__": {"id_": "deba97d4-3a01-453b-a622-bc523ee0e4a8", "embedding": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73d5a33c-cb52-45b9-aed5-d8aae20d0605", "node_type": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80dbdd460634ada22976233224fbcc65eb5c3cfdd2f3ce315d1b067d0eb24b0d"}, "2": {"node_id": "edd2db17-e93c-4430-9af2-7419ff9a22f1", "node_type": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3422e55979feef6780a11fb059a769780b92f2a91fe7f6f0ddc4caef18185048"}, "3": {"node_id": "a501cfd6-10e4-49e9-8191-ebee11be4abf", "node_type": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e8408ecdbe6026c7426137ce44b1dca5c8ec7e05f161198023f8d82bf935fe64"}}, "hash": "b4d0095bd4d338fd70aa008c0da1fec664d005136d24cab4d5402ae5e2c165c8", "text": "bacterial ploys to subvert or block normal host cellular processes: mimicking the ligands for host cell receptors or signalling pathways. Useful list of examples )\nLambert, P.A., 2005. Bacterial resistance to antibiotics: modified target \nsites. Adv. Drug Deliv. Rev. 57, 1471\u20131485. (Excellent review dealing with this important topic. Numerous examples drawn from studies with \nmany different bacterial species)\nLevy, S.B., 1998. The challenge of antibiotic resistance. Sci. Am. March, \n32\u201339. (Simple, clear review by an expert in the field; excellent diagrams)\nMcCullough, A.R., Rathbone, J., Parekh, S., Hoffmann, T.C., Del Mar, \nC.B., 2015. Not in my backyard: a systematic review of clinicians\u2019 \nknowledge and beliefs about antibiotic resistance. J. Antimicrob. \nChemother. 70, 2465\u20132473.\nMcCullough, A.R., Parekh, S., Rathbone, J., Del Mar, C.B., Hoffmann, \nT.C., 2016. A systematic review of the public\u2019s knowledge and beliefs about antibiotic resistance. J. Antimicrob. Chemother. 71, 27\u201333.\nNesme, J., Simonet, P., 2015. The soil resistome: a critical review on \nantibiotic resistance origins, ecology and dissemination potential in telluric bacteria. Environ. Microbiol. 17, 913\u2013930. (An excellent review which deals with the importance of soil dwelling bacteria as the source of \nresistance genes. Very informative and easy to read. Highly recommended)\nPawlowski, A.C., Wang, W., Koteva, K., Barton, H.A., McArthur, A.G., \nWright, G.D., 2016. A diverse intrinsic antibiotic resistome from a cave bacterium. Nat. Commun. 7, 13803. (Analyses the resistance genes in a particular bacterium isolated from deep caves and compares it with the \nsurface dwelling species, finding five novel resistance mechanisms. Read in \nconjunction with Bhullar et al. 2012, above )\nSandegren, L., Andersson, D.I., 2009. Bacterial gene amplification: \nimplications for the evolution of antibiotic resistance. Nat. Rev. \nMicrobiol. 7, 578\u2013588.\nShlaes, D.M., 2003. The abandonment of antibacterials: why and \nwherefore? Curr. Opin. Pharmacol. 3, 470\u2013473. (A good review that explains the reasons underlying the resistance problem and the regulatory and other hurdles that must be overcome before new antibacterials appear on \nto the market; almost apocalyptic in tone)\nSt Georgiev, V., 2000. Membrane transporters and antifungal drug \nresistance. Curr. Drug Targets 1, 184\u2013261. (Discusses various aspects of multidrug resistance in disease-causing fungi in the context of targeted drug \ndevelopment)\nVan Bambeke, F., Pages, J.M., Lee, V.J., 2006. Inhibitors of bacterial \nefflux pumps as adjuvants in antibiotic treatments and diagnostic tools for detection of resistance by efflux. Recent. Pat. Antiinfect. Drug Discov. 1, 157\u2013175.\nvan Belkum, A., 2000. Molecular epidemiology of methicillin-resistant \nStaphylococcus aureus strains: state of affairs and tomorrow\u2019s possibilities. Microb. Drug Resist. 6, 173\u2013187.\nVolpato, J.P., Pelletier, J.N., 2009. Mutational \u2018hot-spots\u2019 in mammalian, \nbacterial and protozoal dihydrofolate reductases associated with antifolate resistance: sequence and structural comparison. Drug", "start_char_idx": 3098, "end_char_idx": 6206, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a501cfd6-10e4-49e9-8191-ebee11be4abf": {"__data__": {"id_": "a501cfd6-10e4-49e9-8191-ebee11be4abf", "embedding": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73d5a33c-cb52-45b9-aed5-d8aae20d0605", "node_type": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80dbdd460634ada22976233224fbcc65eb5c3cfdd2f3ce315d1b067d0eb24b0d"}, "2": {"node_id": "deba97d4-3a01-453b-a622-bc523ee0e4a8", "node_type": null, "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4d0095bd4d338fd70aa008c0da1fec664d005136d24cab4d5402ae5e2c165c8"}}, "hash": "e8408ecdbe6026c7426137ce44b1dca5c8ec7e05f161198023f8d82bf935fe64", "text": "reductases associated with antifolate resistance: sequence and structural comparison. Drug Resist. \nUpdat. 12, 28\u201341.\nWalsh, C., 2000. Molecular mechanisms that confer antibacterial drug \nresistance. Nature 406, 775\u2013781. (Excellent review outlining the mechanisms of action of antibiotics and the resistance ploys of bacteria; very \ngood diagrams)\nWoodford, N., 2005. Biological counterstrike: antibiotic resistance \nmechanisms of Gram-positive cocci. Clin. Microbiol. Infect. 3, 2\u201321. ( A \nuseful reference that classifies antibiotic resistance as one of the major public health concerns of the 21st century and discusses drug treatment for \nresistant strains)\nWright, G.D., 2005. Bacterial resistance to antibiotics: enzymatic \ndegradation and modification. Adv. Drug Deliv. Rev. 57, 1451\u20131470. (This comprehensive review gives details of the many pathways that have \nevolved in bacteria to destroy antibiotics. A little complex, but fascinating reading)\nZasloff, M., 2002. Antimicrobial peptides of multicellular organisms. \nNature 415, 389\u2013395. (Thought-provoking article about the potent broad-spectrum antimicrobial peptides possessed by both animals and plants, \nwhich are used to fend off a wide range of microbes; it is suggested that \nexploiting these might be one answer to the problem of antibiotic resistance)\nUseful web resources\nThe Global Antibiotic Resistance Partnership (GARP) see https://\nwww.cddep.org/garp/home. (This, largely charity funded, organisation \ncomprises many national working groups that seek to understand antibiotic \nusage in countries around the world and make recommendations for sensible and sustainable usage based upon knowledge of local conditions)\nThe World Health Organisation (WHO) hosts web pages that deal \nwith the global problem of antibiotics and the regularly-updated Antibiotic Resistance Fact Sheet (see http://www.who.int/\nmediacentre/factsheets/fs194/en) contains definitive information on \nthe current situation around the world.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6186, "end_char_idx": 8651, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5e123bd4-0a1c-4f81-a5d7-7cde4863143c": {"__data__": {"id_": "5e123bd4-0a1c-4f81-a5d7-7cde4863143c", "embedding": null, "metadata": {"page_label": "667", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "136baecb-c566-41a3-86bd-fb9bd7b2f0d7", "node_type": null, "metadata": {"page_label": "667", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84d4022e57d92846b31ceaaf2a6350b4aab2c209d1acfa515e4db07ae0bb3058"}, "3": {"node_id": "df2dc1e5-e165-421b-95cf-f1645ac8e5d9", "node_type": null, "metadata": {"page_label": "667", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f6e082825c97746d61d294d5ca675d5f57aad4d937f12561325a12fbbbeb579c"}}, "hash": "0d83be56663c6700f45b27dff3b97ce96bc9bea7dd82071c0d56e8827f46a98b", "text": "661\nOVERVIEW\nIn this chapter we develop the ideas introduced in \nthe previous chapter. A detailed discussion of bacteriol -\nogy is beyond the scope of this book, but information about some clinically significant pathogens is included to provide necessary context. The major classes of \nantibacterial\n1 drugs are described, along with their \nmechanism of action, relevant pharmacokinetic proper -\nties and adverse effects. We conclude with an overview \nof new directions in research in this vital area.\nINTRODUCTION\nIn 1928, Alexander Fleming, working at St Mary\u2019s Hospital \nin London, discovered that a culture plate on which \nstaphylococci were being grown had become contaminated \nwith a mould of the genus Penicillium . He made the crucial \nobservation that bacterial growth in the vicinity of the mould \nhad been inhibited. He subsequently isolated the mould \nin pure culture and demonstrated that it produced an antibacterial substance, which he called penicillin. This \nsubstance was subsequently prepared in bulk, extracted and its antibacterial effects analysed by Florey, Chain and their colleagues at Oxford in 1940. Their experiment showed that it was non-toxic to the host but killed the pathogens \nin infected mice, and thus ushered in the \u2018antibiotic era\u2019. \nSince then, many new types of antibiotics have been dis -\ncovered and the practice of medicine would be unthinkable \nwithout them.\nGram staining and bacterial cell wall structure\nMost bacteria are classified as being either gram-positive or \ngram-negative , depending on whether they stain with Gram \nstain . This reflects fundamental differences in the structure \nof their cell walls and has important implications for the \naction of antibiotics.\nThe cell wall of gram-positive organisms is a relatively \nsimple structure. It is some 15\u201350 nm thick and comprises \nabout 50% peptidoglycan (see Ch. 51), 40%\u201345% acidic polymer together with 5%\u201310% proteins and polysaccha -\nrides. The cell surface is highly polar and negatively charged and this influences the penetration of some antibiotics.\nThe cell wall of gram-negative organisms is much more \ncomplex. From the plasma membrane outwards, it consists of the following:\u2022\tA\tperiplasmic space containing enzymes and other \ncomponents.\n\u2022\tA\tpeptidoglycan layer 2 nm in thickness, forming 5% of \nthe cell wall mass, which is often linked to outwardly projecting lipoprotein molecules.\n\u2022\tAn\touter membrane consisting of a lipid bilayer, similar \nin some respects to the plasma membrane, that \ncontains protein molecules and (on its inner aspect) \nlipoproteins linked to the peptidoglycan. Other proteins form transmembrane water-filled channels, \ntermed porins, through which some hydrophilic \nantibiotics can move freely (see also Ch. 9).\n\u2022\tComplex polysaccharides forming important components of the outer surface. These differ between strains of \nbacteria and are the main determinants of their antigenicity. They are also the source of endotoxin, a lipopolysaccharide which, when shed in vivo, triggers \nvarious aspects of the inflammatory reaction by \nactivating complement and cytokines, causing fever, etc. (see Ch. 7).\nDifficulty in penetrating this complex outer layer explains why some antibiotics are less active against gram-negative than gram-positive bacteria. It is also one reason for the \nextraordinary antibiotic resistance exhibited by Pseudomonas \naeruginosa, a pathogen that can cause life-threatening infec -\ntions in neutropenic patients and those with burns and wounds, as well as chronic bronchial infection in patients \nwith cystic fibrosis. The cell wall lipopolysaccharide is also a major barrier to penetration of some antibiotics, including \nbenzylpenicillin, meticillin,", "start_char_idx": 0, "end_char_idx": 3722, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "df2dc1e5-e165-421b-95cf-f1645ac8e5d9": {"__data__": {"id_": "df2dc1e5-e165-421b-95cf-f1645ac8e5d9", "embedding": null, "metadata": {"page_label": "667", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "136baecb-c566-41a3-86bd-fb9bd7b2f0d7", "node_type": null, "metadata": {"page_label": "667", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "84d4022e57d92846b31ceaaf2a6350b4aab2c209d1acfa515e4db07ae0bb3058"}, "2": {"node_id": "5e123bd4-0a1c-4f81-a5d7-7cde4863143c", "node_type": null, "metadata": {"page_label": "667", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0d83be56663c6700f45b27dff3b97ce96bc9bea7dd82071c0d56e8827f46a98b"}}, "hash": "f6e082825c97746d61d294d5ca675d5f57aad4d937f12561325a12fbbbeb579c", "text": "of some antibiotics, including \nbenzylpenicillin, meticillin, the macrolides, rifampicin, \nfusidic acid and vancomycin.\nAntibiotics that interfere with bacterial cell wall synthesis \n(e.g. penicillins) or inhibit crucial enzymes (such as the \nquinolones) generally kill bacteria (i.e. they are bactericidal ), \nwhile those that inhibit protein synthesis, such as the tet-racyclines, tend to be bacteriostatic, that is they prevent \ngrowth and replication. The distinction is not, however, clinically relevant, as the outcome depends critically on the host response in dealing with compromised bacterial \npopulations.\nIn discussing the pharmacology of antibacterial drugs, \nit is convenient to divide them into different groups based upon their mechanism of action.\nANTIBACTERIAL AGENTS THAT INTERFERE \nWITH FOLATE SYNTHESIS OR ACTION\nSULFONAMIDES\nIn a landmark discovery in the 1930s, prior to the advent \nof penicillin, Domagk demonstrated that it was possible Antibacterial drugs 52 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER SECTION 5\n1Strictly speaking, the term \u2018antibiotic\u2019 only applies to antibacterials that \nare produced by one organism to kill others (e.g. penicillin) in contrast \nto synthetic compounds such as the sulfonamides. In practice, however, \nthis distinction is often ignored as many antibacterial drugs are \u2018semi-synthetic\u2019 (e.g. flucloxacillin).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3661, "end_char_idx": 5520, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "472a59da-4db7-4def-905c-61d4626e1ec6": {"__data__": {"id_": "472a59da-4db7-4def-905c-61d4626e1ec6", "embedding": null, "metadata": {"page_label": "668", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3adc6ca8-f998-4c22-9283-360037d88142", "node_type": null, "metadata": {"page_label": "668", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2a68def0c640fce81abee54d393da5c8a4be7cd2593160e6a018eb6777dd9c87"}, "3": {"node_id": "98349972-ecad-4cd1-982f-f861acf224ca", "node_type": null, "metadata": {"page_label": "668", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b0c0324673f31895be9d11741d75ad7e6fbc76d6ac90e023b28f6c74e6b1ef1"}}, "hash": "32378cdc5789753719a5e2de5366e214445f02a7a01a22b9bf4a1024d1ef4678", "text": "52 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n662in the synthesis of folic acid, required for the synthesis \nof DNA and RNA in bacteria (see Ch. 51). Sulfonamides \ncompete with PABA for the enzyme dihydropteroate \nsynthetase, and the effect of the sulfonamide may be \novercome by adding excess PABA. This is why some local \nanaesthetics, which are PABA esters (such as procaine; \nsee Ch. 44), can antagonise the antibacterial effect of these \nagents.\nSulfonamide action is vitiated in the presence of pus or \nproducts of tissue breakdown, because these contain \nthymidine and purines, which bacteria utilise directly, bypassing the requirement for folic acid. Resistance, which \nis common, is plasmid-mediated (see Ch. 51) and results \nfrom the synthesis of a bacterial enzyme insensitive to the drugs.\n\u25bc Pharmacokinetic aspects. Most sulfonamides can be given orally \nand, apart from sulfasalazine, are well absorbed and widely distributed \nin the body. There is a risk of sensitisation or allergic reactions when \nthese drugs are given topically. The drugs pass into inflammatory exudates and cross both placental and blood\u2013brain barriers. They are \nmetabolised mainly in the liver, the major product being an acetylated \nderivative that lacks antibacterial action.\nUnwanted effects. Serious adverse effects necessitating cessation of \ntherapy include hepatitis, hypersensitivity reactions (rashes including Stevens\u2013Johnson syndrome and toxic epidermal necrolysis, fever, \nanaphylactoid reactions \u2013 see Ch. 58), bone marrow depression and \nacute renal failure due to interstitial nephritis or crystalluria. This last effect results from the precipitation of acetylated metabolites in \nthe urine (Ch. 30). Cyanosis caused by methaemoglobinaemia may \noccur, but is a lot less alarming than it looks. Mild to moderate side effects include nausea and vomiting, headache and mental \ndepression.\nTRIMETHOPRIM\nMechanism of action\nTrimethoprim is chemically related to the antimalarial drug \npyrimethamine (Ch. 55), both being folate antagonists. \nStructurally (see Fig. 52.1), it resembles the pteridine moiety \nof folate and the similarity is close enough to fool the bacterial dihydrofolate reductase, which is many times more \nsensitive to trimethoprim than is the equivalent enzyme \nin humans.\nTrimethoprim is active against most common bacterial \npathogens as well as protozoa, and is used to treat various urinary, pulmonary and other infections. It is sometimes given in combination with sulfamethoxazole as co-\ntrimoxazole (see Fig. 52.1). Because sulfonamides inhibit \na different stage on the same bacterial metabolic pathway, \nthey can potentiate the action of trimethoprim (Fig. 52.2). for a drug to suppress a bacterial infection. The drug was a dye called prontosil,\n2 which proved to be an inactive \nprodrug that was metabolised in vivo to an active product, \nsulfanilamide (Fig. 52.1). Many sulfonamides have been \ndeveloped since, but their importance has declined in the face of increasing resistance. The only sulfonamide drugs \nstill commonly used as systemic antibacterials are sulfameth -\noxazole (usually in combination with trimethoprim as \nco-trimoxazole ) and sulfasalazine (poorly absorbed in the \ngastrointestinal (GI) tract, used to treat ulcerative colitis \nand Crohn\u2019s disease; see Chs 27 and 31). Silver sulfadiazine \nis", "start_char_idx": 0, "end_char_idx": 3379, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "98349972-ecad-4cd1-982f-f861acf224ca": {"__data__": {"id_": "98349972-ecad-4cd1-982f-f861acf224ca", "embedding": null, "metadata": {"page_label": "668", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3adc6ca8-f998-4c22-9283-360037d88142", "node_type": null, "metadata": {"page_label": "668", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2a68def0c640fce81abee54d393da5c8a4be7cd2593160e6a018eb6777dd9c87"}, "2": {"node_id": "472a59da-4db7-4def-905c-61d4626e1ec6", "node_type": null, "metadata": {"page_label": "668", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "32378cdc5789753719a5e2de5366e214445f02a7a01a22b9bf4a1024d1ef4678"}}, "hash": "6b0c0324673f31895be9d11741d75ad7e6fbc76d6ac90e023b28f6c74e6b1ef1", "text": "disease; see Chs 27 and 31). Silver sulfadiazine \nis used topically, for example, to treat infected burns. Some drugs with quite different clinical uses (e.g. the antiplatelet \ndrug prasugrel , Ch. 25, and the carbonic anhydrase inhibitor \nacetazolamide, Ch. 30), are sulfonamides and share some \nof the off-target adverse effects of this class.\nMechanism of action\nSulfanilamide is a structural analogue of p-aminobenzoic \nacid (PABA; see Fig. 52.1), which is an essential precursor NCH2 CO\nNH NH CHCOOH\n(CH2)2COOH\nSO2NH2 H2NS O2NH H2NN\nN\nCH2OCH3\nOCH3OCH3Pteridine ring p-Aminobenzoic\nacid (PABA)Glutamic acid\nFolic acid\nSulfanilamide\nTrimethoprim (dihydrofolate reductase inhibitor)Sulfadiazine\nNH2N\nOHNNH2N\nNH2N N\nFig. 52.1 Structures of two representative sulfonamides \nand trimethoprim. The structures illustrate the relationship \nbetween the sulfonamides and the p-aminobenzoic acid moiety \nin folic acid (orange box), as well as between the antifolate \ndrugs and the pteridine moiety (orange). Co-trimoxazole is a \nmixture of sulfamethoxazole and trimethoprim. Clinical uses of sulfonamides \n\u2022\tCombined \twith \ttrimethoprim (co-trimoxazole) for \nPneumocystis carinii (now known as P. jirovecii), for \ntoxoplasmosis and nocardiasis.\n\u2022\tCombined \twith \tpyrimethamine for drug-resistant \nmalaria (Table 55.1) and for toxoplasmosis.\n\u2022\tIn\tinflammatory \tbowel \tdisease: \tsulfasalazine \n(sulfapyridine\u2013aminosalicylate combination) is used (see \nCh. 31).\n\u2022\tFor\tinfected \tburns \t(silver \tsulfadiazine) \tgiven\ttopically\n2Domagk believed, wrongly, that the staining property of azo dyes, \nsuch as prontosil, was responsible for their antibacterial selectivity. He \nused prontosil \u2013 a red dye \u2013 to treat his young daughter for a life-\nthreatening streptococcal infection. She survived, but was left with permanently red-stained skin \u2013 testament to its lack of selectivity for the \ninvading bacteria.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3326, "end_char_idx": 5700, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b36f3c58-70ef-4e57-a9e4-bbcaeca1de3b": {"__data__": {"id_": "b36f3c58-70ef-4e57-a9e4-bbcaeca1de3b", "embedding": null, "metadata": {"page_label": "669", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6374004c-8a86-4b16-b370-33289c90f13f", "node_type": null, "metadata": {"page_label": "669", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6a56092c44628762870889baf102870ddeda0ab455e02a3a7b3dc1760abc2e9"}, "3": {"node_id": "f85999df-885d-4a7c-af6c-f8d40abb6d11", "node_type": null, "metadata": {"page_label": "669", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4ecbf58bb146b14fb98af18bb909628b55e7cdd64153c9e1da9298becee89f64"}}, "hash": "6ac6781fff6d40e53222528e7bdf510d0569ba6078fc5fb31fcdb613a01defb0", "text": "52 ANTIbACTERIA l DRUGS\n663\u03b2-LACTAM ANTIBIOTICS AND OTHER \nAGENTS THAT INTERFERE WITH \nBACTERIAL WALL OR MEMBRANE \nSYNTHESIS\nPENICILLINS\nThe remarkable antibacterial effects of systemic penicillin \nin humans were clearly demonstrated in 1941.3 A small \namount of penicillin, extracted laboriously from crude \ncultures in the laboratories of the Dunn School of Pathology \nin Oxford, was given to a desperately ill policeman with septicaemia and multiple abscesses. Although sulfonamides \nwere available, they would have had no effect in the pres -\nence of pus. Intravenous injections of penicillin were given \nevery 3 h. All of the patient\u2019s urine was collected, and each \nday the bulk of the excreted penicillin was extracted and \nreused. After 5 days, the patient\u2019s condition was vastly \nimproved, and there was obvious resolution of the abscesses. \nFurthermore, there seemed to be no toxic effects of the drug. Unfortunately, when the supply of penicillin was \nfinally exhausted his condition gradually deteriorated and \nhe died a month later.\nPenicillins, often combined with other antibiotics, remain \ncrucially important in antibacterial chemotherapy, but regrettably they are destroyed by bacterial amidases and \n\u03b2-lactamases (penicillinases; Fig. 52.3). This forms the basis of one of the principal types of antibiotic resistance.\nMechanisms of action\nAll \u03b2-lactam antibiotics interfere with the synthesis of the \nbacterial cell wall peptidoglycan (see Ch. 51, Fig. 51.3). After \nattachment to penicillin-binding proteins on bacteria (there may \nbe seven or more types in different organisms), they inhibit \nthe transpeptidation enzyme that cross-links the peptide \nchains attached to the backbone of the peptidoglycan.\nThe final bactericidal event is the inactivation of an \ninhibitor of autolytic enzymes in the cell wall, leading to lysis of the bacterium. Some organisms, referred to as \n\u2018tolerant\u2019, have defective autolytic enzymes in which case lysis does not occur in response to the drug. Resistance to penicillin may result from a number of different causes \nand is discussed in detail in Chapter 51.\nTypes of penicillin and their antimicrobial activity\nThe first penicillins were the naturally occurring benzylpeni -\ncillin (penicillin G ) and its congeners, including phenoxy -\nmethylpenicillin (penicillin V). Benzylpenicillin is active against a wide range of organisms and is the drug of first \nchoice for many infections (see clinical box). Its main \ndrawbacks are poor absorption in the GI tract (which means \nit must be given by injection) and its susceptibility to bacte -\nrial \u03b2-lactamases.\nSemisynthetic penicillins , incorporating different side-chains \nattached to the penicillin nucleus (at R\n1 in Fig. 52.3), include \n\u03b2-lactamase-resistant penicillins (e.g. meticillin ,4 flucloxacillin , In the United Kingdom, the use of co-trimoxazole is gener -\nally restricted to the treatment of Pneumocystis carinii (now \nknown as P. jirovecii ) pneumonia (a fungal infection), toxo -\nplasmosis (a protozoan infection) or nocardiasis (a bacterial infection).\n\u25bc Pharmacokinetic aspects. Trimethoprim is well absorbed orally, \nand widely distributed throughout the tissues and body fluids. It \nreaches high concentrations in the lungs and kidneys, and fairly high \nconcentrations in the cerebrospinal fluid (CSF). When given with \nsulfamethoxazole,", "start_char_idx": 0, "end_char_idx": 3373, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f85999df-885d-4a7c-af6c-f8d40abb6d11": {"__data__": {"id_": "f85999df-885d-4a7c-af6c-f8d40abb6d11", "embedding": null, "metadata": {"page_label": "669", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6374004c-8a86-4b16-b370-33289c90f13f", "node_type": null, "metadata": {"page_label": "669", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d6a56092c44628762870889baf102870ddeda0ab455e02a3a7b3dc1760abc2e9"}, "2": {"node_id": "b36f3c58-70ef-4e57-a9e4-bbcaeca1de3b", "node_type": null, "metadata": {"page_label": "669", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6ac6781fff6d40e53222528e7bdf510d0569ba6078fc5fb31fcdb613a01defb0"}}, "hash": "4ecbf58bb146b14fb98af18bb909628b55e7cdd64153c9e1da9298becee89f64", "text": "fluid (CSF). When given with \nsulfamethoxazole, about half the dose of each is excreted within 24 h. \nBecause trimethoprim is a weak base, its elimination by the kidney increases with decreasing urinary pH.\nUnwanted effects. Folate deficiency, with resultant megaloblastic \nanaemia (see Ch. 26) can be caused by long-term administration of trimethoprim. Other unwanted effects include nausea, vomiting, blood \ndisorders and rashes.PABA\nFolateDihydropteroate\nsynthetase\nDihydrofolate\nreductase\nTetrahydrofolate\nSynthesis of\nthymidylate etc.\nDNASulfonamides\nTrimethoprim\nFig. 52.2 The action of sulfonamides and trimethoprim on \nbacterial folate synthesis. See Chapter 26 for more detail of \ntetrahydrofolate synthesis, and Table 51.1 for comparisons of \nantifolate drugs. PABA, p-aminobenzoic acid. \n3Although topical penicillin had actually been used with success in five \npatients with eye infections 10 years previously by Paine, a graduate of \nSt Mary\u2019s who had obtained some penicillin mould from Fleming.\n4Meticillin (previous name: methicillin) was the first \u03b2-lactamase-\nresistant penicillin. It is not now used clinically because it was associated with interstitial nephritis, but is remembered in the acronym \n\u2018MRSA\u2019 \u2013 meticillin-resistant Staphylococcus aureus, which are resistant to other \u03b2-lactamase-resistant penicillins as well as meticillin.Antimicrobial agents that interfere \nwith the synthesis or action \nof folate \n\u2022\tSulfonamides \tare \tbacteriostatic; \tthey \tact \tby \tinterfering \t\nwith folate synthesis and thus with nucleotide \nsynthesis. Unwanted effects include crystalluria and hypersensitivities.\n\u2022\tTrimethoprim\n\tis\tbacteriostatic. \tIt \tacts \tby \tantagonising \t\nfolate.\n\u2022\tCo-trimoxazole is a mixture of trimethoprim with \nsulfamethoxazole, which affects bacterial nucleotide \nsynthesis at two points in the pathway.\n\u2022\tPyrimethamine and proguanil are also antimalarial \nagents (see Ch. 55).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3326, "end_char_idx": 5724, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dbd15765-a0bb-42fe-84b0-34cd41fc352c": {"__data__": {"id_": "dbd15765-a0bb-42fe-84b0-34cd41fc352c", "embedding": null, "metadata": {"page_label": "670", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c178c693-0687-4790-baf6-145b3074f427", "node_type": null, "metadata": {"page_label": "670", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a8ad036fd59edfec5b7e69fbd22492748f557abdbfde7be0b9a3ce0bc94bdd5"}, "3": {"node_id": "bb166b83-783a-4b65-8dcc-bf3883a830b8", "node_type": null, "metadata": {"page_label": "670", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4e88a747b6b0f02602ac5cd316dc4263952a1bb4a5638840fbb7fed71b94b8e1"}}, "hash": "521106028668b60aa48ce59db96bd5eec13d3213e30f6b291cfa86e551a7b99e", "text": "52 SECTION 5 \u2003\u2003DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n664CHOH\nCOOHS R3H3C NB\nO\nCarbapenem nucleus\n(high resistance to \u03b2-lactamases)NCO\nR1H\nSO3HCH3\nNB\nO\nMonobactam nucleus\n(\u03b2-lactamase resistant)NCO\nR1H\nCOOHCH2 R2NB A\nO\nCephalosporin nucleusS\n\u03b2-Lactamase\nCOOHCH CH2OHNB\nO\nClavulanic acid\n(inhibits many \u03b2-lactamases) ONCO\nR1H\nCOOHCH3CH3\nNB A\nO\nPenicillin nucleusS\n\u03b2-LactamaseAmidase\nFig. 52.3 Basic structures of four \ngroups of \u03b2-lactam antibiotics and \nclavulanic acid. The structures illustrate \nthe \u03b2-lactam ring (marked B ;\toutlined\tin \norange) and the sites of action of bacterial \nenzymes\tthat\tinactivate\t these\tantibiotics\t\n(A, thiazolidine ring). Various substituents \nare added at R 1, R 2 and R 3 to produce \nagents\twith\tdifferent\tproperties.\t In\t\ncarbapenems, the stereochemical \nconfiguration of the part of the \u03b2-lactam \nring shown shaded in orange here is \ndifferent from the corresponding part of \nthe\tpenicillin\tand\tcephalosporin\t molecules;\t\nthis is probably the basis of the \n\u03b2-lactamase resistance of the \ncarbapenems. The \u03b2-lactam ring of \nclavulanic\t acid\tis\tthought\tto\tbind\tstrongly\t\nto \u03b2-lactamase, meanwhile protecting \nother \u03b2-lactams from the enzyme. \nClinical uses of the penicillins \n\u2022\tPenicillins\t are\tgiven\tby\tmouth\tor,\tin\tmore\tsevere\t\ninfections,\t intravenously,\t and\toften\tin\tcombination\t with\t\nother antibiotics.\n\u2022\tUses\tare\tfor\tsensitive\torganisms\t and\tmay\t(but\tmay\tnot:\t\nindividual\t sensitivity\t testing\tis\toften\tappropriate\t\ndepending\t on\tlocal\tconditions)\t include:\n\u2013 bacterial meningitis (e.g. caused by Neisseria \nmeningitidis , Streptococcus pneumoniae ):\t\nbenzylpenicillin ,\thigh\tdoses\tintravenously;\n\u2013 bone and joint infections (e.g. with Staphylococcus \naureus):\tflucloxacillin ;\n\u2013 skin and soft tissue infections (e.g. with Streptococcus \npyogenes or S. aureus):\tbenzylpenicillin , \nflucloxacillin ;\tanimal\tbites:\t co-amoxiclav ;\n\u2013 pharyngitis (from S. pyogenes ):\t\nphenoxymethylpenicillin ;\n\u2013 otitis media (organisms commonly include S. \npyogenes , Haemophilus influenzae ):\tamoxicillin ;\u2013 bronchitis \t(mixed\tinfections\t common):\t amoxicillin ;\n\u2013 pneumonia :\tamoxicillin ;\n\u2013 urinary tract infections (e.g. with Escherichia coli ):\t\namoxicillin\n\u2013 gonorrhoea :\tamoxicillin (plus probenecid );\n\u2013 syphilis:\tprocaine benzylpenicillin ;\n\u2013 endocarditis (e.g. with Streptococcus viridans or \nEnterococcus faecalis ):\thigh-dose\t intravenous\t\nbenzylpenicillin \tsometimes\t with\tan\taminoglycoside;\n\u2013 serious infections with Pseudomonas aeruginosa :\t\nticarcillin , piperacillin .\nThis\tlist\tis\tnot\texhaustive.\t Treatment\t with\tpenicillins\t", "start_char_idx": 0, "end_char_idx": 2600, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bb166b83-783a-4b65-8dcc-bf3883a830b8": {"__data__": {"id_": "bb166b83-783a-4b65-8dcc-bf3883a830b8", "embedding": null, "metadata": {"page_label": "670", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c178c693-0687-4790-baf6-145b3074f427", "node_type": null, "metadata": {"page_label": "670", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6a8ad036fd59edfec5b7e69fbd22492748f557abdbfde7be0b9a3ce0bc94bdd5"}, "2": {"node_id": "dbd15765-a0bb-42fe-84b0-34cd41fc352c", "node_type": null, "metadata": {"page_label": "670", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "521106028668b60aa48ce59db96bd5eec13d3213e30f6b291cfa86e551a7b99e"}}, "hash": "4e88a747b6b0f02602ac5cd316dc4263952a1bb4a5638840fbb7fed71b94b8e1", "text": "Treatment\t with\tpenicillins\t is\t\nsometimes\t started\tempirically,\t if\tthe\tlikely\tcausative\t\norganism is one thought to be susceptible to penicillin, \nwhile awaiting the results of laboratory tests to identify the \norganism and determine its antibiotic susceptibility.\ntemocillin ) and broad-spectrum penicillins (e.g. ampicillin , \namoxicillin ). Extended-spectrum penicillins (e.g. ticarcillin , \npiperacillin ) with activity against Pseudomonas have gone \nsome way to overcoming the problem of serious infec -\ntions caused by P. aeruginosa . Amoxicillin and ticarcillin \nare sometimes given in combination with the \u03b2-lactamase \ninhibitor clavulanic acid (e.g. co-amoxiclav ). Pivmecillinam is a prodrug of mecillinam , which also has a wide spectrum \nof action.\n\u25bc Pharmacokinetic aspects. Oral absorption of penicillins varies, \ndepending on their stability in acid and their adsorption to foodstuffs \nin the gut. Penicillins can also be given by intravenous injection. \nPreparations for intramuscular injection are also available, including \nslow-release preparations such as benzathine benzylpenicillin which mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2572, "end_char_idx": 4169, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b84dcf5f-5023-4ca1-b61f-8d0c409d653e": {"__data__": {"id_": "b84dcf5f-5023-4ca1-b61f-8d0c409d653e", "embedding": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "31cafe9e-210a-49b5-befe-867aae8e02b7", "node_type": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "273602d1b9070e26e4c82b5fc904ef0dbfe234fae4f8fe8ce5fa04f8b281a287"}, "3": {"node_id": "31e83e60-ce3b-45d9-a688-baadd2b8bd57", "node_type": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8248c6aaea90793338ff683395f32e01ce8264a0439dc53d5bbc0a917e0ebe88"}}, "hash": "a98b800e583da320eed50fc63294b447a615276a7359956c853ec2fa54cb0bcd", "text": "52 ANTIbACTERIA l DRUGS\n665OTHER \u03b2-LACTAM ANTIBIOTICS\nCarbapenems and monobactams (see Fig. 52.3) were \ndeveloped to deal with \u03b2-lactamase-producing gram-\nnegative organisms resistant to penicillins.\nCARBAPENEMS\nImipenem, an example of a carbapenem, acts in the same way as the other \u03b2-lactams (see Fig. 52.3). It has a very \nbroad spectrum of antimicrobial activity, being active against many aerobic and anaerobic gram-positive and gram-negative organisms. However, many of the \u2018meticillin-\nresistant\u2019 staphylococci are less susceptible, and resistant \nstrains of P. aeruginosa have emerged during therapy. Resistance to imipenem was initially low, but is increasing \nas some organisms now have chromosomal genes that code \nfor imipenem-hydrolysing \u03b2-lactamases. The drug is sometimes given together with cilastatin, which inhibits \nits inactivation by renal enzymes. Meropenem is similar \nbut is not metabolised by the kidney. Ertapenem has a \nbroad spectrum of antibacterial actions but is licensed only for a limited range of indications. Most carbapenems are \nnot orally active, and are used only in special situations.\n\u25bc Unwanted effects are generally similar to those seen with other \n\u03b2-lactams, nausea and vomiting being the most frequently seen. \nNeurotoxicity can occur with high plasma concentrations.\nMONOBACTAMS\nThe main monobactam is aztreonam (see Fig. 52.3), which \nis resistant to most \u03b2-lactamases. It is given by injection \nand has a plasma half-life of 2 h. Aztreonam has an unusual \nspectrum of activity and is effective only against gram-\nnegative aerobic bacilli such as pseudomonas species, \nNeisseria meningitidis and Haemophilus influenzae. It has no \naction against gram-positive organisms or anaerobes.\n\u25bc Unwanted effects are, in general, similar to those of other \u03b2-lactam \nantibiotics, but this agent does not necessarily cross-react immunologi -\ncally with penicillin and its products, and does not usually cause \nallergic reactions in penicillin-sensitive individuals.\nOTHER ANTIBIOTICS THAT INHIBIT BACTERIAL \nCELL WALL PEPTIDOGLYCAN SYNTHESIS\nGLYCOPEPTIDES\nVancomycin is a glycopeptide antibiotic, and teicoplanin \nis similar but longer lasting. Vancomycin inhibits cell wall is useful for treating syphilis since Treponema pallidum is a very slowly \ndividing organism. Intrathecal administration of benzylpenicillin (used \nhistorically to treat meningitis) is no longer used, as it can cause \nconvulsions.5\nThe penicillins are widely distributed in body fluids, passing into \njoints; into pleural and pericardial cavities; into bile, saliva and milk \nand across the placenta. Being lipid-insoluble, they do not enter \nmammalian cells, and cross the blood\u2013brain barrier only if the meninges are inflamed, in which case they may reach therapeutically effective \nconcentrations in the CSF.\nElimination of most penicillins occurs rapidly and is mainly renal, \n90% being through tubular secretion. The relatively short plasma \nhalf-life is a potential problem in the clinical use of benzylpenicillin, although because penicillin works by preventing cell wall synthesis \nin dividing organisms, intermittent rather than continuous exposure \nto the drug can be an advantage.\nUnwanted effects. Penicillins are relatively free from direct toxic effects \n(other than their proconvulsant effect when given intrathecally). The \nmain unwanted effects are hypersensitivity", "start_char_idx": 0, "end_char_idx": 3399, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "31e83e60-ce3b-45d9-a688-baadd2b8bd57": {"__data__": {"id_": "31e83e60-ce3b-45d9-a688-baadd2b8bd57", "embedding": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "31cafe9e-210a-49b5-befe-867aae8e02b7", "node_type": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "273602d1b9070e26e4c82b5fc904ef0dbfe234fae4f8fe8ce5fa04f8b281a287"}, "2": {"node_id": "b84dcf5f-5023-4ca1-b61f-8d0c409d653e", "node_type": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a98b800e583da320eed50fc63294b447a615276a7359956c853ec2fa54cb0bcd"}, "3": {"node_id": "a7f5a7d2-4d84-4bce-b47f-de9f634b7d74", "node_type": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cd5260a2bd3c1b3ea0fce688083760dea0b17304f253849fc646451161b054a5"}}, "hash": "8248c6aaea90793338ff683395f32e01ce8264a0439dc53d5bbc0a917e0ebe88", "text": "effect when given intrathecally). The \nmain unwanted effects are hypersensitivity reactions caused by the \ndegradation products of penicillin, which combine with host protein \nand become antigenic. Rashes and fever are common; a delayed type of serum sickness occurs infrequently. Much more serious is acute \nanaphylactic shock which, although rare, may be fatal. When given \norally, penicillins, particularly the broad-spectrum type, alter the bacterial flora in the gut. This can be associated with GI disturbances \nand in some cases with suprainfection by other, penicillin-insensitive, \nmicroorganisms leading to problems such as pseudomembranous colitis (caused by Clostridium difficile, see later).\nCEPHALOSPORINS AND CEPHAMYCINS\nCephalosporins and cephamycins are \u03b2-lactam antibiotics, \nfirst isolated from fungi. They all have the same mechanism \nof action as penicillins.\nSemisynthetic broad-spectrum cephalosporins have been \nproduced by addition, to the cephalosporin C nucleus, of different side-chains at R\n1 and/or R 2 (see Fig. 52.3). These \nagents are water soluble and relatively acid stable. They vary in susceptibility to \u03b2-lactamases. Many cephalosporins \nand cephamycins are now available for clinical use (see \nlist in Table 52.2). Resistance to this group of drugs has \nincreased because of plasmid-encoded or chromosomal \n\u03b2-lactamase. The latter is present in nearly all gram-negative \nbacteria and it is more active in hydrolysing cephalosporins \nthan penicillins. In several organisms a single mutation \ncan result in high-level constitutive production of this enzyme. Resistance also occurs when there is decreased penetration of the drug as a result of alterations to outer \nmembrane proteins, or mutations of the binding-site \nproteins.\n\u25bc Pharmacokinetic aspects. Some cephalosporins are given orally, \nbut most are given parenterally, intramuscularly (which may be \npainful) or intravenously. After absorption, they are widely distributed \nin the body and some, such as cefotaxime , cefuroxime and ceftriaxone , \ncross the blood\u2013brain barrier. Excretion is mostly via the kidney, \nlargely by tubular secretion, but 40% of ceftriaxone is eliminated in \nthe bile.\nUnwanted effects. Hypersensitivity reactions, very similar to those \nseen with penicillin, may occur, and there may be some cross-\nsensitivity; about 10% of penicillin-sensitive individuals will have \nallergic reactions to cephalosporins. Nephrotoxicity has been reported \n(especially with cefradine), as has drug-induced alcohol intolerance. Diarrhoea is common and can be due to C. difficile.\n5Indeed, penicillins applied topically to the cortex are used to induce \nconvulsions in an animal model of epilepsy (see Ch. 46 ).Clinical uses of the cephalosporins \nCephalosporins are used to treat infections caused by \nsensitive\torganisms. \tAs \twith \tother \tantibiotics, \tpatterns \tof \t\nsensitivity\tvary \tgeographically, \tand \ttreatment \tis \toften \t\nstarted empirically. Many different kinds of infection may \nbe\ttreated, \tincluding:\n\u2022\tsepticaemia (e.g. cefuroxime, cefotaxime)\n\u2022\tpneumonia caused by susceptible organisms\n\u2022\tmeningitis (e.g. ceftriaxone, cefotaxime)\n\u2022\tbiliary tract infection\n\u2022\turinary tract infection (especially in pregnancy or in \npatients\tunresponsive \tto \tother \tdrugs)\n\u2022\tsinusitis (e.g. cefadroxil)mebooksfree.net", "start_char_idx": 3328, "end_char_idx": 6656, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a7f5a7d2-4d84-4bce-b47f-de9f634b7d74": {"__data__": {"id_": "a7f5a7d2-4d84-4bce-b47f-de9f634b7d74", "embedding": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "31cafe9e-210a-49b5-befe-867aae8e02b7", "node_type": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "273602d1b9070e26e4c82b5fc904ef0dbfe234fae4f8fe8ce5fa04f8b281a287"}, "2": {"node_id": "31e83e60-ce3b-45d9-a688-baadd2b8bd57", "node_type": null, "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8248c6aaea90793338ff683395f32e01ce8264a0439dc53d5bbc0a917e0ebe88"}}, "hash": "cd5260a2bd3c1b3ea0fce688083760dea0b17304f253849fc646451161b054a5", "text": "(e.g. cefadroxil)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6696, "end_char_idx": 7192, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2b05c909-d809-4786-9846-e83bfb6181be": {"__data__": {"id_": "2b05c909-d809-4786-9846-e83bfb6181be", "embedding": null, "metadata": {"page_label": "672", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b7db9c1c-a464-466d-8f21-d9933ce4dcc6", "node_type": null, "metadata": {"page_label": "672", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "318e0ce1d57d925d3d2c6261303d233954168f8e2d1f80bb547eed1f766c95b2"}, "3": {"node_id": "f7dabf98-2661-49fb-a7e9-de259ecc4910", "node_type": null, "metadata": {"page_label": "672", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ad14b15effd2f5d0ab3436c22bc64215a59c50112217eda8e8b9bae8e150af9f"}}, "hash": "0aca0f3eb3279892e8f528f15997189a1bb761f7caeff09cbd2389b999a26c73", "text": "52 SECTION 5 \u2003\u2003DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n666synthesis (Ch. 51, Fig. 51.3). It is effective mainly against \ngram-positive bacteria. Vancomycin is not absorbed from \nthe gut and is only given by the oral route for treatment \nof GI infection with C. difficile .\nThe main clinical use of vancomycin is the treatment of \nmethicillin-resistant Staphylococcus aureus (MRSA). It is often \nthe drug of last resort for this condition, an alarming \nconsideration since vancomycin-resistant S. aureus , VRSA, \nhas emerged). It is also valuable in some other serious \ninfections including severe staphylococcal infections in \npatients allergic to both penicillins and cephalosporins.\n\u25bc Pharmacokinetic aspects . For systemic use, it is given intravenously \nand has a plasma half-life of about 8 h.\nUnwanted effects include fever, rashes and phlebitis at the infusion \nsite. Ototoxicity and nephrotoxicity can occur, and hypersensitivity \nreactions are occasionally seen.\nDaptomycin is a relatively new lipopeptide antibacterial \nwith a similar spectrum of actions to vancomycin. It is \nused, in combination with other drugs, for the treatment \nof MRSA. Telavancin (another lipopeptide) is also active \nagainst MRSA and has a longer duration of action than \nvancomycin.\nPOLYMIXINS\nThe polymixin antibiotics comprise polymixin B and \ncolistimethate . They have cationic detergent properties and \ndisrupt the bacterial outer cell membrane (Ch. 51). They \nhave a selective, rapidly bactericidal action on gram-negative \nbacilli, especially pseudomonads and coliform organisms.\n\u25bc Pharmacokinetic aspects. They are not absorbed from the GI tract. \nClinical use of these drugs is limited by their toxicity and is confined \nlargely to gut sterilisation and topical treatment of ear, eye or skin \ninfections caused by susceptible organisms.\nUnwanted effects may be serious and include neurotoxicity and \nnephrotoxicity.\nFosfomycin is a small organic molecule originally found \nin Streptomyces , which blocks peptidoglycan synthesis by \ninactivating a key enzyme Mur A . It has a good spectrum \nof activity but, currently, fairly limited use for the treatment \nof urinary tract infections.\nANTIMICROBIAL AGENTS AFFECTING \nBACTERIAL PROTEIN SYNTHESIS\nTETRACYCLINES\nThe tetracyclines are broad-spectrum antibiotics. The group \nincludes tetracycline , oxytetracycline , demeclocycline , \nlymecycline , doxycycline , minocycline and tigecycline .\nMechanism of action\nFollowing uptake into susceptible organisms by active \ntransport, tetracyclines act by inhibiting protein synthesis \n(see Ch. 51, Fig. 51.4). They are bacteriostatic.\nAntibacterial spectrum\nThe spectrum of antimicrobial activity of the tetracyclines \nis very wide and includes gram-positive and gram-negative \nbacteria, Mycoplasma , Rickettsia , Chlamydia spp., spirochaetes \nand some protozoa (e.g. amoebae). Minocycline is also \neffective against N. meningitidis and has been used to \neradicate this organism from the nasopharynx of carriers. \u03b2-Lactam antibiotics \nBactericidal because they inhibit peptidoglycan synthesis.\nPenicillins\n\u2022\tThe\tfirst\tchoice\tfor\tmany\tinfections.\n\u2022\tBenzylpenicillin :\n\u2013\tgiven\tby\tinjection,\tshort\thalf-life\tand\tis\tdestroyed\t", "start_char_idx": 0, "end_char_idx": 3234, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f7dabf98-2661-49fb-a7e9-de259ecc4910": {"__data__": {"id_": "f7dabf98-2661-49fb-a7e9-de259ecc4910", "embedding": null, "metadata": {"page_label": "672", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b7db9c1c-a464-466d-8f21-d9933ce4dcc6", "node_type": null, "metadata": {"page_label": "672", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "318e0ce1d57d925d3d2c6261303d233954168f8e2d1f80bb547eed1f766c95b2"}, "2": {"node_id": "2b05c909-d809-4786-9846-e83bfb6181be", "node_type": null, "metadata": {"page_label": "672", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0aca0f3eb3279892e8f528f15997189a1bb761f7caeff09cbd2389b999a26c73"}}, "hash": "ad14b15effd2f5d0ab3436c22bc64215a59c50112217eda8e8b9bae8e150af9f", "text": "by\t\n\u03b2-lactamases;\n\u2013\tspectrum:\t gram-positive\t and\tgram-negative\t cocci\t\nand\tsome\tgram-negative\t bacteria;\n\u2013 many staphylococci are now resistant.\n\u2022\t\u03b2-Lactamase-resistant penicillins (e.g. flucloxacillin ):\n\u2013\tgiven\torally;\n\u2013\tspectrum:\t as\tfor\tbenzylpenicillin;\n\u2013 many staphylococci are now resistant.\n\u2022\tBroad-spectrum\t penicillins\t (e.g.\t amoxicillin ):\n\u2013\tgiven\torally;\tthey\tare\tdestroyed\t by\t\u03b2-lactamases;\n\u2013\tspectrum:\t as\tfor\tbenzylpenicillin (although less \npotent);\tthey\tare\talso\tactive\tagainst\tgram-negative\t\nbacteria.\n\u2022\tExtended-spectrum\t penicillins\t (e.g.\t ticarcillin ):\n\u2013\tgiven\torally;\tthey\tare\tsusceptible\t to\t\u03b2-lactamases;\n\u2013\tspectrum:\t as\tfor\tbroad-spectrum\t penicillins;\t they\tare\t\nalso\tactive\tagainst\tpseudomonads.\n\u2022\tUnwanted\t effects\tof\tpenicillins:\t mainly\t\nhypersensitivities.\n\u2022\tA\tcombination\t of\tclavulanic acid plus amoxicillin or \nticarcillin \tis\teffective\tagainst\tmany\t \u03b2-lactamase-\nproducing organisms.\nCephalosporins and cephamycins\n\u2022\tSecond\t choice\tfor\tmany\tinfections.\n\u2022\tOral\tdrugs\t(e.g.\t cefaclor ) are used in urinary \ninfections.\n\u2022\tParenteral\t drugs\t(e.g.\t cefuroxime ,\twhich\tis\tactive\t\nagainst Staphococcus aureus , Haemophilus influenzae , \nEnterobacteriaceae).\n\u2022\tUnwanted\t effects:\tmainly\thypersensitivities.\nCarbapenems\n\u2022\tImipenem is a broad-spectrum antibiotic.\n\u2022\tImipenem\t is\tused\twith\t cilastin,\twhich\tprevents\tits\t\nbreakdown in the kidney.\nMonobactams\n\u2022\tAztreonam :\tactive\tonly\tagainst\tgram-negative\t aerobic\t\nbacteria and resistant to most \u03b2-lactamases.\nHowever, widespread resistance to these agents has \ndecreased their usefulness. This is transmitted mainly by \nplasmids and, because the genes controlling resistance to \ntetracyclines are closely associated with genes for resistance \nto other antibiotics, organisms may develop resistance to \nmany drugs simultaneously.\n\u25bc Pharmacokinetic aspects. The tetracyclines are generally given \norally but can also be administered parenterally. Minocycline and \ndoxycycline are well absorbed orally. The absorption of most other \ntetracyclines is irregular and incomplete but is improved in the absence \nof food. Because tetracyclines chelate metal ions (calcium, magnesium, \niron, aluminium), forming non-absorbable complexes, absorption \nis decreased in the presence of milk, certain antacids and iron \npreparations.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3235, "end_char_idx": 6018, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "10576276-575d-4f56-9db2-371ab39ab7e2": {"__data__": {"id_": "10576276-575d-4f56-9db2-371ab39ab7e2", "embedding": null, "metadata": {"page_label": "673", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54f273ea-09c8-4cf2-b70b-0ebb6d829493", "node_type": null, "metadata": {"page_label": "673", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c0fbfede1689aaa59c3ef9e45cf9c2dd27b7c028ce981c9c570d20a808fca267"}, "3": {"node_id": "92b651f1-113e-43a5-a8a7-67a18b2881af", "node_type": null, "metadata": {"page_label": "673", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c6eb04bc6173ec1b3f06fc392815d8f3b1cdf2c5005f89cb92d8cdd24ec4a3b6"}}, "hash": "cacd9669e0251a392c317533ffcb42466f8e896644dbb0dfe04d3056be77a9d5", "text": "52 ANTIbACTERIA l DRUGS\n667Antibacterial spectrum\nChloramphenicol has a wide spectrum of antimicrobial \nactivity, including gram-negative and gram-positive organ -\nisms and rickettsiae. It is bacteriostatic for most organisms but kills H. influenzae . Resistance, caused by the production \nof chloramphenicol acetyltransferase, is plasmid-mediated.\n\u25bc Pharmacokinetic aspects. Given orally, chloramphenicol is rapidly \nand completely absorbed and reaches its maximum concentration \nin the plasma within 2 h. It can also be given parenterally. The \ndrug is widely distributed throughout the tissues and body fluids \nincluding the CSF. Its half-life is approximately 2 h. About 10% is \nexcreted unchanged in the urine, and the remainder is inactivated in \nthe liver.\nUnwanted effects. The most important unwanted effect of chloram -\nphenicol is severe, idiosyncratic depression of the bone marrow, \nresulting in pancytopenia (a decrease in all blood cell elements) \u2013 an \neffect that, although rare, can occur even with low doses in some \nindividuals. Chloramphenicol must be used with great care in \nnewborns, with monitoring of plasma concentrations, because \ninadequate inactivation and excretion of the drug can result in the \u2018grey baby syndrome\u2019 \u2013 vomiting, diarrhoea, flaccidity, low temperature \nand an ashen-grey colour \u2013 which carries 40% mortality. Hypersensitiv -\nity reactions can occur, as can GI disturbances secondary to alteration \nof the intestinal microbial flora.\nAMINOGLYCOSIDES\nThe aminoglycosides are a group of antibiotics of complex \nchemical structure, resembling each other in antimicrobial \nactivity, pharmacokinetic characteristics and toxicity. The \nmain agents are gentamicin, streptomycin, amikacin, \ntobramycin and neomycin.\nMechanism of action\nAminoglycosides inhibit bacterial protein synthesis (see Ch. 51). There are several possible sites of action. Their \npenetration through the cell membrane of the bacterium \ndepends partly on oxygen-dependent active transport by a polyamine carrier system (which, incidentally, is blocked \nby chloramphenicol) and they have minimal action against \nanaerobic organisms. The effect of the aminoglycosides is bactericidal and is enhanced by agents that interfere with \ncell wall synthesis (e.g. penicillins).\nResistance\nResistance to aminoglycosides is becoming a problem. It \noccurs through several different mechanisms, the most \nimportant being inactivation by microbial enzymes, of which Unwanted effects. The commonest unwanted effects are GI disturbances \ncaused initially by direct irritation and later by modification of the \ngut flora. Vitamin B complex deficiency can occur, as can suprainfec -\ntion. Because they chelate Ca2+, tetracyclines are deposited in growing \nbones and teeth, causing staining and sometimes dental hypoplasia and bone deformities. They should therefore not be given to children, \npregnant women or nursing mothers. Another hazard to pregnant women is hepatotoxicity. Phototoxicity (sensitisation to sunlight) has \nalso been seen, particularly with demeclocycline. Minocycline can \nproduce vestibular disturbances (dizziness and nausea). High doses of tetracyclines can decrease protein synthesis in host cells, an anti-\nanabolic effect that may result in renal damage. Long-term therapy \ncan cause disturbances of the bone marrow.\nCHLORAMPHENICOL\nChloramphenicol was originally isolated from cultures of \nStreptomyces . It inhibits bacterial protein synthesis by binding \nto the 50S ribosomal subunit (see Ch. 51, Fig. 51.4).Miscellaneous antibacterial agents", "start_char_idx": 0, "end_char_idx": 3569, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "92b651f1-113e-43a5-a8a7-67a18b2881af": {"__data__": {"id_": "92b651f1-113e-43a5-a8a7-67a18b2881af", "embedding": null, "metadata": {"page_label": "673", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54f273ea-09c8-4cf2-b70b-0ebb6d829493", "node_type": null, "metadata": {"page_label": "673", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c0fbfede1689aaa59c3ef9e45cf9c2dd27b7c028ce981c9c570d20a808fca267"}, "2": {"node_id": "10576276-575d-4f56-9db2-371ab39ab7e2", "node_type": null, "metadata": {"page_label": "673", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cacd9669e0251a392c317533ffcb42466f8e896644dbb0dfe04d3056be77a9d5"}}, "hash": "c6eb04bc6173ec1b3f06fc392815d8f3b1cdf2c5005f89cb92d8cdd24ec4a3b6", "text": "subunit (see Ch. 51, Fig. 51.4).Miscellaneous antibacterial agents \nthat prevent cell wall or membrane \nsynthesis \n\u2022\tGlycopeptide antibiotics. Vancomycin is bactericidal, \nacting\tby\tinhibiting \tcell \twall \tsynthesis. \tIt \tis \tused \t\nintravenously \tfor \tmultiresistant \tstaphylococcal \t\ninfections and orally for pseudomembranous colitis. \nUnwanted effects include ototoxicity and nephrotoxicity.\n\u2022\tPolymixins (e.g. colistimethate). By disrupting \nbacterial cell membranes these are bactericidal. They are highly neurotoxic and nephrotoxic, and are only used topically.\nClinical uses of tetracyclines \n\u2022\tThe\tuse \tof \ttetracyclines \tdeclined \tbecause \tof \t\nwidespread drug resistance, but has staged a comeback, e.g. for respiratory infections, as resistance has receded with reduced use. Most members of the \ngroup\tare \tmicrobiologically \tsimilar; \tdoxycycline is \ngiven\tonce \tdaily \tand \tmay \tbe \tused \tin \tpatients \twith \t\nrenal impairment. Uses (sometimes in combination \nwith\tother \tantibiotics) \tinclude:\n\u2013 rickettsial and chlamydial infections, brucellosis, \nanthrax\tand \tLyme \tdisease;\n\u2013 as useful second choice, for example in patients \nwith\tallergies, \tfor \tseveral \tinfections \t(see \tTable \t52.1), \t\nincluding\tmycoplasma \tand \tleptospira;\n\u2013 respiratory tract infections (e.g. exacerbations of \nchronic\tbronchitis, \tcommunity-acquired \tpneumonia);\n\u2013\tacne;\n\u2013 inappropriate secretion of antidiuretic hormone (e.g. \nby some malignant lung tumours), causing \nhyponatraemia: \tdemeclocycline inhibits the action \nof this hormone by an entirely distinct action from its antibacterial effect (Ch. 34).Clinical uses of chloramphenicol \n\u2022\tSystemic \tuse \tshould \tbe \treserved \tfor \tserious \tinfections \t\nin which the benefit of the drug outweighs its uncommon but serious haematological toxicity. Such \nuses\tmay\tinclude:\n\u2013 infections caused by Haemophilus influenzae \nresistant\tto \tother \tdrugs;\n\u2013 meningitis in patients in whom penicillin cannot be used;\n\u2013 typhoid fever, but ciprofloxacin or amoxicillin and \nco-trimoxazole \tare\tsimilarly \teffective \tand \tless \t\ntoxic.\n\u2022\tTopical\tuse \tsafe \tand \teffective \tin \tbacterial \tconjunctivitis.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3503, "end_char_idx": 6118, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a47e287e-8685-4c12-9709-ad839f3bd85a": {"__data__": {"id_": "a47e287e-8685-4c12-9709-ad839f3bd85a", "embedding": null, "metadata": {"page_label": "674", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d83765ae-c8fa-4038-a9f2-82b4e1952e91", "node_type": null, "metadata": {"page_label": "674", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "785c24775c537f9110ede891c65f411bb3510716abc645572483473a0ad3cb26"}, "3": {"node_id": "aef7a8b0-6e0e-4df1-b78e-05b328b5ad5a", "node_type": null, "metadata": {"page_label": "674", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6abb3d2ffed69ee4c31c40b3201b55624990427690d98727098f81a0cbd60700"}}, "hash": "c5def1a7a6dc45230941591570f4bb1c34aa4d24222ca42388ee28954098ed02", "text": "52 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n668aeruginosa infections. Amikacin has the widest antimicrobial \nspectrum and can be effective in infections with organisms \nresistant to gentamicin and tobramycin.\n\u25bc Pharmacokinetic aspects. The aminoglycosides are polycations \nand therefore highly polar. They are not absorbed from the gastro -\nintestinal tract and are usually given intramuscularly or intravenously. \nThey cross the placenta but do not cross the blood\u2013brain barrier, although high concentrations can be attained in joint and pleural \nfluids. The plasma half-life is 2\u20133 h. Elimination is virtually entirely \nby glomerular filtration in the kidney, 50%\u201360% of a dose being \nexcreted unchanged within 24 h. If renal function is impaired, \naccumulation occurs rapidly, with a resultant increase in those toxic effects (such as ototoxicity and nephrotoxicity) that are dose related.\nUnwanted effects. Serious, dose-related toxic effects, which may \nincrease as treatment proceeds, can occur with the aminoglycosides, \nthe main hazards being ototoxicity and nephrotoxicity.nine or more are known. Amikacin was designed as a poor \nsubstrate for these enzymes, but some organisms can \ninactivate this agent as well. Resistance as a result of failure \nof penetration can be largely overcome by the concomitant use of penicillin and/or vancomycin, at the cost of an \nincreased risk of severe adverse effects.\nAntibacterial spectrum\nThe aminoglycosides are effective against many aerobic \ngram-negative and some gram-positive organisms. They \nare most widely used against gram-negative enteric organ -\nisms and in sepsis. They may be given together with a \npenicillin in streptococcal infections and those caused by \nListeria spp. and P. aeruginosa (Table 52.1). Gentamicin is \nthe aminoglycoside most commonly used, although \ntobramycin is the preferred member of this group for P. Table 52.1 Some clinically significant pathogenic bacteria\nGenus Morphology Species Disease\nGram-negative\nBordetella Cocci B. pertussis Whooping cough\nBrucella Curved rods B. abortus Brucellosis (cattle and humans)\nCampylobacter Spiral rods C. jejuni Food poisoning\nEscherichia Rods E. coli Septicaemia, wound infections, UTIs\nHaemophilus Rods H. influenzae Acute respiratory tract infection, meningitis\nHelicobacter Motile rods H. pylori Peptic ulcers, gastric cancer\nKlebsiella Capsulated rods K. pneumoniae Pneumonia, septicaemia\nLegionella Flagellated rods L. pneumophila Legionnaires\u2019 disease\nNeisseria Cocci, paired N. gonorrhoeae Gonorrhoea\nPseudomonas Flagellated rods P. aeruginosa Septicaemia, respiratory infections, UTIs\nRickettsiae Cocci or threads Several spp. Tick- and insect-borne infections\nSalmonella Motile rods S. typhimurium Food poisoning\nShigella Rods S. dysenteriae Bacillary dysentery\nYersinia Rods Y. pestis Bubonic plague\nVibrio Flagellated rods V. cholera Cholera\nGram-positiveBacillus Rods, chains B. anthrax Anthrax\nClostridium Rods C. tetani Tetanus\nCorynebacterium Rod C. diphtheria Diphtheria\nMycobacterium RodsM. tuberculosis Tuberculosis\nM. leprae Leprosy\nStaphylococcus Cocci,", "start_char_idx": 0, "end_char_idx": 3134, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "aef7a8b0-6e0e-4df1-b78e-05b328b5ad5a": {"__data__": {"id_": "aef7a8b0-6e0e-4df1-b78e-05b328b5ad5a", "embedding": null, "metadata": {"page_label": "674", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d83765ae-c8fa-4038-a9f2-82b4e1952e91", "node_type": null, "metadata": {"page_label": "674", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "785c24775c537f9110ede891c65f411bb3510716abc645572483473a0ad3cb26"}, "2": {"node_id": "a47e287e-8685-4c12-9709-ad839f3bd85a", "node_type": null, "metadata": {"page_label": "674", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c5def1a7a6dc45230941591570f4bb1c34aa4d24222ca42388ee28954098ed02"}}, "hash": "6abb3d2ffed69ee4c31c40b3201b55624990427690d98727098f81a0cbd60700", "text": "leprae Leprosy\nStaphylococcus Cocci, clusters S. aureus Wound infections, boils, septicaemia\nStreptococcusCocci, pairs S. pneumoniae Pneumonia, meningitis\nCocci, chains S. pyogenes Scarlet fever, rheumatic fever, cellulitis\nOtherChlamydia Gram \u2018uncertain\u2019 C. trachomatis Eye disease, infertility\nTreponema Flagellated spiral rods T. pallidum Syphilis\nUTI, urinary tract infection.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3098, "end_char_idx": 3957, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "48fb80c8-6203-409c-9b6c-87c13f0fe5b4": {"__data__": {"id_": "48fb80c8-6203-409c-9b6c-87c13f0fe5b4", "embedding": null, "metadata": {"page_label": "675", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a24d2522-4f8f-4729-a52b-a2cf8f13363a", "node_type": null, "metadata": {"page_label": "675", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e84092ad726a91a21138f98e0cd055d9cf50d4344d479112cf46a8227e35eb44"}, "3": {"node_id": "c1dfcf40-e0c6-44d6-aa91-b221c0f82793", "node_type": null, "metadata": {"page_label": "675", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a83769d82bd9dba58063c3d7eaba3232bc4ceb23c8b75c08afb01b495a64bcf4"}}, "hash": "11893bfa57c09abdf1e089bfef0563c5492bd2d0b0b776f5bf9c5d4cff2a8f29", "text": "52 ANTIbACTERIAl DRUGS\n669Table 52.2 A general overview of antibacterials and their mechanism of action.\nFamily Examples Typical target organism Cellular target\nSulfonamidesSulfadiazine, sulfamethoxazole (used together \nwith trimethoprim)T. gondii , P. jiroveciiBacterial folate \nsynthesis or action.\nGenerally bacteriostatic.\n\u03b2-lactamsPENICILLINS Benzylpenicillin, \nphenoxymethylpenicillinOverall, mainly gram-positive \nspp.; some gram-negative spp.\nBacterial membrane or \ncell wall /peptidoglycan \nsynthesis.\nGenerally bactericidal.Penicillinase-resistant penicillins\nFlucloxacillin, temocillinUsed for staphylococcal \ninfections\nBroad-spectrum penicillins\nAmoxicillin, ampicillinA wide range of gram-positive \nand gram-negative spp.\nAntipseudomonal penicillins\nPiperacillin, ticarcillin (used with \u03b2-lactamase \ninhibitors)Selected gram-negative spp., \nespecially P. aeruginosa\nMECILLINAMS Pivmecillinam Mainly gram-negative spp.\nCEPHALOSPORINS Cefalcor, cefadroxil, \ncefalexin, cefixime, cefotaxime, cefradine, \nceftaroline, ceftazidime, ceftriaxone, cefuroximeBroad spectrum of activity \nagainst gram-negative and \npositive spp.\nCARBAPENEMS\nErtapenem, imipenem, meropenem.Many gram-negative and \npositive spp. Some anaerobes\nMONOBACTAMS Aztreonam Gram-negative aerobes\nGlycopeptides Vancomycin, teicoplanin, telavancin, \ndaptomycin (actually a lipopeptide)Many gram-positive spp. \nIncluding MRSA.\nPhosphonic \nacidsFosfomycinMany gram-positive and \ngram-negative spp. Treatment \nof UTI.\nPolymixins Colistimethate, polymixin B Gram-negative spp. Bacterial outer cell \nmembrane structure\nTetracyclines Demeclocycline, doxycycline, lymecycline, \nminocycline, oxytetracycline, tetracycline \ntigecyclineBroad-spectrum activity \nagainst many gram-negative \nand gram-positive spp.\nBacterial protein \nsynthesis (multiple \nmechanisms inhibited \nincluding initiation, \ntranspeptidation and \ntranslocation; see text).\nGenerally bacteriostatic.Aminoglycosides Amikacin, gentamicin, neomycin, streptomycin, \ntobramycinMany gram-negative, some \ngram-positive spp.\nMacrolides Azithromycin, clarithromycin, erythromycin, \ntelithromycinSimilar to penicillin\nOxazolidinones Linezolid Gram-positive spp. including \nMRSA\nLincosamides Clindamycin Gram-positive spp. Many \nanaerobes\nAmphenicols ChloramphenicolBroad-spectrum activity \nagainst gram-negative and \ngram-positive spp.\nStreptogramins Quinupristin, dalfopristin Gram-positive spp.\nSteroidals Fusidic acid Narrow spectrum. Gram-\npositive spp.\nQuinolones Ciprofloxacin, levofloxacin, moxifloxacin, \nnalidixic acid, norfloxacin, ofloxacinGram-negative and gram-\npositive spp.\nBacterial DNA \nsynthesis, structure or \nreplication.\nGenerally bacteriostatic.Macrocyclics Fidaxomicin Used to treat Clostridium \ndifficile\nAnsamycins Rifaximin Traveller\u2019s diarrhoea\nNitroimidazoles", "start_char_idx": 0, "end_char_idx": 2818, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c1dfcf40-e0c6-44d6-aa91-b221c0f82793": {"__data__": {"id_": "c1dfcf40-e0c6-44d6-aa91-b221c0f82793", "embedding": null, "metadata": {"page_label": "675", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a24d2522-4f8f-4729-a52b-a2cf8f13363a", "node_type": null, "metadata": {"page_label": "675", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e84092ad726a91a21138f98e0cd055d9cf50d4344d479112cf46a8227e35eb44"}, "2": {"node_id": "48fb80c8-6203-409c-9b6c-87c13f0fe5b4", "node_type": null, "metadata": {"page_label": "675", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "11893bfa57c09abdf1e089bfef0563c5492bd2d0b0b776f5bf9c5d4cff2a8f29"}}, "hash": "a83769d82bd9dba58063c3d7eaba3232bc4ceb23c8b75c08afb01b495a64bcf4", "text": "Traveller\u2019s diarrhoea\nNitroimidazoles Metronidazole and tinidazole Treatment of C. difficile and \nother infections.\nNitrofurans Nitrofurantoin Gram-negative UTIs\nContinuedmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2781, "end_char_idx": 3432, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b0c188ab-15af-4e75-873e-18b9f434f1d8": {"__data__": {"id_": "b0c188ab-15af-4e75-873e-18b9f434f1d8", "embedding": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2b4f64b0-e23a-4c85-8864-c7a9208735d4", "node_type": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61a0e6c999eeabd789048c28853356bbe3d2c419731cbe6b4d5db8ddde559c73"}, "3": {"node_id": "174484c9-e6e9-47bd-a47b-2573eee1e439", "node_type": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f78cc15d5207c8f8a8b2f4bc6c9387e5801a927d5a26b1996f0e08cdc5dfff04"}}, "hash": "0a71d04dc6e092c6cc928ae41eba3eb4ee4786e2779e972670d9af4543776580", "text": "52 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n670The ototoxicity involves progressive damage to, and eventually \ndestruction of, the sensory cells in the cochlea and vestibular organ \nof the ear. The result, usually irreversible, may manifest as vertigo, \nataxia and loss of balance in the case of vestibular damage, and auditory disturbances or deafness in the case of cochlear damage. Any ami -\nnoglycoside may produce both types of effect, but streptomycin and gentamicin are more likely to interfere with vestibular function, whereas neomycin and amikacin mostly affect hearing. Ototoxicity \nis potentiated by the concomitant use of other ototoxic drugs (e.g. \nloop diuretics; Ch. 30) and susceptibility is genetically determined \nvia mitochondrial DNA (see Ch. 12).\nThe nephrotoxicity consists of damage to the kidney tubules and \nmay necessitate dialysis, although function usually recovers if \nadministration ceases as soon as renal toxicity is detected. Nephrotoxic -\nity is more likely to occur in patients with pre-existing renal disease \nor in conditions in which urine volume is reduced, and concomitant \nuse of other nephrotoxic agents (e.g. first-generation cephalosporins, \nvancomycin) increases the risk. As the elimination of these drugs is \nalmost entirely renal, this nephrotoxic action can impair their own \nexcretion and a vicious cycle may develop. Plasma concentrations should be monitored regularly and the dose adjusted accordingly.\nA rare but serious toxic reaction is paralysis caused by neuromuscular \nblockade. This is usually seen only if the agents are given concurrently with neuromuscular-blocking agents. It results from inhibition of the \nCa\n2+ uptake necessary for the exocytotic release of acetylcholine (see \nCh. 14).\nMACROLIDES\nThe term macrolide relates to the structure \u2013 a many-\nmembered lactone ring to which one or more deoxy sugars \nare attached. The main macrolide and related antibiotics \nare erythromycin, clarithromycin and azithromycin. \nTelithromycin is of minor utility.\nMechanism of action\nThe macrolides inhibit bacterial protein synthesis by an effect on ribosomal translocation (Ch. 51, Fig. 51.4). The \ndrugs bind to the same 50S subunit of the bacterial ribosome \nas chloramphenicol and clindamycin, and any of these \ndrugs may compete if given concurrently.\nAntimicrobial spectrum\nThe antimicrobial spectrum of erythromycin is very similar to that of penicillin, and it is a safe and effective alternative \nfor penicillin-sensitive patients. Erythromycin is effective \nagainst gram-positive bacteria and spirochaetes but not against most gram-negative organisms, exceptions being \nN. gonorrhoeae and, to a lesser extent, H. influenzae. Myco-\nplasma pneumoniae, Legionella spp. and some chlamydial \norganisms are also susceptible (see Table 52.1). Resistance Table 52.2 A general overview of antibacterials and their mechanism of action\u2014cont\u2019d\nFamily Examples Typical target organism Cellular target\nAnti-\nmycobacterialsBedaquillone, capreomycin, clofazimine, cycloserine, delamanid, dapsone, ethambutol, isoniazid, pyrazinamide, rifabutin, rifampicin\naMost used for mycobacterial infections onlyVarious unrelated mechanisms (see text)\nMiscellaneous Methenamine Gram-negative UTIsProdrug of formaldehyde (bacteriostatic).\nDrug\tmixtures \t(e.g. \tco-fluampicil \t\u2013 \tflucloxacillin \twith \tampicillin)", "start_char_idx": 0, "end_char_idx": 3382, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "174484c9-e6e9-47bd-a47b-2573eee1e439": {"__data__": {"id_": "174484c9-e6e9-47bd-a47b-2573eee1e439", "embedding": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2b4f64b0-e23a-4c85-8864-c7a9208735d4", "node_type": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61a0e6c999eeabd789048c28853356bbe3d2c419731cbe6b4d5db8ddde559c73"}, "2": {"node_id": "b0c188ab-15af-4e75-873e-18b9f434f1d8", "node_type": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a71d04dc6e092c6cc928ae41eba3eb4ee4786e2779e972670d9af4543776580"}, "3": {"node_id": "0afa5cf3-37f3-47cf-ae78-1540c4c1489e", "node_type": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "496457a115b9a4c5c0e5fd4376cf8ba0c76b9e5ca9e767a133d4ac4674374211"}}, "hash": "f78cc15d5207c8f8a8b2f4bc6c9387e5801a927d5a26b1996f0e08cdc5dfff04", "text": "\t\u2013 \tflucloxacillin \twith \tampicillin) \tare \tnot \tshown.\naThese drugs are often used in combination.\nMRSA,\tmethicillin-resistant \tstaphylococcus \taureus; \tUTI, urinary tract infection.\ncan occur and results from a plasmid-controlled alteration \nof the binding site for erythromycin on the bacterial ribo -\nsome (Ch. 51, Fig. 51.4).\nAzithromycin is less active than erythromycin against \ngram-positive bacteria but is considerably more effective \nagainst H. influenzae and may be more active against \nLegionella. It can be used to treat Toxoplasma gondii, as it \nkills the cysts. Clarithromycin is as active, and its metabolite is twice as active, against H. influenzae as erythromycin. It \nis also effective against Mycobacterium avium-intracellulare \n(which can infect immunologically compromised individuals and elderly patients with chronic lung disease), and it may \nalso be useful in leprosy and against Helicobacter pylori (see \nCh. 31). Both these macrolides are also effective in Lyme \ndisease.\n\u25bc Pharmacokinetic aspects. The macrolides are administered orally \nor parenterally, although intravenous injections can cause local \nthrombophlebitis. They diffuse readily into most tissues but do not \ncross the blood\u2013brain barrier, and there is poor penetration into \nsynovial fluid. The plasma half-life of erythromycin is about 90 min; \nthat of clarithromycin is three times longer, and that of azithromycin 8\u201316 times longer. Macrolides enter and indeed are concentrated \nwithin phagocytes \u2013 azithromycin concentrations in phagocyte lys -\nosomes can be 40 times higher than in the blood \u2013 and they can \nenhance intracellular killing of bacteria by phagocytes.\nErythromycin is partly inactivated in the liver; azithromycin is more \nresistant to inactivation, and clarithromycin is converted to an active \nmetabolite. Inhibition of the P450 cytochrome system by these agents \ncan affect the bioavailability of other drugs leading to clinically important interactions, for example, with theophylline (see Ch. 12). \nThe major route of elimination is in the bile.\nUnwanted effects. GI disturbances are common and unpleasant but \nnot serious. With erythromycin, the following have also been reported: \nhypersensitivity reactions such as rashes and fever, transient hearing disturbances and rarely, following treatment for longer than 2 weeks, \ncholestatic jaundice. Opportunistic infections of the GI tract or vagina \ncan occur.\nOXAZOLIDINONES\nOriginally hailed as the \u2018first truly new class of antibacte -\nrial agents to reach the marketplace in several decades\u2019 \n(Zurenko et al., 2001), the oxazolidinones inhibit bacterial \nprotein synthesis by a novel mechanism: inhibition of \nN-formylmethionyl-tRNA binding to the 70S ribosome. \nLinezolid is the first member of this new antibiotic family \nto be introduced. It is active against a wide variety of gram-positive bacteria and is particularly useful for the \ntreatment of drug-resistant bacteria such as MRSA, penicillin- \nresistant Streptococcus pneumoniae and vancomycin-resistant mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3349, "end_char_idx": 6742, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0afa5cf3-37f3-47cf-ae78-1540c4c1489e": {"__data__": {"id_": "0afa5cf3-37f3-47cf-ae78-1540c4c1489e", "embedding": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2b4f64b0-e23a-4c85-8864-c7a9208735d4", "node_type": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "61a0e6c999eeabd789048c28853356bbe3d2c419731cbe6b4d5db8ddde559c73"}, "2": {"node_id": "174484c9-e6e9-47bd-a47b-2573eee1e439", "node_type": null, "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f78cc15d5207c8f8a8b2f4bc6c9387e5801a927d5a26b1996f0e08cdc5dfff04"}}, "hash": "496457a115b9a4c5c0e5fd4376cf8ba0c76b9e5ca9e767a133d4ac4674374211", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6729, "end_char_idx": 6904, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8a97026c-47e7-4abe-bc1c-21d317c8492f": {"__data__": {"id_": "8a97026c-47e7-4abe-bc1c-21d317c8492f", "embedding": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f0b77fdb-641f-4136-9cf8-1c4107194f19", "node_type": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2fb054e892c59a19f8607a7765d7f6770b1181a6e4af03c7719fffa9e74e8d19"}, "3": {"node_id": "eeccafc1-476d-4eba-b672-9f5981b5348b", "node_type": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a6795a72a19b38c4f3229c58ee2ccd024cc4ac587c85984333651f25fc659371"}}, "hash": "fdc2f150845f6b27fe74a0e6551ee06a50d8a72a86873216ac48dfd4e2476312", "text": "52 ANTIbACTERIA l DRUGS\n671enterococci. The drug is also effective against some anaer -\nobes, such as C. difficile. Most common gram-negative \norganisms are not susceptible to the drug. Linezolid can \nbe used to treat pneumonia, septicaemia, and skin and soft tissue infections. Its use is restricted to serious bacterial \ninfections where other antibiotics have failed, and there \nhave so far been few reports of resistance.\n\u25bc Unwanted effects include thrombocytopenia, diarrhoea, nausea \nand, rarely, rash and dizziness. Linezolid is a non-selective inhibitor \nof monoamine oxidase, and appropriate precautions need to be \nobserved (see Ch. 48).\nFUSIDIC ACID\nFusidic acid is a narrow-spectrum steroidal antibiotic active \nmainly against gram-positive bacteria. It acts by inhibiting \nbacterial protein synthesis (Ch. 51, Fig. 51.4), but resistance \ncommonly emerges if it is used as a single agent. It is used in combination with other anti-staphylococcal agents in \nstaphylococcal sepsis, and is used topically for staphylococ -\ncal infections (e.g. as eye drops or cream).\n\u25bc Pharmacokinetic aspects. As the sodium salt, the drug is well \nabsorbed from the gut and is distributed widely in the tissues. Some \nis excreted in the bile and some metabolised.\nUnwanted effects such as GI disturbances are fairly common. Skin \neruptions and jaundice can occur. Resistance occurs if it is used systemi -\ncally as a single agent so it is always combined with other antibacterial drugs when used systemically.\nSTREPTOGRAMINS\nQuinupristin and dalfopristin are cyclic peptides, which \ninhibit bacterial protein synthesis by binding to the 50S subunit \nof the bacterial ribosome. Dalfopristin changes the structure \nof the ribosome so as to promote the binding of quinupristin. Individually, they exhibit only very modest bacteriostatic \nactivity, but combined together as an intravenous injection \nthey are active against many gram-positive bacteria. The combination is used to treat serious infections, usually where \nno other antibacterial is suitable. For example, the combination \nis effective against MRSA and vancomycin-resistant Enterococ -\ncus faecium . They are not currently used in the United Kingdom.\n\u25bc Pharmacokinetic aspects. Both drugs undergo extensive first-pass \nhepatic metabolism and must therefore be given as an intravenous \ninfusion. The half-life of each compound is 1\u20132 h.\nUnwanted effects include inflammation and pain at the infusion site, \narthralgia, myalgia and nausea, vomiting and diarrhoea. To date, \nresistance to quinupristin and dalfopristin does not seem to be a \nmajor problem.\nCLINDAMYCIN\nThe lincosamide clindamycin is active against gram-positive \ncocci, including many penicillin-resistant staphylococci and \nmany anaerobic bacteria such as Bacteroides spp. It acts in \nthe same way as macrolides and chloramphenicol (Ch. 51, \nFig. 51.4). In addition to its use in infections caused by \nBacteroides organisms, it is used to treat staphylococcal \ninfections of bones and joints. It is also given topically, as eye drops, for staphylococcal conjunctivitis and as an anti-\nprotozoal drug (see Ch. 55).\n\u25bc Unwanted effects consist mainly of GI disturbances, ranging from \nuncomfortable diarrhoea to potentially lethal pseudomembranous \ncolitis, caused by a toxin-forming C. difficile.6Antimicrobial agents affecting \nbacterial protein synthesis", "start_char_idx": 0, "end_char_idx": 3377, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "eeccafc1-476d-4eba-b672-9f5981b5348b": {"__data__": {"id_": "eeccafc1-476d-4eba-b672-9f5981b5348b", "embedding": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f0b77fdb-641f-4136-9cf8-1c4107194f19", "node_type": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2fb054e892c59a19f8607a7765d7f6770b1181a6e4af03c7719fffa9e74e8d19"}, "2": {"node_id": "8a97026c-47e7-4abe-bc1c-21d317c8492f", "node_type": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fdc2f150845f6b27fe74a0e6551ee06a50d8a72a86873216ac48dfd4e2476312"}, "3": {"node_id": "6c21cbec-3ac7-4952-82d5-f1c7147dcc8a", "node_type": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b3edae40a92c414ced1049918f53b41c3b05f74da529ebfb3a54958da1181d87"}}, "hash": "a6795a72a19b38c4f3229c58ee2ccd024cc4ac587c85984333651f25fc659371", "text": "difficile.6Antimicrobial agents affecting \nbacterial protein synthesis \n\u2022\tTetracyclines (e.g. minocycline). These are orally \nactive,\tbacteriostatic, \tbroad-spectrum \tantibiotics. \t\nResistance \tis \tincreasing. \tGI \tdisorders \tare \tcommon. \t\nThey also chelate calcium and are deposited in \ngrowing bone. They are contraindicated in children and pregnant women.\n\u2022\tChloramphenicol\n.\tThis\tis\tan \torally \tactive, \t\nbacteriostatic, broad-spectrum antibiotic. Serious toxic effects are possible, including bone marrow \ndepression \tand \t\u2018grey \tbaby \tsyndrome\u2019. \tIt \tshould \tbe \t\nreserved\tfor \tlife-threatening \tinfections.\n\u2022\tAminoglycosides (e.g. gentamicin ).\tThese\tare \tgiven \t\nby\tinjection. \tThey \tare \tbactericidal, \tbroad-spectrum \t\nantibiotics \t(but \twith \tlow \tactivity \tagainst \tanaerobes, \t\nstreptococci and pneumococci). Resistance is increasing. The main unwanted effects are dose-\nrelated\tnephrotoxicity \tand \tototoxicity. \tSerum \tlevels \t\nshould be monitored. ( Streptomycin is an \nantituberculosis aminoglycoside.)\n\u2022\tMacrolides (e.g. erythromycin ).\tCan\tbe\tgiven \torally \t\nand parenterally. They are bactericidal/bacteriostatic. The antibacterial spectrum is the same as for penicillin. \nErythromycin \tcan \tcause \tjaundice. \tNewer \tagents \tare \t\nclarithromycin and azithromycin.\n\u2022\tLincosamides (e.g. clindamycin ).\tCan\tbe\tgiven \torally \t\nand\tparenterally. \tIt \tcan \tcause \tpseudomembranous \t\ncolitis.\n\u2022\tStreptogramins (e.g. quinupristin/dalfopristin ).\tGiven\t\nby\tintravenous \tinfusion \tas \ta \tcombination. \tConsiderably \t\nless\tactive \twhen \tadministered \tseparately. \tActive \t\nagainst\tseveral \tstrains \tof \tdrug-resistant \tbacteria.\n\u2022\tFusidic acid. This is a narrow-spectrum antibiotic that \nacts\tby\tinhibiting \tprotein \tsynthesis. \tIt \tpenetrates \tbone. \t\nUnwanted \teffects \tinclude \tGI \tdisorders.\n\u2022\tLinezolid .\tGiven\torally \tor \tby \tintravenous \tinjection. \t\nActive\tagainst \tseveral \tstrains \tof \tdrug-resistant \t\nbacteria.\nClinical uses of the \nfluoroquinolones \n\u2022\tComplicated \turinary tract infections (norfloxacin, \nofloxacin).\n\u2022\tPseudomonas aeruginosa respiratory infections in \npatients with cystic fibrosis.\n\u2022\tInvasive \texternal \totitis \t(\u2018malignant \totitis\u2019) \tcaused \tby \tP. \naeruginosa.\n\u2022\tChronic \tgram-negative \tbacillary \tosteomyelitis.\n\u2022\tEradication \tof \tSalmonella typhi in carriers.\n\u2022\tGonorrhoea (norfloxacin, ofloxacin).\n\u2022\tBacterial \tprostatitis (norfloxacin).\n\u2022\tCervicitis (ofloxacin).\n\u2022\tAnthrax.\n6This may also occur with broad-spectrum penicillins and cephalosporins.mebooksfree.net mebooksfree.net", "start_char_idx": 3313, "end_char_idx": 5839, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6c21cbec-3ac7-4952-82d5-f1c7147dcc8a": {"__data__": {"id_": "6c21cbec-3ac7-4952-82d5-f1c7147dcc8a", "embedding": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f0b77fdb-641f-4136-9cf8-1c4107194f19", "node_type": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2fb054e892c59a19f8607a7765d7f6770b1181a6e4af03c7719fffa9e74e8d19"}, "2": {"node_id": "eeccafc1-476d-4eba-b672-9f5981b5348b", "node_type": null, "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a6795a72a19b38c4f3229c58ee2ccd024cc4ac587c85984333651f25fc659371"}}, "hash": "b3edae40a92c414ced1049918f53b41c3b05f74da529ebfb3a54958da1181d87", "text": "mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5905, "end_char_idx": 6352, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bd3ce65a-6ca3-4715-becb-4eefa816a384": {"__data__": {"id_": "bd3ce65a-6ca3-4715-becb-4eefa816a384", "embedding": null, "metadata": {"page_label": "678", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "35c3b872-1067-4f17-bd91-33226ff6ce01", "node_type": null, "metadata": {"page_label": "678", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bd9c76446fca2ecafb54e850793c1381c66234ec6b30a1b697ed08f588a0c82c"}, "3": {"node_id": "b59e1ec7-acc3-4a62-8957-464b0bf33d8d", "node_type": null, "metadata": {"page_label": "678", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7f7a06f10acee1afe12d92aba1f5e348a0f47e65708f229da19c76e83eca992e"}}, "hash": "0fcd462aa0903e1ad390e2e84330935b56a4a1dcf8aa549bf2edbeece936d075", "text": "52 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n672facultative and aerobic gram-negative bacilli and cocci.7 \nResistant strains of S. aureus and P. aeruginosa have emerged.\n\u25bc Pharmacokinetic aspects. Fluoroquinolones are well absorbed \nfollowing oral administration. The drugs accumulate in several tissues, \nparticularly in the kidney, prostate and lung. All quinolones are \nconcentrated in phagocytes. Most fail to cross the blood\u2013brain barrier, but ofloxacin does so. Aluminium and magnesium antacids interfere \nwith the absorption of the quinolones. Elimination of ciprofloxacin \nand norfloxacin is partly by hepatic metabolism by P450 enzymes (which they can inhibit, giving rise to interactions with other drugs) \nand partly by renal excretion. Ofloxacin is excreted in the urine.\nUnwanted effects. In hospitals, infection with C. difficile may prove \nhazardous but otherwise unwanted effects are infrequent, usually \nmild and reversible. The most frequent manifestations are GI disorders and rashes. Arthropathy has been reported in young individuals. \nCentral nervous system (CNS) symptoms \u2013 headache and dizziness \n\u2013 have occurred, as have, less frequently, convulsions associated with CNS pathology or concurrent use of theophylline or a non-steroidal \nanti-inflammatory drug (NSAID) (Ch. 27).\nThere is a clinically important interaction between ciprofloxacin and \ntheophylline (through inhibition of P450 enzymes), which can lead \nto theophylline toxicity in asthmatics treated with the fluoroquinolones. The topic is discussed further in Chapter 29. Moxifloxacin prolongs \nthe electrocardiographic QT interval and is used extensively, following \nFDA guidance, as a positive control in studies in healthy volunteers examining possible effects of new drugs on cardiac repolarisation.\nANTIMICROBIAL AGENTS AFFECTING \nTOPOISOMERASE\nQUINOLONES\nThe quinolones include the broad-spectrum agents cipro-\nfloxacin, levofloxacin, ofloxacin, norfloxacin and moxi-\nfloxacin as well as nalidixic acid , a narrow-spectrum drug \nused in urinary tract infections. Most are fluorinated \n(fluoroquinolones). These agents inhibit topoisomerase II \n(a bacterial DNA gyrase), the enzyme that produces a \nnegative supercoil in DNA and thus permits transcription or replication (Fig. 52.4).\nAntibacterial spectrum and clinical use\nCiprofloxacin is the most commonly used and typical of the group. It is a broad-spectrum antibiotic effective against \nboth gram-positive and gram-negative organisms, including \nthe Enterobacteriaceae (enteric gram-negative bacilli), many organisms resistant to penicillins, cephalosporins and \naminoglycosides, and against H. influenzae, penicillinase-\nproducing Neisseria gonorrhoeae, Campylobacter spp. and \npseudomonads. Of the gram-positive organisms, streptococci and pneumococci are only weakly inhibited, and there is \na high incidence of staphylococcal resistance. Ciprofloxacin should be avoided in MRSA infections. Clinically, the fluoroquinolones are best reserved for infections with F\nDNA gyrase\n(topoisomerase II)NN NO\nCiprofloxacinCOOH\nQuinolonesA\nB\nFig. 52.4 A simplified diagram of the mechanism of action \nof the fluoroquinolones. \t(A)\tAn\texample \tof \ta \tquinolone \t(the \t\nquinolone", "start_char_idx": 0, "end_char_idx": 3250, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b59e1ec7-acc3-4a62-8957-464b0bf33d8d": {"__data__": {"id_": "b59e1ec7-acc3-4a62-8957-464b0bf33d8d", "embedding": null, "metadata": {"page_label": "678", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "35c3b872-1067-4f17-bd91-33226ff6ce01", "node_type": null, "metadata": {"page_label": "678", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bd9c76446fca2ecafb54e850793c1381c66234ec6b30a1b697ed08f588a0c82c"}, "2": {"node_id": "bd3ce65a-6ca3-4715-becb-4eefa816a384", "node_type": null, "metadata": {"page_label": "678", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0fcd462aa0903e1ad390e2e84330935b56a4a1dcf8aa549bf2edbeece936d075"}}, "hash": "7f7a06f10acee1afe12d92aba1f5e348a0f47e65708f229da19c76e83eca992e", "text": "\tof \ta \tquinolone \t(the \t\nquinolone moiety is shown in orange). (B) Schematic diagram of \n(left) the double helix and (right) the double helix in supercoiled \nform\t(see\talso \tFig. \t51.6). \tIn \tessence, \tthe \tDNA \tgyrase \tunwinds \t\nthe\tRNA-induced \tpositive \tsupercoil \t(not \tshown) \tand \tintroduces \t\na\tnegative \tsupercoil. \t\n7When ciprofloxacin was introduced, clinical pharmacologists and \nmicrobiologists sensibly suggested that it should be reserved for \norganisms already resistant to other drugs, to prevent emergence of \nresistance. However, by 1989 it was already estimated that it was prescribed for 1 in 44 of Americans, so it would seem that the horse had \nnot only left the stable but had bolted into the blue!Antimicrobial agents affecting DNA \ntopoisomerase II \n\u2022\tThe\tquinolones \tinterfere \twith \tthe \tsupercoiling \tof \tDNA.\n\u2022\tCiprofloxacin has a wide antibacterial spectrum, \nbeing\tespecially \tactive \tagainst \tgram-negative \tenteric \t\ncoliform organisms, including many organisms \nresistant to penicillins, cephalosporins and \naminoglycosides; \tit \tis \talso \teffective \tagainst \t\nHaemophilus influenzae, penicillinase-producing Neisseria gonorrhoeae, Campylobacter spp. and \npseudomonads. There is a high incidence of \nstaphylococcal resistance.\n\u2022\tUnwanted \teffects \tinclude \tGI \ttract \tupsets, \t\nhypersensitivity \treactions \tand, \trarely, \tcentral \tnervous \t\nsystem disturbances.\nMISCELLANEOUS ANTIBACTERIAL \nAGENTS\nFidaxomicin is a relatively new drug which was originally \ndiscovered in actinomycetes. It inhibits bacterial RNA \npolymerase. It is not used to treat systemic infections as it \nis poorly absorbed from the gut, but has a role in treating C. difficile infections.\nMETRONIDAZOLE\nMetronidazole was introduced as an antiprotozoal agent (see Ch. 55), but it is also active against anaerobic bacteria mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3215, "end_char_idx": 5523, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "530b713e-bd2b-4cb5-b9c9-5df20a586e08": {"__data__": {"id_": "530b713e-bd2b-4cb5-b9c9-5df20a586e08", "embedding": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87a197f0-49c1-40b7-b438-015a555d633f", "node_type": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "baf4cf0a5b69d56603383dcafc6bf344216a32009e95e9e21ad22e802445b3db"}, "3": {"node_id": "00fd511d-73af-4b11-8f1b-9d9b15de644f", "node_type": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "208f5c442cc645244da36f08a1e3dbc8a1372401eb81e574fc655fb79355ae35"}}, "hash": "26fd1b23d9db5e017779c876496d3016b8c739b91a24d5134c959ccb9ae4e4aa", "text": "52 ANTIbACTERIA l DRUGS\n673Treatment is led by the first-line drugs isoniazid, \nrifampicin, rifabutin, ethambutol and pyrazinamide. \nSecond-line drugs include capreomycin, cycloserine, \nstreptomycin (rarely used now in the United Kingdom), \nclarithromycin and ciprofloxacin. These are used to treat \ninfections likely to be resistant to first-line drugs, or when \nthe first-line agents have to be abandoned because of adverse effects. Two newer drugs, bedaquiline and delamanid, \nhave recently been introduced for use in multidrug resistant cases of TB, usually in conjunction with other agents.\nTo decrease the probability of the emergence of resistant \norganisms, combination drug therapy is usually mandatory. \nThis commonly involves:\n\u2022\tan\tinitial \tphase \tof \ttreatment \t(about \t2 \tmonths) \twith \ta \t\ncombination of isoniazid, rifampicin and \npyrazinamide (plus ethambutol if the organism is \nsuspected to be resistant);\n\u2022\ta\tsecond, \tcontinuation \tphase \t(about \t4 \tmonths) \tof \t\ntherapy, with isoniazid and rifampicin. Longer-term \ntreatment is needed for patients with meningitis, \nbone/joint involvement or drug-resistant infection.\nISONIAZID\nThe antibacterial activity of isoniazid is limited to myco-\nbacteria. It halts the growth of resting organisms (i.e. is \nbacteriostatic) but can also kill dividing bacteria. It passes \nfreely into mammalian cells and is thus effective against intracellular organisms. Isoniazid is a prodrug that must \nbe activated by bacterial enzymes before it can exert its \ninhibitory activity on the synthesis of mycolic acids , important \nconstituents of the cell wall peculiar to mycobacteria. \nResistance to the drug, secondary to reduced penetration \ninto the bacterium, may be present, but cross-resistance with other tuberculostatic drugs does not occur.\n\u25bc Pharmacokinetic aspects. Isoniazid is readily absorbed from the \ngastrointestinal tract and is widely distributed throughout the tissues \nand body fluids, including the CSF. An important point is that it \npenetrates well into \u2018caseous\u2019 tuberculous lesions (i.e. necrotic lesions with a cheese-like consistency). Metabolism, which involves acetylation, \ndepends on genetic factors that determine whether a person is a slow \nor rapid acetylator of the drug (see Ch. 12), with slow inactivators enjoying a better therapeutic response. The half-life in slow inactivators \nis 3 h and in rapid inactivators, 1 h. Isoniazid is excreted in the urine \npartly as unchanged drug and partly in the acetylated or otherwise inactivated form.\nUnwanted effects depend on the dosage and occur in about 5% of \nindividuals, the commonest being allergic skin eruptions. A variety \nof other adverse reactions have been reported, including fever, \nhepatotoxicity, haematological changes, arthritic symptoms and vasculitis. Adverse effects involving the central or peripheral nervous \nsystems are largely consequences of pyridoxine deficiency and are \ncommon in malnourished patients unless prevented by supplementa -\ntion of this vitamin. Isoniazid may cause haemolytic anaemia in \nindividuals with glucose 6-phosphate dehydrogenase deficiency, and \nit decreases the metabolism of the antiepileptics phenytoin, ethosux-\nimide and carbamazepine, resulting in an increase in the plasma \nconcentration and toxicity of these drugs.\nRIFAMPICIN\nRifampicin (also called rifampin) acts by binding to, and", "start_char_idx": 0, "end_char_idx": 3376, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "00fd511d-73af-4b11-8f1b-9d9b15de644f": {"__data__": {"id_": "00fd511d-73af-4b11-8f1b-9d9b15de644f", "embedding": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87a197f0-49c1-40b7-b438-015a555d633f", "node_type": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "baf4cf0a5b69d56603383dcafc6bf344216a32009e95e9e21ad22e802445b3db"}, "2": {"node_id": "530b713e-bd2b-4cb5-b9c9-5df20a586e08", "node_type": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "26fd1b23d9db5e017779c876496d3016b8c739b91a24d5134c959ccb9ae4e4aa"}, "3": {"node_id": "8a03456e-c7a6-489b-9661-fa947365a6a1", "node_type": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "60c9afcdad20dc2a90ee9e2b4b2413f9a485525ef7adf8e6c8cbcffdbcbdd839"}}, "hash": "208f5c442cc645244da36f08a1e3dbc8a1372401eb81e574fc655fb79355ae35", "text": "(also called rifampin) acts by binding to, and \ninhibiting, DNA-dependent RNA polymerase in prokaryotic \nbut not in eukaryotic cells (Ch. 51). It is one of the most \nactive antituberculosis agents known, and is also effective against leprosy and most gram-positive bacteria as well as \nmany gram-negative species. It enters phagocytic cells and such as Bacteroides, Clostridia spp. and some streptococci. \nIt is effective in the therapy of pseudomembranous colitis, \nand is important in the treatment of serious anaerobic \ninfections (e.g. sepsis secondary to bowel disease). It has a disulfiram-like action (see Ch. 50), so patients must avoid \nalcohol while taking metronidazole.\nNITROFURANTOIN\nNitrofurantoin is a synthetic compound active against a \nrange of gram-positive and gram-negative organisms. The \ndevelopment of resistance in susceptible organisms is rare, \nand there is no cross-resistance. Its mechanism of action is probably related to its ability to damage bacterial DNA. \nMethanamine has a similar clinical utility to nitrofuran-\ntoin and shares several of its unwanted effects. It exerts its effects following slow conversion (in acidic urine) to \nformaldehyde.\n\u25bc Pharmacokinetic aspects. Nitrofurantoin is given orally and is \nrapidly and totally absorbed from the GI tract and just as rapidly \nexcreted by the kidney. Its use is confined to the treatment of urinary \ntract infections.\nUnwanted effects. GI disturbances are relatively common, and \nhypersensitivity reactions involving the skin and the bone marrow \n(e.g. leukopenia) can occur. Hepatotoxicity and peripheral neuropathy \nhave also been reported.\nANTIMYCOBACTERIAL AGENTS\nThe main mycobacterial infections in humans are tubercu -\nlosis (TB) and leprosy, chronic infections caused by \nMycobacterium tuberculosis and M. leprae, respectively. \nAnother mycobacterial infection is M. avium-intracellulare \n(actually two organisms), which can infect some AIDS \npatients. A particular problem with mycobacteria is that \nthey can survive inside macrophages after phagocytosis, unless these cells are \u2018activated\u2019 by cytokines produced by \nT-helper (Th)1 lymphocytes (see Chs 7 and 19). Drugs in \nthis section are usually considered separately since some of them are specific for mycobacteria or used only to treat these infections for other reasons.\nDRUGS USED TO TREAT TUBERCULOSIS\nFor centuries, TB was a major killer disease, but the introduc -\ntion of streptomycin in the late 1940s followed by isoniazid \nand, in the 1960s, of rifampicin and ethambutol revolu-\ntionised therapy and TB came to be regarded as an easily treatable condition. Regrettably, this is no longer true. Strains \nwith increased virulence or exhibiting multidrug resistance \nare now common (Bloom & Small, 1998), and TB now causes more deaths than any other single agent, even though \ninfection rates are slowly falling. It has been estimated that \none-third of the world\u2019s population (2 billion people) harbour the TB bacillus, 10% of whom will develop the disease at some point in their lifetime. In 2015, the WHO \nestimated that 10.4 million people (including 1 million \nchildren) contracted the disease and some 1.8 million died as a result of the infection. Alarmingly, almost half a million \npeople developed multidrug resistant TB. Poverty-stricken \ncountries in Africa and Asia bear the brunt of the disease, partly because of an ominous synergy between mycobacteria \n(e.g. M. tuberculosis , M.", "start_char_idx": 3338, "end_char_idx": 6796, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8a03456e-c7a6-489b-9661-fa947365a6a1": {"__data__": {"id_": "8a03456e-c7a6-489b-9661-fa947365a6a1", "embedding": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87a197f0-49c1-40b7-b438-015a555d633f", "node_type": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "baf4cf0a5b69d56603383dcafc6bf344216a32009e95e9e21ad22e802445b3db"}, "2": {"node_id": "00fd511d-73af-4b11-8f1b-9d9b15de644f", "node_type": null, "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "208f5c442cc645244da36f08a1e3dbc8a1372401eb81e574fc655fb79355ae35"}}, "hash": "60c9afcdad20dc2a90ee9e2b4b2413f9a485525ef7adf8e6c8cbcffdbcbdd839", "text": "between mycobacteria \n(e.g. M. tuberculosis , M. avium-intracellulare ) and HIV. Infec -\ntions with the latter increase the risk of catching the disease \n20\u201330 fold and about a quarter of HIV-associated deaths \nare caused by TB.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6787, "end_char_idx": 7494, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "27aecc84-8cb6-4cf4-b622-5a30edf725c6": {"__data__": {"id_": "27aecc84-8cb6-4cf4-b622-5a30edf725c6", "embedding": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73da566b-a739-4ac7-8271-c453a1f2bcce", "node_type": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "668d7563409cf76a51ceaa4587073076920656483e80a5d145b6b21ea641d0b0"}, "3": {"node_id": "3792716d-60c9-46ee-b1b1-1fb55a658620", "node_type": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a320f424a4eede337e74e543ad139cf1b36fbd3cd034142e899849a0be5568c5"}}, "hash": "961de5a118ac11939a31f14aef0b6c3e2dc52ea876aa291aaa278d81de4db0c4", "text": "52 SECTION 5 \u2003\u2003DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n674nerve, with consequent deafness and ataxia. The drug should not be \ngiven at the same time as streptomycin or other drugs that may cause \ndeafness.\nCYCLOSERINE\nCycloserine is a broad-spectrum antibiotic that inhibits the \ngrowth of many bacteria, including coliforms and myco -\nbacteria. It is water-soluble and destroyed at acid pH. It \nacts by competitively inhibiting bacterial cell wall synthesis. \nIt does this by preventing the formation of D-alanine and \nthe D-Ala-D-Ala dipeptide that is added to the initial \ntripeptide side-chain on N-acetylmuramic acid, i.e. it \nprevents completion of the major building block of \npeptidoglycan (Ch. 51, Fig. 51.3). It is absorbed orally and \ndistributed throughout the tissues and body fluids, including \nCSF. Its use is limited to TB that is resistant to other drugs.\n\u25bc Pharmacokinetic aspects. Most of the drug is eliminated in active \nform in the urine, but approximately 35% is metabolised.\nUnwanted effects are mainly on the CNS. A wide variety of distur -\nbances may occur, ranging from headache and irritability to depression, \nconvulsions and psychotic states.kills intracellular tubercle bacilli. Resistance can develop \nrapidly in a one-step process in which a chromosomal \nmutation changes its target site on microbial DNA-dependent \nRNA polymerase (see Ch. 51).\n\u25bc Pharmacokinetic aspects . Rifampicin is given orally and is widely \ndistributed in the tissues and body fluids (including CSF), giving \nan orange tinge to saliva, sputum, tears and sweat. It is excreted \npartly in the urine and partly in the bile, some of it undergoing \nenterohepatic cycling. The metabolite retains antibacterial activity but \nis less well absorbed from the GI tract. The half-life is 1\u20135 h, becoming \nshorter during treatment because of induction of hepatic microsomal \nenzymes.\nUnwanted effects are relatively infrequent. The commonest are skin \neruptions, fever and GI l disturbances. Liver damage with jaundice \nhas been reported and has proved fatal in a very small proportion \nof patients, and liver function should be assessed before treatment \nis started. Rifampicin induces hepatic metabolising enzymes (Ch. 11), \nincreasing the degradation of warfarin, glucocorticoids, narcotic \nanalgesics, oral antidiabetic drugs, dapsone and oestrogens, the last \neffect leading to failure of oral contraception.\nETHAMBUTOL\nEthambutol has no effect on organisms other than myco -\nbacteria. It is taken up by the bacteria and exerts a bacte -\nriostatic effect after a period of 24 h, probably by inhibiting \nmycobacterial cell wall synthesis. Resistance emerges rapidly \nif the drug is used alone.\n\u25bc Pharmacokinetic aspects. Ethambutol is given orally and is well \nabsorbed. It can reach therapeutic concentrations in the CSF in \ntuberculous meningitis. In the blood, it is taken up by erythrocytes \nand slowly released. Ethambutol is partly metabolised and is excreted \nin the urine.\nUnwanted effects are uncommon, the most significant being optic \nneuritis, which is dose-related and is more likely to occur if renal \nfunction is decreased. This results in visual disturbances manifesting \ninitially as red\u2013green colour blindness progressing to a decreased \nvisual acuity. Colour vision should be monitored before and during \nprolonged", "start_char_idx": 0, "end_char_idx": 3353, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3792716d-60c9-46ee-b1b1-1fb55a658620": {"__data__": {"id_": "3792716d-60c9-46ee-b1b1-1fb55a658620", "embedding": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73da566b-a739-4ac7-8271-c453a1f2bcce", "node_type": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "668d7563409cf76a51ceaa4587073076920656483e80a5d145b6b21ea641d0b0"}, "2": {"node_id": "27aecc84-8cb6-4cf4-b622-5a30edf725c6", "node_type": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "961de5a118ac11939a31f14aef0b6c3e2dc52ea876aa291aaa278d81de4db0c4"}, "3": {"node_id": "a80e10ac-dffa-4f15-b652-bf62b46c2a3e", "node_type": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f39dd49de93963c26a84e888d0481028560357e3f0a1924456076ebc3f8411a1"}}, "hash": "a320f424a4eede337e74e543ad139cf1b36fbd3cd034142e899849a0be5568c5", "text": "\nvisual acuity. Colour vision should be monitored before and during \nprolonged treatment.\nPYRAZINAMIDE\nPyrazinamide is inactive at neutral pH but tuberculostatic \nat acid pH. It is effective against the intracellular organisms \nin macrophages because, after phagocytosis, the organisms \nare contained in phagolysosomes where the pH is low. The \ndrug probably inhibits bacterial fatty acid synthesis. Resist -\nance develops rather readily, but cross-resistance with \nisoniazid does not occur.\n\u25bc Pharmacokinetic aspects. The drug is well absorbed after oral \nadministration and is widely distributed, penetrating the meninges. \nIt is excreted through the kidney, mainly by glomerular filtration.\nUnwanted effects include gout, which is associated with high concentra -\ntions of plasma urates. GI upsets, malaise and fever have also been \nreported. Serious hepatic damage due to high doses was once a problem \nbut is less likely with lower dose/shorter course regimens now used; \nnevertheless, liver function should be assessed before treatment.\nCAPREOMYCIN\nCapreomycin is a peptide antibiotic given by intramuscular \ninjection. Its principal mechanism of action is thought to \nbe through binding to the 70S ribosomal unit thereby \ninhibiting protein synthesis, but it may have other effects \non the bacterial cell membrane.\n\u25bc Unwanted effects are many and the drug should be used with \ngreat caution. They include kidney damage and injury to the auditory Antituberculosis drugs \nTo\tavoid\tthe\temergence\t of\tresistant\torganisms,\t\ncompound therapy is used (e.g. three drugs initially, \nfollowed by a two-drug regimen later).\nFirst-line drugs\n\u2022\tIsoniazid \tkills\tactively\tgrowing\tmycobacteria\t within\t\nhost\tcells.\tGiven\torally,\tit\tpenetrates\t necrotic\tlesions,\t\nalso\tthe\tcerebrospinal\t fluid\t(CSF).\t\u2018Slow\tacetylators\u2019\t\n(genetically\t determined)\t respond\twell.\tIt\thas\tlow\t\ntoxicity.\tPyridoxine\t deficiency\t increases\t risk\tof\t\nneurotoxicity.\t No\tcross-resistance\t with\tother\tagents.\n\u2022\tRifampicin \tis\ta\tpotent,\torally\tactive\tdrug\tthat\tinhibits\t\nmycobacterial\t RNA\tpolymerase.\t It\tpenetrates\t CSF.\t\nUnwanted\t effects\tare\tinfrequent\t (but\tserious\tliver\t\ndamage\thas\toccurred).\t It\tinduces\thepatic\tdrug-\nmetabolising\t enzymes.\t Resistance\t can\tdevelop\trapidly.\n\u2022\tEthambutol \tinhibits\tgrowth\tof\tmycobacteria.\t It\tis\t\ngiven\torally\tand\tcan\tpenetrate\t CSF.\tUnwanted\t effects\t\nare uncommon, but optic neuritis can occur. \nResistance can emerge rapidly.\n\u2022\tPyrazinamide is tuberculostatic against intracellular \nmycobacteria.\t Given\torally,\tit\tpenetrates\t CSF.\t\nResistance\t can\tdevelop\trapidly.\tUnwanted\t effects\t\ninclude\tincreased\t plasma\turate\tand\tliver\ttoxicity\twith\t\nhigh doses.\nSecond-line drugs\n\u2022\tCapreomycin \tis\tgiven\tintramuscularly.\t Unwanted\t\neffects include damage to the kidney and to the \nauditory\tnerve.\n\u2022\tCycloserine \tis\ta\tbroad-spectrum\t agent.\tIt\tinhibits\tan\t\nearly\tstage\tof\tpeptidoglycan\t synthesis.\t Given\torally,\tit\t\npenetrates\t the\tCSF.\tUnwanted\t", "start_char_idx": 3286, "end_char_idx": 6237, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a80e10ac-dffa-4f15-b652-bf62b46c2a3e": {"__data__": {"id_": "a80e10ac-dffa-4f15-b652-bf62b46c2a3e", "embedding": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73da566b-a739-4ac7-8271-c453a1f2bcce", "node_type": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "668d7563409cf76a51ceaa4587073076920656483e80a5d145b6b21ea641d0b0"}, "2": {"node_id": "3792716d-60c9-46ee-b1b1-1fb55a658620", "node_type": null, "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a320f424a4eede337e74e543ad139cf1b36fbd3cd034142e899849a0be5568c5"}}, "hash": "f39dd49de93963c26a84e888d0481028560357e3f0a1924456076ebc3f8411a1", "text": "the\tCSF.\tUnwanted\t effects\taffect\tmostly\t\nthe\tcentral\tnervous\tsystem.\n\u2022\tStreptomycin , an aminoglycoside antibiotic, acts by \ninhibiting\tbacterial\tprotein\tsynthesis.\t It\tis\tgiven\t\nintramuscularly. Unwanted effects are ototoxicity \n(mainly\tvestibular)\t and\tnephrotoxicity.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6287, "end_char_idx": 7037, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "308fa410-ee08-4ba4-8fd6-a831f6fe575b": {"__data__": {"id_": "308fa410-ee08-4ba4-8fd6-a831f6fe575b", "embedding": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3a09c689-4a83-490f-b715-43d48a92af35", "node_type": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a259ea08a8c21612a53b8597b95c320ecbb4c10dd29742b2aa116dcbfe71a5b"}, "3": {"node_id": "ae735a00-eceb-4fa2-8574-9a75cd6218a9", "node_type": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4f630e7dcbdea642cd619f5c6fc060830de389a538ed58f6ba76c7bc53e84b7"}}, "hash": "b4c57f4d69ffae652e84c144aae1109bafd4e82f61a7e8550549fc241d285a71", "text": "52 ANTIbACTERIA l DRUGS\n675\u25bc Pharmacokinetic aspects . Dapsone is given orally; it is well absorbed \nand widely distributed through the body water and in all tissues. \nThe plasma half-life is 24\u201348 h, but some drug persists in liver, kidney \n(and, to some extent, skin and muscle) for much longer periods. There \nis enterohepatic recycling of the drug, but some is acetylated and \nexcreted in the urine. Dapsone is also used to treat dermatitis herpeti -\nformis, a chronic blistering skin condition associated with coeliac \ndisease.\nUnwanted effects occur fairly frequently and include haemolysis of \nred cells (usually not severe enough to lead to frank anaemia), \nmethaemoglobinaemia, anorexia, nausea and vomiting, fever, allergic \ndermatitis and neuropathy. Lepra reactions (an exacerbation of lepro -\nmatous lesions) can occur, and a potentially fatal syndrome resembling \ninfectious mononucleosis has occasionally been seen.\nCLOFAZIMINE\nClofazimine is a dye of complex structure. Its mechanism \nof action against leprosy bacilli may involve an action on \nDNA. It also has anti-inflammatory activity and is useful \nin patients in whom dapsone causes inflammatory side effects.\n\u25bc Pharmacokinetic aspects. Clofazimine is given orally and accu -\nmulates in the body, being sequestered in the mononuclear phagocyte \nsystem. The plasma half-life may be as long as 8 weeks. The anti-leprotic \neffect is delayed and is usually not evident for 6\u20137 weeks.\nUnwanted effects may be related to the fact that clofazimine is a dye. \nThe skin and urine can develop a reddish colour and the lesions a \nblue\u2013black discoloration. Dose-related nausea, giddiness, headache \nand GI disturbances can also occur.\nPOSSIBLE NEW ANTIBACTERIAL DRUGS\nIn contrast to the rapid discoveries and developments that \ncharacterised the \u2018heroic\u2019 years of antibiotic research span -\nning approximately 1950\u20131980, during which virtually all our existing drugs were produced, the flow has since dried up, with only two completely novel antibiotics introduced \nsince 1980 (Jagusztyn-Krynicka & Wysznska, 2008). At the same time, resistance has been increasing, with about half the infection-related deaths in Europe now attributable to \ndrug resistance (Watson, 2008).\n9\nResistance normally appears within 2 years or so of the \nintroduction of a new agent (Bax et al., 2000). In a disquieting \nreview and meta-analysis, Costelloe et al. (2010) concluded \nthat most patients prescribed antibiotics for a respiratory \nor urinary tract infection develop individual resistance to \nthe drug within a few weeks and that this may persist for \nup to a year after treatment. Since about half the antibiotic use is for veterinary purposes, it is not just human medicine \nthat is implicated in this phenomenon.\nHistorically, antibiotics were one of the mainstays of the \npharmaceutical industry and the medicines they produced were so successful that, by 1970, it was thought that infec -\ntious diseases had been effectively vanquished.\n10 Most of \nthe drugs developed since are the result of incremental changes in the structures of a relatively small number of \nwell-known molecular structures, such as the \u03b2-lactams, DRUGS USED TO TREAT LEPROSY\nLeprosy is one of the most ancient diseases known to mankind and has been mentioned in texts dating back to \n600 BC. The causative organism is M. leprae. It is a chronic \ndisfiguring illness with a long latency and, historically, sufferers", "start_char_idx": 0, "end_char_idx": 3448, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ae735a00-eceb-4fa2-8574-9a75cd6218a9": {"__data__": {"id_": "ae735a00-eceb-4fa2-8574-9a75cd6218a9", "embedding": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3a09c689-4a83-490f-b715-43d48a92af35", "node_type": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a259ea08a8c21612a53b8597b95c320ecbb4c10dd29742b2aa116dcbfe71a5b"}, "2": {"node_id": "308fa410-ee08-4ba4-8fd6-a831f6fe575b", "node_type": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4c57f4d69ffae652e84c144aae1109bafd4e82f61a7e8550549fc241d285a71"}, "3": {"node_id": "592c90b9-c3ff-4059-b9bc-31a595aa871c", "node_type": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa28bf9799e9033b5ec251c062bfa8cbd3ebd1171ea9657c2f76f41197c27c20"}}, "hash": "d4f630e7dcbdea642cd619f5c6fc060830de389a538ed58f6ba76c7bc53e84b7", "text": "\ndisfiguring illness with a long latency and, historically, sufferers have been ostracised and forced to live apart from \ntheir communities, even though the disease is not particu -\nlarly contagious. Once viewed as incurable, the introduction \nin the 1940s of dapsone, and subsequently rifampicin and \nclofazimine in the 1960s, completely changed our perspec -\ntive on leprosy. It is now generally curable, and the global \nfigures show that the prevalence rates for the disease have dropped by 99% over the last 20 years as a result of public \nhealth measures and Multidrug Treatment (MDT) regimens \n(to avoid drug resistance) implemented by WHO and \nsupported by some pharmaceutical companies. The latest \n(2017) figures from the WHO suggest that the disease has \nbeen now eliminated from all but a few small countries. Nevertheless, in 2016, some 210,000 new cases were reported, \nmainly in Asia and Africa.\nThere are two forms:\n\u2022\tPaucibacillary leprosy, leprosy characterised by one to five numb patches, is mainly tuberculoid\n8 in type and is \ngenerally treated for 6 months with dapsone and rifampicin.\n\u2022\tMultibacillary leprosy, characterised by more than five \nnumb skin patches, is mainly lepromatous in type and \nis treated for at least 2 years with rifampicin, dapsone \nand clofazimine.\nDAPSONE\nDapsone is chemically related to the sulfonamides and, because its action is antagonised by PABA, probably acts \nthrough inhibition of bacterial folate synthesis. Resistance \nto the drug has steadily increased since its introduction and treatment in combination with other drugs is now \nrecommended.Antileprosy drugs \n\u2022\tFor\ttuberculoid leprosy :\tdapsone and rifampicin \n(rifampin).\n\u2013 Dapsone is sulfonamide-like and may inhibit folate \nsynthesis. \tIt \tis \tgiven \torally. \tUnwanted \teffects \tare \t\nfairly\tfrequent; \ta \tfew \tare \tserious. \tResistance \tis \t\nincreasing.\n\u2013 Rifampicin (see Antituberculosis drugs box).\n\u2022\tFor\tlepromatous leprosy :\tdapsone, \trifampicin and \nclofazimine.\n\u2013 Clofazimine \tis\ta\tdye\tthat \tis \tgiven \torally \tand \tcan \t\naccumulate \tby \tsequestering \tin \tmacrophages. \tAction \t\nis delayed for 6\u20137 weeks, and its half-life is 8 weeks. \nUnwanted effects include red skin and urine, \nsometimes \tGI \tdisturbances.\n8The difference between tuberculoid and lepromatous disease appears to \nbe that the T cells from patients with the former vigorously produce \ninterferon-\u03b3, which enables macrophages to kill intracellular microbes, \nwhereas in the latter case the immune response is dominated by interleukin-4, which blocks the action of interferon- \u03b3 (see Ch. 19).9The worst offenders are sometimes collectively referred to, rather \nfittingly, as \u2018ESKAPE pathogens\u2019. The acronym is formed of the initial \nletters of E. faecium, S. aureus, K. pneumonia, A. baumanii, P. aeruginosa \nand Enterobacter spp.\n10In 1967 the United States Surgeon General announced (in effect) that \ninfectious diseases had been vanquished, and that the researchers should turn their attention to chronic diseases instead.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3388, "end_char_idx": 6627, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "592c90b9-c3ff-4059-b9bc-31a595aa871c": {"__data__": {"id_": "592c90b9-c3ff-4059-b9bc-31a595aa871c", "embedding": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3a09c689-4a83-490f-b715-43d48a92af35", "node_type": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5a259ea08a8c21612a53b8597b95c320ecbb4c10dd29742b2aa116dcbfe71a5b"}, "2": {"node_id": "ae735a00-eceb-4fa2-8574-9a75cd6218a9", "node_type": null, "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d4f630e7dcbdea642cd619f5c6fc060830de389a538ed58f6ba76c7bc53e84b7"}}, "hash": "aa28bf9799e9033b5ec251c062bfa8cbd3ebd1171ea9657c2f76f41197c27c20", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6641, "end_char_idx": 6944, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "17709f7c-d82c-4c6c-90f5-a1845c8f9207": {"__data__": {"id_": "17709f7c-d82c-4c6c-90f5-a1845c8f9207", "embedding": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3157aec8-ae1d-4b03-b04f-a5941c967e0a", "node_type": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b84bdfef99711d415bbf4cd2564ff0ea88b5621c3f40c33ab286fbf145186640"}, "3": {"node_id": "fcd48e84-f9a4-45b5-9d4c-31ae0bd41f21", "node_type": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "68ad13746257249ad51a947aa4942f5a08ee300eea9b4aef189619230770642b"}}, "hash": "e776dd7837dc4642861b8ecf06eb0164ed98848ec4c349eeac79d7ddc4ce1678", "text": "52 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n676some of those were essentially reformulations of existing \ndrugs. Legislation and government initiatives have been \nintroduced in some countries (e.g. United States) which \npromise fast track FDA approval and extended patent life for those wishing to take the huge financial risks. These, \nand other potentially useful strategies, have been reviewed \nin detail by Renwick et al. (2016).\nCurrent approaches include modification of existing drugs \n(Tillotson, 2016), the isolation and characterisation of new groups of naturally occurring antibiotic substances such \nas the muramycins (Wiegmann et al., 2016), from plants \n(Limsuwan et al., 2009) or bacteria (Sit & Vederas, 2008) \nas well the use of antisense RNA to overcome resistance \nmechanisms (Ji et al., 2013).\nThe latest conceptual tools have all been deployed: \nbioinformatics, utilising information derived from pathogen genome sequencing, is one such approach (Bansal, 2008). \nThe hunt for, and targeting of, bacterial virulence factors \nhas shown promise (Escaich, 2008). New types of screening \nprocedures have been devised (Falconer & Brown, 2009) \nwhich could reveal novel targets, and sophisticated phar-macodynamic profiling is being brought to bear on the \nproblem (Lister, 2006).\nThe world awaits developments with bated breath.to which resistance has developed rapidly. Many phar -\nmaceutical companies scaled down their efforts in the \narea, despite the continuing need for compounds acting \nby novel mechanisms to keep pace with the adaptive \npotential of pathogens. The industry was also discouraged by the fear of inadequate returns from antibiotic drugs which may not recoup their initial outlay \u2013 evidence of \nefficacy is difficult to generate and \u2018success\u2019 is rewarded \nby a product that is used for the shortest duration possible, which physicians will be anxious to restrict in order to \nminimise the emergence of resistance, for diseases that \nare most prevalent in poor countries that cannot afford expensive drugs. These and other complex reasons for \nthe failure to develop new antibiotics have been analysed \nin detail by Coates et al. (2011), who also evaluate many \nnew leads arising from academic and industrial research. \nTheir overall message is rather depressing: they point out \nthat another 20 new classes of antibiotics would need to \nbe discovered in the next 50 years to keep up with the challenges posed by the increasing prevalence of drug \nresistance.\nSo the reality is, unfortunately, that the antibiotic pipeline \nis still far from satisfactory. In the five years leading up to \n2016, the FDA only approved eight new antibiotics and \nREFERENCES AND FURTHER READING \nAntibacterial drugs\nAllington, D.R., Rivey, M.P., 2001. Quinupristine/dalfopristin: a \ntherapeutic review. Clin. Ther. 23, 24\u201344.\nBall, P., 2001. Future of the quinolones. Semin. Resp. Infect 16, 215\u2013224. \n(Good overview of this class of drugs)\nBlondeau, J.M., 1999. Expanded activity and utility of the new \nfluoroquinolones: a review. Clin. Ther. 21, 3\u201315. (Good overview)\nDuran, J.M., Amsden, G.W., 2000. Azithromycin: indications for the \nfuture? Expert Opin. Pharmacother. 1, 489\u2013505.\nGreenwood, D. (Ed.), 1995. Antimicrobial Chemotherapy, third ed. \nOxford University Press, Oxford. (Good all-round textbook)\nLowy, F.D., 1998. Staphylococcus aureus infections. N. Engl. J. Med. 339,", "start_char_idx": 0, "end_char_idx": 3436, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fcd48e84-f9a4-45b5-9d4c-31ae0bd41f21": {"__data__": {"id_": "fcd48e84-f9a4-45b5-9d4c-31ae0bd41f21", "embedding": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3157aec8-ae1d-4b03-b04f-a5941c967e0a", "node_type": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b84bdfef99711d415bbf4cd2564ff0ea88b5621c3f40c33ab286fbf145186640"}, "2": {"node_id": "17709f7c-d82c-4c6c-90f5-a1845c8f9207", "node_type": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e776dd7837dc4642861b8ecf06eb0164ed98848ec4c349eeac79d7ddc4ce1678"}, "3": {"node_id": "c5e8d90d-cc8f-4524-973d-6b7e596fec92", "node_type": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c4f66cffecc58ac9220fafea50d2216bdafffd86f1c858e0b0ec38c1afb6159"}}, "hash": "68ad13746257249ad51a947aa4942f5a08ee300eea9b4aef189619230770642b", "text": "aureus infections. N. Engl. J. Med. 339, \n520\u2013541. (Explains the basis of S. aureus pathogenesis of infection, \nresistance; extensive references; impressive diagrams)\nPerry, C.M., Jarvis, B., 2001. Linezolid: a review of its use in the \nmanagement of serious gram-positive infections. Drugs 61, 525\u2013551.\nShimada, J., Hori, S., 1992. Adverse effects of fluoroquinolones. Prog. \nDrug Res. 38, 133\u2013143.\nZurenko, G.E., Gibson, J.K., Shinabarger, D.L., et al., 2001. \nOxazolidinones: a new class of antibacterials. Curr. Opin. Pharmacol. 1, 470\u2013476. (Easy-to-assimilate review that discusses this relatively new \ngroup of antibacterials)\nResistance (see also reading list in Ch. 51)\nBax, R., Mullan, N., Verhoef, J., 2000. The millennium bugs \u2013 the need \nfor and development of new antibacterials. Int. J. Antimicrob. Agents 16, 51\u201359. (Good review that includes an account of the development of \n\u2018resistance\u2019 and a round-up of potential new drugs)\nBloom, B.R., Small, P.M., 1998. The evolving relation between humans \nand Mycobacterium tuberculosis. Lancet 338, 677\u2013678. (Editorial comment)\nCoates, A.R., Halls, G., Hu, Y., 2011. Novel classes of antibiotics or more \nof the same? Br. J. Pharmacol. 163, 184\u2013194. (A comprehensive review \nthat sets out the challenges we face because of antibiotic resistance. Also \nincludes a survey of potential new leads. Easy to read and highly recommended)\nCostelloe, C., Metcalfe, C., Lovering, A., Mant, D., Hay, A.D., 2010. \nEffect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. \nBMJ 340, c2096. (Details the incidence of resistance following simple \nantibiotic regimes. Truly depressing)\nCourvalin, P., 1996. Evasion of antibiotic action by bacteria. J. \nAntimicrob. Chemother. 37, 855\u2013869. (Covers developments in the understanding of the genetics and biochemical mechanisms of resistance)\nGold, H.S., Moellering, R.C., 1996. Antimicrobial drug resistance. N. \nEngl. J. Med. 335, 1445\u20131453. (Excellent well-referenced review; covers mechanisms of resistance of important organisms to the main drugs; has useful table of therapeutic and preventive strategies, culled from the literature)\nIseman, M.D., 1993. Treatment of multidrug-resistant tuberculosis. N. \nEngl. J. Med. 329, 784\u2013791.\nLivermore, D.M., 2000. Antibiotic resistance in staphylococci. J. \nAntimicrob. Agents 16, S3\u2013S10. (Overview of problems of bacterial resistance)\nMichel, M., Gutman, L., 1997. Methicillin-resistant Staphylococcus aureus \nand vancomycin-resistant enterococci: therapeutic realities and possibilities. Lancet 349, 1901\u20131906. (Excellent review article; good diagrams)\nNicas, T.I., Zeckel, M.L., Braun, D.K., 1997. Beyond vancomycin: new \ntherapies to meet the challenge of glycopeptide resistance. Trends Microbiol. 5, 240\u2013249.\nWatson, R., 2008. Multidrug resistance responsible for half of deaths \nfrom healthcare associated infections in Europe. BMJ 336, 1266\u20131267.\nNew approaches to antibacterial drug discovery\n(These papers have", "start_char_idx": 3403, "end_char_idx": 6441, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c5e8d90d-cc8f-4524-973d-6b7e596fec92": {"__data__": {"id_": "c5e8d90d-cc8f-4524-973d-6b7e596fec92", "embedding": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3157aec8-ae1d-4b03-b04f-a5941c967e0a", "node_type": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b84bdfef99711d415bbf4cd2564ff0ea88b5621c3f40c33ab286fbf145186640"}, "2": {"node_id": "fcd48e84-f9a4-45b5-9d4c-31ae0bd41f21", "node_type": null, "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "68ad13746257249ad51a947aa4942f5a08ee300eea9b4aef189619230770642b"}}, "hash": "5c4f66cffecc58ac9220fafea50d2216bdafffd86f1c858e0b0ec38c1afb6159", "text": "approaches to antibacterial drug discovery\n(These papers have been provided for those who want to learn more about the \nwork under way to develop novel antibacterial drugs. Some are quite \ntechnical in nature)\nBansal, A.K., 2008. Role of bioinformatics in the development of new \nantibacterial therapy. Expert Rev. Anti Infect. Ther. 6, 51\u201365.\nDraenert, R., Seybold, U., Grutzner, E., Bogner, J.R., 2015. Novel \nantibiotics: are we still in the pre-post-antibiotic era? Infection 43, \n145\u2013151.\nEscaich, S., 2008. Antivirulence as a new antibacterial approach for \nchemotherapy. Curr. Opin. Chem. Biol. 12, 400\u2013408.\nFalconer, S.B., Brown, E.D., 2009. New screens and targets in \nantibacterial drug discovery. Curr. Opin. Microbiol. 12, 497\u2013504.\nJagusztyn-Krynicka, E.K., Wyszynska, A., 2008. The decline of antibiotic \nera \u2013 new approaches for antibacterial drug discovery. Pol. J. \nMicrobiol. 57, 91\u201398.\nJi, Y., Lei, T., 2013. Antisense RNA regulation and application in the \ndevelopment of novel antibiotics to combat multidrug resistant bacteria. Sci. Prog. 96, 43\u201360.\nLimsuwan, S., Trip, E.N., Kouwen, T.R., et al., 2009. Rhodomyrtone: a \nnew candidate as natural antibacterial drug from Rhodomyrtus \ntomentosa. Phytomedicine 16, 645\u2013651.\nLister, P.D., 2006. The role of pharmacodynamic research in the \nassessment and development of new antibacterial drugs. Biochem. Pharmacol. 71, 1057\u20131065.\nLoferer, H., 2000. Mining bacterial genomes for antimicrobial targets. \nMol. Med. Today 6, 470\u2013474. (An interesting article focusing on the way mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6414, "end_char_idx": 8435, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f4da3630-314a-4606-b347-93324865c795": {"__data__": {"id_": "f4da3630-314a-4606-b347-93324865c795", "embedding": null, "metadata": {"page_label": "683", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "824fb0fb-f4ae-4ba4-9247-46cba7d4f5d7", "node_type": null, "metadata": {"page_label": "683", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "784d50ed2c12f6770ca05d5a7b0eda11a765232d83e5d10f704815ea360f0c89"}}, "hash": "784d50ed2c12f6770ca05d5a7b0eda11a765232d83e5d10f704815ea360f0c89", "text": "52 ANTIbACTERIA l DRUGS\n677Wiegmann, D., Koppermann, S., Wirth, M., Niro, G., Leyerer, K., \nDucho, C., 2016. Muraymycin nucleoside-peptide antibiotics: \nuridine-derived natural products as lead structures for the \ndevelopment of novel antibacterial agents. Beilstein J. Org. Chem. 12, 769\u2013795.\nUseful website\nhttp://www.who.int. (Once again, the World Health Organization website \nis a mine of information about the demographics and treatment of infectious \ndiseases. The sections on leprosy and tuberculosis are especially worthwhile \nstudying. The site includes photographs, maps and much statistical information, as well as information on drug resistance. Highly \nrecommended)in which a better understanding of the bacterial genome may lead to new \ndrugs)\nO\u2019Neill, A.J., 2008. New antibacterial agents for treating infections \ncaused by multi-drug resistant Gram-negative bacteria. Expert. Opin. Invest. Drugs 17, 297\u2013302.\nRenwick, M.J., Brogan, D.M., Mossialos, E., 2016. A systematic review \nand critical assessment of incentive strategies for discovery and development of novel antibiotics. J. Antibiot. (Tokyo) 69, 73\u201388.\nSit, C.S., Vederas, J.C., 2008. Approaches to the discovery of new \nantibacterial agents based on bacteriocins. Biochem. Cell Biol. 86, 116\u2013123.\nTillotson, G.S., 2016. Trojan horse antibiotics-a novel way to circumvent \ngram-negative bacterial resistance? Infect. Dis. (Auckl.) 9, 45\u201352.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1895, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5a852302-e14e-45bf-8bed-3eaecf363ff9": {"__data__": {"id_": "5a852302-e14e-45bf-8bed-3eaecf363ff9", "embedding": null, "metadata": {"page_label": "684", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d0ad919d-f806-4af9-b586-851f14904b0d", "node_type": null, "metadata": {"page_label": "684", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dac3743f723d621cf6ecd4c5eadb7b999119719affb4613f03032f0601ce41ee"}, "3": {"node_id": "8f6261d4-dbe1-4141-aa5d-70c91feb1286", "node_type": null, "metadata": {"page_label": "684", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "65bf5e170f1e938a27de67f959f1d4f29edb805c73881a32dfe3bd173b3bc797"}}, "hash": "bbaaebd4405ef45d6ecf26e733474b078ac9bd3fa963fe0ae4c9b451a46fabd7", "text": "678\nOVERVIEW\nThis chapter deals with drugs used to treat infections \ncaused by viruses. We first provide some basic \ninformation about viruses, including a simple outline \nof their structure, a list of the main pathogenic species and a brief summary of the life history of an infectious \nspecies. We then continue with a consideration of the \nhost\u2013virus interaction: the defences deployed by the human host against viruses and the strategies \nemployed by viruses to evade these measures. We \nthen discuss the various types of antiviral drugs and their mechanisms of action, with particular reference \nto the treatment of acquired immunodeficiency syn -\ndrome (AIDS), an infection caused by the human \nimmunodeficiency virus (HIV).\nBACKGROUND INFORMATION \nABOUT VIRUSES\nAN OUTLINE OF VIRUS STRUCTURE\nViruses are small (usually in the range 20\u201330 nm) infective \nagents that are incapable of reproduction outside their host \ncells. The free-living virus particle is termed a virion, and \nconsists of segments of nucleic acid (either RNA or DNA) enclosed in a protein coat comprised of symmetrical repeat -\ning structural units and called a capsid (Fig. 53.1). The viral \ncoat, together with the nucleic acid core, is termed the nucleocapsid . Some viruses have a further external lipoprotein \nenvelope, which may be decorated with antigenic viral \nglycoproteins or phospholipids acquired from its host when \nthe nucleocapsid buds through the membranes of the infected cell. Certain viruses also contain enzymes that initiate their replication in the host cell.\nViruses are generally characterised either as DNA or RNA \nviruses , depending on the nature of their nucleic acid content. \nThese two broad categories are conventionally subdivided \ninto subgroups, which classify viruses according to whether \nthey contain single- or double-stranded nucleic acids and how this functions during replication.\nEXAMPLES OF PATHOGENIC VIRUSES\nViruses can infect virtually all living organisms, and they are a common cause of disease in humans. Some important \nexamples are as follows:\n\u2022\tDNA viruses: poxviruses (smallpox), herpesviruses \n(chickenpox, shingles, cold sores, glandular fever), \nadenoviruses (sore throat, conjunctivitis) and papillomaviruses (warts).\u2022\tRNA viruses: orthomyxoviruses (influenza), paramyxoviruses (measles, mumps, respiratory tract \ninfections), rubella virus (German measles), \nrhabdoviruses (rabies), picornaviruses (colds, meningitis, poliomyelitis), retroviruses (AIDS, T-cell \nleukaemia), arenaviruses (meningitis, Lassa fever), \nhepadnaviruses (serum hepatitis) and arboviruses (various arthropod-borne illnesses, e.g. encephalitis, \nyellow fever).\nVIRUS FUNCTION AND LIFE HISTORY\nViruses have no metabolic machinery of their own, so to replicate they must first attach to and penetrate a living \nhost cell \u2013 animal, plant or bacterial \u2013 and hijack the victim\u2019s \nown metabolic processes. The first step in this process is facilitated by polypeptide binding sites on the envelope or \ncapsid which interact with receptors on the host cell. These \n\u2018receptors\u2019 are normal membrane constituents, for example, receptors for cytokines, neurotransmitters or hormones, \nion channels, integral membrane glycoproteins, etc. Some \nexamples are listed in Table 53.1.\nFollowing attachment, the receptor\u2013virus complex enters \nthe cell, often utilising receptor-mediated endocytosis \n(though some viruses bypass this route). The virus coat is \nremoved", "start_char_idx": 0, "end_char_idx": 3458, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8f6261d4-dbe1-4141-aa5d-70c91feb1286": {"__data__": {"id_": "8f6261d4-dbe1-4141-aa5d-70c91feb1286", "embedding": null, "metadata": {"page_label": "684", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d0ad919d-f806-4af9-b586-851f14904b0d", "node_type": null, "metadata": {"page_label": "684", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dac3743f723d621cf6ecd4c5eadb7b999119719affb4613f03032f0601ce41ee"}, "2": {"node_id": "5a852302-e14e-45bf-8bed-3eaecf363ff9", "node_type": null, "metadata": {"page_label": "684", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bbaaebd4405ef45d6ecf26e733474b078ac9bd3fa963fe0ae4c9b451a46fabd7"}}, "hash": "65bf5e170f1e938a27de67f959f1d4f29edb805c73881a32dfe3bd173b3bc797", "text": "\n(though some viruses bypass this route). The virus coat is \nremoved by host cell enzymes (often lysosomal in nature) and the virion is dismantled. This is known as the eclipse \nphase of viral infection because virus particles can no longer \nbe detected. Within the host cell the viral nucleic acid is \nreleased and then utilises the host cellular machinery to \nsynthesise nucleic acids and proteins. These are subsequently \nassembled into new virus particles and released from the cell during the shedding (or budding ) phase. The actual way \nin which this occurs differs between DNA and RNA viruses.\nReplication of DNA viruses\nViral DNA enters the host cell nucleus (and may become incorporated into host DNA), where transcription into \nmRNA occurs catalysed by the host cell RNA polymerase. \nTranslation of the mRNA into virus-specific proteins then \ntakes place. Some of these proteins are enzymes which \nthen synthesise more viral DNA, as well as structural \nproteins comprising the viral coat and envelope. After assembly of coat proteins around the viral DNA, complete \nvirions are released by shedding or after host cell lysis.\nReplication of RNA viruses\nEnzymes within the virion synthesise its mRNA from the \nviral RNA template (sometimes the viral RNA serves as \nits own mRNA). This is translated by the host cell into \nvarious enzymes, including RNA polymerase (which directs \nthe synthesis of more viral RNA), and also into structural \nproteins for the virion. Assembly and release of virions Antiviral drugs53 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER SECTION 5\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3390, "end_char_idx": 5460, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1bc3b0a0-7d2a-49aa-90b7-feea67c86ba0": {"__data__": {"id_": "1bc3b0a0-7d2a-49aa-90b7-feea67c86ba0", "embedding": null, "metadata": {"page_label": "685", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fa5a2fde-e4af-4196-8635-239d3b67ca08", "node_type": null, "metadata": {"page_label": "685", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1122fb580d5a5acec79cef86730f4d851700714bb0688da20587dfe90f338e6a"}, "3": {"node_id": "5821a44d-e113-48f6-9a6a-e5b238907d8e", "node_type": null, "metadata": {"page_label": "685", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9b7f2c0aa946639d1a027097cd97f727d20b2f60c083ad59c9f35ba94e9e52f1"}}, "hash": "8301a9fc6731279b3612f2b982593873a29002e678f461e4c8c5501a9058d5f1", "text": "53 ANTIvIRAl DRUGS\n679RNA-dependent DNA polymerase), which makes a DNA \ncopy of the viral RNA. This DNA copy can then be inte-\ngrated into the host genome, and it is then termed a provirus . \nThe provirus DNA is transcribed into both new viral genome \nRNA as well as mRNA for translation in the host into viral \nproteins, and the completed viruses are again released by \nbudding. Many retroviruses can replicate without killing the host cell.\nLike the DNA viruses, some retroviruses remain dormant \nin the genome being replicated, together with host genetic material. This accounts for the periodic nature of some viral diseases, such as those caused by herpes labialis (cold \nsores) or varicella zoster \u2013 another type of herpes virus (which \ncauses chickenpox and shingles), which can recur when viral replication is reactivated by some factor (or when the \nimmune system is compromised in some way). Other RNA \nretroviruses (e.g. the Rous sarcoma virus) can transform normal cells into malignant cells (a serious concern with \nuse of retroviral vectors for gene therapy, see Ch. 5).\nTHE HOST\u2013VIRUS INTERACTION\nHOST DEFENCES AGAINST VIRUSES\nThe host\u2019s first line of defence is the simple barrier function \nof intact skin, which most viruses are unable to penetrate. \nHowever, broken skin (e.g. at sites of wounds or insect \nbites) and mucous membranes are more vulnerable to viral attack. Should the virus gain entry to the body, then the \nhost will deploy both an innate and, subsequently, an \nadaptive immune response (Ch. 7) to limit the incursion. An infected cell presents viral peptides, complexed with \nmajor histocompatibility complex (MHC) class I molecules \non its surface. This is recognised by T lymphocytes, which then kill the infected cell (Fig. 53.2). Killing may be accom -\nplished by the release of lytic proteins (such as perforins, \ngranzymes) or by triggering the apoptotic pathway of the infected cell by activation of its Fas receptor (\u2018death receptor\u2019, then occurs as explained earlier. The host cell nucleus is \nnot usually involved in replication of RNA viruses, although \nsome (e.g. orthomyxoviruses) replicate exclusively within \nthe host nuclear compartment.\nReplication in retroviruses\nRetroviruses contain RNA but may nevertheless be incor -\nporated in host DNA. To achieve this, the virion in retro -\nviruses1 contains a unique enzyme, reverse transcriptase (virus Lipoprotein envelope\nNucleic acid\ncore\nCoat (capsid)Nucleocapsid\nCapsomere\n(the morphologicalprotein units\nof the coat)\nFig. 53.1 Schematic diagram of the components of a virus \nparticle or virion. \nTable 53.1 Some host cell structures that can function \nas receptors for viruses\nHost cell structureaVirus(es)\nHelper T lymphocytes CD4 \nglycoproteinHIV (causing AIDS)\nCCR5 receptor for chemokines MCP-1 and RANTESHIV (causing AIDS)\nCXCR4 chemokine receptor for cytokine SDF-1HIV (causing AIDS)\nAcetylcholine receptor on skeletal muscleRabies virus\nB lymphocyte complement C3d receptorGlandular fever virus\nT lymphocyte interleukin-2 receptorT-cell leukaemia viruses\n\u03b2-Adrenoceptors Infantile diarrhoea virus\nMHC moleculesAdenovirus (causing sore throat and conjunctivitis) T-cell leukaemia viruses\naFor more detail on complement, interleukin-2, the CD4 \nglycoprotein on helper T lymphocytes, MHC", "start_char_idx": 0, "end_char_idx": 3297, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5821a44d-e113-48f6-9a6a-e5b238907d8e": {"__data__": {"id_": "5821a44d-e113-48f6-9a6a-e5b238907d8e", "embedding": null, "metadata": {"page_label": "685", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fa5a2fde-e4af-4196-8635-239d3b67ca08", "node_type": null, "metadata": {"page_label": "685", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1122fb580d5a5acec79cef86730f4d851700714bb0688da20587dfe90f338e6a"}, "2": {"node_id": "1bc3b0a0-7d2a-49aa-90b7-feea67c86ba0", "node_type": null, "metadata": {"page_label": "685", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8301a9fc6731279b3612f2b982593873a29002e678f461e4c8c5501a9058d5f1"}}, "hash": "9b7f2c0aa946639d1a027097cd97f727d20b2f60c083ad59c9f35ba94e9e52f1", "text": "the CD4 \nglycoprotein on helper T lymphocytes, MHC molecules, etc., see Chapter 7.MCP-1, monocyte chemoattractant protein-1; MHC, major \nhistocompatibility complex; RANTES, regulated on activation normal T cell expressed and secreted; SDF-1, stromal cell-\nderived factor-1.Virus-infected host cell\nLytic\nenzymesMHC-1\nproduct\nAg-\nspecific\nreceptor\nCD8+ killer T cellFas receptor\nFas ligand\nViral peptide\nFig. 53.2 How a CD8+ T cell kills a virus-infected host cell. \nThe virus-infected host cell expresses a complex of virus \npeptides plus major histocompatibility complex class I product (MHC-I) on its surface. This is recognised by the CD8\n+ T cell, \nwhich then releases lytic enzymes into the virus-infected cell. The killer T cell also expresses a Fas ligand which triggers apoptosis in the infected cell by stimulating its Fas \u2018death receptor\u2019. \n1Viruses that can synthesise DNA from an RNA template \u2013 the reverse \nof the normal situation.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3247, "end_char_idx": 4672, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "822074c4-1606-43aa-ab32-37370e6935fa": {"__data__": {"id_": "822074c4-1606-43aa-ab32-37370e6935fa", "embedding": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d4b9959-859f-47dc-aa21-7ba1357b9253", "node_type": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4efd06c5dbc1f4ae5c90987f919fd99d6120c28fcf8ab534763e0ee682a2ddbc"}, "3": {"node_id": "e901335e-d8d0-4eab-a94c-d15feac1f9dc", "node_type": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87fcd90363576d805e4713c4d5918919485b5bfdd7fa4c94173523ef8c2a2b2d"}}, "hash": "77f278c58095773520e35aa7b52011b637675c385b6558a9b22175e11da54203", "text": "53 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n680\u2022\tFooling the \u2018baby turkey\u2019 ploy. Other viruses (e.g. \ncytomegalovirus) get round the \u2018mother turkey \nstrategy\u2019 of NK cells by expressing a homologue of \nMHC class I (the equivalent of a turkey chick\u2019s chirping) that is close enough to the real thing to \nhoodwink NK cells.\nIt is evident that natural selection has equipped pathogenic viruses with many efficacious tactics for circumventing host \ndefences, and understanding these in more detail is likely to suggest new types of antiviral therapy. Fortunately, the \nbiological arms race is not one-sided, and evolution has \nalso equipped the host with sophisticated countermeasures. In the majority of cases these prevail, and most viral infec -\ntions eventually resolve spontaneously, except in immu -\nnocompromised hosts. The situation does not always end happily though; some viral infections, such as Lassa fever \nand Ebola virus infection, have a high mortality and we \nnow discuss a further, grave, example: the HIV virus. This emphasis is appropriate because, whilst the infection \ndevelops more slowly than (e.g.) Ebola virus, HIV exhibits \nmany of the features common to other viral infections, and the sheer scale of the global AIDS problem has pushed \nHIV to the top of the list of antiviral targets.see Ch. 6). The latter may also be triggered indirectly through the release of a cytokine such as tumour necrosis factor \n(TNF)-\u03b1. Natural killer (NK) cells will also react to the absence of normal MHC molecules by killing the cell. This \nis called the \u2018mother turkey\u2019 strategy (kill everything that \ndoes not sound exactly like a baby turkey; see Ch. 7). The virus may escape immune detection by cytotoxic lympho -\ncytes by modifying the expression of the peptide\u2013MHC \ncomplex (see Ch. 7), but still fall victim to NK cells, though \nsome viruses also have a device for evading NK cells as well (see later).\nWithin the cell itself, gene silencing provides a further \nlevel of protection (see Schutze, 2004). Short double-stranded fragments of RNA, such as those that could arise as a result \nof the virus\u2019s attempts to recruit the host\u2019s transcription/\ntranslational machinery, actually cause the gene coding for the RNA to be \u2018silenced\u2019 \u2013 to be switched off. The gene is \nthen no longer able to direct further viral protein synthesis \nand replication is halted. This mechanism can be exploited for experimental purposes in many areas of biology, and \ntailored siRNA ( small- or short-interfering RNA ) is a cheap \nand useful technique to suppress temporarily the expression \nof a particular gene of interest. Attempts to harness the \ntechnique for viricidal purposes have met with some success \n(see Barik, 2004), and are beginning to find their way into therapeutics (see Ch. 5).\nVIRAL PLOYS TO CIRCUMVENT HOST DEFENCES\nViruses have evolved a variety of strategies to ensure successful infection, some entailing redirection of the host\u2019s \nresponse for the advantage of the virus (discussed by \nTortorella et al., 2000). Some examples are discussed later.\nSubversion of the immune response\nViruses can inhibit the synthesis or action of cytokines, \nsuch as interleukin-1, TNF- \u03b1 and antiviral interferons (IFNs) \nthat normally coordinate the innate and adaptive immune responses. For example, following infection, some poxviruses express proteins that mimic the extracellular ligand-binding \ndomains of cytokine receptors. These", "start_char_idx": 0, "end_char_idx": 3469, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e901335e-d8d0-4eab-a94c-d15feac1f9dc": {"__data__": {"id_": "e901335e-d8d0-4eab-a94c-d15feac1f9dc", "embedding": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d4b9959-859f-47dc-aa21-7ba1357b9253", "node_type": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4efd06c5dbc1f4ae5c90987f919fd99d6120c28fcf8ab534763e0ee682a2ddbc"}, "2": {"node_id": "822074c4-1606-43aa-ab32-37370e6935fa", "node_type": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "77f278c58095773520e35aa7b52011b637675c385b6558a9b22175e11da54203"}, "3": {"node_id": "15109ffa-ee7a-4100-994e-0570215ab06c", "node_type": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "89a3c7c7adfa589c791bd1b98254c33dd25bf2b788971fab1eb511fec0387589"}}, "hash": "87fcd90363576d805e4713c4d5918919485b5bfdd7fa4c94173523ef8c2a2b2d", "text": "extracellular ligand-binding \ndomains of cytokine receptors. These pseudoreceptors bind \ncytokines, preventing them from reaching their natural \nreceptors on cells of the immune system and thus moderat -\ning the normal immune response to virus-infected cells. Other viruses that can interfere with cytokine signalling include human cytomegalovirus, Epstein\u2013Barr virus, herpesvirus and adenovirus.\nEvasion of immune detection and attack by \nkiller cells\nOnce within host cells, viruses may also escape immune detection and evade lethal attack by cytotoxic lymphocytes \nand NK cells in various ways, such as:\n\u2022\tInterference with the surface protein markers on the infected \ncells necessary for killer cell recognition and attack. Some \nviruses inhibit generation of the antigenic peptide and/or the presentation of MHC\u2013peptide molecules \nthat signals that the cells are infected. In this way, the \nviruses remain undetected. Examples of viruses that can do this are adenovirus, herpes simplex virus, human cytomegalovirus, Epstein\u2013Barr virus and \ninfluenza virus.\n\u2022\tInterference with the apoptotic pathway. Adenovirus, \nhuman cytomegalovirus and Epstein\u2013Barr virus can \nsubvert this pathway to ensure their own survival.Viruses \n\u2022\tViruses\tare \tsmall \tinfective \tagents \tconsisting \tof \tnucleic \t\nacid (RNA or DNA) enclosed in a protein coat.\n\u2022\tThey\tare \tnot \tcells \tand, \thaving \tno \tmetabolic \tmachinery \t\nof their own, are obligate intracellular parasites, utilising \nthe metabolic processes of the host cell to replicate.\n\u2022\tDNA viruses (e.g. herpes virus) usually enter the host \ncell nucleus and direct the generation of new viruses.\n\u2022\tRNA viruses (e.g. rubella virus) usually direct the \ngeneration of new viruses without involving the host cell nucleus (the influenza virus is an exception).\n\u2022\tRNA retroviruses\n\t(e.g.\tHIV, \tT-cell \tleukaemia \tvirus) \t\ncontain an enzyme, reverse transcriptase, which makes a DNA copy of the viral RNA. This DNA copy is integrated into the host cell genome and directs the \ngeneration of new virus particles.\nHIV AND AIDS\nHIV is an RNA retrovirus. Two forms are known: HIV-1 \nis the principal organism responsible for human AIDS. The \nHIV-2 organism is similar to the HIV-1 virus in that it also \ncauses immune suppression, but it is less virulent. HIV-1 \nis distributed around the world, whereas the HIV-2 virus \nis confined to parts of Africa.\n\u25bc The HIV/AIDS epidemic is overwhelmingly centred on sub-Saharan \nAfrica, which accounts for two-thirds of the total global number of \ninfected persons, and where the adult prevalence is over 10 times \ngreater than in Europe. For a review of the pathogenesis (and many other aspects) of AIDS, see Moss (2013).\nThanks to increased availability of effective drug therapy, the global \nsituation is improving and the number of AIDS-related deaths is \nfalling. Even so, recent statistics (UNAIDS, 2016) suggest that over \n36 million people are presently living with HIV, including over 2 million children (a particularly horrid thought) and that new infections \nare appearing at the rate of about 2 million per year.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3410, "end_char_idx": 6810, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "15109ffa-ee7a-4100-994e-0570215ab06c": {"__data__": {"id_": "15109ffa-ee7a-4100-994e-0570215ab06c", "embedding": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5d4b9959-859f-47dc-aa21-7ba1357b9253", "node_type": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4efd06c5dbc1f4ae5c90987f919fd99d6120c28fcf8ab534763e0ee682a2ddbc"}, "2": {"node_id": "e901335e-d8d0-4eab-a94c-d15feac1f9dc", "node_type": null, "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "87fcd90363576d805e4713c4d5918919485b5bfdd7fa4c94173523ef8c2a2b2d"}}, "hash": "89a3c7c7adfa589c791bd1b98254c33dd25bf2b788971fab1eb511fec0387589", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6823, "end_char_idx": 7046, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "07f320d7-d5d6-4c8c-829c-f3ee0d6c146b": {"__data__": {"id_": "07f320d7-d5d6-4c8c-829c-f3ee0d6c146b", "embedding": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e312db83-3c5b-4dff-ad20-cdd92ef0e117", "node_type": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "996ca9bdd80e1d412af30ea52e696c8ea41120394b42177b44fccabaf56b79c6"}, "3": {"node_id": "f1662d20-383f-4e90-a6ea-271f5afa0fb6", "node_type": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e94cd4dda594c7400d2db60a7f2b81d29e0b9183067519bed658d219ca53d1c2"}}, "hash": "41e2b9293d81af9ec4a770f0f10efc0b887acdf8a92a03a810ce176cc59957de", "text": "53 ANTIvIRAl DRUGS\n681PROGRESS OF INFECTION\nOnce within the cell, the HIV RNA directs synthesis of \nDNA (the provirus) which is integrated with the host DNA, \nundergoes transcription and begins to generate new virions. \nThis process, which takes less than 48 h, can lead to the \nrelease of a staggering 1010 new virus particles each day \n(see Fig. 53.3). Intracellular HIV can remain silent (latent) for a long time.\nViral replication is highly error prone. Many mutations \noccur daily at each site in the HIV genome, so HIV soon escapes recognition by the original cytotoxic lymphocytes. \nAlthough other cytotoxic lymphocytes arise that recognise \nthe altered virus protein(s), further mutations eventually \nallow escape from surveillance by these cells too. It is \nsuggested that wave after wave of cytotoxic lymphocytes \nact against new mutants as they arise, gradually depleting a T-cell repertoire already seriously compromised by the \nloss of CD4\n+ helper T cells, until eventually the immune \nresponse falters or completely fails.\nThere is considerable variability in the progress of the \ndisease, but the usual clinical course of an untreated HIV \ninfection is shown in Fig. 53.4. An initial acute influenza-like \nillness is associated with an increase in the number of virus \nparticles in the blood, their widespread dissemination through the tissues and the seeding of lymphoid tissue \nwith the virion particles. Within a few weeks, this viraemia \nis reduced by the action of cytotoxic lymphocytes as \nexplained earlier.\nThe acute initial illness is followed by a symptom-free \nperiod during which there is reduction in the viraemia accompanied by silent virus replication in the lymph nodes, associated with damage to lymph node architecture and \nthe loss of CD4\n+ lymphocytes and dendritic cells. Clinical \nlatency (median duration 10 years) comes to an end when the immune response finally fails and the signs and symp-\ntoms of AIDS appear \u2013 opportunistic infections (e.g. Pneumocystis pneumonia or tuberculosis), neurological \ndisease (e.g. confusion, paralysis, dementia), bone marrow \ndepression and malignancies such as lymphoma and Kaposi\u2019s \nsarcoma .\n2 Chronic gastrointestinal (GI) infections contribute \nto the severe weight loss. Cardiovascular and kidney damage \ncan also occur. In an untreated patient, death usually follows \nwithin 2 years. The advent of effective drug regimens has greatly improved the prognosis in countries that are able \nto deploy them and patients thus treated may enjoy a \nnear-normal life expectancy.\nThere is evidence that genetic factors play an important \nrole in determining the susceptibility \u2013 or resistance \u2013 to \nHIV (see Flores-Villanueva et al., 2003).\nANTIVIRAL DRUGS\nBecause viruses hijack many of the metabolic processes of the host cell itself, it is difficult to find drugs that are selective \nfor the pathogen. However, there are some enzymes that \nare virus-specific and these have proved to be useful drug targets. Most currently available antiviral agents are effective More optimistically, the overall infection rate amongst adults has \ndeclined by more than 10% since 2010 and by almost 50% in the case \nof children. Global deaths from HIV have also fallen by almost half \nsince 2005 and access to antiretroviral therapy has increased year upon year. Currently some 19 million people are receiving the drugs \n\u2013 approximately half of all those suffering from HIV.\nINDUCTION OF THE DISEASE\nThe interaction of HIV with the host\u2019s immune system \nis complex, and although it involves mainly cytotoxic \nT lymphocytes (CTLs, CD8+ T cells) and CD4+", "start_char_idx": 0, "end_char_idx": 3612, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f1662d20-383f-4e90-a6ea-271f5afa0fb6": {"__data__": {"id_": "f1662d20-383f-4e90-a6ea-271f5afa0fb6", "embedding": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e312db83-3c5b-4dff-ad20-cdd92ef0e117", "node_type": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "996ca9bdd80e1d412af30ea52e696c8ea41120394b42177b44fccabaf56b79c6"}, "2": {"node_id": "07f320d7-d5d6-4c8c-829c-f3ee0d6c146b", "node_type": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "41e2b9293d81af9ec4a770f0f10efc0b887acdf8a92a03a810ce176cc59957de"}, "3": {"node_id": "ec4d3119-43c3-4fa1-9dea-d34752132999", "node_type": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1d86a1bd54e1d7d7e41ebdcc25536f71b1928bc1ec139676b0eacd6d057773a2"}}, "hash": "e94cd4dda594c7400d2db60a7f2b81d29e0b9183067519bed658d219ca53d1c2", "text": "\nT lymphocytes (CTLs, CD8+ T cells) and CD4+ helper T \nlymphocytes (CD4+ cells), other immune cells, such as \nmacrophages, dendritic cells and NK cells, also play a part. Antibodies are produced by the host to various HIV \ncomponents, but it is the action of the CTLs and CD4\n+ \ncells that initially prevents the spread of HIV within \nthe host.\n\u2022\tCytotoxic T lymphocytes (CTLs) directly kill virally \ninfected cells and produce and release antiviral \ncytokines (see Fig. 53.2). The lethal event is lysis of the \ntarget cell, but induction of apoptosis by interaction of Fas ligand (see Ch. 6) on the CTL with Fas receptors \non the virally infected cell also plays a part.\n\u2022\tCD4\n+ cells have an important role as helper cells and \nmay have a direct role in the control of HIV \nreplication (e.g. lysis of target cells: Norris et al., 2004). \nIt is the progressive loss of these cells that is the \ndefining characteristic of HIV infection (see Fig. 53.4 \nlater).\nThe priming of naive T cells to become CTL during the \ninduction phase involves interaction of the T-cell receptor \ncomplex with antigenic HIV peptide, in association with \nMHC class I molecules on the surface of antigen-presenting cells (APCs; see Ch. 7). Priming also requires the presence \nand participation of CD4\n+ cells. It is thought that both types \nof cell need to recognise antigen on the surface of the same APC.\nThe CTLs thus generated are effective during the initial \nstages of the infection but are not able to stop the progression of the disease. It is believed that this is because they become \n\u2018exhausted\u2019 and unable to maintain their protective function. \nDifferent mechanisms may be involved (see Jansen et al., \n2004, and Barber et al., 2006, for further details).\n\u25bc The HIV virion cannily attaches to proteins on the host cell surface \nto gain entry to the cells. The main targets are CD4 (the glycoprotein \nmarker of a particular group of helper T lymphocytes) and CCR5 (a \nco-receptor for certain chemokines, including monocyte chemoat-tractant protein-1 and RANTES; see Ch. 7). CD4\n+ cells normally \norchestrate the immune response to viruses, but by entering these \ncells and using them as virion factories, HIV virtually cripples this \naspect of the immune response. Fig. 53.3 shows an HIV virion infecting a CD4\n+ T cell. Such infected activated cells in lymphoid tissue form \nthe major source of HIV production in HIV-infected individuals; \ninfected macrophages are another source.\nAs for CCR5, evidence from exposed individuals who somehow evade \ninfection indicates that this surface protein has a central role in HIV \npathogenesis. Compounds that inhibit the entry of HIV into cells by blocking CCR5 are now available.\nWhen immune surveillance breaks down, other strains of HIV arise, \nthrough spontaneous mutational events, which recognise other host \ncell surface molecules. A surface glycoprotein, gp120, on the HIV \nenvelope recognises and binds to CD4 and also to the T-cell chemokine co-receptor CXCR4. Another viral glycoprotein, gp41, then causes \nfusion of the viral envelope with the plasma membrane of the cell \n(see Fig. 53.3).2A tumor caused by infection with human herpesvirus 8 (HHV8), also \nknown as Kaposi\u2019s sarcoma-associated herpesvirus (KSHV) or KS agent, \nwas originally described by Moritz Kaposi, a Hungarian dermatologist \npracticing at the University of Vienna in 1872. It became more widely known as one of the", "start_char_idx": 3576, "end_char_idx": 7008, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ec4d3119-43c3-4fa1-9dea-d34752132999": {"__data__": {"id_": "ec4d3119-43c3-4fa1-9dea-d34752132999", "embedding": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e312db83-3c5b-4dff-ad20-cdd92ef0e117", "node_type": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "996ca9bdd80e1d412af30ea52e696c8ea41120394b42177b44fccabaf56b79c6"}, "2": {"node_id": "f1662d20-383f-4e90-a6ea-271f5afa0fb6", "node_type": null, "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e94cd4dda594c7400d2db60a7f2b81d29e0b9183067519bed658d219ca53d1c2"}}, "hash": "1d86a1bd54e1d7d7e41ebdcc25536f71b1928bc1ec139676b0eacd6d057773a2", "text": "the University of Vienna in 1872. It became more widely known as one of the AIDS-defining illnesses in the 1980s.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6970, "end_char_idx": 7562, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cbfb93d3-c829-4797-a4d1-48e2d5f1eb32": {"__data__": {"id_": "cbfb93d3-c829-4797-a4d1-48e2d5f1eb32", "embedding": null, "metadata": {"page_label": "688", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "913484e6-4046-48e9-a730-b53274e33352", "node_type": null, "metadata": {"page_label": "688", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e2a8adc4525d907caed0e3e548b4e64ecbb37308636fe961de14cc3736ce4855"}}, "hash": "e2a8adc4525d907caed0e3e548b4e64ecbb37308636fe961de14cc3736ce4855", "text": "53 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n682hence the importance of pre-exposure prophylaxis wherever \npossible.\nAntiviral drugs, of which many are now available, may \nbe conveniently grouped according to their mechanisms of action. Table 53.2 shows the commonest agents, classified only while the virus is replicating. Because the initial phases of viral infection are often asymptomatic, treatment is often \nnot initiated until the infection is well established. This is \nunfortunate because, as is often the case with infectious diseases, an ounce of prevention is worth a pound of cure, \nCD4\n(6) Transcription of provirusIntegraseEnvelope\ngp120\nReverse\ntranscriptaseRNA\nNucleocapsid\nProtease\nCXCR5/4 ck receptor\nNUCLEUS\nCYTOPLASMGenomic RNAProtease\ninhibitors\n and\nmaturation\ninhibitorsInhibitors\nof viral\nfusionPolypeptides\nmRNAPLASMA MEMBRANE(1) Binding\n(2) Entry\n(3) Uncoating\n(4) Reverse transcriptase \nmakes a double-stranded \nDNA copy of viral RNA(7) Translation \nby host ribosomes(9) Assembly and \nbudding(10) New virion\nReverse\ntranscriptase\ninhibitors(8) Protease action\n(5) DNA copy (+integrase: ) enters nucleus and \nintegrates with host DNA, forming provirusChemokine\nInhibitors\nof viral\nsheddingreceptor\nantagonists\nInhibitors\nof viral\nintegrase\nFig. 53.3 Schematic diagram of infection of a CD4+ T cell by an HIV virion, with the sites of action of the main classes of \nanti-HIV drugs. \tThe\t10\tsteps \tof \tHIV \tinfection, \tfrom \tattachment \tto \tthe \tcell \tto \trelease \tof \tnew \tvirions, \tare \tshown. \tThe \tvirus \tuses \tthe \tCD4 \t\nco-receptor and the chemokine (ck) receptors CCR5/CXCR4 as binding sites to facilitate entry into the cell, where it becomes incorporated \ninto host DNA (steps 1\u20135). When transcription occurs (step 6), the T cell itself is activated and the transcription factor nuclear factor \u03baB \ninitiates transcription of both host cell and provirus DNA. A viral protease cleaves the nascent viral polypeptides (steps 7 and 8) into \nenzymes (integrase, reverse transcriptase, protease) and structural proteins for new virions. These are assembled and released from the cells, initiating a fresh round of infection (steps 9 and 10)\n.\tThe\tsites \tof \taction \tof \tanti-HIV \tdrugs \tare \tshown. \tmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2739, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "025eb361-7199-452c-90cc-278077c0952c": {"__data__": {"id_": "025eb361-7199-452c-90cc-278077c0952c", "embedding": null, "metadata": {"page_label": "689", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "821b4f19-5f6c-4e50-a77b-09918f8c2077", "node_type": null, "metadata": {"page_label": "689", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "39704c5b2eb8512721f5078bf5e24e69449d0943255a7461e7c1bb7cb1c17cc9"}}, "hash": "39704c5b2eb8512721f5078bf5e24e69449d0943255a7461e7c1bb7cb1c17cc9", "text": "53 ANTIvIRAl DRUGS\n6830\n0369 12Constitutional\nsymptomsOpportunistic\ndiseases\n12\nWeeks YearsCD4+ T cells/mm3\nPlasma viraemia titre\n3456789 11 1020040060080010001200\n01:21:41:81:161:321:641:1281:2561:512Death\nClinical latencyPossible acute HIV syndrome\nWide dissemination of virusSeeding of lymphoid organsPrimary infection( )\n( )\nFig. 53.4 Schematic outline of the course of HIV infection. The CD4+ T-cell titre is often expressed as cells/mm3. (Adapted from \nPantaleo et al., 1993.)\nTable 53.2 Drugs used to treat viral infections\nCommon use Drug Mechanism of action Comments\nCytomegalovirusCidofovir, foscarnet, \nganciclovir, valganciclovirNucleoside or nucleotide analogues and other drugs that inhibit viral DNA polymeraseMultiple GI and other SE\nHepatitis BAdefovir, entecavir, lamivudine, telbivudine, tenvofirNucleoside or nucleotide analogues that inhibit reverse transcriptaseMultiple GI and other SE common\nHepatitis CDaclatasvir, ledipasvir, ombitasvir, ritonavirNS 5A Protease inhibitors Ritonavir delays metabolism of other drugs and enhances their effects. Multiple SE common. Ledipasvir used as part of a fixed-dose combination with sofosbuvir.Boceprevir, paritaprevir, simeprevir, telaprevirNS 3/4A protease inhibitors\nDasabuvir, sofosbuvir NS 5B RNA polymerase inhibitors\nRibavirin Nucleoside analogue: uncertain mechanismAlso used for other viral infections. Multiple SE common.\nHepatitis B and C Interferon-\u03b1, pegylated interferon-\u03b1Immuno-stimulant \u2018Flu-like\u2019 SE common\nHerpesAciclovir, famciclovir (PD), idoxuridine, penciclovir, valaciclovirNucleoside and other viral DNA polymerase inhibitorsMultiple SE common. Idoxuridine used for topical ocular usage.\nInosine prabonex Immunomodulator Metabolic SE\nInfluenza A & BOseltamivir Neuraminidase inhibitor Should be given with 2 days of infection. GI side effects common.\nZanamivir Neuraminidase inhibitorShould be given with 2 days of infection. Used in immunocompetent patients. Common SEs include rash.\nAmantadine Blocks ion channel in virus Influenza A only (seldom used today)\nRespiratory syncytial virusPalivizumab Targets viral protein important for internalisation into cellsRibavirin also used\nGI, gastrointestinal; PD, prodrug; SE, side effects.\n(Data from various sources including BNF 2017.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2753, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "739b48cc-99bd-4703-ab40-307bb2290cc9": {"__data__": {"id_": "739b48cc-99bd-4703-ab40-307bb2290cc9", "embedding": null, "metadata": {"page_label": "690", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4f9087d6-e32e-4014-9900-d3ef952f3b28", "node_type": null, "metadata": {"page_label": "690", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ebe6a8c3a7fcbaa4c31298505c6188e09cfb6cf6ea60215fe73ae1489581bbf8"}, "3": {"node_id": "5fcab2b6-fc2b-4c7c-94a2-67c82cc5f249", "node_type": null, "metadata": {"page_label": "690", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7225cf86a376a0dcbcd7fa3e351d804d7d69f6302c4db0e25dc0f921d81a2925"}}, "hash": "58f26c68b6cd3882eb90683fc587eff168e419169a3e51b585fb41aa99cc31dc", "text": "53 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n684Because of rapid mutation, the virus is a constantly \nmoving target, and resistance develops with long-term use \nof zidovudine, particularly in late-stage disease. Further -\nmore, resistant strains can be transferred between individu -\nals. Other factors that underlie the loss of efficacy of the drug are decreased activation of zidovudine to the tris -\nphosphate and increased virus load as the host immune \nresponse fails.\nUnwanted effects include GI disturbances (e.g. nausea, \nvomiting, abdominal pain), blood disorders (sometimes anaemia or neutropenia) and central nervous system (CNS) effects (e.g. insomnia, dizziness, headache), as well as the \nrisk of lactic acidosis (possibly secondary to mitochondrial \ntoxicity) in some patients; all these effects are shared by this entire group of drugs to a greater or lesser extent.\nOther, currently approved, antiviral drugs in this group \ninclude abacavir , adefovir , dipivoxil , didanosine , emtric -\nitabine, entecavir, lamivudine, stavudine, telbivudine \nand tenofovir which are used for hepatitis B as well as \ntreatment.\nNON-NUCLEOSIDE REVERSE TRANSCRIPTASE \nINHIBITORS\nNon-nucleoside reverse transcriptase inhibitors are chemi -\ncally diverse compounds that bind to the reverse tran -\nscriptase enzyme near the catalytic site and inactivate it. \nMost are also inducers, substrates or inhibitors, to varying degrees, of the liver cytochrome P450 enzymes (Ch. 10). \nCurrently available drugs include efavirenz and nevirapine , \nand the related compounds etravirine and rilpivarine.\nEfavirenz (plasma half-life ~50 h) is given orally, once \ndaily. It is 99% bound to plasma albumin, and its CSF \nconcentration is ~1% of that in the plasma. Nevertheless, \nits major adverse effects are insomnia, bad dreams and \nsometimes psychotic symptoms. It is teratogenic.in this manner together with some of the diseases they are \nused to treat, whilst Table 53.3 lists the principal agents \nspecifically used to treat HIV.\nREVERSE TRANSCRIPTASE INHIBITORS\nThese include nucleoside or nucleotide analogues , exemplified \nby zidovudine and tenofovir, respectively. Nucleosides \nare first phosphorylated to the corresponding nucleotides and can then act as false substrates, being further phos-phorylated by host cell enzymes and incorporated into the \ngrowing DNA chain, but causing chain termination. The \n\u03b3-DNA polymerase in the host cell mitochondria is also susceptible to inhibition by these agents. Mammalian \u03b1-DNA \npolymerase is relatively resistant but effects may be seen at high doses and inhibition of host polymerase enzymes may be the basis of some unwanted effects. The main utility of these drugs is the treatment of HIV, but a number of \nthem have useful activity against other viruses also (e.g. \nhepatitis B, which, though not a retrovirus, uses reverse transcriptase for replication).\nZidovudine\nZidovudine (or azidothymidine, AZT) was the first drug to be introduced for the treatment of HIV and retains an \nimportant place in therapy. It can prolong life in HIV-\ninfected individuals and diminish HIV-associated dementia. Given during pregnancy and then to the newborn infant, \nit can reduce mother-to-baby transmission by more than \n20%. It is generally administered orally 2\u20133 times each day but can also be given by", "start_char_idx": 0, "end_char_idx": 3365, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5fcab2b6-fc2b-4c7c-94a2-67c82cc5f249": {"__data__": {"id_": "5fcab2b6-fc2b-4c7c-94a2-67c82cc5f249", "embedding": null, "metadata": {"page_label": "690", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "4f9087d6-e32e-4014-9900-d3ef952f3b28", "node_type": null, "metadata": {"page_label": "690", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ebe6a8c3a7fcbaa4c31298505c6188e09cfb6cf6ea60215fe73ae1489581bbf8"}, "2": {"node_id": "739b48cc-99bd-4703-ab40-307bb2290cc9", "node_type": null, "metadata": {"page_label": "690", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "58f26c68b6cd3882eb90683fc587eff168e419169a3e51b585fb41aa99cc31dc"}}, "hash": "7225cf86a376a0dcbcd7fa3e351d804d7d69f6302c4db0e25dc0f921d81a2925", "text": "It is generally administered orally 2\u20133 times each day but can also be given by intravenous infusion. Its plasma \nhalf-life is 1 h, but the intracellular half-life of the active \ntrisphosphate is 3 h. The concentration in cerebrospinal \nfluid (CSF) is 65% of the plasma level. Most of the drug is metabolised to the inactive glucuronide in the liver, only \n20% of the active form being excreted in the urine.Table 53.3 Drugs used to treat HIV infection\nDrug Mechanism of action Comments\nAbacavir, didanosine, emtricitabine, \nlamivudine, stavudine, tenofovir, zidovudineNucleoside or nucleotide reverse transcriptase inhibitorsThe first anti-HIV drugs. Multiple SE, especially on GI and metabolic systems (e.g. lactic acidosis), are common.\nEfavirenz, etravirine, nevirapine, rilpivirineNon-nucleoside reverse transcriptase inhibitorsMultiple SE common. Not effective againstHIV-2.\nAtazanavir, darunavir, fosamprenavir (PD), indinavir, lopinavir, ritonavir, saquinavir, tipranavirProtease inhibitors Lipodystrophy and many GI-related SE common\nEnfuvirtide Inhibitor of HIV fusion with host cells Often used to treat resistant infections Multiple SE common.\nDolutegravir, elvitegravir, raltegravir HIV integrase inhibitor Multiple SE common\nMaraviroc Chemokine receptor antagonist (CCR5)CCR5 dependent HIV. GI SE common.\nCobicistat Pharmacokinetic enhancer No antiviral activity but prolongs action of atazanavir and darunavir\nThese drugs are seldom given singly, being mostly used in combinations which can be changed to avoid toxicity issues, or if the treatment fails or falters.GI, gastrointestinal; PD, prodrug; SE, side effects.\n(Data from various sources including BNF 2017.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3286, "end_char_idx": 5448, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "709e86d5-3337-4279-acac-aa35c0ace36d": {"__data__": {"id_": "709e86d5-3337-4279-acac-aa35c0ace36d", "embedding": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3360b3fd-b40a-433b-a785-b56da6711465", "node_type": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7c09c5a09f56ca7cfe534f006aaa4e08c4e87d543ee6a4ba9e2371070749e9d9"}, "3": {"node_id": "8b7783a1-9b23-4258-8992-40aa740eb96f", "node_type": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5fcf7af942dbc67a32a3e8a58a61f259cad048ba93376c9637d7c70e35e2874c"}}, "hash": "45d19019a7ba13ad8a2a66fdbb9f6799cad4de9c98ab4ac9a16b8194f489c701", "text": "53 ANTIvIRAl DRUGS\n685concentrations in the CSF. It is excreted by the kidneys, \npartly by glomerular filtration and partly by tubular \nsecretion.\nUnwanted effects are minimal. Local inflammation can \noccur during intravenous injection if there is extravasation of the solution. Renal dysfunction has been reported when \naciclovir is given intravenously; slow infusion reduces \nthe risk. Nausea and headache can occur and, rarely, \nencephalopathy.\nThere are now other drugs with a similar action to aci -\nclovir (see list in Table 53.2). Foscarnet achieves the same \neffect through a slightly different mechanism.Nevirapine has good oral bioavailability, and penetrates \ninto the CSF. It is metabolised in the liver, and the metabolite is excreted in the urine. Nevirapine can prevent mother-\nto-baby transmission of HIV.\nUnwanted effects include rash (common) as well as a cluster \nof other effects.\nPROTEASE INHIBITORS\nIn HIV and many other viral infections, the mRNA tran -\nscribed from the provirus is translated into biochemically \ninert polyproteins. A virus-specific protease then converts \nthe polyproteins into various structural and functional \nproteins by cleavage at the appropriate positions (see Fig. \n53.3). Because this protease does not occur in the host, it \nis a useful target for chemotherapeutic intervention. HIV infection generates two such proteins named Gag and \nGag-Pol . Specific protease inhibitors bind to the site where \ncleavage occurs, and their use, in combination with reverse \ntranscriptase inhibitors, has transformed the therapy of AIDS. In the case of the hepatitis C virus, two protease \ntargets have also been identified, non-structural protein (NS) \n3, a serine protease, and NS 5A, which appears to act as \nan accessory protein for NS3. Examples of current protease inhibitors are shown in Tables 53.2 and 53.3.\nDarunavir , a typical example, binds tightly to the specific \nretropepsin proteases from HIV-1 or HIV-2, inactivating the catalytic site. Ritonavir acts in a similar way but also \ninhibits the P450 enzymes that metabolise these drugs \npotentiating their activity and for this reason is often given \nin combination with other protease inhibitors (e.g. \nlopinavir).\nUnwanted effects that are shared among this group include \nGI disturbances (e.g. nausea, vomiting, abdominal pain), blood disorders (sometimes anaemia or neutropenia) and CNS effects (e.g. insomnia, dizziness, headache) as well as \nthe risk of hyperglycaemia.\nDrug interactions are numerous, clinically important and \nunpredictable. As with other antiretroviral drugs, it is \nessential to look up possible interactions before prescribing \nany other drugs in patients receiving antiretroviral \ntreatment.\nDNA POLYMERASE INHIBITORS\nAciclovir\nThe development of the landmark drug aciclovir (see Table \n53.2) launched the era of effective selective antiviral therapy. \nTypical of drugs of this type, it is a guanosine derivative \nthat is converted to the monophosphate by viral thymidine kinase. This viral enzyme is much more effective in carrying \nout the phosphorylation than the enzyme of the host cell, \nso aciclovir is predominantly activated in infected cells. The host cell kinases then convert the monophosphate to \nthe trisphosphate, the active form that inhibits viral DNA \npolymerase, terminating the nucleotide chain. It is 30 times more potent against the herpes virus enzyme than the host enzyme.", "start_char_idx": 0, "end_char_idx": 3429, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8b7783a1-9b23-4258-8992-40aa740eb96f": {"__data__": {"id_": "8b7783a1-9b23-4258-8992-40aa740eb96f", "embedding": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3360b3fd-b40a-433b-a785-b56da6711465", "node_type": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7c09c5a09f56ca7cfe534f006aaa4e08c4e87d543ee6a4ba9e2371070749e9d9"}, "2": {"node_id": "709e86d5-3337-4279-acac-aa35c0ace36d", "node_type": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "45d19019a7ba13ad8a2a66fdbb9f6799cad4de9c98ab4ac9a16b8194f489c701"}, "3": {"node_id": "cf3969e0-9f41-4467-881f-231cdf7074da", "node_type": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f5ad5c9fd322b068b481da4570860c55cfc0fdd63d6de4d4a5730424a9f31d0b"}}, "hash": "5fcf7af942dbc67a32a3e8a58a61f259cad048ba93376c9637d7c70e35e2874c", "text": "is 30 times more potent against the herpes virus enzyme than the host enzyme. Aciclovir trisphosphate is inactivated within the \nhost cells, presumably by cellular phosphatases. Resistance \ncaused by changes in the viral genes coding for thymidine kinase or DNA polymerase has been reported, and aciclovir-\nresistant herpes simplex virus has been the cause of \npneumonia, encephalitis and mucocutaneous infections in immunocompromised patients.\nAciclovir can be given orally, intravenously or topically. \nWhen it is given orally, only 20% of the dose is absorbed. The drug is widely distributed, and reaches effective Clinical uses of drugs for herpes \nviruses \n\u2022\tVaricella zoster infections (chickenpox, shingles):\n\u2013 orally (e.g. famciclovir) including in \nimmunocompetent patients;\n\u2013 intravenously (e.g. in encephalitis, aciclovir) \nincluding in immunocompromised patients.\n\u2022\tHerpes simplex infections: genital herpes (systemic \nand/ or topical treatment depending on severity, \nwhether immunocompromised and whether or not a first attack), mucocutaneous herpes (e.g. aciclovir or, if unresponsive, foscarnet) and herpes encephalitis (e.g. \nintravenous aciclovir).\n\u2022\tProphylactically:\n\u2013 patients who are to be treated with \nimmunosuppressant drugs or radiotherapy and who are at risk of herpesvirus infection owing to reactivation of a latent virus;\n\u2013 in individuals who suffer from frequent recurrences \nof genital infection with herpes simplex virus.\n\u2022\tCytomegalovirus (CMV)\n\u2013\tCMV,\twhilst \ta \therpes \tvirus, \tis \tless \tsensitive \tto \t\naciclovir than is Herpes simplex or Herpes zoster. \nValaciclovir \tis\tlicensed \tfor \tprevention \tof \tCMV \t\nduring immunosuppression following organ transplantation. Ganciclovir and valagancilclovir \nare\tmore\tactive \tagainst \tCMV \tthan \taciclovir, \tbut \tare \t\nmore toxic; they are used by specialists for serious \nproblems\tsuch \tas \tCMV \tretinitis \tin \tpatients \twith \t\nAIDS.\nNEURAMINIDASE INHIBITORS AND INHIBITORS \nOF VIRAL COAT DISASSEMBLY\nViral neuraminidase is one of three transmembrane proteins \ncoded by the influenza genome. Infection with these RNA \nviruses begins with the attachment of the viral haemag -\nglutinin to neuraminic (sialic) acid residues on host cells. \nThe viral particle then enters the cell by endocytosis. The \nendosome is acidified following influx of H+ through another \nviral protein, the M2 ion channel . This facilitates the dis -\nassembly of the viral structure, allowing the RNA to enter \nthe host nucleus, thus initiating a round of viral replication. Newly replicated virions escape from the host cell by \nbudding from the cell membrane. Viral neuraminidase \npromotes this by severing the bonds linking the particle coat and host sialic acid.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3366, "end_char_idx": 6515, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cf3969e0-9f41-4467-881f-231cdf7074da": {"__data__": {"id_": "cf3969e0-9f41-4467-881f-231cdf7074da", "embedding": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3360b3fd-b40a-433b-a785-b56da6711465", "node_type": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7c09c5a09f56ca7cfe534f006aaa4e08c4e87d543ee6a4ba9e2371070749e9d9"}, "2": {"node_id": "8b7783a1-9b23-4258-8992-40aa740eb96f", "node_type": null, "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5fcf7af942dbc67a32a3e8a58a61f259cad048ba93376c9637d7c70e35e2874c"}}, "hash": "f5ad5c9fd322b068b481da4570860c55cfc0fdd63d6de4d4a5730424a9f31d0b", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6532, "end_char_idx": 6627, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2ba706bb-8414-408c-9a84-cdd457a030e4": {"__data__": {"id_": "2ba706bb-8414-408c-9a84-cdd457a030e4", "embedding": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f274b233-c197-47bc-b410-24f37b7560cc", "node_type": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e1b210443522917fd0c154a01d9239f5676bbbad28fe337c076878db621bcd2"}, "3": {"node_id": "64c00f8d-ae77-4756-8b99-de48b2ed133c", "node_type": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3cdfdb38e03a4d280a90d5e0bbcba0555df3a893202e717a52f5c01d9f60b8c"}}, "hash": "de2c4d20060bbbfc9c10ff90a8690c7abb6300d68aa4803bff169f1586d2aad8", "text": "53 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n686are directed against the virus envelope and can \u2018neutralise\u2019 \nsome viruses and prevent their attachment to host cells. \nIf used before the onset of signs and symptoms, it may \nattenuate or prevent measles, German measles, infectious hepatitis, rabies or poliomyelitis. Hyperimmune globulin, \nspecific against particular viruses, is used against hepatitis B, varicella zoster and rabies.\nPalivizumab\nRelated in terms of its mechanism of action to immuno -\nglobulins is palivizumab, a monoclonal antibody (see Ch. \n5) directed against a glycoprotein on the surface of respira -\ntory syncytial virus. It is used as an intramuscular injection, under specialist supervision, in children at high risk to \nprevent infection by this organism.\nInterferons\nIFNs are a family of inducible proteins synthesised by \nmammalian cells and now generally produced commercially \nby recombinant DNA technology. There are at least three \ntypes, \u03b1, \u03b2 and \u03b3, constituting a family of hormones involved \nin cell growth and regulation and the modulation of immune \nreactions. IFN-\u03b3, termed immune interferon, is produced \nmainly by T lymphocytes as part of an immunological \nresponse to both viral and non-viral antigens, the latter \nincluding bacteria and their products, rickettsiae, protozoa, \nfungal polysaccharides and a range of polymeric chemicals and other cytokines. IFN-\u03b1 and IFN-\u03b2 are produced by B \nand T lymphocytes, macrophages and fibroblasts in response \nto the presence of viruses and cytokines. The general actions \nof the IFNs are described briefly in Chapters 7 and 19.\nThe IFNs bind to specific ganglioside receptors on host \ncell membranes. They induce, in host cell ribosomes, the production of enzymes that inhibit the translation of viral mRNA into viral proteins, thus halting viral replication. \nThey have a broad spectrum of action and inhibit the \nreplication of most viruses in vitro. Given intravenously, \nIFNs have a half-life of 2\u20134 h. They do not cross the blood\u2013\nbrain barrier.\nIFN-\u03b1-2a is used for treatment of hepatitis B infections \nand AIDS-related Kaposi\u2019s sarcomas; IFN- \u03b1-2b is used for \nhepatitis C (a chronic viral infection which can progress insidiously in apparently healthy people, leading to end-\nstage liver disease or liver cancer). There are reports that \nIFNs can prevent reactivation of herpes simplex after trigeminal root section in animals and can prevent spread \nof herpes zoster in cancer patients. Preparations of IFNs \nconjugated with polyethylene glycol (pegylated IFNs) have a longer lifetime in the circulation.\nUnwanted effects are common and resemble the symptoms \nof influenza (which are mediated by cytokine release) including fever, lassitude, headache and myalgia. Repeated injections cause chronic malaise. Bone marrow depression, \nrashes, alopecia and disturbances in cardiovascular, thyroid \nand hepatic function can also occur.\nOTHER AGENTS\nImmunomodulators are drugs that act by modulating the immune response to viruses or use an immune mechanism \nto target a virus or other organism. Inosine pranobex may \ninterfere with viral nucleic acid synthesis but also has \nimmunopotentiating actions on the host. It is sometimes \nused to treat herpes infections of mucosal tissues or skin.\nTribavirin (ribavirin) is a synthetic nucleoside, similar \nin structure to guanosine.", "start_char_idx": 0, "end_char_idx": 3398, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "64c00f8d-ae77-4756-8b99-de48b2ed133c": {"__data__": {"id_": "64c00f8d-ae77-4756-8b99-de48b2ed133c", "embedding": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f274b233-c197-47bc-b410-24f37b7560cc", "node_type": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e1b210443522917fd0c154a01d9239f5676bbbad28fe337c076878db621bcd2"}, "2": {"node_id": "2ba706bb-8414-408c-9a84-cdd457a030e4", "node_type": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "de2c4d20060bbbfc9c10ff90a8690c7abb6300d68aa4803bff169f1586d2aad8"}, "3": {"node_id": "5b38da7e-f415-41b1-bd40-82ab3f2cddfd", "node_type": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "00156fd14ec1b340d9d23ec59f560aac21a197415af30f13d3b03486302409ef"}}, "hash": "f3cdfdb38e03a4d280a90d5e0bbcba0555df3a893202e717a52f5c01d9f60b8c", "text": "is a synthetic nucleoside, similar \nin structure to guanosine. The exact mechanism of action The neuraminidase inhibitors oseltamivir and zanamivir \nare active against both influenza A and B viruses, and are licensed for use at early stages in the infection or when \nuse of the vaccine is impossible. Zanamivir is available as a powder for inhalation, and oseltamivir as an oral prepara -\ntion. Though oseltamivir has been \u2018stockpiled\u2019 by govern -\nments when flu pandemics (e.g. \u2018swine\u2019 flu \u2013 H1N1) are forecast, clinical trials suggest that its efficacy in reducing \ndisease severity is very limited.\nUnwanted effects of oseltamivir include GI symptoms \n(nausea, vomiting, dyspepsia and diarrhoea), but these are \nless frequent and severe in the inhaled preparation. Zan -\namivir commonly causes a rash.\nAmantadine,\n3 quite an old drug (1966) and seldom \nrecommended today, effectively blocks viral M2 ion chan -\nnels, thus inhibiting disassembly. It is active against influenza A virus (an RNA virus) but has no action against influenza B virus. Given orally, amantadine is well absorbed, \nreaches high levels in secretions (e.g. saliva) and most is \nexcreted unchanged via the kidney. Aerosol administration is feasible.\nUnwanted effects are relatively infrequent, occurring in \n5%\u201310% of patients, and are not serious. Dizziness, insomnia and slurred speech are the most common adverse effects.\nDRUGS ACTING THROUGH OTHER \nMECHANISMS\nEnfuvirtide inhibits the fusion of HIV with host cells. It is \ngenerally given by subcutaneous injection in combination \nwith other drugs to treat HIV when resistance becomes a \nproblem or when the patient is intolerant of other antiret -\nroviral drugs.\nUnwanted effects include flu-like symptoms, central effects \nsuch as headache, dizziness, alterations in mood, GI effects and, sometimes, hypersensitivity reactions.\nRaltegravir and related agents act by inhibiting HIV DNA \nintegrase, the enzyme that splices viral DNA into the host genome when forming the provirus. It is used for the treatment of HIV as part of combination therapy, and is \ngenerally reserved for cases that are resistant to other \nantiretroviral agents.\nMaraviroc. CCR5, together with CXCR4, are cell surface \nchemokine receptors that have been exploited by some strains of HIV to gain entry to the cell (see earlier). In patients who harbour \u2018R5\u2019 strains, the chemokine receptor \nantagonist maraviroc may be used, in combination with \nmore conventional antiretroviral drugs. This drug represents \na novel concept in HIV therapy (see Dhami et al., 2009) \nand is the only drug of its type currently available. Its use, in combination with other antiretroviral drugs, is currently \nrestricted to CCR5-tropic HIV infection in patients previ-\nously treated with other antiretrovirals.\nBIOPHARMACEUTICAL ANTIVIRAL DRUGS\nBiopharmaceuticals that have been recruited in the fight against virus infections include immunoglobulin prepara -\ntions, interferons (IFNs) and monoclonal antibodies.\nImmunoglobulins\nPooled immunoglobulin contains antibodies against various viruses present in the population. The antibodies \n3Also used for its mildly beneficial effects in Parkinson\u2019s disease (see \nCh. 41).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3345, "end_char_idx": 6664, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5b38da7e-f415-41b1-bd40-82ab3f2cddfd": {"__data__": {"id_": "5b38da7e-f415-41b1-bd40-82ab3f2cddfd", "embedding": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f274b233-c197-47bc-b410-24f37b7560cc", "node_type": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5e1b210443522917fd0c154a01d9239f5676bbbad28fe337c076878db621bcd2"}, "2": {"node_id": "64c00f8d-ae77-4756-8b99-de48b2ed133c", "node_type": null, "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f3cdfdb38e03a4d280a90d5e0bbcba0555df3a893202e717a52f5c01d9f60b8c"}}, "hash": "00156fd14ec1b340d9d23ec59f560aac21a197415af30f13d3b03486302409ef", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6671, "end_char_idx": 7086, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "82d44596-ad04-42ee-9065-b59743680571": {"__data__": {"id_": "82d44596-ad04-42ee-9065-b59743680571", "embedding": null, "metadata": {"page_label": "693", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "946a0753-5ac7-49fb-8793-0521ae3e0845", "node_type": null, "metadata": {"page_label": "693", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b811c23b1a49914380fe50af4b71322c48048ab36732901a547fbae6bc3eb1f"}, "3": {"node_id": "298b927b-5ff3-4f6c-9469-6d2959ac1649", "node_type": null, "metadata": {"page_label": "693", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fccda251cccdda179194f2012fbc560a018bfad465c20389f2664d96f150b377"}}, "hash": "e4b6241c6d2d95ddca10ad2bc0fcaf0061b2e7e4d2493ef422710306dca541eb", "text": "53 ANTIvIRAl DRUGS\n687treatment failure. This is difficult to achieve because the \ndaily multiple dosing regimens are complex and these drugs \nhave many unwanted effects. Since lifelong treatment is \nnecessary, \u2018treatment fatigue\u2019 is a real issue.\nTo circumvent at least some of these problems, several \n\u2018once-a-day\u2019 formulations have been devised. The first one to be approved, Atripla, comprises a fixed-dose mixture \nof nucleoside and non-nucleoside reverse transcriptase \ninhibitors (tenofovir, emtricitabine and efavirenz). Several \nother proprietary combinations have also been approved with different constituent drugs. It is estimated that switch -\ning to a \u2018once\u2019 daily\u2019 administration doubles the likelihood \nof maintaining the 95% adherence rate that is crucial to \ntreatment success (see Truong et al., 2015).\nUnwelcome interactions can occur between the component \ndrugs of HAART combinations, and there may be inter-individual variations in absorption. Metabolic and \ncardiovascular complications attend the usage of these drugs and pose a problem to patients requiring lifelong therapy \n(see Hester, 2012). Some drugs penetrate poorly into the \nbrain, and this could lead to local proliferation of the virus. So far there is little cross-resistance between the three groups \nof drugs, but the virus has a high mutation rate \u2013 so this \ncould be a problem in the future.\nThe choice of drugs to treat pregnant or breastfeeding \nwomen is difficult. The main aims are to avoid damage to \nthe fetus and to prevent transmission of the disease to the \nneonate. Therapy with zidovudine alone is often used in these cases and although combination therapy is more \neffective, it increases the chance of fetal toxicity. Another \narea that requires special consideration is prophylaxis for individuals who may have been exposed to the virus \naccidentally. Specific guidelines have been developed for \nboth such cases, but they are beyond the scope of this chapter.\nThe AIDS virus has certainly not yet been vanquished. \nIt is not eradicated by drug treatment, but with any of these treatments, lies latent in the host genome of memory T cells, ready to reactivate if therapy is stopped.\nPROSPECTS FOR NEW ANTIVIRAL DRUGS\nAt the beginning of the 1990s, there were only five drugs available to treat viral infections, but this number has \nincreased some 10-fold during the intervening years. Our \nunderstanding of the biology of pathogenic viruses and their actions in the host has grown enormously and this has led to \nthe discovery of new types of antivirals, such as those that \nprevent CCR5 \u2013 and possibly other chemokine receptors \u2013 from serving as an entry portal for HIV. Another potentially \nfruitful lead is HIV maturation inhibitors which prevent pro-\nteolytic processing of viral proteins by binding to the poly -\npeptide chain rather than the protease itself. Compounds such as bevirimat (now discontinued) target the precursor \nof the Gag polyprotein. Since this is the main structural protein responsible for assembly and budding of virion particles the \ndrug effectively inhibits replication (see Salzwedel et al., 2007). \nThe quest for further novel antivirals continues and compu -\ntational biology techniques are being deployed to predict \nresistance to existing drugs based upon the HIV phenotype \nto enhance the quality of clinical treatment (Zazzi et al., 2016).\nThe discovery and development of antiviral drugs and \nthe formulation and implementation of HAART therapy has been a triumph in the fight against HIV, transforming \nthe lives of millions of people in a dramatic manner. is unclear but it interferes with the synthesis of viral mRNA. While it inhibits a wide range of DNA and RNA viruses, including many that affect the lower airways, it is mainly", "start_char_idx": 0, "end_char_idx": 3782, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "298b927b-5ff3-4f6c-9469-6d2959ac1649": {"__data__": {"id_": "298b927b-5ff3-4f6c-9469-6d2959ac1649", "embedding": null, "metadata": {"page_label": "693", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "946a0753-5ac7-49fb-8793-0521ae3e0845", "node_type": null, "metadata": {"page_label": "693", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6b811c23b1a49914380fe50af4b71322c48048ab36732901a547fbae6bc3eb1f"}, "2": {"node_id": "82d44596-ad04-42ee-9065-b59743680571", "node_type": null, "metadata": {"page_label": "693", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4b6241c6d2d95ddca10ad2bc0fcaf0061b2e7e4d2493ef422710306dca541eb"}}, "hash": "fccda251cccdda179194f2012fbc560a018bfad465c20389f2664d96f150b377", "text": "DNA and RNA viruses, including many that affect the lower airways, it is mainly \nused in aerosol or tablet form to treat infections with respira-\ntory syncytial virus (an RNA paramyxovirus). It has also \nbeen shown to be effective in hepatitis C as well as Lassa \nfever, an extremely serious arenavirus infection. When given \npromptly to victims of the latter disease, it has been shown \nto reduce to fatality rates (usually about 76%) by approxi -\nmately eight-fold.\nAntiviral drugs \nMost antiviral drugs generally fall into the following \ngroups:\u2022\tNucleoside (or nucleotide) analogues that inhibit the \nviral reverse transcriptase enzyme, preventing \nreplication (e.g. lamivudine, zidovudine).\n\u2022\tNon-nucleoside analogues that have the same effect (e.g. efavirenz).\n\u2022\tInhibitors of proteases that prevent viral protein \nprocessing (e.g. saquinavir, indinavir).\n\u2022\tInhibitors of viral DNA polymerase that prevent \nreplication (e.g. aciclovir, famciclovir).\n\u2022\tInhibitors of HIV integrase that prevent the \nincorporation of viral DNA into the host genome (ratelgravir).\n\u2022\tInhibitors of viral fusion with cells (e.g. enfuvirtide).\n\u2022\tInhibitors of viral entry that block the use of host cell \nsurface receptors, which are used as entry points by viruses (maraviroc).\n\u2022\tInhibitors of viral capsule disassembly (e.g. \namantadine).\n\u2022\tInhibitors of neuraminidase that prevent viral escape \nfrom infected cells (e.g. oseltamivir).\n\u2022\tImmunomodulators that generally enhance host defences (e.g. interferons and inosine pranobex).\n\u2022\tImmunoglobulin and related preparations that contain \nneutralising antibodies to various viruses.\nCOMBINATION THERAPY FOR HIV\nBecause the two main classes of antiviral drugs used to \ntreat HIV (reverse transcriptase inhibitors and protease \ninhibitors) have different mechanisms of action (see Fig. \n53.3), they can usefully be deployed in combinations and this has dramatically improved the prognosis of the disease. \nSuch combination treatment is known as Highly Active \nAntiretroviral Therapy (HAART). A typical HAART three- \nor four-drug combination would involve two nucleoside reverse transcriptase inhibitors with either a non-nucleoside \nreverse transcriptase inhibitor or one or two protease inhibitors.\nUsing a HAART protocol, HIV replication is inhibited, \nthe presence in the plasma of HIV RNA is reduced to undetectable levels and patient survival is greatly prolonged \u2013 so much so that near-normal life spans can now be \nachieved, given prompt diagnosis and treatment and good \npatient compliance. The latter is a key point \u2013 a rate of 95% or more is required to achieve this result and prevent mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3703, "end_char_idx": 6820, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9eabf94b-9bc5-419b-b404-d4f2a4920def": {"__data__": {"id_": "9eabf94b-9bc5-419b-b404-d4f2a4920def", "embedding": null, "metadata": {"page_label": "694", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "702d2f78-e8bc-4269-a420-7572689557f5", "node_type": null, "metadata": {"page_label": "694", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b97fb19ba63e027f272ef5a5ba5c08518630370bb554863e3febc4ab872ef165"}, "3": {"node_id": "1c58e2f4-2c87-4084-8e0d-edd7b9bc0890", "node_type": null, "metadata": {"page_label": "694", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8eee4b06f111f296bee2e859d87444233c8cff81538730f178d789633ec95ca5"}}, "hash": "57c76fde1e09577a895d61726d7a93d07225988601fdd1092760a5d643ab9f88", "text": "53 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n688However, the ultimate weapon in the fight against HIV \nwould be vaccination. This has proved to be highly effective \nin the past against diseases such as polio and smallpox, \nand more recently against influenza (both types), hepatitis B and other pathogens.\nUnfortunately, and despite some encouraging results in \nanimal models, the prospect of an imminent introduction of a vaccine against HIV (and sadly many other viruses) \nstill seems rather distant (Pollara et al. , 2017). Some success \nwas reported in a vaccine trial (RV144), which tested a combination of two vaccines that had proved ineffective \nwhen given separately (see Rerks-Ngarm et al., 2017). Although the benefits claimed in the trial were later ques -\ntioned ( Desrosiers, 2017 ), a further trial (HVTN 702) using \nthe same vaccine is currently in progress in South Africa at the time of writing.\nPart of the problem in designing vaccines is antigenic \ndrift, a process whereby the virus mutates, thus presenting \nshifting antigenic structures and minimising the chance of an effective and long-lasting immune response. A vaccine \nwhich induces broad neutralising antibody production by the \nhost is today considered to be a key objective. The problem \nof HIV vaccines is the subject of numerous reviews (see, for example, Cohen & Frahm, 2017).\nDrug mechanisms in HIV infections \n\u2022\tReverse \ttranscriptase \tinhibitors \t(RTIs):\n\u2013 nucleoside (or nucleotide) analogue RTIs are \nphosphorylated by host cell enzymes to give the \n5\u2032-trisphosphate, which competes with the equivalent \nhost cellular trisphosphates that are essential \nsubstrates for the formation of proviral DNA by viral reverse transcriptase (examples are zidovudine and \nabacavir); they are used in combination with protease \ninhibitors.\n\u2013 non-nucleoside RTIs are chemically diverse \ncompounds that bind to the reverse transcriptase near the catalytic site and denature it; an example is \nnevirapine.\u2022\tProtease \tinhibitors \tinhibit \tcleavage \tof \tthe \tnascent \tviral \t\nprotein into functional and structural proteins. They are \noften used in combination with RTIs. An example is saquinavir.\n\u2022\tCombination \ttherapy \tis \tessential \tin \ttreating \tHIV; \tthis \t\ncharacteristically comprises two nucleoside RTIs with either a non-nucleoside RTI or one or two protease \ninhibitors.\tOther \tdrugs, \tsuch \tas \tthe \tHIV \tintegrase \t\ninhibitor ratelgravir, the chemokine receptor antagonist \nmaraviroc \tand\tthe\tHIV \tfusion \tinhibitor \tenfuvirtide, may \nalso be used in such combination therapy regimens. \u2018Once daily\u2019 combination therapies greatly improve \npatient compliance.\nTreatment of HIV/AIDS \n\u2022\tCurrent \ttreatment \t(supervised \tby \texperienced \tphysicians) \t\nis not curative, but aims to optimise quantity and quality \nof life using highly active antiretroviral treatment (HAART). This consists of combinations of drugs (e.g. of two \nnucleoside reverse transcriptase inhibitors with either a \nnon-nucleoside reverse transcriptase inhibitor or with a boosted protease inhibitor or with an integrase inhibitor). Drugs with additive or synergistic therapeutic effects are \nselected to minimise the emergence of resistance, \nminimise toxicity and optimise adherence to lifelong therapy.\u2022\tPlasma\tviral \tload \tand \tCD4+ cell count are monitored; \nviral sensitivity is determined before starting treatment and before changing drugs if the viral load increases.\n\u2022\tTreatment", "start_char_idx": 0, "end_char_idx": 3470, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1c58e2f4-2c87-4084-8e0d-edd7b9bc0890": {"__data__": {"id_": "1c58e2f4-2c87-4084-8e0d-edd7b9bc0890", "embedding": null, "metadata": {"page_label": "694", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "702d2f78-e8bc-4269-a420-7572689557f5", "node_type": null, "metadata": {"page_label": "694", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b97fb19ba63e027f272ef5a5ba5c08518630370bb554863e3febc4ab872ef165"}, "2": {"node_id": "9eabf94b-9bc5-419b-b404-d4f2a4920def", "node_type": null, "metadata": {"page_label": "694", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "57c76fde1e09577a895d61726d7a93d07225988601fdd1092760a5d643ab9f88"}}, "hash": "8eee4b06f111f296bee2e859d87444233c8cff81538730f178d789633ec95ca5", "text": "starting treatment and before changing drugs if the viral load increases.\n\u2022\tTreatment \tis \tstarted \tbased \ton \tCD4+ cell count and aims \nto reduce viral load as much as possible for as long as possible.\n\u2022\tSpecial\tsituations \t(e.g. \tprophylaxis \tfollowing \taccidental \t\nexposure via needle-stick injury, treatment of children and during pregnancy) are best managed by \nspecialists.\nREFERENCES AND FURTHER READING\nViral infections in general\nHanazaki, K., 2004. Antiviral therapy for chronic hepatitis B: a review. \nCurr. Drug Targets Inflamm. Allergy 3, 63\u201370. (Reviews the use of IFN \nand lamivudine, alone or in combination, in the treatment of this viral \ninfection)\nLauer, G.M., Walker, B.D., 2001. Hepatitis C virus infection. \nN. Engl. J. Med. 345, 41\u201352. (Comprehensive review of pathogenesis, clinical characteristics, natural history and treatment of hepatitis C infection)\nSchmidt, A.C., 2004. Antiviral therapy for influenza: a clinical and \neconomic comparative review. Drugs 64, 2031\u20132046. (A useful review of influenza biology, together with a comprehensive evaluation of drug \ntreatments, their mechanisms of action and relative economic costs)\nWhitley, R.J., Roizman, B., 2001. Herpes simplex virus infections. Lancet \n357, 1513\u20131518. (A concise review of the viral replication cycle and the pathogenesis and treatment of herpes simplex virus infections)HIV infections\nBarber, D.L., Wherry, E.J., Masopust, D., et al., 2006. Restoring function \nin exhausted CD8 T cells during chronic viral infection. Nature 439, \n682\u2013687. (Deals with a potential mechanism whereby the exhaustion of T \ncells may be reversed)\nJansen, C.A., Piriou, E., Bronke, C., et al., 2004. Characterisation of \nvirus-specific CD8(+) effector T cells in the course of HIV-1 infection: \nlongitudinal analyses in slow and rapid progressors. Clin. Immunol. \n11, 299\u2013309.\nLevy, J.A., 2001. The importance of the innate immune system in \ncontrolling HIV infection and disease. Trends Immunol. 22, 312\u2013316. (Stresses the role of innate immunity in the response to HIV; clear exposition \nof the various components of the innate and adaptive immune systems, as well as the role of non-cytotoxic CD8\n+ cell response to HIV)\nMoss, J.A., 2013. HIV/AIDS review. Radiol. Technol. 84, 247\u2013267. (This \npaper was written to update radiologists and radiographers and is therefore mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3385, "end_char_idx": 6217, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "efdbcf4d-26fb-4523-8e4b-a1dc7e058caa": {"__data__": {"id_": "efdbcf4d-26fb-4523-8e4b-a1dc7e058caa", "embedding": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b26aa5bf-23ad-46cb-bedf-09dae771c4b8", "node_type": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c028e889cafdc34a0355971bd930ff5cb44ea0ad776d5ced958619f0f815cab"}, "3": {"node_id": "d3630afa-ba93-48ee-b7e8-7a53b4d17528", "node_type": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2df2a465d7d8a88d1558648fedfd81b3c341d6d55c47fe7b93369904d6086ab4"}}, "hash": "80d3f3b8df7a770f16be3a783aa641748cedc63119dc51e3d2acae8b62fe4bfd", "text": "53 ANTIvIRAl DRUGS\n689Flores-Villanueva, P.O., Hendel, H., Caillat-Zucman, S., et al., 2003. \nAssociations of MHC ancestral haplotypes with resistance/\nsusceptibility to AIDS disease development. J. Immunol. 170, \n1925\u20131929. (A paper that deals with the hereditary component of HIV \nsusceptibility/resistance; interesting, but complex for the non-geneticist)\nKaufman, D.R., Barouch, D.H., 2009. Translational mini-review series on \nvaccines for HIV: T lymphocyte trafficking and vaccine-elicited mucosal immunity. Clin. Exp. Immunol. 157, 165\u2013173. (This paper, \ntogether with the paper by Rhee et al. below, review new research that seeks \nto design better HIV vaccines through an increased understanding of the innate and adaptive immune systems. They are fairly advanced but \nworthwhile if you are interested in the topic)\nKilby, J.M., Eron, J.J., 2003. Novel therapies based on mechanisms of \nHIV-1 cell entry. N. Engl. J. Med. 348, 2228\u20132238. (Excellent review on this innovative strategy)\nKitabwalla, M., Ruprecht, R.M., 2002. RNA interference: a new weapon \nagainst HIV and beyond. N. Engl. J. Med. 347, 1364\u20131368. (An article in the series \u2018Clinical implications of basic research\u2019)\nMoore, J.P., Stevenson, M., 2000. New targets for inhibitors of HIV-1 \nreplication. Nat. Rev. Mol. Cell Biol. 1, 40\u201349. (Excellent coverage of stages of the viral life cycle that might be susceptible to new drugs. \nIntroduces various potentially promising chemical compounds)\nPollara, J., Easterhoff, D., Fouda, G.G., 2017. Lessons learned from \nhuman HIV vaccine trials. Curr. Opin. HIV AIDS 12, 216\u2013221.\nRerks-Ngarm, S., Pitisuttithum, P., Excler, J.L., et al., 2017. Randomized, \ndouble-blind evaluation of late boost strategies for HIV-uninfected vaccine recipients in the RV144 HIV vaccine efficacy trial. J. Infect. \nDis. 215, 1255\u20131263.\nRhee, E.G., Barouch, D.H., 2009. Translational mini-review series on \nvaccines for HIV: harnessing innate immunity for HIV vaccine development. Clin. Exp. Immunol. 157, 174\u2013180. (See review of Kaufman \n& Barouch above)\nSalzwedel, K., Martin, D.E., Sakalian, M., 2007. Maturation inhibitors: a \nnew therapeutic class targets the virus structure. AIDS Rev. 9, 162\u2013172.\nZazzi, M., Cozzi-Lepri, A., Prosperi, M.C., 2016. Computer-aided \noptimization of combined anti-retroviral therapy for HIV: new \ndrugs, new drug targets and drug resistance. Curr. HIV Res. 14, \n101\u2013109.\nBooks\nPisani, E., 2008. The Wisdom of Whores. Granta Books, London. (An \nentertaining and informative account of efforts made to pioneer HIV \nprogrammes in developing countries and the many bureaucratic and other \nobstacles that had to be surmounted. See also www.wisdomofwhores.com/ subtitled \u2018Of sex and science. Elisabeth Pisani\u2019s blog about HIV and other \nsundry things\u2019. Highly recommended)\nUseful Web resources\nhttps://www.aidsinfo.nih.gov/. (The official HIV/AIDS site of the US \nNational Institutes of Health. Authoritative and up-to-date information on every", "start_char_idx": 0, "end_char_idx": 2974, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d3630afa-ba93-48ee-b7e8-7a53b4d17528": {"__data__": {"id_": "d3630afa-ba93-48ee-b7e8-7a53b4d17528", "embedding": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b26aa5bf-23ad-46cb-bedf-09dae771c4b8", "node_type": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c028e889cafdc34a0355971bd930ff5cb44ea0ad776d5ced958619f0f815cab"}, "2": {"node_id": "efdbcf4d-26fb-4523-8e4b-a1dc7e058caa", "node_type": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "80d3f3b8df7a770f16be3a783aa641748cedc63119dc51e3d2acae8b62fe4bfd"}, "3": {"node_id": "0ed1dfe7-7a46-4815-ba4a-7a1f9758850a", "node_type": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "950be42225057be1f83d71f173a579305c98f0c632851b44f017fb705d83afcf"}}, "hash": "2df2a465d7d8a88d1558648fedfd81b3c341d6d55c47fe7b93369904d6086ab4", "text": "the US \nNational Institutes of Health. Authoritative and up-to-date information on every aspect of this disease and its treatment, including data on drugs and \ndrug action as well as the results of recent clinical trials and the latest progress in developing a vaccine. Also includes links to downloadable \u2018Apps\u2019 \non HIV and its therapy. Superb)\nhttp://www.unaids.org/. (The official site of the United Nations \nProgramme on HIV/AIDS. It focuses on the demographics of the epidemic with various resources that bring home the enormous problems in dealing \nwith this disease. Prepare to be appalled)an excellent introduction to all matters related to HIV/AIDS. Highly recommended)\nMurphy, P.M., 2001. Viral exploitation and subversion of the immune \nsystem through chemokine mimicry. Nat. Immunol. 2, 116\u2013122. (Excellent description of virus\u2013immune system interaction)\nNorris, P.J., Moffett, H.F., Brander, C., et al., 2004. Fine specificity and \ncross-clade reactivity of HIV type 1 Gag-specific CD4+ T cells. AIDS \nRes. Hum. Retroviruses 20, 315\u2013325.\nPantaleo, G., Graziosi, C., Fauci, A.S., 1993. New concepts in the \nimmunopathogenesis of human immunodeficiency virus infection. N. Engl. J. Med. 328, 327\u2013335.\nSchutze, N., 2004. siRNA technology. Mol. Cell. Endocrinol. 213, \n115\u2013119. (An article explaining the siRNA concept)\nTortorella, D., Gewurz, B.E., Furman, M.H., et al., 2000. Viral subversion \nof the immune system. Annu. Rev. Immunol. 18, 861\u2013926. (A comprehensive and clearly written review of the various mechanisms by \nwhich viruses elude detection and destruction by the host immune system)\nMechanisms of antiviral drug action\nde Clercq, E., 2002. Strategies in the design of antiviral drugs. Nat. Rev. \nDrug Discov. 1, 13\u201324. (Outstanding article describing the rationale behind current and future strategies for antiviral drug development)\nHester, E.K., 2012. HIV medications: an update and review of metabolic \ncomplications. Nutr. Clin. Pract. 27, 51\u201364. (Deals with the problems encountered by many patients who may have to take HAART medication for \nyears)\nGubareva, L., Kaiser, L., Hayden, F.G., 2000. Influenza virus \nneuraminidase inhibitors. Lancet 355, 827\u2013835. (Admirable coverage of this topic; lucid summary and clear diagrams of the influenza virus and its replication cycle; description of the structure and the action of, and resistance \nto, zanamivir and oseltamivir, and the relevant pharmacokinetic aspects and \nclinical efficacy)\nCombination treatment for HIV\nFlexner, C., 2000. Dual protease inhibitor therapy in HIV-infected \npatients: pharmacologic rationale and clinical benefits. Annu. Rev. \nPharmacol. Toxicol. 40, 649\u2013674. (Review emphasising interactions \nbetween individual protease inhibitors and the potential benefits and disadvantages of dual therapy)\nRichman, D.D., 2001. HIV chemotherapy. Nature 410, 995\u20131001. \n(Outstanding article; covers pathogenesis and natural history of HIV infection and the impact on viral dynamics and immune function of \nantiretroviral therapy; discusses the main antiretroviral drugs, drug \nresistance of HIV and targets for new drugs; excellent figures and comprehensive references)\nTruong, W.R., Schafer, J.J., Short, W.R., 2015. Once-daily, single-tablet", "start_char_idx": 2898, "end_char_idx": 6137, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0ed1dfe7-7a46-4815-ba4a-7a1f9758850a": {"__data__": {"id_": "0ed1dfe7-7a46-4815-ba4a-7a1f9758850a", "embedding": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "b26aa5bf-23ad-46cb-bedf-09dae771c4b8", "node_type": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c028e889cafdc34a0355971bd930ff5cb44ea0ad776d5ced958619f0f815cab"}, "2": {"node_id": "d3630afa-ba93-48ee-b7e8-7a53b4d17528", "node_type": null, "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2df2a465d7d8a88d1558648fedfd81b3c341d6d55c47fe7b93369904d6086ab4"}}, "hash": "950be42225057be1f83d71f173a579305c98f0c632851b44f017fb705d83afcf", "text": "J.J., Short, W.R., 2015. Once-daily, single-tablet \nregimens for the treatment of HIV-1 infection. P T 40, 44\u201355.\nNew leads in antiviral drug therapy\nBarik, S., 2004. Control of nonsegmented negative-strand RNA virus \nreplication by siRNA. Virus Res. 102, 27\u201335. (Interesting article \nexplaining how siRNA technology might be used to inhibit viral replication)\nCohen, K.W., Frahm, N., 2017. Current views on the potential for \ndevelopment of a HIV vaccine. Expert Opin. Biol. Ther. 17, 295\u2013303.\nDesrosiers, R.C., 2017. Protection against HIV acquisition in the RV144 \nTrial. J. Virol. 91, e00905\u201300917.\nDhami, H., Fritz, C.E., Gankin, B., et al., 2009. The chemokine system \nand CCR5 antagonists: potential in HIV treatment and other novel \ntherapies. J. Clin. Pharm. Ther. 34, 147\u2013160. (Excellent and easy-to-read \nreview of this area. Helpful diagrams)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6164, "end_char_idx": 7498, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "83f30758-1bd8-4b3e-a000-464ec0fc4d90": {"__data__": {"id_": "83f30758-1bd8-4b3e-a000-464ec0fc4d90", "embedding": null, "metadata": {"page_label": "696", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "03b383b8-f8d8-4a3a-ab6f-3a2e147612e3", "node_type": null, "metadata": {"page_label": "696", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cba030689b4e156b1e264c5a3c8d31a56e2f03acd81b12c7bdb3c12c5780616c"}, "3": {"node_id": "42eebaec-c21e-4fc8-986c-83afba39ebc3", "node_type": null, "metadata": {"page_label": "696", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3728e305d94fefddfcedf360073d729025836cb534b04c7f470d80f6c22e0286"}}, "hash": "8a74ae81c474f4a3732ffa435d5aee2f1b64c6f2051841ea2c0510efbdc169e1", "text": "690\nOVERVIEW\nFungal infections (mycoses) are widespread in the \npopulation. In temperate climates, such as the United \nKingdom, they are generally associated with the skin \n(e.g. \u2018athlete\u2019s foot\u2019) or mucous membranes (e.g. \u2018thrush\u2019) .\n1 In otherwise healthy people, these infections \nare mainly minor, being more of a nuisance than a \nthreat. However, they become a more serious problem \nwhen the immune system is compromised or when the organism gains access to the systemic circulation. \nWhen this occurs, the infection can be fatal. In this \nchapter, we will briefly review the main types of fungal infections and discuss the drugs that can be \nused to treat them.\nFUNGI AND FUNGAL INFECTIONS\nFungi are non-motile eukaryotic cells. Unlike green plants, \nthey cannot photosynthesise and many are parasitic or \nsaprophytic in nature. Thousands of species have been \ncharacterised. Many are of economic importance, either because they are edible (e.g. mushrooms), useful in manu-\nfacturing other products (e.g. yeast in brewing and in the \nproduction of antibiotics) or because of the damage they cause to other animals, crops or foodstuffs.\nApproximately 50 species are pathogenic in humans. \nThese organisms are present in the environment or may co-exist with humans as commensals without causing any \novert risks to health. However, since the 1970s there has \nbeen a steady increase in the incidence of serious secondary \nsystemic fungal infections, causing some 2 million deaths per year, usually in immunologically vulnerable individuals. \nOne of the contributory factors has been the widespread \nuse of broad-spectrum antibiotics, which eradicate the non-pathogenic bacterial populations that normally compete \nwith fungi for nutritional resources. Other causes include \nthe spread of AIDS and the use of immunosuppressant, and cancer chemotherapy agents. The result has been an \nincreased prevalence of opportunistic infections, that is, \ninfections that exploit vulnerabilities in host immune \nsystems. Older people, diabetics, pregnant women and burn \nwound victims are particularly at risk of fungal infections \nsuch as candidiasis . Primary systemic fungal infections, once \nrare in the temperate world, are also now encountered \nmore often because of increased international travel.Clinically important fungi may be classified into four \nmain types on the basis of morphological and other char -\nacteristics. Of particular taxonomic significance is the presence of hyphae \u2013 filamentous projections that can knit \ntogether to form a complex mycelium, a mat-like structure \nthat is responsible for the characteristic appearance of \nmoulds. Fungi are remarkably specific in their choice of \npreferred location. The main groups are:\n\u2022\tyeasts\t(e.g. \tCryptococcus neoformans)\n\u2022\tyeast-like \tfungi \tthat \tproduce \ta \tstructure \tresembling \ta \t\nmycelium (e.g. Candida albicans)\n\u2022\tfilamentous \tfungi \twith \ta \ttrue \tmycelium \t(e.g. \t\nAspergillus fumigatus)\n\u2022\t\u2018dimorphic\u2019 \tfungi \twhich, \tdepending \ton \tnutritional \t\nconstraints, may grow as either yeasts or filamentous fungi (e.g. Histoplasma capsulatum\n2)\nAs a general rule, most fungi only cause systemic infections \nin immunocompromised individuals but the dimorphic \nfungi can infect healthy individuals.\nAnother organism, Pneumocystis carinii (also known as \nP. jirovecii), described in Ch. 55, shares characteristics of both protozoa and fungi; it is an important opportunistic pathogen in patients with compromised immune systems \n(e.g. those", "start_char_idx": 0, "end_char_idx": 3502, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "42eebaec-c21e-4fc8-986c-83afba39ebc3": {"__data__": {"id_": "42eebaec-c21e-4fc8-986c-83afba39ebc3", "embedding": null, "metadata": {"page_label": "696", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "03b383b8-f8d8-4a3a-ab6f-3a2e147612e3", "node_type": null, "metadata": {"page_label": "696", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cba030689b4e156b1e264c5a3c8d31a56e2f03acd81b12c7bdb3c12c5780616c"}, "2": {"node_id": "83f30758-1bd8-4b3e-a000-464ec0fc4d90", "node_type": null, "metadata": {"page_label": "696", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8a74ae81c474f4a3732ffa435d5aee2f1b64c6f2051841ea2c0510efbdc169e1"}}, "hash": "3728e305d94fefddfcedf360073d729025836cb534b04c7f470d80f6c22e0286", "text": "pathogen in patients with compromised immune systems \n(e.g. those suffering from AIDS), but is not susceptible to \nantifungal drugs.\nDrugs vary in their efficacy between the different fungal \ngroups. Table 54.1 gives examples of each type of organism and lists some of the diseases they cause and the most common choice of drug.\nSuperficial fungal infections can be classified into the \ndermatomycoses and candidiasis. Dermatomycoses include infections of the skin, hair and nails ( onychomycosis). They \nare most commonly caused by Trichophyton, Microsporum \nor Epidermophyton, giving rise to circular rashes known \nas \u2018ringworm\u2019 or, generically, tinea (not to be confused \nwith genuine helminth infections; see Ch. 56). Tinea capitis \naffects the scalp; Tinea cruris, the groin (\u2018dhobie itch\u2019); \nTinea pedis, the feet (\u2018athlete\u2019s foot\u2019); and Tinea corporis, \nthe body. Superficial candidiasis, caused by a yeast-like \norganism, may infect the mucous membranes of the mouth \nor vagina (thrush), or the skin. Secondary bacterial infec -\ntions may complicate the course and treatment of these \nconditions.\nSystemic (or \u2018disseminated\u2019) fungal diseases are much \nmore serious than superficial infections. The common -\nest in the United Kingdom is candidiasis. Other serious conditions include cryptococcal meningitis, endocarditis Antifungal drugs54 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER SECTION 5\n1However, they may also \u2018infect\u2019 buildings too and contribute to the \n\u2018sick building syndrome\u2019.2Histoplasma is a common asymptomatic infection in the American \nmid-west. It is carried by bats and hence infects spelunkers (cavers).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3437, "end_char_idx": 5559, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "276d0ce3-e077-454a-969f-0ce74774c7d0": {"__data__": {"id_": "276d0ce3-e077-454a-969f-0ce74774c7d0", "embedding": null, "metadata": {"page_label": "697", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73e6c147-499c-4776-a814-42ef8bd7e9d2", "node_type": null, "metadata": {"page_label": "697", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c1122c4e092d44631019817be4d51ad7784028c31a46e41a9d532fef2a19ebe"}, "3": {"node_id": "9f67646b-ddf2-43be-8f29-84a3a4d08ec4", "node_type": null, "metadata": {"page_label": "697", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1cc15f1c8985ec31dd749f69198645c3bad4c9ff8e47da0622bcf49a35e81d24"}}, "hash": "c9f682e1bd98400318edf7d8c24102bb990cc679a68ff1b9ce14db0b4f357a02", "text": "54 ANTIFUNGA l DRUGS\n691Like other polyene antibiotics (see Ch. 52), the site of \namphotericin action is the fungal cell membrane. The \nhydrophilic core of the doughnut-shaped amphotericin \nmolecule creates a transmembrane ion channel, causing gross disturbances in ion balance including the loss of \nintracellular K\n+, altering cellular permeability and disrupting \ntransport systems. Amphotericin has a selective action, binding avidly to the membranes of fungi and some pro-\ntozoa, less avidly to mammalian cells and not at all to bacteria. The basis of this relative specificity is the drug\u2019s \ngreater avidity for ergosterol , a fungal membrane sterol that \nis not found in animal cells (where cholesterol is the principal \nsterol). Amphotericin is active against most fungi and yeasts, \nand is the gold standard for treating disseminated infections \ncaused by organisms including Aspergillus and Candida. \nAmphotericin also enhances the antifungal effect of flucy-\ntosine, providing a useful synergistic combination.\nPharmacokinetic aspectsAmphotericin is very poorly absorbed when given orally, \nand this route is used only for treating fungal infections \nof the upper gastrointestinal (GI) tract. It can be used topi -\ncally, but for systemic infections it is generally administered, \nformulated in liposomes or other lipid-containing prepara -\ntions, by slow intravenous infusion. This improves the \npharmacokinetics and reduces the (considerable) burden \nof side effects.\nAmphotericin is very highly protein-bound. It penetrates \ntissues and membranes poorly, although it is found in fairly high concentrations in inflammatory exudates and may cross \nthe blood\u2013brain barrier quite readily when the meninges are inflamed. Intravenous amphotericin is essential in the treat -\nment of cryptococcal meningitis, often with flucytosine. It is excreted very slowly via the kidney, traces being found in the urine for 2 months or more after administration has ceased.\nUnwanted effectsThe commonest (indeed almost invariable) adverse effects \nof amphotericin include rigors, fever, chills and headache \nduring drug infusion; hypotension and anaphylactoid reactions occur in more severely affected individuals. The \n(considerably more expensive) liposome-encapsulated and \nlipid-complexed preparations have no greater efficacy than (particularly of artificial valves), pulmonary aspergillosis, \nand rhinocerebral mucormycosis. Invasive pulmonary aspergillosis is now a leading cause of death in recipients \nof bone marrow transplants or those with neutropenia. \nColonisation by Aspergillus of the lungs of patients with \nasthma or cystic fibrosis can lead to a condition termed \nallergic bronchopulmonary aspergillosis.\nIn other parts of the world, systemic fungal infections \ninclude blastomycosis, histoplasmosis (which produces characteristic calcifications on chest X-rays), coccidi -\nomycosis and paracoccidiomycosis; these are often \nprimary infections, that is, they are not secondary to \nreduced immunological function or altered commensal \nmicroorganisms.\nIn addition to a free-floating lifestyle, some fungi can \ndevelop and grow in biofilms, that is, fungal communities \nattached to the surface of inert (e.g. catheters) or living (e.g. implants) surfaces. Such colonies are highly resistant to stress and to antifungal drugs, making them very difficult \nto treat.\nDRUGS USED TO TREAT FUNGAL \nINFECTIONS\nThe current therapeutic agents can be broadly classified \ninto two groups: first, the naturally\u2013occurring", "start_char_idx": 0, "end_char_idx": 3519, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9f67646b-ddf2-43be-8f29-84a3a4d08ec4": {"__data__": {"id_": "9f67646b-ddf2-43be-8f29-84a3a4d08ec4", "embedding": null, "metadata": {"page_label": "697", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "73e6c147-499c-4776-a814-42ef8bd7e9d2", "node_type": null, "metadata": {"page_label": "697", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9c1122c4e092d44631019817be4d51ad7784028c31a46e41a9d532fef2a19ebe"}, "2": {"node_id": "276d0ce3-e077-454a-969f-0ce74774c7d0", "node_type": null, "metadata": {"page_label": "697", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c9f682e1bd98400318edf7d8c24102bb990cc679a68ff1b9ce14db0b4f357a02"}}, "hash": "1cc15f1c8985ec31dd749f69198645c3bad4c9ff8e47da0622bcf49a35e81d24", "text": "agents can be broadly classified \ninto two groups: first, the naturally\u2013occurring antifungal \nantibiotics such as the polyenes and echinocandins , and second, \nsynthetic drugs including azoles and fluorinated pyrimidines . \nBecause many infections are superficial, there are many topical preparations. Many antifungal agents are quite toxic, \nand when systemic therapy is required this is generally undertaken under strict medical supervision.\nFig. 54.1 shows sites of action of common antifungal \ndrugs.\nANTIFUNGAL ANTIBIOTICS\nAmphotericin\nAmphotericin (also called amphotericin B) is a mixture \nof antifungal substances derived from cultures of Strepto-\nmyces. Structurally, these are very large (\u2018macrolide\u2019) molecules belonging to the polyene group of antifungal agents.Table 54.1 Some clinically significant fungal infections and a typical first choice of antifungal drug therapy\nOrganism(s) responsible Principal disease(s) Common drug treatments\nYeasts Cryptococcus neoformans Meningitis Amphotericin, flucytosine, fluconazole\nYeast-like \nfungusCandida albicansThrush (and other superficial infection) Fluconazole, itraconazole\nSystemic candidiasisEchinocandins, amphotericin, fluconazole, other azoles\nFilamentous fungiTrichophyton spp.Epidermophyton floccosumMicrosporum spp.All these organisms cause skin and nail infections and are referred to as tinea or \u2018ringworm\u2019Itraconazole, terbinafine, griseofulvin\nAspergillus fumigatus Pulmonary aspergillosisAmphotericin, capsofungin, voriconazole, other azoles\nDimorphic fungiHistoplasma capsulatum Histoplasmosis\nItraconazole, amphotericin Coccidioides immitis Coccidiomycosis\nBlastomyces dermatitidis Blastomycosismebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3438, "end_char_idx": 5591, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f785ea96-a9df-4990-b95a-202acba76b4b": {"__data__": {"id_": "f785ea96-a9df-4990-b95a-202acba76b4b", "embedding": null, "metadata": {"page_label": "698", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1c37999a-a28f-44ac-a644-fb728c9bf3e6", "node_type": null, "metadata": {"page_label": "698", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b816810a7d46a5fbb3edd80b908ed79848d36e9e5fb6e7ce23be42a001261a7d"}, "3": {"node_id": "24e9854c-d2d0-445c-b893-e88b347a58ca", "node_type": null, "metadata": {"page_label": "698", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f9af0ba3e95d708808f3be5d8a3b7e131b1ce126e2ed9c66141895892746557"}}, "hash": "f4ac37e0668e42738a47da17eca761d64a1d773d16d6fc13b9e6b220dd60e9af", "text": "54 SECTION 5 \u2003\u2003DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n692with mitosis by binding to fungal microtubules. It can \nbe used to treat dermatophyte infections of skin or nails \nwhen local administration is ineffective, but treatment \nneeds to be prolonged. It has largely been superseded by \nother drugs.\nPharmacokinetic aspects\nGriseofulvin is given orally. It is poorly soluble in water, \nand absorption varies with the type of preparation, in \nparticular with particle size. It is taken up selectively by \nnewly formed skin and concentrated in the keratin. The \nplasma half-life is 24 h, but it is retained in the skin for \nmuch longer. It potently induces cytochrome P450 enzymes \nand causes several clinically important drug interactions.\nUnwanted effects\nUnwanted effects with griseofulvin use are infrequent, but \nthe drug can cause GI upsets, headache and photosensitivity. \nAllergic reactions (rashes, fever) may also occur. The drug \nshould not be given to pregnant women.\nEchinocandins\nEchinocandins comprise a ring of six amino acids linked \nto a lipophilic side-chain. All drugs in this group are \nsynthetic modifications of echinocandin B , which is found \nnaturally in Aspergillus nidulans . As a group, the echino -\ncandins are fungicidal for Candida and fungistatic for \nAspergillus . The drugs inhibit the synthesis of 1,3- \u03b2-glucan, \na glucose polymer that is necessary for maintaining the \nstructure of fungal cell walls. In the absence of this polymer, the native drug but cause much less frequent and less severe \ninfusion reactions.\nThe most serious unwanted effect of amphotericin is \nrenal toxicity. Some reduction of renal function occurs in \nmore than 80% of patients receiving the drug; although \nthis generally improves after treatment is stopped, some \nimpairment of glomerular filtration may remain. Hypoka -\nlaemia occurs in 25% of patients, due to the primary action \nof the drug on fungi spilling over into renal tubular cells, \ncausing potassium loss, which often requires potassium \nchloride supplementation. Hypomagnesaemia also occurs \nfor the same reason. Acid-base disturbance and anaemia \ncan be further problems. Other unwanted effects include \nimpaired hepatic function and thrombocytopenia. The drug \nis irritant to the endothelium of the veins, and can cause \nlocal thrombophlebitis. Intrathecal injections can cause \nneurotoxicity, and topical applications cause a rash.\nNystatin\nNystatin (also called fungicidin ) is a polyene macrolide \nantibiotic similar in structure to amphotericin and with the \nsame mechanism of action. It is given orally, but is not \nabsorbed through mucous membranes or skin, and its use \nis mainly limited to Candida infections of the skin, mucous \nmembranes and the GI tract. Unwanted effects may include \nnausea, vomiting and diarrhoea.\nGriseofulvin\nGriseofulvin is a narrow-spectrum antifungal agent iso -\nlated from cultures of Penicillium griseofulvum . It interferes Nucleus\n\u03b2-glucan rich\nfungal cell wall\nErgosterol-rich fungal\ncell membraneDNAGriseofulvinAmphotericin\nFlucytosineMicrotubule system\nEchinocandins\nErgosterol\nLanosterol\nSqualeneAzoles\nTerbinafine\nNaftifine\nAmorolfine\nFig. 54.1 Sites of action of common antifungal drugs. Fungi are morphologically very", "start_char_idx": 0, "end_char_idx": 3264, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "24e9854c-d2d0-445c-b893-e88b347a58ca": {"__data__": {"id_": "24e9854c-d2d0-445c-b893-e88b347a58ca", "embedding": null, "metadata": {"page_label": "698", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1c37999a-a28f-44ac-a644-fb728c9bf3e6", "node_type": null, "metadata": {"page_label": "698", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b816810a7d46a5fbb3edd80b908ed79848d36e9e5fb6e7ce23be42a001261a7d"}, "2": {"node_id": "f785ea96-a9df-4990-b95a-202acba76b4b", "node_type": null, "metadata": {"page_label": "698", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f4ac37e0668e42738a47da17eca761d64a1d773d16d6fc13b9e6b220dd60e9af"}}, "hash": "4f9af0ba3e95d708808f3be5d8a3b7e131b1ce126e2ed9c66141895892746557", "text": "of action of common antifungal drugs. Fungi are morphologically very diverse organisms, and this schematic diagram \nof a \u2018typical\u2019 fungal cell is not intended to be structurally accurate. The principal sites of action of the main antifungal agents mentioned in \nthis chapter are indicated as shown in red-bordered boxes . mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3195, "end_char_idx": 3997, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8acb8557-9d2f-422e-80d6-a2ac7bf8c1e7": {"__data__": {"id_": "8acb8557-9d2f-422e-80d6-a2ac7bf8c1e7", "embedding": null, "metadata": {"page_label": "699", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "163975db-1ec0-406a-83c4-89dfc0e981c0", "node_type": null, "metadata": {"page_label": "699", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cd9b352d88f7e7cd76475a79ba2378bd9f097196d0109a3566cf44f41f9b9c33"}, "3": {"node_id": "f5365285-f210-4453-92ce-f46855f6c904", "node_type": null, "metadata": {"page_label": "699", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cbd13e484616e5a3fe68e487d85598d2a17d45eee785470df856ca1680215d30"}}, "hash": "dd5f0e0360af370be59090b56747a5837a731e67b5067c01cfc5e34d63221ab5", "text": "54 ANTIFUNGA l DRUGS\n693cerebrospinal fluid and ocular fluids, and is used to treat \nmost types of fungal meningitis. Fungicidal concentrations \nare also achieved in vaginal tissue, saliva, skin and nails. It \nhas a half-life of ~25 h, and is mainly excreted unchanged \nin the urine.\nUnwanted effects\nUnwanted effects, which are generally mild, include nausea, headache and abdominal pain. However, exfoliative skin \nlesions (including, on occasion, Stevens\u2013Johnson syndrome\n3) \nhave been seen in some individuals \u2013 primarily in AIDS patients who are being treated with multiple drugs. Hepatitis \nhas been reported, although this is rare, and fluconazole, in the doses usually used, does not inhibit steroidogenesis \nand hepatic drug metabolism to the same extent as occurs \nwith ketoconazole.\nItraconazole\nItraconazole is active against a range of dermatophytes. It may be given orally but, after absorption (which is variable) \nundergoes extensive hepatic metabolism. It is highly lipid-\nsoluble (and water-insoluble), and a formulation in which the drug is retained within pockets of \u03b2-cyclodextrin is \navailable. In this form, itraconazole can be administered intravenously, thereby overcoming the problem of variable absorption from the GI tract. Administered orally, its half-life \nis about 36 h, and it is excreted in the urine. It does not \npenetrate the cerebrospinal fluid.\nUnwanted effects\nThe most serious are hepatoxicity and Stevens\u2013Johnson syndrome. GI disturbances, headache and allergic skin \nreactions can occur. Inhibition of steroidogenesis has \nnot been reported. Drug interactions as a result of inhi -\nbition of cytochrome P450 enzymes occur (similar to \nketoconazole).\nMiconazole\nMiconazole is generally used topically (often as a gel) for oral and other infections of the GI tract or for skin or mucosal \nfungal infection. If significant systemic absorption occurs, \ndrug interactions can present a problem.\nOther azoles\nClotrimazole, econazole, tioconazole and sulconazole are used only for topical application. Clotrimazole interferes \nwith amino acid transport into the fungus by an action on \nthe cell membrane. It is active against a wide range of fungi, including candidal organisms. These drugs are \nsometimes combined with anti-inflammatory glucocorticoids \n(see Ch. 27). Posacanazole and voriconazole are used mainly for the treatment of invasive life-threatening infections such \nas aspergillosis.\nOTHER \u2003ANTIFUNGAL \u2003DRUGS\nFlucytosine is a synthetic, orally active antifungal agent \nthat is effective against a limited range (mainly yeasts) of \nsystemic fungal infections. In fungal, but not human, cells \nit is converted to the antimetabolite 5-fluorouracil which fungal cells lose integrity and lyse. Resistance genes have been identified in Candida\n (Chen et al., 2011).\nCaspofungin is active in vitro against a wide variety of \nfungi, and it has proved effective in the treatment of candidi -\nasis and forms of invasive aspergillosis that are refractory to amphotericin. Oral absorption is poor, and it is given intravenously, once daily. Anidulafungin is used mainly \nfor invasive candidiasis; again it is given intravenously. The principal side effects of both drugs include nausea, vomiting and diarrhoea, and rash. The relatively new \nmicafungin is also mainly used for treating invasive candidi -\nasis. It shares many of the side effects of the group but \nmay also cause serious", "start_char_idx": 0, "end_char_idx": 3427, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f5365285-f210-4453-92ce-f46855f6c904": {"__data__": {"id_": "f5365285-f210-4453-92ce-f46855f6c904", "embedding": null, "metadata": {"page_label": "699", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "163975db-1ec0-406a-83c4-89dfc0e981c0", "node_type": null, "metadata": {"page_label": "699", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cd9b352d88f7e7cd76475a79ba2378bd9f097196d0109a3566cf44f41f9b9c33"}, "2": {"node_id": "8acb8557-9d2f-422e-80d6-a2ac7bf8c1e7", "node_type": null, "metadata": {"page_label": "699", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd5f0e0360af370be59090b56747a5837a731e67b5067c01cfc5e34d63221ab5"}}, "hash": "cbd13e484616e5a3fe68e487d85598d2a17d45eee785470df856ca1680215d30", "text": "It shares many of the side effects of the group but \nmay also cause serious hepatotoxicity.\nSYNTHETIC ANTIFUNGAL DRUGS\nAZOLES\nThe azoles are a group of synthetic fungistatic agents with \na broad spectrum of antifungal activity. Clotrimazole, \neconazole, fenticonazole, ketoconazole, miconazole, tio-\nconazole and sulconazole (not United Kingdom) are based \non the imidazole nucleus and itraconazole , posaconazole , \nvoriconazole and fluconazole are triazole derivatives.\nThe azoles inhibit the fungal cytochrome P450 3A enzyme, \nlanosine 14 \u03b1-demethylase, which is responsible for convert -\ning lanosterol to ergosterol, the main sterol in the fungal cell membrane. The resulting depletion of ergosterol alters the fluidity of the membrane, and this interferes with the action of membrane-associated enzymes. The net effect is \nan inhibition of replication. Azoles also inhibit the trans -\nformation of candidal yeast cells into hyphae \u2013 the invasive \nand pathogenic form of the parasite. Depletion of membrane \nergosterol reduces the binding of amphotericin.\nKetoconazole\nKetoconazole was the first azole that could be given orally \nto treat systemic fungal infections. It is effective against \nseveral different types of organism (see Table 54.1). It is, \nhowever, toxic, and relapse is common after apparently successful treatment. It is well absorbed from the GI tract. \nIt is distributed widely throughout the tissues and tissue \nfluids but does not reach therapeutic concentrations in the central nervous system unless high doses are given. It is \ninactivated in the liver and excreted in bile and in urine. \nIts half-life in the plasma is 8 h.\nUnwanted effects\nThe main hazard of ketoconazole is liver toxicity, which is \nrare but can prove fatal. Liver function is monitored before \nand during treatment. Other side effects that occur are GI disturbances and pruritus. Inhibition of adrenocortical \nsteroid and testosterone synthesis has been recorded with \nhigh doses, the latter resulting in gynaecomastia in some male patients. There may be adverse interactions with \nother drugs. Ciclosporin and astemizole compete with \nketoconazole for cytochrome P450 mixed function oxidase \nenzymes, causing increased plasma concentrations of keto -\nconazole and often that of the interacting drugs themselves. \nHistamine H\n2-receptor antagonists and antacids decrease \nthe absorption of ketoconazole and rifampicin reduces \nthe plasma concentration by induction of metabolising \nenzymes.\nFluconazole\nFluconazole is well absorbed and can be given orally \nor intravenously. It reaches high concentrations in the 3This is a severe and sometimes fatal condition involving blistering of \nthe skin, mouth, GI tract, eyes and genitalia, often accompanied by \nfever, polyarthritis and kidney failure.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3352, "end_char_idx": 6628, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dc318a46-37e2-442f-864b-e9215810bf2e": {"__data__": {"id_": "dc318a46-37e2-442f-864b-e9215810bf2e", "embedding": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9baa1273-862f-43ce-807e-0544963129ad", "node_type": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8dcf455ea454dd9d1235cfc174f047ee1b7a2f2f4d8e4c3c2a9b66ccf5021e0f"}, "3": {"node_id": "0705d0f0-eeed-44f9-a976-8bb5641a5f0e", "node_type": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4596cc9aeffb0619bad06d31bff43437f0e2226bd1d616f8540c5ad45ef72731"}}, "hash": "c71aa4ba2c173fc34d062c2a26648a1ed5ba99a6ae128dafc173ee406fdbe114", "text": "54 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n694FUTURE DEVELOPMENTS\nFungal infections are on the rise because of the prevalence \nof cancer chemotherapy and transplant-associated immu-\nnosuppression. Many existing drugs have low efficacy, and \nproblems with toxicity and new strains of commensal-turned-pathogenic fungi are emerging. Furthermore, \nincreasing numbers of fungal strains are becoming resistant \nto the current antifungal drugs as they develop resistance genes or acquire naturally occurring protective mutations \n(although, fortunately, drug resistance is not transferable \nin fungi), and the capacity of some species to develop biofilms exacerbates this problem (although also offering \nother opportunities for drug design; see de Mello et al., \n2017).\nThere is therefore a pressing need for more antifungals. \nEncouragingly, new synthetic compounds are in develop -\nment, including novel azole drugs (see, for example, Zeichner, 2015) as well as some further developments, some \nwith novel mechanisms of action.\nThe development of new inhibitors of \u03b2-glucan has been \nreviewed by Hector and Bierer (2011); new targets such as V-ATPase are being assessed (Zhang & Rao, 2012) while \nthe prospect of discovering new naturally occurring anti-fungals (like the antibiotic drugs already mentioned) \ncontinues to attract attention (Dhankhar et al., 2012).\nAn ideal solution would be an antifungal vaccine(s). The \nidea was first mooted in the 1960s, but has so far met with \nlimited success in animals (see Torosantucci et al., 2005) \nand none have reached the clinic. A problem in the past has been understanding how the immune system combats \nfungal infection but recently many issues have now been \nclarified and this should aid vaccine design in the future. Progress in this area has been reviewed by Medici and Del \nPoeta (2015), Nanjappa and Klein (2014) and Datta and Hamad (2015).\nOne problem with this approach is that the development \nof active vaccine-induced immunity is dependent upon the functioning of the patient\u2019s immune system and it is precisely immunocompromised patients who often require treatment.inhibits thymidylate synthetase and thus DNA synthesis (see Chs 6 and 57). If given alone, drug resistance commonly arises during treatment, so it is usually combined with amphotericin for severe systemic infections such as candidi -\nasis and cryptococcal meningitis.\nFlucytosine is usually given by intravenous infusion \n(because such patients are often too ill to take medicine by \nmouth) but can also be given orally. It is widely distributed \nthroughout the body fluids, including the cerebrospinal fluid. About 90% is excreted unchanged via the kidneys, \nand the plasma half-life is 3\u20135 h. The dosage should be \nreduced if renal function is impaired.\nUnwanted effects include GI disturbances, anaemia, \nneutropenia, thrombocytopenia and alopecia (possibly due to formation of fluorouracil [Ch. 57] from flucytosine by gut bacteria), but these are usually manageable. Uracil is \nreported to decrease the toxic effects on the bone marrow \nwithout impairing the antimycotic action. Hepatitis has been reported but is rare.\nTerbinafine is a highly lipophilic, keratinophilic fungicidal \ncompound active against a wide range of skin pathogens. It is particularly useful against nail infections. It acts by selectively inhibiting the enzyme squalene epoxidase , which \nis involved in the synthesis of ergosterol from squalene in the fungal cell wall. The accumulation of squalene within", "start_char_idx": 0, "end_char_idx": 3548, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0705d0f0-eeed-44f9-a976-8bb5641a5f0e": {"__data__": {"id_": "0705d0f0-eeed-44f9-a976-8bb5641a5f0e", "embedding": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9baa1273-862f-43ce-807e-0544963129ad", "node_type": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8dcf455ea454dd9d1235cfc174f047ee1b7a2f2f4d8e4c3c2a9b66ccf5021e0f"}, "2": {"node_id": "dc318a46-37e2-442f-864b-e9215810bf2e", "node_type": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c71aa4ba2c173fc34d062c2a26648a1ed5ba99a6ae128dafc173ee406fdbe114"}, "3": {"node_id": "343a8cd4-2ebe-446f-bf8b-6fcbc4e0afd2", "node_type": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ef3fe7dfd9954a198b56144e9954f69d57e421eabdba5c9afefaae77bdadcf0c"}}, "hash": "4596cc9aeffb0619bad06d31bff43437f0e2226bd1d616f8540c5ad45ef72731", "text": "squalene in the fungal cell wall. The accumulation of squalene within the cell is toxic to the organism.\nWhen used to treat ringworm or fungal infections of the \nnails, it is given orally. The drug is rapidly absorbed and is taken up by skin, nails and adipose tissue. Given topically, \nit penetrates skin and mucous membranes. It is metabolised \nin the liver by the cytochrome P450 system, and the metabolites are excreted in the urine.\nUnwanted effects occur in about 10% of individuals and \nare usually mild and self-limiting. They include GI distur -\nbances, rashes, pruritus, headache and dizziness. Joint and \nmuscle pains have been reported and, more rarely, \nhepatitis.\nNaftifine (not United Kingdom) is similar in action to \nterbinafine. Among other developments, a morpholine derivative, amorolfine , which interferes with fungal sterol \nsynthesis, is available as a nail lacquer, being effective against onychomycoses.\nREFERENCES AND FURTHER READING\nChen, S.C., Slavin, M.A., Sorrell, T.C., 2011. Echinocandin antifungal \ndrugs in fungal infections: a comparison. Drugs 71, 11\u201341. (A very \ncomprehensive review of the echinocandin drugs, including comments upon \nthe phenomenon of drug resistance)\nDatta, K., Hamad, M., 2015. Immunotherapy of fungal infections. \nImmunol. Invest. 44, 738\u2013776. (A comprehensive paper covering many aspects of fungal immunity and prospects for immunotherapy)\nde Mello, T.P., de Souza Ramos, L., Braga-Silva, L.A., et al., 2017. \nFungal biofilm - a real obstacle against an efficient therapy: lessons from Candida. Curr. Top. Med. Chem. (A paper which deals with the \ngrowing problems of fungal biofilms and describes potential novel ways of inhibiting their formation)\nDeepe, G.S., Jr., 2004. Preventative and therapeutic vaccines for fungal \ninfections: from concept to implementation. Expert Rev. Vaccines 3, 701\u2013709. (An interesting, and optimistic, overview of the quest for antifungal vaccines)\nDenning, D.W., 2003. Echinocandin antifungal drugs. Lancet 362, \n1142\u20131151. (General review on the echinocandins, focusing on their clinical use)\nDhankhar, S., Dhankhar, S., Kumar, M., Ruhil, S., Balhara, M., Chhillar, \nA.K., 2012. Analysis toward innovative herbal antibacterial and antifungal drugs. Recent Pat. Antiinfect. Drug Discov. 7, 242\u2013248. ( The \nquest for more naturally occurring antifungals continues with the identification of potential new active compounds)\nDodds, E.S., Drew, R.H., Perfect, J.R., 2000. Antifungal \npharmacodynamics: review of the literature and clinical applications. Pharmacotherapy 20, 1335\u20131355. (Good review of antifungals used to treat systemic infections; somewhat clinical in tone)\nGupta, A.K., Tomas, E., 2003. New antifungal agents. Dermatol. Clin. \n21, 565\u2013576. (Quite a comprehensive review that deals mainly with the newer antifungals, their mechanisms of action and resistance)\nHadrich, I., Makni, F., Neji, S., et al., 2012. Invasive aspergillosis: \nresistance to antifungal drugs. Mycopathologia 174, 131\u2013141. (Mainly deals with the mechanisms of resistance of aspergillus to conventional", "start_char_idx": 3490, "end_char_idx": 6571, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "343a8cd4-2ebe-446f-bf8b-6fcbc4e0afd2": {"__data__": {"id_": "343a8cd4-2ebe-446f-bf8b-6fcbc4e0afd2", "embedding": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9baa1273-862f-43ce-807e-0544963129ad", "node_type": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8dcf455ea454dd9d1235cfc174f047ee1b7a2f2f4d8e4c3c2a9b66ccf5021e0f"}, "2": {"node_id": "0705d0f0-eeed-44f9-a976-8bb5641a5f0e", "node_type": null, "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4596cc9aeffb0619bad06d31bff43437f0e2226bd1d616f8540c5ad45ef72731"}}, "hash": "ef3fe7dfd9954a198b56144e9954f69d57e421eabdba5c9afefaae77bdadcf0c", "text": "(Mainly deals with the mechanisms of resistance of aspergillus to conventional \nantifungal drugs)\nHector, R.F., Bierer, D.E., 2011. New beta-glucan inhibitors as antifungal \ndrugs. Expert Opin. Ther. Pat. 21, 1597\u20131610. (A review of new patents in the area. Strictly for those who want to go into the subject in depth)\nLupetti, A., Nibbering, P.H., Campa, M., et al., 2003. Molecular targeted \ntreatments for fungal infections: the role of drug combinations. Trends \nMol. Med. 9, 269\u2013276. (Interesting and accessible article that deals with the \nuse of combination antifungal therapy. Some good diagrams)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6552, "end_char_idx": 7636, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3c237c4c-0c26-49ab-83c5-d63c4c9550c2": {"__data__": {"id_": "3c237c4c-0c26-49ab-83c5-d63c4c9550c2", "embedding": null, "metadata": {"page_label": "701", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f0a70f30-0211-4cb3-a9d7-7ddb320258b5", "node_type": null, "metadata": {"page_label": "701", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6382212bb48076022d78de3f296c73a13949d7b55f8a5a1c9087e5cb05f85ac7"}}, "hash": "6382212bb48076022d78de3f296c73a13949d7b55f8a5a1c9087e5cb05f85ac7", "text": "54 ANTIFUNGA l DRUGS\n695Intern. Med. J. 38, 496\u2013520. (A very comprehensive review of the treatment \nof fungal infections. Clinical in tone)\nTorosantucci, A., Bromuro, C., Chiani, P., et al., 2005. A novel \nglyco-conjugate vaccine against fungal pathogens. J. Exp. Med. 202, 597\u2013606. (An experimental paper demonstrating the development of a novel \ntype of vaccine effective against Candida infections in mice)\nZeichner, J.A., 2015. New topical therapeutic options in the management \nof superficial fungal infections. J. Drugs Dermatol. 14, s35\u2013s41.\nZhang, Y., Rao, R., 2012. The V-ATPase as a target for antifungal drugs. \nCurr. Protein Pept. Sci. 13, 134\u2013140. (The title is self explanatory)\nUseful Web resources\nhttp://www.fungionline.org.uk (This site is sponsored by the British \nMycological Society. It deals with the basic biology of fungi and contains many useful diagrams and images as well as links to other resources and \nvideo clips. It doesn\u2019t specifically relate to the pathology of fungal infections or drug therapy, but is very interesting for those wishing to delve more \ndeeply into the biology of these unique organisms)Medici, N.P., Del Poeta, M., 2015. New insights on the development of \nfungal vaccines: from immunity to recent challenges. Mem. Inst. Oswaldo Cruz 110, 966\u2013973. (Discusses the need for, and the problems \nassociated with, fungal vaccines. Very readable)\nNanjappa, S.G., Klein, B.S., 2014. Vaccine immunity against fungal \ninfections. Curr. Opin. Immunol. 28, 27\u201333. (This paper reviews developments, our understanding of fungal immunity and how this applies to vaccine design. It also includes a list of vaccine candidates)\nNoel, T., 2012. The cellular and molecular defense mechanisms of the \nCandida yeasts against azole antifungal drugs. J. Mycol. Med. 22, 173\u2013178. (Another paper that discusses resistance mechanisms, in this case \nto the azoles)\nSant, D.G., Tupe, S.G., Ramana, C.V., et al., 2016. Fungal cell \nmembrane-promising drug target for antifungal therapy. J. Appl. \nMicrobiol. 121 (6), 1498\u20131510. (Useful review of drug action at the fungal \nmembrane and of potential new targets for pharmacotherapy)\nThursky, K.A., Playford, E.G., Seymour, J.F., et al., 2008. \nRecommendations for the treatment of established fungal infections. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2765, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1300a016-3dd4-4a83-b4fa-462d289c1db4": {"__data__": {"id_": "1300a016-3dd4-4a83-b4fa-462d289c1db4", "embedding": null, "metadata": {"page_label": "702", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "93d5d317-0d42-4f6c-b643-99e764970f25", "node_type": null, "metadata": {"page_label": "702", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50442fb561d32ffa97a815e9a12fb9640fbe43ce183cf339785ee0a37e670da3"}, "3": {"node_id": "4a3f40b7-d4a6-49de-8e15-8a04e9b4e191", "node_type": null, "metadata": {"page_label": "702", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86bdd270e1a7e0d310d9f0d1c88d82dc88bcbf9cec2d8f34f883494f11cff059"}}, "hash": "7bc936cb8b077ab7a75d66146b16296705a25a021f153ec39019b454a97ef375", "text": "696\nOVERVIEW\nProtozoa are motile, unicellular eukaryotic organisms \nthat have colonised virtually every habitat and ecologi -\ncal niche. As a group, the protozoa are responsible for an enormous burden of illness in humans as well as domestic and wild animal populations. Historically, \nmalaria has been one of mankind\u2019s greatest afflictions. \nEven today there are over 200 million cases of malaria each year and some half a million deaths. In this \nchapter, we will first review some general features \nof protozoa, discuss the interactions of these parasites with their hosts and then consider the therapy of \neach group of diseases in turn. In view of its global \nimportance, malaria is the main topic.\nBACKGROUND\nProtozoa may be conveniently classified into four main \ngroups on the basis of their mode of locomotion: amoebas, \nflagellates and sporozoa are easily characterised, but the final \ngroup comprises ciliates and other organisms of uncertain \naffiliation, such as the Pneumocystis jirovecii mentioned in \nthe last chapter. Protozoa have diverse feeding behaviour, \nwith some being parasitic. Many have extremely complex life cycles, sometimes involving several hosts, reminiscent \nof the helminths discussed in Chapter 56. Table 55.1 lists \nsome of these clinically important organisms, together with the diseases that they cause and an overview of anti-infective drugs.\nHOST\u2013PARASITE INTERACTIONS\nWhile mammals have developed very efficient mechanisms for defending themselves against invading parasites, many \nspecies have, in turn, evolved sophisticated evasion tactics. \nOne common parasite ploy is to take refuge within the cells of the host, where antibodies cannot reach them. Most \nprotozoa do this, for example, Plasmodium species take up \nresidence in red cells, Leishmania species infect macrophages \nexclusively, while Trypanosoma species invade many other \ncell types. The host deals with these intracellular fugitives \nby deploying cytotoxic CD8\n+ T cells and T helper (Th)1 \npathway cytokines, such as interleukin (IL)-2, tumour \nnecrosis factor (TNF)-\u03b1 and interferon-\u03b3. These cytokines \n(see Ch. 19) activate macrophages, which can then kill the infected cells along with the intracellular parasites.\nAs we explained in Chapter 7, the Th1 pathway responses \ncan be down-regulated by Th2 pathway cytokines (e.g. transforming growth factor-\u03b2, IL-4 and IL-10). Some intracellular parasites have exploited this fact by stimulating the production of Th2 cytokines thus reducing their vulner -\nability to Th1-driven activated macrophages. For example, the invasion of macrophages by Leishmania species induces \ntransforming growth factor- \u03b2, IL-10, inactivates complement \npathways, and down-regulates many other intracellular \ndefence mechanisms (Singh et al., 2012). Similar mechanisms \noperate during worm infestations (see Ch. 56).\nToxoplasma gondii has evolved a different gambit \u2013 up-\nregulation of host defence responses. The definitive (i.e. where sexual recombination occurs) host of this protozoon is the cat, but humans can inadvertently become intermedi -\nate hosts, harbouring the asexual form of the parasite. In humans, T. gondii infects numerous cell types and has a \nhighly virulent replicative stage. To ensure that its host \nsurvives, it stimulates production of interferon- \u03b3, modulating \nthe host\u2019s cell-mediated responses to promote encystment \n(and thus persistence) of the parasite in the tissues.\nMALARIA AND ANTIMALARIAL DRUGS\nMalaria1 is caused by parasites belonging to the genus \nPlasmodium. Four main", "start_char_idx": 0, "end_char_idx": 3560, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4a3f40b7-d4a6-49de-8e15-8a04e9b4e191": {"__data__": {"id_": "4a3f40b7-d4a6-49de-8e15-8a04e9b4e191", "embedding": null, "metadata": {"page_label": "702", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "93d5d317-0d42-4f6c-b643-99e764970f25", "node_type": null, "metadata": {"page_label": "702", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "50442fb561d32ffa97a815e9a12fb9640fbe43ce183cf339785ee0a37e670da3"}, "2": {"node_id": "1300a016-3dd4-4a83-b4fa-462d289c1db4", "node_type": null, "metadata": {"page_label": "702", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7bc936cb8b077ab7a75d66146b16296705a25a021f153ec39019b454a97ef375"}}, "hash": "86bdd270e1a7e0d310d9f0d1c88d82dc88bcbf9cec2d8f34f883494f11cff059", "text": "by parasites belonging to the genus \nPlasmodium. Four main species infect humans: P. vivax, P. \nfalciparum, P. ovale and P. malariae. A related parasite that \ninfects monkeys, P. knowlesi, can also infect humans and \nis causing increasing concern in some regions, such as \nSouth-east Asia. The insect vector in all cases is the female \nAnopheles mosquito. This breeds in stagnant water and the \ndisease it spreads is one of the major killers on our planet.\nMalaria was eradicated from most temperate countries \nin the 20th century, and the WHO attempted to eradicate malaria elsewhere using the powerful \u2018residual\u2019 insecticides and the highly effective antimalarial drugs, such as chlo-\nroquine , which had, by then, become available. By the end \nof the 1950s, the incidence of malaria had dropped dramati -\ncally. However, it was clear by the 1970s that the attempt \nat eradication had failed, largely because of the increasing \nresistance of the mosquito to the insecticides, and of the parasite to antimalarial drugs.\nLargely because of a massive increase in spending (cur -\nrently about US$3 billion) on public health campaigns such as the Roll Back Malaria programme (which is sponsored \nby a partnership of transnational organisations including \nthe WHO and the World Bank), the global malaria mortality rate has fallen by approximately a quarter over the last 5 \nyears, with some geographical areas achieving almost 50% \nreduction (e.g. western Pacific and South-east Asia). Even so, the overall statistics make gloomy reading. According Antiprotozoal drugs55 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER SECTION 5\n1The disease was once considered to arise from marshy land, hence the \nLatin name \u2018mal aria\u2019, meaning bad or poisonous air.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3502, "end_char_idx": 5736, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0d7e4768-40bc-47f5-8105-f6356dee3cee": {"__data__": {"id_": "0d7e4768-40bc-47f5-8105-f6356dee3cee", "embedding": null, "metadata": {"page_label": "703", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "89b4b17a-0bbb-4663-b108-7dd405842cab", "node_type": null, "metadata": {"page_label": "703", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "901356fe711471739120f76b1162682b571cf38583af77fdcd83c4816a61590f"}, "3": {"node_id": "82b0b296-93a6-480e-88cc-b9773f79366b", "node_type": null, "metadata": {"page_label": "703", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1351d892fa93001dc82fb74980652fb2d66b3539fdf6f3414d08022e21180f7f"}}, "hash": "0fac11fee2202c6705325085a3aeee31f4d5837271d8faca860fa9b91b035107", "text": "55 ANTIpROTO zOAl DRUGS\n697to the 2016 WHO report, half the world\u2019s population is at \nrisk from the disease and it remains a significant public health problem in more than 100 countries. In 2015, there were an estimated 212 million cases and >400,000 deaths \nfrom the disease. More than 90% of these occurred in sub-Saharan Africa, and most of the victims children. Even those who survive may suffer from lasting mental impair -\nment. Other high-risk groups include pregnant women, refugees and labourers entering endemic regions. Malaria also imposes a huge economic burden on countries where the disease is rife.\nAlso of concern is the fact that malaria has gained a \nfoothold in other countries where it is not normally endemic. In Europe, for example, virtually all reported cases ( >6000 \nin 2014) of the disease are imported malaria\n2 and this figure \nhas remained fairly constant, unlike the global fall in cases. This phenomenon is partly due to increasing international travel, partly due to immigration from countries where the disease is endemic and (possibly) partly caused by global warming.\nThe symptoms of malaria include fever, shivering, pain \nin the joints, headache, repeated vomiting, generalised convulsions and coma. Symptoms become apparent only 7\u20139 days after being bitten by an infected mosquito. By far the most dangerous parasite is P. falciparum.Table 55.1. Principal protozoal infections and common drug treatments\nType Species Disease Common drug treatment\nAmoeba Entamoeba histolytica Amoebic dysentery Metronidazole, tinidazole, diloxanide\nFlagellatesTrypanosoma brucei \nrhodesienseTrypanosoma brucei gambienseSleeping sicknessSuramin, pentamidine, melarpasol, eflornithine, nifurtimox\nTrypanosoma cruzi Chagas disease Nifurtimox, benznidazole\nLeishmania tropicaLeishmania donovaniLeishmania mexicanaLeishmania braziliensisKala-azarChiclero\u2019s ulcerEspundiaOriental soreSodium stibogluconate, amphotericin pentamidine isethionate\nTrichomonas vaginalis Vaginitis Metronidazole, tinidazole\nGiardia lamblia Diarrhoea, steatorrhoea Metronidazole, tinidazole, mepacrine\nSporozoaPlasmodium falciparum\na\nPlasmodium vivaxPlasmodium ovalePlasmodium malarariaeMalignant tertian malariaBenign tertian malariaBenign tertian malariaQuartan malariaArtemether, atovaquone, chloroquine, clindamycin, dapsone, doxycycline, lumefantrine, mefloquine, primaquine, proguanil, pyrimethamine, quinine, sulfadoxine, tafenoquine and tetracycline\nToxoplasma gondiiEncephalitis, congenital malformations, eye diseasePyrimethamine\u2013sulfadiazine\nCiliates and others Pneumocystis carinii\nbPneumoniaCo-trimoxazole, atovaquone, pentamidine isethionate\naSee also Table 55.2.\nbThis organism is of uncertain classification. See text for details and Chapter 54 for further comments.\nMalaria \n\u2022\tMalaria\tis\tcaused\tby\tvarious\tspecies\tof\tplasmodia, \t\nwhich\tare\tcarried\tby\tthe\tfemale\tAnopheles mosquito. \nSporozoites (the asexual form of the parasite) are \nintroduced into the host following insect bite and these \ndevelop\tin\tthe\tliver\tinto:\n\u2013\tschizonts \t(the\tpre-erythrocytic", "start_char_idx": 0, "end_char_idx": 3066, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "82b0b296-93a6-480e-88cc-b9773f79366b": {"__data__": {"id_": "82b0b296-93a6-480e-88cc-b9773f79366b", "embedding": null, "metadata": {"page_label": "703", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "89b4b17a-0bbb-4663-b108-7dd405842cab", "node_type": null, "metadata": {"page_label": "703", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "901356fe711471739120f76b1162682b571cf38583af77fdcd83c4816a61590f"}, "2": {"node_id": "0d7e4768-40bc-47f5-8105-f6356dee3cee", "node_type": null, "metadata": {"page_label": "703", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0fac11fee2202c6705325085a3aeee31f4d5837271d8faca860fa9b91b035107"}}, "hash": "1351d892fa93001dc82fb74980652fb2d66b3539fdf6f3414d08022e21180f7f", "text": "\t(the\tpre-erythrocytic \tstage),\twhich\tliberate\t\nmerozoites \t\u2013\tthese\tinfect\tred\tblood\tcells,\tforming\t\nmotile\ttrophozoites, \twhich,\tafter\tdevelopment, \t\nrelease\tanother\tbatch\tof\terythrocyte-infecting \t\nmerozoites, \tcausing\tfever;\tthis\tconstitutes \tthe\t\nerythrocytic cycle;\n\u2013\tdormant \thypnozoites, \twhich\tmay\tliberate\tmerozoites \t\nlater\t(the\texoerythrocytic \tstage).\n\u2022\tThe\tmain\tmalarial\tparasites\tcausing\ttertian\t(\u2018every\tthird\t\nday\u2019)\tmalaria\tare:\n\u2013 P. vivax,\twhich\tcauses\tbenign\ttertian\tmalaria;\n\u2013 P. falciparum ,\twhich\tcauses\tmalignant\ttertian\t\nmalaria;\tunlike\tP. vivax,\tthis\tplasmodium \thas\tno\t\nexoerythrocytic \tstage.\n\u2022\tSome\tmerozoites \tdevelop\tinto\tgametocytes, \tthe\t\nsexual\tforms\tof\tthe\tparasite.\tWhen\tingested\tby\tthe\t\nmosquito, \tthese\tgive\trise\tto\tfurther\tstages\tof\tthe\t\nparasite\u2019s\tlife\tcycle\twithin\tthe\tinsect.\n2\u2018Airport malaria\u2019 is caused by infected mosquitoes in aircraft arriving \nfrom areas where the disease is endemic; \u2018baggage malaria\u2019 is caused by \ntheir presence in luggage arriving from such areas; and \u2018runway malaria\u2019 has been contracted by unlucky passengers who have stopped in endemic areas, but have not even left the aircraft.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3044, "end_char_idx": 4671, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "26c01f07-c886-48b5-bfe9-d35dc400ad3d": {"__data__": {"id_": "26c01f07-c886-48b5-bfe9-d35dc400ad3d", "embedding": null, "metadata": {"page_label": "704", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "37bc8f0e-a4a2-4cfd-a63f-ace28d18fa35", "node_type": null, "metadata": {"page_label": "704", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f8c3990b548909f1d48d1bf1226da558be477d1a37d1e7eb28aa6f658766c22"}, "3": {"node_id": "bffd59aa-5bd5-40ea-bf91-03e8cce95fe9", "node_type": null, "metadata": {"page_label": "704", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2eb387b7b05778d960688a61c2a5ba107704a5d773ed5177f6969b613cd1dc7c"}}, "hash": "629125c33d32ccd786e542fec580c7669ba93d359fc05085c4015148ab0a775a", "text": "55 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n698When sporozoites enter the human host they disappear \nfrom the bloodstream within 30 min and enter the paren -\nchymal cells of the liver where, during the next 10\u201314 days, \nthey undergo a pre-erythrocytic stage of development and \nmultiplication. The parasitised liver cells then rupture, \nand a host of fresh merozoites are released. These bind to \nand enter erythrocytes and form motile intracellular parasites \ntermed trophozoites . During the erythrocytic stage , the parasite \nremodels the host cell, inserting parasite proteins and \nphospholipids into the red cell membrane. The host\u2019s \nhaemoglobin is transported to the parasite\u2019s food vacuole, where it is digested, providing a source of amino acids. Free haem, which would be toxic to the plasmodium, is \nrendered harmless by polymerisation to haemozoin. Some THE LIFE CYCLE OF THE MALARIA PARASITE\nThe life cycle of the parasite consists of a sexual cycle , which \ntakes place in the female Anopheles mosquito, and an asexual \ncycle, which occurs in humans (Fig. 55.1 and the \u2018Malaria\u2019 \nbox). Therefore the mosquito, not the human, is the definitive \nhost for plasmodia. Indeed, it has been said that the only \nfunction of humans is to enable the parasite to infect more \nmosquitoes so that further sexual recombination can occur.\n\u25bc The sexual cycle in the mosquito involves fertilisation of the female \ngametocyte by the male gametocyte, with the formation of a zygote, \nwhich develops into an oocyst (sporocyst). A further stage of division \nand multiplication takes place, leading to rupture of the sporocyst \nwith release of sporozoites , which then migrate to the mosquito\u2019s salivary \nglands and thus enter the human host following mosquito bites.Sporozoites\nOocyst ZygoteGametocytes\ntaken upHUMAN\nBiteINFECTED\nMOSQUITOS\nSporozoites\ninoculated\nCapillaryEpidermis3a\n2a\n1aLIVER3b\n2b\n1b4\nLiver cellBLOODErythrocyte\n98765\n121110\n10C. Site of action of \ndrugs used for \nchemoprophylaxis\nB. Site of action of drugs \nused for radical cure\n(P. vivax and P. ovale only)\nD. Site of action \nof drugs which \nprevent \ntransmissionA. Site of action of \ndrugs used to treat \nthe acute attack\nFig. 55.1 The life cycle of the malarial parasite and the site of action of antimalarial drugs. \tThe\tinfection \tis \tinitiated \tby \tthe \tbite \tof \t\nan infected female Anopheles \tmosquito, \twhich \tintroduces \tthe \tparasite \tinto \tthe \tblood. \tThis \tthen \tenters \ta \tpre- \tor \texoerythrocytic \tcycle \tin \tthe \t\nliver\tand\tan \terythrocytic \tcycle \tin \tthe \tblood: \t(1a)\tfrom\tthe\tblood \tstream \tthe \tsporozoite \tenters \tinto \tliver \tcells \t(the \tparasite \tis \tshown \tas \ta \tsmall \t\ncircle\tcontaining \tdots, \tand \tthe \tliver \tcell \tnucleus \tas \ta \tblue \toval); \t(2a and 3a) \tthe\tschizont \tdevelops \tin \tthe \tliver \tcells; \t(4)\tthese\teventually \t\nrupture\treleasing \tmerozoites \t(some \tmay \tenter \tfurther \tliver \tcells \tand \tbecome \tresting \tforms \tof \tthe", "start_char_idx": 0, "end_char_idx": 2976, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bffd59aa-5bd5-40ea-bf91-03e8cce95fe9": {"__data__": {"id_": "bffd59aa-5bd5-40ea-bf91-03e8cce95fe9", "embedding": null, "metadata": {"page_label": "704", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "37bc8f0e-a4a2-4cfd-a63f-ace28d18fa35", "node_type": null, "metadata": {"page_label": "704", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0f8c3990b548909f1d48d1bf1226da558be477d1a37d1e7eb28aa6f658766c22"}, "2": {"node_id": "26c01f07-c886-48b5-bfe9-d35dc400ad3d", "node_type": null, "metadata": {"page_label": "704", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "629125c33d32ccd786e542fec580c7669ba93d359fc05085c4015148ab0a775a"}}, "hash": "2eb387b7b05778d960688a61c2a5ba107704a5d773ed5177f6969b613cd1dc7c", "text": "\tand \tbecome \tresting \tforms \tof \tthe \tparasite, \thypnozoites). \t(5)\tMerozoites \t\nenter into red cells and form motile trophozoites (6);\tfollowing \tdivision \tand \tmultiplication \t(7 and 8)\tschizonts \tdevelop \tin \tred \tcells \tthat \t\neventually \t(9)\trupture\treleasing \tfurther \tmerozoites, \tmost \tof \twhich \tparasitise \tother \tred \tcells. \tSometimes \t(10\u201312)\tmerozoites \tdevelop \tinto \t\nmale\tand\tfemale \tgametocytes \tin \tred \tcells. \tThese \tcan \tconstitute \ta \tfresh \tsource \tof \tinfective \tmaterial \tif \tthe \tblood \tis \tthen \tconsumed \tby \t\nanother mosquito. (1b)\tResting\tform \tof \tparasite \tin \tliver \t(hypnozoite). \t(2b and 3b) \tGrowth\tand \tmultiplication \tof \thypnozoites. \tSites \tof \tdrug \t\naction\tare \tas \tfollows. \t(A) \tDrugs \tused \tto \ttreat \tthe \tacute \tattack \t(also \tcalled \t\u2018blood \tschizonticidal \tagents\u2019 \tor \t\u2018drugs \tfor \tsuppressive \tor \tclinical \t\ncure\u2019).\t(B)\tDrugs \tthat \taffect \tthe \texoerythrocytic \thypnozoites \tand \tresult \tin \ta \t\u2018radical\u2019 \tcure \tof \tP. vivax and P. ovale.\t(C)\tDrugs \tthat \tblock \tthe \t\nlink\tbetween \tthe \texoerythrocytic \tstage \tand \tthe \terythrocytic \tstage; \tthey \tare \tused \tfor \tchemoprophylaxis \t(also \ttermed \tcausal prophylactics ) \nand\tprevent \tthe \tdevelopment \tof \tmalarial \tattacks. \t(D) \tDrugs \tthat \tprevent \ttransmission \tand \tthus \tprevent \tincrease \tof \tthe \thuman \treservoir \tof \t\nthe disease. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2939, "end_char_idx": 4767, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c7b22798-90e9-4e1c-b07f-057e16bd1d20": {"__data__": {"id_": "c7b22798-90e9-4e1c-b07f-057e16bd1d20", "embedding": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "40933187-de17-4052-9263-51e64d8d9622", "node_type": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f8320c201fe87504c3a12d686dfacecb48728d96a31236031e4677bd9096b3f3"}, "3": {"node_id": "2861fd16-726c-4aa4-8571-e42e8a65d44e", "node_type": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43e80b44b9c879eb60c005fc63592e319a0a1f95d0d29cb3c7206d65065f262d"}}, "hash": "1ec6e4be3a5079a87747cdc40d0778d41449fe0105f709c042dca6839545f5c2", "text": "55 ANTIpROTO zOAl DRUGS\n699of their action against the different stages of the life cycle \nof the parasite (see Fig. 55.1). Fig. 55.2 shows chemical \nstructures of some significant agents and Fig. 55.3 sum -\nmarises what is known about their molecular targets.\nThe use of drugs for the treatment of malaria has changed \nconsiderably during the last half-century, mainly because \nresistance developed to chloroquine and other successful \nearly drug combinations (see Butler et al., 2010). Where \nthis has occurred, therapy has largely been abandoned in favour of artemisinin-based combination regimes (ACT). \nOnly antimalarial drugs in common use are described in \nthis chapter. For a brief summary of currently recommended treatment regimens, see the \u2018Antimalarial drugs\u2019 box and \nTable 55.2. The WHO \u2018malaria\u2019 page (see reading list) \nprovides links to their latest recommendations covering all areas in the world.\nDrugs used to treat the acute attack\nBlood schizonticidal agents (see Fig. 55.1, site A) are used to treat the acute attack but also produce a \u2018suppressive\u2019 \nor \u2018clinical\u2019 cure. They act on the erythrocytic forms of the \nplasmodium. In the case of P. falciparum or P. malariae, \nwhich have no exoerythrocytic stage, these drugs effect a \ncure; however, with P. vivax or P. ovale , the drugs suppress antimalarial drugs act by inhibiting the haem polymerase enzyme responsible for this step.\n\u25bc Following mitotic replication, the parasite in the red cell is termed \na schizont, and its rapid growth and division, schizogony. Another \nphase of multiplication results in the production of further merozoites, \nwhich are released when the red cell ruptures. These merozoites then \nbind to and enter fresh red cells, and the erythrocytic cycle begins again. In certain forms of malaria, some sporozoites entering the liver \ncells form hypnozoites, or \u2018sleeping\u2019 forms of the parasite, which can \nbe reactivated months or years later to continue an exoerythrocytic \ncycle of multiplication.\nMalaria parasites can multiply in the body at a phenomenal \nrate \u2013 a single parasite of P. vivax can give rise to 250 million \nmerozoites in 14 days. To appreciate the action required \nof an antimalarial drug, note that destruction of 94% of the \nparasites every 48 h will serve only to maintain equilibrium \nand will not further reduce their number or their propensity for proliferation. Some merozoites, on entering red cells, \ndifferentiate into male and female gametocytes. These can \ncomplete their cycle only when taken up again by the mosquito, when it sucks the blood from the infected host.\nThe periodic episodes of fever that characterise malaria \nresult from the synchronised rupture of red cells with release of merozoites and cell debris. The rise in temperature is \nassociated with a rise in the concentration of TNF- \u03b1 in the \nplasma. Relapses of malaria are likely to occur with those \nforms of malaria that have an exoerythrocytic cycle, because the dormant hypnozoite form in the liver may emerge after \nan interval of weeks or months to start the infection again.\n\u25bc The characteristic clinical presentations of the different forms of \nhuman malaria are as follows (see Fig. 55.1 for details):\n\u2022\tP. falciparum , which has an erythrocytic cycle of 48 h in humans, \nproduces malignant tertian malaria \u2013 \u2018tertian\u2019 because the fever \nwas believed to recur every third day (actually it varies), \n\u2018malignant\u2019 because it is the most severe form of malaria and is \nresponsible for most malaria deaths. The plasmodium induces adhesion molecules on the infected cells, which then stick to", "start_char_idx": 0, "end_char_idx": 3602, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2861fd16-726c-4aa4-8571-e42e8a65d44e": {"__data__": {"id_": "2861fd16-726c-4aa4-8571-e42e8a65d44e", "embedding": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "40933187-de17-4052-9263-51e64d8d9622", "node_type": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f8320c201fe87504c3a12d686dfacecb48728d96a31236031e4677bd9096b3f3"}, "2": {"node_id": "c7b22798-90e9-4e1c-b07f-057e16bd1d20", "node_type": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ec6e4be3a5079a87747cdc40d0778d41449fe0105f709c042dca6839545f5c2"}, "3": {"node_id": "d4e5763a-baab-4451-84ba-b155485c682a", "node_type": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4d0461e417ea603565c8edba30f6887bd58c7ca42b27c1000e5a05a1e12a986f"}}, "hash": "43e80b44b9c879eb60c005fc63592e319a0a1f95d0d29cb3c7206d65065f262d", "text": "induces adhesion molecules on the infected cells, which then stick to \nuninfected red cells, forming clusters (rosettes), and also adhere \nto and pack the vessels of the microcirculation, interfering with tissue blood flow and causing organ dysfunction including renal \nfailure and encephalopathy (cerebral malaria). P. falciparum does \nnot have an exoerythrocytic stage, so if the erythrocytic stage is \neradicated, relapses do not occur.\n\u2022\tP. vivax produces benign tertian malaria, less severe than \nfalciparum malaria and rarely fatal. Exoerythrocytic forms may \npersist for years and cause relapses.\n\u2022\tP. ovale, which has a 48-h cycle and an exoerythrocytic stage, is \nthe cause of a rare form of malaria.\n\u2022\tP. malariae has a 72-h cycle, causes quartan malaria and has no exoerythrocytic cycle.\nIndividuals living in areas where malaria is endemic may \nacquire a natural immunity, but this may be lost if the \nindividual is absent from the area for more than 6 months. \nThe best way to prevent malaria is to prevent mosquito bites by suitable clothing, insect repellents and bed nets. \nBed nets sprayed with insecticides such as permethrin are \nvery effective and form the cornerstone of many public health campaigns.\nANTIMALARIAL DRUGS\nMost current drugs are only effective against the erythrocytic phase of the parasitic life cycle ( primaquine is an exception). \nSome are used prophylactically to prevent malaria (Table 55.2), while others are directed towards treating acute attacks. In general, antimalarial drugs are classified in terms Table 55.2 Examples of drug treatment and \nchemoprophylaxis of malariaa\nTo treat \u2026 Typical drug choices\nInfection with \nPlasmodium falciparumQuinine followed by doxycycline or clindamycin;Sometimes pyrimethamine with sulfadoxine if appropriateorMalarone\nb or Riametc\nInfection with unknown or mixed organismsQuinine, Malarone or Riamet\nInfection with P. malariae, \nP. vivax or P. ovaleChloroquine (if not in a resistant area) or\nQuinine, Malarone or Riamet (if in a chloroquine-resistant area)possibly followed by primaquine in the case of P. vivax or P. ovale\nChemoprophylaxis (short-term)Malarone or doxycycline\nChemoprophylaxis (long-term)Malarone, mefloquine, doxycycline, chloroquine and proguanil can be used depending upon the duration required\naIt\tmust\tbe \tappreciated \tthat \tthis \tis \tonly \ta \tsummary, \tnot \ta \t\ndefinitive\tguide \tto \tprescription, \tas \tthe \trecommended \tdrug \t\ncombinations \tvary \tdepending \ton \tthe \tpatient, \tthe \tarea \tvisited, \t\nthe\toverall \trisk \tof \tinfection, \tthe \tpresence \tof \tresistant \tforms \tof \t\nthe disease and so on. This information is based on current UK recommendations (source: British National Formulary 2017).\nbMalarone\tis \ta \tproprietary \tfixed-dose \tcombination \tof \t\natovaquone \tand \tproguanil \thydrochloride.\ncRiamet\tis\ta \tproprietary \tfixed-dose \tcombination \tof \tartemether \t\nand lumefantrine.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3544, "end_char_idx": 6730, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d4e5763a-baab-4451-84ba-b155485c682a": {"__data__": {"id_": "d4e5763a-baab-4451-84ba-b155485c682a", "embedding": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "40933187-de17-4052-9263-51e64d8d9622", "node_type": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f8320c201fe87504c3a12d686dfacecb48728d96a31236031e4677bd9096b3f3"}, "2": {"node_id": "2861fd16-726c-4aa4-8571-e42e8a65d44e", "node_type": null, "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "43e80b44b9c879eb60c005fc63592e319a0a1f95d0d29cb3c7206d65065f262d"}}, "hash": "4d0461e417ea603565c8edba30f6887bd58c7ca42b27c1000e5a05a1e12a986f", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6758, "end_char_idx": 6981, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fe3a07ab-0784-4a00-9341-c164b4d02b49": {"__data__": {"id_": "fe3a07ab-0784-4a00-9341-c164b4d02b49", "embedding": null, "metadata": {"page_label": "706", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f8604e30-9ee1-495c-96b3-0276f84ac890", "node_type": null, "metadata": {"page_label": "706", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ae6e438d74d8d8299fa6c86b4eb1418ad7096883d166c24ad848c441e4eed83"}, "3": {"node_id": "dd6106bc-56b0-4e24-a876-ebdd851b61f5", "node_type": null, "metadata": {"page_label": "706", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3df5988741cbc4b96ae39c39221d0463c6f09b078330a53a466c5d1ff6d29b1b"}}, "hash": "2882f23e289cc523c9741108e7afb53d261f04b5f9cb7cfa6e1fdb055da1e83f", "text": "55 SECTION 5 \u2003\u2003DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n700ProguanilClH2NN H2 N\nNH N\nHC\n(CH3)2\nPyrimethamineH2NN H2 N\nN\nCH2CH3Cl\nArtemisininHH\nOH\nOO\nSulfadoxineHN H2NS O2N\nN\nOCH3 OCH3\nDapsoneNH3 H2N SO\nO\nArtemetherHH\nOH\nOOO\nO\nO\nO\nQuinoline-methanols\nMefloquineCF3CF3CHOHNH\nNQuinineCH3OCHOHCH\nNCH2\nN4-Aminoquinoline\nChloroquineClNH CH CH2\nNCH2 CH2C2H5\nC2H5NCH3\nPrimaquineNH CH CH2\nCH3CH2 CH2 NH2CH3O\nN8-Aminoquinoline5\n86\n74\n13\n2\nLumefantrineCl\nCl\nHOCl\nNA B\nC D\nFig. 55.2 Structures of some significant antimalarial drugs. \t(A)\tDrugs\tthat\tact\ton\tthe\tfolic\tacid\tpathway\tof\tthe\tplasmodia.\t Folate\t\nantagonists\t (pyrimethamine,\t proguanil)\t inhibit\tdihydrofolate\t reductase;\t the\trelationship\t between\tthese\tdrugs\tand\tthe\tpteridine\tmoiety\tis\t\nshown\tin\torange.\tSulfones\t(e.g.\tdapsone)\t and\tsulfonamides\t (e.g.\tsulfadoxine)\t compete\twith\tp-aminobenzoic\t acid\tfor\tdihydropteroate\t\nsynthetase\t (relationship\t shown\tin\torange box ;\tsee\talso\tChs\t51\tand\t52).\t(B)\tArtemisinin\t and\ta\tderivative\t artemether.\t Note\tthe\tendoperoxide\t\nbridge structure (in orange) \tthat\tis\tcrucial\tto\ttheir\taction.\t(C)\tSome\tquinolone\t antimalarials.\t The\tquinoline\tmoiety\tis\tshown\tin\torange . (D) The \naryl\tamino\talcohol\tlumefantrine.\t\nAntimalarial therapy and the parasite life cycle \nDrugs used in the treatment of malaria are directed at \nseveral\tsites\tof\taction\tbecause\tno\tsingle\tagent\tis\table\tto\t\ntarget\tall\tof\tthe\tparasite\u2019s\t life\tcycle:\n\u2022\tDrugs\tused\tto\ttreat\tthe\tacute\tattack\tof\tmalaria\tact\ton\t\nthe\tparasites\t in\tthe\tblood;\tthese\tcan\tcure\tinfections\t with\t\nparasites (e.g. P. falciparum )\tthat\thave\tno\texoerythrocytic\t\nstage.\u2022\tDrugs\tused\tfor\tprophylaxis\t act\ton\tmerozoites\t emerging\t\nfrom\tliver\tcells.\n\u2022\tDrugs\tused\tfor\t\u2018radical\tcure\u2019\tare\tactive\tagainst\tparasites\t\nin\tthe\tliver.\n\u2022\tSome\tdrugs\tact\ton\tgametocytes\t and\tprevent\t\ntransmission\t by\tthe\tmosquito.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 2289, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dd6106bc-56b0-4e24-a876-ebdd851b61f5": {"__data__": {"id_": "dd6106bc-56b0-4e24-a876-ebdd851b61f5", "embedding": null, "metadata": {"page_label": "706", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f8604e30-9ee1-495c-96b3-0276f84ac890", "node_type": null, "metadata": {"page_label": "706", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ae6e438d74d8d8299fa6c86b4eb1418ad7096883d166c24ad848c441e4eed83"}, "2": {"node_id": "fe3a07ab-0784-4a00-9341-c164b4d02b49", "node_type": null, "metadata": {"page_label": "706", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2882f23e289cc523c9741108e7afb53d261f04b5f9cb7cfa6e1fdb055da1e83f"}}, "hash": "3df5988741cbc4b96ae39c39221d0463c6f09b078330a53a466c5d1ff6d29b1b", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2258, "end_char_idx": 2321, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6aba187e-be93-4a12-80fd-f3f864eec3fd": {"__data__": {"id_": "6aba187e-be93-4a12-80fd-f3f864eec3fd", "embedding": null, "metadata": {"page_label": "707", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1f7674ab-a4e1-4bf0-8842-3f14e59d8edf", "node_type": null, "metadata": {"page_label": "707", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bacd1c13f26fe29ff0cbbaee0a020424504f5c146825f704d8142a6a340851a7"}, "3": {"node_id": "0492c6ea-049b-4c71-b665-c1a54ecd4a7b", "node_type": null, "metadata": {"page_label": "707", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "92ebd076f183a2a704b1c3e37c4a1a737dfa30820b9f051622b91c541e4c27b2"}}, "hash": "e8b76183b0051fbbb0347c5589f28cf52e6155678f6690b957dc68dabfb38674", "text": "55 ANTIpROTO zOAl DRUGS\n701Fig. 55.1, site B). Only the 8-aminoquinolines (e.g. primaquine \nand tafenoquine ) have this action. These drugs also destroy \ngametocytes and thus reduce the spread of infection.\nDrugs used for chemoprophylaxis\nDrugs used for chemoprophylaxis (also known as causal \nprophylactic drugs ) block the link between the exoerythrocytic \nstage and the erythrocytic stage, and thus prevent the development of malarial attacks. True causal prophylaxis \u2013 the prevention of infection by the killing of the sporozoites \non entry into the host \u2013 is not feasible with present drugs, \nalthough it may be possible in the future with vaccines. Clinical attacks can be prevented by chemoprophylactic \ndrugs that kill the parasites when they emerge from the \nliver after the pre-erythrocytic stage (see Fig. 55.1, site C). The drugs used for this purpose are mainly artemisinin derivatives, chloroquine, lumefantrine, mefloquine, pro -\nguanil, pyrimethamine, dapsone and doxycycline. They are often used in combinations.\n\u25bc Chemoprophylactic agents are given to individuals who intend \ntravelling to an area where malaria is endemic. Administration should \nPyrimethamine\nProguanol\nDapsone\nSulfadoxineErrythrocyte\nPrecursors\nFolic acid\nNucleusNucleotidesMetabolic poolAAs\nAAsAAsHm\nHz HbHb\nNew proteins\nRibosomesATPLipids\nFolate\nsynthesisArtemisinChloroquine\nMefloquine\nPrimaquine\nQuinine\nDigestive vacuoleParasite vacuole\nActivated\nArtemisinDoxycycline\nClindamycin\nAtovaquine\nTafenoquine\nFig. 55.3 Schematic diagram showing the sites of action of antimalarial drug targets in plasmodia. During the erythrocytic stage of \ninfection\tthe \tparasite \tlives \twithin \terythrocytes \tin \ta \tparasitophorus vacuole and feeds on haemoglobin (Hb) which is imported into the \ndigestive vacuole \twhere\tit\tis \tmetabolised \tto \tamino \tacids \t(AAs) \tfor \tuse \tby \tthe \tparasite. \tThe \thaem \t(Hm) \tresidue \tremaining \tis \ttoxic \tto \tthe \t\nparasite\tso \tthis \tis \tmetabolised \tto \thaemozoin \t(Hz). \tSome \tquinolone \tantimalarials \t(e.g. \tchloroquine) \tprevent \tthe \tdetoxification \tof \thaem, \tthus \t\npoisoning\tthe \tparasite. \tOther \tdrugs \t(e.g. \tpyrimethamine) \tprevent \tthe \tsynthesis \tof \tfolic \tacid \twhich \tis \tessential \tfor \tnucleotide \tsynthesis, \t\ntarget\tthe \tsynthesis \tof \tnascent \tproteins \tby \tribosomes \t(e.g. \tantibiotics \tsuch \tas \tclindamycin) \tor \tinhibit \tmitochondrial \tfunction \t(e.g. \t\natovaquone). \tArtemisinin \tand \tits \tderivatives \tenter \tthe \tdigestive \tvacuole \twhere \tthey \tare \t\u2018activated\u2019 \tby \thaem \tto \tform \tcompounds \tthat \treact \t\nwith,\tand\tthus \tdamage, \tproteins \tand \tlipids. \t(After \tBlasco \tet \tal., \t2017.)\nthe actual attack but exoerythrocytic forms can", "start_char_idx": 0, "end_char_idx": 2684, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0492c6ea-049b-4c71-b665-c1a54ecd4a7b": {"__data__": {"id_": "0492c6ea-049b-4c71-b665-c1a54ecd4a7b", "embedding": null, "metadata": {"page_label": "707", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1f7674ab-a4e1-4bf0-8842-3f14e59d8edf", "node_type": null, "metadata": {"page_label": "707", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bacd1c13f26fe29ff0cbbaee0a020424504f5c146825f704d8142a6a340851a7"}, "2": {"node_id": "6aba187e-be93-4a12-80fd-f3f864eec3fd", "node_type": null, "metadata": {"page_label": "707", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e8b76183b0051fbbb0347c5589f28cf52e6155678f6690b957dc68dabfb38674"}}, "hash": "92ebd076f183a2a704b1c3e37c4a1a737dfa30820b9f051622b91c541e4c27b2", "text": "re-emerge later to cause relapses.\nThis group of drugs includes:\n\u2022\tartemisinin \tand \trelated \tcompounds \tderived \tfrom \tthe \t\nChinese herb qinghao, which are usually used in combination with other drugs;\n\u2022\tthe\tquinoline\u2013methanols \t(e.g. \tquinine and mefloquine) \nand various 4-aminoquinolines (e.g. chloroquine);\n\u2022\tagents \tthat \tinterfere \teither \twith \tthe \tsynthesis \tof \tfolate \t\n(e.g. dapsone) or with its action (e.g. pyrimethamine \nand proguanil);\n\u2022\tatovaquone, which affects mitochondrial function.\nCombinations of these agents are frequently used. Some antibiotics, such as the tetracycline doxycycline (see Ch. \n52), have proved useful when combined with the above agents. They have an antiparasite effect in their own right, but also control other concomitant infections.\nDrugs that effect a radical cure\nTissue schizonticidal agents effect a \u2018radical\u2019 cure by eradicating P. vivax and P. ovale parasites in the liver (see mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2685, "end_char_idx": 4097, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9570d1d7-480d-4d20-9d99-0512873500ee": {"__data__": {"id_": "9570d1d7-480d-4d20-9d99-0512873500ee", "embedding": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c6662409-82b7-4984-8270-ad6a24514c0c", "node_type": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4de03348e502d83ec9cebf74f8cb8396eb9664f2b697a04c57905784e436c8c"}, "3": {"node_id": "1ff9f342-76e2-4762-99a2-1cf991916f47", "node_type": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "512804f2b54c6ad22ae13f61a6d3bac69d75c5f8bba95b19b782a4040d22c42f"}}, "hash": "12e37f09a87df62fa33205bf2b53d802cd2d215c081045ac79883ab89f762acf", "text": "55 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n702completely absorbed, extensively distributed throughout \nthe tissues and concentrated in parasitised red cells. Release \nfrom tissues and infected erythrocytes is slow. The drug \nis metabolised in the liver and excreted in the urine, 70% as unchanged drug and 30% as metabolites. Elimination \nis slow, the major phase having a half-life of 50 h, and a \nresidue persists for weeks or months.\nUnwanted effects\nChloroquine has few adverse effects when given for chemoprophylaxis. However, unwanted effects, including \nnausea and vomiting, dizziness and blurring of vision, \nheadache and urticarial symptoms, can occur when larger doses are administered to treat acute attacks of malaria. \nLarge doses have also sometimes resulted in retinopathies \nand hearing loss. Bolus intravenous injections of chloroquine may cause hypotension and, if high doses are used, fatal \ndysrhythmias. Chloroquine is considered to be safe for use \nby pregnant women.\nAmodiaquine has very similar action to chloroquine. It \nwas withdrawn several years ago because of the risk of \nagranulocytosis, but has now been reintroduced in several \nareas of the world where chloroquine resistance is endemic.\nQUININE\nQuinine, derived from cinchona bark, has been used for the treatment of \u2018fevers\u2019 since the 16th century, when Jesuit \nmissionaries brought the bark, and the knowledge of its \naction, to Europe from Peru. It is a blood schizonticidal drug effective against the erythrocytic forms of all four \nspecies of Plasmodium (see Fig. 55.1, site A), but it has no \neffect on exoerythrocytic forms or on the gametocytes of P. falciparum. Its mechanism of action is the same as that \nof chloroquine, but quinine is not so extensively concentrated \nin the plasmodium as chloroquine, so other mechanisms could also be involved. With the emergence and spread of chloroquine resistance, quinine is now the main chemo-\ntherapeutic agent for P. falciparum in certain parts of the \nworld. Pharmacological actions on host tissue include a depressant action on the heart, a mild oxytocic effect on \nthe uterus in pregnancy, a slight blocking action on the \nneuromuscular junction and a weak antipyretic effect.\nResistance\nSome degree of resistance to quinine has developed because of increased expression of plasmodial drug efflux \ntransporters.\nPharmacokinetic aspects\nQuinine is well absorbed and is usually administered orally \nas a 7-day course, but it can also be given by slow intravenous \ninfusion for severe P. falciparum infections and in patients \nwho are vomiting. A loading dose may be required, but \nbolus intravenous administration is contraindicated because \nof the risk of cardiac dysrhythmias. The half-life of the \ndrug is 10 h ; it is metabolised in the liver and the metabolites \nare excreted in the urine within about 24 h.\nUnwanted effects\nQuinine has a bitter taste, and oral compliance is often \npoor.3 It is irritant to the gastric mucosa and can cause start at least 1 week before entering the area and should be continued \nthroughout the stay and for at least a month afterwards. No chemo-\nprophylactic regimen is 100% effective, and unwanted effects may \noccur. A further problem is the complexity of some regimens, which require different drugs to be taken at different times, and the fact \nthat different agents may be required for different travel destinations. \nFor a brief summary of currently commonly recommended regimens of chemoprophylaxis, see Table", "start_char_idx": 0, "end_char_idx": 3527, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1ff9f342-76e2-4762-99a2-1cf991916f47": {"__data__": {"id_": "1ff9f342-76e2-4762-99a2-1cf991916f47", "embedding": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c6662409-82b7-4984-8270-ad6a24514c0c", "node_type": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4de03348e502d83ec9cebf74f8cb8396eb9664f2b697a04c57905784e436c8c"}, "2": {"node_id": "9570d1d7-480d-4d20-9d99-0512873500ee", "node_type": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "12e37f09a87df62fa33205bf2b53d802cd2d215c081045ac79883ab89f762acf"}, "3": {"node_id": "51decfe3-df04-4bc5-876a-362efc5c73ab", "node_type": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "289f632a045018853af4005751ca91b4772b60562a0f4505f89683a4062e35b0"}}, "hash": "512804f2b54c6ad22ae13f61a6d3bac69d75c5f8bba95b19b782a4040d22c42f", "text": "brief summary of currently commonly recommended regimens of chemoprophylaxis, see Table 55.2.\nDrugs used to prevent transmission\nSome drugs (e.g. primaquine, proguanil and pyrimethamine) \ncan also destroy gametocytes (see Fig. 55.1, site D), prevent -\ning transmission by the mosquito and thus diminishing the human reservoir of the disease, although they are rarely used for this action alone.\nDrug resistance\nParasite resistance is a serious and ongoing problem with almost all antimalarial drugs, with the possible exception \nof lumefantrine. In many cases, resistant strains of the \nparasite appear within a decade, or even less, of the introduc -\ntion of a novel drug. Most of the resistance is due to the \nappearance of spontaneously arising point mutations in \n(for example) target proteins such as dihydrofolate reductase (which confers resistance to antifolate drugs such as pro -\nguanil) or in the mitochondrial cytochrome B subunit (which confers resistance to atovaquone). Mutations in parasite transporters that facilitate entry, or control the exit of, quinolone drugs into the digestive vacuoles can also confer \nresistance and mutations in other enzymes are also thought \nto be important (see Blasco et al., 2017).\nA rather alarming development is the increase in multidrug \nresistance in certain parts of the world. This may be linked to poor compliance, poor drugs or local variations in host \nimmune responses to infection\nCHLOROQUINE\nThe 4-aminoquinoline chloroquine dates from the 1940s but is still widely used as a blood schizonticidal agent (see \nFig. 55.1, site A), effective against the erythrocytic forms \nof all four plasmodial species (where resistance is not an issue), but it does not have any effect on sporozoites, \nhypnozoites or gametocytes. It is uncharged at neutral pH \nand can therefore diffuse freely into the parasite lysosome. At the acid pH of the lysosome, it is converted to a proto -\nnated, membrane-impermeable form and is \u2018trapped\u2019 inside the parasite. Its chief antimalarial action derives from an inhibition of haem polymerase , the enzyme that polymerises \ntoxic free haem to haemozoin. This poisons the parasite \nand prevents it from utilising the amino acids from hae-\nmoglobin proteolysis. Chloroquine is also used as a disease-modifying antirheumatoid drug (Ch. 27) and also has some \nquinidine-like actions on the heart (Ch. 22).\nResistance\nP. falciparum is now resistant to chloroquine in most parts \nof the world. Resistance appears to result from enhanced \nefflux of the drug from parasitic vesicles as a result of muta -\ntions in plasmodia transporter genes (Baird, 2005). Resistance \nof P. vivax to chloroquine is also a growing problem.\nAdministration and pharmacokinetic aspects\nChloroquine is generally administered orally, but severe falciparum malaria may be treated by frequent intramuscular \nor subcutaneous injection of small doses, or by slow continu -\nous intravenous infusion. Following oral dosing, it is 3Hence the invention of palatable drinks containing the drug, including, \nof course, the famous \u2018tonic\u2019 drunk together with gin, vodka and other \nbeverages.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3451, "end_char_idx": 6889, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "51decfe3-df04-4bc5-876a-362efc5c73ab": {"__data__": {"id_": "51decfe3-df04-4bc5-876a-362efc5c73ab", "embedding": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c6662409-82b7-4984-8270-ad6a24514c0c", "node_type": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e4de03348e502d83ec9cebf74f8cb8396eb9664f2b697a04c57905784e436c8c"}, "2": {"node_id": "1ff9f342-76e2-4762-99a2-1cf991916f47", "node_type": null, "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "512804f2b54c6ad22ae13f61a6d3bac69d75c5f8bba95b19b782a4040d22c42f"}}, "hash": "289f632a045018853af4005751ca91b4772b60562a0f4505f89683a4062e35b0", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6919, "end_char_idx": 7142, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3c005d7b-64f2-48e9-bda1-7008ad71b3e0": {"__data__": {"id_": "3c005d7b-64f2-48e9-bda1-7008ad71b3e0", "embedding": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "934e1cc3-02ca-499e-883e-8b44043eeb2d", "node_type": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0e0b016fa9660facb6c6f8a6f8c1e8fe1769913d5b55b7a7d85633935b76f5c4"}, "3": {"node_id": "759d327c-54a4-4618-a6d2-0f7df03affe3", "node_type": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "def6e186f086bc17e787516b32e6d84f60dcea9f81e917984821a847dd8d6bb2"}}, "hash": "51de3f9c04136d3c17802478eedadd0adb47a27e9d85491b094a83dc3d8a7508", "text": "55 ANTIpROTO zOAl DRUGS\n703DRUGS \u2003AFFECTING \u2003FOLATE \u2003METABOLISM\nSulfonamides and sulfones, used as antibacterial drugs (see \nCh. 52), inhibit the synthesis of folate in plasmodia by \ncompeting with p-aminobenzoic acid. Pyrimethamine and \nproguanil inhibit dihydrofolate reductase, which prevents the utilisation of folate in DNA synthesis. Used together, \nthey block the folate pathway at different points, and thus \nact synergistically.\nThe main sulfonamide used in malaria treatment is \nsulfadoxine , and the only sulfone used is dapsone. Details \nof these drugs are given in Chapter 52. The sulfonamides and sulfones are active against the erythrocytic forms of P. falciparum but are less active against those of P. vivax; \nthey have no activity against the sporozoite or hypnozoite forms of the plasmodia. Pyrimethamine\u2013sulfadoxine has been extensively used for chloroquine-resistant malaria, \nbut unfortunately resistance to this combination has \ndeveloped in many areas.\nPyrimethamine is similar in structure to the antibacterial \ndrug trimethoprim (see Ch. 52). Proguanil has a slightly \ndifferent structure but its (active) metabolite can assume a similar configuration. Both drugs have a greater affinity \nfor the plasmodium enzyme than for the human enzyme. \nThey have a slow action against the erythrocytic forms of the parasite (see Fig. 55.1, site A), and proguanil is believed \nto have an additional effect on the initial hepatic stage (see \n1a to 3a in Fig. 55.1) but not on the hypnozoites of P. vivax \n(see Fig. 55.1, site B). Pyrimethamine is used only in \ncombination with either a sulfone or a sulfonamide.\nResistance\nPoint mutations in the enzymes of the folate synthesis \npathway confer resistance to these drugs.\nPharmacokinetic aspects\nBoth pyrimethamine and proguanil are given orally and are well, although slowly, absorbed. Pyrimethamine has a \nplasma half-life of 4 days, and effective \u2018suppressive\u2019 plasma \nconcentrations may last for 14 days; it is taken once a week. \nThe half-life of proguanil is 16 h. It is a prodrug and is \nmetabolised in the liver to its active form, cycloguanil , which \nis excreted mainly in the urine. It must be taken daily.\nUnwanted effects\nThese drugs have few untoward effects in therapeutic doses. Larger doses of the pyrimethamine\u2013dapsone combination \ncan cause serious reactions such as haemolytic anaemia, \nagranulocytosis and lung inflammation. The pyrimethamine\u2013sulfadoxine combination can cause serious skin reactions, \nblood dyscrasias and allergic alveolitis; it is no longer \nrecommended for chemoprophylaxis. In high doses, pyrimethamine may inhibit mammalian dihydrofolate \nreductase and cause a megaloblastic anaemia (see Ch. 26) \nand folic acid supplements should be given if this drug is used during pregnancy. Resistance to antifolate drugs arises from single-point mutations in the genes encoding parasite \ndihydrofolate reductase.\nPRIMAQUINE\nPrimaquine is an 8-aminoquinoline drug, which is (almost \nuniquely among clinically available antimalarial drugs) \nactive against liver hypnozoites (see Fig. 55.2). Etaquine \nand tafenoquine are more active and slowly metabolised \nanalogues of primaquine. These drugs can effect a radical nausea and vomiting. \u2018Cinchonism\u2019 \u2013", "start_char_idx": 0, "end_char_idx": 3245, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "759d327c-54a4-4618-a6d2-0f7df03affe3": {"__data__": {"id_": "759d327c-54a4-4618-a6d2-0f7df03affe3", "embedding": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "934e1cc3-02ca-499e-883e-8b44043eeb2d", "node_type": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0e0b016fa9660facb6c6f8a6f8c1e8fe1769913d5b55b7a7d85633935b76f5c4"}, "2": {"node_id": "3c005d7b-64f2-48e9-bda1-7008ad71b3e0", "node_type": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "51de3f9c04136d3c17802478eedadd0adb47a27e9d85491b094a83dc3d8a7508"}, "3": {"node_id": "fd84e580-e733-4524-a864-898783c366a0", "node_type": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5d992bd57f7d7678c8776ea594a0b226cea4203542cf82f95eac5446bfa2b69e"}}, "hash": "def6e186f086bc17e787516b32e6d84f60dcea9f81e917984821a847dd8d6bb2", "text": "effect a radical nausea and vomiting. \u2018Cinchonism\u2019 \u2013 characterised by nausea, dizziness, tinnitus, headache and blurring of \nvision \u2013 is likely to occur if the plasma concentration exceeds \n30\u201360 \u00b5mol/L. Excessive plasma levels may also cause \nhypotension, cardiac dysrhythmias and severe central \nnervous system (CNS) disturbances such as delirium \nand coma.\nOther, infrequent, unwanted reactions that have been \nreported are bone marrow depression (mainly thrombo -\ncytopenia) and hypersensitivity reactions. Quinine can \nstimulate insulin release. Patients with marked falciparum \nparasitaemia can have low blood sugar for this reason and \nalso because of glucose consumption by the parasite. This can make a differential diagnosis between a coma caused by cerebral malaria and hypoglycaemia difficult. A rare \nresult of treating malaria with quinine, or of erratic and \ninappropriate use of quinine, is Blackwater fever , a severe \nand often fatal condition in which acute haemolytic anaemia \nis associated with renal failure.\nMEFLOQUINE\nMefloquine (see Fig. 55.2) is a blood schizonticidal com -\npound active against P. falciparum and P. vivax (see Fig. \n55.1, site A); however, it has no effect on hepatic forms of \nthe parasites, so treatment of P. vivax infections should be \nfollowed by a course of primaquine to eradicate the hyp -\nnozoites. Mefloquine acts in the same way as quinine, and is frequently combined with pyrimethamine.\nResistance\nP. falciparum is resistant to mefloquine in some areas \u2013 particularly in South-East Asia \u2013 and is thought to be caused, \nas with quinine, by increased expression in the parasite of \ndrug efflux transporters.\nPharmacokinetic aspects and unwanted effects\nMefloquine is given orally and is rapidly absorbed. It has a slow onset of action and a very long plasma half-life (up \nto 30 days), which may be the result of enterohepatic cycling \nor tissue storage.\nWhen mefloquine is used for treatment of the acute \nattack, about 50% of subjects complain of gastrointestinal (GI) disturbances. Transient CNS side effects \u2013 giddiness, confusion, dysphoria and insomnia \u2013 can occur, and \nthere have been a few reports of aberrant atrioventricular \nconduction and serious, but rare, skin diseases. Rarely, mefloquine may provoke severe neuropsychiatric reac-tions. Mefloquine is contraindicated in pregnant women \nor in those liable to become pregnant within 3 months \nof stopping the drug, because of its long half-life and uncertainty about its teratogenic potential. When used \nfor chemoprophylaxis, the unwanted actions are usually \nmilder, but the drug should not be used in this way unless there is a high risk of acquiring chloroquine-resistant \nmalaria.\nLUMEFANTRINE\nThis aryl amino alcohol drug is related to an older com -\npound, halofantrine, which is now seldom used. Lume -\nfantrine is never used alone but in combination with artemether . Its mode of action is probably to prevent parasite \ndetoxification of haem. The pharmacokinetics of the com-\nbination is complex and the reader is referred to Ezzet et al. \n(1998) for more details. Unwanted effects of the combination may include GI and CNS symptoms.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3201, "end_char_idx": 6575, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fd84e580-e733-4524-a864-898783c366a0": {"__data__": {"id_": "fd84e580-e733-4524-a864-898783c366a0", "embedding": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "934e1cc3-02ca-499e-883e-8b44043eeb2d", "node_type": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0e0b016fa9660facb6c6f8a6f8c1e8fe1769913d5b55b7a7d85633935b76f5c4"}, "2": {"node_id": "759d327c-54a4-4618-a6d2-0f7df03affe3", "node_type": null, "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "def6e186f086bc17e787516b32e6d84f60dcea9f81e917984821a847dd8d6bb2"}}, "hash": "5d992bd57f7d7678c8776ea594a0b226cea4203542cf82f95eac5446bfa2b69e", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6589, "end_char_idx": 6892, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8da5638d-a7c7-41e2-9b41-6b30e5f4829a": {"__data__": {"id_": "8da5638d-a7c7-41e2-9b41-6b30e5f4829a", "embedding": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "30462aee-5f4f-4597-8fcb-2d1345e4d00b", "node_type": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ebbf1ce1bffffb857bb0d94b10e0d9cdd1718c24f39ab2d4c4a8bda64fbd4074"}, "3": {"node_id": "41c00075-900f-4332-aeb2-bad18e712981", "node_type": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc4486e67f8829c5daf45bf43fb21151ef43e2931b920fd37894fcdbba20ac1b"}}, "hash": "4f4640a21e1f6bc0e7e58eb2fde5ab4bbc2c903587ec2d446450c8ccf5615f35", "text": "55 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n704derivatives are effective against multidrug-resistant P. \nfalciparum in sub-Saharan Africa and, combined with \nmefloquine, against multidrug-resistant P. falciparum in \nSouth-east Asia.\nPharmacokinetic aspects\nDerivatives of artemisinin, which include artesunate (a \nwater-soluble derivative available in some countries) and artemether, have higher activity and are better absorbed. \nThe compounds are concentrated in parasitised red cells and, entering the digestive vacuoles, their unusual \u2018endop -\neroxide bridge\u2019 is activated by haem iron, giving rise to highly reactive oxygen containing compounds. These cause irreversible damage to parasite proteins, lipid membranes \nand other targets. These drugs are without effect on liver \nhypnozoites. Artemisinin can be given orally, intramuscu -\nlarly or by suppository, artemether orally or intramuscularly, and artesunate intramuscularly or intravenously. They are \nrapidly absorbed and widely distributed, and are converted \nin the liver to the active metabolite dihydroartemisinin. \nThe half-life of artemisinin is about 4 h, of artesunate, 45 min \nand of artemether, 4\u201311 h.\nUnwanted effects are few. Transient heart block, decrease \nin blood neutrophil count and brief episodes of fever have \nbeen reported. In animal studies, artemisinin causes an \nunusual injury to some brain stem nuclei, particularly those involved in auditory function; however, there have been \nno reported incidences of neurotoxicity in humans.\nIn rodent studies, artemisinin potentiated the effects of \nmefloquine, primaquine and tetracycline, was additive with chloroquine and antagonised the sulfonamides and the \nfolate antagonists. For this reason, artemisinin derivatives are frequently used in combination with other antimalarial drugs as part of ACT regimes; for example, artemether is \noften given in combination with lumefantrine.\nResistance\nInitially resistance was not a major problem but, alarmingly, \nreports that the parasite in some areas of the world (e.g. \nSouth-east Asia) was becoming less sensitive to these drugs \n\u2013 either alone or in ACT combinations \u2013 began to appear \nabout a decade ago (Blasco et al., 2017). The situation is \nmonitored very carefully.\nATOVAQUONE\nAtovaquone is a hydroxynaphthoquinone drug used prophylactically to prevent malaria, and to treat cases \nresistant to other drugs. It acts primarily to inhibit the \nparasite\u2019s mitochondrial electron transport chain, possibly by mimicking the natural substrate ubiquinone. Atovaquone \nis usually used in combination with the antifolate drug \nproguanil, because they act synergistically. The mecha-nism underlying this synergism is not known, but it is \nspecific for this particular pair of drugs, because other \nantifolate drugs or electron transport inhibitors have no such synergistic effect. When combined with proguanil, atovaquone is highly effective and well tolerated. Few \nunwanted effects of such combination treatment have been \nreported, but abdominal pain, nausea and vomiting can occur. Pregnant or breastfeeding women should not take \natovaquone.\nResistance\nResistance to atovaquone alone is rapid and results from a single-point mutation in the gene for cytochrome B. cure of P. vivax and P. ovale malaria in which the parasites have a dormant stage in the liver. Primaquine does not \naffect sporozoites and has little", "start_char_idx": 0, "end_char_idx": 3433, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "41c00075-900f-4332-aeb2-bad18e712981": {"__data__": {"id_": "41c00075-900f-4332-aeb2-bad18e712981", "embedding": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "30462aee-5f4f-4597-8fcb-2d1345e4d00b", "node_type": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ebbf1ce1bffffb857bb0d94b10e0d9cdd1718c24f39ab2d4c4a8bda64fbd4074"}, "2": {"node_id": "8da5638d-a7c7-41e2-9b41-6b30e5f4829a", "node_type": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4f4640a21e1f6bc0e7e58eb2fde5ab4bbc2c903587ec2d446450c8ccf5615f35"}, "3": {"node_id": "8ae1e107-a857-4751-baaf-10469156dc68", "node_type": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7c273967df639a083bc644a53fc27407ece72d7342b314ed100b4a924e35c3c"}}, "hash": "bc4486e67f8829c5daf45bf43fb21151ef43e2931b920fd37894fcdbba20ac1b", "text": "in the liver. Primaquine does not \naffect sporozoites and has little if any action against the \nerythrocytic stage of the parasite. However, it has a game -\ntocidal action and is the most effective antimalarial drug \nfor preventing transmission of all four species of plasmodia. \nIt is almost invariably used in combination with another drug, usually chloroquine. The pharmacology of primaquine \nand similar drugs has been reviewed by Shanks et al. (2001).\nResistance\nResistance to primaquine is (happily) scarce, although evidence of a decreased sensitivity of some P. vivax strains \nhas been reported.\nPharmacokinetic aspects\nPrimaquine is given orally and is well absorbed. Its metabo -\nlism is rapid, and very little drug is present in the body \nafter 10\u201312 h. The half-life is 3\u20136 h. Tafenoquine is metabo -\nlised much more slowly and therefore has the advantage \nthat it can be given on a weekly basis.\nUnwanted effects\nPrimaquine has few unwanted effects in most patients when \nused in normal therapeutic dosage. Dose-related GI symp -\ntoms can occur, and large doses may cause methaemoglo -\nbinaemia with cyanosis.\nPrimaquine can however cause haemolysis in individuals \nwith the X chromosome-linked genetic metabolic condition, glucose 6-phosphate dehydrogenase deficiency , in red cells (Ch. \n12). When this deficiency is present, the red cells are not \nable to regenerate NADPH, which is depleted by the oxidant \nmetabolic derivatives of primaquine. As a consequence, the metabolic functions of the red cells are impaired and haemolysis occurs. The deficiency of the enzyme occurs in \nup to 15% of black males and is also fairly common in \nsome other ethnic groups. Glucose 6-phosphate dehydro -\ngenase activity should be estimated before giving \nprimaquine.\nARTEMISININ \u2003AND \u2003RELATED \u2003COMPOUNDS\nThe importance of this group is that they are often the only \ndrugs that can currently effectively treat resistant P. falci-\nparum . These sesquiterpene lactones are derived from sweet \nwormwood , qinghao , a traditional Chinese remedy for fevers. \nThe scientific name, conferred on the herb by Linnaeus, is \nArtemisia.4 Artemisinin, a poorly soluble chemical extract \nfrom Artemisia , is a fast-acting blood schizonticide effective \nin treating the acute attack of malaria (including chloroquine-\nresistant and cerebral malaria). In randomised trials, artemisinins have cured attacks of malaria, including \ncerebral malaria, more rapidly and with fewer unwanted \neffects than other antimalarial agents. Artemisinin and \n4Artemisia extracts have been used for thousands of years in China for \ntreating \u2018fevers\u2019. Artemisia, was the wife and sister of the 4th-century \nking of Halicarnassus. She was so distraught at his death that she \nmixed his ashes with whatever she drank to make it bitter. Since sweet wormwood is noted for its extreme bitterness it was named in her \nhonour. The biologically active compound artemisinin was isolated by \nChinese chemists in 1972. This was ignored in the West for more than 10 years, until the WHO recognised its importance and, in 2002, placed \nit on their list of \u2018essential drugs\u2019 for malaria treatment. In 2015, the \nChinese pharmacologist Yoyou Tu was awarded the Nobel Prize for her role in developing this drug.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3376, "end_char_idx": 6865, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ae1e107-a857-4751-baaf-10469156dc68": {"__data__": {"id_": "8ae1e107-a857-4751-baaf-10469156dc68", "embedding": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "30462aee-5f4f-4597-8fcb-2d1345e4d00b", "node_type": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ebbf1ce1bffffb857bb0d94b10e0d9cdd1718c24f39ab2d4c4a8bda64fbd4074"}, "2": {"node_id": "41c00075-900f-4332-aeb2-bad18e712981", "node_type": null, "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bc4486e67f8829c5daf45bf43fb21151ef43e2931b920fd37894fcdbba20ac1b"}}, "hash": "d7c273967df639a083bc644a53fc27407ece72d7342b314ed100b4a924e35c3c", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6876, "end_char_idx": 7179, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bde6da4e-8607-4f86-9ef5-5bb403f4a172": {"__data__": {"id_": "bde6da4e-8607-4f86-9ef5-5bb403f4a172", "embedding": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6379baca-d8c7-4875-9cad-a6a426fc3d9b", "node_type": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d96698169191eabd69727dabf9df6b8a63a6d289dfa60308e995abefc0c32bc"}, "3": {"node_id": "1e56b6a9-922e-4014-942d-fd5659ca9f69", "node_type": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "865f469f201ac758b0e9edd1a8093612ad0f8ee0861e7dbdcfacdd15b3e97ee5"}}, "hash": "45cd5e03ecc534a4467d54921ef90f26db56a75b71b83ebaf486e4c3a27bc96c", "text": "55 ANTIpROTO zOAl DRUGS\n705which would otherwise prove lethal to the parasite. It is this process \nthat produces the characteristic bloody diarrhoea and abdominal pain, \nalthough a chronic intestinal infection may be present in the absence \nof dysentery. In some patients, an amoebic granuloma (amoeboma) \nmay be present in the intestinal wall. The trophozoites may also \nmigrate through the damaged intestinal tissue into the portal blood \nand hence the liver, giving rise to the most common extra-intestinal symptom of the disease \u2013 amoebic liver abscesses.Resistance to combined treatment with atovaquone and \nproguanil is less common.\nPOTENTIAL NEW ANTIMALARIAL DRUGS\nMalaria has been dubbed a \u2018re-emerging disease\u2019, largely because of the increasing appearance of resistant strains \nof the parasite. No new synthetic drug has been discovered \nfor over 40 years and so progress has become a matter of \nsome urgency. Successes, both in the search for new entities \n(see Thota, 2016; Mishra et al., 2017) and new targets (e.g. \nAchieng et al., 2017; Deu, 2017), coupled with a better \nunderstanding of the pharmacokinetic aspects of current \ndrugs (Na-Bangchang & Karbwang, 2009; Basore et al., \n2015), should enable better treatment regimes. Held et al. \n(2015) have reviewed novel antimalarials in phase II development.\nBut perhaps the most significant advance has come \nthrough the application of synthetic biology to solve the problem of artemisinin production. Artemisinin is notori -\nously difficult to synthesise by conventional chemical techniques and awkward to harvest in large amounts. Using genetically modified yeast transfected with genes from \nArtemisia it has been possible to produce large amounts of \nthe precursor artemisinic acid , which can be easily converted \ninto artemisinin (Paddon et al., 2013), thus relieving the \ndesperate shortage of the drug.\nThe prospects for an effective malaria vaccine have also \nincreased dramatically over the last decade and some \ncandidate vaccines (especially for P. falciparum ) are undergo -\ning field trials organised by the WHO and others. Discussion \nis beyond the scope of this chapter but the reader is referred \nto Hoffman et al. (2015) and Matuschewski (2017) for more \ninformation.\nAMOEBIASIS AND AMOEBICIDAL DRUGS\nAmoebiasis is caused by infection with one or more strains \nof Entamoeba organisms. Infection may be asymptomatic \nor provoke a range of GI symptoms, some of which may be serious. The main organism of concern is Entamoeba \nhistolytica, the causative agent of amoebiasic dysentery, \nwhich can produce a severe colitis (dysentery) and, some -\ntimes, liver abscesses.\n\u25bc The infection is encountered around the world, but more often in \nwarmer climates and is associated with poor sanitation. Approximately \n500 million people are thought to harbour the disease, with \n40,000\u2013100,000 deaths occurring each year as a result. It is considered \nto be the second-leading cause of death from parasitic diseases worldwide.\nThe organism has a simple life cycle, and humans are the chief hosts. \nInfection, generally spread by poor hygiene, follows the ingestion of \nthe mature cysts in water or food that is contaminated with human \nfaeces. The infectious cysts pass into the colon, where they develop into trophozoites. These motile organisms adhere to colonic epithelial \ncells, utilising a galactose-containing lectin on the host cell membrane. \nHere, the trophozoites feed, multiply, encyst and eventually pass out in the faeces,", "start_char_idx": 0, "end_char_idx": 3517, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1e56b6a9-922e-4014-942d-fd5659ca9f69": {"__data__": {"id_": "1e56b6a9-922e-4014-942d-fd5659ca9f69", "embedding": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6379baca-d8c7-4875-9cad-a6a426fc3d9b", "node_type": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d96698169191eabd69727dabf9df6b8a63a6d289dfa60308e995abefc0c32bc"}, "2": {"node_id": "bde6da4e-8607-4f86-9ef5-5bb403f4a172", "node_type": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "45cd5e03ecc534a4467d54921ef90f26db56a75b71b83ebaf486e4c3a27bc96c"}, "3": {"node_id": "3f10b076-22eb-45e5-a1c0-5312aa10c5b7", "node_type": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fcb32efb42f3b2ba60ed0c252523234f3c516b7608616f6369857d206e153901"}}, "hash": "865f469f201ac758b0e9edd1a8093612ad0f8ee0861e7dbdcfacdd15b3e97ee5", "text": "feed, multiply, encyst and eventually pass out in the faeces, thus completing their life cycle. Some individuals are \nsymptomless \u2018carriers\u2019 and harbour the parasite without developing \novert disease, but cysts are present in their faeces and they can infect other individuals. The cysts can survive outside the body for at least \na week in a moist and cool environment.\nThe trophozoite lyses the colonic mucosal cells (hence \u2018histolytica\u2019) \nusing proteases, amoebapores (peptides that form pores in cell mem -\nbranes) or by inducing host cell apoptosis. The organism then invades the submucosa, where it secretes factors to modify the host response Antimalarial drugs \n\u2022\tChloroquine is a blood schizonticide that is \nconcentrated in the parasite and inhibits the haem \npolymerase. \tOrally \tactive; \thalf-life \t50 \th. \tUnwanted \neffects:\tgastrointestinal \t(GI) \tdisturbances, \tdizziness \t\nand\turticaria. \tBolus \tintravenous \tinjections \tcan \tcause \t\ndysrhythmias. \tResistance \tis \tnow \tcommon.\n\u2022\tQuinine\tis\ta\tblood \tschizonticide. \tIt \tmay \tbe \tgiven \torally \t\nor\tintravenously; \thalf-life \t10 \th. \tUnwanted effects :\tGI\t\ntract\tdisturbances, \ttinnitus, \tblurred \tvision \tand, \tin \tlarge \t\ndoses,\tdysrhythmias \tand \tcentral \tnervous \tsystem \t\ndisturbances. \tIt \tis \tusually \tgiven \tin \tcombination \ttherapy \t\nwith:\n\u2013 pyrimethamine ,\ta\tfolate\tantagonist \tthat \tacts \tas \ta \t\nslow\tblood \tschizonticide \t(orally \tactive; \thalf-life \t4 \t\ndays),\tand \teither\n\u2013 dapsone,\ta\tsulfone \t(orally \tactive; \thalf-life \t24\u201348 \th), \t\nor\n\u2013 sulfadoxine ,\ta\tlong-acting \tsulfonamide \t(orally \t\nactive;\thalf-life \t7\u20139 \tdays).\n\u2022\tProguanil ,\ta\tfolate\tantagonist, \tis \ta \tslow \tblood \t\nschizonticide \twith \tsome \taction \ton \tthe \tprimary \tliver \t\nforms of P. vivax.\tOrally\tactive; \thalf-life \t16 \th.\n\u2022\tMefloquine \tis\ta\tblood \tschizonticidal \tagent \tactive \t\nagainst P. falciparum and P. vivax,\tand\tacts \tby \t\ninhibiting\tthe \tparasite \thaem \tpolymerase. \tOrally \tactive; \t\nhalf-life\t30 \tdays. \tThe \tonset \tof \taction \tis \tslow. \t\nUnwanted effects :\tGI\tdisturbances, \tneurotoxicity \tand \t\npsychiatric \tproblems.\n\u2022\tPrimaquine \tis\teffective \tagainst \tthe \tliver \thypnozoites \t\nand\tis\talso \tactive \tagainst \tgametocytes. \tOrally \tactive; \t\nhalf-life\t36 \th. \tUnwanted effects :\tGI\ttract\tdisturbances \t\nand,\twith\tlarge \tdoses, \tmethaemoglobinaemia. \t\nErythrocyte \thaemolysis \tin \tindividuals \twith \tgenetic \t\ndeficiency \tof", "start_char_idx": 3466, "end_char_idx": 5858, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3f10b076-22eb-45e5-a1c0-5312aa10c5b7": {"__data__": {"id_": "3f10b076-22eb-45e5-a1c0-5312aa10c5b7", "embedding": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "6379baca-d8c7-4875-9cad-a6a426fc3d9b", "node_type": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d96698169191eabd69727dabf9df6b8a63a6d289dfa60308e995abefc0c32bc"}, "2": {"node_id": "1e56b6a9-922e-4014-942d-fd5659ca9f69", "node_type": null, "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "865f469f201ac758b0e9edd1a8093612ad0f8ee0861e7dbdcfacdd15b3e97ee5"}}, "hash": "fcb32efb42f3b2ba60ed0c252523234f3c516b7608616f6369857d206e153901", "text": "\tglucose \t6-phosphate \tdehydrogenase.\n\u2022\tArtemisinin \tderivatives \tare \tnow \twidely \tused \t\nparticularly \tin \tcombination \twith \tother \tdrugs \tsuch \tas \t\nlumefantrine .\tThey\tare \tfast-acting \tblood \t\nschizonticidal \tagents \tthat \tare \teffective \tagainst \tboth \tP. \nfalciparum and P. vivax.\n\u2022\tArtesunate \tis\twater-soluble \tand \tcan \tbe \tgiven \torally \tor \t\nby\tintravenous, \tintramuscular \tor \trectal \tadministration. \t\nSide effects are rare. Resistance is so far uncommon.\n\u2022\tAtovaquone (in combination with proguanil) is used \nfor\tprevention, \tand \tfor \tthe \ttreatment \tof, \tacute \t\nuncomplicated P. falciparum malaria. The drug \ncombination \tis \teffective \torally. \tIt \tis \tgiven \tat \tregular \t\nintervals\tover \t3 \tto \t4 \tdays. \tUnwanted effects :\t\ndiarrhoea, \tnausea \tand \tvomiting. \tResistance \tto \t\natovaquone \tdevelops \trapidly \tif \tit \tis \tgiven \talone.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 5911, "end_char_idx": 7247, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7e884c76-46cb-4ffc-bfa1-27b6fd76807f": {"__data__": {"id_": "7e884c76-46cb-4ffc-bfa1-27b6fd76807f", "embedding": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "393b064a-6e73-4cf6-a041-27b6ca6056d7", "node_type": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3db54edf80c7b4422c4b985d389b2f04c8326e536775039eee4127f4c370386f"}, "3": {"node_id": "fc10f9f6-5f3e-42b3-9557-d30b291aec22", "node_type": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "02e4b813fc010ec0cb50daad4993b6abbe33dfd4af926a2292ef3d83a078baf1"}}, "hash": "1e817b3e152cb0df298fea819667ecbedb578f9bcef8fe1d9770f37324b89c5f", "text": "55 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n706unrest, famine and AIDS encourage the spread of the disease \nby reducing the chances of distributing medication or \nbecause patients are immunocompromised. Related trypano -\nsome infections also pose a major risk to livestock and thus \nhave a secondary impact on human health and well-being. \nIn the case of Chagas disease, some 7 million people are \nbelieved to harbour the infection.The use of drugs to treat this condition depends largely on the site and type of infection. The drugs of choice for \nthe various forms of amoebiasis are:\n\u2022\tmetronidazole (or tinidazole) followed by diloxanide \nfor acute invasive intestinal amoebiasis resulting in \nacute severe amoebic dysentery;\n\u2022\tdiloxanide \tfor \tchronic \tintestinal \tamoebiasis;\n\u2022\tmetronidazole \tfollowed \tby \tdiloxanide \tfor \thepatic \t\namoebiasis;\n\u2022\tdiloxanide \tfor \tthe \tasymptomatic \t\u2018carrier\u2019 \tstate.\nThese agents are often used in combination.\nMETRONIDAZOLE\nMetronidazole kills the trophozoites of E. histolytica but \nhas no effect on the cysts. It is the drug of choice for invasive amoebiasis of the intestine or the liver, but it is less effective \nagainst organisms in the lumen of the gut. Metronidazole is activated by anaerobic organisms to a compound that \ndamages DNA, leading to parasite apoptosis.\nMetronidazole is usually given orally and is rapidly and \ncompletely absorbed. Rectal and intravenous preparations are also available. It is distributed rapidly throughout the \ntissues, reaching high concentrations in the body fluids, including the cerebrospinal fluid. Some is metabolised, but most is excreted in urine.\nUnwanted effects are mild. The drug has a metallic, \nbitter taste in the mouth but causes few unwanted effects in therapeutic doses. Minor GI disturbances have been \nreported, as have CNS symptoms (dizziness, headache, \nsensory neuropathies). Metronidazole causes a disulfiram-like reaction to alcohol (see Ch. 50), which should be strictly \navoided. Metronidazole should not be used in pregnancy.\nTinidazole is similar to metronidazole in its mechanism \nof action and unwanted effects, but is eliminated more \nslowly, having a half-life of 12\u201314 h.\nDILOXANIDE\nDiloxanide or, more commonly, an insoluble ester, diloxa -\nnide furoate, are the drugs of choice for the asymptomatic infected patient, and are often given as a follow-up after \nthe disease has been reversed with metronidazole. Both drugs have a direct amoebicidal action, affecting the para -\nsites before encystment. Diloxanide furoate is given orally, and acts without being absorbed. Unwanted GI or other effects may be seen but it has an excellent safety profile.\nOther drugs that are sometimes used include the antibiotic \nparomomycin (see reading list for further information).\nTRYPANOSOMIASIS AND \nTRYPANOCIDAL DRUGS\nTrypanosomes belong to the group of pathogenic flagellate \nprotozoa. Two subtypes of Trypanosoma brucei (rhodesiense \nand gambiense ) cause sleeping sickness in Africa (also called \nHAT \u2013 Human African Trypanosomiasis). In South America, another species Trypanosoma cruzi, causes Chagas disease \n(also known as American trypanosomiasis).\nAlmost eliminated by 1960, HAT re-emerged but, thanks \nto concerted public health", "start_char_idx": 0, "end_char_idx": 3274, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fc10f9f6-5f3e-42b3-9557-d30b291aec22": {"__data__": {"id_": "fc10f9f6-5f3e-42b3-9557-d30b291aec22", "embedding": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "393b064a-6e73-4cf6-a041-27b6ca6056d7", "node_type": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3db54edf80c7b4422c4b985d389b2f04c8326e536775039eee4127f4c370386f"}, "2": {"node_id": "7e884c76-46cb-4ffc-bfa1-27b6fd76807f", "node_type": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1e817b3e152cb0df298fea819667ecbedb578f9bcef8fe1d9770f37324b89c5f"}, "3": {"node_id": "810ca288-e8ae-4354-a227-99a8717c19ea", "node_type": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "64493e75ba2c2617bbd00c149452b8b5f089712a84d08939f4fd75a1cb22e72a"}}, "hash": "02e4b813fc010ec0cb50daad4993b6abbe33dfd4af926a2292ef3d83a078baf1", "text": "by 1960, HAT re-emerged but, thanks \nto concerted public health campaigns, the number of cases \nis now falling again. In 2017, WHO reported less than 20,000 \ncases out of some 65 million people at risk of contracting sleeping sickness. The disease caused by T. b. rhodesiense \nis the more aggressive form albeit less widespread. Civil Drugs used in amoebiasis \nAmoebiasis \tis \tcaused \tby \tinfection \twith \tEntamoeba \nhistolytica ,\twhich\tcauses \tdysentery \tand \tliver \tabscesses. \t\nThe\torganism \tmay \tbe \tpresent \tin \tmotile \tinvasive \tform \tor \t\nas\ta\tcyst. \tThe \tmain \tdrugs \tare:\n\u2022\tMetronidazole \tgiven\torally \t(half-life \t7 \th). \tActive \t\nagainst\tthe \tinvasive \tform \tin \tgut \tand \tliver \tbut \tnot \tthe \t\ncysts.\tUnwanted \teffects \t(rare); \tgastrointestinal \t(GI) \t\ndisturbances \tand \tcentral \tnervous \tsystem \tsymptoms. \t\nTinidazole \tis\tsimilar. \tFollow-on \ttreatment \tdirected \tat \t\nthe GI lumen is needed to ensure eradication.\n\u2022\tDiloxanide \tis\ta\tluminal \tagent \tgiven \torally \twith \tno \t\nserious\tunwanted \teffects. \tIt \tis \tactive, \twhile \t\nunabsorbed, \tagainst \tthe \tnon-invasive \tform \tin \tthe \tGI \t\ntract.\n\u25bc The vector of HAT is the tsetse fly. In both types of the disease, \nthere is an initial local lesion at the site of entry, which may (in the \ncase of T. b. rhodesiense ) develop into a painful chancre (ulcer or sore). \nThis is followed by bouts of parasitaemia and fever as the parasite enters the haemolymphatic system. The parasites and the toxins they release during the second phase of the disease cause organ damage. \nThis manifests as \u2018sleeping sickness\u2019 when parasites reach the CNS \ncausing somnolence and progressive neurological breakdown. Left untreated, such infections are fatal.\nT. cruzi is spread through other blood-sucking insects, including the \n\u2018kissing bugs\u2019. The initial phases of the infection are similar but para -\nsites damage the heart, muscles and sometimes liver, spleen, bone and intestine. Many people harbour chronic infections. The cure rate is good if treatment begins immediately after infection, but is less \nsuccessful if delayed.\nThe main drugs used for HAT are suramin, with penta-\nmidine as an alternative, in the haemolymphatic stage of \nthe disease, and the arsenical melarsoprol for the late stage \nwith CNS involvement and eflornithine (see Burchmore \net al., 2002; Burri & Brun, 2003). All have toxic side effects. \nNifurtimox, eflornithine and benznidazole are used in \nChagas disease: however, there is no totally effective treat -\nment for this form of trypanosomiasis.\nSURAMIN\nSuramin was introduced into the therapy of trypanosomiasis in 1920. The drug binds firmly to host plasma proteins, \nand the complex enters the trypanosome by endocytosis, \nand is then liberated by lysosomal proteases. It inhibits key parasite enzymes inducing gradual destruction of \norganelles, such that the organisms are cleared from the \ncirculation after a short interval.\nThe drug is given by slow intravenous injection. The \nblood concentration drops rapidly during the first few hours and then more slowly over the succeeding days. A residual concentration remains for 3\u20134 months. Suramin tends to accumulate in", "start_char_idx": 3221, "end_char_idx": 6384, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "810ca288-e8ae-4354-a227-99a8717c19ea": {"__data__": {"id_": "810ca288-e8ae-4354-a227-99a8717c19ea", "embedding": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "393b064a-6e73-4cf6-a041-27b6ca6056d7", "node_type": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3db54edf80c7b4422c4b985d389b2f04c8326e536775039eee4127f4c370386f"}, "2": {"node_id": "fc10f9f6-5f3e-42b3-9557-d30b291aec22", "node_type": null, "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "02e4b813fc010ec0cb50daad4993b6abbe33dfd4af926a2292ef3d83a078baf1"}}, "hash": "64493e75ba2c2617bbd00c149452b8b5f089712a84d08939f4fd75a1cb22e72a", "text": "concentration remains for 3\u20134 months. Suramin tends to accumulate in mononuclear phagocytes, and in the cells \nof the proximal tubule in the kidney.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6370, "end_char_idx": 6997, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1a282cc5-b4ac-479d-a23e-5b6b92f98a57": {"__data__": {"id_": "1a282cc5-b4ac-479d-a23e-5b6b92f98a57", "embedding": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "573e05cf-5cb6-4afe-bb11-7dbb36686a40", "node_type": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce72764d538a613a3f867888d45823b8a3f13d5a103d42a2edbda7397651e0a7"}, "3": {"node_id": "71bcad65-2c29-4990-8a94-c37a7e563d27", "node_type": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "54974feb35d5d02aabe86110adbfc419b513134ab94199a103c95ed6bc38e670"}}, "hash": "cc9007994c6d2014045ad35efa584349124d07587047f49510a9fa2950d6283e", "text": "55 ANTIpROTO zOAl DRUGS\n707non-flagellated intracellular form (amastigote) in the mononuclear \nphagocytes of the infected mammalian host. Within these cells, the \nparasites thrive in modified phagolysosomes. By deploying an array \nof countermeasures (Singh et al., 2012), they promote the generation \nof Th2 cytokines and subvert the macrophage\u2019s microbiocidal systems \nto ensure their survival. The amastigotes multiply, and eventually the \ninfected cell releases a new crop of parasites into the haemolymphatic \nsystem, where they can infect further macrophages and possibly \nother cells.\nDifferent species of Leishmania exist in different geographical areas \nand cause distinctive clinical manifestations (see Table 55.1). Typical \npresentations include:\n\u2022\ta\tcutaneous form, which presents as an unpleasant chancre \n(\u2018oriental sore\u2019, \u2018Chiclero\u2019s ulcer\u2019 and other names) that may heal spontaneously but can leave scarring. This is the most common \nform and is found in the Americas, some Mediterranean countries and parts of central Asia;\n\u2022\ta\tmucocutaneous form (\u2018espundia\u2019 and other names), which \npresents as large ulcers of the mucous membranes of the mouth, \nnose and throat; most cases are seen in South America;\n\u2022\ta\tserious \tvisceral form (\u2018kala-azar\u2019 and other names), where the \nparasite spreads through the bloodstream causing hepatomegaly, splenomegaly, anaemia and intermittent fever. \nThis manifestation is encountered mainly in the Indian subcontinent and West Africa.\nThe main drugs used in visceral leishmaniasis are \npentavalent antimony compounds such as sodium sti-\nbogluconate and pentamidine as well as amphotericin \n(see Ch. 54), which is sometimes used as a follow-up treatment. Miltefosine , an antitumour drug, is also used \nin some countries (not United Kingdom), as is meglu-\nmine antimoniate.\nSodium stibogluconate is given intramuscularly or by \nslow intravenous injection in a 10-day course. It is rapidly \neliminated in the urine, 70% being excreted within 6 h. \nMore than one course of treatment may be required. The mechanism of action of sodium stibogluconate is not clear, \nbut the drug may increase production of toxic oxygen free \nradicals in the parasite.\nUnwanted effects include anorexia, vomiting, bradycardia \nand hypotension. Coughing and substernal pain may occur during intravenous infusion. Reversible hepatitis and pancreatitis are common.\nMiltefosine (hexadecylphosphocholine) is also effective \nin the treatment of both cutaneous and visceral leishma -\nniasis. The drug may be given orally and is well tolerated. Side effects are mild and include nausea and vomiting. In \nvitro, the drug induces DNA fragmentation and apoptosis \nin the parasites\nOther drugs, such as antibiotics and antifungals, may \nbe given concomitantly with the above agents. They may have some action on the parasite in their own right, but their main utility is to control the spread of secondary \ninfections.\nResistance to current drugs, particularly the pentavalent \nantimonials (possibly caused by increased expression of an antimonial efflux pump), is a serious problem and there \nis no immediate prospect of a vaccine. The pharmacology of current drugs and prospects for new agents have been \nreviewed by Singh et al. (2012).\nTRICHOMONIASIS\nThe principal Trichomonas organism that produces disease \nin humans is T. vaginalis . Virulent strains cause inflamma -\ntion of the", "start_char_idx": 0, "end_char_idx": 3407, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "71bcad65-2c29-4990-8a94-c37a7e563d27": {"__data__": {"id_": "71bcad65-2c29-4990-8a94-c37a7e563d27", "embedding": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "573e05cf-5cb6-4afe-bb11-7dbb36686a40", "node_type": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce72764d538a613a3f867888d45823b8a3f13d5a103d42a2edbda7397651e0a7"}, "2": {"node_id": "1a282cc5-b4ac-479d-a23e-5b6b92f98a57", "node_type": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cc9007994c6d2014045ad35efa584349124d07587047f49510a9fa2950d6283e"}, "3": {"node_id": "e1d0a57b-e795-478f-a133-34d791a8a56f", "node_type": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "77835e0674087a5ed0d20ddf0700e3ce61d15ec98b6282b6dfe6ed2e5e2c49b1"}}, "hash": "54974feb35d5d02aabe86110adbfc419b513134ab94199a103c95ed6bc38e670", "text": "T. vaginalis . Virulent strains cause inflamma -\ntion of the vagina and sometimes of the urethra in males. The main drug used in therapy is metronidazole (Ch. 52), Unwanted effects are common. Suramin is relatively toxic, \nparticularly in malnourished patients, the main organ affected being the kidney. Many other slowly developing \nadverse effects have been reported, including optic atrophy, \nadrenal insufficiency, skin rashes, haemolytic anaemia and agranulocytosis. A small proportion of individuals have \nan immediate idiosyncratic reaction to suramin injections, \nwhich may include nausea, vomiting, shock, seizures and loss of consciousness.\nPENTAMIDINE\nPentamidine has a direct trypanocidal action in vitro. It is rapidly taken up into parasites by a high-affinity energy-\ndependent carrier and is thought to interact with their DNA. \nThe drug is administered intravenously or by deep intra -\nmuscular injection, usually daily for 10\u201315 days. After \nabsorption from the injection site, it binds strongly to tissues \n(especially in the kidney) and is eliminated slowly, only 50% of a dose being excreted over 5 days. Fairly high \nconcentrations of the drug persist in the kidney, the liver \nand the spleen for several months, but it does not penetrate the blood\u2013brain barrier. It is also active in Pneumocystis \npneumonia (Ch. 52). Its usefulness is limited by its unwanted \neffects \u2013 an immediate decrease in blood pressure, with \ntachycardia, breathlessness and vomiting, and later serious toxicity, such as kidney damage, hepatic impairment, blood \ndyscrasias and hypoglycaemia.\nMELARSOPROL\n\u25bc This is an organic arsenical compound that is used mainly when \nthe CNS is involved. It is given intravenously and enters the CNS in \nhigh concentrations, where it is able to kill the parasite. It is a highly \ntoxic drug that produces many unwanted effects including \nencephalopathy and, sometimes, immediate fatality. As such, it is only administered under strict supervision.\nEFLORNITHINE\n\u25bc Eflornithine inhibits the parasite ornithine decarboxylase enzyme. \nIt shows good activity against T. b. gambiense and is used as a back-up for melarsoprol, although unfortunately it has limited activity against \nT. b. rhodesiense. Side effects are common and may be severe, but are \nreadily reversed when treatment is discontinued. Combined therapy with nifurtimox and eflornithine has yielded promising results in \npatients with late-stage disease.\nThere is an urgent need for new agents to treat trypanosome \ninfections, partly because of the toxicity of existing drugs \nand partly because of developing drug resistance. There \nis some cause for optimism and new agents, as well as new treatment modalities, are under investigation (Barrett, 2010; \nBrun et al., 2011).\nOTHER PROTOZOAL INFECTIONS AND \nDRUGS USED TO TREAT THEM\nLEISHMANIASIS\nLeishmania organisms are flagellate protozoa and leishma-\nniasis , the infection that they cause, is spread by the sandfly. \nAccording to the WHO (2017 figures) between 0.7 and 1.0 million new cases and 20,000\u201330,000 deaths are recorded each year. With increasing international travel, leishmaniasis \nis being imported into new areas and opportunistic infec -\ntions are now being reported (particularly in AIDS patients).\n\u25bc The vector is the female sandfly. The parasite exists in a flag -\nellated form (promastigote) in the gut of the infected insect, and a mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3357, "end_char_idx": 6822, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e1d0a57b-e795-478f-a133-34d791a8a56f": {"__data__": {"id_": "e1d0a57b-e795-478f-a133-34d791a8a56f", "embedding": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "573e05cf-5cb6-4afe-bb11-7dbb36686a40", "node_type": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ce72764d538a613a3f867888d45823b8a3f13d5a103d42a2edbda7397651e0a7"}, "2": {"node_id": "71bcad65-2c29-4990-8a94-c37a7e563d27", "node_type": null, "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "54974feb35d5d02aabe86110adbfc419b513134ab94199a103c95ed6bc38e670"}}, "hash": "77835e0674087a5ed0d20ddf0700e3ce61d15ec98b6282b6dfe6ed2e5e2c49b1", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6810, "end_char_idx": 7289, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "72e5f73f-562b-44f6-bb3c-0de534267fc5": {"__data__": {"id_": "72e5f73f-562b-44f6-bb3c-0de534267fc5", "embedding": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a43c6992-1b2f-4686-9048-b915c497a3b9", "node_type": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29fe80af0b6e337b10e921fff49b32ba18c284f8bab11078cf3789f33fd80692"}, "3": {"node_id": "e1ccf6bf-2745-41b3-a334-1f8d554cd5aa", "node_type": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f571778f7bdc37889669fde03e087840be8039da78bc33d8ca5047a5b0f30a0"}}, "hash": "0a604179c3b1c2caa5469a910748e8c1ff67a868db811c4704f6da71b3790938", "text": "55 SECTION 5 \u2003\u2003DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n708clarithromycin or azithromycin (see Ch. 52) have shown \npromise.\nPNEUMOCYSTIS\nFirst recognised in 1909, Pneumocystis carinii (now known \nas P. jirovecii ; see also Ch. 54) shares structural features \nwith both protozoa and fungi, leaving its precise classifica -\ntion uncertain. Previously considered to be a widely dis -\ntributed but largely innocuous microorganism, it is now \nrecognised as an important cause of opportunistic infections \nin immunocompromised patients. It is common in AIDS, \nwhere P. carinii pneumonia is often the presenting symptom \nas well as a leading cause of death.\nHigh-dose co-trimoxazole (Chs 51 and 52) is the drug of \nchoice in serious cases, with parenteral pentamidine as an \nalternative. Treatment of milder forms of the disease (or \nprophylaxis) can be effected with atovaquone, trimethoprim\u2013\ndapsone, or clindamycin\u2013primaquine combinations.\nFUTURE DEVELOPMENTS\nAntiprotozoal pharmacology is a huge global challenge, \nwith each species posing its own distinct problems to the \nwould-be designer of new antiprotozoal drugs. But it is \nnot simply a lack of new drugs that is the problem: for \neconomic reasons, the countries and populations most \naffected often lack an efficient infrastructure for the distribu -\ntion and safe administration of the drugs that we already \npossess. Cultural attitudes, civil wars, famine, the circulation \nof counterfeit or defective drugs, drought and natural \ndisasters also exacerbate this problem.although resistance to this drug is on the increase. High \ndoses of tinidazole are also effective, with few side effects.\nGIARDIASIS\nGiardia lamblia colonises the upper GI tract in its trophozoite \nform, and the cysts pass out in the faeces. Infection is then \nspread by ingestion of food or water contaminated with \nfaecal matter containing the cysts. It is encountered world -\nwide, and epidemics caused by bad sanitation are not \nuncommon. Metronidazole is the drug of choice, and \ntreatment is usually very effective. Tinidazole or mepacrine \nmay be used as an alternative.\nTOXOPLASMOSIS\nThe cat is the definitive host of Toxoplasma gondii , a patho -\ngenic member of this group of organisms (i.e. it is the only \nhost in which the sexual cycle can occur). It expels the \ninfectious cysts in its faeces; humans can inadvertently \nbecome intermediate hosts, harbouring the asexual form \nof the parasite. Ingested oocysts develop into sporozoites, \nthen to trophozoites, and finally encyst in the tissues. In \nmost individuals, the disease is asymptomatic or self-\nlimiting, although intrauterine infections can severely \ndamage the developing fetus and it may cause fatal gen -\neralised infection in immunosuppressed patients or those \nwith AIDS, in whom toxoplasmic encephalitis may occur. In \nhumans, T. gondii infects numerous cell types and has a \nhighly virulent replicative stage.\nThe treatment of choice is pyrimethamine\u2013sulfadiazine \n(to be avoided in pregnant patients); trimethoprim\u2013 \nsulfamethoxazole (co-trimoxazole, see Ch. 52) or \ncombinations of pyrimethamine with clindamycin , \nREFERENCES AND FURTHER READING\nHost\u2013parasite interactions\nBrenier-Pinchart, M.P., Pelloux,", "start_char_idx": 0, "end_char_idx": 3239, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "e1ccf6bf-2745-41b3-a334-1f8d554cd5aa": {"__data__": {"id_": "e1ccf6bf-2745-41b3-a334-1f8d554cd5aa", "embedding": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a43c6992-1b2f-4686-9048-b915c497a3b9", "node_type": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29fe80af0b6e337b10e921fff49b32ba18c284f8bab11078cf3789f33fd80692"}, "2": {"node_id": "72e5f73f-562b-44f6-bb3c-0de534267fc5", "node_type": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0a604179c3b1c2caa5469a910748e8c1ff67a868db811c4704f6da71b3790938"}, "3": {"node_id": "f6cc06d4-4f16-448b-94b3-c276b13e4878", "node_type": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "21ad7ff1eae07922fd3e7da0546d727b6de6fb21fe4da4b6979f50c809adf641"}}, "hash": "2f571778f7bdc37889669fde03e087840be8039da78bc33d8ca5047a5b0f30a0", "text": "interactions\nBrenier-Pinchart, M.P., Pelloux, H., Derouich-Guergour, D., et al., 2001. \nChemokines in host\u2013parasite interactions. Trends Parasitol. 17, \n292\u2013296. ( Good review of role of immune system )\nLanghorne, J., Duffy, P.E., 2016. Expanding the antimalarial toolkit: \ntargeting host-parasite interactions. J. Exp. Med. 213, 143\u2013153. \n(Thought-provoking paper exploring opportunities for antimalarial drug \ndiscovery offered by insights into host-parasite interactions. A little \ntechnical )\nMalaria\nAchieng, A.O., Rawat, M., Ogutu, B., et al., 2017. Antimalarials: \nmolecular drug targets and mechanism of action. Curr. Top. Med. \nChem. 17, 2114\u20132128. ( A comprehensive review dealing largely with the \nidentification of new chemical target compounds for drug development )\nBaird, J.K., 2005. Effectiveness of antimalarial drugs. N. Engl. J. Med. \n352, 1565\u20131577. ( An excellent overview covering many aspects of drug \ntherapy, drug resistance and the socioeconomic factors affecting the treatment \nof this disease \u2013 thoroughly recommended )\nBasore, K., Cheng, Y., Kushwaha, A.K., Nguyen, S.T., Desai, S.A., 2015. \nHow do antimalarial drugs reach their intracellular targets? Front. \nPharmacol. 6, 91.\nBlasco, B., Leroy, D., Fidock, D.A., 2017. Antimalarial drug resistance: \nlinking Plasmodium falciparum parasite biology to the clinic. Nat. Med. \n23, 917\u2013928.\nButler, A.R., Khan, S., Ferguson, E., 2010. A brief history of malaria \nchemotherapy. J. R. Coll. Physicians Edinb. 40, 172\u2013177. ( Deals with the \nsubject from a historical perspective beginning with the discovery of quinine \nand including recent developments in artemisinin synthesis. Good overview )\nDeu, E., 2017. Proteases as antimalarial targets: strategies for genetic, \nchemical, and therapeutic validation. FEBS J. 284 (16), 2604\u20132628. ( The \nmalarial parasite needs to digest haemoglobin, and obviously proteases are \nimportant for this. The author reviews new approaches to target these to \ndevelop new drugs. Some good diagrams )Ezzet, F., Mull, R., Karbwang, J., 1998. Population pharmacokinetics and \ntherapeutic response of CGP 56697 (artemether + benflumetol) in \nmalaria patients. Br. J. Clin. Pharmacol. 46, 553\u2013561. ( Deals with the \npharmacokinetics of this increasingly important combination therapy )\nFidock, D.A., Rosenthal, P.J., Croft, S.L., et al., 2004. Antimalarial drug \ndiscovery: efficacy models for compound screening. Nat. Rev. Drug \nDiscov. 3, 509\u2013520. ( Useful review dealing with mechanisms of antimalarial \ndrug action and new concepts for screening future candidates )\nFoley, M., Tilley, L., 1997. Quinoline antimalarials: mechanisms of \naction and resistance. Int. J. Parasitol. 27, 231\u2013240. ( Good, short review; \nuseful diagrams )\nGreenwood, B.M., Fidock, D.A., Kyle, D.E., et al., 2008. Malaria: \nprogress, perils, and prospects for eradication. J. Clin. Invest. 118, \n1266\u20131276. ( Good overview of the disease, its current and future treatment )\nGorobets, N.Y., Sedash, Y.V.,", "start_char_idx": 3197, "end_char_idx": 6183, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f6cc06d4-4f16-448b-94b3-c276b13e4878": {"__data__": {"id_": "f6cc06d4-4f16-448b-94b3-c276b13e4878", "embedding": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a43c6992-1b2f-4686-9048-b915c497a3b9", "node_type": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29fe80af0b6e337b10e921fff49b32ba18c284f8bab11078cf3789f33fd80692"}, "2": {"node_id": "e1ccf6bf-2745-41b3-a334-1f8d554cd5aa", "node_type": null, "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2f571778f7bdc37889669fde03e087840be8039da78bc33d8ca5047a5b0f30a0"}}, "hash": "21ad7ff1eae07922fd3e7da0546d727b6de6fb21fe4da4b6979f50c809adf641", "text": "treatment )\nGorobets, N.Y., Sedash, Y.V., Singh, B.K., et al., 2017. An overview of \ncurrently available antimalarials. Curr. Top. Med. Chem. 17, \n2143\u20132157.\nHeld, J., Jeyaraj, S., Kreidenweiss, A., 2015. Antimalarial compounds in \nPhase II clinical development. Expert Opin. Investig. Drugs 24, \n363\u2013382.\nHoffman, S.L., Vekemans, J., Richie, T.L., Duffy, P.E., 2015. The march \ntoward malaria vaccines. Am. J. Prev. Med. 49, S319\u2013S333. ( Deals with \nthe development of malaria vaccines. Some useful information and good \ndiagrams, but a bit technical in places )\nLanteri, C.A., Johnson, J.D., Waters, N.C., 2007. Recent advances in \nmalaria drug discovery. Recent. Pat. Antiinfect. Drug Discov. 2, \n95\u2013114. ( This comprehensive review focuses mainly upon chemical leads but \nalso has a good section on drug targets and ways of optimising existing \ntherapies )\nMatuschewski, K., 2017. Vaccines against malaria-still a long way to go. \nFEBS J. 284 (16), 2560\u20132568. ( An excellent, and cool headed, update on the \nvaccine issue. Straightforward reading )\nMishra, M., Mishra, V.K., Kashaw, V., et al., 2017. Comprehensive \nreview on various strategies for antimalarial drug discovery. Eur. J. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6185, "end_char_idx": 7854, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5383705f-fb4e-4031-b7ec-a8501fcc6fca": {"__data__": {"id_": "5383705f-fb4e-4031-b7ec-a8501fcc6fca", "embedding": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5832e1d3-b9ba-4d50-89cf-289f182b5903", "node_type": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16dac48e5fab3b6e35ae68b5105b0988c2a1620e428664717641631b2e3d1ccb"}, "3": {"node_id": "16d162aa-a1d5-4246-8ab6-49685fa00938", "node_type": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "11cf52d7bc58f4290ef7422afbf665a0fefab1dc53c53cb0e6106a58c13cb215"}}, "hash": "5f51d298d0c03fc827e814c621713c991932a8324afc8da872b552a430eaed9c", "text": "55 ANTIpROTO zOAl DRUGS\n709in which their usage might be improved. Discusses how new agents might be \ndeveloped using (for example) a systems biology approach)\nBrun, R., Don, R., Jacobs, R.T., Wang, M.Z., Barrett, M.P., 2011. \nDevelopment of novel drugs for human African trypanosomiasis. Future Microbiol. 6, 677\u2013691.\nBurchmore, R.J., Ogbunude, P.O., Enanga, B., Barrett, M.P., 2002. \nChemotherapy of human African trypanosomiasis. Curr. Pharm. Des. 8, 256\u2013267. (Very good concise article; nice discussion of future therapeutic \npossibilities)\nBurri, C., Brun, R., 2003. Eflornithine for the treatment of human \nAfrican trypanosomiasis. Parasitol. Res. 90 (Suppl. 1), S49\u2013S52. (The title is self- explanatory)\nDenise, H., Barrett, M.P., 2001. Uptake and mode of action of drugs \nused against sleeping sickness. Biochem. Pharmacol. 61, 1\u20135. (Good coverage of drug therapy)\nGehrig, S., Efferth, T., 2008. Development of drug resistance in \nTrypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. \nTreatment of human African trypanosomiasis with natural products \n(Review). Int. J. Mol. Med. 22, 411\u2013419. (Good overview of drug therapy including sections on mechanisms of drug resistance)\nKeiser, J., Stich, A., Burri, C., 2001. New drugs for the treatment of \nhuman African trypanosomiasis: research and development. Trends Parasitol. 17, 42\u201349. (Excellent review of a devastating disease)\nLeishmaniasis\nHandman, E., Bullen, D.V.R., 2002. Interaction of Leishmania with the \nhost macrophage. Trends Parasitol. 18, 332\u2013334. (Very good article \ndescribing how this parasite colonises macrophages and evades intracellular \nkilling; easy to read)\nMishra, J., Saxena, A., Singh, S., 2007. Chemotherapy of leishmaniasis: \npast, present and future. Curr. Med. Chem. 14, 1153\u20131169. (Self-explanatory title!)\nSingh, N., Kumar, M., Singh, R.K., 2012. Leishmaniasis: current status of \navailable drugs and new potential drug targets. Asian Pac. J. Trop. Med. 5, 485\u2013497. (Excellent article dealing with the use of drugs to combat leishmaniasis. Also deals with resistance mechanisms in some detail. Highly \nrecommended)\nPneumocystis pneumonia\nWarren, E., George, S., You, J., Kazanjian, P., 1997. Advances in the \ntreatment and prophylaxis of Pneumocystis carinii pneumonia. Pharmacotherapy 17, 900\u2013916.\nUseful Web resources\nhttp://malaria.who.int/. (The WHO home page containing the major \ninformation on malaria \u2013 a terrific starting point for further investigation. Other useful sites cover trypanosomiasis, leishmaniasis and other important \nprotozozoal diseases)\nhttp://www.mmv.org/. (The Web page of the Medicines for Malaria \nVenture, a private\u2013public partnership established to bring together funding and expertise from a number of sources to tackle malaria)Med. Chem. 125, 1300\u20131320. (Good review of many aspects of malaria and its treatment. Recommended)\nMuregi, F.W., Wamakima, H.N., Kimani, F.T., 2012. Novel drug targets in \nmalaria parasite with potential to yield antimalarial drugs with long useful therapeutic lives. Curr. Pharm. Des. 18, 3505\u20133521. (Good account \nof anti-malarial pharmacology and", "start_char_idx": 0, "end_char_idx": 3112, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "16d162aa-a1d5-4246-8ab6-49685fa00938": {"__data__": {"id_": "16d162aa-a1d5-4246-8ab6-49685fa00938", "embedding": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5832e1d3-b9ba-4d50-89cf-289f182b5903", "node_type": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16dac48e5fab3b6e35ae68b5105b0988c2a1620e428664717641631b2e3d1ccb"}, "2": {"node_id": "5383705f-fb4e-4031-b7ec-a8501fcc6fca", "node_type": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5f51d298d0c03fc827e814c621713c991932a8324afc8da872b552a430eaed9c"}, "3": {"node_id": "785a3f7c-c764-4193-8374-6388bb9aa2df", "node_type": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53e055f85938f77cb98327ddb443d84a65a89099e3256725edf839664ee3fb33"}}, "hash": "11cf52d7bc58f4290ef7422afbf665a0fefab1dc53c53cb0e6106a58c13cb215", "text": "3505\u20133521. (Good account \nof anti-malarial pharmacology and how their usage might be improved)\nNa-Bangchang, K., Karbwang, J., 2009. Current status of malaria \nchemotherapy and the role of pharmacology in antimalarial drug research and development. Fundam. Clin. Pharmacol. 23, 387\u2013409. \n(Excellent overview of the whole area stressing the contribution that pharmacology makes to the development of new drugs. Highly recommended)\nO\u2019Brien, C., 1997. Beating the malaria parasite at its own game. Lancet \n350, 192. (Clear, succinct coverage of mechanisms of action and resistance of current antimalarials and potential new drugs; useful diagram)\nPaddon, C.J., Westfall, P.J., Pitera, D.J., et al., 2013. High-level \nsemi-synthetic production of the potent antimalarial artemisinin. Nature 25, 528\u2013532. (The use of synthetic biology techniques to produce \nartemesinic acid in yeast so that the global supply of artemisinin can be \nincreased. A real tour de force)\nShanks, G.D., Kain, K.C., Keystone, J.S., 2001. Malaria \nchemoprophylaxis in the age of drug resistance. II. Drugs that may be available in the future. Clin. Infect. Dis. 33, 381\u2013385. (A useful look ahead to new drugs)\nThota, S., Yerra, R., 2016. Drug discovery and development of \nantimalarial agents: recent advances. Curr. Protein Pept. Sci. 17, 275\u2013279. (Excellent review of the rather alarming development of resistance \nto antimalarials. Also includes a lot of useful information about how these \ndrugs act. Some excellent diagrams. Highly recommended)\nAmoebiasis\nHaque, R., Huston, C.D., Hughes, M., et al., 2003. Amebiasis. N. Engl. J. \nMed. 348, 1565\u20131573. (Good review; concentrates on the pathogenesis of the disease but has a useful table of drugs and their side effects)\nStanley, S.L., 2001. Pathophysiology of amoebiasis. Trends Parasitol. 17, \n280\u2013285. (A good account of the human disease that incorporates some results from animal models also easy-to-read)\nStanley, S.L., 2003. Amoebiasis. Lancet 361, 1025\u20131034. (Comprehensive \nand easy-to-read account of this disease, covering all aspects from diagnosis to treatment. Excellent)\nTrypanosomiasis\nAksoy, S., Gibson, W.C., Lehane, M.J., 2003. Interactions between tsetse \nand trypanosomes with implications for the control of \ntrypanosomiasis. Adv. Parasitol. 53, 1\u201383. (A very substantial and \ncomprehensive article covering the biology of the tsetse fly, which also discusses alternative methods from controlling the insect population. Less \ngood on drug therapy, but if you are interested in the biology of the insect \nvector of trypanosomiasis, then this is for you)\nBarrett, M.P., 2010. Potential new drugs for human African \ntrypanosomiasis: some progress at last. Curr. Opin. Infect. Dis. 23, 603\u2013608. (An account of the pharmacology of current trypanicides and ways mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3060, "end_char_idx": 6247, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "785a3f7c-c764-4193-8374-6388bb9aa2df": {"__data__": {"id_": "785a3f7c-c764-4193-8374-6388bb9aa2df", "embedding": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5832e1d3-b9ba-4d50-89cf-289f182b5903", "node_type": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16dac48e5fab3b6e35ae68b5105b0988c2a1620e428664717641631b2e3d1ccb"}, "2": {"node_id": "16d162aa-a1d5-4246-8ab6-49685fa00938", "node_type": null, "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "11cf52d7bc58f4290ef7422afbf665a0fefab1dc53c53cb0e6106a58c13cb215"}}, "hash": "53e055f85938f77cb98327ddb443d84a65a89099e3256725edf839664ee3fb33", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6253, "end_char_idx": 6396, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4e9bb654-1d1c-4053-aa80-cc132131e6b1": {"__data__": {"id_": "4e9bb654-1d1c-4053-aa80-cc132131e6b1", "embedding": null, "metadata": {"page_label": "716", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54633e0b-1288-474d-b9c1-400c750002a4", "node_type": null, "metadata": {"page_label": "716", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "09628e9683650c47f053d87ea1a0698d9b033ae068bd9af779b75fe8d9d098d9"}, "3": {"node_id": "8888c9df-152a-450e-9c28-9851206923da", "node_type": null, "metadata": {"page_label": "716", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "35ecc9a8a705faa1f227d7cfa300e3ccfc479679a2b4e0972d87a64d7abfcbcf"}}, "hash": "883d77020df093de1fd52815667a151cad6205f55850595e4a8a4c01793c0f35", "text": "710\nOVERVIEW\nSome 1.5 billion people around the world suffer from \nhelminthiasis \u2013 infection with various species of para -\nsitic helminths (worms). Inhabitants of tropical or \nsubtropical low-income countries are most at risk; children often become infected at birth (polyparasi -\ntaemia is common) and may remain so throughout their lives. The clinical consequences of helminthiasis vary: for example, threadworm infections mainly \ncause discomfort but infection with schistosomiasis \n(bilharzia) or hookworm is associated with serious \nmorbidity. Anaemia, nutritional problems and cognitive impairment are common in helminth-infected children. \nHelminthiasis is often co-endemic with malaria, tuberculosis and HIV/AIDS, adding to the disease \nburden as well as interfering with vaccination cam -\npaigns. Helminth infections are an even greater \nconcern in veterinary medicine, affecting both domestic \npets and farm animals leading to significant loss of \nlivestock. Because of its prevalence and economic significance, the pharmacological treatment of hel -\nminthiasis is therefore of great practical therapeutic importance.\nHELMINTH INFECTIONS\nThe helminths comprise two major groups: the nemathel-\nminths (nematodes, roundworms) and the platyhelminths (flat -\nworms). The latter group is subdivided into the trematodes \n(flukes) and the cestodes (tapeworms). Almost 350 species of \nhelminths have been found in humans, and most colonise the \ngastrointestinal (GI) tract. The global range and occurrence \nof helminthiasis has been reviewed by Lustigman et al. \n(2012).\nHelminths have a complex life cycle, often involving \nseveral host species. Infection may occur in many ways, \nwith poor hygiene a major contributory factor. Humans \nare generally the primary (or definitive) host for helminth \ninfections, in the sense that they harbour the sexually mature \nreproductive form. Direct ingestion is common: eggs or \nlarvae in the faeces of infected humans, enter the soil and \nsubsequently are ingested and infect the secondary ( intermedi-\nate) host. In some cases, the eggs or larvae may persist in the human host and become encysted , covered with granula -\ntion tissue, giving rise to cysticercosis . Encysted larvae may \nlodge in the muscles and viscera or, more seriously, in the eye or the brain.\nApproximately 20 helminth species are considered to be \nclinically significant and these fall into two main categories \u2013 those in which the worm lives in the host\u2019s alimentary canal, and those in which the worm lives in other tissues of the host\u2019s body.\nThe main examples of intestinal worms are:\n\u2022\tTapeworms: Taenia saginata, Taenia solium, Hymenolepis \nnana and Diphyllobothrium latum. Some 85 million \npeople in Asia, Africa and parts of America harbour \none or other of these tapeworm species. Only the first two are likely to be seen in the United Kingdom. \nCattle and pigs are the usual intermediate hosts of the \nmost common tapeworms (T. saginata and T. solium). \nHumans become infected by eating raw or \nundercooked meat containing the larvae, which have \nencysted in the animals\u2019 muscle tissue. H. nana may exist as both the adult (the intestinal worm) and the \nlarval stage in the same host, which may be human or \nrodent, although some insects (fleas, grain beetles) can also serve as intermediate hosts. The infection is usually asymptomatic. D. latum has two sequential \nintermediate hosts: a freshwater crustacean and a \nfreshwater fish. Humans become infected by eating raw or incompletely cooked fish containing the ", "start_char_idx": 0, "end_char_idx": 3549, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8888c9df-152a-450e-9c28-9851206923da": {"__data__": {"id_": "8888c9df-152a-450e-9c28-9851206923da", "embedding": null, "metadata": {"page_label": "716", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "54633e0b-1288-474d-b9c1-400c750002a4", "node_type": null, "metadata": {"page_label": "716", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "09628e9683650c47f053d87ea1a0698d9b033ae068bd9af779b75fe8d9d098d9"}, "2": {"node_id": "4e9bb654-1d1c-4053-aa80-cc132131e6b1", "node_type": null, "metadata": {"page_label": "716", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "883d77020df093de1fd52815667a151cad6205f55850595e4a8a4c01793c0f35"}}, "hash": "35ecc9a8a705faa1f227d7cfa300e3ccfc479679a2b4e0972d87a64d7abfcbcf", "text": "fish. Humans become infected by eating raw or incompletely cooked fish containing the \nlarvae.\n\u2022\tIntestinal roundworms: Ascaris lumbricoides (common \nroundworm), Enterobius vermicularis (threadworm, \ncalled pinworm in the United States), Trichuris \ntrichiura (whipworm), Strongyloides stercoralis (threadworm in the United States), Necator americanus \nand Ancylostoma duodenale (hookworms). Again, \nundercooked meat or contaminated food is an \nimportant cause of infection by roundworm, \nthreadworm and whipworm, whereas hookworm is \ngenerally acquired when their larvae penetrate the skin. Intestinal blood loss is a common cause of \nanaemia in regions where hookworm is endemic.\nThe main examples of worms that live elsewhere in host \ntissues are:\n\u2022\tFlukes: Schistosoma haematobium, Schistosoma mansoni \nand Schistosoma japonicum. These cause schistosomiasis \n(bilharzia). The adult worms of both sexes live and \nmate in the veins or venules of the bladder or the gut wall. The female lays eggs that pass into the bladder \nor gut, triggering inflammation in these organs. This \nresults in haematuria in the former case and, occasionally, loss of blood in the faeces in the latter. The eggs hatch in water after discharge from the body \nand thus enter the secondary host \u2013 in this case a \nparticular species of snail. After a period of development in this host, free-swimming cercariae \nemerge. These are capable of infecting humans by \npenetration of the skin. About 200 million people are infected with schistosomes in this manner.Antihelminthic drugs56 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER SECTION 5\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3463, "end_char_idx": 5564, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4545a408-a4b8-4821-a5ac-945cfd4775d1": {"__data__": {"id_": "4545a408-a4b8-4821-a5ac-945cfd4775d1", "embedding": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a815a454-ef65-4187-a0da-eb5914e18a94", "node_type": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "abba2ea887ffe7e387802bfeb9c145384ebda820f9937880aa1049b26f855354"}, "3": {"node_id": "715b144d-ed6a-409e-8dab-f0a74f0d5510", "node_type": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23258ee2d412d39b2e4e597d4bfe759a701aa3f1dfbcce84cdc76df8f7eff53b"}}, "hash": "16193ebe9043a768a75f58f968dfce53a650ba08b4c94a3388de0cf17403b034", "text": "56 ANTIHE lMINTHIC DRUGS\n711damaging the worm such that the host immune system \ncan eliminate it, or by altering parasite metabolism (e.g. \nby affecting microtubule function). Because the metabolic \nrequirements of these parasites vary greatly from one species to another, drugs that are highly effective against one type \nof worm may be ineffective against others.\nTo bring about its action, the drug must penetrate the \ntough exterior cuticle of the worm or gain access to its alimentary tract. This may present difficulties, because \nhelminths have different lifestyles with some worms being exclusively haemophagous (\u2018blood-eating\u2019), while others are \nbest described as \u2018tissue grazers\u2019. A further complication \nis that many helminths possess active drug efflux pumps \nthat reduce the concentration of the drug in the parasite. The route of administration and dose of antihelminthic \ndrugs are therefore important. In a reversal of the normal \norder of things, several antihelminthic drugs used in human medicine were originally developed for veterinary use.\nSome individual antihelminthic drugs are described \nbriefly below and indications for their use are given in Table 56.1. Many of these drugs are unlicensed in the United \nKingdom but are used on a \u2018named patient\u2019 basis\n2: in some \ncases (e.g. mebendazole) restricted dosage forms are available from pharmacies.\nBENZIMIDAZOLES\nThis group includes mebendazole, tiabendazole and \nalbendazole, which are widely used broad-spectrum antihelminthics. They are thought to act by inhibiting the \npolymerisation of helminth \u03b2-tubulin, thus interfering with \nmicrotubule-dependent functions such as glucose uptake. \nThey have a selective inhibitory action, being 250\u2013400 times \nmore effective in producing this effect in helminth, than in mammalian, tissue. However, the effect takes time to \ndevelop and the worms may not be expelled for several \ndays. Cure rates are generally between 60% and 100% with most parasites.\nOnly 10% of mebendazole is absorbed after oral admin -\nistration, but a fatty meal increases absorption. It is rapidly metabolised, the products being excreted in the urine and \nthe bile within 24\u201348 h. It is generally given as a single \ndose for threadworm, and twice daily for 3 days for hookworm and roundworm infestations. Tiabendazole is \nrapidly absorbed from the GI tract, very rapidly metabolised \nand excreted in the urine in conjugated form. It may be given twice daily for 3 days for guinea worm and Stron-\ngyloides infestations, and for up to 5 days for hookworm and roundworm infestations. Albendazole is also poorly absorbed but, as with mebendazole, absorption is increased \nby food, especially fats. It is metabolised extensively by \npresystemic metabolism to sulfoxide and sulfone metabo -\nlites. The former is likely to be the pharmacologically active species.\nUnwanted effects are few with albendazole or mebendazole, \nalthough GI disturbances can occasionally occur. Unwanted effects with tiabendazole are more frequent but usually \ntransient, the commonest being GI disturbances, although \u2022\tTissue roundworms: Trichinella spiralis, Dracunculus \nmedinensis (guinea worm) and the filariae, which include Wuchereria bancrofti, Loa loa, Onchocerca volvulus and \nBrugia malayi. The adult filariae live in the lymphatics, \nconnective tissues or mesentery of the host and \nproduce live embryos or microfilariae, which find their \nway into the bloodstream and may be ingested by mosquitoes or other biting insects.", "start_char_idx": 0, "end_char_idx": 3504, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "715b144d-ed6a-409e-8dab-f0a74f0d5510": {"__data__": {"id_": "715b144d-ed6a-409e-8dab-f0a74f0d5510", "embedding": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a815a454-ef65-4187-a0da-eb5914e18a94", "node_type": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "abba2ea887ffe7e387802bfeb9c145384ebda820f9937880aa1049b26f855354"}, "2": {"node_id": "4545a408-a4b8-4821-a5ac-945cfd4775d1", "node_type": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "16193ebe9043a768a75f58f968dfce53a650ba08b4c94a3388de0cf17403b034"}, "3": {"node_id": "fbcb12c1-221c-4420-9ff0-92e3376c12c5", "node_type": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5885a3be78eb1e9e280c58527e2c80eb3b101adbcca9323f861cd38beb4e1777"}}, "hash": "23258ee2d412d39b2e4e597d4bfe759a701aa3f1dfbcce84cdc76df8f7eff53b", "text": "the bloodstream and may be ingested by mosquitoes or other biting insects. After a period of \ndevelopment within this secondary host, the larvae \npass into the mouth parts of the insect and thus infect the next victim. Major filarial diseases are caused by Wuchereria or Brugia, which cause obstruction of \nlymphatic vessels, producing elephantiasis \u2013 hugely \nswollen legs. Other related diseases are onchocerciasis (in which the presence of microfilariae in the eye \ncauses \u2018river blindness\u2019 \u2013 a leading preventable cause \nof blindness in Africa and Latin America) and loiasis (in which the microfilariae cause inflammation in the \nskin and other tissues). Trichinella spiralis causes \ntrichinosis; the larvae from the viviparous female worms in the intestine migrate to skeletal muscle, \nwhere they become encysted. In guinea worm disease,\n1 \nlarvae of D. medinensis released from crustaceans in wells and waterholes are ingested and migrate from \nthe intestinal tract to mature and mate in the tissues; the gravid female then migrates to the subcutaneous \ntissues of the leg or the foot, and may protrude \nthrough an ulcer in the skin. The worm may be up to a metre in length and must be removed surgically or \nby slow mechanical winding of the worm on to a stick \nover a period of days, to ensure that the worm does not break, because the remains would putrefy.\n\u2022\tHydatid tapeworm. These are cestodes of the \nEchinococcus species for which dogs are the primary \nhosts, and sheep the intermediate hosts. The primary, intestinal stage does not occur in humans, but under \ncertain circumstances humans can function as the \nintermediate host, in which case the larvae develop into hydatid cysts within the tissues, sometimes with \nfatal consequences.\nSome nematodes that generally live in the GI tract of animals may infect humans and penetrate tissues. A skin infestation, termed creeping eruption or cutaneous larva migrans , is caused \nby the larvae of dog and cat hookworms which often enter through the foot. Visceral larva migrans is caused by larvae of cat and dog roundworms of the Toxocara genus.\nANTIHELMINTHIC DRUGS\nThe first effective antihelminthic drugs (also known as anthelmintics) were discovered in the 20th century and \nincorporated toxic metals such as arsenic ( atoxyl) or anti-\nmony ( tartar emetic ). They were used to treat trypanosome \nand schistosome infestations.\nCurrent antihelminthic drugs generally act by paralysing \nthe parasite (e.g. by preventing muscular contraction), by \n1Now, happily, eliminated from many parts of the world. There are no \neffective drug treatments for guinea worm disease, but clean drinking \nwater or filtering larval-contaminated water through nylon mesh tights \nhave helped reduce global infection from 3.5 million to 5 in only 30 years \u2013 the first globally-eradicated parasitic disease.2A situation in which the physician seeks access to an unlicensed drug \nfrom a pharmaceutical company to use in a named individual. The \ndrug is either a \u2018newcomer\u2019 that has shown promise in clinical trials but \nhas not yet been licensed or, as in these instances, an established drug that has not been licensed because the company has not applied for a \nproduct license for this indication (possibly for commercial reasons).mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3442, "end_char_idx": 7018, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fbcb12c1-221c-4420-9ff0-92e3376c12c5": {"__data__": {"id_": "fbcb12c1-221c-4420-9ff0-92e3376c12c5", "embedding": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a815a454-ef65-4187-a0da-eb5914e18a94", "node_type": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "abba2ea887ffe7e387802bfeb9c145384ebda820f9937880aa1049b26f855354"}, "2": {"node_id": "715b144d-ed6a-409e-8dab-f0a74f0d5510", "node_type": null, "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "23258ee2d412d39b2e4e597d4bfe759a701aa3f1dfbcce84cdc76df8f7eff53b"}}, "hash": "5885a3be78eb1e9e280c58527e2c80eb3b101adbcca9323f861cd38beb4e1777", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7034, "end_char_idx": 7257, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a55736ee-f709-49ad-b261-f20e50389d71": {"__data__": {"id_": "a55736ee-f709-49ad-b261-f20e50389d71", "embedding": null, "metadata": {"page_label": "718", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "328ebc9f-4903-48b9-b789-cca91563ef28", "node_type": null, "metadata": {"page_label": "718", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "731478f7524964cde2aa4d7cbf5e51d043d9cab97710ef9bd71664f85b26a95d"}, "3": {"node_id": "2fc12e60-b9ce-4085-ae9b-58978f5c97e0", "node_type": null, "metadata": {"page_label": "718", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "58dc159e8b00671a178aad8583d93f8ee47a5a6d1f4fea4a02ca953ce665c841"}}, "hash": "d22a648a11c1c6afb5c7e121894dd02447f102543b0d989d280212907848acef", "text": "56 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n712transitory and rarely of clinical importance. Effects may \nbe more marked in patients with a heavy worm load because \nof products released from the dead worms. Praziquantel \nis considered safe for pregnant and lactating women, an important property for a drug that is commonly used in \nnational disease control programmes. Some resistance has \ndeveloped to the drug.\nPIPERAZINE\nPiperazine (discontinued in United Kingdom) can be used to treat infections with the common roundworm ( A. lum-\nbricoides ) and the threadworm ( E. vermicularis ). It reversibly \ninhibits neuromuscular transmission in the worm, probably by mimicking GABA (Ch. 39), at GABA-gated chloride \nchannels in nematode muscle. The paralysed worms are \nexpelled alive by normal intestinal peristaltic movements. It is administered with a stimulant laxative such as senna \n(Ch. 31) to facilitate expulsion of the worms.\nPiperazine is given orally and some, but not all, is \nabsorbed. It is partly metabolised, and the remainder is eliminated, unchanged, via the kidney. The drug has little \npharmacological action in the host. When used to treat \nroundworm, piperazine is effective in a single dose. For threadworm, a longer course (7 days) at lower dosage is \nnecessary.\nUnwanted effects may include GI disturbances, urticaria \nand bronchospasm. Some patients experience dizziness, paraesthesia, vertigo and incoordination. The drug should \nnot be given to pregnant patients or to those with compro -\nmised renal or hepatic function.headache, dizziness and drowsiness have been reported and allergic reactions (fever, rashes) may also occur. \nMebendazole is considered unsuitable for pregnant women \nor children less than 2 years old.\nPRAZIQUANTEL\nPraziquantel is a highly effective broad-spectrum antihel -\nminthic drug that was introduced over 20 years ago. It is \nthe drug of choice for all forms of schistosomiasis and is \nthe agent generally used in large-scale schistosome eradica -\ntion programmes. It is also effective in cysticercosis. The \ndrug affects not only the adult schistosomes but also the \nimmature forms and the cercariae \u2013 the form of the parasite that infects humans by penetrating the skin.\nPraziquantel disrupts Ca\n2+ homeostasis in the parasite \nby binding to consensus protein kinase C-binding sites in \na \u03b2 subunit of schistosome voltage-gated calcium channels \n(Greenberg, 2005). This induces an influx of Ca2+, a rapid \nand prolonged contraction of the musculature, and eventual paralysis and death of the worm. Praziquantel also disrupts \nthe tegument of the parasite, unmasking novel antigens, and may thus make the worm more susceptible to the host\u2019s \nnormal immune responses.\nGiven orally, praziquantel is well absorbed; much of the \ndrug is rapidly metabolised to inactive metabolites on first passage through the liver, and the metabolites are excreted \nin the urine. The plasma half-life of the parent compound \nis 60\u201390 min.\nPraziquantel has minimal side effects in therapeutic \ndosage. Such unwanted effects as do occur are usually Table 56.1 Principal drugs used in helminth infections and some common indications\nHelminth Principal drug(s) used\nThreadworm \n(pinworm)Enterobius vermicularis Mebendazole, piperazine (not United Kingdom).\nStrongyloides stercoralis (threadworm in the United States) Ivermectin, albendazole,", "start_char_idx": 0, "end_char_idx": 3406, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2fc12e60-b9ce-4085-ae9b-58978f5c97e0": {"__data__": {"id_": "2fc12e60-b9ce-4085-ae9b-58978f5c97e0", "embedding": null, "metadata": {"page_label": "718", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "328ebc9f-4903-48b9-b789-cca91563ef28", "node_type": null, "metadata": {"page_label": "718", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "731478f7524964cde2aa4d7cbf5e51d043d9cab97710ef9bd71664f85b26a95d"}, "2": {"node_id": "a55736ee-f709-49ad-b261-f20e50389d71", "node_type": null, "metadata": {"page_label": "718", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d22a648a11c1c6afb5c7e121894dd02447f102543b0d989d280212907848acef"}}, "hash": "58dc159e8b00671a178aad8583d93f8ee47a5a6d1f4fea4a02ca953ce665c841", "text": "(threadworm in the United States) Ivermectin, albendazole, mebendazole\nCommon roundwormAscaris lumbricoides Levamisole, mebendazole, piperazine (not United Kingdom)\nOther roundworm (filariae)Lymphatic filariasis \u2018elephantiasis\u2019. (Wuchereria bancrofti, Brugia malayi )Diethylcarbamazine, ivermectin\nSubcutaneous filariasis \u2018eyeworm\u2019 (Loa loa ) Diethylcarbamazine\nOnchocerciasis \u2018river blindness\u2019 (Onchocerca volvulus) Ivermectin\nGuinea worm ( Dracunculus medinensis) Praziquantel, mebendazole\nTrichiniasis (Trichinella spiralis) Tiabendazole, mebendazole\nCysticercosis (infection with larval Taenia solium ) Praziquantel, albendazole\nTapeworm (Taenia saginata , Taenia solium ) Praziquantel, niclosamide\nHydatid disease ( Echinococcus granulosus) Albendazole\nHookworm (Ancylostoma duodenale, Necator americanus) Mebendazole, albendazole, Levamisole\nWhipworm (Trichuris trichiura) Mebendazole, albendazole, diethylcarbamazine\nBlood flukes (Schistosoma spp.)Bilharziasis: S. haematobium , S. mansoni, S. japonicum Praziquantel\nCutaneous larva migransAncylostoma caninum Albendazole, tiabendazole, ivermectin\nVisceral larva migransToxocara canis Albendazole, tiabendazole, diethylcarbamazinemebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3348, "end_char_idx": 5014, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "88a0bc59-e8ba-4d7d-ba9b-8a514256eda7": {"__data__": {"id_": "88a0bc59-e8ba-4d7d-ba9b-8a514256eda7", "embedding": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "52633cee-4636-4bfc-8c36-03532c05cea0", "node_type": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7fda58f51aabd4d9e0f3ee313c1da1578cccb7ba1bee79e981e6e45ef9623bf"}, "3": {"node_id": "994b2ecb-59e5-469d-82e3-1e651a865ffb", "node_type": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a2f76f59909a902b40cc3ce92186a77bb0c3b23e9b3cd747aba16f530a0f6fab"}}, "hash": "1249cd922ccd829d277d89e6fb5f654228a4f82ff3110bc5a4d30fc0dd20522b", "text": "56 ANTIHE lMINTHIC DRUGS\n713in humans. It is frequently used in global public health \ncampaigns,3 and is the first choice of drug for the treatment \nof many filarial infections. It yields good results against \nW. bancrofti , which causes elephantiasis. A single dose kills \nthe immature microfilariae of O. volvulus but not the adult \nworms. Ivermectin is also the drug of choice for onchocer -\nciasis, which causes river blindness and reduces the incidence \nof this disease by up to 80%. It is also active against some roundworms: common roundworms, whipworms, and \nthreadworms of both the UK ( E. vermicularis) and US ( S. \nstercoralis) variety, but not hookworms.\nChemically, ivermectin is a semisynthetic agent derived \nfrom a group of natural substances, the avermectins , obtained \nfrom an actinomycete organism. The drug is given orally \nand has a half-life of 11 h. It is thought to kill the worm \neither by opening glutamate-gated chloride channels (found \nonly in invertebrates) and increasing Cl\u2212 conductance; by \nbinding to GABA receptors or by binding to a novel allosteric \nsite on the acetylcholine nicotinic receptor to cause an \nincrease in transmission, leading to motor paralysis.\nUnwanted effects include skin rashes and itching but in \ngeneral the drug is very well tolerated. One interesting exception in veterinary medicine is the CNS toxicity seen in Collie dogs.\n4\nRESISTANCE TO ANTIHELMINTHIC DRUGS\nResistance to antihelminthic drugs is a widespread and growing problem affecting not only humans but also the \nanimal health market. Understanding of the mechanisms \nof helminth mutations in drug-resistant forms is not as well understood or researched, as with other microbes. \nDuring the 1990s, helminth infections in sheep (and, to a \nlesser extent, cattle) developed varying degrees of resistance to a number of different drugs. Parasites that develop such \nresistance pass this ability on to their offspring, leading to \ntreatment failure. The widespread use of antihelminthic agents in farming has been blamed for the spread of resistant species.\nThere are probably several molecular mechanisms that \ncontribute to drug resistance. The presence of the P-glycoprotein transporter (Ch. 10) in some species of \nnematode has already been mentioned, and agents such \nas verapamil that block the transporter in trypanosomes \ncan partially reverse resistance to the benzimidazoles. \nHowever, some aspects of benzimidazole resistance may \nbe attributed to alterations in their high-affinity binding to parasite \u03b2-tubulin. Likewise, resistance to levamisole is \nassociated with changes in the structure of the target acetylcholine nicotinic receptor.\nOf great significance is the way in which helminths evade \nthe host\u2019s immune system. Even though they may reside in immunologically exposed sites such as the lymphatics or the bloodstream, many are long-lived and may co-exist \nwith their hosts for many years without seriously affecting \ntheir health, or in some cases without even being noticed. It is striking that the two major families of helminths, while DIETHYLCARBAMAZINE\nDiethylcarbamazine is a piperazine derivative that is active \nin filarial infections caused by B. malayi, W. bancrofti and \nL. loa . Diethylcarbamazine rapidly removes the microfilariae \nfrom the blood circulation and has a limited effect on the adult worms in the lymphatics, but it has little action on \nmicrofilariae in vitro. It may act by changing the parasite \nsuch that it becomes susceptible to the host\u2019s normal immune responses or by interfering with helminth arachidonate", "start_char_idx": 0, "end_char_idx": 3587, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "994b2ecb-59e5-469d-82e3-1e651a865ffb": {"__data__": {"id_": "994b2ecb-59e5-469d-82e3-1e651a865ffb", "embedding": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "52633cee-4636-4bfc-8c36-03532c05cea0", "node_type": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7fda58f51aabd4d9e0f3ee313c1da1578cccb7ba1bee79e981e6e45ef9623bf"}, "2": {"node_id": "88a0bc59-e8ba-4d7d-ba9b-8a514256eda7", "node_type": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1249cd922ccd829d277d89e6fb5f654228a4f82ff3110bc5a4d30fc0dd20522b"}, "3": {"node_id": "7e16904a-cc87-4efe-85d4-23e94c756169", "node_type": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ffcb04633b64470aae2c1eb5e7b4a1db82400667ab4933ecbdaf02999088540"}}, "hash": "a2f76f59909a902b40cc3ce92186a77bb0c3b23e9b3cd747aba16f530a0f6fab", "text": "normal immune responses or by interfering with helminth arachidonate \nmetabolism.\nThe drug is absorbed following oral administration and \nis distributed throughout the cells and tissues of the body, \nexcepting adipose tissue. It is partly metabolised, and both \nthe parent drug and its metabolites are excreted in the \nurine, being cleared from the body within about 48 h.\nUnwanted effects are common but transient, subsiding \nwithin a day or so even if the drug is continued. Side effects from the drug itself include GI disturbances, joint pain, \nheadache and a general feeling of weakness. Allergic side effects referable to the products of the dying filariae are \ncommon and vary with the species of worm. In general, \nthese start during the first day\u2019s treatment and last 3\u20137 days; they include skin reactions, enlargement of lymph \nglands, dizziness, tachycardia, and GI and respiratory \ndisturbances. When these symptoms disappear, larger doses of the drug can be given without further problem. The drug is not used in patients with onchocerciasis, in whom \nit can have serious unwanted effects.\nNICLOSAMIDE\nNiclosamide is widely used for the treatment of tapeworm \ninfections together with praziquantel. The scolex (the head \nof the worm that attaches to the host intestine) and a \nproximal segment are irreversibly damaged by the drug, such that the worm separates from the intestinal wall and \nis expelled. For T. solium , the drug is given in a single dose \nafter a light meal, usually followed by a purgative 2 h later \nin case the damaged tapeworm segments release ova, which \nare not affected by the drug. For other tapeworm infections, \nthis precaution is not necessary. There is negligible absorp -\ntion of the drug from the GI tract.\nUnwanted effects: nausea, vomiting, pruritus and light-\nheadedness may occur but generally such effects are few, \ninfrequent and transient.\nLEVAMISOLE\nLevamisole is effective in infections with the common roundworm (A. lumbricoides). It has a nicotine-like action \n(Ch. 14), stimulating and subsequently blocking the \nneuromuscular junctions. The paralysed worms are then expelled in the faeces. Ova are not killed. Given orally the \ndrug is rapidly absorbed and is widely distributed crossing \nthe blood\u2013brain barrier. It is metabolised in the liver to inactive metabolites, which are excreted via the kidney. Its \nplasma half-life is 4 h. It has immunomodulatory effects \nand has in the past been used to treat various solid tumours.\nIt can cause central nervous system (CNS) and GI dis -\nturbances as well as several other unwanted effects, including agranulocytosis. The drug has been withdrawn from North American markets.\nIVERMECTIN\nFirst introduced in 1981 as a veterinary drug, ivermectin \nis a safe and highly effective broad-spectrum antiparasitic 3Ivermectin is supplied by the manufacturers free of charge in countries \nwhere river blindness is endemic. Because the worms develop slowly, a \nsingle annual dose of ivermectin is sufficient to prevent the disease.\n4A multidrug-resistance (MDR) gene (see Ch. 3) coding for a transporter \nthat expels ivermectins from the CNS, is mutated to an inactive form in Collie dogs.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3528, "end_char_idx": 7019, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7e16904a-cc87-4efe-85d4-23e94c756169": {"__data__": {"id_": "7e16904a-cc87-4efe-85d4-23e94c756169", "embedding": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "52633cee-4636-4bfc-8c36-03532c05cea0", "node_type": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d7fda58f51aabd4d9e0f3ee313c1da1578cccb7ba1bee79e981e6e45ef9623bf"}, "2": {"node_id": "994b2ecb-59e5-469d-82e3-1e651a865ffb", "node_type": null, "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a2f76f59909a902b40cc3ce92186a77bb0c3b23e9b3cd747aba16f530a0f6fab"}}, "hash": "1ffcb04633b64470aae2c1eb5e7b4a1db82400667ab4933ecbdaf02999088540", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7032, "end_char_idx": 7255, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "cbe51620-79db-464f-a562-ae8450662825": {"__data__": {"id_": "cbe51620-79db-464f-a562-ae8450662825", "embedding": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a631282f-2472-4aed-b9c0-c303f4f84594", "node_type": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c6af996405f2268bfdbeff3836d5fd3d888a3d6f87b6911c4a0c9650d976b99"}, "3": {"node_id": "6d05eadc-bb32-4737-b28e-5681e42a2017", "node_type": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6efe312a02ab07d96f46ab0d9a3513338fc25b160cd7569f99f2e50d1243aaa3"}}, "hash": "129a9c0732f8398ac0b9fe49b863d2025484497f224824b59e76fdbc40490081", "text": "56 SECTION 5\u2003\u2003 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n714On the negative side however, helminth infections may undermine \nthe efficacy of tuberculosis and other vaccination programmes that \ndepend upon a vigorous Th1 response (see, for example, Elias et al., \n2006 and Apiwattanakul et al., 2014).\nVACCINES AND OTHER NOVEL \nAPPROACHES\nDespite the enormity of the clinical (and economic) problems \nassociated with helminth infection, there are few novel \nantihelminthic drugs in development, possibly because the \nsimilarity between helminth and mammalian targets makes achieving selective toxicity difficult. New candidates such \nas tribendimidine are being assessed in a range of human \ninfections and have shown promise in liver fluke infection \n(Duthaler et a l., 2016 ) and some new veterinary drugs (e.g. \nderquantel ) also tested in humans (see Prichard et al., 2012). \nThe identification of new parasite metabolic enzymes as \ntargets may help with future drug design (Timson, 2016).\nPublic health measures to eliminate helminth infections \ndepend upon promoting better sanitation and mass drug administration programmes (e.g. McCarty et al., 2014). The \ndevelopment of effective anti-helminth vaccines would be \na major step forward in this endeavour. Using surface protein and glycoprotein antigens as immunogens, some \nsuccess has been achieved with veterinary vaccines (e.g. \nSciutto et al., 2013; Bassetto & Amarante, 2015). The use of \nsophisticated tools such as genomics, transcriptomics, \nproteomics, metabolomics, lipidomics (collectively known \nas \u2018OMICS\u2019) to identify novel antigens may facilitate progress \n(Loukas et al., 2011).evolving separately, deploy similar strategies to evade \ndestruction by the immune system. Clearly, this must be \nof major survival value for the species.\n\u25bc In addition to rapidly changing external antigens, which hamper \nimmune recognition, it appears that many helminths secrete immu -\nnomodulatory products that steer the host\u2019s immune system away from \na local Th1 response (see Ch. 7), which would damage the parasite, and \ninstead promote a modified systemic Th2 type of response. This is associ -\nated with the production by the host of \u2018anti-inflammatory\u2019 cytokines \nsuch as interleukin-10 and is favourable to, or at least better tolerated by, \nthe parasites. The immunology underlying this is fascinating but complex (see e.g. Harris, 2011; Harnett, 2014; McNeilly & Nisbet, 2014).\nIronically, the ability of helminths to modify the host immune response in this way may confer some survival value on the hosts themselves. \nFor example, in addition to the local anti-inflammatory effect exerted \nby helminth infections, rapid wound healing is also seen. Clearly, this is of advantage to parasites that must penetrate tissues without \nkilling the host, but may also be beneficial to the host as well. It has \nbeen proposed that helminth infections may mitigate some forms of malaria and other diseases, possibly conferring survival advantages \nin populations where these diseases are endemic. The deliberate, \n\u2018therapeutic\u2019 ingestion of helminths by patients has been evaluated \nas an (admittedly unappealing) strategy to induce remission of \ninflammatory diseases such as Crohn\u2019s disease, ulcerative colitis and \neven multiple sclerosis (see Ch. 31; Summers et al., 2005 a & b; Heylen \net al., 2014; Benzel et al., 2012; Peon & Terrazas, 2016), although their \neffectiveness in clinical trials is mixed.\nOn the basis that", "start_char_idx": 0, "end_char_idx": 3511, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "6d05eadc-bb32-4737-b28e-5681e42a2017": {"__data__": {"id_": "6d05eadc-bb32-4737-b28e-5681e42a2017", "embedding": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a631282f-2472-4aed-b9c0-c303f4f84594", "node_type": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c6af996405f2268bfdbeff3836d5fd3d888a3d6f87b6911c4a0c9650d976b99"}, "2": {"node_id": "cbe51620-79db-464f-a562-ae8450662825", "node_type": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "129a9c0732f8398ac0b9fe49b863d2025484497f224824b59e76fdbc40490081"}, "3": {"node_id": "8a032517-cf5c-4cf6-9295-8a643080056a", "node_type": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2661dee7ff743d9929730f53b2a28e5f6aff6da810ef9793b7d6f473d819f28"}}, "hash": "6efe312a02ab07d96f46ab0d9a3513338fc25b160cd7569f99f2e50d1243aaa3", "text": "although their \neffectiveness in clinical trials is mixed.\nOn the basis that Th2 responses reciprocally inhibit the development \nof Th1 diseases, it has also been hypothesised that the comparative absence of Crohn\u2019s disease, as well as some other autoimmune diseases, \nin the developing world may be associated with the high incidence of \nparasite infection, and that the rise of these disorders in the West is associated with superior sanitation and reduced helminth infection! \nThis type of argument is generally known as the \u2018hygiene hypothesis\u2019.\nREFERENCES AND FURTHER READING\nGeneral papers on helminths and their diseases\nBoatin, B.A., Basanez, M.G., Prichard, R.K., et al., 2012. A research \nagenda for helminth diseases of humans: towards control and \nelimination. PLoS Negl. Trop. Dis. 6, e1547. (Discussion of the \noverall strategies that would be required to eliminate helminth \ninfections)\nHorton, J., 2003. Human gastrointestinal helminth infections: are they \nnow neglected diseases? Trends Parasitol. 19, 527\u2013531. (Accessible \nreview on helminth infections and their treatments)\nLustigman, S., Prichard, R.K., Gazzinelli, A., et al., 2012. A research \nagenda for helminth diseases of humans: the problem of \nhelminthiases. PLoS Negl. Trop. Dis. 6, e1582. (Another paper in this \nseries, dealing mainly with the distribution of helminth diseases around the \nworld)\nMcCarty, T.R., Turkeltaub, J.A., Hotez, P.J., 2014. Global progress \ntowards eliminating gastrointestinal helminth infections. Curr. Opin. Gastroenterol. 30, 18\u201324.\nAntihelminthic drugs\nBurkhart, C.N., 2000. Ivermectin: an assessment of its pharmacology, \nmicrobiology and safety. Vet. Hum. Toxicol. 42, 30\u201335. (Useful paper \nthat focuses on ivermectin pharmacology)\nCroft, S.L., 1997. The current status of antiparasite chemotherapy. \nParasitology 114, S3\u2013S15. (Rather dated but provides a comprehensive coverage of many drugs still in current use)\nGeary, T.G., Sangster, N.C., Thompson, D.P., 1999. Frontiers in \nanthelmintic pharmacology. Vet. Parasitol. 84, 275\u2013295. (Thoughtful account of the difficulties associated with drug treatment. A little dated but \nstill relevant)\nGreenberg, R.M., 2005. Are Ca\n2+ channels targets of praziquantel action? \nInt. J. Parasitol. 35, 1\u20139. (Interesting review on praziquantel action)\nPrichard, R., Tait, A., 2001. The role of molecular biology in veterinary \nparasitology. Vet. Parasitol. 98, 169\u2013194. (Excellent review of the application of molecular biology to understanding the problem of drug \nresistance and to the development of new antihelminthic agents)Prichard, R.K., Basanez, M.G., Boatin, B.A., et al., 2012. A research \nagenda for helminth diseases of humans: intervention for control and \nelimination. PLoS Negl. Trop. Dis. 6, e1549. (Another providing a useful \nreview of new antihelminthic drugs)\nRobertson, A.P., Bjorn, H.E., Martin, R.J., 2000. Pyrantel resistance alters \nnematode nicotinic acetylcholine receptor single channel properties. Eur. J. Pharmacol. 394, 1\u20138. (A research paper describing the interactions \nof", "start_char_idx": 3446, "end_char_idx": 6508, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8a032517-cf5c-4cf6-9295-8a643080056a": {"__data__": {"id_": "8a032517-cf5c-4cf6-9295-8a643080056a", "embedding": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a631282f-2472-4aed-b9c0-c303f4f84594", "node_type": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1c6af996405f2268bfdbeff3836d5fd3d888a3d6f87b6911c4a0c9650d976b99"}, "2": {"node_id": "6d05eadc-bb32-4737-b28e-5681e42a2017", "node_type": null, "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6efe312a02ab07d96f46ab0d9a3513338fc25b160cd7569f99f2e50d1243aaa3"}}, "hash": "b2661dee7ff743d9929730f53b2a28e5f6aff6da810ef9793b7d6f473d819f28", "text": "394, 1\u20138. (A research paper describing the interactions \nof praziquantel and levamisole with the nematode nicotinic receptor and a proposed mechanism of drug resistance)\nTimson, D.J., 2016. Metabolic enzymes of helminth parasites: \npotential as drug targets. Curr. Protein Pept. Sci. 17, 280\u2013295. (A paper describing attempts to identify further targets form \nselectively toxic drugs. Describes the advantages and pitfalls of \ncurrent approaches)\nAntihelminthic vaccines\nBassetto, C.C., Amarante, A.F., 2015. Vaccination of sheep and cattle \nagainst haemonchosis. J. Helminthol. 89, 517\u2013525. (Reviews the progress \nand setbacks associated with vaccination against gastrointestinal nematodes \nand the importance of the choice of antigens used)\nHarris, N.L., 2011. Advances in helminth immunology: optimism for \nfuture vaccine design? Trends Parasitol. 27, 288\u2013293. (An easy-to-read paper reviewing the latest advances in helminth vaccine immunology. Some good diagrams)\nLoukas, A., Gaze, S., Mulvenna, J.P., et al., 2011. Vaccinomics for the \nmajor blood feeding helminths of humans. OMICS 15, 567\u2013577. (Describes how parasite genomics and proteomics is assisting in the \nhunt for new vaccine targets in hookworms and schistisomes. A little \ntechnical)\nSciutto, E., Fragoso, G., Hernandez, M., et al., 2013. Development of the \nS3Pvac vaccine against porcine Taenia solium cysticercosis: a historical review. J. Parasitol. 99, 686\u2013692. (Review of a successful experimental \nvaccine. Mainly of interest because of the way that the vaccine was prepared \nusing a mixture of peptides. A little technical)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6515, "end_char_idx": 8600, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f67686df-d7a8-45aa-9b47-7068097b4428": {"__data__": {"id_": "f67686df-d7a8-45aa-9b47-7068097b4428", "embedding": null, "metadata": {"page_label": "721", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87b86fd4-4b2b-425e-8a7c-b425d382c83a", "node_type": null, "metadata": {"page_label": "721", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7650b64c0d040cae4bea28cbcce0e3895f9736d994f5cabcbd8852a7e7b7dc68"}, "3": {"node_id": "db78cd02-06df-4187-ac96-c33f7c408976", "node_type": null, "metadata": {"page_label": "721", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bdb8d2fb3f73b9aa4f47f9118bcb422e89d64eb079d29d74c445d3abc3de6371"}}, "hash": "8649d2a576361e0acd572e69fbe0ef41bc1402ca0b4ca42ea76f70fb3f2852c4", "text": "56 ANTIHElMINTHIC DRUGS\n715Heylen, M., Ruyssers, N.E., Gielis, E.M., et al., 2014. Of worms, mice \nand man: an overview of experimental and clinical helminth-based \ntherapy for inflammatory bowel disease. Pharmacol. Ther. 143, \n153\u2013167. ( Good overview of the whole area of \u2018helminth therapy\u2019 and easy to \nfollow. Recommended )\nMcNeilly, T.N., Nisbet, A.J., 2014. Immune modulation by helminth \nparasites of ruminants: implications for vaccine development and host \nimmune competence. Parasite 21, 51. ( The authors highlight evidence \nsuggesting that helminth infections can affect the ability of cattle to control \nother disease as well as interfering with vaccination campaigns )\nPeon, A.N., Terrazas, L.I., 2016. Immune-regulatory mechanisms of \nclassical and experimental multiple sclerosis drugs: a special focus on \nhelminth-derived treatments. Curr. Med. Chem. 23, 1152\u20131170. \n(Reviews the immunomodulatory action of many drug treatments for MS \nand compares the action of helminth-derived immunomodulators. Includes a \nsubstantial amount of information about the immunology of MS )\nSummers, R.W., Elliott, D.E., Urban, J.F., Jr., Thompson, R., Weinstock, \nJ.V., 2005a. Trichuris suis therapy in Crohn\u2019s disease. Gut 54, 87\u201390. \n(This paper and the one below, by the same authors, describe the action of \ntherapeutic whipworm administration in small scale trials of Crohn\u2019s and \nulcerative colitis. Interesting reading )\nSummers, R.W., Elliott, D.E., Urban, J.F., Jr., Thompson, R.A., \nWeinstock, J.V., 2005b. Trichuris suis therapy for active ulcerative \ncolitis: a randomized controlled trial. Gastroenterology 128, 825\u2013832.Immune evasion by helminths and therapeutic exploitation\nApiwattanakul, N., Thomas, P.G., Iverson, A.R., McCullers, J.A., 2014. \nChronic helminth infections impair pneumococcal vaccine responses. \nVaccine 32, 5405\u20135410. ( The title is pretty explanatory )\nBenzel, F., Erdur, H., Kohler, S., et al., 2012. Immune monitoring \nof Trichuris suis egg therapy in multiple sclerosis patients. \nJ. Helminthol. 86, 339\u2013347. ( An interesting account of a small study \nwith MS patients describing how whipworm eggs modulated their \nimmunological profile )\nDuthaler, U., Sayasone, S., Vanobbergen, F., et al., 2016. \nSingle-ascending-dose pharmacokinetic study of tribendimidine in \nopisthorchis viverrini-infected patients. Antimicrob. Agents \nChemother. 60, 5705\u20135715. ( Deals with the development of a new drug for \ntreatment of opisthorchiasis, a parasitic disease caught from undercooked fish \nin SE Asia. Mainly pharmaceutical in tone )\nElias, D., Akuffo, H., Britton, S., 2006. Helminths could influence the \noutcome of vaccines against TB in the tropics. Parasite Immunol. 28, \n507\u2013513. ( Easy-to-read introduction to this phenomenon for those who want \nto follow up this topic )\nHarnett, W., 2014. Secretory products of helminth parasites as \nimmunomodulators. Mol. Biochem. Parasitol. 195, 130\u2013136. ( An \ninteresting account of the isolation and identification of immunomodulatory \nproducts secreted by helminths and how these caould be used to", "start_char_idx": 0, "end_char_idx": 3082, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "db78cd02-06df-4187-ac96-c33f7c408976": {"__data__": {"id_": "db78cd02-06df-4187-ac96-c33f7c408976", "embedding": null, "metadata": {"page_label": "721", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "87b86fd4-4b2b-425e-8a7c-b425d382c83a", "node_type": null, "metadata": {"page_label": "721", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7650b64c0d040cae4bea28cbcce0e3895f9736d994f5cabcbd8852a7e7b7dc68"}, "2": {"node_id": "f67686df-d7a8-45aa-9b47-7068097b4428", "node_type": null, "metadata": {"page_label": "721", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8649d2a576361e0acd572e69fbe0ef41bc1402ca0b4ca42ea76f70fb3f2852c4"}}, "hash": "bdb8d2fb3f73b9aa4f47f9118bcb422e89d64eb079d29d74c445d3abc3de6371", "text": "\nproducts secreted by helminths and how these caould be used to treat \ngastrointestinal diseases )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3019, "end_char_idx": 3596, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a26bb304-112c-40ee-aaf0-207adf6b3353": {"__data__": {"id_": "a26bb304-112c-40ee-aaf0-207adf6b3353", "embedding": null, "metadata": {"page_label": "722", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1b709d07-214c-4bc2-a9da-87497010940c", "node_type": null, "metadata": {"page_label": "722", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d270745a518e801859cf158fa4b97e5788bf11882e1a023dfa400c61d398be01"}, "3": {"node_id": "c0c75989-17bf-4f35-8b68-5ab5f275e90b", "node_type": null, "metadata": {"page_label": "722", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a052b8928d9c95de960f60ef35e05595224dd10be143e05558a0cba82f2ae3d2"}}, "hash": "3276762a6f0adc6c035610bc014d62d869d320a0c0073a0dc4d94874ada8ecb4", "text": "716\nOVERVIEW\nCancer is one of the great challenges for pharmacol -\nogy. A wealth of new drugs have been brought onto \nthe market, due in part to the often terminal nature \nof the disease and the willingness of a sufferer to try a novel treatment in the hope of extending their \nlife. Many of the toxicities associated with cancer \ntreatments are tolerated in the hope of a cure. Com -\npanies continually strive to improve cancer drug \neffectiveness without increasing toxicity, resulting in \na range of new anticancer therapies that have evolved and improved over recent decades. In this chapter, \nwe consider cancer in general and anticancer drug \ntherapy. We discuss first the pathogenesis of cancer and then describe the drugs that can be used to treat \nmalignant disease. Finally, we consider the extent to \nwhich our new knowledge of cancer biology is leading to new therapies.\nINTRODUCTION\n\u2018Cancer\u2019 is characterised by uncontrolled multiplication \nand spread of abnormal forms of the body\u2019s own cells. It \nis second only to cardiovascular disease as cause of death \nin developed nations and one in every two people born after 1960 will be diagnosed with some form of cancer \nduring their lifetime. According to Cancer Research UK \n(2016), over 356,000 new cases were reported in the United Kingdom in 2014 and mortality was in excess of 163,000 \n(global figure, 8.8 million). Cancer is responsible for \napproximately 30% of all deaths in the United Kingdom. Lung and bowel cancer are the commonest malignancies, closely followed by breast and prostate cancer. Statistics \nfrom most other countries in the developed world tell much \nthe same story.\nA comparison of the incidence of cancer over the past \n100 years or so gives the impression that the disease is increasing in developed countries, but this is not so. Cancer occurs mainly in later life and, with advances in public \nhealth and medical science, many more people now live \nto an age where malignancy is common.\n1The terms cancer, malignancy and malignant tumour are \noften used synonymously.2 Both benign and malignant \ntumours manifest uncontrolled proliferation, but the latter \nare distinguished by their capacity for de-differentiation , their \ninvasiveness and their ability to metastasise (spread to other \nparts of the body). The appearance of these abnormal characteristics reflects altered patterns of gene expression \nin the cancer cells, resulting from inherited or acquired mutations.\nThere are three main approaches to treating established \ncancer \u2013 surgical excision , irradiation and drug therapy (previ -\nously often called chemotherapy, but now often including \nhormonal and biological agents as described below and in \nChs 5 and 36) \u2013 and the relative value of each of these \napproaches depends on the disease and the stage of its development. Drug therapy may be used on its own or as \nan adjunct to other forms of therapy.\nCompared with that of bacterial diseases, cancer \nchemotherapy presents a difficult conceptual problem. Microorganisms differ qualitatively from human cells \n(see Ch. 51), but cancer cells and normal cells are so similar in most respects that it is more difficult to find \ngeneral, exploitable, biochemical differences between them. \nConventional cytotoxic drugs act on all cells and rely on a \nsmall margin of selectivity to be useful as anticancer agents, \nbut the scope of cancer therapy has now broadened to \ninclude drugs that affect either the hormonal regulation of tumour growth, or the defective cell cycle controls that \nunderlie malignancy (see Ch. 6 and Weinberg et al., 1996; \nCroce, 2008). Numerous biopharmaceuticals including monoclonal antibodies (see Ch. 5), as well as other novel \nimmunomodulators, have transformed the chemotherapeutic \nlandscape.\nTHE PATHOGENESIS OF CANCER\nIt is important to consider the pathobiology in more detail \nto understand how anticancer drugs work and may be \nimproved on in", "start_char_idx": 0, "end_char_idx": 3940, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c0c75989-17bf-4f35-8b68-5ab5f275e90b": {"__data__": {"id_": "c0c75989-17bf-4f35-8b68-5ab5f275e90b", "embedding": null, "metadata": {"page_label": "722", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1b709d07-214c-4bc2-a9da-87497010940c", "node_type": null, "metadata": {"page_label": "722", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d270745a518e801859cf158fa4b97e5788bf11882e1a023dfa400c61d398be01"}, "2": {"node_id": "a26bb304-112c-40ee-aaf0-207adf6b3353", "node_type": null, "metadata": {"page_label": "722", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3276762a6f0adc6c035610bc014d62d869d320a0c0073a0dc4d94874ada8ecb4"}}, "hash": "a052b8928d9c95de960f60ef35e05595224dd10be143e05558a0cba82f2ae3d2", "text": "more detail \nto understand how anticancer drugs work and may be \nimproved on in future.\nCancer cells manifest, to varying degrees, four charac-\nteristics that distinguish them from normal cells. These are\n\u2022\tUncontrolled proliferation\n\u2022\tDe-differentiation and loss of function\n\u2022\tInvasiveness\n\u2022\tMetastasisAnticancer drugs57 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER SECTION 5\n1Cancer in general is a disease of older age \u2013 you have to be around \nlong enough for all the mutations to accumulate in a cell and create a \ncancer phenotype that escapes the body\u2019s immune surveillance system. \nClinical oncologists are gradually improving their treatment. Their goal is to keep you alive long enough so that you die of something other \nthan cancer: a measure of their success.2Blood cell malignancies \u2013 lymphomas and leukaemias \u2013 are non \ntumour-forming, and at times not referred to as cancers. Along with myelomas, they are generally classed as \u2018blood cancers\u2019. In this account, \n\u2018cancer\u2019 is used to cover all malignancy types.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3861, "end_char_idx": 5373, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f80ecce0-a5cc-4c80-b9e7-cae8ec9a3151": {"__data__": {"id_": "f80ecce0-a5cc-4c80-b9e7-cae8ec9a3151", "embedding": null, "metadata": {"page_label": "723", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d4d457bd-59d0-47f5-9357-66dbd081d633", "node_type": null, "metadata": {"page_label": "723", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f34ea8113e15ed2af2aae7163cd5985d76512efec04da77e983f34ea03b2bb20"}, "3": {"node_id": "a49c275b-dc76-4275-a9f9-4440a0976e13", "node_type": null, "metadata": {"page_label": "723", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "de088df90ec6e8debefad25e795d818f6e2e6f8c624eedae0117eac8a08f30a7"}}, "hash": "ebd14fe7609726a8a1679a788cbed7c0f66d733213548e5072158ef617ab390e", "text": "57 ANTICANCER DRUGS\n717\u2022\ttelomerase expression;\n\u2022\tlocal blood supply, resulting from tumour-directed \nangiogenesis.\nPotentially all the genes coding for the above components \ncould be regarded as oncogenes or tumour suppressor genes (Fig. 57.2), although not all are equally prone to malignant transformation and malignant transformation of several \ncomponents is needed for the development of cancer.\nResistance to apoptosis\nApoptosis is programmed cell death (Ch. 6), and mutations \nin antiapoptotic genes are usually a prerequisite for cancer; \nindeed, resistance to apoptosis is a hallmark of malignant \ndisease. It can be brought about by inactivation of proap -\noptotic factors or by activation of antiapoptotic factors.\nTelomerase expression\nTelomeres are specialised structures that cap the ends of chromosomes \u2013 like the small metal tubes on the end of \nshoelaces \u2013 protecting them from degradation, rearrange -\nment and fusion with other chromosomes. Furthermore, \nDNA polymerase cannot easily duplicate the last few \nnucleotides at the ends of DNA, and telomeres prevent \nloss of these \u2018end\u2019 genes. With each round of cell division, a portion of the telomere is eroded, so that eventually it \nbecomes non-functional. At this point, DNA replication \nceases and the cell becomes senescent.\n3\nHealthy stem cells express telomerase, a terminal transferase \nenzyme that maintains and elongates telomere ends. While \nit is absent from most fully differentiated somatic cells, \nabout 95% of late-stage malignant tumours express telom -\nerase enzymes to continuously rebuild the telomere end \nand extend the cell\u2019s replicative ability, thus elongating \nthe telomere ends and effectively conferring \u2018immortality\u2019 \non cancer cells (see Buys, 2000; Keith et al., 2004).\nThe control of tumour-related blood vessels\nThe factors described above lead to the uncontrolled proliferation of individual cancer cells, but other factors, \nparticularly blood supply, determine the actual growth of \na solid tumour. Tumours 1\u20132 mm in diameter can obtain \nnutrients by diffusion, but their further expansion requires \nangiogenesis, the development of new blood vessels in \nresponse to growth factors produced by the growing tumour \nitself (see Griffioen & Molema, 2000).\nDE-DIFFERENTIATION AND LOSS OF FUNCTION\nThe multiplication of normal cells in a tissue begins with division of the undifferentiated stem cells giving rise to \ntwo daughter cells, one of which differentiates to become \na mature non-dividing cell, ready to perform functions \nappropriate to that differentiated tissue. One of the main THE GENESIS OF A CANCER CELL\nA normal cell turns into a cancer cell because of one or, more often, several mutations in its DNA. These can be \ninherited or acquired, usually through exposure to viruses \nor carcinogens (e.g. tobacco products, ultraviolet radiation, \nasbestos). A good example is breast cancer; women who \ninherit a single defective copy of either of the tumour \nsuppressor genes BRCA1 and BRCA2 have a significantly increased risk of developing breast cancer. However, car -\ncinogenesis is a complex multistage process, usually involving more than one genetic change as well as other, epigenetic factors (hormonal, co-carcinogen and tumour \npromoter effects \u2013 see later) that do not themselves produce \ncancer but which increase the likelihood that the genetic \nmutation(s) will eventually result in cancer. These mutations \naccumulate and lead to \u2018genomic instability\u2019, which is a \nhallmark of carcinogenesis.\nThere are two main categories of relevant genetic change:\n1. The activation of proto-oncogenes to oncogenes.", "start_char_idx": 0, "end_char_idx": 3630, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "a49c275b-dc76-4275-a9f9-4440a0976e13": {"__data__": {"id_": "a49c275b-dc76-4275-a9f9-4440a0976e13", "embedding": null, "metadata": {"page_label": "723", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d4d457bd-59d0-47f5-9357-66dbd081d633", "node_type": null, "metadata": {"page_label": "723", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f34ea8113e15ed2af2aae7163cd5985d76512efec04da77e983f34ea03b2bb20"}, "2": {"node_id": "f80ecce0-a5cc-4c80-b9e7-cae8ec9a3151", "node_type": null, "metadata": {"page_label": "723", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ebd14fe7609726a8a1679a788cbed7c0f66d733213548e5072158ef617ab390e"}}, "hash": "de088df90ec6e8debefad25e795d818f6e2e6f8c624eedae0117eac8a08f30a7", "text": "The activation of proto-oncogenes to oncogenes. \nProto-oncogenes are genes that normally control cell division, apoptosis and differentiation (see Ch. 6), but \nwhich can be converted by viruses or carcinogens to oncogenes that induce malignant change.\n2. The inactivation of tumour suppressor genes. \nNormal cells contain genes that suppress \nmalignant change \u2013 termed tumour suppressor \ngenes (anti-oncogenes) \u2013 and mutations of these genes are commonly involved in many different cancers. \nThe loss of function of tumour suppressor genes can \nbe the critical event in carcinogenesis.\nAbout 30 tumour suppressor genes and 100 dominant \noncogenes have been identified. The changes that lead to \nmalignancy are a result of point mutations, gene amplifica -\ntion or chromosomal translocation (see Hanahan & \nWeinberg, 2011).\nTHE SPECIAL CHARACTERISTICS OF \nCANCER CELLS\nUNCONTROLLED PROLIFERATION\nIt is not generally true that cancer cells proliferate faster \nthan normal cells. Many healthy cells, in the bone marrow \nand the epithelium of the gastrointestinal (GI) tract (for \nexample), undergo continuous rapid division. Some cancer cells multiply slowly (e.g. those in plasma cell tumours) and \nsome much more rapidly (e.g. the cells of Burkitt\u2019s lymphoma ). \nThe significant issue is that cancer cells have escaped from the \nmechanisms that normally regulate cell division and tissue growth; the normal brakes on cell division, present in a healthy cell, have \nbeen cut. It is this, rather than their rate of proliferation, that distinguishes them from normal cells.\nWhat are the changes that lead to the uncontrolled \nproliferation of tumour cells? Inactivation of tumour sup -\npressor genes or transformation of proto-oncogenes into oncogenes can confer autonomy of growth on a cell and \nthus result in uncontrolled proliferation by producing \nchanges in cellular systems (Fig. 57.1), including:\n\u2022\tgrowth factors, their receptors and signalling pathways;\n\u2022\tthe\tcell cycle transducers, for example, cyclins, \ncyclin-dependent kinases (cdks) or the cdk inhibitors;\n\u2022\tthe\tapoptotic machinery that normally disposes of \nabnormal cells;3Once eroded down, telomere ends signal cells to stop replicating \nforever, which is why we humans have a limited life-span. Cancer cells \nhowever express telomerases to constantly build upon the telomere-\nend, and as such have lost this \u2018end replication\u2019 signal to limit their lifetime \u2013 some cancer cell lines have been replicating in the laboratory \nfor many decades. The entire weight of an individual tumour line \ngrown in all laboratories worldwide, means that the original single cancer cell has now amassed many, many tonnes of itself in total \n\u2013 much heavier than the individual tumour it was derived from. The \npatient may have mouldered in the grave, but their cancer cells go marching on \u2013 theoretically forever!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3583, "end_char_idx": 6926, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9605d696-9027-4e5c-9c3a-4d186adaf51d": {"__data__": {"id_": "9605d696-9027-4e5c-9c3a-4d186adaf51d", "embedding": null, "metadata": {"page_label": "724", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "19b60a1c-de6e-416e-8895-8029a8b41a1b", "node_type": null, "metadata": {"page_label": "724", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e96f298ac63cf36b27ba51bdfd300868e3b9ae70b0b0978ea579e32d6a610944"}, "3": {"node_id": "3ed5c8d8-122b-44b2-9dee-6e68d58d19cd", "node_type": null, "metadata": {"page_label": "724", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "24889cdcfb506abca489ec26b61e2dab42bb7d8c0e141e53176cc7eaf10cdf63"}}, "hash": "0b11c2e8e9d4f0155fc4e6de5a50c4b6702f5b1700bb5c28b43d889518ef212f", "text": "57 SECTION 5 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n718METASTASIS\nMetastases are secondary tumours (\u2018secondaries\u2019) formed by \ncells that have been released from the initial or primary \ntumour and which have reached other sites through blood \nvessels or lymphatics, by transportation on other cells or as a result of being shed into body cavities. Often, the \nprimary tumour is asymptomatic and it is not until the \ncancer spreads that the secondary tumours cause symptoms leading to diagnosis of illness. As such, metastases are the \nprincipal cause of mortality and morbidity in most solid \ntumours and constitute a major problem for cancer therapy\n4 \n(see Chambers et al., 2002).\nAs discussed earlier, displacement or aberrant migration \nof normal cells would lead to programmed cell death as a \nresult of withdrawal of the necessary antiapoptotic factors. \nCancer cells that metastasise have undergone a series of characteristics of cancer cells is that they de-differentiate to varying degrees. In general, poorly differentiated \ncancers carry a worse prognosis than well-differentiated \ncancers.\nINVASIVENESS\nNormal cells, other than those of the blood and lymphoid \ntissues, are not generally found outside their \u2018designated\u2019 \ntissue of origin. This is because, during differentiation and \ntissue or organ growth, they develop certain spatial relation -\nships with respect to each other. These relationships are \nmaintained by various tissue-specific survival factors that \nprevent apoptosis (see Ch. 6). In this way, any cells that escape accidentally lose these survival signals and die.\nFor example, whilst the cells of the normal mucosal \nepithelium of the rectum proliferate continuously as the lining is shed, they remain as a lining epithelium. A cancer of the rectal mucosa, in contrast, invades other surrounding \ntissues. Cancer cells have not only lost, through mutation, \nthe restraints that act on normal cells, but also secrete enzymes (e.g. metalloproteinases; see Ch. 6) that break \ndown the extracellular matrix, enabling them to move \naround.Growth factors\nGrowth factor\nreceptors\nPLASMA MEMBRANE\nAdapter proteinsRas\nGTP Kinase 1\nKinase 2\nKinase 3Cytosolic\ntransducers\nNuclear\ntransducers\nCell cycle\ntransducersNUCLEUS\nEarly response genes\nDelayed reponse\ngenes\nPositive regulators \nof the cell cycle:\u2022 cyclins\n\u2022 cyclin-dependent kinases (cdks)Negative regulators \nof the cell cycle:\n\u2022 p53 protein\n\u2022 Rb protein\n\u2022 cdk inhibitorsCYTOSOL\nMutation of the delayed response nuclear proto-oncogenes...can alter expression of the regulators of the cell cycle, e.g. more than 50% of human tumours have mutations of the tumour supressor gene that \ncodes for p53 proteinc-jun/c-fos\nc-mycTranscription\nfactors\n(Jun, Fos, Myc)Colorectal\nLung, neural tissueProto-\noncogeneProto-oncogene\nproductsCancer Anticancer\ndrugs\nGenes for\ngrowth factors\ne.g. for IGFGrowth factors\ne.g. IGFProstate, breast\ncolorectal, etc.Research in\nprogress\nGene for\nEGF receptors\n(e.g. c-erbB)Her2*\n(a receptor\ntyrosine kinase)Breast Inhibited by\ntrastuzumab\n(aka Herceptin)\nGene for\nPDGF\n(c-sis)PDGF\n(a receptor\ntyrosine kinase)Chronic myeloid\nleukaemiaInhibited by\nimatinib\n(aka Glivec)\nc-ras Ras proteins 30% of\nall tumoursRas inhibitors\nin clinical", "start_char_idx": 0, "end_char_idx": 3261, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3ed5c8d8-122b-44b2-9dee-6e68d58d19cd": {"__data__": {"id_": "3ed5c8d8-122b-44b2-9dee-6e68d58d19cd", "embedding": null, "metadata": {"page_label": "724", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "19b60a1c-de6e-416e-8895-8029a8b41a1b", "node_type": null, "metadata": {"page_label": "724", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e96f298ac63cf36b27ba51bdfd300868e3b9ae70b0b0978ea579e32d6a610944"}, "2": {"node_id": "9605d696-9027-4e5c-9c3a-4d186adaf51d", "node_type": null, "metadata": {"page_label": "724", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0b11c2e8e9d4f0155fc4e6de5a50c4b6702f5b1700bb5c28b43d889518ef212f"}}, "hash": "24889cdcfb506abca489ec26b61e2dab42bb7d8c0e141e53176cc7eaf10cdf63", "text": "proteins 30% of\nall tumoursRas inhibitors\nin clinical trial\nabl Abl tyrosine\nkinase\n(cytoplasmic)Chronic myeloid\nleukaemiaInhibited by\nimatinib\n(aka Glivec)\nLeukaemiasc-src\nGenes for\nJAK, LckCytoplasmic\ntyrosine\nkinaseBreast, pancreas,\nbone\nResearch in\nprogress\nFig. 57.1 Signal transduction pathways initiated by growth factors and their relationship to cancer development. A few examples \nof proto-oncogenes and the products they code for are given in the table, with examples of the cancers that are associated with their \nconversion to oncogenes. Many growth factor receptors are receptor tyrosine kinases, the cytosolic transducers including adapter proteins that bind to phosphorylated tyrosine residues in the receptors. Ras proteins are guanine nucleotide-binding proteins and have GTPase action; decreased GTPase action means that Ras remains activated. EGF, epidermal growth factor; IGF, insulin-like growth factor; PDGF, \nplatelet-derived growth factor. *Her2 is also termed her2/neu. \n4Although not widely accepted, there is a school of thought that \nmaintaining the primary tumour\u2019s integrity and stopping it spreading \nwould prolong life in the cancer sufferer. It may seem anathema to \nnurture a tumour to keep it happy and avoid stressing it, to prevent any metastatic behaviour.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3208, "end_char_idx": 4984, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "58b564f2-4d82-4e6e-b541-33669933a6c3": {"__data__": {"id_": "58b564f2-4d82-4e6e-b541-33669933a6c3", "embedding": null, "metadata": {"page_label": "725", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3d576bd2-1e23-46ba-bc20-904c5ce866ed", "node_type": null, "metadata": {"page_label": "725", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c2869ec7359c01f9c0a1fd26a0fd4d2e4e054cf82e0336aecd4922ea73837ea9"}, "3": {"node_id": "78ba5ebf-ce29-4a69-a124-fbbe33f352bf", "node_type": null, "metadata": {"page_label": "725", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "21c79977359320bd93d3463b0dd41ee7517f8ad2cba8fe3c66fdfef30e36a18f"}}, "hash": "0507a7d71ace96dfde36f93085e8a379d304e4fc1ac7844243251fb7707e1a87", "text": "57 ANTICANCER DRUGS\n719GENERAL PRINCIPLES OF CYTOTOXIC \nANTICANCER DRUGS\nIn experiments with rapidly growing transplantable leu -\nkaemias in mice, it has been found that a given therapeutic \ndose of a cytotoxic drug5 destroys a constant fraction of \nthe malignant cells. If used to treat a tumour with 1011 cells, \na dose of drug that kills 99.99% of cells will still leave 10 million (10\n7) viable malignant cells. As the same principle \nholds for fast-growing tumours in humans, schedules for chemotherapy are aimed at producing as near a total cell \nkill as possible because, in contrast to the situation that occurs in microorganisms, little reliance can be placed on \nthe host\u2019s immunological defence mechanisms against the \nremaining cancer cells. If a tumour is removed (or at least de-bulked) surgically, any remaining micro-metastases are \nnow more accessible to chemotherapy, hence its use as adjuvant therapy in these circumstances.\nOne of the major difficulties in treating cancer is that \ntumour growth is usually far advanced before cancer is \ndiagnosed. Let us suppose that a tumour arises from a single \ncell and that the growth is exponential, as it may well be during the initial stages. \u2018Doubling\u2019 times vary, being, for \nexample, approximately 24 h with Burkitt\u2019s lymphoma, 2 \nweeks in the case of some leukaemias, and 3 months with mammary cancers. Approximately 30 doublings would be \nrequired to produce a cell mass with a diameter of 2 cm, \ncontaining 109 cells. Such a tumour is within the limits of \ndiagnostic procedures, although it could easily go unnoticed. \nA further 10 doublings would produce 1012 cells, a tumour \nmass that is likely to be lethal, and which would measure \nabout 20 cm in diameter if it were one solid mass.\nHowever, continuous exponential growth of this sort \ndoes not usually occur. In the case of most solid tumours, as opposed to leukaemias (tumours of white blood cells), \nthe growth rate falls as the neoplasm grows. This is partly because the tumour outgrows its blood supply, and partly \nbecause not all the cells proliferate continuously. The cells \nof a solid tumour can be considered as belonging to three compartments:\n1. Compartment A consists of dividing cells, possibly being continuously in the cell cycle.\n2. Compartment B consists of resting cells (G 0 phase) which, \nalthough not dividing, are potentially able to do so.\n3. Compartment C consists of cells that are no longer able to divide but which contribute to the tumour volume.\nEssentially, only cells in compartment A, which may form \nas little as 5% of some solid tumours, are susceptible to \nthe main current cytotoxic drugs. The cells in compartment \nC do not constitute a problem, but the existence of compart -\nment B makes cancer chemotherapy difficult, because these \ncells are not very sensitive to cytotoxic drugs and are liable \nto re-enter compartment A following chemotherapy.\nBenign tumours can still grow (often more slowly) but are \ncharacteristically unable to metastasise and spread, and are thus considered much less dangerous to the individual. One \nexample of such is basal cell carcinoma (BCC) skin cancer genetic changes that alter their responses to the regulatory factors that control the cellular architecture of normal tissues, \nenabling them to establish themselves \u2018extraterritorially\u2019. \nTumour-induced growth of new blood vessels locally favours metastasis.\nSecondary tumours occur more frequently in some \ntissues than in others. For example, metastases of mammary cancers are often found in brain, lung, bone and", "start_char_idx": 0, "end_char_idx": 3575, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "78ba5ebf-ce29-4a69-a124-fbbe33f352bf": {"__data__": {"id_": "78ba5ebf-ce29-4a69-a124-fbbe33f352bf", "embedding": null, "metadata": {"page_label": "725", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3d576bd2-1e23-46ba-bc20-904c5ce866ed", "node_type": null, "metadata": {"page_label": "725", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c2869ec7359c01f9c0a1fd26a0fd4d2e4e054cf82e0336aecd4922ea73837ea9"}, "2": {"node_id": "58b564f2-4d82-4e6e-b541-33669933a6c3", "node_type": null, "metadata": {"page_label": "725", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0507a7d71ace96dfde36f93085e8a379d304e4fc1ac7844243251fb7707e1a87"}}, "hash": "21c79977359320bd93d3463b0dd41ee7517f8ad2cba8fe3c66fdfef30e36a18f", "text": "metastases of mammary cancers are often found in brain, lung, bone and liver. The \nreason for this is that breast cancer cells express chemokine \nreceptors such as CXCR4 (see Ch. 19) on their surfaces, and chemokines that recognise these receptors are expressed at \nhigh level in these tissues but not in others (e.g. kidney), \nfacilitating the selective accumulation of cells at these sites, providing a microenvironmental niche for them to reside \nand thrive. Similarly, lung cancer most commonly spreads \nto brain, bone and adrenal gland; malignant melanoma to brain; colorectal and ovarian tumours most commonly \nspread to liver and pancreatic cancer typically to liver \nand lung.Other factorsAltered gene expression\nProto-oncogenes \nOncogenes\nsis, erbB, ras, myc, \ngene for cyclin D, etc.Decreased expression \nof tumour suppressor \ngenes: p53, Rb1, etc.Chemicals, viruses,\nirradiation, etc.\nAcquired mutations Inherited mutations\nUncontrolled cell proliferation,\nde-differentiationDecreased apoptosis,\nalterations in telomerase\nProduction of metalloproteinases, etc.\nInvasion of nearby tissue by tumour cells\nAngiogenesis\nMetastasis\nDevelopment of secondary tumoursDevelopment of primary tumour\nFig. 57.2 Simplified outline of the genesis of cancer. The \ndiagram summarises the information given in the text. The \ngenesis of cancer is usually multifactorial, involving more than one genetic change. \u2018Other factors\u2019, as specified above, may involve the actions of promoters, co-carcinogens, hormones, etc. which, while not themselves carcinogenic, increase the likelihood that genetic mutation(s) will result in cancer. \n5The term cytotoxic drug applies to any drug that can damage or kill \ncells. In practice, it is used more restrictively to refer to drugs that \ninhibit cell division and are therefore potentially useful in cancer \nchemotherapy.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3505, "end_char_idx": 5855, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "db22eb19-def8-43c4-93c4-8c31cfa0a7cb": {"__data__": {"id_": "db22eb19-def8-43c4-93c4-8c31cfa0a7cb", "embedding": null, "metadata": {"page_label": "726", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "68d942ed-693b-4ba8-9531-f50cced531fe", "node_type": null, "metadata": {"page_label": "726", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eead33d08e1769b26202fe7184e9b16c51da0269c9a564a5c00e59ccda463dd5"}, "3": {"node_id": "b45fdf29-0a38-4bb3-943f-7ed8d392d341", "node_type": null, "metadata": {"page_label": "726", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9d33fd2ae750baa7659258e9d9772710a35bb9ffc1f1de00801fcaa2ada9ed3b"}}, "hash": "d2a21385ad62f1ea7a23182c712cb31fa44300bffd6da951e5b5fa45175c9fb7", "text": "57 SECTION 5 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n720\u2022\tantimetabolites, which block or subvert one or more \nof the metabolic pathways involved in DNA \nsynthesis;\n\u2022\tcytotoxic antibiotics, i.e. substances of microbial \norigin that prevent mammalian cell division;\n\u2022\tplant derivatives (e.g. vinca alkaloids, taxanes, camptothecins): most of these specifically affect microtubule function and hence the formation of the \nmitotic spindle.\n\u2022\tHormones, especially steroids and their antagonists \n(Chs 34 and 36).\n\u2022\tProtein kinase inhibitors which inhibit growth factor \nreceptor signal transduction (see Krause & van Etten, \n2005) and other non-proliferative effects of tyrosine kinases, such as cell adhesion.\n\u2022\tMonoclonal antibodies.\n\u2022\tMiscellaneous agents.\nThe clinical use of anticancer drugs is the province of the specialist, who selects treatment regimens appropriate to the patient with the objective of curing, prolonging life or \nproviding palliative therapy.\n6 There are over 80 drugs \navailable in the United Kingdom for this purpose and they are often used in combination. The principal treatments \nare listed in Table 57.1. For reasons of space, we restrict our discussion of mechanisms of action to common examples \nfrom each group. A textbook (Airley, 2009) provides detailed \ninformation.which continues to expand but will not metastasise; unlike malignant melanoma skin cancer, which readily metastasises \nto threaten critical organs, such as the brain. BCC still has the \npotential to transform from its benign form into a malignant form, and kill. Conversely, malignant tumours may senesce \nto become benign. Either way, it is always prudent to remove \nbenign tumours in case they develop into a malignant form and gain any potential to metastasise.\nMost current anticancer drugs, particularly cytotoxic \nagents, affect only one characteristic aspect of cancer cell biology \u2013 cell division \u2013 but have no specific inhibitory effect on invasiveness, the loss of differentiation or the \ntendency to metastasise. In many cases, the antiproliferative \naction results from an action during S phase of the cell cycle, and the resultant damage to DNA initiates apoptosis. \nFurthermore, because their main target is cell division, they \nwill affect all rapidly dividing normal tissues, and therefore are likely to produce, to a greater or lesser extent, the \nfollowing general toxic effects:\n\u2022\tbone marrow toxicity (myelosuppression) with \ndecreased leukocyte production and thus decreased \nresistance to infection;\n\u2022\timpaired wound healing;\n\u2022\tloss of hair (alopecia);\n\u2022\tdamage \tto \tGI \tepithelium (including oral mucous \nmembranes);\n\u2022\tdepression of growth in children;\n\u2022\tsterility;\n\u2022\tteratogenicity;\n\u2022\tcarcinogenicity \u2013 because many cytotoxic drugs are mutagens.\nRapid cell destruction also entails extensive purine catabo -\nlism, and urates may precipitate in the renal tubules and cause kidney damage. Finally, in addition to specific toxic effects associated with individual drugs, virtually all \ncytotoxic drugs produce severe nausea and vomiting, an \n\u2018inbuilt deterrent\u2019 now thankfully largely overcome by modern antiemetic drug prophylaxis (Ch. 31).\nCytotoxic drugs, along with surgery and radiotherapy, \nremain the mainstay of cancer treatment, but newer treat -\nments based on targeting the specific malfunctions of cell \ncycle control that characterise cancer cells, and on increasing \ntheir susceptibility to immunological attack, are becoming increasingly important. These include hormone antagonists, \nkinase inhibitors and", "start_char_idx": 0, "end_char_idx": 3562, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b45fdf29-0a38-4bb3-943f-7ed8d392d341": {"__data__": {"id_": "b45fdf29-0a38-4bb3-943f-7ed8d392d341", "embedding": null, "metadata": {"page_label": "726", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "68d942ed-693b-4ba8-9531-f50cced531fe", "node_type": null, "metadata": {"page_label": "726", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eead33d08e1769b26202fe7184e9b16c51da0269c9a564a5c00e59ccda463dd5"}, "2": {"node_id": "db22eb19-def8-43c4-93c4-8c31cfa0a7cb", "node_type": null, "metadata": {"page_label": "726", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d2a21385ad62f1ea7a23182c712cb31fa44300bffd6da951e5b5fa45175c9fb7"}}, "hash": "9d33fd2ae750baa7659258e9d9772710a35bb9ffc1f1de00801fcaa2ada9ed3b", "text": "increasingly important. These include hormone antagonists, \nkinase inhibitors and monoclonal antibodies \u2013 drugs that \nare not cytotoxic in the conventional sense, and have a different range of side effects. Described later, they herald \na significant shift in pharmacological approaches to cancer \ntreatment. Often these newer types of therapy are guided by the genomic profile of the cancer they target \u2013 a principle \nthat is coming more and more into reality for most drugs \naimed at treating cancer.\nANTICANCER DRUGS\nThe main anticancer drugs can be divided into the following general categories:\n\u2022\tCytotoxic drugs. These include:\n\u2022\talkylating agents and related compounds, which act \nby forming covalent bonds with DNA and thus \nimpeding replication;Cancer pathogenesis and cancer \nchemotherapy: general principles \n\u2022\tCancer\tarises \tas \ta \tresult \tof \ta \tseries \tof \tgenetic \tand \t\nepigenetic changes, the main genetic lesions being:\n\u2013 inactivation of tumour suppressor genes;\n\u2013 the activation of oncogenes (mutation of the normal \ngenes controlling cell division and other processes).\n\u2022\tCancer\tcells \thave \tfour \tcharacteristics \tthat \tdistinguish \t\nthem from normal cells:\n\u2013 uncontrolled proliferation;\n\u2013 loss of function because of lack of capacity to \ndifferentiate;\n\u2013 invasiveness;\n\u2013 the ability to metastasise.\n\u2022\tCancer\tcells \thave \tuncontrolled \tproliferation \toften \t\nbecause of changes in:\n\u2013 growth factors and/or their receptors;\n\u2013 intracellular signalling pathways, particularly those \ncontrolling the cell cycle and apoptosis;\n\u2013 telomerase expression.\n\u2022\tProliferation \tmay \tbe \tsupported \tby \ttumour-related \t\nangiogenesis.\n\u2022\tMost\tanticancer \tdrugs \tare \tantiproliferative \t\u2013 \tmost \t\ndamage DNA and thereby initiate apoptosis. They also \naffect rapidly dividing normal cells and are thus likely to depress bone marrow, impair healing and depress \ngrowth. Most cause nausea, vomiting, sterility, hair \nloss and teratogenicity.\n6You will have gathered that many anticancer drugs are toxic. \u2018To be an \noncologist,\u2019 one practitioner commented, \u2018one has to hate cancer more \nthan one loves life.\u2019mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3481, "end_char_idx": 6067, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "914697c4-feb7-4bcb-9f42-cd5445f3d6c4": {"__data__": {"id_": "914697c4-feb7-4bcb-9f42-cd5445f3d6c4", "embedding": null, "metadata": {"page_label": "727", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a5ff1d49-6663-4608-8c83-898dfd1798d3", "node_type": null, "metadata": {"page_label": "727", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cd95dc107dc99bb17a19cf692822fd033a94a1e24954fa07be33e05351bde1ee"}, "3": {"node_id": "8e50b7c7-b7b6-4798-b90b-b0edb7c4f81d", "node_type": null, "metadata": {"page_label": "727", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5f643c3fd51492a1f5c3a9f0c1cddb3f531ba4f949fcd559f6df7779d4567a31"}}, "hash": "fb6bbc5c11857acc0998a38e2eb985af92ce2be9d1dd43e13713442786600507", "text": "57 ANTICANCER DRUGS\n721Table 57.1 An overview of anticancer drugs\nType Group Examples Main mechanism\nAlkylating, and \nrelated, agentsNitrogen mustardsBendamustine, chlorambucil, cyclophosphamide, estramustine,\na ifosfamide, melphalan\nIntrastrand cross-linking of DNANitrosoureas Carmustine, lomustine\nPlatinum compounds Carboplatin, cisplatin, oxaliplatin\nOtherBusulfan, dacarbazine, hydroxycarbamide, mitobronitol, procarbazine treosulfan, thiotepa, temozolomide\nAntimetabolitesFolate antagonists Methotrexate, pemetrexed, raltitrexed\nBlocking the synthesis of DNA and/or RNAPyrimidine pathwayAzacitidine, capecitabine, cytarabine, decitabine, fluorouracil gemcitabine, tegafur\nPurine pathwayCladribine, clofarabine, fludarabine, mercaptopurine, nelarabine, pentostatin, tioguanine\nCytotoxic antibioticsAnthracyclines(Amsacrine), daunorubicin, doxorubicin, epirubicin, idarubicin, (mitoxantrone)Multiple effects on DNA/RNA synthesis and topoisomerase actionOther Bleomycin, dactinomycin, mitomycin, trabectedin\nPlant derivatives and similar compoundsTaxanes Cabazitaxel, docetaxel, paclitaxel\nMicrotubule assembly; prevents spindle formationVinca alkaloidsVinblastine, vincristine, vindesine, vinflunine, vinorelbine (eribulin).\nCampothecins Irinotecan, topotecan\nInhibition of topoisomerase\nOther Etoposide\nHormones/antagonistsHormones/analoguesBuserelin, diethylstilboestrol, ethinyloestradiol, goserelin, histrelin, lanreotide, leuprorelin, medroxyprogesterone, megesterol, norhisterone, triptorelin, octreotide, pasreotideAct as physiological agonists, antagonists or hormone synthesis inhibitors to disrupt hormone-dependent tumour growthAntagonistsBicalutamide, cyproterone, degarelix, flutamide, fulvestrant, mitotane, tamoxifen, toremifene\nAromatase inhibitors Anastrozole, exemastine, letrozole\nProtein kinase inhibitorsTyrosine, or other kinase, inhibitorsAcalabrutinib, axitinib, crizotinib, dasatinib, erlotinib, gefitinib, ibrutinib, imatinib, lapatinib, nilotinib, pazopanib, ponatinib, ruxolitinib, sunitinib, vandetanib, vemurafenibInhibition of kinases involved in growth factor receptor transduction\nPan-kinase inhibitors Everolimus, sorafenib, temsirolimus\nMonoclonal antibodiesAnti-EGF, EGF-2 Panitumumab, trastuzumab Blocks cell proliferation\nAnti-CD20/CD30/ CD52 Brentuximab, ofatumumab, rituximabInhibition of lymphocyte proliferation\nAnti-CD3/EpCAM CatumaxomabBinds adhesion molecules promoting cell killing\nAnti-PD-1/PD-L1 or CTLA4Nivolumab, pembrolizumab, atezolizumab, ipilimumabImmune checkpoint inhibitors that prevent immune cell suppression\nAnti-VEGF Bevacizumab Prevents angiogenesis\nMiscellaneousRetinoid X receptor antagonistBexaroteneInhibits cell proliferation and differentiation\nProteasome inhibitor BortezomibActivation of programmed cell", "start_char_idx": 0, "end_char_idx": 2780, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8e50b7c7-b7b6-4798-b90b-b0edb7c4f81d": {"__data__": {"id_": "8e50b7c7-b7b6-4798-b90b-b0edb7c4f81d", "embedding": null, "metadata": {"page_label": "727", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a5ff1d49-6663-4608-8c83-898dfd1798d3", "node_type": null, "metadata": {"page_label": "727", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cd95dc107dc99bb17a19cf692822fd033a94a1e24954fa07be33e05351bde1ee"}, "2": {"node_id": "914697c4-feb7-4bcb-9f42-cd5445f3d6c4", "node_type": null, "metadata": {"page_label": "727", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb6bbc5c11857acc0998a38e2eb985af92ce2be9d1dd43e13713442786600507"}}, "hash": "5f643c3fd51492a1f5c3a9f0c1cddb3f531ba4f949fcd559f6df7779d4567a31", "text": "inhibitor BortezomibActivation of programmed cell death\nEnzyme Cristantaspase Depletes asparagine\nPhotoactivated cytotoxicsPorfimer, temoporfinAccumulate in cells and kills them when activated by light\naA combination of oestrogen and chlormethine. Drugs in parentheses have similar pharmacological actions but are not necessarily \nchemically related.CD, cluster of differentiation; EGF, epidermal growth factor; EpCAM,\n epithelial cell adhesion molecule; PD, programmed cell death protein; \nVEGF, vascular endothelial growth factor.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2731, "end_char_idx": 3742, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7b4cb45e-362f-48a2-8df6-f54bac92e4a0": {"__data__": {"id_": "7b4cb45e-362f-48a2-8df6-f54bac92e4a0", "embedding": null, "metadata": {"page_label": "728", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a959d420-0663-4941-aa64-a03f9fb6a83b", "node_type": null, "metadata": {"page_label": "728", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f02ae14f4a73a6a81c0e9972289e4d2d08dbe4dd0ba9d5046b38dc39a3604fb"}, "3": {"node_id": "68317455-5165-472d-8a8a-416e549755e6", "node_type": null, "metadata": {"page_label": "728", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "138445a8dffc9aa54fd587c58aeb1c1b456e08874770464d37d5cad6ecf68706"}}, "hash": "664a95c12c35039356f38217a7b769230fa4306c4b16ccaded0832e7b9333cbb", "text": "57 SECTION 5 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n722(R-N -bis-[2-chloroethyl]) is shown in Fig. 57.4. In the body, \neach 2-chloroethyl side-chain undergoes an intramolecular \ncyclisation with the release of a Cl\u2212. The highly reactive \nethylene immonium derivative so formed can interact with DNA (see Figs 57.3 and 57.4) and other molecules.\nCyclophosphamide is probably the most commonly used \nalkylating agent. It is inactive until metabolised in the liver by the P450 mixed function oxidases (see Ch. 10). It has a \npronounced effect on lymphocytes and can also be used as an immunosuppressant (see Ch. 27). It is given orally \nor by intravenous injection. Important toxic effects are \nnausea and vomiting, bone marrow depression and haemor -\nrhagic cystitis. This last effect (which also occurs with the related drug ifosfamide ) is caused by the metabolite acrolein \nand can be ameliorated by increasing fluid intake and administering compounds that are sulfhydryl donors, such as N-acetylcysteine or mesna (sodium-2-mercaptoethane \nsulfonate). These agents react with acrolein, forming a non-toxic compound. (See also Chs 10 and 58.)\n\u25bc Other nitrogen mustards used include bendamustine , ifosfamide, \nchlorambucil and melphalan. Estramustine is a combination of \nchlormethine (mustine) with an oestrogen. It has both cytotoxic and \nhormonal action, and is used for the treatment of prostate cancer.ALKYLATING AGENTS AND RELATED \nCOMPOUNDS\nAlkylating agents and related compounds contain chemical \ngroups that can form covalent bonds with particular \nnucleophilic substances in the cell (such as DNA). With \nalkylating agents themselves, the first step is the formation of a carbonium ion \u2013 a carbon atom with only six electrons \nin its outer shell. Such ions are highly reactive and react instantaneously with an electron donor such as an amine, hydroxyl or sulfhydryl group. Most of the cytotoxic anti -\ncancer alkylating agents are bifunctional, i.e. they have two \nalkylating groups (Fig. 57.3).\n\u25bc The nitrogen at position 7 (N7) of guanine, being strongly nucleo -\nphilic, is probably the main molecular target for alkylation in DNA \n(see Fig. 57.3), although N1 and N3 of adenine and N3 of cytosine \nmay also be affected. A bifunctional agent, by reacting with two groups, can cause intra- or inter-chain cross-linking. This interferes \nnot only with transcription, but also with DNA replication, which is \nprobably the critical effect of anticancer alkylating agents.\nAll alkylating agents depress bone marrow function and \ncause hair loss and diarrhoea. Depression of gametogenesis, \nleading to sterility, and an increased risk of a second \nmalignancy occur with prolonged use.\nAlkylating agents are among the most commonly \nemployed of all anticancer drugs. Only a few commonly used examples will be dealt with here.\nNitrogen mustards\nNitrogen mustards are related to the \u2018mustard gas\u2019 used during the First World War,\n7 their basic formula AT\nCG\nCG\nTA\nCG\nGCSugar\u2013phosphate backbone\nBifunctional \nalkylating agents \ncan cause \nintrastrand linking \nand cross-linking\nFig. 57.3 The effects of bifunctional alkylating agents on \nDNA. Note the cross-linking of two guanines. A, adenine; C, \ncytosine; G, guanine; T, thymine. NCH2CH2Cl\nCH2CH2ClR", "start_char_idx": 0, "end_char_idx": 3280, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "68317455-5165-472d-8a8a-416e549755e6": {"__data__": {"id_": "68317455-5165-472d-8a8a-416e549755e6", "embedding": null, "metadata": {"page_label": "728", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "a959d420-0663-4941-aa64-a03f9fb6a83b", "node_type": null, "metadata": {"page_label": "728", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3f02ae14f4a73a6a81c0e9972289e4d2d08dbe4dd0ba9d5046b38dc39a3604fb"}, "2": {"node_id": "7b4cb45e-362f-48a2-8df6-f54bac92e4a0", "node_type": null, "metadata": {"page_label": "728", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "664a95c12c35039356f38217a7b769230fa4306c4b16ccaded0832e7b9333cbb"}}, "hash": "138445a8dffc9aa54fd587c58aeb1c1b456e08874770464d37d5cad6ecf68706", "text": "T, thymine. NCH2CH2Cl\nCH2CH2ClR NCH2\nCH2\nCH2CH2ClR\nNCH2\nH2C\nCH2CH2ClRO\nNH2 NN\nNNH+\nDNA chain\nN\nClCH2CH2R\nDNA chainCH2CH2 O\nNH2 NN\nNNHCl\u2212\n(1)\n(3)(2)\nLoss of the second\nCl\u2212 in a further set of\nreactions gives a\ncross-link\nFig. 57.4 An example of alkylation and cross-linking of \nDNA by a nitrogen mustard. A bis(chloroethyl)amine (1) \nundergoes intramolecular cyclisation, forming an unstable \nethylene immonium cation (2)\tand\treleasing \tCl\u2212, the tertiary \namine being transformed to a quaternary ammonium compound. The strained ring of the ethylene immonium intermediate opens to form a reactive carbonium ion (in yellow box) (3) , which reacts \nimmediately with N7 of guanine (in green circle) to give \n7-alkylguanine (bond shown in blue) , the N7 being converted to \na quaternary ammonium nitrogen. These reactions can then be \nrepeated\twith \tthe \tother \t\u2013CH 2CH 2Cl\tto\tgive\ta \tcross-link. \t\n7It was the clinical insight of Alfred Goodman and Louis Gilman that led \nto the testing of (what became the first effective anticancer drug) mustine, \na modified and stable version of \u2018mustard gas\u2019, to treat lymphomas. They \nalso wrote what was to become a famous textbook of pharmacology.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3249, "end_char_idx": 4913, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "513659ad-dcca-4aee-93b3-7fb2bc75de6f": {"__data__": {"id_": "513659ad-dcca-4aee-93b3-7fb2bc75de6f", "embedding": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "aa9917eb-d28d-441d-92c2-161a2c2fafdf", "node_type": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bf542c1b6433befbb63303194c2d2ceb6cac0f82032e63710da40c5ef72a7818"}, "3": {"node_id": "73ba7301-3bd9-4a73-a8f5-9d4101196808", "node_type": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a4d26d80b1bdb505855c1b2064bd96b49ea591c1266a8f1825e8b84e9641150e"}}, "hash": "797e02415f5bd5878a2f09a8d119541012435a02845c33684eca6e4b56f387ce", "text": "57 ANTICANCER DRUGS\n723turn are essential for DNA synthesis and cell division. (This \ntopic is also dealt with in Chs 26, 51 and 55.) The main \naction of the folate antagonists is to interfere with thymi -\ndylate synthesis. Folates consist of three elements: a pteridine \nring, p-aminobenzoic acid and glutamic acid; methotrexate \nis structurally closely related (Fig. 57.5). Its effect on thy -\nmidylate synthesis is summarised in Fig. 57.6.\nMethotrexate is usually given orally but can also be given \nintramuscularly, intravenously or intrathecally. It has low lipid solubility and thus does not readily cross the blood\u2013brain barrier. It is, however, actively taken up into cells by the folate transport system and is metabolised to polyglu -\ntamate derivatives, which are retained in the cell for weeks or months even in the absence of extracellular drug. Resistance to methotrexate may develop in tumour cells \nby a variety of mechanisms.\nUnwanted effects include depression of the bone marrow \nand damage to the epithelium of the GI tract. Pneumonitis can occur. In addition, high-dose regimens \u2013 doses 10 times \ngreater than the standard doses, sometimes used in patients with methotrexate resistance \u2013 can lead to nephrotoxicity. \nThis is caused by precipitation of the drug or a metabolite \nin the renal tubules. High-dose regimens must be followed by \u2018rescue\u2019 with folinic acid (a form of FH\n4).\nAlso chemically related to folate are raltitrexed, which \ninhibits thymidylate synthetase, and pemetrexed, which \ninhibits thymidylate transferase.\nPyrimidine analogues\nFluorouracil, an analogue of uracil, also interferes with 2\u2032-deoxythymidylate (dTMP) synthesis (see Fig. 57.6). It is \nconverted into a \u2018fraudulent\u2019 nucleotide, fluorodeoxyuridine \nmonophosphate (FdUMP). This interacts with thymidylate Nitrosoureas\nExamples include lomustine and carmustine. As they are \nlipid soluble and cross the blood\u2013brain barrier, they are \nused to treat tumours of the brain and meninges. However, \nmost nitrosoureas have a severe cumulative depressive effect on the bone marrow that starts 3\u20136 weeks after initia -\ntion of treatment.\nOther alkylating agents\nBusulfan has a selective effect on the bone marrow, depress-ing the formation of granulocytes and platelets in low dosage \nand of red cells in higher dosage. It has little or no effect \non lymphoid tissue or the GI tract. It is used in chronic granulocytic leukaemia.\nDacarbazine, a prodrug, is activated in the liver, and \nthe resulting compound is subsequently cleaved in the target cell to release an alkylating derivative. Unwanted \neffects include myelotoxicity and severe nausea and vomit -\ning. Temozolomide is a related compound with a restricted \nusage (malignant glioma).\nProcarbazine inhibits DNA and RNA synthesis and \ninterferes with mitosis at interphase. Its effects may be \nmediated by the production of active metabolites. It is given orally, and its main use is in Hodgkin\u2019s disease. It causes \ndisulfiram -like actions with alcohol (see Ch. 50), exacerbates \nthe effects of central nervous system depressants and, \nbecause it is a weak monoamine oxidase inhibitor, can \nproduce hypertension if given with certain sympathomimetic \nagents (see Ch. 48). Other alkylating agents in clinical use include hydroxycarbamide, mitobronitol, thiotepa and", "start_char_idx": 0, "end_char_idx": 3321, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "73ba7301-3bd9-4a73-a8f5-9d4101196808": {"__data__": {"id_": "73ba7301-3bd9-4a73-a8f5-9d4101196808", "embedding": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "aa9917eb-d28d-441d-92c2-161a2c2fafdf", "node_type": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bf542c1b6433befbb63303194c2d2ceb6cac0f82032e63710da40c5ef72a7818"}, "2": {"node_id": "513659ad-dcca-4aee-93b3-7fb2bc75de6f", "node_type": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "797e02415f5bd5878a2f09a8d119541012435a02845c33684eca6e4b56f387ce"}, "3": {"node_id": "9fb8bd80-998e-4229-94e4-1cdd819f2cb0", "node_type": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "831a05c5164236268cc89895be52fa18d96288b421b5fe7e046668030dfc1ceb"}}, "hash": "a4d26d80b1bdb505855c1b2064bd96b49ea591c1266a8f1825e8b84e9641150e", "text": "agents in clinical use include hydroxycarbamide, mitobronitol, thiotepa and \ntreosulfan.\nPlatinum compounds\nCisplatin is a water-soluble planar coordination complex containing a central platinum atom surrounded by two \nchlorine atoms and two ammonia groups. Its action is \nanalogous to that of the alkylating agents. When it enters the cell, Cl\n\u2013 dissociates, leaving a reactive complex that \nreacts with water and then interacts with DNA. It causes \nintrastrand cross-linking, probably between N7 and O6 of \nadjacent guanine molecules, which results in local denatura -\ntion of DNA.\nCisplatin has revolutionised the treatment of solid \ntumours of the testes and ovary. Therapeutically, it is given by slow intravenous injection or infusion. It is seriously \nnephrotoxic, and strict regimens of hydration and diuresis \nmust be instituted. It has low myelotoxicity but causes very severe nausea and vomiting. The 5-HT\n3 receptor antagonists \n(e.g. ondansetron ; see Chs 16, 31 and 40) are very effective \nin preventing this and have transformed cisplatin-based chemotherapy. Tinnitus and hearing loss in the high-frequency range may occur, as may peripheral neuropathies, \nhyperuricaemia and anaphylactic reactions.\n\u25bc Carboplatin is a derivative of cisplatin. Because it causes less \nnephrotoxicity, neurotoxicity, ototoxicity, nausea and vomiting than \ncisplatin (although it is more myelotoxic), it is sometimes given on \nan outpatient basis. Oxaliplatin is another platinum-containing compound with a restricted application.\nANTIMETABOLITES\nFolate antagonists\nThe main folate antagonist in cancer chemotherapy is \nmethotrexate (see also Ch. 27 for its use as an immunosup -\npressant in rheumatology). Folates are essential for the synthesis of purine nucleotides and thymidylate, which in Anticancer drugs: alkylating agents \nand related compounds \n\u2022\tAlkylating \tagents \thave \tgroups \tthat \tform \tcovalent \t\nbonds with cell substituents; a carbonium ion is the \nreactive intermediate. Most have two alkylating groups and can cross-link DNA. This causes defective \nreplication and chain breakage.\n\u2022\tTheir\tprincipal \teffect \toccurs \tduring \tDNA \tsynthesis \tand \t\nthe resulting damage triggers apoptosis.\n\u2022\tUnwanted \teffects \tinclude \tmyelosuppression, \tsterility \t\nand risk of non-lymphocytic leukaemia.\n\u2022\tThe\tmain \talkylating \tagents \tare:\n\u2013 nitrogen mustards, for example \ncyclophosphamide, which is converted to \nphosphoramide mustard (the cytotoxic molecule); cyclophosphamide myelosuppression affects \nparticularly the lymphocytes.\n\u2013 nitrosoureas, for example lomustine, may act on \nnon-dividing cells, can cross the blood\u2013brain barrier \nand cause delayed, cumulative myelotoxicity.\n\u2022\tPlatinum \tcompounds \t(e.g. \tcisplatin) cause intrastrand \nlinking in DNA. Cisplatin has low myelotoxicity but \ncauses severe nausea and vomiting, and can be \nnephrotoxic. It has revolutionised the treatment of \ngerm cell tumours.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3255, "end_char_idx": 6526, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9fb8bd80-998e-4229-94e4-1cdd819f2cb0": {"__data__": {"id_": "9fb8bd80-998e-4229-94e4-1cdd819f2cb0", "embedding": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "aa9917eb-d28d-441d-92c2-161a2c2fafdf", "node_type": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bf542c1b6433befbb63303194c2d2ceb6cac0f82032e63710da40c5ef72a7818"}, "2": {"node_id": "73ba7301-3bd9-4a73-a8f5-9d4101196808", "node_type": null, "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a4d26d80b1bdb505855c1b2064bd96b49ea591c1266a8f1825e8b84e9641150e"}}, "hash": "831a05c5164236268cc89895be52fa18d96288b421b5fe7e046668030dfc1ceb", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6546, "end_char_idx": 6721, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ac68b27f-0582-4904-b3ec-bb99188fedf2": {"__data__": {"id_": "ac68b27f-0582-4904-b3ec-bb99188fedf2", "embedding": null, "metadata": {"page_label": "730", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "84105cb1-2cc1-4ae7-a44c-562a2de806af", "node_type": null, "metadata": {"page_label": "730", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c76fb44304a7a6a752dc5a6d550087c09eceb142e0a2fd709b9e415309d45a1b"}, "3": {"node_id": "106a3097-b438-407c-ad1c-65a18dc3e4fd", "node_type": null, "metadata": {"page_label": "730", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "15accae6d774cdede35d38f0d06739b9391d602b838d48c123ce26b4163841fd"}}, "hash": "74c11736afe27ce97d4b93de563ea81e74029f9ef972241a97bee5a690319601", "text": "57 SECTION 5 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n724drug enters the target cell and undergoes the same phos -\nphorylation reactions as the endogenous nucleoside to give \ncytosine arabinoside trisphosphate, which inhibits DNA \npolymerase (Fig. 57.7). The main unwanted effects are on the bone marrow and the GI tract.\nGemcitabine, an analogue of cytarabine, has fewer \nunwanted actions, the main ones being an influenza-like syndrome and mild myelotoxicity. It is often given in \ncombination with other drugs such as cisplatin. Azacitidine \nand decitabine inhibit DNA methylase.\nPurine analogues\nThe main anticancer purine analogues include cladribine , \nclofarabine , fludarabine , pentostatin , nelarabine , mercap -\ntopurine and tioguanine.\nFludarabine is metabolised to the trisphosphate and \ninhibits DNA synthesis by actions similar to those of cyta -\nrabine. It is myelosuppressive. Pentostatin has a different \nmechanism of action. It inhibits adenosine deaminase, the enzyme that transforms adenosine to inosine. This action \ninterferes with critical pathways in purine metabolism and \ncan have significant effects on cell proliferation. Cladribine, mercaptopurine and tioguanine are used mainly in the treatment of leukaemia.\nCYTOTOXIC ANTIBIOTICS\nThis is a widely used group of drugs that mainly produce their effects through direct action on DNA. As a rule, they \nshould not be given together with radiotherapy, as the \ncumulative burden of toxicity is very high.\nDoxorubicin and the anthracyclines\nDoxorubicin, idarubicin, daunorubicin and epirubicin \nare widely used anthracycline antibiotics; mitoxantrone \n(mitozantrone) is a derivative.\nDoxorubicin has several cytotoxic actions. It binds to \nDNA and inhibits both DNA and RNA synthesis, but its \nmain cytotoxic action appears to be mediated through an \neffect on topoisomerase II (a DNA gyrase; see Ch. 51), the activity of which is markedly increased in proliferating \ncells. During replication of the DNA helix, reversible \nswivelling needs to take place around the replication fork synthetase but cannot be converted into DTMP. The result \nis inhibition of DNA but not RNA or protein synthesis.\nFluorouracil is usually given parenterally. The main \nunwanted effects are GI epithelial damage and myelotoxic -\nity. Cerebellar disturbances can also occur. Two other \ndrugs, capecitabine and tegafur, are metabolised to \nfluorouracil.\nCytarabine (cytosine arabinoside [ara-C]) is an analogue \nof the naturally occurring nucleoside 2 \u2032-deoxycytidine. The Pteridine ring p-Aminobenzoic\nacid (PABA)Glutamyl residues\nN\nN\nNN\nCH2 CO\nnN\nRH2N\nCO\nNH CHCOOH\nCH2CH2 OH\nOH1\n2\n3\n45691 078\nN\nN\nNN\nCH2\nNH2CH3CO\nnNH2N\nCO\nNH CHCOOH\nCH2CH2 OHFolic acid\nMethotrexate\nFig. 57.5 Structure of folic acid and methotrexate. Both compounds are shown as polyglutamates. In tetrahydrofolate, one-carbon \ngroups (R, in orange box) are transported on N5 or N10 or both (shown dotted) . The points at which methotrexate differs from \nendogenous folic acid are", "start_char_idx": 0, "end_char_idx": 3023, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "106a3097-b438-407c-ad1c-65a18dc3e4fd": {"__data__": {"id_": "106a3097-b438-407c-ad1c-65a18dc3e4fd", "embedding": null, "metadata": {"page_label": "730", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "84105cb1-2cc1-4ae7-a44c-562a2de806af", "node_type": null, "metadata": {"page_label": "730", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c76fb44304a7a6a752dc5a6d550087c09eceb142e0a2fd709b9e415309d45a1b"}, "2": {"node_id": "ac68b27f-0582-4904-b3ec-bb99188fedf2", "node_type": null, "metadata": {"page_label": "730", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "74c11736afe27ce97d4b93de563ea81e74029f9ef972241a97bee5a690319601"}}, "hash": "15accae6d774cdede35d38f0d06739b9391d602b838d48c123ce26b4163841fd", "text": ". The points at which methotrexate differs from \nendogenous folic acid are shown in the blue boxes. \nDHFRDHFR\nThymidylate\nsynthetaseF(glu)n FH2(glu)nFH4(glu)n\nFH4(glu)n +\none-carbon unit\ndTMP dUMPMethotrexate\nFluorouracil\nFig. 57.6 Simplified diagram of action of methotrexate \nand fluorouracil on thymidylate synthesis. Tetrahydrofolate \npolyglutamate \tFH4(glu) n functions as a carrier of a one-carbon \nunit, providing the methyl group necessary for the conversion of \n2\u2032-deoxyuridylate \t(dUMP) \tto \t2\u2032-deoxythymidylate (dTMP) by \nthymidylate synthetase. This one-carbon transfer results in the \noxidation\tof \tFH4(glu) n\tto\tFH2(glu) n. Fluorouracil is converted to \nFdUMP,\twhich \tinhibits \tthymidylate \tsynthetase. \tDHFR, \ndihydrofolate reductase. mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2949, "end_char_idx": 4180, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d5ba6433-4c54-43de-b00a-68a1b891fc92": {"__data__": {"id_": "d5ba6433-4c54-43de-b00a-68a1b891fc92", "embedding": null, "metadata": {"page_label": "731", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2743d383-507a-4ff0-a7b8-8f8ebdf28f64", "node_type": null, "metadata": {"page_label": "731", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8e101fa894b12eb3465aae4be6775612a71e4244577cd31f84eac8ed27cad45"}, "3": {"node_id": "d84fcd63-b58d-4dd6-a414-3f6f31ab19b5", "node_type": null, "metadata": {"page_label": "731", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "094070a8d231157776d7cd2b19127571fd36aa3ebcac9014ec12680005725a9a"}}, "hash": "2322e500de2111b36ed6772fdfc8ecb02d2934d74942ecaf9c4f1a117d486223", "text": "57 ANTICANCER DRUGS\n725and heart failure. This action may be the result of generation \nof free radicals. Marked hair loss frequently occurs.\nDactinomycin\nDactinomycin intercalates in the minor groove of DNA \nbetween adjacent guanosine\u2013cytosine pairs, interfering with \nthe movement of RNA polymerase along the gene and \nthus preventing transcription. There is also evidence that \nit has a similar action to that of the anthracyclines on \ntopoisomerase II. It produces most of the toxic effects \noutlined previously, except cardiotoxicity. It is mainly used \nfor treating paediatric cancers.\nBleomycins\nThe bleomycins are a group of metal-chelating glycopep -\ntide antibiotics that degrade preformed DNA, causing \nchain fragmentation and release of free bases. This \naction is thought to involve chelation of ferrous iron and \ninteraction with oxygen, resulting in the oxidation of \nthe iron and generation of superoxide and/or hydroxyl \nradicals. Bleomycin is most effective in the G 2 phase of \nthe cell cycle and mitosis, but it is also active against \nnon-dividing cells (i.e. cells in the G 0 phase; Ch. 6, Fig. \n6.4). It is often used to treat germline cancer. In contrast \nto most anticancer drugs, bleomycin causes little myelo -\nsuppression: its most serious toxic effect is pulmonary \nfibrosis, which occurs in 10% of patients treated and is \nreported to be fatal in 1%. Allergic reactions can also occur. \nAbout half the patients manifest mucocutaneous reactions \n(the palms are frequently affected), and many develop \nhyperpyrexia.\nMitomycin\nFollowing enzymic activation, mitomycin functions as \na bifunctional alkylating agent, binding preferentially \nat O6 of the guanine nucleus. It cross-links DNA and \nmay also degrade DNA through the generation of free \nradicals. It causes marked delayed myelosuppression \nand can also cause kidney damage and fibrosis of lung \ntissue.\nin order to prevent the daughter DNA molecule becoming \ninextricably entangled during mitotic segregation. The \n\u2018swivel\u2019 is produced by topoisomerase II, which \u2018nicks\u2019 \nboth DNA strands and subsequently reseals the breaks. \nDoxorubicin intercalates in the DNA, and its effect is, in \nessence, to stabilise the DNA\u2013topoisomerase II complex \nafter the strands have been nicked, thus halting the process \nat this point.\nDoxorubicin is given by intravenous infusion. Extravasa -\ntion at the injection site can cause local necrosis. In addition \nto the general unwanted effects, the drug can cause cumula -\ntive, dose-related cardiac damage, leading to dysrhythmias DNA polymerase\nPPS SP S P S P S PCTGA\nGA TSS P\nSS P S P S PCTGA\nGASS P\nCS PP PPS\nCIncoming \ndeoxyribonucleoside \ntrisphosphate\nTemplate\nCytarabine\nFig. 57.7 The mechanism of action of cytarabine (cytosine \narabinoside). For details of DNA polymerase action, see Fig. \n51.5.\tCytarabine\t is\tan\tanalogue\t of\tcytosine.\t\nAnticancer drugs: antimetabolites \nAntimetabolites block or subvert pathways of DNA \nsynthesis.\n\u2022\tFolate antagonists . Methotrexate inhibits \ndihydrofolate reductase, preventing generation of \ntetrahydrofolate interfering with thymidylate synthesis.\n\u2022\tPyrimidine analogues . Fluorouracil is converted to a \n\u2018fraudulent\u2019 nucleotide and inhibits thymidylate \nsynthesis.", "start_char_idx": 0, "end_char_idx": 3240, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "d84fcd63-b58d-4dd6-a414-3f6f31ab19b5": {"__data__": {"id_": "d84fcd63-b58d-4dd6-a414-3f6f31ab19b5", "embedding": null, "metadata": {"page_label": "731", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "2743d383-507a-4ff0-a7b8-8f8ebdf28f64", "node_type": null, "metadata": {"page_label": "731", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8e101fa894b12eb3465aae4be6775612a71e4244577cd31f84eac8ed27cad45"}, "2": {"node_id": "d5ba6433-4c54-43de-b00a-68a1b891fc92", "node_type": null, "metadata": {"page_label": "731", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2322e500de2111b36ed6772fdfc8ecb02d2934d74942ecaf9c4f1a117d486223"}}, "hash": "094070a8d231157776d7cd2b19127571fd36aa3ebcac9014ec12680005725a9a", "text": "nucleotide and inhibits thymidylate \nsynthesis. Cytarabine in its trisphosphate form inhibits \nDNA polymerase. They are potent myelosuppressives.\n\u2022\tPurine analogues . Mercaptopurine is converted into \nfraudulent nucleotide. Fludarabine in its trisphosphate \nform inhibits DNA polymerase and is \nmyelosuppressive. Pentostatin inhibits adenosine \ndeaminase \u2013 a critical pathway in purine metabolism.Anticancer drugs: cytotoxic \nantibiotics \n\u2022\tDoxorubicin inhibits DNA and RNA synthesis; the \nDNA effect is mainly through interference with \ntopoisomerase\t II\taction.\tUnwanted\t effects\tinclude\t\nnausea, vomiting, myelosuppression and hair loss. It is \ncardiotoxic in high doses.\n\u2022\tBleomycin causes fragmentation of DNA chains. It \nacts\ton\tnon-dividing\t cells.\tUnwanted\t effects\tinclude\t\nfever, allergies, mucocutaneous reactions and \npulmonary fibrosis. There is virtually no \nmyelosuppression.\n\u2022\tDactinomycin intercalates in DNA, interfering with \nRNA polymerase and inhibiting transcription. It also \ninterferes with the action of topoisomerase II. \nUnwanted\t effects\tinclude\tnausea,\tvomiting\tand\t\nmyelosuppression.\n\u2022\tMitomycin is activated to give an alkylating \nmetabolite.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3193, "end_char_idx": 4853, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "470a863d-392c-4d15-816f-043b02eae415": {"__data__": {"id_": "470a863d-392c-4d15-816f-043b02eae415", "embedding": null, "metadata": {"page_label": "732", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ef361d66-cb3c-4c63-b4e9-36e1e79922cd", "node_type": null, "metadata": {"page_label": "732", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f2446bb794b61416863252851200a0182656aa9312386a26c115f656149e2805"}, "3": {"node_id": "dac65288-bc46-4672-a1bd-2072ab0eee86", "node_type": null, "metadata": {"page_label": "732", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8689ce26c7700ab9a6f44a136f2ca2b193bce84447621cdbfd8d361ba81f0d5c"}}, "hash": "52ea532839d4806b6be8a7f6b2fe8f12a7ed6e066ecd90ea00942f935622c099", "text": "57 SECTION 5 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n726HORMONES\nTumours arising in hormone-sensitive tissues (e.g. breast, \nuterus, prostate gland) may be hormone-dependent , an effect \nrelated to the presence of hormone receptors in the malig -\nnant cells, gauged by the receptors present in screened \nbiopsy samples. Their growth can be inhibited by hormone \nagonists or antagonists, or by agents that inhibit the synthesis \nof the hormone.\nHormones or their analogues that have inhibitory actions \non target tissues can be used in treatment of tumours of \nthose tissues. Such procedures alone rarely effect a cure \nbut do retard tumour growth and mitigate the symptoms \nof the cancer, and thus play an important part in the clinical \nmanagement of sex hormone-dependent tumours.\nGlucocorticoids\nGlucocorticoids such as prednisolone have marked inhibi -\ntory effects on lymphocyte proliferation (see Chs 27 and \n34) and are used in the treatment of leukaemias and \nlymphomas. The ability of dexamethasone to lower raised \nintracranial pressure is exploited in treating patients with \nbrain tumours. Glucocorticoids mitigate some of the side \neffects of anticancer drugs, such as nausea and vomiting, \nmaking them useful as supportive therapy when treating \nother cancers, as well as in palliative care.\nOestrogens\nDiethylstilboestrol and ethinyloestradiol are still occasion -\nally used in the palliative treatment of androgen-dependent \nprostatic tumours. These tumours can also be treated with \ngonadotrophin-releasing hormone analogues (see Ch. 34).\nProgestogens\nProgestogens such as megestrol , norehisterone and \nmedroxyprogesterone have a role in treatment of endo -\nmetrial cancer.\nGonadotrophin-releasing hormone analogues\nAs explained in Chapter 36, analogues of the gonadotrophin-\nreleasing hormones, such as goserelin , buserelin , leuprore -\nlin and triptorelin , can, when administered chronically, \ninhibit gonadotrophin release. These agents are therefore \nused to treat advanced breast cancer in premenopausal \nwomen and prostate cancer. The effect of the transient surge \nof testosterone secretion that can occur in patients treated PLANT DERIVATIVES\nSeveral naturally occurring plant products exert potent \ncytotoxic effects and have a use as anticancer drugs.\nVinca alkaloids\nThe vinca alkaloids are derived from the Madagascar \nperiwinkle ( Catharanthus roseus ). The principal members \nof the group are vincristine , vinblastine and vindesine . \nVinflunine , a fluorinated vinca alkaloid, and vinorelbine \nare semisynthetic vinca alkaloids with similar properties. \nThe drugs bind to tubulin and inhibit its polymerisation \ninto microtubules, preventing spindle formation in dividing \ncells and causing arrest at metaphase. Their effects become \nmanifest only during mitosis. They also inhibit other cellular \nactivities that require functioning microtubules, such as \nleukocyte phagocytosis and chemotaxis, as well as axonal \ntransport in neurons.\nThe adverse effects of vinca alkaloids differ from other \nanticancer drugs. Vincristine has very mild myelosuppres -\nsive activity but is neurotoxic and commonly causes par-\naesthesia (sensory changes), abdominal pain and weakness. \nVinblastine is less neurotoxic but causes leukopenia, while \nvindesine has both moderate myelotoxicity and neurotoxic -\nity. All members of the", "start_char_idx": 0, "end_char_idx": 3374, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dac65288-bc46-4672-a1bd-2072ab0eee86": {"__data__": {"id_": "dac65288-bc46-4672-a1bd-2072ab0eee86", "embedding": null, "metadata": {"page_label": "732", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ef361d66-cb3c-4c63-b4e9-36e1e79922cd", "node_type": null, "metadata": {"page_label": "732", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f2446bb794b61416863252851200a0182656aa9312386a26c115f656149e2805"}, "2": {"node_id": "470a863d-392c-4d15-816f-043b02eae415", "node_type": null, "metadata": {"page_label": "732", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "52ea532839d4806b6be8a7f6b2fe8f12a7ed6e066ecd90ea00942f935622c099"}}, "hash": "8689ce26c7700ab9a6f44a136f2ca2b193bce84447621cdbfd8d361ba81f0d5c", "text": "has both moderate myelotoxicity and neurotoxic -\nity. All members of the group can cause reversible hair loss.\nPaclitaxel and related compounds\nThese taxanes are derived from a naturally occurring \ncompound found in the bark of the Pacific yew tree ( Taxus \nspp.). The group includes paclitaxel and the semisynthetic \nderivatives docetaxel and cabazitaxel . These agents act on \nmicrotubules, stabilising them (in effect \u2018freezing\u2019 them) \nin the polymerised state, achieving a similar effect to that \nof the vinca alkaloids. These drugs are usually given by \nintravenous infusion. They are generally used to treat breast \nand lung cancer and paclitaxel, given with carboplatin, is \nthe treatment of choice for ovarian cancer.\nUnwanted effects , which can be serious, include bone \nmarrow suppression and cumulative neurotoxicity. Resistant \nfluid retention (particularly oedema of the legs) can occur \nwith docetaxel. Hypersensitivity to these compounds is \ncommon and requires pretreatment with corticosteroids \nand antihistamines.\nCamptothecins\nThe camptothecins irinotecan and topotecan , isolated from \nthe stem of the tree Camptotheca acuminata , bind to and \ninhibit topoisomerase I, high levels of which are present \nthroughout the cell cycle. Diarrhoea and reversible bone \nmarrow depression occur but, in general, these alkaloids \nhave fewer unwanted effects than most other anticancer \nagents.\nEtoposide\nEtoposide is derived from mandrake root ( Podophyllum \npeltatum ). Its mode of action is not clearly known, but it \nmay act by inhibiting mitochondrial function and nucleoside \ntransport, as well as having an effect on topoisomerase II \nsimilar to doxorubicin. Unwanted effects include nausea and \nvomiting, myelosuppression and hair loss.\n\u25bc Compounds from marine sponges. Eribulin is a naturally occurring \ncompound from marine sponges. Its main inhibitory action on cell \ndivision is through inhibition of microtubule function. Trabectedin , \nanother compound derived from marine sponges, also disrupts DNA \nbut utilises a superoxide-related mechanism.Anticancer drugs: plant derivatives \n\u2022\tVincristine (and related alkaloids) inhibit mitosis at \nmetaphase by binding to tubulin. It is relatively \nnon-toxic but can cause unwanted neuromuscular \neffects.\n\u2022\tEtoposide inhibits DNA synthesis by an action on \ntopoisomerase II and also inhibits mitochondrial \nfunction.\tCommon\t unwanted\t effects\tinclude\tvomiting,\t\nmyelosuppression and alopecia.\n\u2022\tPaclitaxel (and other taxanes) stabilise microtubules, \ninhibiting mitosis; it is relatively toxic and \nhypersensitivity reactions occur.\n\u2022\tIrinotecan and topotecan inhibit topoisomerase I; \nThey have relatively few toxic effects.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3302, "end_char_idx": 6485, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f41caaa6-dbf1-43d4-af30-e15d8b6442c4": {"__data__": {"id_": "f41caaa6-dbf1-43d4-af30-e15d8b6442c4", "embedding": null, "metadata": {"page_label": "733", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "49187293-8812-4194-aadf-3e1e851372e6", "node_type": null, "metadata": {"page_label": "733", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "966f0ea42d5a2582eab78b4b2e078903edda44608f40bf8a4c236ec0aff8ddcf"}, "3": {"node_id": "14286f08-d675-4be5-92de-0c97abc355cf", "node_type": null, "metadata": {"page_label": "733", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "58dc93599dbd8a46a0b776342811e5f357169f8671d111871bc7f8962595c2ea"}}, "hash": "768f95f137485b3e48bec98b81a4b7c1295d6ca35c5f18ecdcfb8b939a87e7b9", "text": "57 ANTICANCER DRUGS\n727This advantage is offset in most instances as they are often \ngiven in combination with more traditional drugs. Several \nmonoclonals are in current clinical use. Their high cost is \na significant problem.\nRituximab\nRituximab is a monoclonal antibody that is used (in combination with other chemotherapeutic agents) for \ntreatment of certain types of lymphoma, including non-\nHodgkin\u2019s lymphoma. It lyses B lymphocytes by binding \nto the calcium-channel forming CD20 protein and activating \ncomplement. It also sensitises resistant cells to other \nchemotherapeutic drugs. It provides progression-free survival in 40%\u201350% of cases when combined with standard \nchemotherapy (R-CHOP; rituximab\u2013cyclophosphamide, \nhydroxydaunorubicin [doxorubicin], oncovin [vincristine] plus prednisolone).\nThe drug is given by infusion, and its plasma half-life \nis approximately 3 days when first given, increasing \nwith each administration to about 8 days by the fourth administration.\nUnwanted effects include hypotension, chills and fever \nduring the initial infusions and subsequent hypersensitivity reactions. A cytokine release reaction can occur and has been \nfatal. The drug may exacerbate cardiovascular disorders.\n\u25bc Alemtuzumab is another monoclonal antibody that lyses B \nlymphocytes, and is used in the treatment of resistant chronic lym -\nphocytic leukaemia. It may also cause a similar cytokine release reaction \nto that with rituximab. Ofatumumab is similar. Brentuximab addition -\nally targets T cells but in a different manner. It is a conjugate of a \ncytotoxic drug attached to an antibody that binds to CD30 on malignant \ncells. It is used to treat Hodgkin\u2019s lymphoma.\nTrastuzumab\nTrastuzumab (Herceptin) is a humanised murine mono-\nclonal antibody that binds to an oncogenic protein termed \nHER2 (the human epidermal growth factor receptor 2), a \nmember of the wider family of receptors with integral tyrosine kinase activity (see Fig. 57.1). There is some evidence \nthat, in addition to inducing host immune responses, \ntrastuzumab induces cell cycle inhibitors p21 and p27 (Ch. 6, Fig. 6.2). Tumour cells, in about 25% of breast cancer \npatients, overexpress this receptor and the cancer proliferates \nrapidly. Early results show that trastuzumab given with standard chemotherapy has resulted in a 79% 1-year survival rate in treatment-naive patients with this aggressive form \nof breast cancer. The drug is often given with a taxane such \nas docetaxel. Unwanted effects are similar to those with rituximab.in this way for prostate cancer must be prevented by an \nantiandrogen such as cyproterone. Degaralix is a \ngonadotrophin-releasing hormone antagonist used for the \ntreatment of prostate cancer.\nSomatostatin analogues\nAnalogues of somatostatin such as octreotide and lanreotide \n(see Ch. 34) are used to relieve the symptoms of neuroen-\ndocrine tumours, including hormone-secreting tumours of \nthe GI tract such as VIPomas, glucagonomas, carcinoid tumours and gastrinomas. These tumours express \nsomatostatin receptors, activation of which inhibits cell \nproliferation as well as hormone secretion.\nHORMONE ANTAGONISTS\nIn addition to the hormones themselves, hormone antago -\nnists can also be effective in the treatment of several types \nof hormone-sensitive tumours.\nAntioestrogens\nAn antioestrogen,", "start_char_idx": 0, "end_char_idx": 3339, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "14286f08-d675-4be5-92de-0c97abc355cf": {"__data__": {"id_": "14286f08-d675-4be5-92de-0c97abc355cf", "embedding": null, "metadata": {"page_label": "733", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "49187293-8812-4194-aadf-3e1e851372e6", "node_type": null, "metadata": {"page_label": "733", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "966f0ea42d5a2582eab78b4b2e078903edda44608f40bf8a4c236ec0aff8ddcf"}, "2": {"node_id": "f41caaa6-dbf1-43d4-af30-e15d8b6442c4", "node_type": null, "metadata": {"page_label": "733", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "768f95f137485b3e48bec98b81a4b7c1295d6ca35c5f18ecdcfb8b939a87e7b9"}}, "hash": "58dc93599dbd8a46a0b776342811e5f357169f8671d111871bc7f8962595c2ea", "text": "tumours.\nAntioestrogens\nAn antioestrogen, tamoxifen, is remarkably effective in \nsome cases of hormone-dependent breast cancer and may \nhave a role in preventing these cancers. In breast tissue, \ntamoxifen competes with endogenous oestrogens for the oestrogen receptors and therefore inhibits the transcription \nof oestrogen-responsive genes. Tamoxifen has less disruptive \neffects due to it being a partial agonist at the oestrogen receptor types found in endometrium, bone and the \ncardiovascular system. Tamoxifen is also reported to have \ncardioprotective effects, partly by virtue of its ability to protect low-density lipoproteins against oxidative damage, or by inhibition of cholesterol esterification and foam cell \nformation (Ch. 24). Other oestrogen receptor antagonists \ninclude toremifene and fulvestrant.\nUnwanted effects are similar to those experienced by women \nfollowing the menopause. Potentially more serious are hyperplastic events in the endometrium, which may progress to malignant changes, and the risk of thromboembolism.\nAromatase inhibitors such as anastrozole , letrozole and \nexemestane, which suppress the synthesis of oestrogen from androgens in the adrenal cortex (but not in the ovary), \nare also effective in the treatment of breast cancer in \npostmenopausal (but not in premenopausal) women, in whom they are somewhat more effective than tamoxifen.\nAntiandrogens\nThe androgen antagonists flutamide, cyproterone and \nbicalutamide may be used either alone or in combination \nwith other agents to treat tumours of the prostate. They \nare also used to control the testosterone surge (\u2018flare\u2019) that is seen when treating patients with gonadorelin analogues. \nDegarelix does not cause this flare.\nMONOCLONAL ANTIBODIES\nMonoclonal antibodies (see Ch. 5) are relatively recent \nadditions to the anticancer armamentarium. In some cases, \nbinding of the antibody to its target activates the host\u2019s \nimmune mechanisms and the cancer cell is killed by complement-mediated lysis or by killer T cells (see Ch. 7). \nOther monoclonal antibodies attach to and inactivate growth \nfactors or their receptors on cancer cells, thus inhibiting the survival pathway and promoting apoptosis (Ch. 6, Fig. \n6.5). Unlike most of the cytotoxic drugs described above, \nthey offer the prospect of highly targeted therapy without many of the side effects of conventional chemotherapy. Anticancer agents: hormones \nHormones \tor \ttheir \tantagonists \tare \tused \tin \thormone-\nsensitive tumours:\n\u2022\tGlucocorticoids for leukaemias and lymphomas.\n\u2022\tTamoxifen for breast tumours.\n\u2022\tGonadotrophin-releasing hormone analogues for prostate and breast tumours.\n\u2022\tAntiandrogens for prostate cancer.\n\u2022\tAromatase inhibitors for postmenopausal breast \ncancer.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3298, "end_char_idx": 6525, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2c43f025-2c87-49e7-b358-20d8dd664f0e": {"__data__": {"id_": "2c43f025-2c87-49e7-b358-20d8dd664f0e", "embedding": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dcde77b8-16da-411c-a7a4-3b1909d6c9dc", "node_type": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdf7667c58eadb710a09c41d6f0c3415f8bed6400488887a0fdbfb2bfddf4b94"}, "3": {"node_id": "2d13dea1-27ab-450a-ab2a-a50d47db9828", "node_type": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86123cbebbc77d91bebe83f72f257fe9c44bad76f82d1d57f12e6d9e39ceb9d6"}}, "hash": "965b79b074a112634f290db405fa61f911970ca7d6ba4db56378bcb76a75d07e", "text": "57 SECTION 5 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n728has transformed the (hitherto poor) prognosis of patients \nwith CML. It also inhibits platelet-derived growth factor \nreceptor (a receptor tyrosine kinase; see Fig. 57.1) and the \nc-kit receptor (CD117) whose ligand is stem cell factor (SCF), and is licensed for the treatment of c-kit positive \nGastroI ntestinal Stromal Tumours (GISTs), not susceptible \nto surgery.\nThe drug is given orally. The half-life is about 18 h, and \nthe main site of metabolism is in the liver, where approxi -\nmately 75% of the drug is converted to a metabolite that is also biologically active. The bulk (81%) of the metabolised \ndrug is excreted in the faeces.\nUnwanted effects include GI symptoms (pain, diarrhoea, \nnausea), fatigue, headaches and sometimes rashes. Resist-ance to imatinib, resulting from mutation of the kinase gene, is a growing problem. It results in little or no cross-\nresistance to other kinase inhibitors. Various second \n(nilotinib, dasatinib, bosutinib) and third (ponatinib) \ngeneration Bcr/Abl tyrosine kinase inhibitors have been developed to combat, to varying degrees, a typical drug-\nresistant mutation in Bcr/Abl (T315I) occurring in imatinib-\ntreated CML patients.\n\u25bc Many similar tyrosine kinase inhibitors have recently been \ndeveloped, including axitinib , crizotinib , erlotinib , gefitinib , imatinib , \nlapatinib, pazopanib, sunitinib and vandentanib. Ruxolitinib inhibits \nthe JAK1 and JAK2 kinases and vemurafenib inhibits BRAF kinase. \nSorafenib, everolimus and temsirolimus are pan-kinase inhibitors \nwith a similar utility. Ibrutinib and acalabrutinib inhibit Bruton\u2019s \nTyrosine Kinase (BTK) (see Ch. 7). They covalently modify residue \nC481 on BTK and irreversibly inhibit its cellular actions, which include chemotaxis and secretion of factors necessary for adhesion to the \nmicroenvironment. Interestingly their effectiveness in B lymphoid \nleukaemias and lymphomas, derives from the ability to prevent \nmigration and adhesion of these cancer cells to their resident tissues. \nLymphocytosis (the extrusion of B cells from lymph nodes, spleen and bone marrow into the peripheral blood) is one of the first effects \nof these drugs, and is a marker of their chemotherapeutic effect. Thus, \nsuch anticancer drugs with cellular responses other than simple cytotoxic actions, represent a new approach to chemotherapeutics.\u25bc\n Two mechanistically related compounds are panitumumab and \ncetuximab, which bind to epidermal growth factor (EGF) receptors \n(also overexpressed in a high proportion of tumours). They are used \nfor the treatment of colorectal cancer usually in combination with other agents.\nBevacizumab\nBevacizumab is a humanised monoclonal antibody that is \nused for the treatment of colorectal cancer and now used in \na wide range of other cancers. It neutralises VEGF (vascular \nendothelial growth factor), thereby preventing the angio -\ngenesis that is crucial to tumour survival. It is administered by intravenous infusion and is generally combined with \nother agents. A closely related preparation is also given by direct injection into the eye to retard the progress of acute \nmacular degeneration (AMD), a common cause of blindness associated with increased retinal", "start_char_idx": 0, "end_char_idx": 3283, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "2d13dea1-27ab-450a-ab2a-a50d47db9828": {"__data__": {"id_": "2d13dea1-27ab-450a-ab2a-a50d47db9828", "embedding": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dcde77b8-16da-411c-a7a4-3b1909d6c9dc", "node_type": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdf7667c58eadb710a09c41d6f0c3415f8bed6400488887a0fdbfb2bfddf4b94"}, "2": {"node_id": "2c43f025-2c87-49e7-b358-20d8dd664f0e", "node_type": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "965b79b074a112634f290db405fa61f911970ca7d6ba4db56378bcb76a75d07e"}, "3": {"node_id": "05236e35-079f-490f-9348-69ecec7333bb", "node_type": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "471fa7b4485ccaa971e3ad0515033dc042ac049e952b0b73b51d507a2e627968"}}, "hash": "86123cbebbc77d91bebe83f72f257fe9c44bad76f82d1d57f12e6d9e39ceb9d6", "text": "degeneration (AMD), a common cause of blindness associated with increased retinal vascularisation.\nCatumaxomab\nCatumaxomab attaches to an epithelial adhesion molecule, \nEpCAM, which is overexpressed in some malignant cells. \nIt is given by intraperitoneal injection to treat malignant \nascites, a collection of fluid and cancer cells in the peritoneal cavity. The antibody binds to this adhesion molecule and \nalso to T lymphocytes and antigen-presenting cells, thus \nfacilitating the action of the immune system in clearing the cancer.\nNivolumab\nNivolumab is a fully humanised monoclonal antibody (mAb) against Programmed cell Death protein-1 (PD-1) \nwhich is a cell surface receptor that dampens down the immune system to promote self-tolerance and suppress T-cell activation. Its ligand is PD-L1. Nivolumab has been \nused to re-prime the immune system so that it will recognise \nand destroy cancer cells that have previously evaded immunosurveillance. It has been approved for the treatment \nof metastatic melanoma, lymphoma, lung, kidney and head \nand neck cancers. Pembrolizumab is another approved variant of a PD-1 mAb. Atezolizumab is a mAb against \nPD-L1 approved in 2016 for the treatment of bladder cancer.\nIpilimumab\nApproved in 2011 for the treatment of melanoma, ipili-mumab targets the immune checkpoint system known as \ncytotoxic T-lymphocyte-associated protein 4 (CTLA-4) which \nfunctions similarly to the PD-1 system to \u2018stand down\u2019 the immune system. Cancers often employ both these mecha -\nnisms to evade immunodetection. Inhibitors of both systems are called \u2018immune checkpoint inhibitors \u2019. Ipilimumab has \nbeen used in the treatment of melanoma, with efficacy \nshown in combating lung and pancreatic cancers. Trials \ncombining both PD-1 and CTLA-4 inhibitors have proven that combined therapy of these checkpoint inhibitors will be a useful strategy to reactivate our immune systems and \ntarget it against cancer cells in general.\nPROTEIN KINASE INHIBITORS\nImatinib\nHailed as a conceptual breakthrough in targeted chemo-\ntherapy, imatinib (see Savage & Antman, 2002) is a \nsmall-molecule inhibitor of signalling pathway kinases. It inhibits an oncogenic cytoplasmic kinase (Bcr/Abl, see Fig. 57.1. and Fig. 57.8), considered to be a unique factor in \nthe pathogenesis of chronic myeloid leukaemia (CML). It Anticancer drugs: monoclonal \nantibodies and protein kinase \ninhibitors \n\u2022\tMany\ttumours \toverexpress \tgrowth \tfactor \treceptors \t\nthat therefore stimulate cell proliferation and tumour \ngrowth. This can be inhibited by:\n\u2013 monoclonal antibodies, which bind to the \nextracellular domain of the epidermal growth factor (EGF) receptor (e.g. panitumumab), the oncogenic \nreceptor\thuman \tepidermal \tgrowth \tfactor \t2 \t[HER2] \t\nreceptor (e.g. trastuzumab), or which neutralise the growth factors themselves (e.g. vascular endothelial \ngrowth\tfactor \t[VEGF]; \tbevacizumab);\n\u2013 protein kinase inhibitors, which prevent downstream \nsignalling triggered by growth factors by inhibiting specific oncogenic kinases (e.g. imatinib; bcr/abl) \nor by inhibiting specific receptor tyrosine kinases \n(e.g. EGF receptor; erlotinib) or several receptor-\nassociated kinases (e.g. sorafenib).\n\u2022\tSome\tmonoclonals \tact \tdirectly \ton \tlymphocyte", "start_char_idx": 3213, "end_char_idx": 6462, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "05236e35-079f-490f-9348-69ecec7333bb": {"__data__": {"id_": "05236e35-079f-490f-9348-69ecec7333bb", "embedding": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "dcde77b8-16da-411c-a7a4-3b1909d6c9dc", "node_type": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cdf7667c58eadb710a09c41d6f0c3415f8bed6400488887a0fdbfb2bfddf4b94"}, "2": {"node_id": "2d13dea1-27ab-450a-ab2a-a50d47db9828", "node_type": null, "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "86123cbebbc77d91bebe83f72f257fe9c44bad76f82d1d57f12e6d9e39ceb9d6"}}, "hash": "471fa7b4485ccaa971e3ad0515033dc042ac049e952b0b73b51d507a2e627968", "text": "\tact \tdirectly \ton \tlymphocyte \tcell \t\nsurface proteins to cause lysis (e.g. rituximab), \nthereby preventing proliferation.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6503, "end_char_idx": 7105, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c07d2187-c881-4f09-86a2-a1bab89e3b9b": {"__data__": {"id_": "c07d2187-c881-4f09-86a2-a1bab89e3b9b", "embedding": null, "metadata": {"page_label": "735", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3871c736-4790-4847-996c-22fd46db6e65", "node_type": null, "metadata": {"page_label": "735", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "191c2b3f61645b039d4b2b8b15b8d59049e915b8132299e3ca66d7530a8effca"}, "3": {"node_id": "28fc88dc-b6f8-4f12-b3f5-b6ce2ad2c211", "node_type": null, "metadata": {"page_label": "735", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8227569d1594b03da6980c01bb81cf776067febb1b59356ad6fbd490675dba0f"}}, "hash": "fb2e73a7d4e6db1bffe4856c334f62d25a470245ad5a8268618053a75c8ce89a", "text": "57 ANTICANCER DRUGS\n729MISCELLANEOUS AGENTS\nCrisantaspase\n\u25bc Crisantaspase is a preparation of the enzyme asparaginase, given \nby injection. It converts asparagine to aspartic acid and ammonia, \nand is active against tumour cells, such as those of acute lymphoblastic \nleukaemia, that have lost the capacity to synthesise asparagine and therefore require an exogenous source. As most normal cells are able \nto synthesise asparagine, the drug has a fairly selective action and \nhas very little suppressive effect on the bone marrow, the mucosa of the GI tract or hair follicles. It may cause nausea and vomiting, central \nnervous system depression, anaphylactic reactions and liver damage.\nHydroxycarbamide\n\u25bc Hydroxycarbamide (hydroxyurea) is a urea analogue that inhibits \nribonucleotide reductase, thus interfering with the conversion of ribonucleotides to deoxyribonucleotides. It is mainly used to treat \npolycythaemia rubra vera (a myeloproliferative disorder of the red cell \nlineage) and (in the past) chronic myelogenous leukaemia. Its use (in \nsomewhat lower dose) in sickle cell anaemia is described in Chapter \n25. It has the familiar spectrum of unwanted effects, bone marrow depression being significant.\nBortezomib\n\u25bc Bortezomib is a boron-containing tripeptide that inhibits cellular \nproteasome function. For some reason, rapidly dividing cells are more \nsensitive than normal cells to this drug, making it a useful anticancer \nagent. It is mainly used for the treatment of myeloma (a clonal malignancy of plasma cells).\nThalidomide\n\u25bc Investigations of the notorious teratogenic effect of thalidomide \nshowed that it has multiple effects on gene transcription, angiogenesis \nand proteasome function, leading to trials of its efficacy as an anticancer EGFPDGFR HER-2 EGFR VEGFR\nDownstream signallingPDGF\nTrastuzumab\nK\nK\nablKP-Cetuximab\nKP-Bevacizumab\nKP-VEGF\nImatinib\nFig. 57.8 The mechanism of action of anticancer monoclonal antibodies and protein kinase inhibitors. Many tumours overexpress \ngrowth\tfactor \treceptors \tsuch \tas \tepidermal \tgrowth \tfactor \treceptor \t(EGFR), \tthe \tproto-oncogene \thuman \tepidermal \tgrowth \tfactor \t2 \t(HER2) \tor \t\nvascular endothelial growth factor receptor (VEGFR). Therapeutic monoclonals can prevent this by interacting directly with the receptor itself \n(e.g. trastuzumab, cetuximab) or with the ligand (e.g. bevacizumab). An alternate way of reducing this drive on cell proliferation is by inhibiting the downstream signalling cascade. The receptor tyrosine kinases are good targets as are some oncogenic kinases such as bcr/abl. K, kinase domain in receptor; P-, phosphate group; PDGFR, platelet-derived growth factor receptor. \n8Thalidomide had earlier been found, unexpectedly when used as a sedative, \nto cause shrinkage of the cutaneous swellings of leprosy ( Ch. 52 ), and is \napproved for this indication as well as for myeloma.drug.8 In the event, it proved efficacious in myeloma, for which it is \nnow widely used. The main adverse effect of thalidomide, apart from \nteratogenesis (irrelevant in myeloma treatment), is peripheral \nneuropathy, leading to irreversible weakness and sensory loss. It also increases the incidence of thrombosis and stroke.\nA thalidomide derivative lenalidomide is thought to", "start_char_idx": 0, "end_char_idx": 3268, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "28fc88dc-b6f8-4f12-b3f5-b6ce2ad2c211": {"__data__": {"id_": "28fc88dc-b6f8-4f12-b3f5-b6ce2ad2c211", "embedding": null, "metadata": {"page_label": "735", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3871c736-4790-4847-996c-22fd46db6e65", "node_type": null, "metadata": {"page_label": "735", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "191c2b3f61645b039d4b2b8b15b8d59049e915b8132299e3ca66d7530a8effca"}, "2": {"node_id": "c07d2187-c881-4f09-86a2-a1bab89e3b9b", "node_type": null, "metadata": {"page_label": "735", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fb2e73a7d4e6db1bffe4856c334f62d25a470245ad5a8268618053a75c8ce89a"}}, "hash": "8227569d1594b03da6980c01bb81cf776067febb1b59356ad6fbd490675dba0f", "text": "and stroke.\nA thalidomide derivative lenalidomide is thought to have fewer \nadverse effects, but unlike thalidomide, can cause bone marrow \ndepression and neutropenia.\nBiological response modifiers and others\n\u25bc A gents that enhance the host\u2019s response are referred to as biological \nresponse modifiers . Some, for example interferon- \u03b1 (and its pegylated \nderivative), are used in treating some solid tumours and lymphomas, \nand aldesleukin (recombinant interleukin-2) is used in some cases \nof renal tumours. Tretinoin (a form of vitamin A; see Ch. 28) is a \npowerful inducer of differentiation in leukaemic cells and is used as an adjunct to chemotherapy to induce remission. A related compound is bexarotene , a retinoid X receptor antagonist (see Ch. 3) that inhibits \ncell proliferation and differentiation.\nPorfimer and temoporfin are haematoporphyrin photosensitising \nagents. They accumulate in cells and kill them when excited by the \nappropriate wavelength light. They are usually used in cases where the light source can be selectively aimed at the tumour (e.g. in the \ncase of obstructing oesophageal tumours).\nRESISTANCE TO ANTICANCER DRUGS\nThe resistance that neoplastic cells manifest to cytotoxic \ndrugs is said to be primary (present when the drug is first mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3205, "end_char_idx": 4958, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4314dc0c-6ac6-48bc-a8e0-3583670b074d": {"__data__": {"id_": "4314dc0c-6ac6-48bc-a8e0-3583670b074d", "embedding": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "da5d256b-325c-4098-9e91-5697a7ec84bb", "node_type": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8febe632b83cfbd7f61b501d3c8f7e5ea7d8a06d4028563ab0d5428b65f764c"}, "3": {"node_id": "68d4c72e-b304-4707-82c1-ce259dd30328", "node_type": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c6d0a17ce251ff6c133658e5b2da39df4c8ab7002b60eeed7d480f8cc3481f5"}}, "hash": "fbe5169979005f420400c9fa1f5786c2627cad9ce00e7d4ec95663a0b2cb0af8", "text": "57 SECTION 5 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n730CONTROL OF EMESIS AND MYELOSUPPRESSION\nEMESIS\nThe nausea and vomiting induced by many cancer chemo -\ntherapy agents are a serious deterrent to patient compliance \n(see also Ch. 31). It is a particular problem with cisplatin but \nalso complicates therapy with many other compounds, such as the alkylating agents. 5-hydroxytryptamine (HT)\n3-receptor \nantagonists such as ondansetron or granisetron (see Chs 16 \nand 31) are effective against cytotoxic drug-induced vomiting and have revolutionised cisplatin chemotherapy. Of the other antiemetic agents available, metoclopramide, given intra-\nvenously in high dose, has proved useful and is often combined with dexamethasone (Ch. 34) or lorazepam (Ch. \n45), both of which further mitigate the unwanted effects of \nchemotherapy. As metoclopramide commonly causes \nextrapyramidal side effects in children and young adults, diphenhydramine (Ch. 27) can be used instead.\nMYELOSUPPRESSION\nMyelosuppression limits the use of many anticancer agents. Regimens contrived to surmount the problem have included \nremoval of some of the patient\u2019s own bone marrow prior \nto treatment, purging it of cancer cells (using specific mono -\nclonal antibodies) and replacing it after cytotoxic therapy is \nfinished. A protocol in which aliquots of stem cells, harvested \nfrom the blood following administration of the growth factor molgramostim, which increases their abundance in blood, \nare expanded in vitro using further haemopoietic growth \nfactors (Ch. 26) is now frequently used. The use of such growth factors after replacement of the marrow has been successful in some cases. A further possibility is the introduc -\ntion, into the extracted bone marrow, of the mutated gene that confers multidrug resistance, so that when replaced, the marrow cells (but not the cancer cells) will be resistant \nto the cytotoxic action of the anticancer drugs. Folinic acid \nmay be given as a supplement to prevent anaemia or as a \n\u2018rescue\u2019 after high-dose methotrexate.\nFUTURE DEVELOPMENTS\nAs the reader will have judged by now, our current approach to cancer chemotherapy embraces an eclectic mixture of \ndrugs \u2013 some very old and some very new \u2013 in an attempt \nto target cancer cells selectively. Real therapeutic progress has been achieved, although \u2018cancer\u2019 as a disease (actually \nmany different diseases with a similar outcome) remains \na massive challenge for future generations of researchers. In this therapeutic area, probably more than in any other, \nthe debate about the risk\u2013benefit of treatment and the patient \nquality of life issues has taken centre stage and remains a major area of concern (see Duric & Stockler, 2001; Klastersky \n& Paesmans, 2001).\nOf the recent advances in drug therapy, the tyrosine \nkinase inhibitors and the biopharmaceuticals have arguably been the most innovative advances. Further drugs of the \nkinase inhibitor type are under active investigation (see \nVargas et al., 2013), as are anti-angiogenic drugs (similar \nto bevacizumab; see Ferrarotto & Hoff, 2013). Novel drugs \ntargeting HER2-receptor in breast cancer have been reviewed \nby Abramson and Arteaga (2011). Warner and Gustafsson \n(2010) have highlighted the opportunities afforded by the \ndiscovery of a further isoform of the oestrogen receptor \nfor the treatment of hormone-dependent breast and other given) or acquired (developing during treatment with the drug). \nAcquired resistance may result from either adaptation of the", "start_char_idx": 0, "end_char_idx": 3530, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "68d4c72e-b304-4707-82c1-ce259dd30328": {"__data__": {"id_": "68d4c72e-b304-4707-82c1-ce259dd30328", "embedding": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "da5d256b-325c-4098-9e91-5697a7ec84bb", "node_type": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8febe632b83cfbd7f61b501d3c8f7e5ea7d8a06d4028563ab0d5428b65f764c"}, "2": {"node_id": "4314dc0c-6ac6-48bc-a8e0-3583670b074d", "node_type": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "fbe5169979005f420400c9fa1f5786c2627cad9ce00e7d4ec95663a0b2cb0af8"}, "3": {"node_id": "0d5eda2a-5225-488a-baf9-5442379bd017", "node_type": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5794641f284e8ef5dc32f51dfd02488611eb4bc5256017ec07d25100479c34bb"}}, "hash": "5c6d0a17ce251ff6c133658e5b2da39df4c8ab7002b60eeed7d480f8cc3481f5", "text": "during treatment with the drug). \nAcquired resistance may result from either adaptation of the \ntumour cells or mutation , with the emergence of cells that are \nless susceptible or resistant to the drug and consequently have a selective advantage over the sensitive cells. The fol -\nlowing are examples of various mechanisms of resistance. \nSee Mimeault et al. (2008) for a critical appraisal of this issue.\n\u2022\tDecreased accumulation of cytotoxic drugs in cells as a \nresult of the increased expression of cell surface, \nenergy-dependent drug transport proteins. These are \nresponsible for multidrug resistance to many structurally dissimilar anticancer drugs (e.g. \ndoxorubicin, vinblastine and dactinomycin; see \nGottesman et al., 2002). An important member of this \ntransporter group is P-glycoprotein (P-gp/MDR1; see \nCh. 9). P-glycoprotein protects cells against \nenvironmental toxins. It functions as a hydrophobic \n\u2018vacuum cleaner\u2019, picking up foreign chemicals, such as drugs, as they enter the cell membrane and \nexpelling them. Non-cytotoxic agents that reverse \nmultidrug resistance are being investigated as potential adjuncts to treatment.\n\u2022\tA decrease in the amount of drug taken up by the cell (e.g. in the case of methotrexate).\n\u2022\tInsufficient activation of the drug. Some drugs require metabolic activation to manifest their antitumour \nactivity. If this fails, they may no longer be effective. \nExamples include conversion of fluorouracil to FdUMP, phosphorylation of cytarabine and \nconversion of mercaptopurine to a fraudulent \nnucleotide.\n\u2022\tIncrease in inactivation (e.g. cytarabine and \nmercaptopurine).\n\u2022\tIncreased concentration of target enzyme (methotrexate).\n\u2022\tDecreased requirement for substrate (crisantaspase).\n\u2022\tIncreased utilisation of alternative metabolic pathways \n(antimetabolites).\n\u2022\tRapid repair of drug-induced DNA damage (alkylating \nagents).\n\u2022\tAltered activity of target, for example modified \ntopoisomerase II (doxorubicin).\n\u2022\tMutations in various genes, giving rise to resistant target molecules. For example, the p53 gene, C481S mutation in BTK gene developing in ibrutinib resistance, and overexpression of the Bcl-2 gene family \n(several cytotoxic drugs).\nCOMBINATION THERAPIES\nTreatment with combinations of anticancer agents increases \nthe cytotoxicity against cancer cells without necessarily \nincreasing the general toxicity. For example, methotrexate, \nwhich mainly has myelosuppressive toxicity, may be used in a regimen with vincristine, which has mainly neurotoxic -\nity. The few drugs we possess with low myelotoxicity, such as cisplatin and bleomycin, are good candidates for combina -\ntion regimens. Treatment with combinations of drugs also \ndecreases the possibility of the development of resistance \nto individual agents. Drugs are often given in large doses intermittently in several courses, with intervals of 2\u20133 weeks between courses, rather than in small doses continuously, \nbecause this permits the bone marrow to regenerate during \nthe intervals. Furthermore, it has been shown that the same total dose of an agent is more effective when given in one \nor two large doses than in multiple small doses.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net", "start_char_idx": 3450, "end_char_idx": 6953, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0d5eda2a-5225-488a-baf9-5442379bd017": {"__data__": {"id_": "0d5eda2a-5225-488a-baf9-5442379bd017", "embedding": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "da5d256b-325c-4098-9e91-5697a7ec84bb", "node_type": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b8febe632b83cfbd7f61b501d3c8f7e5ea7d8a06d4028563ab0d5428b65f764c"}, "2": {"node_id": "68d4c72e-b304-4707-82c1-ce259dd30328", "node_type": null, "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5c6d0a17ce251ff6c133658e5b2da39df4c8ab7002b60eeed7d480f8cc3481f5"}}, "hash": "5794641f284e8ef5dc32f51dfd02488611eb4bc5256017ec07d25100479c34bb", "text": "mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6987, "end_char_idx": 7178, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "38335114-d298-47b3-a44e-599b02c6f7f1": {"__data__": {"id_": "38335114-d298-47b3-a44e-599b02c6f7f1", "embedding": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cbd9d134-26d9-4d3d-b787-42c1502518e7", "node_type": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07f1addccfd1a08bb6c211e4c3c8aac425cd787daf37c76280427ceec7d53d23"}, "3": {"node_id": "33bf7ac6-bd56-48db-8509-3a4809874849", "node_type": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29cc4d872c216f30fe8bb0813f86e167a0c104a5c4ce01acbbd451358cebd60e"}}, "hash": "7808e33ef0a3177f3c4f98736dc6ee463f170707801485581c3712c4eca27a50", "text": "57 ANTICANCER DRUGS\n731in about 85% of cancers, and prostanoids originating from this source \nmay activate signalling pathways that enable cells to escape from \napoptotic death. The literature has been controversial but the balance \nof evidence now favours the notion that COX-2 may be a potentially \nimportant target for anticancer drug development (see Khan et al., \n2011). COX-2 inhibitors could therefore be useful in the treatment of some cancers, either alone or in combination with conventional \nchemotherapeutic agents (Ghosh et al., 2010; Kraus et al., 2013). \nIronically, some authors ( Gurpinar et a l., 2013 ) argue that the mecha -\nnism of action of these inhibitors in cancer models is unrelated to \nCOX inhibition. No doubt these apparent paradoxes will be resolved \nwith the passage of time.\nMuch work is going into genotyping of tumour tissue as \na guide to selecting the best drug combination to use in \ntreating an individual patient, based on the particular genetic \nabnormality present in the tumour cells (see Patel et al., \n2013; Dagogo-Jack & Shaw, 2018 for reviews). This approach, \nstill in its early stages, is an example of personalised \nmedicine (see Ch.12), and is beginning to yield promising \napproaches to optimising treatment, tailored to individual cases of a variety of cancers, such as melanoma and lung \ncancer, and is expected to develop rapidly. Analysis of \ncirculating tumour DNA in blood is a possibility, obviating the need for biopsies.cancers. Additionally, recent advances in BTK inhibitors \nprimarily targeting non-cytotoxic signalling mechanisms, \nplus the use of immune checkpoint inhibitors to reset our immune systems so it can once more recognise and destroy \ncancer cells, are interesting paradigms for the future of \nintelligent cancer drug design. Moreover, the use of genetically-modified cells as \u2018living drug\u2019 anticancer thera -\npies are becoming a reality. For example, chimaeric antigen \nreceptor T cells (CAR-T cells) have been approved for the \ntreatment of acute lymphoblastic leukaemia, with trials underway for other cancer types. These cells express modi -\nfied antigens that target and kill cancer cells. Advances in gene-editing technology (e.g. CRISPR-Cas9 and TALENs) have made it possible for patients to receive cancer-killing \naltered T cells generated from either their own T cells or \nfrom a donor (Delhove & Qasim, 2017). Impressive break -\nthroughs have been seen with these \u2018living drugs\u2019 in cancer \npatients whose previous treatment failed using standard \nchemotherapy.\n\u25bc For years, epidemiological and experimental evidence has been \naccumulating, which suggests that chronic use of cyclo-oxygenase \n(COX) inhibitors (see Ch. 27) protects against cancer of the GI tract \nand possibly other sites as well. The COX-2 isoform is overexpressed \nREFERENCES AND FURTHER READING\nGeneral textbook\nAirley, R., 2009. Anticancer Drugs. Wiley-Blackwell, Chichester. ( Recent \ntextbook covering all aspects from basic pharmacology to clinical use)\nMechanisms of carcinogenesis\nBuys, C.H.C.M., 2000. Telomeres, telomerase and cancer. N. Engl. J. \nMed. 342, 1282\u20131283. (Clear, concise coverage)\nChambers, A.F., Groom, A.C., MacDonald, I.C., 2002. Dissemination \nand growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2, \n563\u2013567. (Review; stresses the importance of metastases in most cancer \ndeaths, discusses the mechanisms involved in metastasis and raises the \npossibility of targeting these in anticancer drug development)\nCroce, C.M., 2008. Oncogenes", "start_char_idx": 0, "end_char_idx": 3538, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "33bf7ac6-bd56-48db-8509-3a4809874849": {"__data__": {"id_": "33bf7ac6-bd56-48db-8509-3a4809874849", "embedding": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cbd9d134-26d9-4d3d-b787-42c1502518e7", "node_type": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07f1addccfd1a08bb6c211e4c3c8aac425cd787daf37c76280427ceec7d53d23"}, "2": {"node_id": "38335114-d298-47b3-a44e-599b02c6f7f1", "node_type": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7808e33ef0a3177f3c4f98736dc6ee463f170707801485581c3712c4eca27a50"}, "3": {"node_id": "bbfd5402-1690-48a2-ac78-e62e2606aac1", "node_type": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dee9962e004180cebc80b38a676c052425b5502c850b90994fa834d4be23de03"}}, "hash": "29cc4d872c216f30fe8bb0813f86e167a0c104a5c4ce01acbbd451358cebd60e", "text": "in anticancer drug development)\nCroce, C.M., 2008. Oncogenes and cancer. N. Engl. J. Med. 358, \n502\u2013511. (Good review of the most significant oncogenes involved in carcinogenesis)\nGriffioen, A., Molema, G., 2000. Angiogenesis: potentials for \npharmacologic intervention in the treatment of cancer, \ncardiovascular diseases and chronic inflammation. Pharmacol. Rev. 52, 237\u2013268. (Comprehensive review covering virtually all aspects of \nangiogenesis and the potential methods of modifying it to produce an \nantineoplastic effect)\nHanahan, D., Weinberg, R.A., 2011. Hallmarks of cancer: the next \ngeneration. Cell 144, 646\u2013674. (Excellent review on the mechanisms underlying carcinogenesis, cancer development and metastasis)\nMimeault, M., Hauke, R., Batra, S.K., 2008. Recent advances on the \nmolecular mechanisms involved in the drug resistance of cancer cells and novel targeting therapies. Clin. Pharmacol. Ther. 83, 673\u2013691. (Comprehensive review covering all aspects of this field)\nWeinberg, R.A., 1996. How cancer arises. Sci. Am. 275 (3), 62\u201370. \n(Simple, clear overview, listing main oncogenes, tumour suppressor genes and the cell cycle; excellent diagrams)\nAnticancer therapy\nGottesman, M.M., Fojo, T., Bates, S.E., 2002. Multidrug resistance in \ncancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2, \n48\u201356. (Outlines cellular mechanisms of resistance; describes ATP-dependent transporters, emphasising those in human cancer; considers resistance reversal strategies)\nKrause, D.S., Van Etten, R., 2005. Tyrosine kinases as targets for cancer \ntherapy. N. Engl. J. Med. 353, 172\u2013187. (Excellent review on tyrosine kinases as targets; good diagrams and tables as well as a highly readable \nstyle)\nSavage, D.G., Antman, K.H., 2002. Imatinib mesylate \u2013 a new oral \ntargeted therapy. N. Engl. J. Med. 346, 683\u2013693. (Review with detailed coverage of this drug for chronic myelogenous leukaemia; very good \ndiagrams)New directions and miscellaneous\nAbramson, V., Arteaga, C.L., 2011. New strategies in \nHER2-overexpressing breast cancer: many combinations of targeted \ndrugs available. Clin. Cancer Res. 17, 952\u2013958. (Deals mainly with ways \nin which the use of existing biologics can be optimized, but also discusses several new therapeutic directions)\nDagogo-Jack, I., Shaw, A.T., 2018. Tumour heterogeneity and resistance \nto cancer therapies. Nat. Rev. Clin. Oncol. 15, 81\u201394. (Excellent review of tumour heterogeneity and personalizing therapy)\nDelhove, J.M.K.M., Qasim, W., 2017. 2017 genome-edited T Cell \ntherapies. Curr. Stem Cell Rep. 3 (2), 124\u2013136.\nDuric, V., Stockler, M., 2001. Patients\u2019 preferences for adjuvant \nchemotherapy in early breast cancer. Lancet Oncol. 2, 691\u2013697. ( The \ntitle is self-explanatory; deals with patients\u2019 assessment of quality of life issues)\nFerrarotto, R., Hoff, P.M., 2013. Antiangiogenic drugs for colorectal \ncancer: exploring new possibilities. Clin. Colorectal Cancer 12, 1\u20137. (Good review of this field, clinical in tone and content)\nGhosh, N., Chaki, R., Mandal, V., Mandal, S.C., 2010. COX-2 as a target", "start_char_idx": 3485, "end_char_idx": 6554, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bbfd5402-1690-48a2-ac78-e62e2606aac1": {"__data__": {"id_": "bbfd5402-1690-48a2-ac78-e62e2606aac1", "embedding": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cbd9d134-26d9-4d3d-b787-42c1502518e7", "node_type": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07f1addccfd1a08bb6c211e4c3c8aac425cd787daf37c76280427ceec7d53d23"}, "2": {"node_id": "33bf7ac6-bd56-48db-8509-3a4809874849", "node_type": null, "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "29cc4d872c216f30fe8bb0813f86e167a0c104a5c4ce01acbbd451358cebd60e"}}, "hash": "dee9962e004180cebc80b38a676c052425b5502c850b90994fa834d4be23de03", "text": "V., Mandal, S.C., 2010. COX-2 as a target \nfor cancer chemotherapy. Pharmacol. Rep. 62, 233\u2013244. (Excellent review of this, often controversial, area)\nGurpinar, E., Grizzle, W.E., Piazza, G.A., 2013. COX-independent \nmechanisms of cancer chemoprevention by anti-inflammatory drugs. Front. Oncol. 3, 1\u201381. (A contrarian viewpoint on the target of action of \nCOX-2 inhibitors in cancer. Interesting reading)\nKeith, W.N., Bilsland, A., Hardie, M., Evans, T.R., 2004. Drug insight: \ncancer cell immortality \u2013 telomerase as a target for novel cancer gene therapies. Nat. Clin. Pract. Oncol. 1, 88\u201396.\nKhan, Z., Khan, N., Tiwari, R.P., Sah, N.K., Prasad, G.B., Bisen, P.S., \n2011. Biology of COX-2: an application in cancer therapeutics. Curr. Drug Targets 12, 1082\u20131093.\nKlastersky, J., Paesmans, M., 2001. Response to chemotherapy, quality \nof life benefits and survival in advanced non-small lung cancer: review of literature results. Lung Cancer 34, S95\u2013S101. (Another paper \nthat addresses quality of life issues surrounding chemotherapy)\nKraus, S., Naumov, I., Arber, N., 2013. COX-2 active agents in the \nchemoprevention of colorectal cancer. Recent Results Cancer Res. 191, 95\u2013103.\nPatel, L., Parker, B., Yang, D., Zhang, W., 2013. Translational genomics \nin cancer research: converting profiles into personalized cancer medicine. Cancer Biol. Med. 10, 214\u2013220. (Discusses prospects for personalised cancer therapy based on genotyping)\nTookman, L., Roylance, R., 2010. New drugs for breast cancer. Br. Med. \nBull. 96, 111\u2013129. (Easy-to-read account of the use and actions of biologics in breast cancer and a review of some promising new leads in the field. \nRecommended)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6567, "end_char_idx": 8718, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "13f37eea-a34a-42d4-bcd2-b75f0b9c16a6": {"__data__": {"id_": "13f37eea-a34a-42d4-bcd2-b75f0b9c16a6", "embedding": null, "metadata": {"page_label": "738", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3ec37538-f2d6-481d-9b1a-b53dd91ccfca", "node_type": null, "metadata": {"page_label": "738", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6e06a9a68a9d1a7b8c62305d23c9343714d2a013ea9664068c474d0d6466ed19"}}, "hash": "6e06a9a68a9d1a7b8c62305d23c9343714d2a013ea9664068c474d0d6466ed19", "text": "57 SECTION 5 DRUGS USED FOR THE TREATMENT OF INFECTIONS AND CANCER\n732Useful Web resources\nhttp://www.cancer.org/. (The US equivalent of the website below. The best \nsections for you are those marked Health Information Seekers and \nProfessionals)\nhttp://www.cancerresearchuk.org/. (The website of Cancer Research UK, \nthe largest cancer charity in the UK. Contains valuable data on the epidemiology and treatment of cancer, including links to clinical trials. An \nexcellent resource)Vargas, L., Hamasy, A., Nore, B.F., Smith, C.I., 2013. Inhibitors of BTK \nand ITK: state of the new drugs for cancer, autoimmunity and \ninflammatory diseases. Scand. J. Immunol. 78, 130\u2013139. (An \nexcellent account of this area together with a discussion of \u2018loss of function\u2019 \nmutations in these kinases that may predispose towards cancer. Good \ndiagrams)\nWarner, M., Gustafsson, J.A., 2010. The role of estrogen receptor beta \n(ERbeta) in malignant diseases \u2013 a new potential target for antiproliferative drugs in prevention and treatment of cancer. \nBiochem. Biophys. Res. Commun. 396, 63\u201366. (The title is self explanatory. A thought-provoking paper if you have an interest in oestrogen \nreceptors and cancer)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 1680, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "4072d420-a4b3-4e6c-b114-e0c4ee19cdcc": {"__data__": {"id_": "4072d420-a4b3-4e6c-b114-e0c4ee19cdcc", "embedding": null, "metadata": {"page_label": "739", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "85b34f45-e8cf-4ff5-8f38-98ce7ab8e47e", "node_type": null, "metadata": {"page_label": "739", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b625e9d84664331ea83350a52bcb39f4a96188d10dc6f301dc85a5e7e2213ecb"}, "3": {"node_id": "1a077ec0-bdf4-4077-b905-8bf591aaefa8", "node_type": null, "metadata": {"page_label": "739", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5f1c3d8966becf46f7b199aa68997d66fc19bb3228f532bf4b58dbf68bc789a9"}}, "hash": "e449863cbf3a8dcec36cc988d950c60e77eb890b19d988a8f4467657d7927306", "text": "733\nOVERVIEW\nThis chapter addresses harmful effects of drugs, both \nin the context of therapeutic use \u2013 so-called adverse \ndrug reactions \u2013 and of deliberate or accidental \noverdose. We are concerned here with serious harm, sometimes life-threatening or irreversible, distinct from \nthe minor side effects that virtually all drugs produce, \nas described throughout this book. The classification of adverse drug reactions is considered, followed by \naspects of drug toxicity, namely toxicity testing in \ndrug development, mechanisms of toxin-induced cell damage, mutagenesis and carcinogenicity, teratogen -\nesis and allergic reactions.\nINTRODUCTION\nParacelsus, a 16th-century alchemist, is credited with the \naphorism that all drugs are poisons: \u2018\u2026 the dosage makes \nit either a poison or a remedy\u2019. Today, toxic effects of drugs \nremain clinically important in the context of overdose (self-poisoning accounts for approximately 10% of the \nworkload of emergency medicine departments in the United \nKingdom; by contrast, homicidal poisoning is extremely uncommon). Some susceptible individuals may experience \ndose-related toxicity even during therapeutic dosing and \nsome of this susceptibility is genetically determined. There are now a wide range of genetic tests for identification and risk prediction of susceptible individuals, although relatively \nfew of these tests are routinely used in current clinical \npractice (Ch. 12).\nRigorous toxicity testing in animals (see p. 740), including \ntests for carcinogenicity, teratogenicity and organ-specific toxicities, is carried out on potential new drugs during development (see Ch. 60), often leading to abandonment of \nthe compound before it is tested in humans. These toxicity \nstudies form part of the package of information routinely submitted to regulatory agencies by drug companies seeking \napproval to market a new drug. Nevertheless, harmful \neffects are often encountered after a drug is marketed for human use, due to the emergence of adverse effects not \ndetected in animals. These harms are usually referred to as \n\u2018adverse drug reactions\u2019 (ADRs) and are of great concern to drug regulatory authorities, which are charged with \nestablishing the safety, as well as the efficacy, of drugs. \nUnpredictable events are of particular concern. Some ADRs are predictable as a consequence of the main pharmacological effect of the drug and are relatively easily recognised, but \nsome (e.g. immunological reactions), are unpredictable, \nsometimes serious, and likely to occur only in some \npatients.Clinically important ADRs are common, costly and often \navoidable (see Pirmohamed et al., 2004).1 Any organ can \nbe the principal target, and several organ systems can be \ninvolved simultaneously. The symptoms and signs some -\ntimes closely shadow drug administration and discontinu -\nation, but in other cases adverse effects only occur during prolonged use (osteoporosis during continued high-dose \nglucocorticoid therapy [Ch. 34], or tardive dyskinesia during \ncontinuous use of antipsychotic drugs [Ch. 47], for example). \nSome adverse effects occur on ending treatment, either \nwithin a few days (e.g. tachycardia on abrupt discontinu-ation of \u03b2-adrenoceptor blockade) or after a delay, first \nappearing months or years after treatment is discontinued, \nas in the case of some second malignancies following suc -\ncessful chemotherapy. Consequently, anticipating, avoiding, \nrecognising and responding to ADRs are among the most \nchallenging and important parts of clinical practice. Evalu -\nation of harm from unexpected or rare adverse reactions \nafter long periods of therapy is especially problematic. \nPrecise estimates of risk are seldom obtainable in such \ncircumstances.\nCLASSIFICATION OF ADVERSE", "start_char_idx": 0, "end_char_idx": 3765, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1a077ec0-bdf4-4077-b905-8bf591aaefa8": {"__data__": {"id_": "1a077ec0-bdf4-4077-b905-8bf591aaefa8", "embedding": null, "metadata": {"page_label": "739", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "85b34f45-e8cf-4ff5-8f38-98ce7ab8e47e", "node_type": null, "metadata": {"page_label": "739", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b625e9d84664331ea83350a52bcb39f4a96188d10dc6f301dc85a5e7e2213ecb"}, "2": {"node_id": "4072d420-a4b3-4e6c-b114-e0c4ee19cdcc", "node_type": null, "metadata": {"page_label": "739", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e449863cbf3a8dcec36cc988d950c60e77eb890b19d988a8f4467657d7927306"}}, "hash": "5f1c3d8966becf46f7b199aa68997d66fc19bb3228f532bf4b58dbf68bc789a9", "text": "obtainable in such \ncircumstances.\nCLASSIFICATION OF ADVERSE DRUG \nREACTIONS\nHarmful effects of drugs may or may not be related to the \nknown mechanism of action of the drug. In either case, \nindividual variation (see Ch. 12) is a major factor in deter -\nmining the response of a particular patient and their \nsusceptibility to harm. Aronson and Ferner (2003) have \nsuggested that ADRs are described according to the dose, \ntime course and susceptibility (DoTS). Potential susceptibil -\nity factors such as age and co-morbid conditions are thereby explicitly considered.\nADVERSE EFFECTS RELATED TO THE KNOWN \nPHARMACOLOGICAL ACTION OF THE DRUG\nMany adverse effects related to the known pharmacological \nactions of the drug are predictable, at least if these actions \nare well understood. They are sometimes referred to as \ntype A (\u2018augmented\u2019) adverse reactions in the Rawlins and Thomson classification, and are related to dose and indi -\nvidual susceptibility (Lee, 2005). Many such reactions have been described in previous chapters. For example, postural hypotension occurs with \u03b1\n1-adrenoceptor antagonists, Harmful effects of drugs 58 SPECIAL TOPICS SECTION 6\n1Of hospital admissions in the United Kingdom, 6.5% were due to \nADRs, at a projected annual cost of \u00a3466 million. Antiplatelet drugs, \ndiuretics, non-steroidal anti-inflammatory drugs and anticoagulants \nbetween them accounted for 50% of the ADRs, and 2.3% of the patients died. Most events were avoidable.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3705, "end_char_idx": 5657, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f04bd8f0-0fa4-4d50-aa7c-750cb483ce34": {"__data__": {"id_": "f04bd8f0-0fa4-4d50-aa7c-750cb483ce34", "embedding": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ebd1dedc-b77b-4fb5-bb89-c3d690f17e01", "node_type": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "644f7276ab4e2dc5ea75ceaa44abfb45f5c875c9aa42cc2af751c9b17c1907dc"}, "3": {"node_id": "889b935d-59a8-4047-ba94-4e8ded9cf084", "node_type": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d7312ab9ccc3d2e7034217066582edd32989b46c608b0986778a2471df85d23"}}, "hash": "2a4a8fdc39ad1888892d405ab747ad17a31fafdbea4e606bbab9b1b25978c358", "text": "58 SECTION 6\u2003\u2003 SPECIAL TOPICS\n734abnormalities, and a detailed postmortem examination at \nthe end of the trial to detect any gross or histological \nabnormalities. Toxicity testing is performed with doses well \nabove the expected therapeutic range, and establishes which tissues or organs are likely \u2018targets\u2019 of toxic effects of the \ndrug. Recovery studies are performed to assess whether \ntoxic effects are reversible, and particular attention is paid to irreversible changes such as carcinogenesis or neurode -\ngeneration. The basic premise is that toxic effects caused by a drug are similar in humans and other animals. There are, however, wide interspecies variations, especially in drug-metabolising enzymes; consequently, a toxic metabolite \nformed in one species may not be formed in another, and \nso toxicity testing in animals is not always a reliable guide. Pronethalol, the first \u03b2 -adrenoceptor antagonist synthesised, \nwas not developed because it caused carcinogenicity in mice; it subsequently emerged that carcinogenicity occurred only in the one strain tested \u2013 but by then other \u03b2 blockers \nwere already in development.\nToxic effects can range from negligible to so severe as \nto preclude further development of the compound. Inter-\nmediate levels of toxicity are more acceptable in drugs \nintended for severe illnesses (e.g. AIDS or cancers), and decisions on whether or not to continue development are \noften difficult. If development does proceed, safety monitor -\ning can be concentrated on the system \u2018flagged\u2019 as a potential \ntarget of toxicity by the animal studies.\n2 Safety of a drug \n(as distinct from toxicity) can be established only during \nuse in humans.bleeding with anticoagulants, sedation with anxiolytics and \nso on. In many instances, this type of unwanted effect is \nreversible, and the problem can often be dealt with by \nadjusting the dose to obtain a more favourable balance between efficacy and safety. Such effects are sometimes \nserious (e.g. intracerebral bleeding caused by anticoagulants, \nhypoglycaemic coma from insulin), and occasionally they are not easily reversible, for example, drug dependence \nproduced by opioid analgesics (see Ch. 50).\nSome adverse effects related to the main action of a drug \nresult in discrete events rather than graded symptoms, and \ncan be difficult to detect. For example, drugs that block \ncyclo-oxygenase (COX)-2 (including \u2018coxibs\u2019, for example, \nrofecoxib , celecoxib , and valdecoxib , as well as conventional \nnon-steroidal anti-inflammatory drugs [NSAIDs]), increase \nthe risk of myocardial infarction in a dose-dependent manner \n(Ch. 27). This potential was predictable from the ability of these drugs to inhibit prostacyclin biosynthesis and increase \narterial blood pressure, and early studies gave a hint of \nsuch problems. The effect was difficult to prove because of the high background incidence of coronary thrombosis, \nand it was only when placebo-controlled trials were per -\nformed for another indication (in the hope that COX-2 \ninhibitors could prevent bowel cancer) that this effect was \nconfirmed unequivocally.\nADVERSE EFFECTS UNRELATED TO THE KNOWN \nPHARMACOLOGICAL ACTION OF THE DRUG\nAdverse effects unrelated to the main pharmacological effect \nmay be predictable when a drug is taken in excessive dose, \nfor example, paracetamol hepatotoxicity (see later) or \naspirin -induced tinnitus; or when susceptibility is increased, \nfor example, during pregnancy or by a predisposing disorder such as glucose 6-phosphate dehydrogenase deficiency or \na mutation in the mitochondrial DNA that predisposes to aminoglycoside ototoxicity (Ch. 12).\nUnpredictable reactions unrelated to the main effect of", "start_char_idx": 0, "end_char_idx": 3700, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "889b935d-59a8-4047-ba94-4e8ded9cf084": {"__data__": {"id_": "889b935d-59a8-4047-ba94-4e8ded9cf084", "embedding": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ebd1dedc-b77b-4fb5-bb89-c3d690f17e01", "node_type": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "644f7276ab4e2dc5ea75ceaa44abfb45f5c875c9aa42cc2af751c9b17c1907dc"}, "2": {"node_id": "f04bd8f0-0fa4-4d50-aa7c-750cb483ce34", "node_type": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2a4a8fdc39ad1888892d405ab747ad17a31fafdbea4e606bbab9b1b25978c358"}, "3": {"node_id": "3d85ba75-a87b-42ee-8f26-45acfaf936b9", "node_type": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b4b9c37c3b8fb6fd963d9b81500ba607cd91ce53d0426c221d444039c7ac6a44"}}, "hash": "8d7312ab9ccc3d2e7034217066582edd32989b46c608b0986778a2471df85d23", "text": "(Ch. 12).\nUnpredictable reactions unrelated to the main effect of \nthe drug (sometimes termed idiosyncratic reactions, or type \nB for Bizarre in the Rawlins and Thomson classification) are often initiated by a chemically reactive metabolite rather \nthan the parent drug. Examples of such ADRs, which are \noften immunological in nature, include drug-induced hepatic or renal damage, bone marrow suppression, carcinogenesis \nand disordered fetal development. Uncommon but severe \nunpredictable adverse effects that have been mentioned in earlier chapters include aplastic anaemia from chloram-\nphenicol and anaphylaxis in response to penicillin. They \nare usually severe \u2013 otherwise they would go unrecognised \u2013 and their existence is important in establishing the safety \nof medicines. The unpredictable nature of such reactions \nmeans that adjustment of the recommended therapeutic regimen (e.g. using a lower dose) may not prevent them.\nMeyler\u2019s Side Effects of Drug is a comprehensive source \nof regularly updated and detailed textbook coverage of ADRs and their clinical manifestations (Aronson, 2015).\nDRUG TOXICITY\nTOXICITY TESTING\nToxicity testing in animals is carried out on new drugs to identify potential hazards before they are administered to \nhumans. It involves the use of a wide range of tests in \ndifferent species, with long-term administration of the drug, regular monitoring for physiological or biochemical Types of drug toxicity \n\u2022\tToxic\teffects \tof \tdrugs \tcan \tbe:\n\u2013\trelated\tto \tthe \tprincipal \tpharmacological \taction \t(e.g. \t\nbleeding\twith \tanticoagulants), \tand \tcan \tusually \tbe \t\npredicted\tfrom \tknowledge \tof \tthe \ttarget \tsites;\n\u2013\tunrelated \tto \tthe \tprincipal \tpharmacological \taction \t\n(e.g.\tliver\tdamage \twith \tparacetamol ),\tThis\tcan \tbe \t\ndifficult\tto \tpredict, \tand \tis \tsometimes \treferred \tto \tas \t\n\u2018off-target\u2019, \tcollateral, \tor \tbystander \tdamage.\n\u2022\tSome\tadverse \treactions \tthat \toccur \twith \tordinary \t\ntherapeutic \tdosage \tare \tinitially \tunpredictable, \tserious \t\nand\tuncommon \t(e.g. \tagranulocytosis \twith \t\ncarbimazole ).\tSuch\treactions \t(termed \tidiosyncratic) \t\nare\talmost \tinevitably \tdetected \tonly \tafter \twidespread \t\nuse\tof\ta\tnew \tdrug. \tIt \tis \tsometimes \tpossible \tto \tdevelop \t\na\ttest\tto\texclude \tsusceptible \tsubjects \tfrom \tdrug \t\nexposure\t(e.g. \tmitochondrial \tDNA \tvariants/increased \t\nsusceptibility \tto \taminoglycoside \tototoxicity).\n\u2022\tAdverse \teffects \tunrelated \tto \tthe \tmain \taction \tof \ta \tdrug \t\nare\toften\tcaused \tby \treactive \tmetabolites \tand/or \t\nimmunological \treactions.\n2The value of toxicity testing is illustrated by experience with \ntriparanol, a cholesterol-lowering drug marketed in the United States in \n1959. Three years later, a team from the FDA, acting on a tip-off, paid \nthe manufacturer a surprise visit that revealed falsification of toxicology data demonstrating cataracts in rats and dogs. The drug was \nwithdrawn, but some patients who had been taking it for a year or \nmore did develop cataracts. Regulatory authorities now require that toxicity testing is performed under a tightly defined code of practice \n(Good Laboratory Practice), which incorporates many safeguards to \nminimise the risk of error or fraud.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3644, "end_char_idx": 6991, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3d85ba75-a87b-42ee-8f26-45acfaf936b9": {"__data__": {"id_": "3d85ba75-a87b-42ee-8f26-45acfaf936b9", "embedding": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "ebd1dedc-b77b-4fb5-bb89-c3d690f17e01", "node_type": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "644f7276ab4e2dc5ea75ceaa44abfb45f5c875c9aa42cc2af751c9b17c1907dc"}, "2": {"node_id": "889b935d-59a8-4047-ba94-4e8ded9cf084", "node_type": null, "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8d7312ab9ccc3d2e7034217066582edd32989b46c608b0986778a2471df85d23"}}, "hash": "b4b9c37c3b8fb6fd963d9b81500ba607cd91ce53d0426c221d444039c7ac6a44", "text": "mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7001, "end_char_idx": 7384, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "135451c2-a93b-4ec0-b7ed-3062988fb2b2": {"__data__": {"id_": "135451c2-a93b-4ec0-b7ed-3062988fb2b2", "embedding": null, "metadata": {"page_label": "741", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e8a9cb1f-18b9-44d9-87f7-abb90923f9cc", "node_type": null, "metadata": {"page_label": "741", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e3378b5ed538497cf7115ccf08303e17e645930330e324d39dd845512a361e0"}, "3": {"node_id": "895af03b-adaf-4aa0-9574-37eb1b20ee81", "node_type": null, "metadata": {"page_label": "741", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1bdc711a6115c28d96ca19e3699f8c0c6518d7fe148acfac793852e260bd5dd6"}}, "hash": "b18f9b65392cbe674f3ce88ffc863aa584e726312b4eaef72e7ce75839a51653", "text": "58 HArmfu L E ff ECTS O f drug S\n735Lipid peroxidation\n\u25bc Peroxidation of unsaturated lipids can be initiated either by reactive \nmetabolites or by reactive oxygen species (Fig. 58.1). Lipid peroxy -\nradicals (ROO\u2022) can produce lipid hydroperoxides (ROOH), which \nproduce further lipid peroxyradicals. This chain reaction \u2013 a peroxida -\ntive cascade \u2013 may eventually affect much of the membrane lipid. \nDefence mechanisms, for example GSH peroxidase and vitamin E, protect against this. Cell damage results from alteration of membrane \npermeability or from reactions of the products of lipid peroxidation \nwith proteins.\nReactive oxygen species\n\u25bc Reduction of molecular oxygen to superoxide anion (O 2\u2212\u2022) may \nbe followed by enzymic conversion to hydrogen peroxide (H 2O2), \nhydroperoxyl (HOO\u2022) and hydroxyl (OH\u2022) radicals or singlet oxygen. \nThese reactive oxygen species are cytotoxic, both directly and through \nlipid peroxidation, and are important in excitotoxicity and neurode -\ngeneration (Ch. 41, Fig. 41.2).\nDepletion of glutathione\n\u25bc The GSH redox cycle protects cells from oxidative stress. GSH \ncan be depleted by accumulation of normal oxidative products of \ncell metabolism, or by the action of toxic chemicals. GSH is normally \nmaintained in a redox couple with its disulfide, GSSG. Oxidising \nspecies convert GSH to GSSG, GSH being regenerated by NADPH-dependent GSSG reductase. When cellular GSH falls to about 20%\u201330% \nof normal, cellular defence against toxic compounds is impaired and \ncell death can result.\nModification of sulfhydryl groups\n\u25bc Modification of sulfhydryl groups can be produced either by \noxidising species that alter sulfhydryl groups reversibly or by GENERAL MECHANISMS OF TOXIN-INDUCED \nCELL DAMAGE AND CELL DEATH\nToxic concentrations of drugs or drug metabolites can cause \nnecrosis; however, programmed cell death (apoptosis; see \nCh. 6) is increasingly recognised to be of equal or greater \nimportance, especially in chronic toxicity.\nChemically reactive drug metabolites can form covalent \nbonds with target molecules, or can damage tissue by non-covalent mechanisms. The liver is of great importance in drug metabolism (Ch. 10), and hepatocytes are exposed \nto high concentrations of nascent metabolites. Drugs and \ntheir polar metabolites are concentrated in renal tubular fluid as water is reabsorbed, so renal tubules are exposed to higher concentrations than are other tissues. Several \nhepatotoxic drugs (e.g. paracetamol) are also nephrotoxic. \nConsequently, hepatic or renal damage are common reasons for abandoning development of drugs during toxicity testing \nand chemical pathology tests of hepatic damage (usually \nlevels of transaminase enzymes measured in blood plasma or serum) and renal function (usually creatinine concentra -\ntion) are routine.\nNON-COVALENT \u2003INTERACTIONS\n\u25bc Reactive metabolites of drugs are implicated in several potentially \ncytotoxic, non-covalent processes, including:\n\u2022\tlipid\tperoxidation\n\u2022\tgeneration \tof \ttoxic \treactive \toxygen \tspecies\n\u2022\tdepletion \tof \treduced \tglutathione \t(GSH)\n\u2022\tmodification \tof \tsulfhydryl \tgroupsP450\nmixed function\noxidasesToxic dose of\nparacetamol\nN-Acetyl-p-benzoquinone", "start_char_idx": 0, "end_char_idx": 3185, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "895af03b-adaf-4aa0-9574-37eb1b20ee81": {"__data__": {"id_": "895af03b-adaf-4aa0-9574-37eb1b20ee81", "embedding": null, "metadata": {"page_label": "741", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e8a9cb1f-18b9-44d9-87f7-abb90923f9cc", "node_type": null, "metadata": {"page_label": "741", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "8e3378b5ed538497cf7115ccf08303e17e645930330e324d39dd845512a361e0"}, "2": {"node_id": "135451c2-a93b-4ec0-b7ed-3062988fb2b2", "node_type": null, "metadata": {"page_label": "741", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b18f9b65392cbe674f3ce88ffc863aa584e726312b4eaef72e7ce75839a51653"}}, "hash": "1bdc711a6115c28d96ca19e3699f8c0c6518d7fe148acfac793852e260bd5dd6", "text": "dose of\nparacetamol\nN-Acetyl-p-benzoquinone imine\n(NAPBQI)\nGSH\nLipid\nperoxidationNAPBQI\u2013\nprotein\nadductsNAPBQI\u2013GSH\nadduct\nIncreased\nmembrane\npermeabilityGSH depletion\nOxidative stress\nCELL DEATHSustained\nincrease in\n[Ca2+]i\nStimulation of\nCa2+-activated\ndegradative enzymesOxidation of SH groups on\ncellular Ca2+ ATPases\nFig. 58.1 \tPotential mechanisms of liver \ncell death resulting from the metabolism \nof paracetamol to N-acetyl-p-\nbenzoquinone imine (NAPBQI). \tGSH,\t\nglutathione. \t(Based \ton \tdata \tfrom \tBoobis, \t\nA.R.\tet\tal., \t1989. \tTrends \tPharmacol. \tSci. \t\n10,\t275\u2013280 \tand \tNelson, \tS.D., \tPearson, \t\nP.G.,\t1990. \tAnnu. \tRev. \tPharmacol. \tToxicol. \t\n30,\t169.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3142, "end_char_idx": 4291, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8905ce39-2381-4a4d-a303-e534d8461d58": {"__data__": {"id_": "8905ce39-2381-4a4d-a303-e534d8461d58", "embedding": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7cbcdc0-3c9e-4104-afd3-2ba6e5ff08fa", "node_type": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ccd2b830826601dd1d3462e62f893cf06333e5488ef7e4e35ad5604421dcce38"}, "3": {"node_id": "49ca8324-780d-4f90-8602-c6b1e1661ac3", "node_type": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7d4363904d084edccec306919d8c8d99bac6b28c9e860d3bd788b16a47437127"}}, "hash": "45ed0db24aff27009b91c9e94855fe8e3b4eefb86839af9b21820f8e4a391422", "text": "58 SECTION 6\u2003\u2003 SPECIAL TOPICS\n736uncommon, but the mechanism of liver injury is often \nuncertain (e.g. statins; Ch. 24). It is not always necessary \nto discontinue a drug when such mild laboratory abnormali -\nties occur, but the occurrence of cirrhosis as a result of long-term low-dose methotrexate treatment for arthritis \nor psoriasis (see Chs 27 and 28) argues for caution. Hepa -\ntotoxicity of a different kind, namely reversible obstructive \njaundice, occurs with chlorpromazine (Ch. 47) and andro -\ngens (Ch. 36).\nHepatotoxicity caused by paracetamol overdose remains \na common cause of death following self-poisoning. An outline is given in Chapter 27. Paracetamol poisoning \nexemplifies many of the general mechanisms of cell damage \noutlined previously. With toxic doses of paracetamol, the enzymes catalysing the normal conjugation reactions are \nsaturated, and mixed-function oxidases instead convert the \ndrug to the reactive metabolite N-acetyl-p-benzoquinone \nimine (NAPBQI). As explained in Chapter 10, paracetamol \ntoxicity is increased in patients in whom P450 enzymes \nhave been induced, for instance by chronic excessive consumption of alcohol. NAPBQI initiates several of the \ncovalent and non-covalent interactions described previously \nand illustrated in Fig. 58.1. Oxidative stress from GSH depletion is important in leading to cell death. Regeneration \nof GSH from GSSG depends on the availability of cysteine, \nthe intracellular availability of which can be limiting. Acetylcysteine or methionine can substitute for cysteine, \nincreasing GSH availability; they are used to treat patients \nwith paracetamol poisoning.\nLiver damage can also be produced by immunological \nmechanisms (see p. 741), which have been particularly \nimplicated in halothane hepatitis (see Ch. 42).covalent interaction. Free sulfhydryl groups have a critical role in the \ncatalytic activity of many enzymes. Important targets for sulfhydryl \nmodification by reactive metabolites include the cytoskeletal protein \nactin GSH reductase and Ca2+-transporting ATPases in the plasma \nmembrane and endoplasmic reticulum. These maintain cytoplasmic \nCa2+ concentration at approximately 0.1 \u00b5mol/L in the face of an \nextracellular Ca2+ concentration of more than 1 mmol/L. A sustained \nrise in cell Ca2+ occurs with inactivation of these enzymes (or with \nincreased membrane permeability; see earlier), and this compromises cell viability. Lethal processes leading to cell death after acute Ca\n2+ \noverload include activation of degradative enzymes (neutral proteases, phospholipases, endonucleases) and protein kinases, mitochondrial \ndamage and cytoskeletal alterations (e.g. modification of association between actin and actin-binding proteins).\nCOVALENT \u2003INTERACTIONS\nTargets for covalent interactions include DNA, proteins/\npeptides, lipids and carbohydrates. Covalent bonding to \nDNA is a basic mechanism of mutagenic chemicals; this is \ndealt with later. Several non-mutagenic chemicals also form covalent bonds with macromolecules, but the relationship \nbetween this and cell damage is incompletely understood. \nFor example, the cholinesterase inhibitor paraoxon (the active metabolite of the insecticide parathion) binds ace-\ntylcholinesterase at the neuromuscular junction (Ch. 14) \nand causes necrosis of skeletal muscle. One toxin from an exceptionally poisonous", "start_char_idx": 0, "end_char_idx": 3370, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "49ca8324-780d-4f90-8602-c6b1e1661ac3": {"__data__": {"id_": "49ca8324-780d-4f90-8602-c6b1e1661ac3", "embedding": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7cbcdc0-3c9e-4104-afd3-2ba6e5ff08fa", "node_type": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ccd2b830826601dd1d3462e62f893cf06333e5488ef7e4e35ad5604421dcce38"}, "2": {"node_id": "8905ce39-2381-4a4d-a303-e534d8461d58", "node_type": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "45ed0db24aff27009b91c9e94855fe8e3b4eefb86839af9b21820f8e4a391422"}, "3": {"node_id": "9b73f36e-b823-49f6-a799-7cf629b98fbc", "node_type": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3d3008bfbe32089fce2fe17cc13416cdc920be942af07e83b0a81338e33db197"}}, "hash": "7d4363904d084edccec306919d8c8d99bac6b28c9e860d3bd788b16a47437127", "text": "necrosis of skeletal muscle. One toxin from an exceptionally poisonous toadstool, Amanita phalloides, \nbinds actin, and another binds RNA polymerase, interfer -\ning with actin depolymerisation and protein synthesis, \nrespectively.\nGeneral mechanisms of cell \ndamage and cell death \n\u2022\tDrug-induced \tcell \tdamage/death \tis \tusually \tcaused \tby \t\nreactive\tmetabolites \tof \tthe \tdrug, \tinvolving \tnon-covalent \t\nand/or\tcovalent \tinteractions \twith \ttarget \tmolecules. \tCell \t\ndeath\toften \toccurs \tby \tapoptosis.\n\u2022\tNon-covalent \tinteractions \tinclude:\n\u2013\tlipid\tperoxidation \tvia \ta \tchain \treaction;\n\u2013\tgeneration \tof \tcytotoxic \treactive \toxygen \tspecies;\n\u2013\tdepletion \tof \treduced \tglutathione;\n\u2013\tmodification \tof \tsulfhydryl \tgroups \ton \tkey \tenzymes \t\n(e.g.\tCa2+-ATPase)\tand \tstructural \tproteins.\n\u2022\tCovalent \tinteractions, \tfor \texample \tadduct \tformation \t\nbetween\ta \tmetabolite \tof \tparacetamol \t(NAPBQI: \t\nN-acetyl-p -benzoquinone \timine) \tand \tcellular \t\nmacromolecules \t(see \tFig. \t58.1). \tCovalent \tbinding \tto \t\nprotein\tcan \tproduce \tan \timmunogen; \tbinding \tto \tDNA \t\ncan\tcause \tcarcinogenesis \tand \tteratogenesis.Hepatotoxicity \n\u2022\tHepatocytes \tare \texposed \tto \treactive \tmetabolites \tof \t\ndrugs\tas\tthese \tare \tformed \tby \tP450 \tenzymes.\n\u2022\tLiver\tdamage \tis \tproduced \tby \tseveral \tmechanisms \tof \t\ncell\tinjury; \tparacetamol \texemplifies \tmany \tof \tthese \t\n(see\tFig.\t58.1).\n\u2022\tSome\tdrugs \t(e.g. \tchlorpromazine ,\tco-amoxiclav) \tcan \t\ncause\treversible \tcholestatic \tjaundice.\n\u2022\tImmunological \tmechanisms \tare \tsometimes \timplicated \t\n(e.g.\thalothane).\nHEPATOTOXICITY\nMany therapeutic drugs cause liver damage, manifested clinically as hepatitis or (in less severe cases) only by labora -\ntory tests (e.g. increased activity of plasma aspartate transaminase, an enzyme released from damaged liver cells). Paracetamol and halothane cause hepatotoxicity by \nthe mechanisms of cell damage outlined above. Genetic differences in drug metabolism (see Ch. 12) have been implicated in some instances (e.g. isoniazid, phenytoin). \nMild drug-induced abnormalities of liver function are not NEPHROTOXICITY\nDrug-induced nephrotoxicity is a common clinical problem: NSAIDs (Table 58.1) and angiotensin-converting enzyme \n(ACE) inhibitors are among the commonest precipitants \nof acute renal failure, usually caused by the principal pharmacological actions of these drugs. Chronic kidney \ndisease, associated with renal tubular or papillary damage, \nmay be caused by a wide range of drugs, including ami-noglycoside antibiotics, antiviral drugs and lithium. \nNephrotoxic drugs are often well tolerated in healthy people, \nbut can cause renal failure in old people or children, or those with concurrent renal disease.\nMUTAGENESIS AND ASSESSMENT OF \nGENOTOXIC POTENTIAL\nDrug-induced mutagenesis is one important cause of carcino -\ngenesis and teratogenesis. Registration", "start_char_idx": 3310, "end_char_idx": 6170, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9b73f36e-b823-49f6-a799-7cf629b98fbc": {"__data__": {"id_": "9b73f36e-b823-49f6-a799-7cf629b98fbc", "embedding": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "e7cbcdc0-3c9e-4104-afd3-2ba6e5ff08fa", "node_type": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ccd2b830826601dd1d3462e62f893cf06333e5488ef7e4e35ad5604421dcce38"}, "2": {"node_id": "49ca8324-780d-4f90-8602-c6b1e1661ac3", "node_type": null, "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "7d4363904d084edccec306919d8c8d99bac6b28c9e860d3bd788b16a47437127"}}, "hash": "3d3008bfbe32089fce2fe17cc13416cdc920be942af07e83b0a81338e33db197", "text": "of pharmaceuticals mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6232, "end_char_idx": 6730, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "da61718e-5fda-4b8f-9529-c183e7793606": {"__data__": {"id_": "da61718e-5fda-4b8f-9529-c183e7793606", "embedding": null, "metadata": {"page_label": "743", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "24d815db-c7d5-4247-98ab-8cbc2d54902f", "node_type": null, "metadata": {"page_label": "743", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3341344d7af0febd28c18cc5f2c8ca83c7890af3213a697c9c6df1a674230f42"}, "3": {"node_id": "1676516a-a439-4b97-80a1-77bd05fe66ef", "node_type": null, "metadata": {"page_label": "743", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d86398c333eb2a9184e691274bff94069e60bc08c5679df0a44821d8860ad6e8"}}, "hash": "62b0aaeb98a9a940899f3f506fdd2f27ee29628c47845da3773ed21c6e26a51d", "text": "58 HArmfu L E ff ECTS O f drug S\n737Table 58.1 Adverse effects of non-steroidal anti-\ninflammatory drugs on the kidney\nCause Adverse effects\nPrincipal pharmacological \naction (i.e. inhibition of prostaglandin biosynthesis)Acute ischaemic renal failureSodium retention (leading to or exacerbating hypertension and/or heart failure)Water retentionHyporeninaemic hypoaldosteronism (leading to hyperkalaemia)\nUnrelated to principal pharmacological action (allergic-type interstitial nephritis)Renal failure\nProteinuria\nUnknown whether or not \nrelated to principal pharmacological action (analgesic nephropathy)Papillary necrosis\nChronic renal failure\n(Adapted\tfrom \tMurray \t& \tBrater, \t1993.)\nrequires a comprehensive assessment of their genotoxic \npotential. Because no single test is adequate, the usual \napproach is to carry out a battery of in vitro and in vivo \ntests for genotoxicity, usually comprising tests for gene mutation in bacteria, in vitro and in vivo tests for chromo -\nsome damage, and in vivo tests for reproductive toxicity and carcinogenicity (see later).\nBIOCHEMICAL \u2003MECHANISMS \u2003OF \u2003MUTAGENESIS\nChemical agents cause mutation by covalent modification of DNA. Certain mutations result in carcinogenesis, because \nthe affected DNA sequence codes for a protein that regulates \ncell growth. It usually requires more than one mutation in a cell to initiate the changes that result in malignancy, \nmutations in proto-oncogenes (which regulate cell growth) \nand tumour suppressor genes (which code for products that inhibit the transcription of oncogenes) being particularly \nimplicated (see Chs 6, 12 and 57).\n\u25bc Most chemical carcinogens act by modifying bases in DNA, \nparticularly guanine, the O6 and N7 positions of which readily \ncombine covalently with reactive metabolites of chemical carcinogens. \nSubstitution at the O6 position is the more likely to produce a perma -\nnent mutagenic effect, because N7 substitutions are usually quickly \nrepaired.\nThe accessibility of bases in DNA to chemical attack is greatest when \nDNA is in the process of replication (i.e. during cell division). The Nephrotoxicity \n\u2022\tRenal\ttubular \tcells \tare \texposed \tto \thigh \tconcentrations \t\nof\tdrugs\tand \tmetabolites \tas \turine \tis \tconcentrated.\n\u2022\tRenal\tdamage \tcan \tcause \tpapillary \tand/or \ttubular \t\nnecrosis.\n\u2022\tInhibition \tof \tprostaglandin \tsynthesis \tby \tnon-steroidal \t\nanti-inflammatory \tdrugs \tcauses \tvasoconstriction \tand \t\nlowers\tglomerular \tfiltration \trate.likelihood of genetic damage by many mutagens is therefore related \nto the frequency of cell division. The developing fetus is particularly susceptible, and mutagens are also potentially teratogenic for this \nreason (see p. 739). This is also important in relation to mutagenesis \nof germ cells, particularly in girls, because in humans the production of primary oocytes occurs by a rapid succession of mitotic divisions \nvery early in embryogenesis. Each primary oocyte then undergoes \nonly two further divisions much later in life, at the time of ovulation. It is consequently during early pregnancy that germ cells of the \ndeveloping female embryo are most likely to undergo mutagenesis, \nthe mutations being transmitted to progeny conceived many years \nlater. In the male, germ cell divisions occur throughout life, and \nsensitivity of germ cells to mutagens is continuously present.\nMutagenesis and carcinogenicity \n\u2022\tMutagenesis \tinvolves \tmodification \tof \tDNA.\n\u2022\tMutation \tof \tproto-oncogenes \tor \ttumour \tsuppressor", "start_char_idx": 0, "end_char_idx": 3499, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1676516a-a439-4b97-80a1-77bd05fe66ef": {"__data__": {"id_": "1676516a-a439-4b97-80a1-77bd05fe66ef", "embedding": null, "metadata": {"page_label": "743", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "24d815db-c7d5-4247-98ab-8cbc2d54902f", "node_type": null, "metadata": {"page_label": "743", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3341344d7af0febd28c18cc5f2c8ca83c7890af3213a697c9c6df1a674230f42"}, "2": {"node_id": "da61718e-5fda-4b8f-9529-c183e7793606", "node_type": null, "metadata": {"page_label": "743", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "62b0aaeb98a9a940899f3f506fdd2f27ee29628c47845da3773ed21c6e26a51d"}}, "hash": "d86398c333eb2a9184e691274bff94069e60bc08c5679df0a44821d8860ad6e8", "text": "\tof \tproto-oncogenes \tor \ttumour \tsuppressor \t\ngenes\tleads \tto \tcarcinogenesis. \tMore \tthan \tone \t\nmutation\tis \tusually \trequired.\n\u2022\tDrugs\tare \trelatively \tuncommon \t(but \tnot \tunimportant) \t\ncauses\tof \tbirth \tdefects \tand \tcancers.\nCARCINOGENESIS\nAlteration of DNA is the first step in carcinogenesis (see \nChs 6 and 57). Carcinogenic compounds can interact directly \nwith DNA (genotoxic carcinogens) or act at a later stage \nto increase the likelihood that mutation will result in a tumour (epigenetic carcinogens; Fig. 58.2).\nMEASUREMENT \u2003OF \u2003MUTAGENICITY \u2003AND \u2003\nCARCINOGENICITY\nMuch effort has gone into developing assays to detect muta -\ngenicity and carcinogenicity. In vitro tests for mutagenicity \nare used to screen large numbers of compounds but are unreliable as predictors of carcinogenicity. Whole-animal tests for carcinogenicity are expensive and time-consuming \nbut are usually required by regulatory authorities before \na new drug is licensed for use in humans. The main limitation of this kind of study is that there are important \nspecies differences, mainly to do with the metabolism \nof the foreign compound and the formation of reactive \nproducts.\nThe widely used Ames test for mutagenicity measures \nthe effect of substances on the rate of back-mutation (i.e. reversion from mutant to wild-type form) in Salmonella \ntyphimurium.\n\u25bc The wild-type strain can grow in a medium containing no added \namino acids, because it can synthesise all the amino acids it needs. \nA mutant form of the organism cannot make histidine in this way \nand therefore grows only on a medium containing this amino acid. \nThe Ames test involves growing the mutant form on a medium containing a small amount of histidine, plus the drug to be tested. \nAfter several divisions, the histidine becomes depleted, and the only \ncells that continue dividing are those that have back-mutated to the wild type. A count of colonies following subculture on plates deficient \nin histidine gives a measure of the mutation rate.\nPrimary carcinogens cause mutation by a direct action on bacterial \nDNA, but most carcinogens have to be converted to an active metabolite \n(see Fig. 58.2). Therefore it is necessary to include, in the culture, \nenzymes that catalyse the necessary conversion. An extract of liver \nfrom a rat treated with phenobarbital to induce liver enzymes is \nusually employed. There are many variations based on the same \nprinciple.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3455, "end_char_idx": 6367, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8a302f4f-bce7-4535-b67d-8e6f53207594": {"__data__": {"id_": "8a302f4f-bce7-4535-b67d-8e6f53207594", "embedding": null, "metadata": {"page_label": "744", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cb4188f6-905c-41eb-8fbc-0f9d944bf68b", "node_type": null, "metadata": {"page_label": "744", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "abd668c5e97614e27ba48098a3f5f7a2f268136e21dfab0c7cbeb2765e658cef"}, "3": {"node_id": "1ed6c64f-5c19-4784-a3fa-be87a772866a", "node_type": null, "metadata": {"page_label": "744", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a206a027367f61912a80a33134a914161e114ce13075cc0d04458c5faae0d3b5"}}, "hash": "816522395b66deaedcfb9dd3f48dd0f1b493582bc7af8ceb1431f8086cff0c31", "text": "58 SECTION 6\u2003\u2003 SPECIAL TOPICS\n738Malignant transformationOncogene expressionAlteration\nof DNA\n(mutation)Reactive\nmetaboliteCo-\ncarcinogenPromoter\nMetabolising\nenzymesSecondary\ncarcinogenPrimary\ncarcinogen\nFig. 58.2 \tSequence of events in mutagenesis and \ncarcinogenesis. \tAlterations \tto \tmethylation \tand \tacetylation \t\npatterns\tof \tDNA \tand \thistones \tin \tan \tepigenetic \tmanner \tcan \t\nchange\tgene \texpression \tduring \ttranscription, \ttranslation \tor \teven \t\nafter\ttranslation, \tto \tincrease \tthe \tlikelihood \tof \tcarcinoma \t\nformation. \tCarcinogens \n\u2022\tCarcinogens \tcan \tbe:\n\u2013\tgenotoxic, \ti.e. \tcausing \tmutations \tdirectly \t(primary \t\ncarcinogens) \tor \tafter \tconversion \tto \treactive \t\nmetabolites \t(secondary \tcarcinogens);\n\u2013\tepigenetic, \ti.e. \tincreasing \tthe \tpossibility \tthat \ta \t\nmutagen\twill \tcause \tcancer, \talthough \tnot \tthemselves \t\nmutagenic.\n\u2022\tNew\tdrugs \tare \ttested \tfor \tmutagenicity \tand \t\ncarcinogenicity.\n\u2022\tThe\tAmes \ttest \tfor \tmutagenicity \tmeasures \tback-\nmutation,\tin \thistidine-free \tmedium, \tof \ta \tmutant \t\nSalmonella typhimurium \t(which,\tunlike \tthe \twild \ttype, \t\ncannot\tgrow \twithout \thistidine) \tin \tthe \tpresence \tof:\n\u2013\tthe\tchemical \tto \tbe \ttested;\n\u2013\ta\tliver\tmicrosomal \tenzyme \tpreparation \tfor \t\ngenerating \treactive \tmetabolites.\n\u2022\tColony\tgrowth \tindicates \tthat \tmutagenesis \thas \t\noccurred.\tThe \ttest \tis \trapid \tand \tinexpensive, \tbut \tsome \t\nfalse-positives \tand \tfalse-negatives \toccur.\n\u2022\tCarcinogenicity \ttesting:\n\u2013\tinvolves \tchronic \tdosing \tof \tgroups \tof \tanimals;\n\u2013\tis\texpensive \tand \ttime-consuming;\n\u2013\tdoes\tnot \treadily \tdetect \tepigenetic \tcarcinogens.\nOther short-term in vitro tests for genotoxic chemicals \ninclude measurements of mutagenesis in mouse lymphoma \ncells, and assays for chromosome aberrations and sister \nchromatid exchanges in Chinese hamster ovary cells. \nHowever, all the in vitro tests give some false-positive and some false-negative results.\nIn vivo tests for carcinogenicity entail detection of tumours \nin groups of test animals. Carcinogenicity tests are inevitably slow, because there is usually a latency of months or years \nbefore tumours develop. Furthermore, tumours can develop \nspontaneously in control animals, and the results often provide only equivocal evidence of carcinogenicity of the test drug, making it difficult for industry and regulatory \nauthorities to decide on further development and possible \nlicensing of a product. None of the tests so far described can reliably detect epigenetic carcinogens. To do this, tests \nthat measure the effect of the substance on tumour formation \nin the presence of a threshold dose of a separate genotoxic agent are being evaluated.\nFew therapeutic drugs in clinical use are known to \nincrease the risk of cancer, the most important groups being drugs that act on DNA, i.e. cytotoxic and immunosuppres -\nsant drugs (Chs 57 and 27, respectively), and sex hormones (e.g. oestrogens, Ch.", "start_char_idx": 0, "end_char_idx": 2916, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "1ed6c64f-5c19-4784-a3fa-be87a772866a": {"__data__": {"id_": "1ed6c64f-5c19-4784-a3fa-be87a772866a", "embedding": null, "metadata": {"page_label": "744", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "cb4188f6-905c-41eb-8fbc-0f9d944bf68b", "node_type": null, "metadata": {"page_label": "744", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "abd668c5e97614e27ba48098a3f5f7a2f268136e21dfab0c7cbeb2765e658cef"}, "2": {"node_id": "8a302f4f-bce7-4535-b67d-8e6f53207594", "node_type": null, "metadata": {"page_label": "744", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "816522395b66deaedcfb9dd3f48dd0f1b493582bc7af8ceb1431f8086cff0c31"}}, "hash": "a206a027367f61912a80a33134a914161e114ce13075cc0d04458c5faae0d3b5", "text": "36).\nTERATOGENESIS \u2003AND \u2003DRUG-INDUCED \u2003\u2003\nCONGENITAL \u2003ANOMALIES\nTeratogenesis signifies the production of gross structural malformations during fetal development, in distinction \nfrom other kinds of drug-induced fetal damage such as \ngrowth retardation, dysplasia (e.g. iodide-associated goitre) or the asymmetrical limb reduction resulting from vaso -\nconstriction caused by cocaine (see Ch. 50) in an otherwise \nnormally developing limb.\nOther congenital anomalies may relate to neurobehav -\nioural function. For instance, many psychoactive drugs (see \nCh. 46) administered during pregnancy are known, or \nsuspected, to increase the risk of cognitive and behavioural problems in offspring. Examples of drugs that affect fetal \ndevelopment adversely are given in Table 58.2.\nThe importance of X irradiation and rubella infection as \ncauses of fetal malformation was recognised early in the 20th century, but it was not until 1960 that drugs were \nimplicated as causative agents in teratogenesis: the shocking experience with thalidomide led to a widespread reappraisal \nof many other drugs in clinical use, and to the setting up of drug regulatory bodies in many countries. Most birth defects (about 70%) occur with no recognisable causative \nfactor. Drug or chemical exposure during pregnancy is \nestimated to account for only approximately 1% of all fetal malformations. Fetal malformations are common, so the \nabsolute numbers of children affected are substantial.\nMECHANISM \u2003OF \u2003TERATOGENESIS\nThe timing of the teratogenic insult in relation to fetal \ndevelopment is critical in determining the type and extent \nof damage. Mammalian fetal development passes through \nthree phases (Table 58.3):\n1. Blastocyst formation\n2. Organogenesis\n3. Histogenesis and maturation of function\nCell division is the main process occurring during blastocyst formation. During this phase, drugs can kill the embryo \nby inhibiting cell division, but provided the embryo survives, \nits subsequent development does not generally seem to be mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 2917, "end_char_idx": 5420, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "efff6660-b6fb-4d05-8b79-f6816fd69584": {"__data__": {"id_": "efff6660-b6fb-4d05-8b79-f6816fd69584", "embedding": null, "metadata": {"page_label": "745", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d2185314-dfe4-4307-9d47-b5211bde3391", "node_type": null, "metadata": {"page_label": "745", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6fe779b03ddff6f7032ae0da0cbbadf21ad9a2007b8e89b2b5a9a1e9175dd4f2"}, "3": {"node_id": "c61c63a3-9d7f-494a-9f87-deabe72fe25d", "node_type": null, "metadata": {"page_label": "745", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82d5bc5648e855078b8992f08372a2f18d7b35d15037f580b6fb8f17a4b5db21"}}, "hash": "258767933af610af41a068cee4227524ff8886c31e7f682c53422e7db790ba79", "text": "58 HArmfu L E ff ECTS O f drug S\n739Adapted from Juchau, M.R., 1989. Bioactivation in chemical \nteratogenesis. Ann Rev Pharmacol Toxicol 29, 165.Table 58.2 Some drugs reported to have adverse effects on human fetal development\nAgent Effect(s)Risk of congenital \nanomalyaSee chapter\nThalidomide Phocomelia, heart defects, gut atresia, etc. K This chapter\nWarfarin Saddle nose; retarded growth; defects of limbs, \neyes, central nervous systemK 25\nCorticosteroids Cleft palate and congenital cataract \u2013 rare \u2014 34\nAndrogens Masculinisation in female \u2014 36\nOestrogens Testicular atrophy in male \u2014 36\nStilbestrol Vaginal adenosis in female fetus, also vaginal or cervical cancer20+ years later 36\nPhenytoin Cleft lip/palate, microcephaly, mental retardation K 46\nValproate Neural tube defects (e.g. spina bifida, facial anomalies)K 46\nCarbamazepine Retardation of fetal head growth S 46\nCytotoxic drugs (especially folate antagonists)Hydrocephalus, cleft palate, neural tube defects, etc.K 57\nAminoglycosides Deafness \u2014 52\nTetracycline Staining of bones and teeth, thin tooth enamel, impaired bone growthS 52\nEthanol Fetal alcohol syndrome K 50\nNicotine Altered neurological function K 49\nRetinoids Hydrocephalus, etc. K 28\nAngiotensin-converting enzyme inhibitorsOligohydramnios, renal failure K 23\naK,\tknown\tto \tcarry \ta \thigh \trisk \tof \tcongenital \tanomaly \t(in \texperimental \tanimals \tand/or \thumans); \tS, \tsuspected \tof \tcausing \tor \tincreasing \trisk \tof \t\ncongenital \tanomaly \t(in \texperimental \tanimals \tand/or \thumans).\nTable 58.3 The nature of drug effects on fetal development\nStage Gestation period in humans Main cellular process(es) Affected by\nBlastocyst formation 0\u201316 days Cell division Cytotoxic drugs, ? alcohol\nOrganogenesis 17\u201360 days approximatelyDivision Teratogens\nMigration Teratogens\nDifferentiation Teratogens\nDeath Teratogens\nHistogenesis and functional maturation60 days to term As above Miscellaneous drugs (e.g. alcohol, nicotine, antithyroid drugs, steroids)\ncompromised. Ethanol is an exception, affecting develop-\nment even at this very early stage (Ch. 50).\nDrugs can cause gross malformations if administered \nduring organogenesis (days 17\u201360 in humans). The structural organisation of the embryo occurs in a well-defined \nsequence: eye and brain, skeleton and limbs, heart and \nmajor vessels, palate, genitourinary system. The type of malformation produced thus depends on the time of \nexposure to the teratogen.\nThe cellular mechanisms by which teratogenic substances \nproduce their effects are not at all well understood. There is a considerable overlap between mutagenicity and \nteratogenicity. In one large survey, among 78 compounds, \n34 were both teratogenic and mutagenic, 19 were negative in \nboth tests and 25 (among them thalidomide) were positive in one but not the other. Damage to DNA is important but \nnot the only factor. The control of morphogenesis is poorly \nunderstood; vitamin A derivatives (retinoids) are involved and are potent teratogens (see p. 741 and Ch. 28). Known \nteratogens also include several drugs (e.g. methotrexate \nand phenytoin) that do not react directly with DNA \nbut which inhibit its synthesis by their effects on folate mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3306, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c61c63a3-9d7f-494a-9f87-deabe72fe25d": {"__data__": {"id_": "c61c63a3-9d7f-494a-9f87-deabe72fe25d", "embedding": null, "metadata": {"page_label": "745", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d2185314-dfe4-4307-9d47-b5211bde3391", "node_type": null, "metadata": {"page_label": "745", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "6fe779b03ddff6f7032ae0da0cbbadf21ad9a2007b8e89b2b5a9a1e9175dd4f2"}, "2": {"node_id": "efff6660-b6fb-4d05-8b79-f6816fd69584", "node_type": null, "metadata": {"page_label": "745", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "258767933af610af41a068cee4227524ff8886c31e7f682c53422e7db790ba79"}}, "hash": "82d5bc5648e855078b8992f08372a2f18d7b35d15037f580b6fb8f17a4b5db21", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3259, "end_char_idx": 3674, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5ea37e51-daad-468d-b795-65752fef9456": {"__data__": {"id_": "5ea37e51-daad-468d-b795-65752fef9456", "embedding": null, "metadata": {"page_label": "746", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d7052c2a-2ce6-458c-afb6-04402a14c86c", "node_type": null, "metadata": {"page_label": "746", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "727a253d5ba832c1e64c719ebd239225a5800f970840272c4a3d1e1d9aab69ea"}, "3": {"node_id": "028eac7a-5161-4a62-b82f-6a9cb08ccd72", "node_type": null, "metadata": {"page_label": "746", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1ad0d9785dc21b6d3a97b36956f340e08a98f3b88a590c5f9949893c3c380958"}}, "hash": "4de06ac30b7d2cb680f295cea2ce03913de1499290a4c2afd6f714731da472b2", "text": "58 SECTION 6\u2003\u2003 SPECIAL TOPICS\n740to thalidomide teratogenicity. Thalidomide was marketed \nenergetically and successfully, and the first suspicion of its \nteratogenicity arose early in 1961 with reports of a sudden \nincrease in the incidence of phocomelia (\u2018seal limbs\u2019, an absence of development of the long bones of the arms \nand legs) that had hitherto been virtually unknown. At \nthis time, a million tablets were being sold daily in West Germany. Reports of phocomelia came simultaneously \nfrom Hamburg and Sydney, and the connection with \nthalidomide was made.\n3 The drug was withdrawn late in \n1961, by which time an estimated 10,000 malformed babies \nhad been born (Fig. 58.3 illustrates the use of data linkage \nin detecting delayed ADRs). Epidemiological investigation showed very clearly the correlation between the time of \nexposure and the type of malfunction produced (Table 58.4). \nThough the mechanism is not clearly understood, inhibition metabolism (see Ch. 26). Administration of folate during \npregnancy reduces the frequency of both spontaneous and drug-induced malformations, especially neural tube \ndefects.\nThe fetus depends on an adequate supply of nutrients \nduring the final stage of histogenesis and functional matura -\ntion, and development is regulated by a variety of hormones. \nGross structural malformations do not arise from exposure \nto mutagens at this stage, but drugs that interfere with the supply of nutrients or with the hormonal milieu may have \ndeleterious effects on growth and development. Exposure \nof a female fetus to androgens at this stage can cause masculinisation. Stilbestrol (a synthetic oestrogen, now \nseldom used, licensed to treat breast or prostate cancer) was commonly given to pregnant women with a history of recurrent miscarriage during the 1950s (for unsound \nreasons). Used in this way it caused dysplasia of the vagina \nof female infants and an increased incidence of carcinoma of the vagina, a rare malignancy with almost no background incidence, in such offspring in their teens and twenties. \nAngiotensin II plays an important part in the later stages \nof fetal development and in renal function in the fetus, and ACE inhibitors and angiotensin receptor antagonists (Ch. \n23) cause oligohydramnios and renal failure if administered \nduring later stages of pregnancy, and fetal malformations if given earlier.\nTESTING \u2003FOR \u2003TERATOGENICITY\nThe thalidomide disaster dramatically brought home the need for teratogenicity studies on new therapeutic drugs. \nDetection of drug-induced teratogenesis in humans is a \nparticularly difficult problem because the \u2018spontaneous\u2019 malformation rate is high (3%\u201310%, depending on the \ndefinition of a significant malformation) and highly variable \nbetween different regions, age groups and social classes. Large-scale long-term studies are required, and the results \nare often inconclusive.\n\u25bc Studies using embryonic stem cells in assessing developmental \ntoxicity are showing some promise. In vitro methods, based on the \nculture of cells, organs or whole embryos, have, however, not so far \nbeen developed to a level where they satisfactorily predict teratogen -\nesis in vivo, and most regulatory authorities require teratogenicity \ntesting in a rodent and a non-rodent species (e.g. rabbit). Pregnant \nfemales are dosed at various levels during the critical period of \norganogenesis, and the fetuses are examined for structural abnor -\nmalities. However, poor cross-species correlation means that tests \nof this kind are not reliably predictive in humans, and it is usually \nrecommended that new drugs are not used in pregnancy unless it is \nessential.\nSOME \u2003DEFINITE \u2003AND", "start_char_idx": 0, "end_char_idx": 3679, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "028eac7a-5161-4a62-b82f-6a9cb08ccd72": {"__data__": {"id_": "028eac7a-5161-4a62-b82f-6a9cb08ccd72", "embedding": null, "metadata": {"page_label": "746", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "d7052c2a-2ce6-458c-afb6-04402a14c86c", "node_type": null, "metadata": {"page_label": "746", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "727a253d5ba832c1e64c719ebd239225a5800f970840272c4a3d1e1d9aab69ea"}, "2": {"node_id": "5ea37e51-daad-468d-b795-65752fef9456", "node_type": null, "metadata": {"page_label": "746", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4de06ac30b7d2cb680f295cea2ce03913de1499290a4c2afd6f714731da472b2"}}, "hash": "1ad0d9785dc21b6d3a97b36956f340e08a98f3b88a590c5f9949893c3c380958", "text": "pregnancy unless it is \nessential.\nSOME \u2003DEFINITE \u2003AND \u2003PROBABLE \u2003HUMAN \u2003TERATOGENS\nAlthough many drugs have been found to be teratogenic \nin varying degrees in experimental animals, relatively few \nare known to be teratogenic in humans (see Table 58.2). \nSome of the more important ones are discussed later.\nThalidomide\nThalidomide is almost unique in producing, at therapeutic dosage, virtually 100% malformed infants when taken in the \nfirst 3\u20136 weeks of gestation. It was introduced in 1957 as a \nhypnotic and sedative with the special feature that it was much less hazardous in overdosage than barbiturates, and \nit was even recommended specifically for use in pregnancy \n(with the advertising slogan \u2018the safe hypnotic\u2019). It had been subjected to toxicity testing only in mice, which are resistant 3A severe peripheral neuropathy, leading to irreversible paralysis and \nsensory loss, was reported within a year of the drug\u2019s introduction and \nsubsequently confirmed in many reports. The drug company \nresponsible was less than punctilious in acting on these reports (see Sj\u00f6str\u00f6m & Nilsson, 1972), which were soon eclipsed by the discovery \nof teratogenic effects, but the neurotoxic effect was severe enough in its \nown right to have necessitated restriction of the drug from general use. Today, use of thalidomide has had a resurgence related to several \nhighly specialised applications. It is prescribed by specialists (in \ndermatology, oncology and in HIV infection, among others) under tightly controlled and restricted conditions.1962 1961 1960 1959 1958 1957050100\nThalidomide sales\n(1960=100)\nPhocomelia and related\nfetal abnormalities(1961=100)\nFig. 58.3 \tIncidence of major fetal abnormalities in \nWestern Europe following the introduction and withdrawal \nof thalidomide, linked to sales data for thalidomide. \t\nTable 58.4 Thalidomide teratogenesis\nDay of gestation Type of deformity\n21\u201322 Malformation of earsCranial nerve defects\n24\u201327 Phocomelia of arms\n28\u201329 Phocomelia of arms and legs\n30\u201336 Malformation of handsAnorectal stenosismebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3624, "end_char_idx": 6157, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "19f9a5f3-12d0-449e-8464-e287ead2891a": {"__data__": {"id_": "19f9a5f3-12d0-449e-8464-e287ead2891a", "embedding": null, "metadata": {"page_label": "747", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "09bd840b-bfcc-4ef9-a2e9-d2ea19dab7b4", "node_type": null, "metadata": {"page_label": "747", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5cf6131b011ee21c7369250392132798e2fbe88d64ce159a2377bca01faf67e9"}, "3": {"node_id": "59254e9f-ff9e-4ed1-827f-031265c17a3f", "node_type": null, "metadata": {"page_label": "747", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "3626de98e942e73910bc56bbcca38b8a08de1602edf3cd9309783d7bd30cb1a6"}}, "hash": "44f122a3890c5dfa1516c79cec9e8d5dcd650cd773243567067ecec98016f4fd", "text": "58 HArmfu L E ff ECTS O f drug S\n741IMMUNOLOGICAL REACTIONS \nTO DRUGS\nBiological agents (Ch. 5) may provoke an immune response; \nantidrug antibodies to insulin are common in diabetic \npatients, though they seldom cause problems (Ch. 32), but \nantidrug antibodies to erythropoietin and thrombopoietin can have serious consequences for patients treated with these \nagents (see Ch. 26). Measurement of antidrug antibodies is \nnow routine during development of biological products. Seemingly trivial differences in manufacturing process (e.g. \nbetween different batches, or when a new manufacturer \nmakes a copy of a biological product after it is no longer protected by patent \u2013 so-called biosimilar products) can result in marked changes in immunogenicity.\nAllergic reactions of various kinds are a common form \nof adverse drug reaction. Low molecular-weight drugs are not immunogenic in themselves. A drug or its metabolites \ncan, however, act as a hapten by interacting with protein \nto form a stable immunogenic conjugate (Ch. 7). The immunological basis of some allergic drug reactions has \nbeen well worked out, but often it is inferred from the \nclinical characteristics of the reaction, and direct evidence of an immunological mechanism is lacking. The existence \nof an allergic reaction is suggested by its delayed onset, or \noccurrence only after repeated exposure to the drug. Allergic reactions are generally unrelated to the main action of the \ndrug, and conform to syndromes associated with types I, \nII, III and IV of the Gell and Coombs classification (see later and Ch. 7).\nThe overall incidence of allergic drug reactions is variously \nreported as being between 2% and 25%. Most are minor skin eruptions. Serious reactions (e.g. anaphylaxis, haemolysis and bone marrow depression) are rare. Penicillins, which \nare the commonest cause of drug-induced anaphylaxis, \nproduce this response in an estimated 1 in 50,000 patients exposed. Rashes can be severe, and fatalities occur with \nStevens\u2013Johnson syndrome (provoked, for example, by \nsulfonamides), and toxic epidermal necrolysis (TEN, which can be caused, for example, by allopurinol). The \nassociation between carbamazepine-induced TEN and of blood vessel formation (angiogenesis) is thought to be \ninvolved.\nCytotoxic drugs\nMany alkylating agents (e.g. chlorambucil and cyclophos -\nphamide) and antimetabolites (e.g. azathioprine and \nmercaptopurine ) cause malformations when used in early \npregnancy but more often lead to abortion (see Ch. 57). Folate antagonists (e.g. methotrexate) produce a much \nhigher incidence of major malformations, evident in both \nliveborn and stillborn fetuses.\nRetinoids\nEtretinate, a retinoid (i.e. vitamin A derivative) with marked effects on epidermal differentiation, is a known \nteratogen and causes a high proportion of serious abnor -\nmalities (notably skeletal deformities) in exposed fetuses. \nDermatologists use retinoids to treat skin diseases, including \nseveral, such as acne and psoriasis, that are common in \nyoung women. Etretinate accumulates in subcutaneous fat and is eliminated extremely slowly, detectable amounts \npersisting for many months after chronic dosing is discon -\ntinued. Because of this, women should avoid pregnancy \nfor at least 2 years after treatment. Acitretin is an active metabolite of etretinate. It is equally teratogenic, but tissue \naccumulation is less pronounced and elimination may be \nmore rapid.\nHeavy metals\nLead, cadmium and mercury all cause fetal malformation", "start_char_idx": 0, "end_char_idx": 3518, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "59254e9f-ff9e-4ed1-827f-031265c17a3f": {"__data__": {"id_": "59254e9f-ff9e-4ed1-827f-031265c17a3f", "embedding": null, "metadata": {"page_label": "747", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "09bd840b-bfcc-4ef9-a2e9-d2ea19dab7b4", "node_type": null, "metadata": {"page_label": "747", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5cf6131b011ee21c7369250392132798e2fbe88d64ce159a2377bca01faf67e9"}, "2": {"node_id": "19f9a5f3-12d0-449e-8464-e287ead2891a", "node_type": null, "metadata": {"page_label": "747", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "44f122a3890c5dfa1516c79cec9e8d5dcd650cd773243567067ecec98016f4fd"}}, "hash": "3626de98e942e73910bc56bbcca38b8a08de1602edf3cd9309783d7bd30cb1a6", "text": "metals\nLead, cadmium and mercury all cause fetal malformation \nin humans. The main evidence comes from Minamata \ndisease, named after the locality in Japan where an \nepidemic occurred when the local population ate fish contaminated with methylmercury that had been used as \nan agricultural fungicide. This impaired brain develop -\nment in exposed fetuses, resulting in cerebral palsy and \nmental retardation, often with microcephaly. Mercury, like \nother heavy metals, inactivates many enzymes by forming \ncovalent bonds with sulfhydryl and other groups, and this is believed to be responsible for these developmental \nabnormalities.\nAntiepileptic drugs (see\u2003Ch. \u200346)\nCongenital malformations are increased two- to three-fold in babies of epileptic mothers, especially of mothers treated \nwith two or more antiepileptic drugs during the first tri -\nmester, and in association with above-therapeutic plasma \nconcentrations. Many antiepileptic drugs have been \nimplicated, including phenytoin (particularly cleft lip/\npalate), valproate (neural tube defects) and carbamazepine \n(spina bifida and hypospadias, a malformation of the male \nurethra) (Ch. 46). The relative risks attributable to different \nantiepileptic drugs are not well defined, but valproate is considered to be particularly harmful (rate of congenital anomalies of about 10%, compared with 2%\u20133% in the \ngeneral population), and is contraindicated in women of \nchildbearing age.\nWarfarin\nAdministration of warfarin (Ch. 25) in the first trimester \nis associated with nasal hypoplasia and various central \nnervous system abnormalities, affecting roughly 25% of \nexposed babies. In the last trimester, it must not be used because of the risk of intracranial haemorrhage in the baby \nduring delivery.Teratogenesis and drug-induced \nfetal damage \n\u2022\tTeratogenesis \tmeans \tproduction \tof \tgross \tstructural \t\nmalformations \tof \tthe \tfetus \t(e.g. \tthe \tabsence \tof \tlimbs \t\nafter\tthalidomide ).\tLess\tcomprehensive \tdamage \tcan \t\nbe\tproduced \tby \tseveral \tdrugs \t(see \tTable \t58.2). \tLess \t\nthan\t1%\tof \tcongenital \tfetal \tdefects \tare \tattributed \tto \t\ndrugs\tgiven \tto \tthe \tmother.\n\u2022\tGross\tmalformations \tare \tproduced \tonly \tif \tteratogens \t\nact\tduring \torganogenesis. \tThis \toccurs \tduring \tthe \tfirst \t\n3\tmonths\tof \tpregnancy \tbut \tafter \tblastocyst \tformation. \t\nDrug-induced \tfetal \tdamage \tis \trare \tduring \tblastocyst \t\nformation\t(exception: \tfetal \talcohol \tsyndrome) \tand \tafter \t\nthe\tfirst\t3\tmonths \t(exception: \tangiotensin-converting \t\nenzyme\t[ACE] \tinhibitors \tand \tsartans).\n\u2022\tThe\tmechanisms \tof \taction \tof \tteratogens \tare \tnot \tclearly \t\nunderstood, \talthough \tDNA \tdamage \tis \ta \tfactor.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3457, "end_char_idx": 6602, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ea102655-0498-4feb-8d9f-684a098f69c3": {"__data__": {"id_": "ea102655-0498-4feb-8d9f-684a098f69c3", "embedding": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2dc44a1-21db-4f79-89a4-6839ad919550", "node_type": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b33bc64eb334811eeb6d513e73eebf3ffbd006d2259c877098e406d66b58243a"}, "3": {"node_id": "18d81235-ce36-49f4-ae1d-84a96c164c60", "node_type": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "643fd8b6d4eb300a3d9135d846cc3b6448bf816dcadb9fc9260b29d669924ba9"}}, "hash": "ed0730f77b5e5137fe2bca775c35e1cd69dd40762aca56f06086341508c21cfd", "text": "58 SECTION 6 \u2003\u2003SPECIAL TOPICS\n742negative. Other specialised tests are available to detect the \npresence of specific immunoglobulin E in the plasma, or \nto measure histamine release from the patient\u2019s basophils, \nbut these are not used routinely.\nHAEMATOLOGICAL\u2003 REACTIONS\nDrug-induced haematological reactions can be produced \nby type II, III or IV hypersensitivity. Type II reactions can \naffect any or all of the formed elements of the blood, which \nmay be destroyed by effects either on the circulating blood \ncells themselves or on their progenitors in the bone marrow. \nThey involve antibody binding to a drug\u2013macromolecule \ncomplex on the cell surface membrane. The antigen\u2013antibody \nreaction activates complement, leading to lysis, or provokes \nattack by killer lymphocytes or phagocytic leukocytes (Ch. \n7). Haemolytic anaemia has been most commonly reported \nwith sulfonamides and related drugs (Ch. 52) and with an \nantihypertensive drug, methyldopa (Ch. 15), which is still \nwidely used to treat hypertension during pregnancy. With \nmethyldopa, significant haemolysis occurs in less than 1% \nof patients, but the appearance of antibodies directed against \nthe surface of red cells is detectable in 15% by the Coombs \ntest. The antibodies are directed against Rh antigens, but \nit is not known how methyldopa produces this effect.\nDrug-induced agranulocytosis (complete absence of cir -\nculating neutrophils) is usually delayed 2\u201312 weeks after \nbeginning drug treatment but may then be sudden in \nonset. It often presents with mouth ulcers, a severe sore \nthroat or other infection. Serum from the patient lyses \nleukocytes from other individuals, and circulating anti -\nleukocyte antibodies can usually be detected immunologi -\ncally. Drugs associated with agranulocytosis include \nNSAIDs, especially phenylbutazone , carbimazole (Ch. 35) \nand clozapine (Ch. 47) and sulfonamides and related \ndrugs (e.g. thiazides and sulfonylureas ). Agranulocytosis is \nrare but life-threatening. Recovery when the offending \ndrug is stopped is often slow or absent. Antibody-mediated \nleukocyte destruction must be distinguished from the \ndirect effect of cytotoxic drugs (see Ch. 56), which cause \ngranulocytopenia that is rapid in onset, predictably related \nto dose and reversible.\nThrombocytopenia (reduction in platelet numbers) can be \ncaused by type II reactions to quinine (Ch. 55), heparin \n(Ch. 25) and thiazide diuretics (Ch. 30).\nSome drugs (notably chloramphenicol ) can suppress all \nthree haemopoietic cell lineages, giving rise to aplastic \nanaemia (anaemia with associated agranulocytosis and \nthrombocytopenia).\nThe distinction between type III and type IV hypersensitiv -\nity reactions in the causation of haematological reactions is \nnot clear cut, and either or both mechanisms can be involved.\nALLERGIC\u2003 LIVER\u2003 DAMAGE\nMost drug-induced liver damage results from the direct \ntoxic effects of drugs or their metabolites, as described \nabove. However, hypersensitivity reactions are sometimes \ninvolved, a particular example being halothane -induced \nhepatic necrosis (see Ch. 42). Trifluoracetylchloride , a reactive \nmetabolite of halothane, couples to a macromolecule to \nform an immunogen. Most patients with halothane-induced \nliver damage have antibodies that react with halothane\u2013\ncarrier conjugates. Halothane\u2013protein antigens can be \nexpressed on the surface of", "start_char_idx": 0, "end_char_idx": 3400, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "18d81235-ce36-49f4-ae1d-84a96c164c60": {"__data__": {"id_": "18d81235-ce36-49f4-ae1d-84a96c164c60", "embedding": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2dc44a1-21db-4f79-89a4-6839ad919550", "node_type": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b33bc64eb334811eeb6d513e73eebf3ffbd006d2259c877098e406d66b58243a"}, "2": {"node_id": "ea102655-0498-4feb-8d9f-684a098f69c3", "node_type": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ed0730f77b5e5137fe2bca775c35e1cd69dd40762aca56f06086341508c21cfd"}, "3": {"node_id": "fe612762-7a93-4348-8702-d52a20926a29", "node_type": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a4a72ef1d18db469ffef7a7f504a6650593e798de10cb3d648cc4ecb18e86d06"}}, "hash": "643fd8b6d4eb300a3d9135d846cc3b6448bf816dcadb9fc9260b29d669924ba9", "text": "Halothane\u2013protein antigens can be \nexpressed on the surface of hepatocytes. Destruction of the \ncells occurs by type II hypersensitivity reactions involving \nkiller T cells, and type III reactions can also contribute.the gene for a particular human leukocyte antigen (HLA) \nallele HLAB*1502 in people of Asian ancestry is mentioned \nin Chapter 12. Susceptibility to severe rashes in response \nto abacavir is closely linked to the variant HLAB*5701 \nand this forms the basis of a clinically useful genomic \ntest (Ch. 12).\nIMMUNOLOGICAL MECHANISMS\nThe formation of an immunogenic conjugate between a \nsmall molecule and an endogenous protein requires covalent \nbonding. In most cases, reactive metabolites, rather than \nthe drug itself, are responsible. Such reactive metabolites \ncan be produced during drug oxidation or by photoactiva -\ntion in the skin. They may also be produced by the action \nof toxic oxygen metabolites generated by activated leuko -\ncytes. Rarely (e.g. in drug-induced lupus erythematosus), \nthe reactive moiety interacts to form an immunogen with \nnuclear components (DNA, histone) rather than proteins. \nConjugation with a macromolecule is usually essential, \nalthough penicillin is an exception because it can form \nsufficiently large polymers in solution to elicit an anaphy -\nlactic reaction in a sensitised individual even without \nconjugation to protein, although penicillin\u2013protein conju -\ngates can also act as the immunogen.\nCLINICAL TYPES OF ALLERGIC RESPONSE \nTO DRUGS\nHypersensitivity reactions of types I, II and III (Ch. 7) are \nantibody-mediated reactions, while type IV is cell mediated. \nUnwanted reactions to drugs involve both antibody- and \ncell-mediated reactions. The more important clinical \nmanifestations of hypersensitivity include anaphylactic \nshock, haematological reactions, allergic liver damage and \nother hypersensitivity reactions.\nANAPHYLACTIC\u2003 SHOCK\nAnaphylactic shock \u2013 see also Chapters 7 and 29 \u2013 is a type \nI hypersensitivity response. It is a sudden and life-threatening \nreaction that results from the release of histamine, leuko -\ntrienes and other mediators. The main features include \nurticarial rash, swelling of soft tissues, bronchoconstriction \nand hypotension.\nPenicillins account for about 75% of anaphylactic deaths, \nreflecting the frequency with which they are used in clinical \npractice. Other drugs that can cause anaphylaxis include \nenzymes, such as asparaginase (Ch. 57); therapeutic \nmonoclonal antibodies (Ch. 5); hormones, for example, \ncorticotropin (Ch. 34); heparin (Ch. 25); dextrans; radiologi -\ncal contrast agents; vaccines; and other serological products. \nAnaphylaxis with local anaesthetics (Ch. 44), the antiseptic \nchlorhexidine and with many other drugs (sometimes as \na consequence of contaminants such as latex used to seal \nreusable vials or of excipients and colouring agents rather \nthan the drug itself) can occur. Treatment of anaphylaxis \nis mentioned in Chapter 29.\nIt is sometimes feasible to carry out a skin test for the \npresence of hypersensitivity, which involves injecting a \nminute dose intradermally. A patient who reports that she \nor he is allergic to a drug such as penicillin may actually \nbe allergic to fungal contaminants, which were common \nin early preparations, rather than to penicillin itself. The \nuse of penicilloylpolylysine as a skin test reagent for penicil -\nlin allergy is an improvement over the use of penicillin \nitself, because it bypasses the need for conjugation of the \ntest substance,", "start_char_idx": 3347, "end_char_idx": 6882, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "fe612762-7a93-4348-8702-d52a20926a29": {"__data__": {"id_": "fe612762-7a93-4348-8702-d52a20926a29", "embedding": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "c2dc44a1-21db-4f79-89a4-6839ad919550", "node_type": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b33bc64eb334811eeb6d513e73eebf3ffbd006d2259c877098e406d66b58243a"}, "2": {"node_id": "18d81235-ce36-49f4-ae1d-84a96c164c60", "node_type": null, "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "643fd8b6d4eb300a3d9135d846cc3b6448bf816dcadb9fc9260b29d669924ba9"}}, "hash": "a4a72ef1d18db469ffef7a7f504a6650593e798de10cb3d648cc4ecb18e86d06", "text": "because it bypasses the need for conjugation of the \ntest substance, thereby reducing the likelihood of a false mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6868, "end_char_idx": 7459, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b57aa8cf-6621-4b80-bc72-d806736a7c35": {"__data__": {"id_": "b57aa8cf-6621-4b80-bc72-d806736a7c35", "embedding": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "13aaaa90-26b0-429b-8e4a-18729a195c4d", "node_type": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82a468af417a831c02e85304ba53a7a1b3268bde4defc20d2b982a81fee001cb"}, "3": {"node_id": "32cb72e8-dbb0-4192-9246-b015ca3bd5ae", "node_type": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0031c65a3131b8b872e38a4c2090ecdd77526fa9572fbc7370c626c0fbf14511"}}, "hash": "41b70e29e993f95f655328542af036140c85389357d2be74b373f152c0e0ce25", "text": "58 HArmfuL EffECTS Of drugS\n743OTHER\u2003 HYPERSENSITIVITY\u2003 REACTIONS\nThe clinical manifestations of type IV hypersensitivity \nreactions are diverse, ranging from minor skin rashes to \ngeneralised autoimmune disease. Fever may accompany \nthese reactions. Rashes can be antibody mediated but are \nusually cell mediated. They range from mild eruptions to \nfatal exfoliation. Stevens\u2013Johnson syndrome is a very severe \ngeneralised rash that extends into the alimentary tract and \ncarries an appreciable mortality. In some cases, the lesions \nare photosensitive, probably because ultraviolet light \nconverts the drug to reactive products.\n\u25bc Some drugs (notably hydralazine and procainamide ) can produce \nan autoimmune syndrome resembling systemic lupus erythematosus. \nThis is a multisystem disorder in which there is immunological damage \nto many organs and tissues (including joints, skin, lung, central nervous \nsystem and kidney) caused particularly, but not exclusively, by type \nIII hypersensitivity reactions. The prodigious array of antibodies \ndirected against \u2018self\u2019 components has been termed an \u2018autoimmune \nthunderstorm\u2019. The antibodies react with determinants shared by \nmany molecules, for example, the phosphodiester backbone of DNA, \nRNA and phospholipids. In drug-induced systemic lupus erythema -\ntosus, the immunogen may result from the reactive drug moiety \ninteracting with nuclear material, and joint and pulmonary damage \nis common. The condition usually resolves when treatment with the \noffending drug is stopped.Allergic reactions to drugs \n\u2022\tDrugs\tor\ttheir\treactive\tmetabolites\t can\tbind\tcovalently\t\nto\tproteins\tto\tform\timmunogens.\t Penicillin \t(which\tcan\t\nalso\tform\timmunogenic\t polymers)\t is\tan\timportant\t\nexample.\n\u2022\tDrug-induced\t allergic\t(hypersensitivity)\t reactions\t may\t\nbe\tantibody\tmediated\t (types\tI,\tII,\tIII)\tor\tcell\tmediated\t\n(type\tIV).\tImportant\t clinical\tmanifestations\t include\tthe\t\nfollowing:\n\u2013\tanaphylactic\t shock\t(type\tI):\tmany\tdrugs\tcan\tcause\t\nthis,\tand\tmost\tdeaths\tare\tcaused\tby\tpenicillin ;\n\u2013\thaematological\t reactions\t (type\tII,\tIII\tor\tIV):\tincluding\t\nhaemolytic\t anaemia\t(e.g.\t methyldopa ),\t\nagranulocytosis\t (e.g.\t carbimazole ),\t\nthrombocytopenia\t (e.g.\t quinine)\tand\taplastic\t\nanaemia\t(e.g.\t chloramphenicol );\n\u2013\thepatitis\t (types\tII,\tIII):\tfor\texample,\t halothane ,\t\nphenytoin ;\n\u2013\trashes\t (type\tI,\tIV):\tare\tusually\tmild\tbut\tcan\tbe\t\nlife-threatening\t (e.g.\tStevens\u2013Johnson\t syndrome);\n\u2013\tdrug-induced\t systemic\tlupus\terythematosus\t (mainly\t\ntype\tII):\tantibodies\t to\tnuclear\tmaterial\tare\tformed\t\n(e.g.\t hydralazine ).\nREFERENCES AND FURTHER READING\nAdverse drug reactions\nAronson, J.K., Ferner, R.E., 2003. Joining the DoTS: a new approach to \nclassifying adverse drug reactions. Br. Med. J. 327, 1222\u20131225. \n(Description of ADRs in terms of dose, time course and susceptibility )\nAronson, J.K. (Ed.), 2015. Meyler\u2019s Side Effects of Drugs: The \nInternational Encyclopedia of Adverse Drug Reactions and \nInteractions, sixteenth ed. Elsevier", "start_char_idx": 0, "end_char_idx": 2985, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "32cb72e8-dbb0-4192-9246-b015ca3bd5ae": {"__data__": {"id_": "32cb72e8-dbb0-4192-9246-b015ca3bd5ae", "embedding": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "13aaaa90-26b0-429b-8e4a-18729a195c4d", "node_type": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82a468af417a831c02e85304ba53a7a1b3268bde4defc20d2b982a81fee001cb"}, "2": {"node_id": "b57aa8cf-6621-4b80-bc72-d806736a7c35", "node_type": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "41b70e29e993f95f655328542af036140c85389357d2be74b373f152c0e0ce25"}, "3": {"node_id": "bce158eb-fe8b-46cb-a1bb-6ca55a99b4fc", "node_type": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bffc6e3004ee47c2a2ad00a389b413e945800e58ee928cf609add133d9d3e4c1"}}, "hash": "0031c65a3131b8b872e38a4c2090ecdd77526fa9572fbc7370c626c0fbf14511", "text": "Encyclopedia of Adverse Drug Reactions and \nInteractions, sixteenth ed. Elsevier Science.\nLee, A. (Ed.), 2005. Adverse Drug Reactions, second ed. Pharmaceutical \nPress, London, pp. 12\u201338. ( Good reference text covering classification and \nadverse reactions according to organ system )\nPirmohamed, M., James, S., Meakin, S., et al., 2004. Adverse drug \nreactions as cause of admission to hospital: prospective analysis of \n18820 patients. Br. Med. J. 329, 15\u201319. ( A sobering analysis, emphasising \nthe frequency and cost of adverse drug reactions, most of which were \navoidable. Drugs most commonly implicated were aspirin and other \nNSAIDs, diuretics, warfarin; the most common reaction was gastrointestinal \nbleeding )\nTalbot, J., Aronson, J.K. (Eds.), 2012. Stephens\u2019 Detection and Evaluation \nof Adverse Drug Reactions, sixth ed. Wiley\u2013Blackwell, Oxford. \n(Invaluable reference book that is also readable )\nDrug toxicity: general and mechanistic aspects\nBhogal, N., Grindon, C., Combes, R., Balls, M., 2005. Toxicity testing: \ncreating a revolution based on new technologies. Trends Biotechnol. \n23, 299\u2013307. ( Reviews current and likely future value of new technologies in \nrelation to toxicological evaluation )\nTimbrell, J.A., 2009. Principles of Biochemical Toxicity. Informa \nHealthcare, New York.\nWalker, D.K., 2004. The use of pharmacokinetic and pharmacodynamic \ndata in the assessment of drug safety in early drug development. Br. J. \nClin. Pharmacol. 58, 601\u2013608. ( Pharmacokinetic profile is a factor in \nassessing safety during early drug development, especially in relation to \nsafety parameters such as QT interval prolongation, where free plasma \nconcentrations are predictive; procedures are available that allow this on the \nmicrodose scale \u2013 potential limitations are discussed )Wobus, A.M., Loser, P., 2011. Present state and future perspectives of \nusing pluripotent stem cells in toxicology research. Arch. Toxicol. 85, \n79\u2013117. ( Describes methods for selection and differentiation of cardiac and \nhepatic cells from human pluripotent stem cells )\nDrug toxicity: carcinogenesis, teratogenesis\nBriggs, G.G., Freeman, R.K., Towers, C.V., Forinash, A.V., 2017. Drugs \nin Pregnancy and Lactation, eleventh ed. Lippincott, Williams & \nWilkins, Philadelphia. ( Invaluable reference guide to fetal and neonatal risk \nfor clinicians caring for pregnant women )\nSj\u00f6str\u00f6m, H., Nilsson, R., 1972. Thalidomide and the Power of the Drug \nCompanies. Penguin Books, London.\nDrug toxicity: organ involvement\nMurray, M.C., Brater, D.C., 1993. Renal toxicity of the nonsteroidal \nanti-inflammatory drugs. Annu. Rev. Pharmacol. Toxicol. 33, 435\u2013465.\nPark, B.K., Kitteringham, N.R., Maggs, J.L., et al., 2005. The role of \nmetabolic activation in drug-induced hepatotoxicity. Annu. Rev. \nPharmacol. Toxicol. 45, 177\u2013202. ( Reviews evidence for reactive metabolite \nformation from hepatotoxic drugs such as paracetamol, tamoxifen, diclofenac \nand troglitazone, and the current hypotheses of how this leads to liver \ninjury )\nRitter, J.M., Harding, I., Warren, J.B., 2009. Precaution, cyclooxygenase \ninhibition, and cardiovascular risk. Trends Pharmacol. Sci. 30, \n503\u2013514.\nSvensson, C.K., Cowen, E.W., Gaspari, A.A., 2001.", "start_char_idx": 2915, "end_char_idx": 6143, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "bce158eb-fe8b-46cb-a1bb-6ca55a99b4fc": {"__data__": {"id_": "bce158eb-fe8b-46cb-a1bb-6ca55a99b4fc", "embedding": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "13aaaa90-26b0-429b-8e4a-18729a195c4d", "node_type": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "82a468af417a831c02e85304ba53a7a1b3268bde4defc20d2b982a81fee001cb"}, "2": {"node_id": "32cb72e8-dbb0-4192-9246-b015ca3bd5ae", "node_type": null, "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "0031c65a3131b8b872e38a4c2090ecdd77526fa9572fbc7370c626c0fbf14511"}}, "hash": "bffc6e3004ee47c2a2ad00a389b413e945800e58ee928cf609add133d9d3e4c1", "text": "Cowen, E.W., Gaspari, A.A., 2001. Cutaneous drug \nreactions. Pharmacol. Rev. 53, 357\u2013380. ( Covers epidemiology, clinical \nmorphology and mechanisms. Assesses current knowledge of four types of \ncutaneous drug reaction: immediate-type immune mediated, delayed-type \nimmune mediated, photosensitivity and autoimmune. Also reviews the role of \nviral infection as predisposing factor )\nValentin, J.P., 2010. Reducing QT liability and proarrhythmic risk in \ndrug discovery and development. Br. J. Pharmacol. 159, 5\u201311. ( See also \naccompanying articles in this themed section on QT safety )mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 6181, "end_char_idx": 7246, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ace68216-d5df-48a2-afe9-ea227dc7296a": {"__data__": {"id_": "ace68216-d5df-48a2-afe9-ea227dc7296a", "embedding": null, "metadata": {"page_label": "750", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f9d2ef38-7bd3-445a-ad65-c8ffeaa3df06", "node_type": null, "metadata": {"page_label": "750", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "208f6bc0b4dcbde6c4afe6d999b44ad81652e65f02eecf07c550e192325963a7"}, "3": {"node_id": "f12dcde1-a91f-4a3b-a2b8-f97ddf8c52d4", "node_type": null, "metadata": {"page_label": "750", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a758489f61eebd180806757819383f8adddcccf4ccbc79d9cbc7998c6e3ccb8f"}}, "hash": "d322e105b96417f2f39d5bdd005f8b5d239479dc43b88328ecb1dc6fa004ea82", "text": "744\nOVERVIEW\nThe term lifestyle denotes that such drugs are used \nfor non-medical purposes. It is a diverse group that \nincludes drugs of abuse, drugs used to enhance \nathletic or other performance, as well as those taken for cosmetic purposes or for purely social reasons. \nMany lifestyle drugs have dual uses and are also \nemployed as conventional therapeutics for other indications; their pharmacology is described elsewhere \nin this book. In this chapter we present an overall \nsummary of lifestyle drugs and discuss some of the social and medico-legal problems associated with their \ngrowing use.\nDrugs used to enhance sporting performance, while \nbeing officially prohibited, represent a special category \nof lifestyle drugs. Once again, many types of sub -\nstances are used for this purpose, including some \nestablished medicines. We discuss specific issues \nrelating to their use in competitive sports.\nWHAT ARE LIFESTYLE DRUGS?\nThis is a question that is sometimes difficult to answer. \nHere we define them as drugs or medicines that are taken \nby choice to give pleasure (e.g. cannabis, alcohol, cocaine), \nto improve performance (e.g. drugs in sport, cognition-enhancing drugs) or to improve appearance (e.g. botox, \nslimming aids for the non-obese), in other words, to satisfy an aspiration or a non-health-related goal rather than to treat a clinical condition. Put simply, they are drugs taken \nby choice by people who are not ill, and a better term might \nbe lifestyle uses as many are conventional therapeutic agents. \nExamples include the use of the antihypertensive minoxidil \nfor treating baldness. Oral contraceptives, which clearly \nlie in the domain of mainstream medicine, could also be \nconsidered lifestyle drugs. Also included are food supple -\nments and other related preparations (sometimes referred \nto as nutraceuticals) that are consumed because of some \nclaimed benefit \u2013 even though there is often no good evidence that they are effective.\nCLASSIFICATION OF LIFESTYLE DRUGS\nThe lifestyle category covers lifestyle uses of a wide variety \nof drugs and medicines and cuts across the pharmacological \nclassification used throughout this book. The scheme in \nTable 59.1 is based largely on the work of Gilbert et al. \n(2000) and Young (2003). It embraces drugs that have been \nused for lifestyle choices based on historical precedent, such as oral contraceptives, as well as agents used to manage potentially debilitating lifestyle illnesses such as addiction \nto smoking (e.g. bupropion; see Ch. 50). It also includes \ndrugs such as caffeine and alcohol that are consumed on \na massive scale around the world, and drugs of abuse such as cocaine as well as nutritional supplements.\nParticularly topical is the controversial use of \u2018neuro-\nenhancers\u2019, such as modafinil and methylphenidate (Ch. 49) which, under some circumstances can improve intel -\nlectual performance (see Sahakian & Morein-Zamir, 2007; \nSahakian & LaBuzetta, 2015, for example).\n1 The use of drugs \nthat improve cognitive defects in conditions such as \ndementia (Ch. 41), schizophrenia (Ch. 47) and depression \n(Ch. 48) is generally seen as desirable even though current drugs are only marginally effective. But watch this space! \n(see Chs. 41 and 49). Extending the use of existing and \nfuture drugs to give healthy people an advantage in competi-tive situations is much more controversial. The possibility, \nnot yet realised, of finding drugs able to prolong life by \nretarding the functional and degenerative changes charac -\nteristic of old age, is another social and ethical minefield.\nFor a more complete discussion of human enhancement \nby pharmacological means, see Buchanan (2011) and Flower \n(2012).\nOver time, drugs", "start_char_idx": 0, "end_char_idx": 3730, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "f12dcde1-a91f-4a3b-a2b8-f97ddf8c52d4": {"__data__": {"id_": "f12dcde1-a91f-4a3b-a2b8-f97ddf8c52d4", "embedding": null, "metadata": {"page_label": "750", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f9d2ef38-7bd3-445a-ad65-c8ffeaa3df06", "node_type": null, "metadata": {"page_label": "750", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "208f6bc0b4dcbde6c4afe6d999b44ad81652e65f02eecf07c550e192325963a7"}, "2": {"node_id": "ace68216-d5df-48a2-afe9-ea227dc7296a", "node_type": null, "metadata": {"page_label": "750", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "d322e105b96417f2f39d5bdd005f8b5d239479dc43b88328ecb1dc6fa004ea82"}}, "hash": "a758489f61eebd180806757819383f8adddcccf4ccbc79d9cbc7998c6e3ccb8f", "text": "Buchanan (2011) and Flower \n(2012).\nOver time, drugs can switch between \u2018lifestyle\u2019 and \n\u2018clinical\u2019 categories. For example, cocaine was used as a lifestyle drug by South American Indians. Early explorers commented that it \u2018satisfies the hungry, gives new strength \nto the weary and exhausted and makes the unhappy forget \ntheir sorrows\u2019. Originally adopted into European medicine as a local anaesthetic (Ch. 44), it is now largely returned \nto lifestyle drug status and, regrettably, is the basis of an \nillegal multimillion dollar international drugs industry. Cannabis is another good example of a drug that has been \nconsidered (in the West at least) as a purely recreational \ndrug but which is now (as a plant extract containing tet-rahydrocannabinol and cannabidiol ) licensed for various \nclinical uses (see Chs 20, 43 and 50). There are many other examples (Flower, 2004).\nMany widely used lifestyle \u2018drugs\u2019 or \u2018sports supplements\u2019 \nconsist of natural products (e.g. Ginkgo extracts, melatonin, \nSt John\u2019s wort, Cinchona extracts), the manufacture and sale of which have historically not been regulated.\n2 Their \ncomposition is therefore highly variable, and their efficacy Lifestyle and drugs in sport59 SPECIAL TOPICS SECTION 6\n1Drugs intended to give a competitive advantage in sport are, of course, \nconsidered unfair, banned and very actively policed. Will there come a \ntime when taking drugs to improve examination performance will \nbecome illegal, with similar surveillance methods and sanctions? See Bostrom and Sandberg (2009) for a discussion of this ethical minefield.\n2Happily, this is changing. Since 2014, the United Kingdom Medicines \nand Healthcare Products Regulatory Agency has a Herbal Medicines \nAdvisory Committee designed to fulfil this demanding role.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3677, "end_char_idx": 5942, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8ba95bb0-7867-489a-9112-3772232413b0": {"__data__": {"id_": "8ba95bb0-7867-489a-9112-3772232413b0", "embedding": null, "metadata": {"page_label": "751", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f2860091-ab12-492f-98c0-9e2b001839fe", "node_type": null, "metadata": {"page_label": "751", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2298c729346cd6bef25505805ed189a0e26b17255971ee535cc730806bfc80d"}, "3": {"node_id": "44f3d5b6-a5c0-41cc-bf7a-3330c590217c", "node_type": null, "metadata": {"page_label": "751", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "52c953b3380b049d852a6fdf43d3883ab570c428837d87a97c7278ca56ef1f15"}}, "hash": "c2c99e81a7f96cd905c8c01c67c8a2b1a310843c995b7a49af118613829e32b3", "text": "59 LIfESTyLE A nd drug S I n SPO r T\n745Chemsex \u2013 having sex often with multiple partners under \nthe influence of a combination of psychoactive drugs in \nsessions lasting several hours or days \u2013 has become \nincreasingly popular amongst certain gay men (see McCall \net al., 2015 for a fuller description). The drugs commonly \ntaken include mephedrone , \u03b3-hydroxybutyrate (GHB), and \nmethamphetamine (see Chs 39 and 49).\nDRUGS IN SPORT\nThe use of drugs to enhance performance (\u2018doping\u2019) in elite sporting competitions such as the Olympic games is evi -\ndently widespread, although officially prohibited. The World Anti-Doping Agency (WADA: http://www.wada-ama.org), which was established partly in response to some high-\nprofile doping cases and drug-induced deaths among \nathletes, publishes an annually updated list of prohibited substances that may not be used by sportsmen or and safety generally untested. Many contain active sub -\nstances that, like synthetic drugs, can produce harmful as \nwell as beneficial effects.\nDRUGS AND SEX\nA myriad of foods and natural products have been claimed \nto have aphrodisiac properties but the validity of such \nclaims remain largely unsubstantiated. Enhanced libido \nmay be a therapeutically useful outcome, e.g. pramipexole , \na dopamine receptor agonist, is sometimes used to coun -\nteract the decrease in libido induced by serotonin-selective reuptake inhibitor (SSRI) antidepressant drugs. From a lifestyle perspective, drugs associated with sexual activity \nare used not only to enhance performance and/or pleasure \nbut also to prevent negative consequences such as unwanted pregnancies and HIV infection. Table 59.2 provides a resume of various lifestyle drugs associated with sexual activity.Table 59.1 Some examples of lifestyle drugs and medicines (excluding drugs in sport)\nCategory Example(s) Primary clinical use \u2018Lifestyle\u2019 use Chapter\nMedicines approved \nfor specific indications but which also have other \u2018lifestyle\u2019 uses.Sildenafil\naErectile dysfunction Erectile enhancement 36\nOral contraceptives Preventing conception Preventing conception 36\nOrlistat Obesity Weight loss 33\nSibutramineAnorectic agent (withdrawn in Europe)Weight loss33\nMedicines approved for specific indications which can also be used to satisfy \u2018lifestyle choices\u2019 or to treat \u2018lifestyle diseases\u2019Minoxidil Hypertension Regrowth of hair 23\nMethylphenidate ADHDImproving academic performance49\nModafinil Treatment of ADHD Cognitive enhancement 49\nOpiates Analgesia \u2018Recreational\u2019 usage 43, 50\nDrugs that have only minor, or no, current clinical use but which fall into the lifestyle categoryAlcohol None as suchWidespread component of drinks50\nBotulinum toxin Relief of muscle spasm Cosmetic alteration 14\nCaffeine Migraine treatmentWidespread component of drinks16, 49\nCannabisManaging chronic pain, nausea and possibly muscle spasm\u2018Recreational\u2019 usage 20, 50\nDrugs (generally illegal) that have no clinical utility but which are used to satisfy lifestyle requirements\nbMethylenedioxy-methamphetamine (MDMA, \u2018ecstasy\u2019)None \u2018Recreational\u2019 usage 49\nTobacco (nicotine)Nicotine preparations for tobacco addiction\u2018Recreational\u2019 usage 50\nCocaine (some formulations)Local anaesthesia (largely obsolete)\u2018Recreational\u2019 usage 43\naObviously only in men. However, in some countries, flibanserin is used to increase female sexual desire and may turn out to be a new \naddition to this category.\nbIn addition, there are countless herbal preparations and other natural products, largely unregulated, which", "start_char_idx": 0, "end_char_idx": 3522, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "44f3d5b6-a5c0-41cc-bf7a-3330c590217c": {"__data__": {"id_": "44f3d5b6-a5c0-41cc-bf7a-3330c590217c", "embedding": null, "metadata": {"page_label": "751", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "f2860091-ab12-492f-98c0-9e2b001839fe", "node_type": null, "metadata": {"page_label": "751", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "b2298c729346cd6bef25505805ed189a0e26b17255971ee535cc730806bfc80d"}, "2": {"node_id": "8ba95bb0-7867-489a-9112-3772232413b0", "node_type": null, "metadata": {"page_label": "751", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c2c99e81a7f96cd905c8c01c67c8a2b1a310843c995b7a49af118613829e32b3"}}, "hash": "52c953b3380b049d852a6fdf43d3883ab570c428837d87a97c7278ca56ef1f15", "text": "there are countless herbal preparations and other natural products, largely unregulated, which are marketed as health-\npromoting, life-enhancing and beneficial for many disorders, despite lack of rigorous evidence of therapeutic efficacy. Examples include numerous vitamin preparations, fish oils, melatonin, ginseng, Echinacea, Ginkgo and much besides.\nADHD, attention deficit hyperactivity disorder.\n(From Flower, 2004, after Gilbert et al., 2000 and Young, 2003.)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3428, "end_char_idx": 4374, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "76b6b919-4e56-41ad-a612-83c64560a187": {"__data__": {"id_": "76b6b919-4e56-41ad-a612-83c64560a187", "embedding": null, "metadata": {"page_label": "752", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5dcae384-96ae-4e96-a215-4d22e30c67d0", "node_type": null, "metadata": {"page_label": "752", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "591d52ea07b8ed5cc026a345300e5d6fa36da53f4a92e75472ee8012d8fd98b6"}, "3": {"node_id": "70e9714e-5452-46d6-ba63-5acf2eb8b347", "node_type": null, "metadata": {"page_label": "752", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "14ae56685d314d3ab55f717d67180a1c176bf6f5ebaa0d3ed394a9f594f8ff58"}}, "hash": "bcd9d95a24ada865c50b9c14b16ec877aa3b8f3c1141ea14cb3d1573ae94488e", "text": "59 SECTION 6\u2003\u2003 SPECIAL TOPICS\n746doping programme had taken place, leading to a ban on \nthe Russian team\u2019s participation in the subsequent Summer \nOlympics and other events.\nTable 59.3 summarises the main classes of drugs currently \nbanned by WADA. While athletes are easily persuaded of the potential of a wide variety of drugs to increase their \nchances of winning, controlled trials of such claims are difficult. In many cases these agents probably produce little \nor no effect although of course, marginal improvements \nin performance (often 1% or less), which are difficult to measure experimentally, may make the difference between winning and losing, and the competitive instincts of athletes \nand their trainers generally carry more weight than scientific \nevidence.\nA brief account of some of the more important drugs in \ncommon use follows. For a broader and more complete coverage, see British Medical Association (2002), Reardon and Creado (2014) and Mottram (2005). Gould (2013) has \nreviewed the potential use of gene therapy in promoting \nathletic performance. Another potential nightmare for the regulators!\nANABOLIC STEROIDS\nAnabolic steroids (Ch. 36) include a large group of compounds with testosterone-like effects, including about 50 named \ncompounds on the prohibited list. New chemical derivatives \n(\u2018designer steroids\u2019), such as tetrahydrogestrinone (THG), \nare regularly developed and offered illicitly to athletes, \nposing a continuing problem to the authorities charged with \ndetecting and identifying them. A further problem is that some of these drugs are endogenous compounds or their \nmetabolites and their concentration can vary dramatically \nfor physiological reasons. This makes it difficult to prove that the substance had been administered illegally. Isotope ratio techniques, based on the fact that endogenous and \nexogenous steroids have slightly different \n12C:13C ratios, \nmay enable the two to be distinguished analytically. Since anabolic steroids produce long-term effects and are normally \nused throughout training, rather than during the event itself, out-of-competition testing is essential.\nWhen given in combination with training and high protein \nintake, anabolic steroids undoubtedly increase muscle mass sportswomen either in, or out of, competition. Drug testing is based mainly on analysis of blood or urine samples \naccording to strictly defined protocols. The chemical \nanalyses, which rely mainly on gas chromatography/mass spectrometry or immunoassay techniques, must be carried \nout by approved laboratories.Table 59.2 Drugs associated with sexual activity\nDrug Function Notes\nOestrogens and \nprogestogens (Ch. 36)Contraception \u2014\nLevonorgestrel (Ch. 36) Postcoital contraception The morning after pill taken to avoid conception by women after unprotected sex\nSildenafil (Chs 21 and 36) Maintain erection To enhance male sexual function\nBenzocaine (Ch. 44) Delay ejaculation Contained in condoms for topical application to the penis\nFlibanserin Enhance female sexual pleasure Not yet available in United Kingdom\nAntiretroviral drugs (Ch. 53) Prophylactic treatment for HIV infection For gay men following unprotected sex\nAmyl nitrite Anal sphincter relaxation Primarily used by gay men\nMethamphetamine (crystal meth)Increase libido and cause frequent or prolonged erectionsOccurs with high dosesTaken along with mephedrone and GHB in chemsex\nGHB, \u03b3-hydroxybutyrate.\nLifestyle drugs \n\u2022\tMore\taccurately \tcalled \tlifestyle uses, these comprise a \ngroup of drugs and medicines taken mainly for \nnon-medical reasons.\n\u2022\tInclude\tprescription \tdrugs \tsuch \tas \tsildenafil and \nmethylphenidate, substances such as alcohol and \ncaffeine, drugs of abuse and various nutritional", "start_char_idx": 0, "end_char_idx": 3725, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "70e9714e-5452-46d6-ba63-5acf2eb8b347": {"__data__": {"id_": "70e9714e-5452-46d6-ba63-5acf2eb8b347", "embedding": null, "metadata": {"page_label": "752", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "5dcae384-96ae-4e96-a215-4d22e30c67d0", "node_type": null, "metadata": {"page_label": "752", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "591d52ea07b8ed5cc026a345300e5d6fa36da53f4a92e75472ee8012d8fd98b6"}, "2": {"node_id": "76b6b919-4e56-41ad-a612-83c64560a187", "node_type": null, "metadata": {"page_label": "752", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "bcd9d95a24ada865c50b9c14b16ec877aa3b8f3c1141ea14cb3d1573ae94488e"}}, "hash": "14ae56685d314d3ab55f717d67180a1c176bf6f5ebaa0d3ed394a9f594f8ff58", "text": "such as alcohol and \ncaffeine, drugs of abuse and various nutritional \npreparations.\n\u2022\tAre\tlinked \tto \tthe \tconcepts \tof \t\u2018self-diagnosis\u2019 \tand \t\n\u2018non-disease\u2019.\n\u2022\tAre\ta\tgrowing \tsector \tof \tthe \tpharmaceutical \tmarket.\n\u2022\tAre\toften \tbrought \tto \tthe \tconsumer\u2019s \tattention \tthrough \t\nthe internet or direct marketing.\n3Apparently including steroids, growth hormone and erythropoietin. He \nwas later stripped of all his sporting honours.Despite these precautions, there have been many instances \nwhere these rules have been flouted both by individual \nathletes or, in some cases, by entire teams. The American \ncyclist Lance Armstrong was a national hero who, having overcome testicular cancer, went on to win the Tour de \nFrance on no less than seven occasions. Persistent accusa -\ntions of drug abuse were strenuously denied until January \n2013, when Armstrong admitted having used a cocktail of \ndrugs to enhance his performance over the course of many \nyears.\n3 It prompted one commentator (Sparling, 2013) to \ndespair of the \u2018charade of drug-free sport\u2019.\nIn 2016, WADA published the results of an investigation \nin Russia, concluding that a large-scale state-sponsored mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3656, "end_char_idx": 5307, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c1961838-3f8e-41f7-8a65-e28fe712f7f5": {"__data__": {"id_": "c1961838-3f8e-41f7-8a65-e28fe712f7f5", "embedding": null, "metadata": {"page_label": "753", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3afc5220-81af-44e6-be83-9c926f482e76", "node_type": null, "metadata": {"page_label": "753", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb5d6bcc0d0c7a4297da3ac7a0a9cae635a07cd2459286582dfcda1bbc476fe8"}, "3": {"node_id": "5d55868c-ff46-412d-87ee-c584832619fa", "node_type": null, "metadata": {"page_label": "753", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "53f2e0dda9c0f426854b3f04142f55ad608413ed63dbd1ed30cd420fed9c39a4"}}, "hash": "c3cfa921e442b07fde275f1573ca7aba4d425f23988ce27b87e4510056f161e5", "text": "59 LIfESTyLE A nd drug S I n SPO r T\n747produce a feeling of physical well-being, increased com -\npetitiveness and aggressiveness, sometimes progressing to \nactual psychosis. Depression is common when the drugs \nare stopped, sometimes leading to long-term psychiatric problems. In attempt to circumvent the rules, other drugs \nthat release androgens, for example, human chorionic and strength but probably not other parameters of sporting \nperformance. However, they have serious long-term effects, \nincluding male infertility, female masculinisation, liver and \nkidney tumours, hypertension and increased cardiovascular risk, and (in adolescents) premature skeletal maturation \ncausing irreversible cessation of growth. Anabolic steroids Table 59.3 Some examples of drugs used in sport\nDrug class Example(s) Effects Detection Notes\nAnabolic agentsAndrogenic steroids \n(testosterone, nandrolone and many others; Ch. 36)Increased muscle development, aggression and competitivenessSerious long-term side effectsUrine or blood samplesMany are endogenous hormones, so results significantly above normal range are required\nClenbuterol (Ch. 15)Combined anabolic and agonist action on \u03b2\n2 adrenoceptors may \nincrease muscle strength\u2014Human chorionic gonadotrophin \nis sometimes used to increase \nandrogen secretion\nHormones and \nrelated substancesErythropoietin (Ch. 26)Increased erythrocyte formation and oxygen transport. Increased blood viscosity causes hypertension and risk of strokes and coronary attacksUsed mainly for endurance sports\naPlasma half-life is short, so detection is difficultUse of other plasma markers indicating erythropoietin administration may be possible\nHuman growth hormone (Ch. 34)Increased lean body mass and reduced fatMay accelerate recovery from tissue injury. Causes cardiac hypertrophy, acromegaly, liver damage and increased cancer riskBlood testingDistinguishing endogenous (highly variable) from exogenous human growth hormone can be difficult\nInsulin (Ch. 32)Sometimes used (with glucose so as to avoid hypoglycaemia) to promote glucose uptake and energy production in muscleProbably ineffective in improving performancePlasma samples \u2014\n\u03b2\n2-Adrenoceptor \nagonistsSalbutamol and others (Ch. 15)Used by runners, cyclists, swimmers, etc. to increase oxygen uptake (by bronchodilatation) and increased cardiac function. Controlled studies show no improvement in performanceUrine samples \u2014\n\u03b2-Adrenoceptor antagonistsPropranolol, etc. (Ch. 15)Used to reduce tremor and anxiety in \u2018precision\u2019 sports (e.g. shooting, gymnastics, diving)Urine samples Not banned in most sports, where they actually impair performance\nCNS \u2018stimulants\u2019Ephedrine and derivatives; amphetamines, cocaine, caffeine (Ch. 49)Many trials show slight increase in muscle strength and performance in non-endurance events (sprint, swimming, field events, etc.)Urine samplesThe most widely used group, along with anabolic steroids\nDiureticsThiazides, furosemide (Ch. 30)Used mainly to achieve rapid weight loss before \u2018weighing in\u2019. Also used to \u2018mask\u2019 the presence of other agents in urine by dilutionUrine samples \u2014\nNarcotic analgesicsCodeine, morphine, etc. (Ch. 43)Used to mask injury-associated painUrine samples \u2014\na\u2018Blood\tdoping\u2019 \t(removal \tof \t1\u20132 \tL \tof \tblood \twell \tahead \tof \tthe \tcompetition, \tfollowed \tby \tre-transfusion \timmediately \tprior \tto \tthe \tevent) \thas \ta \t\nsimilar effect and is even more difficult to detect. Training at altitude or in a hypoxic environment achieves a similar effect and is not banned.mebooksfree.net", "start_char_idx": 0, "end_char_idx": 3536, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5d55868c-ff46-412d-87ee-c584832619fa": {"__data__": {"id_": "5d55868c-ff46-412d-87ee-c584832619fa", "embedding": null, "metadata": {"page_label": "753", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "3afc5220-81af-44e6-be83-9c926f482e76", "node_type": null, "metadata": {"page_label": "753", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "cb5d6bcc0d0c7a4297da3ac7a0a9cae635a07cd2459286582dfcda1bbc476fe8"}, "2": {"node_id": "c1961838-3f8e-41f7-8a65-e28fe712f7f5", "node_type": null, "metadata": {"page_label": "753", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c3cfa921e442b07fde275f1573ca7aba4d425f23988ce27b87e4510056f161e5"}}, "hash": "53f2e0dda9c0f426854b3f04142f55ad608413ed63dbd1ed30cd420fed9c39a4", "text": "a hypoxic environment achieves a similar effect and is not banned.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3455, "end_char_idx": 4000, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3a33df6a-926c-40b0-afe2-a07d1064c1d1": {"__data__": {"id_": "3a33df6a-926c-40b0-afe2-a07d1064c1d1", "embedding": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "68fc85f5-3e31-40a1-b5c6-49b22968f7ab", "node_type": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59ca7af12d1706bd58217bd6fdb02b3024c88c72c21ba8383bdfefef3955498e"}, "3": {"node_id": "7ebf729f-8750-46ba-9847-afbb179d3012", "node_type": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e8822e474dfa415520a600dbb1f3a8b0c568df275863ee848565f878b0482310"}}, "hash": "07d35928752df9ae7cfc9b7330c3d13dd4e71e9230afd9de4f7bd0e3b1a07692", "text": "59 SECTION 6\u2003\u2003 SPECIAL TOPICS\n748strength and reduce muscle fatigue significantly. The \npsychological effect of stimulants is probably as important \nas their physiological effects. Surprisingly, caffeine appears \nto be more consistently effective in improving muscle performance than other more powerful stimulants and is \namongst a few drugs (including nicotine and alcohol) that \nare not prohibited.\nSeveral deaths have occurred among athletes taking \namphetamines and ephedrine-like drugs in endurance events. The main causes are coronary insufficiency, associ -\nated with hypertension; hyperthermia, associated with cutaneous vasoconstriction; and dehydration.\nDrug use by athletes for bona fide clinical reasons is \nallowed under the \u2018Therapeutic Use Exemptions\u2019 scheme. According to this scheme, which was introduced in the \n1990s, an athlete may use a medicine (say, glucocorticoids \nfor asthma) if it is determined clinically that this exemption is justified. Clearly, this system could be open to abuse.\nThe financial and reputational inducements for athletes \ntaking performance enhancing drugs are great whilst the chance of getting caught is quite small, fuelling the search \nfor better and less detectable agents. This in turn poses \nfurther analytical problems for the regulators who must devise screening tests to monitor an increasing range of \nagents, some of which are difficult to assay. The contest \ncontinues as new \u2018designer\u2019 drugs, masking agents (which make it more difficult to detect a particular substance in \nthe blood or urine) or procedures are devised by ingenious \nchemists and physicians.\nDoping is banned in professional sports because it \nconstitutes an unfair advantage for the athletes who \u2018cheat\u2019. \nHowever, many other factors are important in determining \nwhy one athlete may have an advantage over another \u2013 genetic makeup, for example \u2013 so there is no real \u2018level \nplaying field\u2019 to begin with. Indeed some argue that athletes \nshould have unrestricted access to performance enhancing drugs with the proviso that they do not impair the athlete\u2019s \nhealth (see Savulescu et al., 2004), but this view is unlikely \nto gain public acceptance in the near future.\nCONCLUSION\nThe lifestyle drug phenomenon is one aspect of a broader debate about what actually constitutes \u2018disease\u2019 and how \nfar medical science should go to satisfy the aim of human \nenhancement and the needs and aspirations of otherwise healthy individuals, or to alleviate human distress and \ndysfunction in the absence of pathology. Discussion of these \nissues is beyond the scope of this book but can be found in articles cited at the end of this chapter (see Flower, 2004; \n2012).\nThere are several reasons why these drugs \u2013 no matter \nhow we choose to define them \u2013 are of increasing concern. The increasing availability of drugs (some counterfeit) from \n\u2018e-pharmacies\u2019, coupled with the direct advertising by the \npharmaceutical industry to the public that occurs in some countries, will ensure that demand is kept buoyant. Most \nsales are in the developed world and the pharmaceutical \nindustry will undoubtedly develop more lifestyle agents to cater for this lucrative market. The lobbying power of \npatients advocating particular drugs, regardless of the \npotential costs or proven utility, causes major problems for drug regulators and those who set healthcare priorities \nfor state-funded systems of social medicine.gonadotrophin (hCG , Ch. 36) or modify their action, such as \nandrogen receptor modulators (Ch. 4), are increasingly used.\nClenbuterol, is a \u03b2-adrenoceptor agonist (see Ch. 15). \nThrough an unknown mechanism of action, it produces anabolic effects similar to those of androgenic steroids, \nwith apparently fewer adverse effects. It can be detected in urine and its use in sport is", "start_char_idx": 0, "end_char_idx": 3812, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7ebf729f-8750-46ba-9847-afbb179d3012": {"__data__": {"id_": "7ebf729f-8750-46ba-9847-afbb179d3012", "embedding": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "68fc85f5-3e31-40a1-b5c6-49b22968f7ab", "node_type": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59ca7af12d1706bd58217bd6fdb02b3024c88c72c21ba8383bdfefef3955498e"}, "2": {"node_id": "3a33df6a-926c-40b0-afe2-a07d1064c1d1", "node_type": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "07d35928752df9ae7cfc9b7330c3d13dd4e71e9230afd9de4f7bd0e3b1a07692"}, "3": {"node_id": "880f6737-631d-41fe-b1a8-25123314706e", "node_type": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ca4fd470dea59e9a4d01e7988c190542922bf40321b1e74bec1816f1730761fd"}}, "hash": "e8822e474dfa415520a600dbb1f3a8b0c568df275863ee848565f878b0482310", "text": "adverse effects. It can be detected in urine and its use in sport is banned.\nHUMAN GROWTH HORMONE\nThe use of human growth hormone (hGH; see Ch. 34) by \nathletes followed the availability of the recombinant form \nof hGH, used to treat endocrine disorders. It is given by \ninjection and its effects appear to be similar to those of anabolic steroids. hGH is also reported to produce a similar \nfeeling of well-being, although without the accompanying \naggression and changes in sexual development and behav -\niour. It increases lean body mass, reduces fat and improves \nsprint capacity, but its effects on other aspects of athletic \nperformance are unclear. It is claimed to increase the rate of recovery from tissue injury, allowing more intensive training routines. The main adverse effect of hGH is the \ndevelopment of acromegaly, causing overgrowth of the \njaw and thickening of the fingers (Ch. 34), but it may also lead to cardiac hypertrophy and cardiomyopathy, and \npossibly also an increased cancer risk.\nDetection of hGH administration is difficult because \nphysiological secretion is pulsatile, so normal plasma concentrations vary widely. The plasma half-life is short \n(20\u201330 m in), and only trace amounts are excreted in urine. \nHowever, secreted hGH consists of three isoforms varying \nin molecular weight, whereas recombinant hGH contains \nonly one, so measuring the relative amounts of the isoforms \ncan be used to detect the exogenous material. Growth hormone acts partly by releasing insulin-like growth factor \n(IGF) from the liver, and this hormone itself is sometimes \nused by athletes.\nAnother hormone, erythropoietin, which increases \nerythrocyte production (see Ch. 26), is given by injection for days or weeks to increase the erythrocyte count and hence boost the O\n2-carrying capacity of blood. The develop -\nment of recombinant erythropoietin has made it widely \navailable, and detection of its use is difficult. It carries a \nrisk of hypertension, neurologic disease and thrombosis.\nSTIMULANT DRUGS\nThe main drugs of this type used by athletes and officially prohibited are: ephedrine and methylephedrine; various \namphetamines and similar drugs, such as fenfluramine \nand methylphenidate\n4; cocaine; and a variety of other central \nnervous system stimulants such as nikethamide , amiphena -\nzole (no longer used clinically) and strychnine (see Ch. \n49). Caffeine is also used: some commercially available \u2018energy drinks\u2019 contain taurine as well as caffeine. However, \ntaurine is an agonist at glycine and extrasynaptic GABA\nA \nreceptors (see Ch. 40). Its effects on the brain are therefore likely to be inhibitory rather than stimulatory. In this regard, \ntaurine may be responsible for the post-energy-drink low that is experienced once the stimulatory effect of caffeine \nhas worn off.\nIn contrast to steroids, some trials have shown stimulant \ndrugs to improve performance in events such as sprinting, and under experimental conditions they increase muscle \n4Also used to improve academic performance!mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3758, "end_char_idx": 7223, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "880f6737-631d-41fe-b1a8-25123314706e": {"__data__": {"id_": "880f6737-631d-41fe-b1a8-25123314706e", "embedding": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "68fc85f5-3e31-40a1-b5c6-49b22968f7ab", "node_type": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "59ca7af12d1706bd58217bd6fdb02b3024c88c72c21ba8383bdfefef3955498e"}, "2": {"node_id": "7ebf729f-8750-46ba-9847-afbb179d3012", "node_type": null, "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "e8822e474dfa415520a600dbb1f3a8b0c568df275863ee848565f878b0482310"}}, "hash": "ca4fd470dea59e9a4d01e7988c190542922bf40321b1e74bec1816f1730761fd", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7231, "end_char_idx": 7326, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "0f5667e2-9c19-4292-a60f-b9f11325b8f9": {"__data__": {"id_": "0f5667e2-9c19-4292-a60f-b9f11325b8f9", "embedding": null, "metadata": {"page_label": "755", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ffb86c1-af35-473a-9ec0-79c7fa9b03dd", "node_type": null, "metadata": {"page_label": "755", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "896da2eaa8f22b8320e9e1f56d7ffcbade6170938f9f3ea12c4601cd4b70cb99"}, "3": {"node_id": "3998ee1e-8512-4b19-9999-9f05d52cfa7c", "node_type": null, "metadata": {"page_label": "755", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "1bb92a4148898a1b7a6ed3aaacc07452745ffcdd8c605063eb6bde4cab918f0c"}}, "hash": "4c75ef1726d08e1e67725020255c18e2105544747ecc64cdf937cb5633bfab39", "text": "59 LIfESTyLE And drugS In SPOrT\n749REFERENCES AND FURTHER READING\nBostrom, N., Sandberg, A., 2009. Cognitive enhancement: methods, \nethics, regulatory challenges. Sci. Eng. Ethics 15, 343\u2013349. ( Interesting \ndiscussion of a complex problem which will soon have to be faced )\nFlower, R.J., 2004. Lifestyle drugs: pharmacology and the social agenda. \nTrends Pharmacol. Sci. 25, 182\u2013185. ( Accessible review that enlarges on \nsome of the issues raised in this chapter )\nFlower, R., 2012. The Osler Lecture 2012: pharmacology 2.0, medicines, \ndrugs and human enhancement. QJM 105, 823\u2013830. ( Discusses \u2018human \nenhancement\u2019 from a pharmacologist\u2019s viewpoint. Easy to read )\nGilbert, D., Walley, T., New, B., 2000. Lifestyle medicines. BMJ 321, \n1341\u20131344. ( Short but focused review dealing mainly with the clinical \nimplications of the \u2018lifestyle medicine\u2019 phenomenon )\nMcCall, H., Adams, N., Mason, D., Willis, J., 2015. What is chemsex and \nwhy does it matter? BMJ 351, h5790. ( Brief description of the use of \nvarious drugs in chemsex sessions )\nSahakian, B., LaBuzetta, J., 2015. Bad Moves: How Decision Making \nGoes Wrong, and the Ethics of Smart Drugs. OUP Oxford, Oxford. \np. 192. ( A very interesting book which deals at length with the ethics of \nneuroenhancement using a decision-making model to illustrate their effects. \nFascinating reading )\nSahakian, B., Morein-Zamir, S., 2007. Professor\u2019s little helper. Nature \n450, 1157\u20131159. ( Interesting \u2018commentary\u2019 of the use of neuroenhancers, \nespecially by academics, and the ethical questions that this raises. \nRecommended )\nWalley, T., 2002. Lifestyle medicines and the elderly. Drugs Aging 19, \n163\u2013168. ( Excellent review of the whole area and its relevance to the \ntreatment of the elderly )\nYoung, S.N., 2003. Lifestyle drugs, mood, behaviour and cognition. J. \nPsychiatry Neurosci. 28, 87\u201389.\nDrugs in sport\nBritish Medical Association, 2002. Drugs in Sport: The Pressure to \nPerform. BMJ Publications, London. ( Useful coverage of the whole topic )Buchanan, A., 2011. Better Than Human. The Promise and Perils of \nEnhancing Ourselves. Oxford University Press Inc., New York. p. 199. \n(Fascinating book which explores the whole topic of human enhancement \nincluding genetic and pharmacological approaches. Recommended for the \nserious reader )\nGould, D., 2013. Gene doping: gene delivery for Olympic victory. Br. J. \nClin. Pharmacol. 76, 292\u2013298. ( Discusses what must surely be the next \nchallenge to the WADA: deliberately introducing into athletes genes that \ncould boost performance )\nMottram, D.R. (Ed.), 2005. Drugs in Sport, fourth ed. Routledge, \nLondon. ( Comprehensive description of pharmacological and regulatory \naspects of drugs in sport, with balanced discussion of evidence relating to \nefficacy and risk )\nMunby, J., 2010. Drugs in sport. Scott. Med. J. 55, 29\u201330. ( Brief review of \nthe use of drugs in sport \u2013 both professional and amateur \u2013 written from the \npoint of view of a physician )\nReardon, C.L., Creado, S., 2014. Drug abuse in athletes. Subst. Abuse \nRehabil. 5, 95\u2013105. ( A good review of drug abuse in sports and notes about \nthe main types of agents used )\nSparling, P.B.,", "start_char_idx": 0, "end_char_idx": 3170, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "3998ee1e-8512-4b19-9999-9f05d52cfa7c": {"__data__": {"id_": "3998ee1e-8512-4b19-9999-9f05d52cfa7c", "embedding": null, "metadata": {"page_label": "755", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "1ffb86c1-af35-473a-9ec0-79c7fa9b03dd", "node_type": null, "metadata": {"page_label": "755", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "896da2eaa8f22b8320e9e1f56d7ffcbade6170938f9f3ea12c4601cd4b70cb99"}, "2": {"node_id": "0f5667e2-9c19-4292-a60f-b9f11325b8f9", "node_type": null, "metadata": {"page_label": "755", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4c75ef1726d08e1e67725020255c18e2105544747ecc64cdf937cb5633bfab39"}}, "hash": "1bb92a4148898a1b7a6ed3aaacc07452745ffcdd8c605063eb6bde4cab918f0c", "text": "and notes about \nthe main types of agents used )\nSparling, P.B., 2013. The Lance Armstrong saga: a wake-up call for drug \nreform in sports. Curr. Sports Med. Rep. 12, 53\u201354. ( Brief commentary \non the Lance Armstrong affair )\nSavulescu, J., Foddy, B., Clayton, M., 2004. Why we should allow \nperformance enhancing drugs in sport. Br. J. Sports Med. 38, 666\u2013670. \n(The authors put forward a compelling argument for allowing access to \nperformance enhancing drugs, but concentrating more on health of the \nathletes )\nSpedding, M., Spedding, C., 2008. Drugs in sport: a scientist\u2013athlete\u2019s \nperspective: from ambition to neurochemistry. Br. J. Pharmacol. 154, \n496\u2013501. ( Very accessible review written by two brothers, one of whom is an \nOlympic athlete and the other a pharmacologist. Unique insights. Highly \nrecommended )Drugs in sport \n\u2022\tMany\tdrugs\tof\tdifferent\ttypes\tare\tcommonly\t used\tby\t\nathletes with the aim of improving performance in \ncompetition.\n\u2022\tThe\tmain\ttypes\tused\tare:\n\u2013\tanabolic\t agents,\tmainly\tandrogenic\t steroids\tand\t\nclenbuterol ;\n\u2013\thormones,\t particularly\t erythropoietin and human \ngrowth hormone ;\n\u2013\tstimulants,\t mainly\t amphetamine and ephedrine \nderivatives and caffeine;\n\u2013\t\u03b2-adrenoceptor antagonists, to reduce anxiety and \ntremor\tin\t\u2018precision\u2019\t sports.\u2022\tThe\tuse\tof\tdrugs\tin\tsport\tis\tofficially\tprohibited\t \u2013\tin\tmost\t\ncases, in or out of competition.\n\u2022\tDetection\t depends\tmainly\ton\tanalysis\tof\tthe\tdrug\tor\tits\t\nmetabolites\t in\turine\tor\tblood\tsamples.\t Detection\t of\t\nabuse is difficult in the case of endogenous hormones \nsuch as erythropoietin , growth hormone and \ntestosterone .\n\u2022\tControlled\t trials\thave\tmostly\tshown\tthat\tdrugs\tproduce\t\nlittle\timprovement\t in\tsporting\tperformance.\t Anabolic\t\nagents increase body weight and muscle volume without \nclearly increasing strength. The effect of stimulants is \noften psychological rather than physiological.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3106, "end_char_idx": 5472, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8f5d5c47-08f3-4f17-95a3-e8aa7830c766": {"__data__": {"id_": "8f5d5c47-08f3-4f17-95a3-e8aa7830c766", "embedding": null, "metadata": {"page_label": "756", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0219df1b-ec17-413e-baf0-9d4c04d77642", "node_type": null, "metadata": {"page_label": "756", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "161e8a5a174979ebaaf31b824db3ea2fa94a2cc82e58e3a4f11de4fd6a9ed8b2"}, "3": {"node_id": "033fb2e1-314b-4e64-8a65-af53fe175bc9", "node_type": null, "metadata": {"page_label": "756", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "77bfb05467eaac142ac596e50ab7cd0654db515c7ddc5eaf0be1d2a2b24d675c"}}, "hash": "12d6970403dcb27d7305a23f0a8f0f0222e3d2561f558cfb06b8e145a5c92d8e", "text": "750\nOVERVIEW\nWith the development of the pharmaceutical industry \ntowards the end of the 19th century, drug discovery \nbecame a highly focused and managed process and \nmoved from the domain of inventive doctors to that of scientists hired for the purpose. The bulk of modern \ntherapeutics, and of modern pharmacology, is based \non drugs that originated from the laboratories of these pharmaceutical companies, without which neither \nthe practice of therapeutics nor the science of phar -\nmacology would be more than a pale fragment of \nwhat they have become.\nIn this chapter, we outline the main stages of the \nprocess, namely (i) the discovery phase, i.e. the identification of a new chemical entity as a potential \ntherapeutic agent; and (ii) the development phase, \nduring which the compound is tested for safety and efficacy in one or more clinical indications, and suitable \nformulations and dosage forms devised. The aim is \nto achieve registration by one or more regulatory authorities, to allow the drug to be marketed legally \nas a medicine for human use.\nOur account is necessarily brief and superficial, and \nmore detail can be found elsewhere ( Hill & Rang, \n2013).\nTHE STAGES OF A PROJECT\nFig. 60.1 shows in an idealised way the stages of a \u2018typical\u2019 \nproject, aimed at producing a marketable drug that meets \na particular medical need (e.g. to retard the progression of \nParkinson\u2019s disease or cardiac failure, or to treat drug-resistant infections).\nBroadly, the process can be divided into three main \ncomponents:\n1. Drug discovery, during which candidate molecules are chosen on the basis of their pharmacological \nproperties.\n2. Preclinical development, during which a wide range of \nnon-human studies (e.g. toxicity testing, \npharmacokinetic/pharmacodynamic analysis and \nformulation) are performed.\n3. Clinical development, during which the selected compound is tested for efficacy, side effects and \npotential dangers in volunteers and patients.\nThese phases do not necessarily follow in strict succession, \nas indicated in Fig. 60.1, but generally overlap.THE DRUG DISCOVERY PHASE\nGiven the task of planning a project to discover a new drug to treat \u2013 say, Parkinson\u2019s disease \u2013 where does one start? \nAssuming that we are looking for a novel drug rather than \ndeveloping a slightly improved \u2018me-too\u2019 version of a drug already in use,\n1 we first need to choose a new molecular \ntarget.\nTARGET SELECTION\nAs discussed in Chapter 2, drug targets are, with few exceptions, functional proteins (e.g. receptors, enzymes, \ntransport proteins). Although, in the past, drug discovery \nprogrammes were often based \u2013 successfully \u2013 on measuring a complex response in vivo, such as prevention of experi -\nmentally induced seizures, lowering of blood sugar or suppression of an inflammatory response, without the need for prior identification of a drug target, nowadays this is \nrare, and the first step is target identification . This most often \ncomes from biological intelligence. It was known, for \nexample, that inhibiting angiotensin-converting enzyme lowers blood pressure by suppressing angiotensin II forma -\ntion, so it made sense to look for antagonists of the vascular angiotensin II receptor \u2013 hence the successful \u2018sartan\u2019 series of antihypertensive drugs (Ch. 23). Similarly, the knowledge \nthat breast cancer is often oestrogen-sensitive led to the \ndevelopment of aromatase inhibitors such as anastrozole, \nwhich prevents oestrogen synthesis. A recent survey of \n1194 FDA-approved human medicines (Santos et al., 2017) \nnoted that they acted at a total of 893 targets, of which 667 were human proteins (comprising 549 small molecule and \n146 biopharmaceutical", "start_char_idx": 0, "end_char_idx": 3688, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "033fb2e1-314b-4e64-8a65-af53fe175bc9": {"__data__": {"id_": "033fb2e1-314b-4e64-8a65-af53fe175bc9", "embedding": null, "metadata": {"page_label": "756", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "0219df1b-ec17-413e-baf0-9d4c04d77642", "node_type": null, "metadata": {"page_label": "756", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "161e8a5a174979ebaaf31b824db3ea2fa94a2cc82e58e3a4f11de4fd6a9ed8b2"}, "2": {"node_id": "8f5d5c47-08f3-4f17-95a3-e8aa7830c766", "node_type": null, "metadata": {"page_label": "756", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "12d6970403dcb27d7305a23f0a8f0f0222e3d2561f558cfb06b8e145a5c92d8e"}}, "hash": "77bfb05467eaac142ac596e50ab7cd0654db515c7ddc5eaf0be1d2a2b24d675c", "text": "were human proteins (comprising 549 small molecule and \n146 biopharmaceutical drug targets) and a further 189 were \npathogen protein targets. However, there are many other proteins that are thought to play a role in disease (estimates \nrange from a few hundred to several thousand: see Betz, \n2005; http://www.guidetopharmacology.org/lists.jsp) for which we still have no cognate drug. Many of these represent \npotential starting points for drug discovery and await \ntherapeutic exploitation. Selecting valid and \u2018druggable\u2019 \ntargets from this plethora is a major challenge.\nConventional biological wisdom, drawing on a rich fund \nof knowledge of disease mechanisms and chemical signalling Drug discovery and development60 SPECIAL TOPICS SECTION 6\n1Many commercially successful drugs have in the past emerged from \nexactly such \u2018me-too\u2019 projects; examples are the many \u03b2-adrenoceptor-\nblocking drugs developed in the wake of propranolol, and the \u2018triptans\u2019 \nthat followed the introduction of sumatriptan to treat migraine. Quite small improvements (e.g. in pharmacokinetics or side effects), coupled \nwith aggressive marketing, have often proved enough, but the barriers \nto registration are getting higher, so the emphasis has shifted towards developing innovative (first in class) drugs aimed at novel molecular \ntargets.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3611, "end_char_idx": 5413, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "b6aeefb1-d1dd-48b9-97ba-62ecf513f8f0": {"__data__": {"id_": "b6aeefb1-d1dd-48b9-97ba-62ecf513f8f0", "embedding": null, "metadata": {"page_label": "757", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "16832475-1d59-4503-aa10-01305d150f27", "node_type": null, "metadata": {"page_label": "757", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f27c6f636b83ecf258528e3ffeb349e5b31235ad228563067010982da550825f"}, "3": {"node_id": "9a4b7a14-0797-4ffc-9cc2-1c50e11386f7", "node_type": null, "metadata": {"page_label": "757", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c56a3d5b6d04e7e7c2e11adcd57ade5c513e6fba8d4f2be613c810e7d3aaacdd"}}, "hash": "f8b7b6965912fa9e68c20e9d3e55c349f4f828663b9d30ab5400cfbcb1d041f1", "text": "60 Drug DISCO v E ry A n D DE v ELOP m E n T\n751if possible with an optical read-out (e.g. fluorescence or \noptical absorbance), and in a miniaturised multiwell plate \nformat (96-, 384-, 1536- or 3456-well versions are available) \nfor reasons of speed and economy. Robotically controlled assay facilities capable of testing tens of thousands of \ncompounds per day\n2 in several parallel assays are now \ncommonplace in the pharmaceutical industry, and have become the standard starting point for most drug discovery \nprojects. For details on high-throughput screening, see H\u00fcser (2006).\nTo keep such hungry monsters running requires very \nlarge compound libraries. Large companies will typically \nmaintain a growing collection of a million or more synthetic \ncompounds, which will be routinely screened whenever a \nnew assay is set up. Whereas, in the past, compounds were generally synthesised and purified one by one, often taking a week or more for each, the use of combinatorial chemistry \nallows large families of related compounds to be made \nsimultaneously. By coupling such high-speed chemistry to high-throughput assay systems, the time taken over the \ninitial lead-finding stage of projects has been reduced to a \nfew months in most cases, having previously often taken several years. Increasingly, use is being made of X-ray \ncrystallography and other techniques to provide knowledge \nof the three-dimensional structure of the target protein, and computer-based molecular modelling to identify pos -\nsible lead structures within the compound library, in order to reduce the number of compounds to be screened. Molecular modelling can also be used to screen huge \nnumbers of hypothetical \u2013 not yet synthesised \u2013 molecules \nto provide pointers for synthesis and screening of new pathways, coupled with genomic data, is the basis on which \nnovel targets are most often chosen. Disciplines such as \ngenomics, bioinformatics, proteomics and systems analysis are playing an increasing role by revealing new proteins \ninvolved in chemical signalling, new genes involved in \ndisease and new models of disease progression. Space precludes discussion here of this burgeoning area; interested \nreaders are referred to more detailed accounts (Lindsay, \n2003; Kramer & Cohen, 2004; Hill & Rang, 2013; Cutler & \nVoshol, 2015; Kuepfer & Schuppert, 2016).\nOverall, it is evident that in the foreseeable future there \nis ample biological scope in terms of novel drug targets for therapeutic innovation. What limits innovation is not \nthe biology and primary pharmacology, but other factors, \nsuch as poor target selection or the emergence of unforeseen adverse effects during clinical testing, as well as the cost and complexity of drug discovery and development in \nrelation to healthcare economics and increasingly rigorous \nregulatory hurdles.\nLEAD FINDING\nWhen the biochemical target has been decided and the feasibility of the project has been assessed, the next step is \nto find lead compounds. Here we focus on lead compounds \nderived from synthetic chemistry. The development of biopharmaceuticals is described below and in Ch. 5. Com -\nmonly, lead finding involves cloning and expression of the target protein \u2013 normally the human form, because the sequence variation among species is often associated with \npharmacological differences, and it is essential to optimise \nfor activity in humans. An assay system must then be developed, allowing the functional activity of the target protein to be measured. This could be a cell-free enzyme \nassay, a membrane-based binding assay or a cellular \nresponse assay. It must be engineered to run automatically, Target selection\nLead-findingLead optimisationPharmacological \nprofilingPharmacokinetics\nShort-term \ntoxicology\nFormulationSynthesis scale-upPostmarketing \nsurveillanceDRUG \nDISCOVERYPRECLINICAL \nDEVELOPMENT\nPhase I Phase II Phase III Phase IVCLINICAL", "start_char_idx": 0, "end_char_idx": 3905, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "9a4b7a14-0797-4ffc-9cc2-1c50e11386f7": {"__data__": {"id_": "9a4b7a14-0797-4ffc-9cc2-1c50e11386f7", "embedding": null, "metadata": {"page_label": "757", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "16832475-1d59-4503-aa10-01305d150f27", "node_type": null, "metadata": {"page_label": "757", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f27c6f636b83ecf258528e3ffeb349e5b31235ad228563067010982da550825f"}, "2": {"node_id": "b6aeefb1-d1dd-48b9-97ba-62ecf513f8f0", "node_type": null, "metadata": {"page_label": "757", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f8b7b6965912fa9e68c20e9d3e55c349f4f828663b9d30ab5400cfbcb1d041f1"}}, "hash": "c56a3d5b6d04e7e7c2e11adcd57ade5c513e6fba8d4f2be613c810e7d3aaacdd", "text": "\nDEVELOPMENT\nPhase I Phase II Phase III Phase IVCLINICAL DEVELOPMENT\n2\u20135 years\n~100 projects5\u20137 years\n10 5 211.5 years\n20 compounds\nDrug\ncandidateDevelopment\ncompoundRegulatory\nsubmissionDrug approved for \nmarketingPharmacokinetics,\ntolerability,side effects inhealthy volunteersSmall-scaletrials in patientsto assess efficacyand dosage\nLong-term\ntoxicology studiesREGULATORY\nAPPROVAL\nSubmission\nof full date\nand review by\nregulatory\nagencies\n1.21\u20132 yearsLarge-scalecontrolledclinical trials\nFig. 60.1 The stages of development of a \u2018typical\u2019 new drug, i.e. a synthetic compound being developed for systemic use. Only \nthe main activities undertaken at each stage are shown, and the details vary greatly according to the kind of drug being developed. \n2Testing up to 100,000 compounds per day is possible, and is known as \nultra-high throughput screening.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3849, "end_char_idx": 5185, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "5aff2969-1b79-456b-b90d-ab3b14352641": {"__data__": {"id_": "5aff2969-1b79-456b-b90d-ab3b14352641", "embedding": null, "metadata": {"page_label": "758", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "58a7d497-f099-462d-b20c-a5b33804f70c", "node_type": null, "metadata": {"page_label": "758", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eed1dd6d44eac06b3c8f7e19e67b55f89caeab96604326161379fb958d62118b"}, "3": {"node_id": "7a860e60-32bb-4086-8174-f2b1af04c18a", "node_type": null, "metadata": {"page_label": "758", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "dd09f6a7f4701c754ec0d3daae375e17c64db135262211a566fd4aea71294551"}}, "hash": "2b503004bbc1154a34abe650cce2fe57c29b099dac7aa4b3a6ad3265e18e5aeb", "text": "60 SECTION 6 SPECIAL TOPICS\n752like antisocial teenagers, refuse to give up their bad habits. \nIn other cases, the candidate leads, although they produce \nthe desired effects on the target molecule and have no other \nobvious defects, fail to produce the expected effects in animal models of the disease, implying that the target \nprobably would not be a useful one in humans either. The \nvirtuous minority of drugs proceed to the next phase, preclinical development.\nPRECLINICAL DEVELOPMENT\nThe aim of preclinical development is to satisfy all the requirements that have to be met before a new compound \nis deemed ready to be tested for the first time in humans. \nThe work falls into four main categories:\n1. Pharmacological testing to check that the drug does \nnot produce any obviously hazardous acute effects, such as bronchoconstriction, cardiac dysrhythmias, \nblood pressure changes and ataxia (lacking \ncoordinated muscle movement). This is termed safety pharmacology.\n2. Preliminary toxicological testing to eliminate \ngenotoxicity and to determine the maximum non-toxic dose of the drug (usually when given daily for 28 \ndays, and tested in two species). As well as being \nchecked regularly for weight loss and other gross changes, the animals so treated are examined \nminutely post mortem at the end of the experiment to \nsearch for histological and biochemical evidence of \ntissue damage (see also Ch. 58).\n3. Pharmacokinetic and pharmacodynamic (PK/PD) \ntesting,3 including studies on the absorption, \nmetabolism, distribution and elimination (ADME \nstudies) in the species of laboratory animals used for \ntoxicology testing, to link the pharmacological and toxicological effects to plasma concentration and drug \nexposure.\n4. Chemical and pharmaceutical development to assess \nthe feasibility of large-scale synthesis and purification, \nto assess the stability of the compound under various \nconditions and to develop a formulation suitable for \nclinical studies.\nMuch of the work of preclinical development, especially \nthat relating to safety issues, is done under a formal operat -\ning code, known as Good Laboratory Practice (GLP), which \ncovers such aspects as record-keeping procedures, data analysis, instrument calibration and staff training. The aim \nof GLP is to eliminate human error as far as possible and to ensure the reliability of the data submitted to the regula -\ntory authority, and laboratories are regularly monitored for compliance to GLP standards. The strict discipline involved in working to this code is generally ill-suited to \nthe creative research needed in the earlier stages of drug \ndiscovery, so GLP standards are not usually adopted until projects get beyond the discovery phase.\nRoughly half the compounds identified as drug candidates \nfail during the preclinical development phase; for the rest, a detailed dossier (the \u2018investigator brochure\u2019) is prepared for submission alongside specific study protocols to the \nregulatory authority, such as the European Medicines \nAgency or the US FDA, the permission of which is required compound families. Refined in this way, screening is often successful in identifying lead compounds that have the \nappropriate pharmacological activity and are amenable to \nfurther chemical modification.\n\u2018Hits\u2019 detected in the initial screen often turn out to be \nmolecules that have features undesirable in a drug, such as excessive molecular weight or polarity, or possession of groups known to be associated with toxicity. Compu -\ntational \u2018prescreening\u2019 of compound libraries is often used to eliminate such compounds.\nThe hits identified from the primary screen are used as \nthe basis for preparing sets of homologues by combinatorial chemistry to establish the critical structural features neces -\nsary for binding selectively to the target. Several such \niterative cycles of synthesis and screening are usually needed \nto identify one or more lead compounds for the next", "start_char_idx": 0, "end_char_idx": 3957, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "7a860e60-32bb-4086-8174-f2b1af04c18a": {"__data__": {"id_": "7a860e60-32bb-4086-8174-f2b1af04c18a", "embedding": null, "metadata": {"page_label": "758", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "58a7d497-f099-462d-b20c-a5b33804f70c", "node_type": null, "metadata": {"page_label": "758", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "eed1dd6d44eac06b3c8f7e19e67b55f89caeab96604326161379fb958d62118b"}, "2": {"node_id": "5aff2969-1b79-456b-b90d-ab3b14352641", "node_type": null, "metadata": {"page_label": "758", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2b503004bbc1154a34abe650cce2fe57c29b099dac7aa4b3a6ad3265e18e5aeb"}}, "hash": "dd09f6a7f4701c754ec0d3daae375e17c64db135262211a566fd4aea71294551", "text": "and screening are usually needed \nto identify one or more lead compounds for the next stage.\nNatural products as lead compounds\nHistorically, natural products, derived mainly from fungal and plant sources, have proved to be a fruitful source of \nnew therapeutic agents, particularly in the field of anti-\ninfective, anticancer and immunosuppressant drugs. Familiar examples include penicillin, streptomycin \nand many other antibiotics; vinca alkaloids; paclitaxel; ciclosporin and sirolimus (rapamycin). These substances presumably serve a specific protective function, having \nevolved to recognise, with great precision, vulnerable target \nmolecules in an organism\u2019s enemies or competitors. The surface of this resource has barely been scratched, and many companies are actively engaged in generating and \ntesting natural product libraries for lead-finding purposes. \nFungi and other microorganisms are particularly suitable for this, because they are ubiquitous, highly diverse and \neasy to collect and grow in the laboratory. They have also \nhad aeons of evolution to devise an armoury of effective substances fit for specific functions (e.g. anti-bacterial) \nwhich can sometimes be utilised as a starting compound \nin the search for our desired drug. However, compounds obtained from plants, animals or marine organisms are \nmuch more troublesome to produce commercially. Their \nmain disadvantage as lead compounds is that they are often complex molecules that are difficult to synthesise or \nmodify by conventional synthetic chemistry, so that lead \noptimisation may be difficult and commercial production very \nexpensive.\nLEAD OPTIMISATION\nLead compounds found by screening are the basis for the \nnext stage, lead optimisation, where the aim (usually) is \nto increase the potency of the compound on its target and \nto optimise it with respect to other characteristics, such as selectivity and pharmacokinetic properties. In this phase, \nthe tests applied include a broader range of assays in dif -\nferent systems, including studies to measure the activity \nand time course of the compounds in vivo (where possible \nin animal models mimicking aspects of the clinical condition; \nsee Ch. 8), and checking for unwanted effects in animals, evidence of genotoxicity and usually oral availability. The objective of the lead optimisation phase is to identify one \nor more drug candidates suitable for further development.\nAs shown in Fig. 60.1, only about one project in five \nsucceeds in generating a drug candidate, and it can take up to 5 years. The most common problem is that lead \noptimisation proves to be impossible; despite much ingen -\nious and back-breaking chemistry, the lead compounds, \n3Pharmacokinetics is the ways in which the organism changes the drug, \nwhereas pharmacodynamics is the how the drug affects the organism.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3872, "end_char_idx": 7190, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "72dbeabd-4c8b-4e7b-a033-9dce5643164b": {"__data__": {"id_": "72dbeabd-4c8b-4e7b-a033-9dce5643164b", "embedding": null, "metadata": {"page_label": "759", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9acc71af-769f-44e5-84fe-b1072326ed37", "node_type": null, "metadata": {"page_label": "759", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a0440769f80e50d6e50f20863d4176f1dc33838a94bd1f1d22e26b9bb312dae1"}, "3": {"node_id": "c2d93546-c2a4-49c2-a7dd-e05bf7067313", "node_type": null, "metadata": {"page_label": "759", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "9007a98a31149ce2290c5b37697d8b1b4bef5c7c7080d28090f3743332dc58f0"}}, "hash": "aa3165fbde6523dbbf223c57915b1b56bd1dc05824948b2907b480302c0ca52c", "text": "60 Drug DISCO v E ry A n D DE v ELOP m E n T\n753difficult to organise and often take years to complete, \nparticularly if the treatment is designed to retard the \nprogression of a chronic disease. It is not uncommon \nfor a drug that seemed highly effective in the limited patient groups tested in phase II to look much less \nimpressive under the more rigorous conditions of \nphase III trials.\n\u25bc As mentioned earlier, the conduct of trials has to comply with an \nelaborate code known as GCP, covering every detail of the patient \ngroup, data collection methods, recording of information, statistical \nanalysis and documentation.6\nIncreasingly, phase III trials are now required to include a pharma-\ncoeconomic analysis (see Ch. 1), such that not only clinical but also economic benefits of the new treatment are assessed.\nAt the end of phase III, the drug will be submitted to the relevant \nregulatory authority for licensing. The dossier required for this is a \nmassive and detailed compilation of preclinical and clinical data. Evaluation by the regulatory authority normally takes a year or more, \nand further delays often arise when aspects of the submission must \nbe clarified or more data are required. Eventually, about two-thirds of submissions gain marketing approval. Overall, only 11.5% of \ncompounds entering phase I are eventually approved (see Munos, \n2009 ). Increasing this proportion by better compound selection at the \nlaboratory stage is one of the main challenges for the pharmaceutical \nindustry.\n\u2022\tPhase IV studies comprise the obligatory \npost-marketing surveillance designed to detect any \nrare or long-term adverse effects resulting from the \nuse of the drug in a clinical setting in many thousands of patients. Such events may necessitate limiting the \nuse of the drug to particular patient groups, or even \nwithdrawal of the drug.\n7\nDisclosure and publication of trials data\nRecently, concern has been expressed that clinical trials showing negative or inconclusive results are less likely to \nbe published than those giving positive results, so creating \na more favourable impression of a new drug\u2019s clinical efficacy than would be the case if every trial was published. \nTo ensure that all data, good and bad, is published and \navailable to regulatory authorities and researchers, it is now mandatory to register the initiation of any trial in \nhumans and to publish the results in full when the trial is \ncompleted. The difficult question of whether to require all past trials of currently registered drugs is under discussion. The accessibility of past data, much of it in the form of \npaper records in dusty repositories, and the cost of this \nexercise, are serious problems.\nBIOPHARMACEUTICALS\n\u2018Biopharmaceuticals\u2019, i.e. therapeutic agents produced by biotechnology rather than conventional synthetic chemistry, \nare discussed in Chapter 5. Such therapeutic agents now to proceed with studies in humans.\n4 This is not lightly \ngiven, and the regulatory authority may refuse permission or require further work to be done before giving approval.\nNon-clinical development work continues throughout \nthe clinical trials period, when much more data, particularly in relation to long-term and reproductive toxicity in animals, \nhas to be generated. Failure of a compound at this stage is very costly, and considerable efforts are made to eliminate \npotentially toxic compounds much earlier in the drug \ndiscovery process using in vitro, or even in silico, methods.\nCLINICAL DEVELOPMENT\nClinical development proceeds through four distinct but overlapping phases of clinical trials (see Ch. 8). For detailed \ninformation, see Friedman et al. (2010).\n\u2022\tPhase I studies are performed on a small group (normally 20\u201380) of volunteers \u2013 often healthy young \nmen but sometimes patients, and their aim is to check \nfor signs of any potentially dangerous effects, for example on cardiovascular,\n5 respiratory, hepatic or \nrenal function; tolerability (does the drug", "start_char_idx": 0, "end_char_idx": 3983, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "c2d93546-c2a4-49c2-a7dd-e05bf7067313": {"__data__": {"id_": "c2d93546-c2a4-49c2-a7dd-e05bf7067313", "embedding": null, "metadata": {"page_label": "759", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "9acc71af-769f-44e5-84fe-b1072326ed37", "node_type": null, "metadata": {"page_label": "759", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "a0440769f80e50d6e50f20863d4176f1dc33838a94bd1f1d22e26b9bb312dae1"}, "2": {"node_id": "72dbeabd-4c8b-4e7b-a033-9dce5643164b", "node_type": null, "metadata": {"page_label": "759", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "aa3165fbde6523dbbf223c57915b1b56bd1dc05824948b2907b480302c0ca52c"}}, "hash": "9007a98a31149ce2290c5b37697d8b1b4bef5c7c7080d28090f3743332dc58f0", "text": "respiratory, hepatic or \nrenal function; tolerability (does the drug produce any \nunpleasant symptoms, for example, headache, nausea, \ndrowsiness?); and pharmacokinetic properties (is the drug well absorbed? Is absorption affected by food? \nWhat is the time course of the plasma concentration? \nIs there evidence of accumulation or non-linear kinetics?). Phase I studies may also test for \npharmacodynamic effects in volunteers, sometimes \ncalled \u2018proof-of-concept\u2019 studies (e.g. does a novel analgesic compound block experimentally induced pain in humans? How does the desired effect vary \nwith dose?). Just as the regulatory authorities require \nGLP studies, clinical trials need to be performed under equally strict Good Clinical Practice (GCP) conditions.\n\u2022\tPhase II studies are performed on groups of patients (normally 100\u2013300) and are designed to determine clinically beneficial pharmacodynamic effects in \npatients, and if this is confirmed, to establish the dose \nregimen to be used in the definitive phase III study. Often, such studies will cover several distinct clinical \ndisorders (e.g. depression, anxiety states and phobias) \nto identify the possible therapeutic indications for the new compound and the dose required. When new \ndrug targets are being studied, it is not until these \nphase II trials are completed that the team finds out whether or not its initial hypothesis was correct, and \nlack of the expected effect is a common reason for \nfailure.\n\u2022\tPhase III studies are the definitive double-blind, randomised trials, commonly performed as \nmulticentre trials on thousands of patients, aimed at \ncomparing the new drug with commonly used alternatives or placebos. These are extremely costly, \n6Similar strict codes must be followed in laboratory tests to determine \nsafety (Good Laboratory Practice; see text) and drug manufacture \n(Good Manufacturing Practice; GMP).\n7Recent high-profile cases include the withdrawal of rofecoxib (a \ncyclo-oxygenase-2 inhibitor; see Ch. 27) when it was found (in a phase III trial for a new indication) to increase the frequency of heart attacks, \nand of cerivastatin (Ch. 24), a cholesterol-lowering drug found to cause severe muscle damage in a few patients.5QT prolongation, a sign of potentially dangerous cardiac arrhythmias \n(see Ch. 22), is a common cause of failure in early development, and \nregulators demand extensive \u2013 and expensive \u2013 studies to test for this \nrisk. Today, such studies are usually performed on cells expressing the hERG (human Ether-\u00e0-go-go-Related Gene \u2013 no, seriously!) that \nproduces the K\nv11.1 potassium channel. Drugs that inhibit hERG \nchannel activity are routinely screened out, as this implies a fatal QT prolongation side effect.4The rules that will govern the licencing of drugs in the United \nKingdom \u2018post-Brexit\u2019, when it leaves the European Union\u2019s EMA, are yet to be decided.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3915, "end_char_idx": 7276, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8d0b9349-70d1-47dc-b3e4-55977ede2c41": {"__data__": {"id_": "8d0b9349-70d1-47dc-b3e4-55977ede2c41", "embedding": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fccf194d-cd20-475e-a1ec-6e541eaa1196", "node_type": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ba8ef855b7d8a77d015d0c6d1d88d5ed3e84b3ab0da7cda2578f174f5ce5397"}, "3": {"node_id": "ae6cdc74-bca4-4042-8c9c-ddf28bcccdf1", "node_type": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5b2202be5032924d6624d382c138baac7483069e2d674f38b05c55a0b1e5851e"}}, "hash": "4844c14a8affb1c9b80914213a25009ead3da64d46bd825581ccf9d7248d119d", "text": "60 SECTION 6 SPECIAL TOPICS\n754genomics and informatics, amid high expectations that this \nwould bring remarkable dividends in terms of speed, cost \nand success rate. High-throughput screening has undoubt -\nedly emerged as a powerful lead-finding technology, but \noverall the benefits are not yet clear: costs have risen steadily, \nthe success rate has not improved and development times \nhave not decreased.\nFig. 60.2 illustrates the trend in the number of new \ndrugs launched in the major markets worldwide, which had until recently declined steadily despite escalating costs and improved technology, causing serious worries to the industry. There was much speculation as to the \ncauses of the decline, the optimistic view being that \nfewer but better drugs were being introduced, and that the genomics revolution had yet to make its impact. This \noptimism may be well founded, for as Fig. 60.2 shows, the \nnumber of approvals has shown an encouraging upturn in \nrecent years.\nIf the new drugs that are being developed improve the \nquality of medical care, there is room for optimism. In recent (\u2018pre-revolutionary\u2019) years, synthetic drugs aimed \nat new targets (e.g. selective serotonin reuptake inhibitors, \nstatins, kinase inhibitors and several monoclonal antibodies) have made major contributions to patient care. The ability \nof new technologies to make new targets available to the \ndrug discovery machine is beginning to have a real effect on patient care. Creativity remains high, despite the rising \ncosts and declining profits that remain a challenge to the \npharmaceutical industry.\nTrends to watch include the growing armoury of \nbiopharmaceuticals. Recent successful examples include \nmonoclonal antibodies such as trastuzumab (an antibody \ndirected against human epidermal growth factor recep -\ntor 2 \u2013 HER2 \u2013 which is used to treat breast cancers that overexpress this receptor; see Ch. 57) and infliximab (a \ntumour necrosis factor antibody used to treat inflammatory \ndisorders; see Ch. 27); many similar drugs are now available \nand more are in the pipeline. Another likely change will be \nthe use of genotyping to \u2018individualise\u2019 drug treatments, to reduce the likelihood of administering drugs to \u2018non-\nresponders\u2019 (see Evans & Relling, 2004; and Ch. 12, which \nsummarises the current status of \u2018personalised medicine\u2019). The implications for drug discovery will be profound, for \nthe resulting therapeutic compartmentation (or stratifica-\ntion as it is sometimes known) of the patient population \nwill mean that markets will decrease in size, ending the \nreliance on the \u2018blockbusters\u2019 referred to earlier. At the \nsame time, clinical trials will become more complex (and expensive), as different genotypic groups will have to be included in the trial design. The hope is that therapeutic \nefficacy will be improved, not that it will be a route to \ndeveloping drugs more cheaply and quickly. However, there is general agreement that the current modus operandi \nis commercially unsustainable (see Munos, 2009). Costs and \nregulatory requirements are continuing to rise, and the anticipated use of genomics to define subgroups of patients \nlikely to respond to particular therapeutic agents (see Ch. \n12) will mean fragmentation of the market, as we move away from the \u2018one-drug-suits-all\u2019 approach that encour -\naged companies to focus their efforts on blockbuster drugs. More niche products targeted at smaller patient groups will be needed, though each costs as much to develop as a \nblockbuster and carries a similar risk of failure, and in a more \nlimited market \u2013 factors that necessitate higher prices than \nin the past.comprise about 30% of new products registered each year. The principles underlying the development and testing of \nbiopharmaceuticals are basically the same as for", "start_char_idx": 0, "end_char_idx": 3816, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "ae6cdc74-bca4-4042-8c9c-ddf28bcccdf1": {"__data__": {"id_": "ae6cdc74-bca4-4042-8c9c-ddf28bcccdf1", "embedding": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fccf194d-cd20-475e-a1ec-6e541eaa1196", "node_type": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ba8ef855b7d8a77d015d0c6d1d88d5ed3e84b3ab0da7cda2578f174f5ce5397"}, "2": {"node_id": "8d0b9349-70d1-47dc-b3e4-55977ede2c41", "node_type": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "4844c14a8affb1c9b80914213a25009ead3da64d46bd825581ccf9d7248d119d"}, "3": {"node_id": "8730231e-f277-4cfc-b090-2fb9b79a5386", "node_type": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "c446e1c0261e9217a7739da55ad6648f0386da77240187e52e28d84d63041214"}}, "hash": "5b2202be5032924d6624d382c138baac7483069e2d674f38b05c55a0b1e5851e", "text": "underlying the development and testing of \nbiopharmaceuticals are basically the same as for synthetic \ndrugs. In practice, biopharmaceuticals generally run into fewer toxicological problems than synthetic drugs,\n8 but \nmore problems relating to production, quality control, \nimmunogenicity and drug delivery. Walsh (2003) and Revers \nand Furzcon (2010) cover this specialised field in more \ndetail. In 2017 the first gene therapy products (for amyo -\ntrophic lateral sclerosis) and cell-based therapies for advanced cancer (see Ch. 57) were approved \u2013 a significant milestone.\nCOMMERCIAL ASPECTS\nFig. 60.1 shows the approximate time taken for such a project and the attrition rate (at each stage and overall) based on \nrecent data from several large pharmaceutical companies. \nThe key messages are (i) that it is a high-risk business, with only about one drug discovery project in 50 and one \ndevelopment compound in 10 reaching the goal of putting \na new drug on the market, (ii) that it takes a long time \u2013 about 12 years on average and (iii) that it costs a lot of \nmoney to develop one drug \u2013 estimated at a mind-boggling \nUS$3\u20134 billion per drug (see Munos, 2009; DiMasi et al., \n2016).9 For any one project, the costs escalate rapidly as \ndevelopment proceeds, phase III trials and long-term toxicol -\nogy studies being particularly expensive. The time factor \nis crucial, because the new drug has to be patented, usually at the end of the discovery phase, and the period of exclusiv -\nity (20 years in most countries) during which the company is free from competition in the market starts on that date. After 20 years, the patent expires, and other companies, \nwhich have not supported the development costs, are free \nto make and sell the drug much more cheaply, so the revenues for the original company decrease rapidly there -\nafter. Many profitable drugs will reach the end of their \npatent lives before 2018, adding to the industry\u2019s problems. \nReducing the development time after patenting is a major concern for all companies, but so far it has remained stub -\nbornly fixed at around 10 years, partly because the regula -\ntory authorities are demanding more clinical data before they will grant a licence. In practice, only about one drug \nin three that goes on the market brings in enough revenue \nto cover its development costs. Success for the company relies on this one drug generating enough profit to pay for \nthe rest.\n10\nFUTURE PROSPECTS\nSince about 1990, the drug discovery process has been in \nthe throes of a substantial methodological revolution, \nfollowing the rapid ascendancy of molecular biology, \n8The serious toxicity caused to human volunteers in the 2006 phase I \ntrials of the monoclonal antibody TGN 1412 (see Ch. 5) showed that this \ngeneral principle could not be relied on, and led to substantial \ntightening of standards (and a temporary slowdown of the development of biopharmaceuticals).\n9These cost estimates have been strongly challenged by commentators \n(see Angell, 2004) who argue that the pharmaceutical companies \noverestimate their costs several-fold to justify high drug prices.\n10Actually, companies spend at least as much on marketing and \nadministration as on research and development.mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net", "start_char_idx": 3738, "end_char_idx": 7410, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "8730231e-f277-4cfc-b090-2fb9b79a5386": {"__data__": {"id_": "8730231e-f277-4cfc-b090-2fb9b79a5386", "embedding": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "fccf194d-cd20-475e-a1ec-6e541eaa1196", "node_type": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "2ba8ef855b7d8a77d015d0c6d1d88d5ed3e84b3ab0da7cda2578f174f5ce5397"}, "2": {"node_id": "ae6cdc74-bca4-4042-8c9c-ddf28bcccdf1", "node_type": null, "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "5b2202be5032924d6624d382c138baac7483069e2d674f38b05c55a0b1e5851e"}}, "hash": "c446e1c0261e9217a7739da55ad6648f0386da77240187e52e28d84d63041214", "text": "mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 7442, "end_char_idx": 7537, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "195c1153-19ff-4e17-9f03-60502e947525": {"__data__": {"id_": "195c1153-19ff-4e17-9f03-60502e947525", "embedding": null, "metadata": {"page_label": "761", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "334b1806-c41a-4679-8aa2-020cebbab7bf", "node_type": null, "metadata": {"page_label": "761", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "11bb7809813b8a8f8f307a9060c33d649ec25f14b75fafe71495dd991938d7b2"}, "3": {"node_id": "dde09682-71eb-435c-b60d-fdca34c8ab22", "node_type": null, "metadata": {"page_label": "761", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "f06b68a69f9591081d86f908821cc5c7898f11b5e1eb28ba3d7b6edd32e11cf9"}}, "hash": "ab233b53efd07d63447e4e55b1c81e8e87366f7e45d1311fee45e15319fb1a60", "text": "60 Drug DISCO v E ry A n D DE v ELOP m E n T\n755Goldacre, 2012). It needs to be remembered though that, \ndespite its faults, the industry has been responsible for \nmost of the therapeutic advances of the past half-century, \nwithout which medical care would effectively have stood still. Innovation has by no means dried up. Over the last \n5 years, about 30% of newly approved drugs are \u2018first-in-\nclass\u2019, meaning that they act in new ways on molecular targets not previously addressed \u2013 ample scope for future \npharmacologists.A FINAL WORD\nThe pharmaceutical industry in recent years has attracted \nmuch adverse publicity, some of it well deserved, concerning \ndrug pricing and profits, non-disclosure of adverse clinical \ntrials data, reluctance to address major global health problems such as tuberculosis and malaria, aggressive \nmarketing practices and much else (see Angell, 2004; Year19750102030405060\n1980 1985 1990 1995 2000 2005 2010 2015 2020Number of approved new\ndrugs (NCEs)\nR and D spend ($bn)Global sales ($bn/10)Approved R and D spend ($bn) global sales ($bn/10)\nFig. 60.2 Research and development (R&D) spend, sales and new drug registrations, 1980\u20132017. Registrations refer to new \nchemical entities (including biopharmaceuticals, excluding new formulations and combinations of existing registered compounds). The \ndecline in registrations up to 2010 has since seen some reversal in more recent years. (Data from various sources, including the Centre for Medicines Research, Pharmaceutical Research and Manufacturers Association of America.)\nREFERENCES AND FURTHER READING\nAngell, M., 2004. The Truth About the Drug Companies. Random \nHouse, New York. (A powerful broadside directed against the commercial \npractices of pharmaceutical companies)\nBetz, U.A.K., 2005. How many genomics targets can a portfolio afford? \nDrug Discov. Today 10, 1057\u20131063. (Interesting analysis \u2013 despite its odd title \u2013 of approaches to target identification in drug discovery programmes)\nCutler, P., Voshol, H., 2015. Proteomics in pharmaceutical research and \ndevelopment. Proteomics Clin. Appl. 9, 643\u2013650. (Recounts the history of proteomics and follows its development into a useful \u2013 or even essential- \ntool for drug discovery)\nDiMasi, J.A., Grabowski, H.G., Hansen, R.W., 2016. Innovation in the \npharmaceutical industry: new estimates of R&D costs. J. Health Econ. 47, 20\u201333.\nEvans, W.E., Relling, M.V., 2004. Moving towards individualised \nmedicine with pharmacogenomics. Nature 429, 464\u2013468. (Good review article discussing the likely influence of pharmacogenomics on therapeutics)\nFriedman, L.M., Furberg, C.D., DeMets, D.L., 2010. Fundamentals of \nClinical Trials, fourth ed. Mosby, St Louis. (Standard textbook)\nGoldacre, B., 2012. Bad Pharma. Fourth Estate, London. (An outspoken \npolemic, flawed in places, that exposes malpractice in the industry)\nHill, R.G., Rang, H.P. (Eds.), 2013. Drug Discovery and Development, \nsecond ed. Elsevier, Amsterdam. (Short textbook describing the principles and practice of drug discovery and development in the modern era)\nH\u00fcser, J. (Ed.), 2006. High Throughput Screening in Drug Discovery, \nvol. 35. Methods and Principles in Drug Discovery. Wiley\u2013VCH, Weinheim. (Comprehensive textbook covering all aspects of this technology)\nKramer, R., Cohen, D., 2004. Functional genomics to new drug targets. \nNat. Rev. Drug Discov. 3, 965\u2013972. (Describes the various approaches for finding", "start_char_idx": 0, "end_char_idx": 3433, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}, "dde09682-71eb-435c-b60d-fdca34c8ab22": {"__data__": {"id_": "dde09682-71eb-435c-b60d-fdca34c8ab22", "embedding": null, "metadata": {"page_label": "761", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "excluded_embed_metadata_keys": [], "excluded_llm_metadata_keys": [], "relationships": {"1": {"node_id": "334b1806-c41a-4679-8aa2-020cebbab7bf", "node_type": null, "metadata": {"page_label": "761", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "11bb7809813b8a8f8f307a9060c33d649ec25f14b75fafe71495dd991938d7b2"}, "2": {"node_id": "195c1153-19ff-4e17-9f03-60502e947525", "node_type": null, "metadata": {"page_label": "761", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}, "hash": "ab233b53efd07d63447e4e55b1c81e8e87366f7e45d1311fee45e15319fb1a60"}}, "hash": "f06b68a69f9591081d86f908821cc5c7898f11b5e1eb28ba3d7b6edd32e11cf9", "text": "3, 965\u2013972. (Describes the various approaches for finding new drug targets, starting from genomic data)\nKuepfer, L., Schuppert, A., 2016. Systems medicine in pharmaceutical \nresearch and development. Methods Mol. Biol. 1386, 87\u2013104. (A little technical and mainly of interest if you want to dig deep into the subject)\nLindsay, M.A., 2003. Target discovery. Nat. Rev. Drug Discov. 2, \n831\u2013836. (Well-balanced discussion of the application of genomics approaches to discovering new drug targets; more realistic in its stance than \nmany)\nMunos, B., 2009. Lessons from 60 years of pharmaceutical innovation. \nNat. Rev. Drug Discov. 8, 959\u2013968. (Informative summary of the current status of the drug discovery industry, making clear that the modus operandi \nthat has been successful in the past is no longer sustainable)\nSantos, R., Ursu, O., Gaulton, A., et al., 2017. A comprehensive map of \nmolecular drug targets. Nat. Rev. Drug Discov. 16, 19\u201334. (A very comprehensive survey of drugs and their targets. A mine of useful data)\nRevers, L., Furczon, E., 2010. An introduction to biologics and \nbiosimilars. Part II: subsequent entry biologics: biosame or biodifferent? Can. Pharm. J. 143, 184\u2013191.\nWalsh, G., 2003. Biopharmaceuticals, second ed. Wiley, Chichester.(Comprehensive textbook covering all aspects of discovery, development and \napplications of biopharmaceuticals)mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net\nmebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net mebooksfree.net", "start_char_idx": 3376, "end_char_idx": 5229, "text_template": "{metadata_str}\n\n{content}", "metadata_template": "{key}: {value}", "metadata_seperator": "\n"}, "__type__": "1"}}, "docstore/ref_doc_info": {"daef8c7f-68a7-4a78-b143-4aba0b3421b9": {"node_ids": ["e5011731-4122-4588-83d0-19ff6364dcc8", "e5011731-4122-4588-83d0-19ff6364dcc8", "e5011731-4122-4588-83d0-19ff6364dcc8"], "metadata": {"page_label": "1", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c20c8323-7f5f-4553-80b3-1a6d2dff3232": {"node_ids": ["b7f2083c-7828-489d-a91a-99387ea61990", "b7f2083c-7828-489d-a91a-99387ea61990", "b7f2083c-7828-489d-a91a-99387ea61990"], "metadata": {"page_label": "2", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "08ea18da-4415-43d0-bfc5-e4af7a31d8f2": {"node_ids": ["bc1d5998-8b4c-42d7-a90c-0fa61f209ad1", "bc1d5998-8b4c-42d7-a90c-0fa61f209ad1", "bc1d5998-8b4c-42d7-a90c-0fa61f209ad1"], "metadata": {"page_label": "3", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6b6b4aa2-3d5a-4ad2-94ee-8a74e2c01f6c": {"node_ids": ["f6251b43-a4a4-4d52-9280-eb75f885891e", "f6251b43-a4a4-4d52-9280-eb75f885891e", "f6251b43-a4a4-4d52-9280-eb75f885891e"], "metadata": {"page_label": "4", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2fbdcbb4-e5ed-44e8-9db4-a06b11cf5946": {"node_ids": ["608e54d8-1a22-47f6-b62d-72f076ecf05d", "48c9d5b6-fbea-4458-881a-1bf0b6d1a3db", "608e54d8-1a22-47f6-b62d-72f076ecf05d", "48c9d5b6-fbea-4458-881a-1bf0b6d1a3db", "608e54d8-1a22-47f6-b62d-72f076ecf05d", "48c9d5b6-fbea-4458-881a-1bf0b6d1a3db"], "metadata": {"page_label": "5", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b6becbbb-c6af-443b-aa69-2711a3e83fbf": {"node_ids": ["95fe44f7-8f1c-4739-b658-6a679337c8f6", "95fe44f7-8f1c-4739-b658-6a679337c8f6", "95fe44f7-8f1c-4739-b658-6a679337c8f6"], "metadata": {"page_label": "6", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d06b9b0d-9b63-4a60-8114-aace544631b0": {"node_ids": ["f5056f2f-9577-4148-8c95-720a9c306847", "abe6dc81-5c17-4d3d-a1c1-848d79df2747", "f5056f2f-9577-4148-8c95-720a9c306847", "abe6dc81-5c17-4d3d-a1c1-848d79df2747", "f5056f2f-9577-4148-8c95-720a9c306847", "abe6dc81-5c17-4d3d-a1c1-848d79df2747"], "metadata": {"page_label": "7", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e266a6a0-04d8-4009-a7ce-8c713c283fba": {"node_ids": ["0e413ae7-f5cc-45c1-a031-f1ab52756f4f", "3e1bcd33-40a5-4f6f-a7c9-101972f1537f", "cc75a578-e997-4ff8-b522-7791df24a429", "0e413ae7-f5cc-45c1-a031-f1ab52756f4f", "3e1bcd33-40a5-4f6f-a7c9-101972f1537f", "cc75a578-e997-4ff8-b522-7791df24a429", "0e413ae7-f5cc-45c1-a031-f1ab52756f4f", "3e1bcd33-40a5-4f6f-a7c9-101972f1537f", "cc75a578-e997-4ff8-b522-7791df24a429"], "metadata": {"page_label": "8", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "db4a0856-ce64-4060-9d11-a4981a1985c9": {"node_ids": ["19692850-fcb7-4989-9fbd-7a45b0c05404", "395f211d-36d6-4687-91fd-e70e60c0a38c", "19692850-fcb7-4989-9fbd-7a45b0c05404", "395f211d-36d6-4687-91fd-e70e60c0a38c", "19692850-fcb7-4989-9fbd-7a45b0c05404", "395f211d-36d6-4687-91fd-e70e60c0a38c"], "metadata": {"page_label": "9", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b5ad4171-80af-4abf-a713-24a35994b1ba": {"node_ids": ["bf243f19-319f-4950-a05b-d6a362f01b89", "92d40caa-24b5-41e0-9e72-2831bc5d45c2", "bf243f19-319f-4950-a05b-d6a362f01b89", "92d40caa-24b5-41e0-9e72-2831bc5d45c2", "bf243f19-319f-4950-a05b-d6a362f01b89", "92d40caa-24b5-41e0-9e72-2831bc5d45c2"], "metadata": {"page_label": "10", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "135ed7de-f1c0-4daf-9541-7c43693bef51": {"node_ids": ["c585a0a7-7a9b-463d-b7d0-a39717280ad7", "c585a0a7-7a9b-463d-b7d0-a39717280ad7", "c585a0a7-7a9b-463d-b7d0-a39717280ad7"], "metadata": {"page_label": "11", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b5a4db63-f6b1-42b9-b1bb-f4ba855fde52": {"node_ids": ["2218a423-d7af-4985-b365-c76f18132b49", "01fc577c-319b-4aea-8bed-7e4f84eb8457", "2218a423-d7af-4985-b365-c76f18132b49", "01fc577c-319b-4aea-8bed-7e4f84eb8457", "2218a423-d7af-4985-b365-c76f18132b49", "01fc577c-319b-4aea-8bed-7e4f84eb8457"], "metadata": {"page_label": "12", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ce635d5b-812e-4505-9290-f47fcdce1108": {"node_ids": ["99e35b0a-10ed-4e42-8a39-5019b0a57e6f", "ec123fe0-0d47-45bd-89bd-7dce104122bb", "50bfa380-5158-4a44-9d91-2da6017c9a26", "99e35b0a-10ed-4e42-8a39-5019b0a57e6f", "ec123fe0-0d47-45bd-89bd-7dce104122bb", "50bfa380-5158-4a44-9d91-2da6017c9a26", "99e35b0a-10ed-4e42-8a39-5019b0a57e6f", "ec123fe0-0d47-45bd-89bd-7dce104122bb", "50bfa380-5158-4a44-9d91-2da6017c9a26"], "metadata": {"page_label": "13", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c0d7ccc9-7b04-47e5-b913-72d217a1f1c6": {"node_ids": ["cdf44d3b-ed62-4828-b808-e834961c7558", "34713ea0-4ca5-4209-b199-af991552b584", "7093aa4c-f087-4c7b-8955-22af77623995", "cdf44d3b-ed62-4828-b808-e834961c7558", "34713ea0-4ca5-4209-b199-af991552b584", "7093aa4c-f087-4c7b-8955-22af77623995", "cdf44d3b-ed62-4828-b808-e834961c7558", "34713ea0-4ca5-4209-b199-af991552b584", "7093aa4c-f087-4c7b-8955-22af77623995"], "metadata": {"page_label": "14", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5caf8182-1d82-42f4-ad7c-19ea91c92a77": {"node_ids": ["33a37fe6-3527-4886-ae07-9fdac983f0c7", "43fe4d20-827f-43bc-bc04-32dbb980098f", "33a37fe6-3527-4886-ae07-9fdac983f0c7", "43fe4d20-827f-43bc-bc04-32dbb980098f", "33a37fe6-3527-4886-ae07-9fdac983f0c7", "43fe4d20-827f-43bc-bc04-32dbb980098f"], "metadata": {"page_label": "15", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b9c9f479-fe67-4ff5-946b-994e82eef357": {"node_ids": ["8e3942b7-35e0-42a8-8c92-68755db63aef", "2a7894d6-240c-4e18-a6a4-015512d90f4c", "8e3942b7-35e0-42a8-8c92-68755db63aef", "2a7894d6-240c-4e18-a6a4-015512d90f4c", "8e3942b7-35e0-42a8-8c92-68755db63aef", "2a7894d6-240c-4e18-a6a4-015512d90f4c"], "metadata": {"page_label": "16", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d217b749-e809-4bd8-8981-51bee2597e91": {"node_ids": ["fba43e93-a374-4246-91d9-48e62221774d", "647409d2-8dc8-40a0-bd7f-fe8fedb872cb", "fba43e93-a374-4246-91d9-48e62221774d", "647409d2-8dc8-40a0-bd7f-fe8fedb872cb", "fba43e93-a374-4246-91d9-48e62221774d", "647409d2-8dc8-40a0-bd7f-fe8fedb872cb"], "metadata": {"page_label": "17", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "eb1d4577-0462-4846-91ea-60db375e7688": {"node_ids": ["fec75ef9-fdd8-436f-a6e1-38b959544a96", "af9bcc99-788d-4df4-b65f-1da1c9f2a9de", "fec75ef9-fdd8-436f-a6e1-38b959544a96", "af9bcc99-788d-4df4-b65f-1da1c9f2a9de", "fec75ef9-fdd8-436f-a6e1-38b959544a96", "af9bcc99-788d-4df4-b65f-1da1c9f2a9de"], "metadata": {"page_label": "18", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d5b85ddb-7406-48d1-9dd0-3b426ca1008f": {"node_ids": ["2726ad77-a61b-4de5-b014-2f49c65c502b", "f0c7391a-8fd6-45c0-aa1c-cc6e32cff16c", "2726ad77-a61b-4de5-b014-2f49c65c502b", "f0c7391a-8fd6-45c0-aa1c-cc6e32cff16c", "2726ad77-a61b-4de5-b014-2f49c65c502b", "f0c7391a-8fd6-45c0-aa1c-cc6e32cff16c"], "metadata": {"page_label": "19", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9312ded3-2b72-4968-96ff-f8cf24fbca6f": {"node_ids": ["60e1c816-ca53-4e7f-94e8-0fd2d80818ed", "2976c590-f20d-4024-b3e1-dfaee4f55177", "60e1c816-ca53-4e7f-94e8-0fd2d80818ed", "2976c590-f20d-4024-b3e1-dfaee4f55177", "60e1c816-ca53-4e7f-94e8-0fd2d80818ed", "2976c590-f20d-4024-b3e1-dfaee4f55177"], "metadata": {"page_label": "20", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c28f14e0-7718-4e24-8d94-0edb8cf67828": {"node_ids": ["997870ff-e488-4c33-ab76-db7de7e8f4f4", "d938c7c3-d1aa-43f9-97b6-e6d234ce5f8c", "997870ff-e488-4c33-ab76-db7de7e8f4f4", "d938c7c3-d1aa-43f9-97b6-e6d234ce5f8c", "997870ff-e488-4c33-ab76-db7de7e8f4f4", "d938c7c3-d1aa-43f9-97b6-e6d234ce5f8c"], "metadata": {"page_label": "21", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a1d39c54-ef46-4d67-852a-f06d380f0fb7": {"node_ids": ["e8c90c35-e0d8-4dac-a03b-08fd983abb95", "d9484a43-97ad-4bad-93ce-261d73415a18", "e8c90c35-e0d8-4dac-a03b-08fd983abb95", "d9484a43-97ad-4bad-93ce-261d73415a18", "e8c90c35-e0d8-4dac-a03b-08fd983abb95", "d9484a43-97ad-4bad-93ce-261d73415a18"], "metadata": {"page_label": "22", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "de43b34b-5dcb-456b-b0fb-19e0be49f344": {"node_ids": ["9799e5b6-f37c-4e29-a53c-85c8740ea93a", "9799e5b6-f37c-4e29-a53c-85c8740ea93a", "9799e5b6-f37c-4e29-a53c-85c8740ea93a"], "metadata": {"page_label": "23", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bca4a9d3-f04e-41a5-99f3-e0fcf5838fd6": {"node_ids": ["645bbbd7-4670-4755-bc78-06e88474a21c", "3b01edf9-a01e-4ff7-8103-bd3b90ee7b17", "645bbbd7-4670-4755-bc78-06e88474a21c", "3b01edf9-a01e-4ff7-8103-bd3b90ee7b17", "645bbbd7-4670-4755-bc78-06e88474a21c", "3b01edf9-a01e-4ff7-8103-bd3b90ee7b17"], "metadata": {"page_label": "24", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d50f1482-997c-458e-99f5-767dc6d7a44f": {"node_ids": ["25857cda-593f-4e12-9e47-94992cd93b05", "1ce2646e-8ab1-4589-b84e-be16c50d0461", "21f55cc6-6024-4a57-bf66-23f308e6a5ee", "25857cda-593f-4e12-9e47-94992cd93b05", "1ce2646e-8ab1-4589-b84e-be16c50d0461", "21f55cc6-6024-4a57-bf66-23f308e6a5ee", "25857cda-593f-4e12-9e47-94992cd93b05", "1ce2646e-8ab1-4589-b84e-be16c50d0461", "21f55cc6-6024-4a57-bf66-23f308e6a5ee"], "metadata": {"page_label": "25", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "cc3bbac8-c9b3-4f34-83f6-020b173f4fcd": {"node_ids": ["c1427c0d-98eb-431c-8a5b-15bd47be3df8", "3742d94d-500f-4767-8fae-4ad6d2d24bff", "cb2f8b0e-ca46-4ea8-a2ca-fefab23de5c7", "c1427c0d-98eb-431c-8a5b-15bd47be3df8", "3742d94d-500f-4767-8fae-4ad6d2d24bff", "cb2f8b0e-ca46-4ea8-a2ca-fefab23de5c7", "c1427c0d-98eb-431c-8a5b-15bd47be3df8", "3742d94d-500f-4767-8fae-4ad6d2d24bff", "cb2f8b0e-ca46-4ea8-a2ca-fefab23de5c7"], "metadata": {"page_label": "26", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "03fedf93-10c3-41e1-8cca-e57573d8398f": {"node_ids": ["b0c056ad-db75-44a1-908a-ba2759828e38", "930d967e-30f5-4aa9-999c-2ecf77684d77", "b0c056ad-db75-44a1-908a-ba2759828e38", "930d967e-30f5-4aa9-999c-2ecf77684d77", "b0c056ad-db75-44a1-908a-ba2759828e38", "930d967e-30f5-4aa9-999c-2ecf77684d77"], "metadata": {"page_label": "27", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "aa41831b-efe1-4480-a3ba-f5e13d6a5146": {"node_ids": ["42590f5d-b7c7-43b5-ad9e-499261aa3c9f", "c766fc5e-942c-49cc-a06b-e18ba6582e73", "42590f5d-b7c7-43b5-ad9e-499261aa3c9f", "c766fc5e-942c-49cc-a06b-e18ba6582e73", "42590f5d-b7c7-43b5-ad9e-499261aa3c9f", "c766fc5e-942c-49cc-a06b-e18ba6582e73"], "metadata": {"page_label": "28", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1ab4feb1-4db5-4a42-b6e2-2021fa7ac4ec": {"node_ids": ["901c601a-e8e8-4b3a-88c2-2eec11967c90", "2ebccc93-1e0b-464f-84f7-b3e34637d809", "901c601a-e8e8-4b3a-88c2-2eec11967c90", "2ebccc93-1e0b-464f-84f7-b3e34637d809", "901c601a-e8e8-4b3a-88c2-2eec11967c90", "2ebccc93-1e0b-464f-84f7-b3e34637d809"], "metadata": {"page_label": "29", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "443a6172-5f92-41a6-9e66-ac76a804d2f3": {"node_ids": ["d8047bca-73bf-4c57-896d-bbb73225f47b", "191242ae-e34e-4090-a263-5b5e7bb1f6a5", "d8047bca-73bf-4c57-896d-bbb73225f47b", "191242ae-e34e-4090-a263-5b5e7bb1f6a5", "d8047bca-73bf-4c57-896d-bbb73225f47b", "191242ae-e34e-4090-a263-5b5e7bb1f6a5"], "metadata": {"page_label": "30", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "14ac1dab-ba39-4d7b-a06d-9834e17d41de": {"node_ids": ["c729462e-9904-4a57-9c18-36ce6b5540f5", "d91f5410-7ee9-4c66-bced-2b5abc36ccf1", "8aadec16-f20d-4fc8-9b9e-f8f1f6fa1264", "c729462e-9904-4a57-9c18-36ce6b5540f5", "d91f5410-7ee9-4c66-bced-2b5abc36ccf1", "8aadec16-f20d-4fc8-9b9e-f8f1f6fa1264", "c729462e-9904-4a57-9c18-36ce6b5540f5", "d91f5410-7ee9-4c66-bced-2b5abc36ccf1", "8aadec16-f20d-4fc8-9b9e-f8f1f6fa1264"], "metadata": {"page_label": "31", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6a84f021-5c8e-439e-8ade-6387f09dd7ba": {"node_ids": ["f751e2c8-cf66-47c2-83a5-b5660d70b7bf", "f751e2c8-cf66-47c2-83a5-b5660d70b7bf", "f751e2c8-cf66-47c2-83a5-b5660d70b7bf"], "metadata": {"page_label": "32", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4cb59c6c-a42e-4926-a599-79e0f620549e": {"node_ids": ["5cecb105-81e8-43ab-8f17-af9d287dd9d4", "7620fd55-2d65-488f-bcfb-7b4312cb4346", "5cecb105-81e8-43ab-8f17-af9d287dd9d4", "7620fd55-2d65-488f-bcfb-7b4312cb4346", "5cecb105-81e8-43ab-8f17-af9d287dd9d4", "7620fd55-2d65-488f-bcfb-7b4312cb4346"], "metadata": {"page_label": "33", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d5d4fab5-43ca-4deb-9c4c-591c001796a8": {"node_ids": ["c325d348-aca5-4088-84fc-79fbc7bb1b57", "3ce57e86-632b-4989-9dca-7e777ecd5a48", "c325d348-aca5-4088-84fc-79fbc7bb1b57", "3ce57e86-632b-4989-9dca-7e777ecd5a48", "c325d348-aca5-4088-84fc-79fbc7bb1b57", "3ce57e86-632b-4989-9dca-7e777ecd5a48"], "metadata": {"page_label": "34", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "55c91041-228c-4727-9678-2d870c3dfe37": {"node_ids": ["06ed5854-dea8-4204-bd5c-dc1c943afe6c", "df6268ff-7dc2-46a1-9385-63e1a97ed69e", "06ed5854-dea8-4204-bd5c-dc1c943afe6c", "df6268ff-7dc2-46a1-9385-63e1a97ed69e", "06ed5854-dea8-4204-bd5c-dc1c943afe6c", "df6268ff-7dc2-46a1-9385-63e1a97ed69e"], "metadata": {"page_label": "35", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "527c6d2f-0cab-4005-b34e-3c682253eb52": {"node_ids": ["981d003f-d847-46c2-ad6d-69f608dcb9da", "6fb0c097-7282-4629-8011-94a8a0990350", "981d003f-d847-46c2-ad6d-69f608dcb9da", "6fb0c097-7282-4629-8011-94a8a0990350", "981d003f-d847-46c2-ad6d-69f608dcb9da", "6fb0c097-7282-4629-8011-94a8a0990350"], "metadata": {"page_label": "36", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fb79c280-38f0-4153-958c-ae079cb40282": {"node_ids": ["89e46253-0a75-48a5-84f2-167cdd23d5b7", "5e330533-63cb-4e93-9b12-994ab7f3ae66", "2c7fdf7b-a6e2-4be3-8b01-08cbc46c2979", "89e46253-0a75-48a5-84f2-167cdd23d5b7", "5e330533-63cb-4e93-9b12-994ab7f3ae66", "2c7fdf7b-a6e2-4be3-8b01-08cbc46c2979", "89e46253-0a75-48a5-84f2-167cdd23d5b7", "5e330533-63cb-4e93-9b12-994ab7f3ae66", "2c7fdf7b-a6e2-4be3-8b01-08cbc46c2979"], "metadata": {"page_label": "37", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f09c85dc-6142-46ba-8ddc-c342c8587af8": {"node_ids": ["17223ed0-8791-44f3-a9a7-b6fc5c0545c6", "17223ed0-8791-44f3-a9a7-b6fc5c0545c6", "17223ed0-8791-44f3-a9a7-b6fc5c0545c6"], "metadata": {"page_label": "38", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fa9b5a90-45f5-4956-9716-f57f56afa41f": {"node_ids": ["c86dad7a-35a1-462c-bb53-b7f3e54921fc", "883f004b-be84-454b-8906-3bccc985c7ad", "c86dad7a-35a1-462c-bb53-b7f3e54921fc", "883f004b-be84-454b-8906-3bccc985c7ad", "c86dad7a-35a1-462c-bb53-b7f3e54921fc", "883f004b-be84-454b-8906-3bccc985c7ad"], "metadata": {"page_label": "39", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4ccc1653-eb1f-438a-b0c8-acaea70e7dce": {"node_ids": ["67218dc5-1ac9-4edf-b257-efbe9c55ec10", "deffb9e2-e741-4349-9ef8-d7776a00adb5", "67218dc5-1ac9-4edf-b257-efbe9c55ec10", "deffb9e2-e741-4349-9ef8-d7776a00adb5", "67218dc5-1ac9-4edf-b257-efbe9c55ec10", "deffb9e2-e741-4349-9ef8-d7776a00adb5"], "metadata": {"page_label": "40", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "451fb778-e702-4947-afe1-25513cc65c11": {"node_ids": ["49225b95-f6e1-433a-a90c-dcf5b8772f49", "ced54c58-bb38-457c-8d4e-2be835d6b5e9", "49225b95-f6e1-433a-a90c-dcf5b8772f49", "ced54c58-bb38-457c-8d4e-2be835d6b5e9", "49225b95-f6e1-433a-a90c-dcf5b8772f49", "ced54c58-bb38-457c-8d4e-2be835d6b5e9"], "metadata": {"page_label": "41", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3adf4295-e6b7-447d-928f-4c0250af866e": {"node_ids": ["bf837ad2-e0c9-478a-ad5e-2f9c1f0607ae", "42025fea-f86a-4f9f-bc20-b74e98f5ff23", "bf837ad2-e0c9-478a-ad5e-2f9c1f0607ae", "42025fea-f86a-4f9f-bc20-b74e98f5ff23", "bf837ad2-e0c9-478a-ad5e-2f9c1f0607ae", "42025fea-f86a-4f9f-bc20-b74e98f5ff23"], "metadata": {"page_label": "42", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ae696e19-2785-410e-89de-6e9aa91929d0": {"node_ids": ["8804fc0e-7ad8-4afa-b2e2-9c376aa2f67b", "8804fc0e-7ad8-4afa-b2e2-9c376aa2f67b", "8804fc0e-7ad8-4afa-b2e2-9c376aa2f67b"], "metadata": {"page_label": "43", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1bd461c7-3a1d-465e-90b5-a08f35001db6": {"node_ids": ["74ff3fd6-58c1-472f-94ea-c63599cdee26", "74ff3fd6-58c1-472f-94ea-c63599cdee26", "74ff3fd6-58c1-472f-94ea-c63599cdee26"], "metadata": {"page_label": "44", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8d5c07a6-34f2-489d-b907-da3e36d9c70d": {"node_ids": ["1993df21-3ed9-42ad-a120-a7037b4690bc", "579f30f0-7e31-4a68-b681-c7918a138c4c", "1993df21-3ed9-42ad-a120-a7037b4690bc", "579f30f0-7e31-4a68-b681-c7918a138c4c", "1993df21-3ed9-42ad-a120-a7037b4690bc", "579f30f0-7e31-4a68-b681-c7918a138c4c"], "metadata": {"page_label": "45", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "38eaefc4-4af9-4117-9d60-ed3eb7437b0e": {"node_ids": ["9b3017bb-1606-4f91-92c3-e153c1ef8b62", "1a868faf-2a57-476a-ad57-512a4a15071c", "4ead5dd9-7818-4f6c-8607-943feb02bf8a", "9b3017bb-1606-4f91-92c3-e153c1ef8b62", "1a868faf-2a57-476a-ad57-512a4a15071c", "4ead5dd9-7818-4f6c-8607-943feb02bf8a", "9b3017bb-1606-4f91-92c3-e153c1ef8b62", "1a868faf-2a57-476a-ad57-512a4a15071c", "4ead5dd9-7818-4f6c-8607-943feb02bf8a"], "metadata": {"page_label": "46", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "44e7e96e-e9ab-43cd-9165-93344bdf02da": {"node_ids": ["12fab41d-e2b8-406e-bc4d-6c6d6e1f35bd", "12fab41d-e2b8-406e-bc4d-6c6d6e1f35bd", "12fab41d-e2b8-406e-bc4d-6c6d6e1f35bd"], "metadata": {"page_label": "47", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c12437f5-afce-4ef2-b43f-56eb7100a2b6": {"node_ids": ["0831e61c-0bf5-4352-a669-03f46ef7140d", "aef0bbb6-6a34-4a8d-b9d1-8c44a38f9f24", "99937a63-52ed-4da4-8cf8-f7ff7a3da181", "0831e61c-0bf5-4352-a669-03f46ef7140d", "aef0bbb6-6a34-4a8d-b9d1-8c44a38f9f24", "99937a63-52ed-4da4-8cf8-f7ff7a3da181", "0831e61c-0bf5-4352-a669-03f46ef7140d", "aef0bbb6-6a34-4a8d-b9d1-8c44a38f9f24", "99937a63-52ed-4da4-8cf8-f7ff7a3da181"], "metadata": {"page_label": "48", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c924bd17-b0ee-4b91-b2ba-0b773b7e150e": {"node_ids": ["5d234af6-0d0b-4a8a-92ef-c7378fab12a3", "7e29db77-cad8-422f-9bed-9dc06aab329d", "5d234af6-0d0b-4a8a-92ef-c7378fab12a3", "7e29db77-cad8-422f-9bed-9dc06aab329d", "5d234af6-0d0b-4a8a-92ef-c7378fab12a3", "7e29db77-cad8-422f-9bed-9dc06aab329d"], "metadata": {"page_label": "49", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8e356bc3-c376-4fa1-a0a4-966abcd841cb": {"node_ids": ["97a71d97-b388-4830-9410-864ea5d13243", "112f01dd-d54b-4512-8d7e-5ec87902f102", "a8465211-371b-40cc-8ec5-1ce636927049", "97a71d97-b388-4830-9410-864ea5d13243", "112f01dd-d54b-4512-8d7e-5ec87902f102", "a8465211-371b-40cc-8ec5-1ce636927049", "97a71d97-b388-4830-9410-864ea5d13243", "112f01dd-d54b-4512-8d7e-5ec87902f102", "a8465211-371b-40cc-8ec5-1ce636927049"], "metadata": {"page_label": "50", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5e0b0730-73a6-4f06-9a87-27c43e8dbb7c": {"node_ids": ["94871800-d70c-4425-8ece-cb3a0ff5e33c", "99fc101d-0c81-4986-9a02-520c9ffdd24d", "94871800-d70c-4425-8ece-cb3a0ff5e33c", "99fc101d-0c81-4986-9a02-520c9ffdd24d", "94871800-d70c-4425-8ece-cb3a0ff5e33c", "99fc101d-0c81-4986-9a02-520c9ffdd24d"], "metadata": {"page_label": "51", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bda4286b-5944-419d-9879-4f1d143ea96e": {"node_ids": ["d8bce2db-f94a-42cb-9666-25e8f7b0d907", "9f6edab8-468a-4b75-8fbc-83a6d00d4f8b", "d8bce2db-f94a-42cb-9666-25e8f7b0d907", "9f6edab8-468a-4b75-8fbc-83a6d00d4f8b", "d8bce2db-f94a-42cb-9666-25e8f7b0d907", "9f6edab8-468a-4b75-8fbc-83a6d00d4f8b"], "metadata": {"page_label": "52", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f2fc5f8b-f676-4a81-b59a-ab8873e8286c": {"node_ids": ["9aa5bedc-2a7f-420e-8a06-1cdc4a39bf30", "598c42f8-ac09-4e8e-82a6-3a25ed5b4618", "9aa5bedc-2a7f-420e-8a06-1cdc4a39bf30", "598c42f8-ac09-4e8e-82a6-3a25ed5b4618", "9aa5bedc-2a7f-420e-8a06-1cdc4a39bf30", "598c42f8-ac09-4e8e-82a6-3a25ed5b4618"], "metadata": {"page_label": "53", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fe6a6dfc-6763-448e-a127-155f43e5db8f": {"node_ids": ["75da4d16-b915-40a7-866c-9f15077ede58", "fa614868-bbc4-4fb8-9f49-b0bd067419c5", "75da4d16-b915-40a7-866c-9f15077ede58", "fa614868-bbc4-4fb8-9f49-b0bd067419c5", "75da4d16-b915-40a7-866c-9f15077ede58", "fa614868-bbc4-4fb8-9f49-b0bd067419c5"], "metadata": {"page_label": "54", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d20a21e8-617f-4acf-96e9-5767a390d0f3": {"node_ids": ["f6770141-7143-4232-9d58-a5407559fc8d", "44dbac68-49ef-4c9a-8b6f-5866bd6d36f1", "f6770141-7143-4232-9d58-a5407559fc8d", "44dbac68-49ef-4c9a-8b6f-5866bd6d36f1", "f6770141-7143-4232-9d58-a5407559fc8d", "44dbac68-49ef-4c9a-8b6f-5866bd6d36f1"], "metadata": {"page_label": "55", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2cd795c4-1b50-49a8-ba49-8c8057d21a6a": {"node_ids": ["a5628738-a1be-43f8-ae8d-c0a46b6d639c", "072a0792-c6aa-455d-8a5b-c45ea9db4163", "57ba2a49-3d32-45b7-84c7-5c86193ba66a", "a5628738-a1be-43f8-ae8d-c0a46b6d639c", "072a0792-c6aa-455d-8a5b-c45ea9db4163", "57ba2a49-3d32-45b7-84c7-5c86193ba66a", "a5628738-a1be-43f8-ae8d-c0a46b6d639c", "072a0792-c6aa-455d-8a5b-c45ea9db4163", "57ba2a49-3d32-45b7-84c7-5c86193ba66a"], "metadata": {"page_label": "56", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1efe8edc-b934-4ff4-9ce5-4a7955a007cb": {"node_ids": ["bbedbda5-035a-4f18-a208-9fd4b05ba83b", "7c088bfd-965f-46a0-8780-029a2f750d19", "50f06179-9a8b-423c-9216-b66bc76ceb07", "bbedbda5-035a-4f18-a208-9fd4b05ba83b", "7c088bfd-965f-46a0-8780-029a2f750d19", "50f06179-9a8b-423c-9216-b66bc76ceb07", "bbedbda5-035a-4f18-a208-9fd4b05ba83b", "7c088bfd-965f-46a0-8780-029a2f750d19", "50f06179-9a8b-423c-9216-b66bc76ceb07"], "metadata": {"page_label": "57", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "84310896-2912-4cf4-89cb-e43712dcd9d8": {"node_ids": ["20658aac-1419-47ef-8c02-64898af730b3", "73521a5b-44d3-43cf-baeb-45d75aae8882", "20658aac-1419-47ef-8c02-64898af730b3", "73521a5b-44d3-43cf-baeb-45d75aae8882", "20658aac-1419-47ef-8c02-64898af730b3", "73521a5b-44d3-43cf-baeb-45d75aae8882"], "metadata": {"page_label": "58", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1b199d19-5066-4fa6-8bf0-139cea942264": {"node_ids": ["f1fb16e4-d2af-4364-8b94-b9c440f2b97d", "b42b8e16-fcbe-41aa-b2c9-22e7957a2659", "f1fb16e4-d2af-4364-8b94-b9c440f2b97d", "b42b8e16-fcbe-41aa-b2c9-22e7957a2659", "f1fb16e4-d2af-4364-8b94-b9c440f2b97d", "b42b8e16-fcbe-41aa-b2c9-22e7957a2659"], "metadata": {"page_label": "59", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d23970fe-0999-4f8c-87f3-4fb36487aa58": {"node_ids": ["b21a42a2-26aa-47a0-bd18-dce7cd721184", "6118958b-c6eb-46c3-ad6d-f7c1428d2c58", "b21a42a2-26aa-47a0-bd18-dce7cd721184", "6118958b-c6eb-46c3-ad6d-f7c1428d2c58", "b21a42a2-26aa-47a0-bd18-dce7cd721184", "6118958b-c6eb-46c3-ad6d-f7c1428d2c58"], "metadata": {"page_label": "60", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f4c94c80-ba1c-4d5b-bf82-182cb5b20b06": {"node_ids": ["e2a48ae5-d595-4bc6-bab4-660263bddf37", "7a141031-702a-4fcc-9d00-a7497cff1a2c", "3993c164-af7b-4d42-9ccb-e446b2cce491", "e2a48ae5-d595-4bc6-bab4-660263bddf37", "7a141031-702a-4fcc-9d00-a7497cff1a2c", "3993c164-af7b-4d42-9ccb-e446b2cce491", "e2a48ae5-d595-4bc6-bab4-660263bddf37", "7a141031-702a-4fcc-9d00-a7497cff1a2c", "3993c164-af7b-4d42-9ccb-e446b2cce491"], "metadata": {"page_label": "61", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ce7ca287-7bae-4d73-9e1b-53e2877c19dc": {"node_ids": ["b079a0ff-8e6f-4fc9-a6a3-a3eadb315236", "3dbd165f-0d69-4e7d-a7ff-f2fa5fd30754", "b079a0ff-8e6f-4fc9-a6a3-a3eadb315236", "3dbd165f-0d69-4e7d-a7ff-f2fa5fd30754", "b079a0ff-8e6f-4fc9-a6a3-a3eadb315236", "3dbd165f-0d69-4e7d-a7ff-f2fa5fd30754"], "metadata": {"page_label": "62", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bc268ea8-3541-4a54-9ea3-4ec4ef175355": {"node_ids": ["b1c398c3-af7f-44f7-9bf4-a14c6bdbe12b", "e4416dfc-d69f-4b0a-8375-6a316fb4ffcd", "0bf45a48-f030-497a-a8ed-60882a4ad3b8", "b1c398c3-af7f-44f7-9bf4-a14c6bdbe12b", "e4416dfc-d69f-4b0a-8375-6a316fb4ffcd", "0bf45a48-f030-497a-a8ed-60882a4ad3b8", "b1c398c3-af7f-44f7-9bf4-a14c6bdbe12b", "e4416dfc-d69f-4b0a-8375-6a316fb4ffcd", "0bf45a48-f030-497a-a8ed-60882a4ad3b8"], "metadata": {"page_label": "63", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f1e7984c-51a3-4d80-8eff-e2d4ae60ca4e": {"node_ids": ["d501622b-b7b0-448e-b8d0-dc51c10c963e", "45f1da4c-d5db-4178-aa88-c971df6ba348", "d501622b-b7b0-448e-b8d0-dc51c10c963e", "45f1da4c-d5db-4178-aa88-c971df6ba348", "d501622b-b7b0-448e-b8d0-dc51c10c963e", "45f1da4c-d5db-4178-aa88-c971df6ba348"], "metadata": {"page_label": "64", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "418c248c-21b2-42e1-9636-e911e7092d79": {"node_ids": ["1321f416-92f3-4c08-ae4e-4c0175fbcc61", "1321f416-92f3-4c08-ae4e-4c0175fbcc61", "1321f416-92f3-4c08-ae4e-4c0175fbcc61"], "metadata": {"page_label": "65", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ca5fd6e5-9a6a-4a42-9351-a8a2c8b95f6e": {"node_ids": ["fc3e45d1-e539-4a33-b465-35dcfe0f49b0", "fc2a8504-bbee-43c8-8db5-dfbb6cfc95d5", "fc3e45d1-e539-4a33-b465-35dcfe0f49b0", "fc2a8504-bbee-43c8-8db5-dfbb6cfc95d5", "fc3e45d1-e539-4a33-b465-35dcfe0f49b0", "fc2a8504-bbee-43c8-8db5-dfbb6cfc95d5"], "metadata": {"page_label": "66", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "07c80ebe-0826-4842-864f-006768ff70b0": {"node_ids": ["9a34710e-7bd9-4fb6-ab8b-db69789e68f3", "15d8d458-2b02-48f9-bf3d-7687e468f860", "85df5f9b-266c-4ae7-bcf8-a28d0b66ee30", "9a34710e-7bd9-4fb6-ab8b-db69789e68f3", "15d8d458-2b02-48f9-bf3d-7687e468f860", "85df5f9b-266c-4ae7-bcf8-a28d0b66ee30", "9a34710e-7bd9-4fb6-ab8b-db69789e68f3", "15d8d458-2b02-48f9-bf3d-7687e468f860", "85df5f9b-266c-4ae7-bcf8-a28d0b66ee30"], "metadata": {"page_label": "67", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "52a1ce83-0aa5-40f5-a784-d828a084fd3d": {"node_ids": ["e4c25c41-12d3-445f-b38a-2b515d7806d6", "75b8c2fe-a448-4d39-81d5-00e7ec5e839c", "e4c25c41-12d3-445f-b38a-2b515d7806d6", "75b8c2fe-a448-4d39-81d5-00e7ec5e839c", "e4c25c41-12d3-445f-b38a-2b515d7806d6", "75b8c2fe-a448-4d39-81d5-00e7ec5e839c"], "metadata": {"page_label": "68", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f238dff4-b098-41bf-b79c-3024d1e49d07": {"node_ids": ["a324f98f-e2c6-49a5-9c50-6fffde1c6d78", "a12cbc3e-66e9-44c6-854e-0d653bad8073", "a324f98f-e2c6-49a5-9c50-6fffde1c6d78", "a12cbc3e-66e9-44c6-854e-0d653bad8073", "a324f98f-e2c6-49a5-9c50-6fffde1c6d78", "a12cbc3e-66e9-44c6-854e-0d653bad8073"], "metadata": {"page_label": "69", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "af558226-ca59-4531-b13d-0c3483f85ce0": {"node_ids": ["0ad8b8c7-1960-4345-8c86-e2b1f4f9164e", "c52bca6c-3938-42be-b9fb-731c57141b58", "0ad8b8c7-1960-4345-8c86-e2b1f4f9164e", "c52bca6c-3938-42be-b9fb-731c57141b58", "0ad8b8c7-1960-4345-8c86-e2b1f4f9164e", "c52bca6c-3938-42be-b9fb-731c57141b58"], "metadata": {"page_label": "70", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "26046351-e663-453b-88d0-38bd5f628dc4": {"node_ids": ["e858fa5d-087d-4fef-b323-51e5f9df874e", "6be9cdb6-1f8c-4c02-9257-f29af674cd27", "e858fa5d-087d-4fef-b323-51e5f9df874e", "6be9cdb6-1f8c-4c02-9257-f29af674cd27", "e858fa5d-087d-4fef-b323-51e5f9df874e", "6be9cdb6-1f8c-4c02-9257-f29af674cd27"], "metadata": {"page_label": "71", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2b64243f-9d69-4c90-ab25-aaeb96bf5432": {"node_ids": ["61b0b080-e377-47c7-b286-3303de4844bb", "e733db96-f024-4ecc-a12e-4b740af790d4", "61b0b080-e377-47c7-b286-3303de4844bb", "e733db96-f024-4ecc-a12e-4b740af790d4", "61b0b080-e377-47c7-b286-3303de4844bb", "e733db96-f024-4ecc-a12e-4b740af790d4"], "metadata": {"page_label": "72", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "af9152c4-0a69-4bf3-8852-570c8faa5663": {"node_ids": ["2e476019-922d-43d1-8436-9d911b6e2775", "a2d83870-e4f0-4c06-bf17-b67d4b2dca51", "2e476019-922d-43d1-8436-9d911b6e2775", "a2d83870-e4f0-4c06-bf17-b67d4b2dca51", "2e476019-922d-43d1-8436-9d911b6e2775", "a2d83870-e4f0-4c06-bf17-b67d4b2dca51"], "metadata": {"page_label": "73", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "63c747f6-b5df-47ec-ace9-7a918c5f5033": {"node_ids": ["2ebb7c5b-5c02-4d96-899b-956f0e7ea3d8", "cbe6c204-b872-45d2-9935-e111795d69f2", "60dbb3c5-7e9c-48db-b3f2-6613968aa704", "2ebb7c5b-5c02-4d96-899b-956f0e7ea3d8", "cbe6c204-b872-45d2-9935-e111795d69f2", "60dbb3c5-7e9c-48db-b3f2-6613968aa704", "2ebb7c5b-5c02-4d96-899b-956f0e7ea3d8", "cbe6c204-b872-45d2-9935-e111795d69f2", "60dbb3c5-7e9c-48db-b3f2-6613968aa704"], "metadata": {"page_label": "74", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "51d6ccbe-5663-422f-a1af-c24e3bbd7b12": {"node_ids": ["660de627-9f06-4a09-8d20-c603e6a07086", "77a37bd5-b1cb-4d79-9ecc-908838dc3440", "660de627-9f06-4a09-8d20-c603e6a07086", "77a37bd5-b1cb-4d79-9ecc-908838dc3440", "660de627-9f06-4a09-8d20-c603e6a07086", "77a37bd5-b1cb-4d79-9ecc-908838dc3440"], "metadata": {"page_label": "75", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "94517a50-09a8-4f34-a390-5cb644cfd387": {"node_ids": ["dd83b3d6-0dc5-4331-b408-de3d1604f5c9", "2c273a64-bc09-4cd9-a649-fb4e64491e1a", "dd83b3d6-0dc5-4331-b408-de3d1604f5c9", "2c273a64-bc09-4cd9-a649-fb4e64491e1a", "dd83b3d6-0dc5-4331-b408-de3d1604f5c9", "2c273a64-bc09-4cd9-a649-fb4e64491e1a"], "metadata": {"page_label": "76", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "108ae145-5d6c-4074-b880-a88e2125df39": {"node_ids": ["80d3b47c-56bf-4f17-80b8-03191e5a16a2", "0b93104a-fbb9-434d-8e24-3279ef3937c1", "80d3b47c-56bf-4f17-80b8-03191e5a16a2", "0b93104a-fbb9-434d-8e24-3279ef3937c1", "80d3b47c-56bf-4f17-80b8-03191e5a16a2", "0b93104a-fbb9-434d-8e24-3279ef3937c1"], "metadata": {"page_label": "77", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4cff3ca7-6f2e-4b4e-a82f-460d650acd71": {"node_ids": ["b71a1de9-8fe6-4722-8cba-09eb8459e6c7", "8e4eeac6-2e5e-4b1b-b326-d0971d61e8b5", "b71a1de9-8fe6-4722-8cba-09eb8459e6c7", "8e4eeac6-2e5e-4b1b-b326-d0971d61e8b5", "b71a1de9-8fe6-4722-8cba-09eb8459e6c7", "8e4eeac6-2e5e-4b1b-b326-d0971d61e8b5"], "metadata": {"page_label": "78", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7dd86da5-b6d8-4e80-b3f2-9382a9be9efd": {"node_ids": ["2f073e4a-5b9f-47c3-ba13-e3bb7fda1b54", "67b7fe86-1304-494b-80ed-995fac1dfd97", "2f073e4a-5b9f-47c3-ba13-e3bb7fda1b54", "67b7fe86-1304-494b-80ed-995fac1dfd97", "2f073e4a-5b9f-47c3-ba13-e3bb7fda1b54", "67b7fe86-1304-494b-80ed-995fac1dfd97"], "metadata": {"page_label": "79", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e424bc1d-fd47-4aaf-883b-7a0fcfd34468": {"node_ids": ["71756b83-15c6-4b11-a53f-3a44c5cf2148", "d1b053bb-6836-436f-8e37-d3d00175c02d", "71756b83-15c6-4b11-a53f-3a44c5cf2148", "d1b053bb-6836-436f-8e37-d3d00175c02d", "71756b83-15c6-4b11-a53f-3a44c5cf2148", "d1b053bb-6836-436f-8e37-d3d00175c02d"], "metadata": {"page_label": "80", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e9e8e560-f979-4eb6-83a1-5313ac7253ba": {"node_ids": ["e6b36480-6c67-4d9f-b718-1199955fd4c7", "c8e1887c-e273-439d-8d38-b0c41e39e83d", "e6b36480-6c67-4d9f-b718-1199955fd4c7", "c8e1887c-e273-439d-8d38-b0c41e39e83d", "e6b36480-6c67-4d9f-b718-1199955fd4c7", "c8e1887c-e273-439d-8d38-b0c41e39e83d"], "metadata": {"page_label": "81", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bc55bab8-9e1f-4036-bccb-51c5a9e78738": {"node_ids": ["4e53dd9b-f7a0-470f-84d4-dccac2fb1920", "eebda1a3-1672-41cb-b512-dc71a8e092b5", "4e53dd9b-f7a0-470f-84d4-dccac2fb1920", "eebda1a3-1672-41cb-b512-dc71a8e092b5", "4e53dd9b-f7a0-470f-84d4-dccac2fb1920", "eebda1a3-1672-41cb-b512-dc71a8e092b5"], "metadata": {"page_label": "82", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "434e4647-fa83-4200-a0b5-f1d974b88edf": {"node_ids": ["50ecf123-c78c-4203-92c4-d7aebfadfb77", "0ef2d212-1dff-4d79-96f9-7237559920b8", "f573ffa9-5fdf-4ab7-95a0-fa0facec9195", "50ecf123-c78c-4203-92c4-d7aebfadfb77", "0ef2d212-1dff-4d79-96f9-7237559920b8", "f573ffa9-5fdf-4ab7-95a0-fa0facec9195", "50ecf123-c78c-4203-92c4-d7aebfadfb77", "0ef2d212-1dff-4d79-96f9-7237559920b8", "f573ffa9-5fdf-4ab7-95a0-fa0facec9195"], "metadata": {"page_label": "83", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "559cf4ab-e4c0-442f-a93e-93177a9709cd": {"node_ids": ["204ac2cb-39aa-4912-8979-ce7c6734b259", "92705424-bcd9-454f-bba8-10b20c7d5f29", "e2af8eeb-4d89-4996-8c4c-8536a1967da5", "204ac2cb-39aa-4912-8979-ce7c6734b259", "92705424-bcd9-454f-bba8-10b20c7d5f29", "e2af8eeb-4d89-4996-8c4c-8536a1967da5", "204ac2cb-39aa-4912-8979-ce7c6734b259", "92705424-bcd9-454f-bba8-10b20c7d5f29", "e2af8eeb-4d89-4996-8c4c-8536a1967da5"], "metadata": {"page_label": "84", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "86b6e004-dea7-44e1-81d2-98aff8b89b51": {"node_ids": ["e6fa2d4e-8b95-4ee2-b0dd-7e7304c2b52e", "eeb87108-8f11-4858-abe3-b766017ff050", "e6fa2d4e-8b95-4ee2-b0dd-7e7304c2b52e", "eeb87108-8f11-4858-abe3-b766017ff050", "e6fa2d4e-8b95-4ee2-b0dd-7e7304c2b52e", "eeb87108-8f11-4858-abe3-b766017ff050"], "metadata": {"page_label": "85", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d297ec2d-4538-404c-96f1-606872d0d47b": {"node_ids": ["da3a9b5e-f56b-4e04-8b43-ce3cc7064725", "7694f525-45e1-4751-9afc-f2c6ac2abfd1", "6db0efd6-ca6b-410f-a658-a94572f9b686", "8e903659-1ebe-4383-b213-3480babebe5c", "da3a9b5e-f56b-4e04-8b43-ce3cc7064725", "7694f525-45e1-4751-9afc-f2c6ac2abfd1", "6db0efd6-ca6b-410f-a658-a94572f9b686", "8e903659-1ebe-4383-b213-3480babebe5c", "da3a9b5e-f56b-4e04-8b43-ce3cc7064725", "7694f525-45e1-4751-9afc-f2c6ac2abfd1", "6db0efd6-ca6b-410f-a658-a94572f9b686", "8e903659-1ebe-4383-b213-3480babebe5c"], "metadata": {"page_label": "86", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5ee4cec0-21cb-469f-85bd-0eee0c52b017": {"node_ids": ["f5bf7544-62a2-448d-9760-64f4d5152a05", "f5bf7544-62a2-448d-9760-64f4d5152a05", "f5bf7544-62a2-448d-9760-64f4d5152a05"], "metadata": {"page_label": "87", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d4adfd5d-0b7e-4e02-8aa2-661e574d4604": {"node_ids": ["394e5e7b-0379-432e-906d-653e37a19629", "8e335c04-0570-4fce-8c29-3a3329f355fd", "394e5e7b-0379-432e-906d-653e37a19629", "8e335c04-0570-4fce-8c29-3a3329f355fd", "394e5e7b-0379-432e-906d-653e37a19629", "8e335c04-0570-4fce-8c29-3a3329f355fd"], "metadata": {"page_label": "88", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "16dfa785-0672-479a-86a6-891c7f7daeff": {"node_ids": ["665b91f5-954f-4060-9645-adeb2ec558b7", "33a968f1-05fc-4285-b813-0f4254798fcc", "665b91f5-954f-4060-9645-adeb2ec558b7", "33a968f1-05fc-4285-b813-0f4254798fcc", "665b91f5-954f-4060-9645-adeb2ec558b7", "33a968f1-05fc-4285-b813-0f4254798fcc"], "metadata": {"page_label": "89", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d261d037-7e9b-49a5-9063-4f252be69392": {"node_ids": ["c8fdbccc-951b-4ec9-8d7e-e2ad63f1d7c5", "26a399e1-a739-43e7-a787-b9c338334543", "c8fdbccc-951b-4ec9-8d7e-e2ad63f1d7c5", "26a399e1-a739-43e7-a787-b9c338334543", "c8fdbccc-951b-4ec9-8d7e-e2ad63f1d7c5", "26a399e1-a739-43e7-a787-b9c338334543"], "metadata": {"page_label": "90", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "53d9a10f-24c1-47b3-ace5-020773733807": {"node_ids": ["cbfd69db-9482-4d09-a11c-73769cfd00f4", "2b34b785-a141-4655-a90d-7eab6e8e8f74", "a1c19f9e-d8ba-40b5-b6c7-73212c24b656", "cbfd69db-9482-4d09-a11c-73769cfd00f4", "2b34b785-a141-4655-a90d-7eab6e8e8f74", "a1c19f9e-d8ba-40b5-b6c7-73212c24b656", "cbfd69db-9482-4d09-a11c-73769cfd00f4", "2b34b785-a141-4655-a90d-7eab6e8e8f74", "a1c19f9e-d8ba-40b5-b6c7-73212c24b656"], "metadata": {"page_label": "91", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "eadbe98b-2eb5-4a80-a5e0-93f91acdd6a8": {"node_ids": ["87c27c3f-8226-457b-a1e0-c82ec89056b5", "a466e41a-8c86-4653-9e99-592680d38d81", "87c27c3f-8226-457b-a1e0-c82ec89056b5", "a466e41a-8c86-4653-9e99-592680d38d81", "87c27c3f-8226-457b-a1e0-c82ec89056b5", "a466e41a-8c86-4653-9e99-592680d38d81"], "metadata": {"page_label": "92", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fc715357-b3f5-4bbd-8935-bdefdf179b92": {"node_ids": ["7a85acdb-7a47-4aad-b529-9ac31a834f94", "0bf3bb7c-15a8-4dc9-a81a-89a1aae3ca4a", "7a85acdb-7a47-4aad-b529-9ac31a834f94", "0bf3bb7c-15a8-4dc9-a81a-89a1aae3ca4a", "7a85acdb-7a47-4aad-b529-9ac31a834f94", "0bf3bb7c-15a8-4dc9-a81a-89a1aae3ca4a"], "metadata": {"page_label": "93", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "74dacdf4-76e1-4b29-8462-2a1e4f1397cc": {"node_ids": ["47354fed-9314-4ef0-abb4-58b1f19543fb", "17284040-52b0-4567-b2cd-4d7e4d993b20", "cc8f2717-127e-4ab1-8cac-3b3f2c534a4e", "47354fed-9314-4ef0-abb4-58b1f19543fb", "17284040-52b0-4567-b2cd-4d7e4d993b20", "cc8f2717-127e-4ab1-8cac-3b3f2c534a4e", "47354fed-9314-4ef0-abb4-58b1f19543fb", "17284040-52b0-4567-b2cd-4d7e4d993b20", "cc8f2717-127e-4ab1-8cac-3b3f2c534a4e"], "metadata": {"page_label": "94", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7d4dda25-30a4-49b6-9927-6b71e5c7ec19": {"node_ids": ["a5eec967-4b60-456a-8190-2627fdf9b687", "4e8f41a4-33d7-4c82-bac7-c69d81978d21", "a5eec967-4b60-456a-8190-2627fdf9b687", "4e8f41a4-33d7-4c82-bac7-c69d81978d21", "a5eec967-4b60-456a-8190-2627fdf9b687", "4e8f41a4-33d7-4c82-bac7-c69d81978d21"], "metadata": {"page_label": "95", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e98604d1-26a7-42b0-95a4-202faba70a45": {"node_ids": ["187ee27d-98c1-482c-80ca-647f549bed5e", "a37761b4-3cd9-4542-bf1e-1b2b8edf5bf9", "80ecd270-f1bf-4e90-b31b-e671b78c62e3", "187ee27d-98c1-482c-80ca-647f549bed5e", "a37761b4-3cd9-4542-bf1e-1b2b8edf5bf9", "80ecd270-f1bf-4e90-b31b-e671b78c62e3", "187ee27d-98c1-482c-80ca-647f549bed5e", "a37761b4-3cd9-4542-bf1e-1b2b8edf5bf9", "80ecd270-f1bf-4e90-b31b-e671b78c62e3"], "metadata": {"page_label": "96", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a73ccbb6-470f-4e3e-beb5-6c73ce8d3361": {"node_ids": ["e8cbcf2b-c54e-4b64-9f23-05d9337395f5", "568924d6-2905-4a31-8c52-0b0143f4ae64", "27b3c26c-acb4-497b-863d-70058ea96e70", "e8cbcf2b-c54e-4b64-9f23-05d9337395f5", "568924d6-2905-4a31-8c52-0b0143f4ae64", "27b3c26c-acb4-497b-863d-70058ea96e70", "e8cbcf2b-c54e-4b64-9f23-05d9337395f5", "568924d6-2905-4a31-8c52-0b0143f4ae64", "27b3c26c-acb4-497b-863d-70058ea96e70"], "metadata": {"page_label": "97", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e9033864-b226-45f2-80f2-bc671d10b6e8": {"node_ids": ["6215427a-e93d-4249-bc71-a21e3c7ee940", "16645623-0e18-49af-8343-6576d44c69e2", "3b82a1cf-427f-4829-9589-efae4df36d73", "6215427a-e93d-4249-bc71-a21e3c7ee940", "16645623-0e18-49af-8343-6576d44c69e2", "3b82a1cf-427f-4829-9589-efae4df36d73", "6215427a-e93d-4249-bc71-a21e3c7ee940", "16645623-0e18-49af-8343-6576d44c69e2", "3b82a1cf-427f-4829-9589-efae4df36d73"], "metadata": {"page_label": "98", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "be206d83-2285-4564-adec-859ecb1853ec": {"node_ids": ["805c864d-0d56-4773-9ff5-7a885e35dd84", "d4e7d1a6-939a-4ec1-81cd-1611ca8adc95", "805c864d-0d56-4773-9ff5-7a885e35dd84", "d4e7d1a6-939a-4ec1-81cd-1611ca8adc95", "805c864d-0d56-4773-9ff5-7a885e35dd84", "d4e7d1a6-939a-4ec1-81cd-1611ca8adc95"], "metadata": {"page_label": "99", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "551b6a42-8c74-4f54-a581-ae3f30d66d91": {"node_ids": ["3f23568d-d209-43ff-8a7a-09a1396bd307", "384e0a9b-7528-485a-8fb3-f5a94502198a", "16d2ca7b-ecf9-4bfc-897c-41753862c9c7", "3f23568d-d209-43ff-8a7a-09a1396bd307", "384e0a9b-7528-485a-8fb3-f5a94502198a", "16d2ca7b-ecf9-4bfc-897c-41753862c9c7", "3f23568d-d209-43ff-8a7a-09a1396bd307", "384e0a9b-7528-485a-8fb3-f5a94502198a", "16d2ca7b-ecf9-4bfc-897c-41753862c9c7"], "metadata": {"page_label": "100", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e5b2b54a-7b6a-43d2-bc9a-109d23b4a347": {"node_ids": ["1e42e95b-f727-4728-b563-22d63a48d735", "e44672d9-e397-4d81-96ee-c638d48479ba", "1e42e95b-f727-4728-b563-22d63a48d735", "e44672d9-e397-4d81-96ee-c638d48479ba", "1e42e95b-f727-4728-b563-22d63a48d735", "e44672d9-e397-4d81-96ee-c638d48479ba"], "metadata": {"page_label": "101", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e46b303c-f250-46c9-be33-0eea50e6a1c7": {"node_ids": ["146f0be5-66ac-4746-b4a3-32e81d5c18e3", "5bb9fdc9-f998-4edd-abde-f843da32e42c", "146f0be5-66ac-4746-b4a3-32e81d5c18e3", "5bb9fdc9-f998-4edd-abde-f843da32e42c", "146f0be5-66ac-4746-b4a3-32e81d5c18e3", "5bb9fdc9-f998-4edd-abde-f843da32e42c"], "metadata": {"page_label": "102", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9c56fba1-1eb6-4331-9f3f-7dbd63bc1109": {"node_ids": ["21438291-6488-4938-979a-c45500b1e757", "2c1514f1-777e-439c-90a5-d38c34e58a25", "21438291-6488-4938-979a-c45500b1e757", "2c1514f1-777e-439c-90a5-d38c34e58a25", "21438291-6488-4938-979a-c45500b1e757", "2c1514f1-777e-439c-90a5-d38c34e58a25"], "metadata": {"page_label": "103", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4a9cf1f1-aa36-41ec-96f6-75b2f6345c1e": {"node_ids": ["7ef0d6f6-d4a2-46cf-9e96-2754e4d778b0", "c8234730-0c36-4cd1-bed0-9af7c1cc54d5", "b5f3147f-c55b-44f2-9fde-14cadaf87ece", "7ef0d6f6-d4a2-46cf-9e96-2754e4d778b0", "c8234730-0c36-4cd1-bed0-9af7c1cc54d5", "b5f3147f-c55b-44f2-9fde-14cadaf87ece", "7ef0d6f6-d4a2-46cf-9e96-2754e4d778b0", "c8234730-0c36-4cd1-bed0-9af7c1cc54d5", "b5f3147f-c55b-44f2-9fde-14cadaf87ece"], "metadata": {"page_label": "104", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8bbd8faf-a3ab-4288-8e90-26e5345469c4": {"node_ids": ["367c3e8d-383d-4363-bc47-d6c9b9f85985", "6a2f82e6-d943-4338-b1d2-07151d328d7d", "367c3e8d-383d-4363-bc47-d6c9b9f85985", "6a2f82e6-d943-4338-b1d2-07151d328d7d", "367c3e8d-383d-4363-bc47-d6c9b9f85985", "6a2f82e6-d943-4338-b1d2-07151d328d7d"], "metadata": {"page_label": "105", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "68e269cf-0e6e-4866-a060-0b7508b0d38c": {"node_ids": ["18248a49-7cbd-4016-8c8b-3f9b47164ea5", "3572ad87-1e37-491c-b38d-beaf82d9e0f0", "e9b6b475-f705-4d1c-8d1c-db4f72afdc1a", "18248a49-7cbd-4016-8c8b-3f9b47164ea5", "3572ad87-1e37-491c-b38d-beaf82d9e0f0", "e9b6b475-f705-4d1c-8d1c-db4f72afdc1a", "18248a49-7cbd-4016-8c8b-3f9b47164ea5", "3572ad87-1e37-491c-b38d-beaf82d9e0f0", "e9b6b475-f705-4d1c-8d1c-db4f72afdc1a"], "metadata": {"page_label": "106", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "61e96006-6546-4a6b-b2ad-c7bebffc2675": {"node_ids": ["97fa29ab-e644-4f9f-b4da-b4ed2569dd9c", "6b1f4e28-5122-4077-89d7-358f01817061", "97fa29ab-e644-4f9f-b4da-b4ed2569dd9c", "6b1f4e28-5122-4077-89d7-358f01817061", "97fa29ab-e644-4f9f-b4da-b4ed2569dd9c", "6b1f4e28-5122-4077-89d7-358f01817061"], "metadata": {"page_label": "107", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d220d9c1-4db6-4622-bd32-d93bcc8e3a95": {"node_ids": ["f62be533-76cf-4ab3-b573-a3c186e5ca17", "3f049968-6296-4c50-b57c-3839feedb368", "30159b04-274f-4061-904d-93ad66743365", "f62be533-76cf-4ab3-b573-a3c186e5ca17", "3f049968-6296-4c50-b57c-3839feedb368", "30159b04-274f-4061-904d-93ad66743365", "f62be533-76cf-4ab3-b573-a3c186e5ca17", "3f049968-6296-4c50-b57c-3839feedb368", "30159b04-274f-4061-904d-93ad66743365"], "metadata": {"page_label": "108", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c0a25662-8abf-4d2a-8ce9-85ac3dfb02ff": {"node_ids": ["51e43c99-0a46-4d0c-af97-b06e6437dc61", "6e500db8-f5b5-44a4-a660-78ed2205831b", "51e43c99-0a46-4d0c-af97-b06e6437dc61", "6e500db8-f5b5-44a4-a660-78ed2205831b", "51e43c99-0a46-4d0c-af97-b06e6437dc61", "6e500db8-f5b5-44a4-a660-78ed2205831b"], "metadata": {"page_label": "109", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6fb17d2d-d89b-4543-888b-bd06572ac85c": {"node_ids": ["27c7d407-6407-46bf-b75a-a1c1a2281449", "cf0734f3-dc0b-4bcc-9971-c1b36bb93ff5", "32466f12-adc5-4721-81c7-f1c21cce22f7", "27c7d407-6407-46bf-b75a-a1c1a2281449", "cf0734f3-dc0b-4bcc-9971-c1b36bb93ff5", "32466f12-adc5-4721-81c7-f1c21cce22f7", "27c7d407-6407-46bf-b75a-a1c1a2281449", "cf0734f3-dc0b-4bcc-9971-c1b36bb93ff5", "32466f12-adc5-4721-81c7-f1c21cce22f7"], "metadata": {"page_label": "110", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3751be59-962a-4bae-b8b7-e42e4059c160": {"node_ids": ["9e369014-bac7-4a98-b93f-7cdc5d1d14b0", "3b6cddd5-bffe-456e-9217-a4cbbc33ed78", "9e369014-bac7-4a98-b93f-7cdc5d1d14b0", "3b6cddd5-bffe-456e-9217-a4cbbc33ed78", "9e369014-bac7-4a98-b93f-7cdc5d1d14b0", "3b6cddd5-bffe-456e-9217-a4cbbc33ed78"], "metadata": {"page_label": "111", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5a81b037-d520-4060-9e08-e8c70195cf07": {"node_ids": ["9ee187eb-ec86-449a-ba82-a2b55c476a9c", "92fc4f0b-0c1d-4f7a-97e1-77c35513ea8f", "9ee187eb-ec86-449a-ba82-a2b55c476a9c", "92fc4f0b-0c1d-4f7a-97e1-77c35513ea8f", "9ee187eb-ec86-449a-ba82-a2b55c476a9c", "92fc4f0b-0c1d-4f7a-97e1-77c35513ea8f"], "metadata": {"page_label": "112", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d6c3a031-06c5-4854-9c91-907910d0077c": {"node_ids": ["59bd06a0-aa11-4def-9921-ee34102df027", "c20bf026-294c-4ec9-b83a-2ed178b9c05a", "59bd06a0-aa11-4def-9921-ee34102df027", "c20bf026-294c-4ec9-b83a-2ed178b9c05a", "59bd06a0-aa11-4def-9921-ee34102df027", "c20bf026-294c-4ec9-b83a-2ed178b9c05a"], "metadata": {"page_label": "113", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d98ce27f-6b62-4e0f-8dce-defa0068d651": {"node_ids": ["d7c314f0-62d2-432e-9725-42387dd8d28d", "2d50a8b4-06d0-4f74-a1f9-2cae801d95bf", "d7c314f0-62d2-432e-9725-42387dd8d28d", "2d50a8b4-06d0-4f74-a1f9-2cae801d95bf", "d7c314f0-62d2-432e-9725-42387dd8d28d", "2d50a8b4-06d0-4f74-a1f9-2cae801d95bf"], "metadata": {"page_label": "114", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7414a4ad-2973-49f5-87cf-33c0d38fd0bb": {"node_ids": ["0a478be9-4dbd-4e52-a1f1-52c85936bc0c", "dcdae60e-44eb-4939-b839-7753c102748f", "0a478be9-4dbd-4e52-a1f1-52c85936bc0c", "dcdae60e-44eb-4939-b839-7753c102748f", "0a478be9-4dbd-4e52-a1f1-52c85936bc0c", "dcdae60e-44eb-4939-b839-7753c102748f"], "metadata": {"page_label": "115", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "73608b1a-2275-407d-83bf-dc322a0bacc3": {"node_ids": ["c2d01b2c-63cb-4081-9429-1ef20d9144b1", "51bcb4b4-7b56-4f41-a3d7-75a43d49355e", "c2d01b2c-63cb-4081-9429-1ef20d9144b1", "51bcb4b4-7b56-4f41-a3d7-75a43d49355e", "c2d01b2c-63cb-4081-9429-1ef20d9144b1", "51bcb4b4-7b56-4f41-a3d7-75a43d49355e"], "metadata": {"page_label": "116", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2ef94ce3-f862-4939-965f-6fba3393fe3e": {"node_ids": ["0a8de0ea-68ac-49aa-bd9b-c9b386294b44", "b68fa49c-5164-49d7-ad4e-7018c64ed0c7", "649a4a46-132b-44a2-aebf-5503a2fa6b2b", "0a8de0ea-68ac-49aa-bd9b-c9b386294b44", "b68fa49c-5164-49d7-ad4e-7018c64ed0c7", "649a4a46-132b-44a2-aebf-5503a2fa6b2b", "0a8de0ea-68ac-49aa-bd9b-c9b386294b44", "b68fa49c-5164-49d7-ad4e-7018c64ed0c7", "649a4a46-132b-44a2-aebf-5503a2fa6b2b"], "metadata": {"page_label": "117", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "86ee8e7a-f7ad-4ddd-b510-ec59e90e8715": {"node_ids": ["8e07d054-f586-4c94-aabe-70f055a2d80e", "79660338-0c5a-4587-a6b0-d46c545e65f3", "8e07d054-f586-4c94-aabe-70f055a2d80e", "79660338-0c5a-4587-a6b0-d46c545e65f3", "8e07d054-f586-4c94-aabe-70f055a2d80e", "79660338-0c5a-4587-a6b0-d46c545e65f3"], "metadata": {"page_label": "118", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "43bb0877-3aa2-42dd-921c-0663baf7cd22": {"node_ids": ["82e3bc19-dc6e-4515-811d-ea452d3e7eed", "5d362cd5-9435-4006-8e81-fea18d78e913", "58530ce7-a72e-4210-a098-52b6add9287f", "82e3bc19-dc6e-4515-811d-ea452d3e7eed", "5d362cd5-9435-4006-8e81-fea18d78e913", "58530ce7-a72e-4210-a098-52b6add9287f", "82e3bc19-dc6e-4515-811d-ea452d3e7eed", "5d362cd5-9435-4006-8e81-fea18d78e913", "58530ce7-a72e-4210-a098-52b6add9287f"], "metadata": {"page_label": "119", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f6caa8d2-6666-48c1-ab16-6076128dd297": {"node_ids": ["e2d337a9-b7d2-4667-bc33-ea5aec3cf1fc", "40dc5499-34ca-488f-a98e-28f1b2fbc130", "43e9f679-a6f4-4c0d-9ce6-041be89dad5b", "e2d337a9-b7d2-4667-bc33-ea5aec3cf1fc", "40dc5499-34ca-488f-a98e-28f1b2fbc130", "43e9f679-a6f4-4c0d-9ce6-041be89dad5b", "e2d337a9-b7d2-4667-bc33-ea5aec3cf1fc", "40dc5499-34ca-488f-a98e-28f1b2fbc130", "43e9f679-a6f4-4c0d-9ce6-041be89dad5b"], "metadata": {"page_label": "120", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bebbe97a-6ba0-45c7-9d6b-033a087e73fe": {"node_ids": ["c90978d2-af98-4a92-bcc4-2a97d8478c5f", "96567bcd-6ad0-4113-a1fc-a83b8a89f947", "15ae37b9-c52d-4189-9178-997cc157abb5", "c90978d2-af98-4a92-bcc4-2a97d8478c5f", "96567bcd-6ad0-4113-a1fc-a83b8a89f947", "15ae37b9-c52d-4189-9178-997cc157abb5", "c90978d2-af98-4a92-bcc4-2a97d8478c5f", "96567bcd-6ad0-4113-a1fc-a83b8a89f947", "15ae37b9-c52d-4189-9178-997cc157abb5"], "metadata": {"page_label": "121", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2f36838e-a6d9-419d-a03f-fe45f488028a": {"node_ids": ["98b25184-9037-4ea5-9be9-e93b5e1a61e1", "ad16ddb8-d426-4971-b25f-b91294818f66", "98b25184-9037-4ea5-9be9-e93b5e1a61e1", "ad16ddb8-d426-4971-b25f-b91294818f66", "98b25184-9037-4ea5-9be9-e93b5e1a61e1", "ad16ddb8-d426-4971-b25f-b91294818f66"], "metadata": {"page_label": "122", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "07ab4333-e343-4311-9c87-1a54cb27536f": {"node_ids": ["57f670dc-b330-42e9-8869-0c404c3e7657", "28d84a72-5738-451a-a697-3528e8c1da17", "57f670dc-b330-42e9-8869-0c404c3e7657", "28d84a72-5738-451a-a697-3528e8c1da17", "57f670dc-b330-42e9-8869-0c404c3e7657", "28d84a72-5738-451a-a697-3528e8c1da17"], "metadata": {"page_label": "123", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7e9db47e-a794-457e-9cdf-c69acc8f26ce": {"node_ids": ["37d8a102-3ccd-42af-b300-02f3ffb58675", "3f66f6cb-0e56-4e16-a2c7-06b085ff0150", "37d8a102-3ccd-42af-b300-02f3ffb58675", "3f66f6cb-0e56-4e16-a2c7-06b085ff0150", "37d8a102-3ccd-42af-b300-02f3ffb58675", "3f66f6cb-0e56-4e16-a2c7-06b085ff0150"], "metadata": {"page_label": "124", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "304f44ed-0692-43a5-815f-e9880eb2301b": {"node_ids": ["ba20c5ae-1203-4cfa-b9a1-485d621e0576", "17c15225-1113-46bc-9b68-293ee6d5761e", "1feb8d29-005a-43d0-ab32-31caf3e23a13", "ba20c5ae-1203-4cfa-b9a1-485d621e0576", "17c15225-1113-46bc-9b68-293ee6d5761e", "1feb8d29-005a-43d0-ab32-31caf3e23a13", "ba20c5ae-1203-4cfa-b9a1-485d621e0576", "17c15225-1113-46bc-9b68-293ee6d5761e", "1feb8d29-005a-43d0-ab32-31caf3e23a13"], "metadata": {"page_label": "125", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a17dd8f2-8471-4f40-94d1-21ef60f86416": {"node_ids": ["6549fafe-abc1-49e3-8fa8-68332e23251b", "22ef48cc-6a12-46f0-8e36-0938f530f701", "6549fafe-abc1-49e3-8fa8-68332e23251b", "22ef48cc-6a12-46f0-8e36-0938f530f701", "6549fafe-abc1-49e3-8fa8-68332e23251b", "22ef48cc-6a12-46f0-8e36-0938f530f701"], "metadata": {"page_label": "126", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3906f15e-a1ac-4dc7-9c78-380be7d210c7": {"node_ids": ["336e0deb-2a2e-47a6-8e05-9ce863c13d99", "74d33cf4-31e3-4b3f-8391-e15925f25df2", "336e0deb-2a2e-47a6-8e05-9ce863c13d99", "74d33cf4-31e3-4b3f-8391-e15925f25df2", "336e0deb-2a2e-47a6-8e05-9ce863c13d99", "74d33cf4-31e3-4b3f-8391-e15925f25df2"], "metadata": {"page_label": "127", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "caf58547-e1d0-40ae-928f-de73dfd67b76": {"node_ids": ["70848291-718a-4ed6-a573-6122ec5f7508", "04f7e6b7-5cae-4129-9c2c-3c47bcf1d1b0", "70848291-718a-4ed6-a573-6122ec5f7508", "04f7e6b7-5cae-4129-9c2c-3c47bcf1d1b0", "70848291-718a-4ed6-a573-6122ec5f7508", "04f7e6b7-5cae-4129-9c2c-3c47bcf1d1b0"], "metadata": {"page_label": "128", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "de3c56c2-8565-4b8f-846f-d4a23aa926c2": {"node_ids": ["6c5e45ec-8e9e-44ad-b6ab-3dd70aed2f77", "32cbeda5-8234-42b4-a6cd-92a08fcd09ce", "6c5e45ec-8e9e-44ad-b6ab-3dd70aed2f77", "32cbeda5-8234-42b4-a6cd-92a08fcd09ce", "6c5e45ec-8e9e-44ad-b6ab-3dd70aed2f77", "32cbeda5-8234-42b4-a6cd-92a08fcd09ce"], "metadata": {"page_label": "129", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "28c18585-ff3f-40e5-931f-243e0b3cac4f": {"node_ids": ["e1c1509c-e163-4887-85a5-cece63b6c7fe", "4439160c-6fcc-470d-8274-59af86c23d8a", "e1c1509c-e163-4887-85a5-cece63b6c7fe", "4439160c-6fcc-470d-8274-59af86c23d8a", "e1c1509c-e163-4887-85a5-cece63b6c7fe", "4439160c-6fcc-470d-8274-59af86c23d8a"], "metadata": {"page_label": "130", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "274f3b76-0c27-4757-ac3d-753baca11a28": {"node_ids": ["c19ee288-4cee-4533-b6c8-b33411dd502c", "e586b307-102a-49fe-9b28-b0b42cc86b3f", "c19ee288-4cee-4533-b6c8-b33411dd502c", "e586b307-102a-49fe-9b28-b0b42cc86b3f", "c19ee288-4cee-4533-b6c8-b33411dd502c", "e586b307-102a-49fe-9b28-b0b42cc86b3f"], "metadata": {"page_label": "131", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "63680f32-3eed-4ec6-b70e-0dc839ce1408": {"node_ids": ["7d9a9573-b836-4d32-9785-47f49206b760", "3134c9cf-b6f1-4efa-ba9c-fe6b7fce1478", "d74c3130-78c4-4e4a-8dae-2e4a71ac002f", "7d9a9573-b836-4d32-9785-47f49206b760", "3134c9cf-b6f1-4efa-ba9c-fe6b7fce1478", "d74c3130-78c4-4e4a-8dae-2e4a71ac002f", "7d9a9573-b836-4d32-9785-47f49206b760", "3134c9cf-b6f1-4efa-ba9c-fe6b7fce1478", "d74c3130-78c4-4e4a-8dae-2e4a71ac002f"], "metadata": {"page_label": "132", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6dd44b4b-033c-446a-b98b-08686acb43d1": {"node_ids": ["02833468-9df0-4072-ac67-0d314a99792f", "cc212c81-d538-4ec7-b810-ff69a2069cd2", "bb454d1a-ce1e-4c6e-a83b-de079f7efebc", "02833468-9df0-4072-ac67-0d314a99792f", "cc212c81-d538-4ec7-b810-ff69a2069cd2", "bb454d1a-ce1e-4c6e-a83b-de079f7efebc", "02833468-9df0-4072-ac67-0d314a99792f", "cc212c81-d538-4ec7-b810-ff69a2069cd2", "bb454d1a-ce1e-4c6e-a83b-de079f7efebc"], "metadata": {"page_label": "133", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3625a028-cf49-4d4f-bcc9-b1049d6d806b": {"node_ids": ["08671d22-f881-4baf-afd8-6a588ce20637", "1926a2b9-922b-4335-af45-de73d49b09c3", "08671d22-f881-4baf-afd8-6a588ce20637", "1926a2b9-922b-4335-af45-de73d49b09c3", "08671d22-f881-4baf-afd8-6a588ce20637", "1926a2b9-922b-4335-af45-de73d49b09c3"], "metadata": {"page_label": "134", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "73100427-57d7-47c8-adc1-a9f74ccbcaa6": {"node_ids": ["3d3b8780-6c9e-4c02-982a-f604b54faae3", "8c7e0ce7-d0d0-4bc5-a277-ef1d74174e4c", "3d3b8780-6c9e-4c02-982a-f604b54faae3", "8c7e0ce7-d0d0-4bc5-a277-ef1d74174e4c", "3d3b8780-6c9e-4c02-982a-f604b54faae3", "8c7e0ce7-d0d0-4bc5-a277-ef1d74174e4c"], "metadata": {"page_label": "135", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1906ef21-c6c9-40f1-9d63-e8cc7de658d3": {"node_ids": ["7a9d4a86-8db7-41fc-8021-b7152c2240ca", "d54063b6-dbec-4924-a9e6-f1718d8697ec", "edd1f9e9-eeb4-43c2-8f1b-22d0be04f42d", "7a9d4a86-8db7-41fc-8021-b7152c2240ca", "d54063b6-dbec-4924-a9e6-f1718d8697ec", "edd1f9e9-eeb4-43c2-8f1b-22d0be04f42d", "7a9d4a86-8db7-41fc-8021-b7152c2240ca", "d54063b6-dbec-4924-a9e6-f1718d8697ec", "edd1f9e9-eeb4-43c2-8f1b-22d0be04f42d"], "metadata": {"page_label": "136", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "25ce6b27-ee2e-465a-a9de-a8450c8e453b": {"node_ids": ["1c46215d-a5bf-43e6-98fd-5cf6ca4f297f", "bf63903c-8af3-4842-9ff1-367fb8dcc98e", "f851b475-eec3-469c-ba10-e3af8413411a", "1c46215d-a5bf-43e6-98fd-5cf6ca4f297f", "bf63903c-8af3-4842-9ff1-367fb8dcc98e", "f851b475-eec3-469c-ba10-e3af8413411a", "1c46215d-a5bf-43e6-98fd-5cf6ca4f297f", "bf63903c-8af3-4842-9ff1-367fb8dcc98e", "f851b475-eec3-469c-ba10-e3af8413411a"], "metadata": {"page_label": "137", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d1f79cd1-e2c2-433e-90a2-a20d61debba2": {"node_ids": ["d5244149-0cef-402c-801e-e99c38af57d8", "ead9324a-5314-47f1-b9ab-348352ed84bc", "d5244149-0cef-402c-801e-e99c38af57d8", "ead9324a-5314-47f1-b9ab-348352ed84bc", "d5244149-0cef-402c-801e-e99c38af57d8", "ead9324a-5314-47f1-b9ab-348352ed84bc"], "metadata": {"page_label": "138", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3a549ae4-3030-47d2-853a-e833c30cc76a": {"node_ids": ["a327baaa-73e6-40b0-bfed-c363bec408b2", "8a358024-096b-4cba-bc21-a672895f26dc", "a327baaa-73e6-40b0-bfed-c363bec408b2", "8a358024-096b-4cba-bc21-a672895f26dc", "a327baaa-73e6-40b0-bfed-c363bec408b2", "8a358024-096b-4cba-bc21-a672895f26dc"], "metadata": {"page_label": "139", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "76cf222d-11a7-4b46-b259-ea0a75b40846": {"node_ids": ["90b83da5-94f7-4657-bf4f-41e6b08c5932", "afc12c8a-6647-433d-9925-2add8421bbf1", "90b83da5-94f7-4657-bf4f-41e6b08c5932", "afc12c8a-6647-433d-9925-2add8421bbf1", "90b83da5-94f7-4657-bf4f-41e6b08c5932", "afc12c8a-6647-433d-9925-2add8421bbf1"], "metadata": {"page_label": "140", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9172e4dd-4452-42ed-b90c-f98743565b96": {"node_ids": ["446cfb8f-5e51-4a91-ae90-cf40e9380b99", "b7dbfbf1-60ef-4403-8702-d87696596a90", "d74e4bb9-9e67-4404-92df-840b39c390f1", "446cfb8f-5e51-4a91-ae90-cf40e9380b99", "b7dbfbf1-60ef-4403-8702-d87696596a90", "d74e4bb9-9e67-4404-92df-840b39c390f1", "446cfb8f-5e51-4a91-ae90-cf40e9380b99", "b7dbfbf1-60ef-4403-8702-d87696596a90", "d74e4bb9-9e67-4404-92df-840b39c390f1"], "metadata": {"page_label": "141", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "05c7d225-9d45-4c17-b29c-5ac8c09d4c0d": {"node_ids": ["b2fa92ac-48e0-4b49-a331-413bc0897440", "601c4ce1-c194-4936-a449-f85cefb4b761", "3c4eac3e-29dd-4e59-85b9-598437522fac", "b2fa92ac-48e0-4b49-a331-413bc0897440", "601c4ce1-c194-4936-a449-f85cefb4b761", "3c4eac3e-29dd-4e59-85b9-598437522fac", "b2fa92ac-48e0-4b49-a331-413bc0897440", "601c4ce1-c194-4936-a449-f85cefb4b761", "3c4eac3e-29dd-4e59-85b9-598437522fac"], "metadata": {"page_label": "142", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4e478a52-8834-4568-baad-42bbcecb007b": {"node_ids": ["ca0fa20d-90fd-45a4-929f-ca1d5a52bc6d", "a9c49ad1-2db4-451f-9c81-fd8b1242a47c", "ca0fa20d-90fd-45a4-929f-ca1d5a52bc6d", "a9c49ad1-2db4-451f-9c81-fd8b1242a47c", "ca0fa20d-90fd-45a4-929f-ca1d5a52bc6d", "a9c49ad1-2db4-451f-9c81-fd8b1242a47c"], "metadata": {"page_label": "143", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "23124eee-36a5-464f-af92-2b8219e75626": {"node_ids": ["a174fdab-7b6b-4a26-b9f1-eeab34a4968b", "da34b2a8-381b-4247-bb9e-3192f0761d2d", "a174fdab-7b6b-4a26-b9f1-eeab34a4968b", "da34b2a8-381b-4247-bb9e-3192f0761d2d", "a174fdab-7b6b-4a26-b9f1-eeab34a4968b", "da34b2a8-381b-4247-bb9e-3192f0761d2d"], "metadata": {"page_label": "144", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fd8a1d5f-b7e7-4da6-af6d-889c7a6d0f8a": {"node_ids": ["f9eb6eee-bc3e-44e5-a61b-718ae430eae1", "92653808-ff9e-4ee3-821c-7363e5e24792", "bde34af4-4420-4352-9f39-da6f4c16b4aa", "f9eb6eee-bc3e-44e5-a61b-718ae430eae1", "92653808-ff9e-4ee3-821c-7363e5e24792", "bde34af4-4420-4352-9f39-da6f4c16b4aa", "f9eb6eee-bc3e-44e5-a61b-718ae430eae1", "92653808-ff9e-4ee3-821c-7363e5e24792", "bde34af4-4420-4352-9f39-da6f4c16b4aa"], "metadata": {"page_label": "145", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "48be290e-5b34-4eac-b488-ba8f4d5264ef": {"node_ids": ["914b724b-a57c-437c-b031-29ea9e7c103e", "b2c16b7c-14fb-4ecf-9d73-b4e50857569b", "148e8707-bd69-417a-b26c-07175052f97a", "914b724b-a57c-437c-b031-29ea9e7c103e", "b2c16b7c-14fb-4ecf-9d73-b4e50857569b", "148e8707-bd69-417a-b26c-07175052f97a", "914b724b-a57c-437c-b031-29ea9e7c103e", "b2c16b7c-14fb-4ecf-9d73-b4e50857569b", "148e8707-bd69-417a-b26c-07175052f97a"], "metadata": {"page_label": "146", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "eaf97933-456d-456d-9892-432956ba6b4b": {"node_ids": ["8dd11c35-410a-4ff6-9227-e3631d2f9b7c", "8dd11c35-410a-4ff6-9227-e3631d2f9b7c", "8dd11c35-410a-4ff6-9227-e3631d2f9b7c"], "metadata": {"page_label": "147", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "33f0e91a-5c4b-4790-b7d2-f19f24b1a55d": {"node_ids": ["3d6c3d4d-315c-4b7d-9f11-357ba3861f07", "79726254-c1af-485f-8ac4-b1ad9a2cb23f", "3d6c3d4d-315c-4b7d-9f11-357ba3861f07", "79726254-c1af-485f-8ac4-b1ad9a2cb23f", "3d6c3d4d-315c-4b7d-9f11-357ba3861f07", "79726254-c1af-485f-8ac4-b1ad9a2cb23f"], "metadata": {"page_label": "148", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "638feaa1-a6b0-421a-b9a5-bb5990325961": {"node_ids": ["f0f8399a-f0e2-452e-aa85-231699cdeeaf", "bd389323-3c72-4147-9eac-02ae56878502", "f0f8399a-f0e2-452e-aa85-231699cdeeaf", "bd389323-3c72-4147-9eac-02ae56878502", "f0f8399a-f0e2-452e-aa85-231699cdeeaf", "bd389323-3c72-4147-9eac-02ae56878502"], "metadata": {"page_label": "149", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ff47b8c3-5623-4947-8d32-1b3e911f1fc4": {"node_ids": ["7b4175af-eae3-4992-908d-154124bd7f43", "aa49d000-bc96-423a-be8c-c216f43a9e08", "7b4175af-eae3-4992-908d-154124bd7f43", "aa49d000-bc96-423a-be8c-c216f43a9e08", "7b4175af-eae3-4992-908d-154124bd7f43", "aa49d000-bc96-423a-be8c-c216f43a9e08"], "metadata": {"page_label": "150", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d97df45d-02e0-4469-8511-c788726d6024": {"node_ids": ["b3ce1b5f-02d2-485c-8914-3d8a07292b30", "1afd66a4-7eaa-4005-b32f-08f8922e41b4", "b3ce1b5f-02d2-485c-8914-3d8a07292b30", "1afd66a4-7eaa-4005-b32f-08f8922e41b4", "b3ce1b5f-02d2-485c-8914-3d8a07292b30", "1afd66a4-7eaa-4005-b32f-08f8922e41b4"], "metadata": {"page_label": "151", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "eb05d631-5357-4c34-a19b-ce6e809dd7c0": {"node_ids": ["dc8c7d11-0049-418e-9ed3-bb59802cc972", "f3ef9508-1eb3-4e0b-b582-aa0a955fdcf7", "dc8c7d11-0049-418e-9ed3-bb59802cc972", "f3ef9508-1eb3-4e0b-b582-aa0a955fdcf7", "dc8c7d11-0049-418e-9ed3-bb59802cc972", "f3ef9508-1eb3-4e0b-b582-aa0a955fdcf7"], "metadata": {"page_label": "152", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ca35b61b-e782-4dd2-bd02-e039c5a86e8b": {"node_ids": ["38be8a6b-1b56-4f70-90aa-a03bc1ea12b0", "1204d647-08a9-4c6c-81c3-da81d681cb54", "38be8a6b-1b56-4f70-90aa-a03bc1ea12b0", "1204d647-08a9-4c6c-81c3-da81d681cb54", "38be8a6b-1b56-4f70-90aa-a03bc1ea12b0", "1204d647-08a9-4c6c-81c3-da81d681cb54"], "metadata": {"page_label": "153", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4ebcd2d0-4dd0-42b0-b8a7-c0d474a7a5d8": {"node_ids": ["0d0601af-ee22-483d-b97b-e0ca454583c4", "918661fb-1789-4889-8e43-62a36dfe01b1", "0d0601af-ee22-483d-b97b-e0ca454583c4", "918661fb-1789-4889-8e43-62a36dfe01b1", "0d0601af-ee22-483d-b97b-e0ca454583c4", "918661fb-1789-4889-8e43-62a36dfe01b1"], "metadata": {"page_label": "154", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8313d47c-8e42-4ae9-adc0-c72f881ea45d": {"node_ids": ["b68b54a1-d1e2-4e41-ac04-52ffa3aece54", "12e975ce-2ae1-4170-8334-7f26497bda69", "b68b54a1-d1e2-4e41-ac04-52ffa3aece54", "12e975ce-2ae1-4170-8334-7f26497bda69", "b68b54a1-d1e2-4e41-ac04-52ffa3aece54", "12e975ce-2ae1-4170-8334-7f26497bda69"], "metadata": {"page_label": "155", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ce4c54d1-fbf8-4fa5-a264-ad97b022f123": {"node_ids": ["4c3b32ab-d1b7-4db6-ad92-dff87c342cbc", "6d835313-a35a-4337-846b-27bccb3f181f", "4c3b32ab-d1b7-4db6-ad92-dff87c342cbc", "6d835313-a35a-4337-846b-27bccb3f181f", "4c3b32ab-d1b7-4db6-ad92-dff87c342cbc", "6d835313-a35a-4337-846b-27bccb3f181f"], "metadata": {"page_label": "156", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "81af5941-b959-4b1d-824f-30de3496ca4d": {"node_ids": ["ca8f7f67-d41b-484f-8046-dbf9f5ea57b7", "ca8f7f67-d41b-484f-8046-dbf9f5ea57b7", "ca8f7f67-d41b-484f-8046-dbf9f5ea57b7"], "metadata": {"page_label": "157", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4d7bcb60-5d9e-4105-b17c-af8a1988ee80": {"node_ids": ["2278994b-8766-4065-9b64-8652e3259b1c", "68c0b906-16e6-41d8-ae1a-ae95eb1e04bd", "2278994b-8766-4065-9b64-8652e3259b1c", "68c0b906-16e6-41d8-ae1a-ae95eb1e04bd", "2278994b-8766-4065-9b64-8652e3259b1c", "68c0b906-16e6-41d8-ae1a-ae95eb1e04bd"], "metadata": {"page_label": "158", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "078e2284-0b57-4fd2-b67a-a9630c585bbc": {"node_ids": ["d9b7ba0c-0153-4a6f-8584-96ba653c35b3", "2daf7b62-9a93-4ece-8f36-00de033fcc49", "d9b7ba0c-0153-4a6f-8584-96ba653c35b3", "2daf7b62-9a93-4ece-8f36-00de033fcc49", "d9b7ba0c-0153-4a6f-8584-96ba653c35b3", "2daf7b62-9a93-4ece-8f36-00de033fcc49"], "metadata": {"page_label": "159", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "224344af-e9f6-4e94-88ec-e1dfa76512f1": {"node_ids": ["60b5ac3a-6dd9-425b-8d58-4b61eb19c577", "35af1083-b48f-4243-bb1a-2e74c7fc0b74", "60b5ac3a-6dd9-425b-8d58-4b61eb19c577", "35af1083-b48f-4243-bb1a-2e74c7fc0b74", "60b5ac3a-6dd9-425b-8d58-4b61eb19c577", "35af1083-b48f-4243-bb1a-2e74c7fc0b74"], "metadata": {"page_label": "160", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d6c94082-27b9-4bd9-83e7-cd39cd0b8ad2": {"node_ids": ["7d744ee3-b96f-4fa9-9872-564059eb5fd9", "9a650489-83d1-43d3-92fe-9bc4f158c38b", "1471e469-6350-49c6-aa04-dbc1814a712a", "7d744ee3-b96f-4fa9-9872-564059eb5fd9", "9a650489-83d1-43d3-92fe-9bc4f158c38b", "1471e469-6350-49c6-aa04-dbc1814a712a", "7d744ee3-b96f-4fa9-9872-564059eb5fd9", "9a650489-83d1-43d3-92fe-9bc4f158c38b", "1471e469-6350-49c6-aa04-dbc1814a712a"], "metadata": {"page_label": "161", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2f333b79-639c-4bc8-9cb5-55ccdd770842": {"node_ids": ["959274cb-af91-4990-a46d-2df7df9a1153", "404650b7-5139-469d-b38f-b9c5488e693d", "959274cb-af91-4990-a46d-2df7df9a1153", "404650b7-5139-469d-b38f-b9c5488e693d", "959274cb-af91-4990-a46d-2df7df9a1153", "404650b7-5139-469d-b38f-b9c5488e693d"], "metadata": {"page_label": "162", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "754bc852-8f56-4e70-9b15-21bf00a90135": {"node_ids": ["f8279be1-f2de-4735-9e36-ab397a3d3f89", "a2140e28-4d8c-4ab9-9b9e-d75e5cb5cebf", "e8251df0-ad92-4a9e-8116-db91407f09a5", "f8279be1-f2de-4735-9e36-ab397a3d3f89", "a2140e28-4d8c-4ab9-9b9e-d75e5cb5cebf", "e8251df0-ad92-4a9e-8116-db91407f09a5", "f8279be1-f2de-4735-9e36-ab397a3d3f89", "a2140e28-4d8c-4ab9-9b9e-d75e5cb5cebf", "e8251df0-ad92-4a9e-8116-db91407f09a5"], "metadata": {"page_label": "163", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f06a5d4e-0d97-4095-9ae4-a5d7adc918d6": {"node_ids": ["049fdac9-5d2c-46b5-8c84-c14552286b28", "10102bad-9a1a-4cc7-b0d2-62823e0dcba3", "049fdac9-5d2c-46b5-8c84-c14552286b28", "10102bad-9a1a-4cc7-b0d2-62823e0dcba3", "049fdac9-5d2c-46b5-8c84-c14552286b28", "10102bad-9a1a-4cc7-b0d2-62823e0dcba3"], "metadata": {"page_label": "164", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "83df579a-999b-4903-af19-bd51898da017": {"node_ids": ["d83304ff-cb95-48dd-83da-f9412d51bf33", "a5fd2d7a-0165-48a4-934b-ad64d34e1647", "624305f7-cb70-4b6b-8f7e-290e8fd798c1", "d83304ff-cb95-48dd-83da-f9412d51bf33", "a5fd2d7a-0165-48a4-934b-ad64d34e1647", "624305f7-cb70-4b6b-8f7e-290e8fd798c1", "d83304ff-cb95-48dd-83da-f9412d51bf33", "a5fd2d7a-0165-48a4-934b-ad64d34e1647", "624305f7-cb70-4b6b-8f7e-290e8fd798c1"], "metadata": {"page_label": "165", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ce3d5358-8574-47e9-bf56-ca93795acfe2": {"node_ids": ["34bf32f1-44a2-4601-9ece-1aedd89feec7", "c52ef99a-8f59-49a2-a5dd-ca532295be03", "be4e6aad-c56c-436d-b3c1-0f3d0bbc0500", "34bf32f1-44a2-4601-9ece-1aedd89feec7", "c52ef99a-8f59-49a2-a5dd-ca532295be03", "be4e6aad-c56c-436d-b3c1-0f3d0bbc0500", "34bf32f1-44a2-4601-9ece-1aedd89feec7", "c52ef99a-8f59-49a2-a5dd-ca532295be03", "be4e6aad-c56c-436d-b3c1-0f3d0bbc0500"], "metadata": {"page_label": "166", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bc7a119a-6a91-44e0-9732-a2bd363297fb": {"node_ids": ["382a9231-f00a-4a70-9ce8-c81431fb935e", "6c458d90-c688-42cd-a285-a558de298e11", "bca3d97e-0a8d-4d60-a7fd-38e928c95090", "382a9231-f00a-4a70-9ce8-c81431fb935e", "6c458d90-c688-42cd-a285-a558de298e11", "bca3d97e-0a8d-4d60-a7fd-38e928c95090", "382a9231-f00a-4a70-9ce8-c81431fb935e", "6c458d90-c688-42cd-a285-a558de298e11", "bca3d97e-0a8d-4d60-a7fd-38e928c95090"], "metadata": {"page_label": "167", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "65ac99fb-4fb5-41ca-bce6-79346b6cfaa7": {"node_ids": ["19a3aff6-07dc-4ea7-bb1c-bce8bd448c7b", "8f88aa5a-30d6-4131-bac6-06f764f8ab2f", "19a3aff6-07dc-4ea7-bb1c-bce8bd448c7b", "8f88aa5a-30d6-4131-bac6-06f764f8ab2f", "19a3aff6-07dc-4ea7-bb1c-bce8bd448c7b", "8f88aa5a-30d6-4131-bac6-06f764f8ab2f"], "metadata": {"page_label": "168", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b887db02-1ee8-463b-8fe2-4b74bc8da920": {"node_ids": ["4868c63e-d47f-4b73-8f63-1b305829701d", "5ba20086-79b0-4cb7-a96b-b71a4256675f", "2ee3e7c4-a584-4e0f-8230-0d0d29881fcb", "4868c63e-d47f-4b73-8f63-1b305829701d", "5ba20086-79b0-4cb7-a96b-b71a4256675f", "2ee3e7c4-a584-4e0f-8230-0d0d29881fcb", "4868c63e-d47f-4b73-8f63-1b305829701d", "5ba20086-79b0-4cb7-a96b-b71a4256675f", "2ee3e7c4-a584-4e0f-8230-0d0d29881fcb"], "metadata": {"page_label": "169", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6c1c8907-4eff-4222-92e9-036d8df972fd": {"node_ids": ["47d5f94e-5121-43db-85b4-359c99d5bbb1", "c60c83ba-8987-40f9-bc2e-142685b73e85", "47d5f94e-5121-43db-85b4-359c99d5bbb1", "c60c83ba-8987-40f9-bc2e-142685b73e85", "47d5f94e-5121-43db-85b4-359c99d5bbb1", "c60c83ba-8987-40f9-bc2e-142685b73e85"], "metadata": {"page_label": "170", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "87d7e1c1-59b5-44e3-af81-232286fe0460": {"node_ids": ["81ce6e04-5a88-4b1f-bc89-965670eb2c4c", "e45466c9-3438-4239-b49e-0b779934dbe4", "60cb0188-3b5e-499f-a8aa-aa579e72d9ea", "81ce6e04-5a88-4b1f-bc89-965670eb2c4c", "e45466c9-3438-4239-b49e-0b779934dbe4", "60cb0188-3b5e-499f-a8aa-aa579e72d9ea", "81ce6e04-5a88-4b1f-bc89-965670eb2c4c", "e45466c9-3438-4239-b49e-0b779934dbe4", "60cb0188-3b5e-499f-a8aa-aa579e72d9ea"], "metadata": {"page_label": "171", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "71728c91-bcc9-42cc-8857-36a8f4e48c31": {"node_ids": ["a75373c6-5a45-4f86-8344-3e3d3e6b4cda", "a75373c6-5a45-4f86-8344-3e3d3e6b4cda", "a75373c6-5a45-4f86-8344-3e3d3e6b4cda"], "metadata": {"page_label": "172", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2adadb5b-fc95-4760-9ae0-93d6fa79a344": {"node_ids": ["37f67ac2-da52-4ac8-a08d-595c8b5ae4cf", "2d6bc0ca-4ac5-4862-a3b9-b92d6bbba0b9", "37f67ac2-da52-4ac8-a08d-595c8b5ae4cf", "2d6bc0ca-4ac5-4862-a3b9-b92d6bbba0b9", "37f67ac2-da52-4ac8-a08d-595c8b5ae4cf", "2d6bc0ca-4ac5-4862-a3b9-b92d6bbba0b9"], "metadata": {"page_label": "173", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8ee06383-fab5-404c-ae63-cf6ed68fcad6": {"node_ids": ["77a8fcd8-5b61-49bd-91d5-7c5340e2d123", "3dfabd00-d757-42e9-9a07-5665637045e7", "77a8fcd8-5b61-49bd-91d5-7c5340e2d123", "3dfabd00-d757-42e9-9a07-5665637045e7", "77a8fcd8-5b61-49bd-91d5-7c5340e2d123", "3dfabd00-d757-42e9-9a07-5665637045e7"], "metadata": {"page_label": "174", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fbf03dd6-a28c-422c-bbee-08d5e343c2cd": {"node_ids": ["40bebad0-1edc-4978-a9dc-514e8c3977d5", "40bebad0-1edc-4978-a9dc-514e8c3977d5", "40bebad0-1edc-4978-a9dc-514e8c3977d5"], "metadata": {"page_label": "175", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "319e6c49-ccec-47c6-9b76-caa61ea5e016": {"node_ids": ["01665665-7125-4a69-818f-78a8c3732746", "3fac88bf-75bb-491d-a935-65dcdf8584e1", "4723c30e-aeae-4f63-91b0-66e2315f3431", "01665665-7125-4a69-818f-78a8c3732746", "3fac88bf-75bb-491d-a935-65dcdf8584e1", "4723c30e-aeae-4f63-91b0-66e2315f3431", "01665665-7125-4a69-818f-78a8c3732746", "3fac88bf-75bb-491d-a935-65dcdf8584e1", "4723c30e-aeae-4f63-91b0-66e2315f3431"], "metadata": {"page_label": "176", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8f893d7b-6f44-473b-95b3-1dee90e9cb64": {"node_ids": ["fd4c89ea-d0bd-4630-a2c7-9ec85cb73a63", "29c0dde8-6896-4ce8-8ce4-b044792ff7a6", "fd4c89ea-d0bd-4630-a2c7-9ec85cb73a63", "29c0dde8-6896-4ce8-8ce4-b044792ff7a6", "fd4c89ea-d0bd-4630-a2c7-9ec85cb73a63", "29c0dde8-6896-4ce8-8ce4-b044792ff7a6"], "metadata": {"page_label": "177", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9038d23d-b6e8-405b-a623-002d24169ed5": {"node_ids": ["bb14f7c6-e571-4076-94ff-c64ca84a2680", "689fa769-2761-4b5c-a2df-d49230301f91", "bb14f7c6-e571-4076-94ff-c64ca84a2680", "689fa769-2761-4b5c-a2df-d49230301f91", "bb14f7c6-e571-4076-94ff-c64ca84a2680", "689fa769-2761-4b5c-a2df-d49230301f91"], "metadata": {"page_label": "178", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f8dc7d31-c021-4a2f-80d4-39c5d89fe64c": {"node_ids": ["664d9ffd-7067-4174-b75b-48802386d358", "f91b9717-94b9-4bd8-8a66-a865658dc511", "664d9ffd-7067-4174-b75b-48802386d358", "f91b9717-94b9-4bd8-8a66-a865658dc511", "664d9ffd-7067-4174-b75b-48802386d358", "f91b9717-94b9-4bd8-8a66-a865658dc511"], "metadata": {"page_label": "179", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ed5c95ab-7707-4325-ad71-3c0376fb493e": {"node_ids": ["53e8e424-bd02-411b-a478-7804b1ef747d", "0d9e8d95-f399-42b0-8883-0ca268295c8c", "53e8e424-bd02-411b-a478-7804b1ef747d", "0d9e8d95-f399-42b0-8883-0ca268295c8c", "53e8e424-bd02-411b-a478-7804b1ef747d", "0d9e8d95-f399-42b0-8883-0ca268295c8c"], "metadata": {"page_label": "180", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bf6a332a-0836-49e5-ad43-4ea1a2f97f6d": {"node_ids": ["3af372fc-e003-4005-8e46-f7eb25d83a34", "217119c4-3098-456b-b166-9611c6c9ed8f", "3af372fc-e003-4005-8e46-f7eb25d83a34", "217119c4-3098-456b-b166-9611c6c9ed8f", "3af372fc-e003-4005-8e46-f7eb25d83a34", "217119c4-3098-456b-b166-9611c6c9ed8f"], "metadata": {"page_label": "181", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "16b77040-2cfe-4a37-a1f3-5b48343b1019": {"node_ids": ["02c09b02-55b2-4748-bb0b-8325dd772dee", "02c09b02-55b2-4748-bb0b-8325dd772dee", "02c09b02-55b2-4748-bb0b-8325dd772dee"], "metadata": {"page_label": "182", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e16cfc28-71bf-45e6-bdd9-94e670a8f14a": {"node_ids": ["f2264ba6-8609-4e6d-988b-716d5031ed50", "94468084-e547-470a-b086-f702a8ba2457", "f2264ba6-8609-4e6d-988b-716d5031ed50", "94468084-e547-470a-b086-f702a8ba2457", "f2264ba6-8609-4e6d-988b-716d5031ed50", "94468084-e547-470a-b086-f702a8ba2457"], "metadata": {"page_label": "183", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b0e630f4-ec5a-47e0-9c31-b3fd2f0a6c68": {"node_ids": ["db5888f4-7ed8-40ec-a703-dc07b2105bdb", "7dd67af5-e81f-41c5-b444-0c6162e99f9d", "1a9abb1e-24f5-491f-a622-ebd64b270d89", "db5888f4-7ed8-40ec-a703-dc07b2105bdb", "7dd67af5-e81f-41c5-b444-0c6162e99f9d", "1a9abb1e-24f5-491f-a622-ebd64b270d89", "db5888f4-7ed8-40ec-a703-dc07b2105bdb", "7dd67af5-e81f-41c5-b444-0c6162e99f9d", "1a9abb1e-24f5-491f-a622-ebd64b270d89"], "metadata": {"page_label": "184", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0fb1f8a2-bdf8-4bf0-88bc-8c31c5ae0e36": {"node_ids": ["b074302d-f077-47e4-a057-c7ec61ba6dea", "823cbd72-0ba4-40b7-a028-8a7d0216e512", "b074302d-f077-47e4-a057-c7ec61ba6dea", "823cbd72-0ba4-40b7-a028-8a7d0216e512", "b074302d-f077-47e4-a057-c7ec61ba6dea", "823cbd72-0ba4-40b7-a028-8a7d0216e512"], "metadata": {"page_label": "185", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a0bf1ddf-b5c1-4b6a-899e-a8e7ad45902b": {"node_ids": ["8e1d16cb-6ca1-4845-8dc3-943d41efe29c", "6ae9df9b-7bb3-4600-aeb4-1f54aef245e2", "8e1d16cb-6ca1-4845-8dc3-943d41efe29c", "6ae9df9b-7bb3-4600-aeb4-1f54aef245e2", "8e1d16cb-6ca1-4845-8dc3-943d41efe29c", "6ae9df9b-7bb3-4600-aeb4-1f54aef245e2"], "metadata": {"page_label": "186", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8db36e24-62d7-40bf-9f81-83711e111b50": {"node_ids": ["25fd0c30-0db6-4e79-994c-a49efda63ffc", "c78f4413-8239-42dd-b013-b6008d1920e9", "25fd0c30-0db6-4e79-994c-a49efda63ffc", "c78f4413-8239-42dd-b013-b6008d1920e9", "25fd0c30-0db6-4e79-994c-a49efda63ffc", "c78f4413-8239-42dd-b013-b6008d1920e9"], "metadata": {"page_label": "187", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "333a3c20-05a3-468f-8d5f-66fe014292c4": {"node_ids": ["85327d0c-1b6c-46e3-95a9-d04f357ecbf8", "baa66798-96a6-4468-aa17-a0a9391213a8", "85327d0c-1b6c-46e3-95a9-d04f357ecbf8", "baa66798-96a6-4468-aa17-a0a9391213a8", "85327d0c-1b6c-46e3-95a9-d04f357ecbf8", "baa66798-96a6-4468-aa17-a0a9391213a8"], "metadata": {"page_label": "188", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "859e9e4d-a244-49b8-a712-7a4a74570068": {"node_ids": ["3e9b88fa-73b0-4531-9239-b34424c60680", "04b72a2c-8ab0-4a4b-9d4f-6f069be974d0", "3e9b88fa-73b0-4531-9239-b34424c60680", "04b72a2c-8ab0-4a4b-9d4f-6f069be974d0", "3e9b88fa-73b0-4531-9239-b34424c60680", "04b72a2c-8ab0-4a4b-9d4f-6f069be974d0"], "metadata": {"page_label": "189", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "884c0ae6-1eea-4eb3-893b-4a2f878b6f94": {"node_ids": ["f6f62ee1-375f-41a9-9fc5-f196b817a4d0", "f6d4ef3e-27a2-490a-956c-2e56bce0b21d", "f6f62ee1-375f-41a9-9fc5-f196b817a4d0", "f6d4ef3e-27a2-490a-956c-2e56bce0b21d", "f6f62ee1-375f-41a9-9fc5-f196b817a4d0", "f6d4ef3e-27a2-490a-956c-2e56bce0b21d"], "metadata": {"page_label": "190", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2146d6b2-2d26-4f2d-a88a-aa5b95d2a783": {"node_ids": ["791fb779-c035-45e6-a342-55f2ddfc51f9", "dfd6aeac-9eed-433a-b4dc-f0e2e9657cd5", "1b54f372-937a-492a-b4f1-93451e8f8789", "791fb779-c035-45e6-a342-55f2ddfc51f9", "dfd6aeac-9eed-433a-b4dc-f0e2e9657cd5", "1b54f372-937a-492a-b4f1-93451e8f8789", "791fb779-c035-45e6-a342-55f2ddfc51f9", "dfd6aeac-9eed-433a-b4dc-f0e2e9657cd5", "1b54f372-937a-492a-b4f1-93451e8f8789"], "metadata": {"page_label": "191", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c2973ce2-bf8b-4fe8-8e40-bc659bab8aa7": {"node_ids": ["e7ea6979-37fa-42bc-99ea-31a8913923da", "3edbbf1d-ce85-480b-b65c-0ec35171fcd3", "3bc0c0ce-d09f-4052-85f6-e191e5e927af", "e7ea6979-37fa-42bc-99ea-31a8913923da", "3edbbf1d-ce85-480b-b65c-0ec35171fcd3", "3bc0c0ce-d09f-4052-85f6-e191e5e927af", "e7ea6979-37fa-42bc-99ea-31a8913923da", "3edbbf1d-ce85-480b-b65c-0ec35171fcd3", "3bc0c0ce-d09f-4052-85f6-e191e5e927af"], "metadata": {"page_label": "192", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d96c5c0a-ca95-4de3-b3d2-bdf73fd89ac6": {"node_ids": ["024af8d9-dbd0-4b93-84c9-474b50f78319", "b766b9e3-41e0-47f0-91ce-41b24b8be76f", "024af8d9-dbd0-4b93-84c9-474b50f78319", "b766b9e3-41e0-47f0-91ce-41b24b8be76f", "024af8d9-dbd0-4b93-84c9-474b50f78319", "b766b9e3-41e0-47f0-91ce-41b24b8be76f"], "metadata": {"page_label": "193", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d485b745-5e24-4f10-98bf-783d60fffab2": {"node_ids": ["8ce9a216-2d4a-4a4a-b318-10a03c406a4f", "295f7078-2f49-446e-b059-d91c55eaaf27", "8ce9a216-2d4a-4a4a-b318-10a03c406a4f", "295f7078-2f49-446e-b059-d91c55eaaf27", "8ce9a216-2d4a-4a4a-b318-10a03c406a4f", "295f7078-2f49-446e-b059-d91c55eaaf27"], "metadata": {"page_label": "194", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8ec4e6a4-cb49-4cca-903d-2bbdefa4c112": {"node_ids": ["f160a1a9-cbc3-4a8f-abaa-a042655fc386", "6e47cef6-3566-460e-b3a6-7292cd8caa15", "f160a1a9-cbc3-4a8f-abaa-a042655fc386", "6e47cef6-3566-460e-b3a6-7292cd8caa15", "f160a1a9-cbc3-4a8f-abaa-a042655fc386", "6e47cef6-3566-460e-b3a6-7292cd8caa15"], "metadata": {"page_label": "195", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5aeaae6d-4448-49b4-a851-777b28f031ec": {"node_ids": ["480c185a-de7a-4b68-8ae8-f95bb131ce63", "b23d7495-dc38-4b47-8b55-7d5e6b099202", "480c185a-de7a-4b68-8ae8-f95bb131ce63", "b23d7495-dc38-4b47-8b55-7d5e6b099202", "480c185a-de7a-4b68-8ae8-f95bb131ce63", "b23d7495-dc38-4b47-8b55-7d5e6b099202"], "metadata": {"page_label": "196", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f506ce48-764f-42c3-a927-d3048c952f07": {"node_ids": ["87a18f21-26e6-42b7-9e36-9967c0962176", "f719bcf1-051b-45dd-b38a-d3f374b7f509", "87a18f21-26e6-42b7-9e36-9967c0962176", "f719bcf1-051b-45dd-b38a-d3f374b7f509", "87a18f21-26e6-42b7-9e36-9967c0962176", "f719bcf1-051b-45dd-b38a-d3f374b7f509"], "metadata": {"page_label": "197", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "24564321-94c2-48e2-9faa-250076614265": {"node_ids": ["c4f485bf-b5e0-4eba-8f97-cbf674deb6e4", "510fbcb9-51bd-4135-baa9-64c5544b9764", "d3790280-3ab7-4876-93a5-0df2a2b54448", "c4f485bf-b5e0-4eba-8f97-cbf674deb6e4", "510fbcb9-51bd-4135-baa9-64c5544b9764", "d3790280-3ab7-4876-93a5-0df2a2b54448", "c4f485bf-b5e0-4eba-8f97-cbf674deb6e4", "510fbcb9-51bd-4135-baa9-64c5544b9764", "d3790280-3ab7-4876-93a5-0df2a2b54448"], "metadata": {"page_label": "198", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "575d8d5b-c815-4fc4-8dab-2af6ec4728a9": {"node_ids": ["2d80e7f8-9280-4ba2-82ab-1b68f1308272", "ee75f496-cf2d-4264-a817-9b87bee303ad", "2d80e7f8-9280-4ba2-82ab-1b68f1308272", "ee75f496-cf2d-4264-a817-9b87bee303ad", "2d80e7f8-9280-4ba2-82ab-1b68f1308272", "ee75f496-cf2d-4264-a817-9b87bee303ad"], "metadata": {"page_label": "199", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "119b31fa-17bb-415d-99bf-ce595eefb120": {"node_ids": ["84bd0ac4-b9ef-48bb-86be-56ef8829ffa3", "3dd5252b-ab8c-453f-9478-3fc321c7edce", "cd3afcd4-68c7-4e8d-af11-00a80c77cd88", "84bd0ac4-b9ef-48bb-86be-56ef8829ffa3", "3dd5252b-ab8c-453f-9478-3fc321c7edce", "cd3afcd4-68c7-4e8d-af11-00a80c77cd88", "84bd0ac4-b9ef-48bb-86be-56ef8829ffa3", "3dd5252b-ab8c-453f-9478-3fc321c7edce", "cd3afcd4-68c7-4e8d-af11-00a80c77cd88"], "metadata": {"page_label": "200", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f1147ffe-7582-48e2-9797-5710e3f1676a": {"node_ids": ["05565224-f223-408c-ba4e-7a706407c763", "81a5347a-519a-4286-9bff-9e0bd9a0bde1", "05565224-f223-408c-ba4e-7a706407c763", "81a5347a-519a-4286-9bff-9e0bd9a0bde1", "05565224-f223-408c-ba4e-7a706407c763", "81a5347a-519a-4286-9bff-9e0bd9a0bde1"], "metadata": {"page_label": "201", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5b91e2ad-4505-4fe4-b467-5d72c77ae1c1": {"node_ids": ["c86f2ca3-0782-4030-8a29-db674a981453", "6d9b002e-a54a-4d7c-8db2-647cc5057802", "7aa05708-5b99-4839-bae3-cb47ebe6c7a4", "c86f2ca3-0782-4030-8a29-db674a981453", "6d9b002e-a54a-4d7c-8db2-647cc5057802", "7aa05708-5b99-4839-bae3-cb47ebe6c7a4", "c86f2ca3-0782-4030-8a29-db674a981453", "6d9b002e-a54a-4d7c-8db2-647cc5057802", "7aa05708-5b99-4839-bae3-cb47ebe6c7a4"], "metadata": {"page_label": "202", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "53f48a50-6bcd-4ed6-b5b6-1356f7c5890f": {"node_ids": ["897eed84-ad1c-478f-9d4c-f3daae453bfd", "5b058686-57da-4a0f-bf58-9468f175872b", "897eed84-ad1c-478f-9d4c-f3daae453bfd", "5b058686-57da-4a0f-bf58-9468f175872b", "897eed84-ad1c-478f-9d4c-f3daae453bfd", "5b058686-57da-4a0f-bf58-9468f175872b"], "metadata": {"page_label": "203", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "65a7075e-254d-4f76-b909-96c749acd8e8": {"node_ids": ["2cdddb58-3993-4867-bad2-a2970342fbd9", "3b606e49-1883-4fa6-85b9-ddc930414465", "2cdddb58-3993-4867-bad2-a2970342fbd9", "3b606e49-1883-4fa6-85b9-ddc930414465", "2cdddb58-3993-4867-bad2-a2970342fbd9", "3b606e49-1883-4fa6-85b9-ddc930414465"], "metadata": {"page_label": "204", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "eb14bd1a-b712-491d-8a82-6b8c8d7b1061": {"node_ids": ["b7fd384d-bcbd-4d13-a229-c0c6091729b4", "b7fd384d-bcbd-4d13-a229-c0c6091729b4", "b7fd384d-bcbd-4d13-a229-c0c6091729b4"], "metadata": {"page_label": "205", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4183ba17-28e1-4b9b-88b6-9c964ce6a9c9": {"node_ids": ["1520b403-943d-4b13-88cf-f0a6ae8f6b8d", "fcfc858c-f0d5-4059-b4c6-3c5c8e75a493", "6f06a860-1237-4180-bd0b-f3addfd0e354", "1520b403-943d-4b13-88cf-f0a6ae8f6b8d", "fcfc858c-f0d5-4059-b4c6-3c5c8e75a493", "6f06a860-1237-4180-bd0b-f3addfd0e354", "1520b403-943d-4b13-88cf-f0a6ae8f6b8d", "fcfc858c-f0d5-4059-b4c6-3c5c8e75a493", "6f06a860-1237-4180-bd0b-f3addfd0e354"], "metadata": {"page_label": "206", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fc62c00e-813e-4b94-9f59-4784f709b2da": {"node_ids": ["6f71c9e5-7a76-495e-a16b-8b4aa39ff2d9", "90945b90-5c50-4ee8-a55a-93c4dd016407", "6f71c9e5-7a76-495e-a16b-8b4aa39ff2d9", "90945b90-5c50-4ee8-a55a-93c4dd016407", "6f71c9e5-7a76-495e-a16b-8b4aa39ff2d9", "90945b90-5c50-4ee8-a55a-93c4dd016407"], "metadata": {"page_label": "207", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3e416ff4-f607-41fd-b9ed-83dba994ea8a": {"node_ids": ["3a04d944-b78c-4ea6-b94f-508856887a4a", "bfb3ecde-f6e6-40f2-a65e-c51b11ff24b8", "2724ce16-9214-4d87-bc19-49e080540b79", "3a04d944-b78c-4ea6-b94f-508856887a4a", "bfb3ecde-f6e6-40f2-a65e-c51b11ff24b8", "2724ce16-9214-4d87-bc19-49e080540b79", "3a04d944-b78c-4ea6-b94f-508856887a4a", "bfb3ecde-f6e6-40f2-a65e-c51b11ff24b8", "2724ce16-9214-4d87-bc19-49e080540b79"], "metadata": {"page_label": "208", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "25195db6-534b-49b6-bdef-24880a902456": {"node_ids": ["28223e36-c6c9-48d3-bd07-488b0c6d76c9", "e5a7c814-8f21-411d-a56c-6cd30c5d98c5", "28223e36-c6c9-48d3-bd07-488b0c6d76c9", "e5a7c814-8f21-411d-a56c-6cd30c5d98c5", "28223e36-c6c9-48d3-bd07-488b0c6d76c9", "e5a7c814-8f21-411d-a56c-6cd30c5d98c5"], "metadata": {"page_label": "209", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "960cfba2-9407-4a16-97e1-019ca4251dd9": {"node_ids": ["2bb9159d-1969-4015-b01b-e33ab5b091e2", "f36e78b0-f7df-4288-8481-684150c8dbd7", "2bb9159d-1969-4015-b01b-e33ab5b091e2", "f36e78b0-f7df-4288-8481-684150c8dbd7", "2bb9159d-1969-4015-b01b-e33ab5b091e2", "f36e78b0-f7df-4288-8481-684150c8dbd7"], "metadata": {"page_label": "210", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "548c15b1-cd2c-4ad7-a4ce-aaee167fc75c": {"node_ids": ["0e54cae2-d7c3-47e5-8270-f6842180c699", "8dc956bc-7c23-44ab-a1fb-9afe5d6ea402", "0e54cae2-d7c3-47e5-8270-f6842180c699", "8dc956bc-7c23-44ab-a1fb-9afe5d6ea402", "0e54cae2-d7c3-47e5-8270-f6842180c699", "8dc956bc-7c23-44ab-a1fb-9afe5d6ea402"], "metadata": {"page_label": "211", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ca895a7a-4dcf-42e9-a381-3f0ee01cee17": {"node_ids": ["6305dfcd-1cb1-4ac4-be14-c59f36b7040c", "1983d50f-56ab-4a9e-bea5-e078e0e22762", "6305dfcd-1cb1-4ac4-be14-c59f36b7040c", "1983d50f-56ab-4a9e-bea5-e078e0e22762", "6305dfcd-1cb1-4ac4-be14-c59f36b7040c", "1983d50f-56ab-4a9e-bea5-e078e0e22762"], "metadata": {"page_label": "212", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6e37c40c-4d85-4332-9a0b-e684fa078caf": {"node_ids": ["250c6006-8434-49ee-bba6-2212a554ea09", "d9799c5c-251d-42af-8359-368046e17561", "3fdcb52a-fa85-4a01-ae89-54773ed49eb6", "250c6006-8434-49ee-bba6-2212a554ea09", "d9799c5c-251d-42af-8359-368046e17561", "3fdcb52a-fa85-4a01-ae89-54773ed49eb6", "250c6006-8434-49ee-bba6-2212a554ea09", "d9799c5c-251d-42af-8359-368046e17561", "3fdcb52a-fa85-4a01-ae89-54773ed49eb6"], "metadata": {"page_label": "213", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0e8e8fb8-6f97-4fd2-b926-dd2b2289f7f7": {"node_ids": ["dec79278-f773-4924-a0cd-56df0e4aee4e", "dec79278-f773-4924-a0cd-56df0e4aee4e", "dec79278-f773-4924-a0cd-56df0e4aee4e"], "metadata": {"page_label": "214", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f1e253b0-415c-4eec-9e86-01415cbfc2bd": {"node_ids": ["4fde5575-def6-41ab-bd0a-19cf8ec7f22e", "6fd631d9-6c17-456a-a1e9-c91205945518", "46d92ebe-8fc6-4810-a3f3-89c83ebb5b4e", "4fde5575-def6-41ab-bd0a-19cf8ec7f22e", "6fd631d9-6c17-456a-a1e9-c91205945518", "46d92ebe-8fc6-4810-a3f3-89c83ebb5b4e", "4fde5575-def6-41ab-bd0a-19cf8ec7f22e", "6fd631d9-6c17-456a-a1e9-c91205945518", "46d92ebe-8fc6-4810-a3f3-89c83ebb5b4e"], "metadata": {"page_label": "215", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "50858789-c188-4766-b41c-4ab82da440bf": {"node_ids": ["8ef455ee-9141-4a92-8fae-d44b906db305", "7b48b15d-f765-4f78-aebd-792a46f67b54", "e553f738-8abd-4e02-90e3-85edb84a3b61", "8ef455ee-9141-4a92-8fae-d44b906db305", "7b48b15d-f765-4f78-aebd-792a46f67b54", "e553f738-8abd-4e02-90e3-85edb84a3b61", "8ef455ee-9141-4a92-8fae-d44b906db305", "7b48b15d-f765-4f78-aebd-792a46f67b54", "e553f738-8abd-4e02-90e3-85edb84a3b61"], "metadata": {"page_label": "216", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "394d6162-782a-4701-acd5-5352694594cb": {"node_ids": ["0db7928d-d0e8-4e78-9cc9-7c8b4bb3be5f", "ad04fc59-deb5-4342-aaa1-51468e1b2360", "0db7928d-d0e8-4e78-9cc9-7c8b4bb3be5f", "ad04fc59-deb5-4342-aaa1-51468e1b2360", "0db7928d-d0e8-4e78-9cc9-7c8b4bb3be5f", "ad04fc59-deb5-4342-aaa1-51468e1b2360"], "metadata": {"page_label": "217", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2d2e016b-3b75-4279-9b43-550b03801229": {"node_ids": ["97a2ce90-434e-483d-8937-a2c864d50519", "8e1057f3-5412-4e73-8f34-49051886d79a", "6d7c6f87-2d44-4678-8677-7d67822726ca", "97a2ce90-434e-483d-8937-a2c864d50519", "8e1057f3-5412-4e73-8f34-49051886d79a", "6d7c6f87-2d44-4678-8677-7d67822726ca", "97a2ce90-434e-483d-8937-a2c864d50519", "8e1057f3-5412-4e73-8f34-49051886d79a", "6d7c6f87-2d44-4678-8677-7d67822726ca"], "metadata": {"page_label": "218", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5cda025d-fd73-4f4c-ad13-dc33f12a4a74": {"node_ids": ["8dc0111f-bf65-4b3a-ac40-3d821a7acbee", "e6c08247-2f55-4359-bd2f-8f988fabbbaa", "5c094d98-eb65-43db-bfe9-7138681de068", "8dc0111f-bf65-4b3a-ac40-3d821a7acbee", "e6c08247-2f55-4359-bd2f-8f988fabbbaa", "5c094d98-eb65-43db-bfe9-7138681de068", "8dc0111f-bf65-4b3a-ac40-3d821a7acbee", "e6c08247-2f55-4359-bd2f-8f988fabbbaa", "5c094d98-eb65-43db-bfe9-7138681de068"], "metadata": {"page_label": "219", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "18c912ae-0f98-4e58-a28c-d6cbcf9843ca": {"node_ids": ["034f0d7a-1167-4ba4-bc56-34e5c4b952f3", "1a5f47ee-e12b-4dd8-a41f-1866192537cc", "034f0d7a-1167-4ba4-bc56-34e5c4b952f3", "1a5f47ee-e12b-4dd8-a41f-1866192537cc", "034f0d7a-1167-4ba4-bc56-34e5c4b952f3", "1a5f47ee-e12b-4dd8-a41f-1866192537cc"], "metadata": {"page_label": "220", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "515451a5-541a-4908-86cc-9e283f5a90ab": {"node_ids": ["25bc0db2-ddff-4850-a0a7-969e01a40d81", "25bc0db2-ddff-4850-a0a7-969e01a40d81", "25bc0db2-ddff-4850-a0a7-969e01a40d81"], "metadata": {"page_label": "221", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "43ebeb43-2d9e-434a-bb78-d9dc09bdbe67": {"node_ids": ["46a2502e-3483-4a3c-a578-cd0957ea9425", "5c748ed3-3c06-4e8e-843e-31b10469da33", "1d7047f5-4fe0-4581-a670-c96f870412ee", "46a2502e-3483-4a3c-a578-cd0957ea9425", "5c748ed3-3c06-4e8e-843e-31b10469da33", "1d7047f5-4fe0-4581-a670-c96f870412ee", "46a2502e-3483-4a3c-a578-cd0957ea9425", "5c748ed3-3c06-4e8e-843e-31b10469da33", "1d7047f5-4fe0-4581-a670-c96f870412ee"], "metadata": {"page_label": "222", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c848c3b0-a715-4eda-8af5-58b89114c916": {"node_ids": ["9a4312b7-1678-4723-b21d-9ef7b7bfe4c0", "738706ff-0ab9-45ac-bc77-9afce0241364", "9a4312b7-1678-4723-b21d-9ef7b7bfe4c0", "738706ff-0ab9-45ac-bc77-9afce0241364", "9a4312b7-1678-4723-b21d-9ef7b7bfe4c0", "738706ff-0ab9-45ac-bc77-9afce0241364"], "metadata": {"page_label": "223", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ac14d19a-bd21-4bb4-a1fb-50123ed126af": {"node_ids": ["df0db0d6-f595-40ef-a7ed-052d6b6da95f", "7100c01a-2f22-4f66-ba94-ab27768e543b", "df0db0d6-f595-40ef-a7ed-052d6b6da95f", "7100c01a-2f22-4f66-ba94-ab27768e543b", "df0db0d6-f595-40ef-a7ed-052d6b6da95f", "7100c01a-2f22-4f66-ba94-ab27768e543b"], "metadata": {"page_label": "224", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fee661cc-64cd-425c-bc88-4bdcf05df2de": {"node_ids": ["c65f434f-8d12-49bb-ade9-77664172f712", "597fdb15-60bd-4243-ba82-96debb052c8a", "c65f434f-8d12-49bb-ade9-77664172f712", "597fdb15-60bd-4243-ba82-96debb052c8a", "c65f434f-8d12-49bb-ade9-77664172f712", "597fdb15-60bd-4243-ba82-96debb052c8a"], "metadata": {"page_label": "225", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a5b4439a-e942-4634-99b3-45a57ba89e28": {"node_ids": ["82183981-1f50-4cca-addd-985e85f83e8b", "743358ca-5775-43a6-a553-51840100d806", "aecf4001-6a3e-48e1-91a4-13d84799ba31", "82183981-1f50-4cca-addd-985e85f83e8b", "743358ca-5775-43a6-a553-51840100d806", "aecf4001-6a3e-48e1-91a4-13d84799ba31", "82183981-1f50-4cca-addd-985e85f83e8b", "743358ca-5775-43a6-a553-51840100d806", "aecf4001-6a3e-48e1-91a4-13d84799ba31"], "metadata": {"page_label": "226", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bb3a579e-f618-418a-bf1a-74d40ad6fd53": {"node_ids": ["58b0b0fe-ca45-46b8-b85e-0ce8aafcacca", "803a9e21-eb58-48ae-b348-1814de902c9a", "b2aaac40-91cc-4432-b2ea-bd5dfa64d183", "58b0b0fe-ca45-46b8-b85e-0ce8aafcacca", "803a9e21-eb58-48ae-b348-1814de902c9a", "b2aaac40-91cc-4432-b2ea-bd5dfa64d183", "58b0b0fe-ca45-46b8-b85e-0ce8aafcacca", "803a9e21-eb58-48ae-b348-1814de902c9a", "b2aaac40-91cc-4432-b2ea-bd5dfa64d183"], "metadata": {"page_label": "227", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1a9a28bb-86ed-4570-bb88-f3ee8b13fc81": {"node_ids": ["3ebb9065-2204-4fc0-96ce-0021965159b6", "409925ec-eace-4a01-a97a-44c4ab9704e2", "3ebb9065-2204-4fc0-96ce-0021965159b6", "409925ec-eace-4a01-a97a-44c4ab9704e2", "3ebb9065-2204-4fc0-96ce-0021965159b6", "409925ec-eace-4a01-a97a-44c4ab9704e2"], "metadata": {"page_label": "228", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "71f73ac9-92f9-45b7-9dc3-f726ffc23d08": {"node_ids": ["08f04a69-466a-4c22-b549-d13067fb098b", "01404040-3fc6-4c0c-8aa0-0258b49f04ee", "d1f0aa77-8fb7-4e86-9035-de332f668197", "08f04a69-466a-4c22-b549-d13067fb098b", "01404040-3fc6-4c0c-8aa0-0258b49f04ee", "d1f0aa77-8fb7-4e86-9035-de332f668197", "08f04a69-466a-4c22-b549-d13067fb098b", "01404040-3fc6-4c0c-8aa0-0258b49f04ee", "d1f0aa77-8fb7-4e86-9035-de332f668197"], "metadata": {"page_label": "229", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "111b4a9c-dbca-4a85-ad54-c6d023df7d32": {"node_ids": ["d71ca1c6-c347-4859-96bd-aa22af6fc9f0", "c747535a-e722-4d7c-bc99-2f3f7df99a66", "28e78f40-9d3e-400d-b3c1-e25561d04681", "d71ca1c6-c347-4859-96bd-aa22af6fc9f0", "c747535a-e722-4d7c-bc99-2f3f7df99a66", "28e78f40-9d3e-400d-b3c1-e25561d04681", "d71ca1c6-c347-4859-96bd-aa22af6fc9f0", "c747535a-e722-4d7c-bc99-2f3f7df99a66", "28e78f40-9d3e-400d-b3c1-e25561d04681"], "metadata": {"page_label": "230", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "51dd85c2-1bf8-4238-a955-1bc44a65b4ce": {"node_ids": ["9ff2cf88-c722-4cb9-82b1-4fd82abcb335", "f8c81eb4-0413-4939-8db0-b880e2910b22", "9ff2cf88-c722-4cb9-82b1-4fd82abcb335", "f8c81eb4-0413-4939-8db0-b880e2910b22", "9ff2cf88-c722-4cb9-82b1-4fd82abcb335", "f8c81eb4-0413-4939-8db0-b880e2910b22"], "metadata": {"page_label": "231", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b091c834-b87e-4f0c-91e2-27636541094b": {"node_ids": ["817f4c23-57b0-465a-bcaf-be2cda2e9347", "59497e1c-e285-4a18-9ef8-95bb25bd8d92", "817f4c23-57b0-465a-bcaf-be2cda2e9347", "59497e1c-e285-4a18-9ef8-95bb25bd8d92", "817f4c23-57b0-465a-bcaf-be2cda2e9347", "59497e1c-e285-4a18-9ef8-95bb25bd8d92"], "metadata": {"page_label": "232", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "01d36b75-6e23-4975-b146-80c29c49fb53": {"node_ids": ["2ab7290f-395a-4036-8bfb-83e73a4ac9f4", "330bde62-e44d-4b67-8b69-b1f929d44880", "2ab7290f-395a-4036-8bfb-83e73a4ac9f4", "330bde62-e44d-4b67-8b69-b1f929d44880", "2ab7290f-395a-4036-8bfb-83e73a4ac9f4", "330bde62-e44d-4b67-8b69-b1f929d44880"], "metadata": {"page_label": "233", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7bf89b04-ee20-46cd-a8bd-ab1cc29f3360": {"node_ids": ["847eba8d-ad44-4119-bfed-e196044505f7", "5edab9ce-9687-4135-adb2-8609267b36d5", "847eba8d-ad44-4119-bfed-e196044505f7", "5edab9ce-9687-4135-adb2-8609267b36d5", "847eba8d-ad44-4119-bfed-e196044505f7", "5edab9ce-9687-4135-adb2-8609267b36d5"], "metadata": {"page_label": "234", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6b383ff1-bdbb-477d-b5ff-577d8598dfac": {"node_ids": ["73c57b23-38f5-47ee-ad3d-d9b932b9d64d", "70fd9e77-a5ff-401c-bfdc-dcda4a5967a3", "73c57b23-38f5-47ee-ad3d-d9b932b9d64d", "70fd9e77-a5ff-401c-bfdc-dcda4a5967a3", "73c57b23-38f5-47ee-ad3d-d9b932b9d64d", "70fd9e77-a5ff-401c-bfdc-dcda4a5967a3"], "metadata": {"page_label": "235", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7a06d8aa-b385-4082-b494-79734de3d953": {"node_ids": ["69ee1921-1ce7-486b-a6be-80573b9ae7c2", "65d6683d-2b50-49ab-a557-239107980867", "69ee1921-1ce7-486b-a6be-80573b9ae7c2", "65d6683d-2b50-49ab-a557-239107980867", "69ee1921-1ce7-486b-a6be-80573b9ae7c2", "65d6683d-2b50-49ab-a557-239107980867"], "metadata": {"page_label": "236", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9ca4f025-d915-40c5-a850-d0548f4e4f2e": {"node_ids": ["a6dc7ecc-2b94-490e-99a7-f229bc9b0518", "6d1350e7-b6de-442f-9bb1-110f6389493a", "9dc2a7b1-e999-4e12-808b-7baa59f4e1da", "a6dc7ecc-2b94-490e-99a7-f229bc9b0518", "6d1350e7-b6de-442f-9bb1-110f6389493a", "9dc2a7b1-e999-4e12-808b-7baa59f4e1da", "a6dc7ecc-2b94-490e-99a7-f229bc9b0518", "6d1350e7-b6de-442f-9bb1-110f6389493a", "9dc2a7b1-e999-4e12-808b-7baa59f4e1da"], "metadata": {"page_label": "237", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ae98b6f9-d8d1-4d53-afdc-f65c649d45bb": {"node_ids": ["398fd14f-c80b-4a0c-a77c-cfb0b5d4cdb5", "b62899a2-d644-4de8-bbff-16253f60bbce", "e35ae7ab-4226-4917-8f45-fe67f476b802", "398fd14f-c80b-4a0c-a77c-cfb0b5d4cdb5", "b62899a2-d644-4de8-bbff-16253f60bbce", "e35ae7ab-4226-4917-8f45-fe67f476b802", "398fd14f-c80b-4a0c-a77c-cfb0b5d4cdb5", "b62899a2-d644-4de8-bbff-16253f60bbce", "e35ae7ab-4226-4917-8f45-fe67f476b802"], "metadata": {"page_label": "238", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ab09283d-70ae-47de-b6cf-9bcd570b5983": {"node_ids": ["277d381b-a684-4b7d-aded-7c5c6e782d07", "bc2ca772-79b7-47cf-8a59-8da822ed0f3f", "277d381b-a684-4b7d-aded-7c5c6e782d07", "bc2ca772-79b7-47cf-8a59-8da822ed0f3f", "277d381b-a684-4b7d-aded-7c5c6e782d07", "bc2ca772-79b7-47cf-8a59-8da822ed0f3f"], "metadata": {"page_label": "239", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "24859742-b485-48e8-ba7b-39a823af7e05": {"node_ids": ["647cf8e1-85b6-46f0-b27c-408994810ef2", "75b5e800-fc7c-4ade-93ea-a6c3fd7201b7", "647cf8e1-85b6-46f0-b27c-408994810ef2", "75b5e800-fc7c-4ade-93ea-a6c3fd7201b7", "647cf8e1-85b6-46f0-b27c-408994810ef2", "75b5e800-fc7c-4ade-93ea-a6c3fd7201b7"], "metadata": {"page_label": "240", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4ffc575a-d1ea-44f7-ad42-a8f43388f91b": {"node_ids": ["bff04dfe-4731-48a5-8f80-ea134fcc931c", "7817b001-d62f-4a0e-a70e-6e7e5f868223", "bff04dfe-4731-48a5-8f80-ea134fcc931c", "7817b001-d62f-4a0e-a70e-6e7e5f868223", "bff04dfe-4731-48a5-8f80-ea134fcc931c", "7817b001-d62f-4a0e-a70e-6e7e5f868223"], "metadata": {"page_label": "241", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0e1c5a7d-7ae5-41a9-9d0d-59a0dc9b9b3b": {"node_ids": ["5edb0697-e73d-4844-a291-da6e3849917f", "5edb0697-e73d-4844-a291-da6e3849917f", "5edb0697-e73d-4844-a291-da6e3849917f"], "metadata": {"page_label": "242", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2e7abd4b-d20b-44b9-a395-51382fea4aaf": {"node_ids": ["94960a13-8409-4406-9fe1-14cc54908185", "841ad537-bc1b-4386-9b55-2ec3349f249c", "94960a13-8409-4406-9fe1-14cc54908185", "841ad537-bc1b-4386-9b55-2ec3349f249c", "94960a13-8409-4406-9fe1-14cc54908185", "841ad537-bc1b-4386-9b55-2ec3349f249c"], "metadata": {"page_label": "243", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d2741b24-047b-4d6b-8c52-0b318da87c8b": {"node_ids": ["ca932626-3910-4e21-b8fe-184e507f6353", "4a800351-2dbf-4224-b217-72ca67d09284", "43c9c3f3-fc47-4914-89eb-e08eefb28648", "ca932626-3910-4e21-b8fe-184e507f6353", "4a800351-2dbf-4224-b217-72ca67d09284", "43c9c3f3-fc47-4914-89eb-e08eefb28648", "ca932626-3910-4e21-b8fe-184e507f6353", "4a800351-2dbf-4224-b217-72ca67d09284", "43c9c3f3-fc47-4914-89eb-e08eefb28648"], "metadata": {"page_label": "244", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "170f7225-61a9-48f5-92ae-9601012ba88c": {"node_ids": ["164ed92a-57a2-425e-84f6-65ca0bc690fb", "fbf49f7d-7b53-4845-b635-61576c933b6f", "164ed92a-57a2-425e-84f6-65ca0bc690fb", "fbf49f7d-7b53-4845-b635-61576c933b6f", "164ed92a-57a2-425e-84f6-65ca0bc690fb", "fbf49f7d-7b53-4845-b635-61576c933b6f"], "metadata": {"page_label": "245", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c7aed488-8077-41d9-96e1-36d35d3d5c8c": {"node_ids": ["085126dc-f72c-47f0-86c2-0a2d56185848", "9cf43681-1e4d-4d97-b24f-21b156f28ef2", "085126dc-f72c-47f0-86c2-0a2d56185848", "9cf43681-1e4d-4d97-b24f-21b156f28ef2", "085126dc-f72c-47f0-86c2-0a2d56185848", "9cf43681-1e4d-4d97-b24f-21b156f28ef2"], "metadata": {"page_label": "246", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1261ef20-0455-42dc-b685-23b892763d57": {"node_ids": ["f4944ecc-4190-4182-9ae4-3f1378950935", "e45ce403-c30a-42b6-81b1-c2a83016652b", "f4944ecc-4190-4182-9ae4-3f1378950935", "e45ce403-c30a-42b6-81b1-c2a83016652b", "f4944ecc-4190-4182-9ae4-3f1378950935", "e45ce403-c30a-42b6-81b1-c2a83016652b"], "metadata": {"page_label": "247", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c2395193-c2ef-40a0-a452-b208e95c52a6": {"node_ids": ["738679ca-f6b6-4fb8-819e-4a2fd6c972f2", "1d016b09-0260-4238-95ad-a7ffd52cc768", "738679ca-f6b6-4fb8-819e-4a2fd6c972f2", "1d016b09-0260-4238-95ad-a7ffd52cc768", "738679ca-f6b6-4fb8-819e-4a2fd6c972f2", "1d016b09-0260-4238-95ad-a7ffd52cc768"], "metadata": {"page_label": "248", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4fb92235-14fd-4d57-a4dd-2995bc5d91a8": {"node_ids": ["ab07b0a4-8ff8-49f8-a37c-a4a07eb9b148", "f35810d3-a4c7-4dd1-8b74-222ef0941f26", "63ce22d3-a021-458e-8eaf-410b554d596f", "ab07b0a4-8ff8-49f8-a37c-a4a07eb9b148", "f35810d3-a4c7-4dd1-8b74-222ef0941f26", "63ce22d3-a021-458e-8eaf-410b554d596f", "ab07b0a4-8ff8-49f8-a37c-a4a07eb9b148", "f35810d3-a4c7-4dd1-8b74-222ef0941f26", "63ce22d3-a021-458e-8eaf-410b554d596f"], "metadata": {"page_label": "249", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "83ff7cc8-5f61-4ec1-af6a-2861d462fffe": {"node_ids": ["310ec046-7473-44b4-8a3d-b6b7bc7572f9", "8f07c505-aeaf-4ec2-a8d5-7cdc4ad4e789", "310ec046-7473-44b4-8a3d-b6b7bc7572f9", "8f07c505-aeaf-4ec2-a8d5-7cdc4ad4e789", "310ec046-7473-44b4-8a3d-b6b7bc7572f9", "8f07c505-aeaf-4ec2-a8d5-7cdc4ad4e789"], "metadata": {"page_label": "250", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "072a67a1-3885-4e2e-b99f-75aec60378fb": {"node_ids": ["4061034a-68c0-4ea3-8f41-c3a4ac876411", "4061034a-68c0-4ea3-8f41-c3a4ac876411", "4061034a-68c0-4ea3-8f41-c3a4ac876411"], "metadata": {"page_label": "251", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "cf430eb1-c967-4988-9f9d-7a4f01da9fb9": {"node_ids": ["087e1ea3-1584-4555-9928-c7eb5013da8c", "ed391ff7-9e9c-4cbf-9f43-841f91215790", "9e9f9d89-ae4c-4dbf-9e6c-b0a9aec5eb65", "087e1ea3-1584-4555-9928-c7eb5013da8c", "ed391ff7-9e9c-4cbf-9f43-841f91215790", "9e9f9d89-ae4c-4dbf-9e6c-b0a9aec5eb65", "087e1ea3-1584-4555-9928-c7eb5013da8c", "ed391ff7-9e9c-4cbf-9f43-841f91215790", "9e9f9d89-ae4c-4dbf-9e6c-b0a9aec5eb65"], "metadata": {"page_label": "252", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "709d1bcd-b04f-48a0-ab46-c5bda6fd2ed8": {"node_ids": ["c978bf50-6b9a-4b67-a14d-81de40ef151d", "9235f740-7556-4018-a6f6-e1ef890d75ba", "c978bf50-6b9a-4b67-a14d-81de40ef151d", "9235f740-7556-4018-a6f6-e1ef890d75ba", "c978bf50-6b9a-4b67-a14d-81de40ef151d", "9235f740-7556-4018-a6f6-e1ef890d75ba"], "metadata": {"page_label": "253", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2542fe3e-cbef-459b-9d9d-742b13e42aac": {"node_ids": ["11df2f14-ec53-45b1-98f5-aa15a49b738c", "a6304eb3-0330-49aa-9412-6784f38a5c24", "11df2f14-ec53-45b1-98f5-aa15a49b738c", "a6304eb3-0330-49aa-9412-6784f38a5c24", "11df2f14-ec53-45b1-98f5-aa15a49b738c", "a6304eb3-0330-49aa-9412-6784f38a5c24"], "metadata": {"page_label": "254", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "805483ce-1d91-4572-9b46-4ad9a52026e9": {"node_ids": ["68212f43-73b0-41e1-afa1-73df678a3419", "fad17d10-c560-450f-b466-336dd696d1f8", "dbb0b276-b2df-4676-99de-bb96c072d33b", "68212f43-73b0-41e1-afa1-73df678a3419", "fad17d10-c560-450f-b466-336dd696d1f8", "dbb0b276-b2df-4676-99de-bb96c072d33b", "68212f43-73b0-41e1-afa1-73df678a3419", "fad17d10-c560-450f-b466-336dd696d1f8", "dbb0b276-b2df-4676-99de-bb96c072d33b"], "metadata": {"page_label": "255", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5dd18fb9-d145-4191-afe8-5cc39708c5c1": {"node_ids": ["44f279d4-7a92-4186-9ed7-e27cc6d71dec", "88ac092c-b9a0-4900-95b0-2de100fc83a9", "44f279d4-7a92-4186-9ed7-e27cc6d71dec", "88ac092c-b9a0-4900-95b0-2de100fc83a9", "44f279d4-7a92-4186-9ed7-e27cc6d71dec", "88ac092c-b9a0-4900-95b0-2de100fc83a9"], "metadata": {"page_label": "256", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "06a752b8-8976-4f83-96e0-392c0bc480b0": {"node_ids": ["22a185eb-6a55-4b48-bd83-8fd10cd70f76", "c70a7248-c5ea-4718-b2bb-480da2b15f18", "22a185eb-6a55-4b48-bd83-8fd10cd70f76", "c70a7248-c5ea-4718-b2bb-480da2b15f18", "22a185eb-6a55-4b48-bd83-8fd10cd70f76", "c70a7248-c5ea-4718-b2bb-480da2b15f18"], "metadata": {"page_label": "257", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f3e5bdf3-5aeb-4ddb-bc93-cd9a0a727703": {"node_ids": ["01ee1cb4-393e-4e47-9d97-ca343549a26b", "feabec87-faaa-470f-9ffe-d2f6684e0244", "01ee1cb4-393e-4e47-9d97-ca343549a26b", "feabec87-faaa-470f-9ffe-d2f6684e0244", "01ee1cb4-393e-4e47-9d97-ca343549a26b", "feabec87-faaa-470f-9ffe-d2f6684e0244"], "metadata": {"page_label": "258", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6efde898-e39e-49fd-8923-b847e72a2500": {"node_ids": ["bed56d60-530b-4b9e-a3f7-41b0d4a17c4a", "aeeed7e0-503b-45b8-8962-b068c788aed4", "bed56d60-530b-4b9e-a3f7-41b0d4a17c4a", "aeeed7e0-503b-45b8-8962-b068c788aed4", "bed56d60-530b-4b9e-a3f7-41b0d4a17c4a", "aeeed7e0-503b-45b8-8962-b068c788aed4"], "metadata": {"page_label": "259", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1a101154-e58c-45f2-b6a1-32147d7510a1": {"node_ids": ["db1725aa-2145-4e8c-9d7c-c7204cd9d267", "b2714eeb-1196-4a91-a0f2-f2e0fb3202a8", "db1725aa-2145-4e8c-9d7c-c7204cd9d267", "b2714eeb-1196-4a91-a0f2-f2e0fb3202a8", "db1725aa-2145-4e8c-9d7c-c7204cd9d267", "b2714eeb-1196-4a91-a0f2-f2e0fb3202a8"], "metadata": {"page_label": "260", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e5bb3759-1b12-4934-9e4a-948dbda45f87": {"node_ids": ["e8660b83-019b-441a-a7fa-d1febd0772c0", "273aa6cb-48bf-475b-a165-8751e0ae1901", "e8660b83-019b-441a-a7fa-d1febd0772c0", "273aa6cb-48bf-475b-a165-8751e0ae1901", "e8660b83-019b-441a-a7fa-d1febd0772c0", "273aa6cb-48bf-475b-a165-8751e0ae1901"], "metadata": {"page_label": "261", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d07c9ed3-871b-4ecb-a69e-bf56af097ac2": {"node_ids": ["d9d626f0-4692-4085-896b-ae380abad62c", "5bc0ed95-3dd6-4574-a521-6b373a120c33", "d9d626f0-4692-4085-896b-ae380abad62c", "5bc0ed95-3dd6-4574-a521-6b373a120c33", "d9d626f0-4692-4085-896b-ae380abad62c", "5bc0ed95-3dd6-4574-a521-6b373a120c33"], "metadata": {"page_label": "262", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "be2f3034-7ccf-4a55-9adc-7bce860d4ff1": {"node_ids": ["fb818fbf-85c5-4dbd-902d-177cdab20f47", "45ec4382-3cd2-401d-8409-f14acfa0eb0d", "8c6312f3-b762-426c-a972-ef5c85acb921", "fb818fbf-85c5-4dbd-902d-177cdab20f47", "45ec4382-3cd2-401d-8409-f14acfa0eb0d", "8c6312f3-b762-426c-a972-ef5c85acb921", "fb818fbf-85c5-4dbd-902d-177cdab20f47", "45ec4382-3cd2-401d-8409-f14acfa0eb0d", "8c6312f3-b762-426c-a972-ef5c85acb921"], "metadata": {"page_label": "263", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "90827983-ec76-4563-819a-add08efb3b8a": {"node_ids": ["16ba4a63-7363-4d7a-89d4-793772ed3c6e", "e9cd2716-d6ba-4548-933f-6ff245d8871e", "df96f13e-6fb3-40c8-a485-41be17aaae1f", "16ba4a63-7363-4d7a-89d4-793772ed3c6e", "e9cd2716-d6ba-4548-933f-6ff245d8871e", "df96f13e-6fb3-40c8-a485-41be17aaae1f", "16ba4a63-7363-4d7a-89d4-793772ed3c6e", "e9cd2716-d6ba-4548-933f-6ff245d8871e", "df96f13e-6fb3-40c8-a485-41be17aaae1f"], "metadata": {"page_label": "264", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a296fb4a-5590-4c21-b40a-8c9e83748489": {"node_ids": ["8d09f956-55b9-4ab0-8649-72fab8c903e0", "939770d1-7efb-4dd1-a69e-11020dcc3509", "57770bff-358c-42a8-bbd7-f09e5f9c7ba7", "8d09f956-55b9-4ab0-8649-72fab8c903e0", "939770d1-7efb-4dd1-a69e-11020dcc3509", "57770bff-358c-42a8-bbd7-f09e5f9c7ba7", "8d09f956-55b9-4ab0-8649-72fab8c903e0", "939770d1-7efb-4dd1-a69e-11020dcc3509", "57770bff-358c-42a8-bbd7-f09e5f9c7ba7"], "metadata": {"page_label": "265", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "679606f7-c43d-46cc-8790-86b178958081": {"node_ids": ["72b4caf1-4d9c-424b-9dc3-16c6a7f19058", "b7faf5f0-c887-479d-98dd-6bb56f8fdfe0", "72b4caf1-4d9c-424b-9dc3-16c6a7f19058", "b7faf5f0-c887-479d-98dd-6bb56f8fdfe0", "72b4caf1-4d9c-424b-9dc3-16c6a7f19058", "b7faf5f0-c887-479d-98dd-6bb56f8fdfe0"], "metadata": {"page_label": "266", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b82c8bf2-5027-4eb8-8a41-8fafd5622f5e": {"node_ids": ["4a3f9c60-0e4c-4d17-ae5c-34a986ae9679", "b436f740-9208-45e3-864d-d4a16ae46fa0", "4a3f9c60-0e4c-4d17-ae5c-34a986ae9679", "b436f740-9208-45e3-864d-d4a16ae46fa0", "4a3f9c60-0e4c-4d17-ae5c-34a986ae9679", "b436f740-9208-45e3-864d-d4a16ae46fa0"], "metadata": {"page_label": "267", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a1285979-8783-4eac-87ef-5ab5a642135f": {"node_ids": ["5259ef40-939e-4b53-8771-d4124fad0d97", "e7aab2a8-cf64-4b1a-abb9-7d60e8b26c1b", "5259ef40-939e-4b53-8771-d4124fad0d97", "e7aab2a8-cf64-4b1a-abb9-7d60e8b26c1b", "5259ef40-939e-4b53-8771-d4124fad0d97", "e7aab2a8-cf64-4b1a-abb9-7d60e8b26c1b"], "metadata": {"page_label": "268", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "93aa463c-e0ba-43fc-93a0-8d937e112bf3": {"node_ids": ["d5afa1a4-3fa9-4f9a-87a3-30a66d2f11ee", "40d56eef-c52c-4f21-92ed-c8d8f2e677bc", "19d21ec3-3841-4c4a-af65-e983fbab3692", "d5afa1a4-3fa9-4f9a-87a3-30a66d2f11ee", "40d56eef-c52c-4f21-92ed-c8d8f2e677bc", "19d21ec3-3841-4c4a-af65-e983fbab3692", "d5afa1a4-3fa9-4f9a-87a3-30a66d2f11ee", "40d56eef-c52c-4f21-92ed-c8d8f2e677bc", "19d21ec3-3841-4c4a-af65-e983fbab3692"], "metadata": {"page_label": "269", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c1784347-127a-488d-8348-de75e2a7de63": {"node_ids": ["8d9e67b4-ba5b-496e-9568-bb1fc127d52a", "0b60ad39-cfb0-40e2-b550-4725c0083455", "8d9e67b4-ba5b-496e-9568-bb1fc127d52a", "0b60ad39-cfb0-40e2-b550-4725c0083455", "8d9e67b4-ba5b-496e-9568-bb1fc127d52a", "0b60ad39-cfb0-40e2-b550-4725c0083455"], "metadata": {"page_label": "270", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d0aca54a-e8bd-44ca-8884-405fd1af4ad1": {"node_ids": ["cff8110f-fc40-465a-a90c-390d34ae6c9c", "64fba9ee-9450-443a-b380-d26a6c69b1e8", "cff8110f-fc40-465a-a90c-390d34ae6c9c", "64fba9ee-9450-443a-b380-d26a6c69b1e8", "cff8110f-fc40-465a-a90c-390d34ae6c9c", "64fba9ee-9450-443a-b380-d26a6c69b1e8"], "metadata": {"page_label": "271", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f480beaf-4895-44ab-a422-6dd3a9a90b03": {"node_ids": ["58ddaee7-d5d5-4201-8a3d-e80d3a30432e", "fc9d41ec-8a68-4782-b2f9-ad5902ad0ec7", "58ddaee7-d5d5-4201-8a3d-e80d3a30432e", "fc9d41ec-8a68-4782-b2f9-ad5902ad0ec7", "58ddaee7-d5d5-4201-8a3d-e80d3a30432e", "fc9d41ec-8a68-4782-b2f9-ad5902ad0ec7"], "metadata": {"page_label": "272", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "717887a0-3f1f-4590-af1c-d188db215b32": {"node_ids": ["c81736b7-f2c3-48e6-918f-f0e0b14d2842", "279feb6a-1486-48db-8fae-b01adb80e5cc", "c81736b7-f2c3-48e6-918f-f0e0b14d2842", "279feb6a-1486-48db-8fae-b01adb80e5cc", "c81736b7-f2c3-48e6-918f-f0e0b14d2842", "279feb6a-1486-48db-8fae-b01adb80e5cc"], "metadata": {"page_label": "273", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0df4b4e8-3bab-4d7a-b235-a392e6b6a045": {"node_ids": ["0ebc1a54-33b3-456b-915c-16c71081aa31", "2831c48f-ed44-43df-9eae-1214bcfa33af", "0ebc1a54-33b3-456b-915c-16c71081aa31", "2831c48f-ed44-43df-9eae-1214bcfa33af", "0ebc1a54-33b3-456b-915c-16c71081aa31", "2831c48f-ed44-43df-9eae-1214bcfa33af"], "metadata": {"page_label": "274", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d9d5661d-0a9e-4e66-8c62-3bc58315541d": {"node_ids": ["56fbf341-b84d-43c8-8f35-60f849a7da4c", "2b6ad75c-5fdc-434a-ab59-141da865c8d0", "74d5fb38-ccba-418a-a638-8988ad5a2da1", "bfb74446-5a60-446c-ab35-1808c1431451", "56fbf341-b84d-43c8-8f35-60f849a7da4c", "2b6ad75c-5fdc-434a-ab59-141da865c8d0", "74d5fb38-ccba-418a-a638-8988ad5a2da1", "bfb74446-5a60-446c-ab35-1808c1431451", "56fbf341-b84d-43c8-8f35-60f849a7da4c", "2b6ad75c-5fdc-434a-ab59-141da865c8d0", "74d5fb38-ccba-418a-a638-8988ad5a2da1", "bfb74446-5a60-446c-ab35-1808c1431451"], "metadata": {"page_label": "275", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "de184d90-8a77-4d83-a264-83f1a1d8bd84": {"node_ids": ["e6008c04-48ea-47ad-b6a9-d2d16e810bab", "6040bc08-06d9-4ce6-9b26-d45176267882", "e6008c04-48ea-47ad-b6a9-d2d16e810bab", "6040bc08-06d9-4ce6-9b26-d45176267882", "e6008c04-48ea-47ad-b6a9-d2d16e810bab", "6040bc08-06d9-4ce6-9b26-d45176267882"], "metadata": {"page_label": "276", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5342547c-59cf-4c84-a929-cdd4be65305a": {"node_ids": ["044917f7-4322-4510-875c-68fa43cc5cc2", "c47e6e0b-8b97-433e-95ce-d6a007e55e55", "044917f7-4322-4510-875c-68fa43cc5cc2", "c47e6e0b-8b97-433e-95ce-d6a007e55e55", "044917f7-4322-4510-875c-68fa43cc5cc2", "c47e6e0b-8b97-433e-95ce-d6a007e55e55"], "metadata": {"page_label": "277", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1afcf0bb-0c68-4bb8-8602-3ba2ca328169": {"node_ids": ["9e4a00f9-ab38-4a45-91f1-5ae5774c0f1c", "d55e0371-0ca8-4958-8a72-2c5481b25d97", "9e4a00f9-ab38-4a45-91f1-5ae5774c0f1c", "d55e0371-0ca8-4958-8a72-2c5481b25d97", "9e4a00f9-ab38-4a45-91f1-5ae5774c0f1c", "d55e0371-0ca8-4958-8a72-2c5481b25d97"], "metadata": {"page_label": "278", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d70c1bfe-e16e-4ce0-a658-57419ecb6553": {"node_ids": ["7531f3db-e115-4dfb-afd5-a70fb60ed18f", "a1c52e32-8920-472a-8379-330d8f5be91c", "7531f3db-e115-4dfb-afd5-a70fb60ed18f", "a1c52e32-8920-472a-8379-330d8f5be91c", "7531f3db-e115-4dfb-afd5-a70fb60ed18f", "a1c52e32-8920-472a-8379-330d8f5be91c"], "metadata": {"page_label": "279", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f7751953-61be-4c38-87d5-3296b3de73ed": {"node_ids": ["9cb42c91-ff17-4fd4-a6aa-533a2bae6729", "3676a575-787a-4028-860d-92317bd836d2", "419990c3-1ac8-4f06-8849-e2e7e27a8fb4", "9cb42c91-ff17-4fd4-a6aa-533a2bae6729", "3676a575-787a-4028-860d-92317bd836d2", "419990c3-1ac8-4f06-8849-e2e7e27a8fb4", "9cb42c91-ff17-4fd4-a6aa-533a2bae6729", "3676a575-787a-4028-860d-92317bd836d2", "419990c3-1ac8-4f06-8849-e2e7e27a8fb4"], "metadata": {"page_label": "280", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "01a39b72-8bc8-414d-ac57-b166f28a2544": {"node_ids": ["8b7d0e5b-4651-4bf3-b0d8-d6a5503d69b2", "2c53765a-56c1-48ed-9d78-7d879d512cd7", "8b7d0e5b-4651-4bf3-b0d8-d6a5503d69b2", "2c53765a-56c1-48ed-9d78-7d879d512cd7", "8b7d0e5b-4651-4bf3-b0d8-d6a5503d69b2", "2c53765a-56c1-48ed-9d78-7d879d512cd7"], "metadata": {"page_label": "281", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6873dfdb-094a-49ad-90df-453be6c00b8a": {"node_ids": ["b41f6a80-4a3e-412b-8814-b69b97401683", "a80438bc-0369-47cb-94b2-53fb835987d7", "b41f6a80-4a3e-412b-8814-b69b97401683", "a80438bc-0369-47cb-94b2-53fb835987d7", "b41f6a80-4a3e-412b-8814-b69b97401683", "a80438bc-0369-47cb-94b2-53fb835987d7"], "metadata": {"page_label": "282", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "97497838-610a-45cd-9620-2a36d02d869f": {"node_ids": ["56a0e6b9-b839-4d33-b3db-8d51255697f0", "21b54023-5f78-4403-932e-fbb9c9664fc2", "56a0e6b9-b839-4d33-b3db-8d51255697f0", "21b54023-5f78-4403-932e-fbb9c9664fc2", "56a0e6b9-b839-4d33-b3db-8d51255697f0", "21b54023-5f78-4403-932e-fbb9c9664fc2"], "metadata": {"page_label": "283", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ade2c52b-f06e-46de-b11a-eb18896fc798": {"node_ids": ["f51487ec-4c73-4110-b1c0-881f0be33cc2", "666233cf-c6ce-453d-9a60-c6bb4c27f83c", "621a0770-1a93-4d19-a02f-458780730291", "f51487ec-4c73-4110-b1c0-881f0be33cc2", "666233cf-c6ce-453d-9a60-c6bb4c27f83c", "621a0770-1a93-4d19-a02f-458780730291", "f51487ec-4c73-4110-b1c0-881f0be33cc2", "666233cf-c6ce-453d-9a60-c6bb4c27f83c", "621a0770-1a93-4d19-a02f-458780730291"], "metadata": {"page_label": "284", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "62807d3a-5e23-487b-b916-94a21a8f6499": {"node_ids": ["9dd422ae-18f5-47e1-9718-cfec930ea23f", "78b5686a-65fb-49f6-a8fe-3f0056af5bc2", "4829c3e4-24ac-4cf5-8cfe-61db4b1f5f7f", "9dd422ae-18f5-47e1-9718-cfec930ea23f", "78b5686a-65fb-49f6-a8fe-3f0056af5bc2", "4829c3e4-24ac-4cf5-8cfe-61db4b1f5f7f", "9dd422ae-18f5-47e1-9718-cfec930ea23f", "78b5686a-65fb-49f6-a8fe-3f0056af5bc2", "4829c3e4-24ac-4cf5-8cfe-61db4b1f5f7f"], "metadata": {"page_label": "285", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "965806fe-f867-4cb4-8531-b9cf2577130e": {"node_ids": ["254862c7-9e13-4df1-b217-f64ca03fc5e3", "56a39164-b80f-485f-b1d7-0372c18fd5b4", "254862c7-9e13-4df1-b217-f64ca03fc5e3", "56a39164-b80f-485f-b1d7-0372c18fd5b4", "254862c7-9e13-4df1-b217-f64ca03fc5e3", "56a39164-b80f-485f-b1d7-0372c18fd5b4"], "metadata": {"page_label": "286", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2d36bd17-f2bb-444f-b35f-6cfb23804a5f": {"node_ids": ["fa4ff7ac-be03-4a2e-bed2-19cb38f85302", "9df91b08-b219-4ea3-9db2-04ab844fa90b", "22dc2746-df01-45fb-ac99-a26114bae1d7", "fa4ff7ac-be03-4a2e-bed2-19cb38f85302", "9df91b08-b219-4ea3-9db2-04ab844fa90b", "22dc2746-df01-45fb-ac99-a26114bae1d7", "fa4ff7ac-be03-4a2e-bed2-19cb38f85302", "9df91b08-b219-4ea3-9db2-04ab844fa90b", "22dc2746-df01-45fb-ac99-a26114bae1d7"], "metadata": {"page_label": "287", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e18a258b-3ab4-4693-b182-f2336d0bf7e6": {"node_ids": ["88b9b458-3d2a-4970-b35d-b8664498bda5", "be376c17-09de-4d91-992c-f8ed41f18c4b", "88b9b458-3d2a-4970-b35d-b8664498bda5", "be376c17-09de-4d91-992c-f8ed41f18c4b", "88b9b458-3d2a-4970-b35d-b8664498bda5", "be376c17-09de-4d91-992c-f8ed41f18c4b"], "metadata": {"page_label": "288", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b8b8ee3d-f697-4b26-813f-020c6807c013": {"node_ids": ["9d59313e-e667-4254-bfa6-42b8b511ca23", "4e50a060-3d75-4e0d-8911-b5acbfc10efb", "9d59313e-e667-4254-bfa6-42b8b511ca23", "4e50a060-3d75-4e0d-8911-b5acbfc10efb", "9d59313e-e667-4254-bfa6-42b8b511ca23", "4e50a060-3d75-4e0d-8911-b5acbfc10efb"], "metadata": {"page_label": "289", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8a890c37-be29-45d8-b10b-7c6eacd772e8": {"node_ids": ["22e2fa36-bab5-4101-baf6-7bbcdc85497f", "840df9c1-8d6a-489b-98d1-f40f1e9b59e8", "22e2fa36-bab5-4101-baf6-7bbcdc85497f", "840df9c1-8d6a-489b-98d1-f40f1e9b59e8", "22e2fa36-bab5-4101-baf6-7bbcdc85497f", "840df9c1-8d6a-489b-98d1-f40f1e9b59e8"], "metadata": {"page_label": "290", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5d3f734f-7aa8-4cc4-8305-11ce4ace3134": {"node_ids": ["22486a56-2c49-4545-b5f1-13e0c51c9de7", "876bd4db-8406-437f-adab-46e582d5ada3", "22486a56-2c49-4545-b5f1-13e0c51c9de7", "876bd4db-8406-437f-adab-46e582d5ada3", "22486a56-2c49-4545-b5f1-13e0c51c9de7", "876bd4db-8406-437f-adab-46e582d5ada3"], "metadata": {"page_label": "291", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2d0d00bb-5ec9-4fac-9b5e-5806eeb67be2": {"node_ids": ["97ba3211-56cf-40f2-9b8b-2e73982ee48b", "24803293-5e0c-4788-9bb1-14cd7e359145", "f4c3c32a-f6af-4649-a12d-4a7fdd93a32a", "97ba3211-56cf-40f2-9b8b-2e73982ee48b", "24803293-5e0c-4788-9bb1-14cd7e359145", "f4c3c32a-f6af-4649-a12d-4a7fdd93a32a", "97ba3211-56cf-40f2-9b8b-2e73982ee48b", "24803293-5e0c-4788-9bb1-14cd7e359145", "f4c3c32a-f6af-4649-a12d-4a7fdd93a32a"], "metadata": {"page_label": "292", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "dc809377-d7d4-4a32-97ce-dca18a43d36c": {"node_ids": ["d8866ee8-c843-4e1e-b26a-d124967f0357", "278c11b5-cc1c-4dd2-9ace-7967b1d979c6", "d8866ee8-c843-4e1e-b26a-d124967f0357", "278c11b5-cc1c-4dd2-9ace-7967b1d979c6", "d8866ee8-c843-4e1e-b26a-d124967f0357", "278c11b5-cc1c-4dd2-9ace-7967b1d979c6"], "metadata": {"page_label": "293", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f725e3e0-f87c-483e-b003-1dd81349d039": {"node_ids": ["7c77754d-8247-4327-8f32-8b3dd61908fe", "098ca88f-aade-46a3-ac1e-c3393817f27b", "7c77754d-8247-4327-8f32-8b3dd61908fe", "098ca88f-aade-46a3-ac1e-c3393817f27b", "7c77754d-8247-4327-8f32-8b3dd61908fe", "098ca88f-aade-46a3-ac1e-c3393817f27b"], "metadata": {"page_label": "294", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "dff9fe2c-8751-475b-9c0d-d75a78f3d941": {"node_ids": ["1c4435d3-3d05-4f8e-91ad-7d3ef857edc5", "c2d90c87-bd25-4292-807f-c11c5a900fa4", "1c4435d3-3d05-4f8e-91ad-7d3ef857edc5", "c2d90c87-bd25-4292-807f-c11c5a900fa4", "1c4435d3-3d05-4f8e-91ad-7d3ef857edc5", "c2d90c87-bd25-4292-807f-c11c5a900fa4"], "metadata": {"page_label": "295", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "00b9e78e-cb31-47ec-b5e1-60073983b237": {"node_ids": ["000cadd2-701d-430e-817e-fb533c5d2013", "cbea3a24-a0ae-4a76-9605-a52e91a7108f", "000cadd2-701d-430e-817e-fb533c5d2013", "cbea3a24-a0ae-4a76-9605-a52e91a7108f", "000cadd2-701d-430e-817e-fb533c5d2013", "cbea3a24-a0ae-4a76-9605-a52e91a7108f"], "metadata": {"page_label": "296", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b3fc432a-d74f-428e-9dce-e4cb4ae4bf08": {"node_ids": ["a9c00889-77c7-4399-8a1d-e54b58327241", "8616bfec-2715-4f5d-b091-0144b21d50cb", "a9c00889-77c7-4399-8a1d-e54b58327241", "8616bfec-2715-4f5d-b091-0144b21d50cb", "a9c00889-77c7-4399-8a1d-e54b58327241", "8616bfec-2715-4f5d-b091-0144b21d50cb"], "metadata": {"page_label": "297", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "dd1a954d-5089-464f-a52d-920c8ba7a668": {"node_ids": ["7a7dc427-d4da-4a0a-ad3b-736d2cb2c643", "c43c89b0-9c2c-4cf3-8820-6cddd54b1061", "4d6eb0de-40b6-4b98-9228-d3a544d99de3", "7a7dc427-d4da-4a0a-ad3b-736d2cb2c643", "c43c89b0-9c2c-4cf3-8820-6cddd54b1061", "4d6eb0de-40b6-4b98-9228-d3a544d99de3", "7a7dc427-d4da-4a0a-ad3b-736d2cb2c643", "c43c89b0-9c2c-4cf3-8820-6cddd54b1061", "4d6eb0de-40b6-4b98-9228-d3a544d99de3"], "metadata": {"page_label": "298", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "34449fc1-fa4f-4a77-ad27-a3b3ffd96108": {"node_ids": ["2f68fe2e-5dbe-4506-a6c1-c18a22574f4b", "6fd8f0fa-78c8-4f88-a6d8-c46f1ba2bd64", "2f68fe2e-5dbe-4506-a6c1-c18a22574f4b", "6fd8f0fa-78c8-4f88-a6d8-c46f1ba2bd64", "2f68fe2e-5dbe-4506-a6c1-c18a22574f4b", "6fd8f0fa-78c8-4f88-a6d8-c46f1ba2bd64"], "metadata": {"page_label": "299", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "30b2a322-3cb2-4dea-af94-10276e2e1991": {"node_ids": ["c9ac673e-8fa3-42c7-8f73-291dedce7034", "f3acde98-db65-45a7-b85d-eea928c2dcd3", "c9ac673e-8fa3-42c7-8f73-291dedce7034", "f3acde98-db65-45a7-b85d-eea928c2dcd3", "c9ac673e-8fa3-42c7-8f73-291dedce7034", "f3acde98-db65-45a7-b85d-eea928c2dcd3"], "metadata": {"page_label": "300", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e15bedf3-1b5c-4cb4-a145-db3f7620034f": {"node_ids": ["8ebc3e9b-3df0-475c-8f39-557486261b2d", "865b6145-d42d-4006-8dc5-7683f6e905b2", "8ebc3e9b-3df0-475c-8f39-557486261b2d", "865b6145-d42d-4006-8dc5-7683f6e905b2", "8ebc3e9b-3df0-475c-8f39-557486261b2d", "865b6145-d42d-4006-8dc5-7683f6e905b2"], "metadata": {"page_label": "301", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5d152b95-1f45-4b8d-bedb-d001a7b105d9": {"node_ids": ["538ca174-8aa1-4bd8-97e6-cd4adcfbde2c", "aa7b47e7-098b-4ada-97bc-4edf5251c059", "538ca174-8aa1-4bd8-97e6-cd4adcfbde2c", "aa7b47e7-098b-4ada-97bc-4edf5251c059", "538ca174-8aa1-4bd8-97e6-cd4adcfbde2c", "aa7b47e7-098b-4ada-97bc-4edf5251c059"], "metadata": {"page_label": "302", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3cb4c5bb-bf97-4956-8549-2a1bef7d6fe2": {"node_ids": ["e2e74ca3-63a9-4386-8939-b3d312085092", "27ccde05-4595-4107-9273-4fad0ee8cd92", "e2e74ca3-63a9-4386-8939-b3d312085092", "27ccde05-4595-4107-9273-4fad0ee8cd92", "e2e74ca3-63a9-4386-8939-b3d312085092", "27ccde05-4595-4107-9273-4fad0ee8cd92"], "metadata": {"page_label": "303", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1f6a82bb-5f49-4ac7-acf1-88fdcda8a3cd": {"node_ids": ["6b090398-4e3a-4ff9-b534-169fe23c5e2f", "24c18645-dc96-419a-be4b-a3985fb9b47e", "39058389-376e-416e-8f24-f205c62f4051", "6b090398-4e3a-4ff9-b534-169fe23c5e2f", "24c18645-dc96-419a-be4b-a3985fb9b47e", "39058389-376e-416e-8f24-f205c62f4051", "6b090398-4e3a-4ff9-b534-169fe23c5e2f", "24c18645-dc96-419a-be4b-a3985fb9b47e", "39058389-376e-416e-8f24-f205c62f4051"], "metadata": {"page_label": "304", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1e1f477d-b3e4-4339-aaef-e19072eabc45": {"node_ids": ["bb21f84f-7208-43e3-8283-a671f57102eb", "b3ce1938-bf63-4ff0-b72d-d1ca3046b59c", "bb21f84f-7208-43e3-8283-a671f57102eb", "b3ce1938-bf63-4ff0-b72d-d1ca3046b59c", "bb21f84f-7208-43e3-8283-a671f57102eb", "b3ce1938-bf63-4ff0-b72d-d1ca3046b59c"], "metadata": {"page_label": "305", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "74241bfb-346c-4263-b1d3-c3a60eb1faff": {"node_ids": ["1f4ef9e6-281d-4a8b-8099-bf3295bfa2ba", "6baea516-1503-41f1-bd98-7fd0e636c04b", "1f4ef9e6-281d-4a8b-8099-bf3295bfa2ba", "6baea516-1503-41f1-bd98-7fd0e636c04b", "1f4ef9e6-281d-4a8b-8099-bf3295bfa2ba", "6baea516-1503-41f1-bd98-7fd0e636c04b"], "metadata": {"page_label": "306", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2f9a9d6f-fef1-4373-a7cd-3c799f648cb7": {"node_ids": ["b50f958e-797c-4e6a-b905-551cb15ce276", "44ccfb8f-4598-4ccc-a577-111fd7d4bb04", "b50f958e-797c-4e6a-b905-551cb15ce276", "44ccfb8f-4598-4ccc-a577-111fd7d4bb04", "b50f958e-797c-4e6a-b905-551cb15ce276", "44ccfb8f-4598-4ccc-a577-111fd7d4bb04"], "metadata": {"page_label": "307", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e18459e0-d931-4f4c-970a-459a840b1730": {"node_ids": ["56635e51-559c-42da-935e-7104ac375746", "4e38276f-346e-4461-ba58-a19ec2fb1b7c", "56635e51-559c-42da-935e-7104ac375746", "4e38276f-346e-4461-ba58-a19ec2fb1b7c", "56635e51-559c-42da-935e-7104ac375746", "4e38276f-346e-4461-ba58-a19ec2fb1b7c"], "metadata": {"page_label": "308", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "202f634d-ec7e-4f70-b38d-eb484183b4a8": {"node_ids": ["1864cf02-c775-4040-bd6b-593d60ed50fb", "1864cf02-c775-4040-bd6b-593d60ed50fb", "1864cf02-c775-4040-bd6b-593d60ed50fb"], "metadata": {"page_label": "309", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "54451b4b-0434-4f6d-8060-c2d71fa15224": {"node_ids": ["50550adb-59d8-4fda-ac3b-196af774fa62", "f3c866ac-2c2e-4e76-8cf0-0fe1e9da24b6", "50550adb-59d8-4fda-ac3b-196af774fa62", "f3c866ac-2c2e-4e76-8cf0-0fe1e9da24b6", "50550adb-59d8-4fda-ac3b-196af774fa62", "f3c866ac-2c2e-4e76-8cf0-0fe1e9da24b6"], "metadata": {"page_label": "310", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "84b84774-dd69-4949-831b-ceb576285395": {"node_ids": ["bbfc5d51-4b8d-4533-956d-819c6d9490cb", "40b8f786-635d-411d-a4a5-ff9a9bcb7acb", "bbfc5d51-4b8d-4533-956d-819c6d9490cb", "40b8f786-635d-411d-a4a5-ff9a9bcb7acb", "bbfc5d51-4b8d-4533-956d-819c6d9490cb", "40b8f786-635d-411d-a4a5-ff9a9bcb7acb"], "metadata": {"page_label": "311", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c1b3f474-9f24-48a5-8ee0-f0ad0726b314": {"node_ids": ["281b1df8-8953-4e05-aea2-0624b46acbca", "7e8fd38c-0cb0-46ca-9ba4-d7b81ab66c3b", "281b1df8-8953-4e05-aea2-0624b46acbca", "7e8fd38c-0cb0-46ca-9ba4-d7b81ab66c3b", "281b1df8-8953-4e05-aea2-0624b46acbca", "7e8fd38c-0cb0-46ca-9ba4-d7b81ab66c3b"], "metadata": {"page_label": "312", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "51a8a76e-df44-45b9-80e5-dad1255fa4f5": {"node_ids": ["02f2bf07-52c5-494d-ae2c-15c3c16a6640", "8b398b2c-91e4-4c35-a00d-5589db0564f5", "45687dde-01c8-40a5-a0f6-970816d61147", "02f2bf07-52c5-494d-ae2c-15c3c16a6640", "8b398b2c-91e4-4c35-a00d-5589db0564f5", "45687dde-01c8-40a5-a0f6-970816d61147", "02f2bf07-52c5-494d-ae2c-15c3c16a6640", "8b398b2c-91e4-4c35-a00d-5589db0564f5", "45687dde-01c8-40a5-a0f6-970816d61147"], "metadata": {"page_label": "313", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8a8ec880-be50-4c33-ac3e-f94994930d49": {"node_ids": ["13b59beb-f4a9-4707-809c-69f260fb0bb8", "3cc186d2-a8f4-4817-aa1f-b7491ee2d583", "13b59beb-f4a9-4707-809c-69f260fb0bb8", "3cc186d2-a8f4-4817-aa1f-b7491ee2d583", "13b59beb-f4a9-4707-809c-69f260fb0bb8", "3cc186d2-a8f4-4817-aa1f-b7491ee2d583"], "metadata": {"page_label": "314", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9c4638a2-db7f-4a28-805e-c633176a6859": {"node_ids": ["4493a09c-59dd-40cb-a3f3-c0cc1376ec6e", "f479fec0-999f-40a7-aee7-3bf1810cfc34", "399b2ce1-297f-4042-9c19-a989cc33d029", "4493a09c-59dd-40cb-a3f3-c0cc1376ec6e", "f479fec0-999f-40a7-aee7-3bf1810cfc34", "399b2ce1-297f-4042-9c19-a989cc33d029", "4493a09c-59dd-40cb-a3f3-c0cc1376ec6e", "f479fec0-999f-40a7-aee7-3bf1810cfc34", "399b2ce1-297f-4042-9c19-a989cc33d029"], "metadata": {"page_label": "315", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e9fe91ec-1a3f-42fc-b243-3b9b66880a54": {"node_ids": ["70e1d3bc-8661-4eed-b19e-0963fa8bda60", "0c75b4df-f82e-404e-b1b1-e0a57a483bf6", "70e1d3bc-8661-4eed-b19e-0963fa8bda60", "0c75b4df-f82e-404e-b1b1-e0a57a483bf6", "70e1d3bc-8661-4eed-b19e-0963fa8bda60", "0c75b4df-f82e-404e-b1b1-e0a57a483bf6"], "metadata": {"page_label": "316", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fbbafa90-14ef-47d0-a3da-80dbe4fe6404": {"node_ids": ["8907c030-fd56-437b-b4f5-9046b326f91b", "bef1a3e4-dc92-41d3-aa90-35260885285c", "3b7083b4-0398-4516-8955-56aa3f11c5f3", "8907c030-fd56-437b-b4f5-9046b326f91b", "bef1a3e4-dc92-41d3-aa90-35260885285c", "3b7083b4-0398-4516-8955-56aa3f11c5f3", "8907c030-fd56-437b-b4f5-9046b326f91b", "bef1a3e4-dc92-41d3-aa90-35260885285c", "3b7083b4-0398-4516-8955-56aa3f11c5f3"], "metadata": {"page_label": "317", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "54427b83-c87e-441c-879b-063731937468": {"node_ids": ["144548b5-8573-4810-9ae8-35ae6826e923", "21c8694d-d5d4-4fc2-a155-301f54e018b5", "144548b5-8573-4810-9ae8-35ae6826e923", "21c8694d-d5d4-4fc2-a155-301f54e018b5", "144548b5-8573-4810-9ae8-35ae6826e923", "21c8694d-d5d4-4fc2-a155-301f54e018b5"], "metadata": {"page_label": "318", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f36cf705-0214-4c5d-aa90-3f7e277e3148": {"node_ids": ["2ac00aa5-cf80-458c-9adc-8af22595ffa8", "174d1584-ebfd-4a81-92b9-d44872301c8f", "2ac00aa5-cf80-458c-9adc-8af22595ffa8", "174d1584-ebfd-4a81-92b9-d44872301c8f", "2ac00aa5-cf80-458c-9adc-8af22595ffa8", "174d1584-ebfd-4a81-92b9-d44872301c8f"], "metadata": {"page_label": "319", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9f7980e6-ef40-45b8-96aa-eef217c39644": {"node_ids": ["591b2554-9a04-4264-9a54-e2696fff63ec", "8aa2132b-d0c9-4c83-b653-71b316d799ad", "591b2554-9a04-4264-9a54-e2696fff63ec", "8aa2132b-d0c9-4c83-b653-71b316d799ad", "591b2554-9a04-4264-9a54-e2696fff63ec", "8aa2132b-d0c9-4c83-b653-71b316d799ad"], "metadata": {"page_label": "320", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "730e17c9-c104-432f-aeb9-78e71b942c2d": {"node_ids": ["ff885003-9c67-451c-bbe8-223a505f745f", "7a0876d5-265a-4fb5-8964-478ce5bdbb80", "ff885003-9c67-451c-bbe8-223a505f745f", "7a0876d5-265a-4fb5-8964-478ce5bdbb80", "ff885003-9c67-451c-bbe8-223a505f745f", "7a0876d5-265a-4fb5-8964-478ce5bdbb80"], "metadata": {"page_label": "321", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f1b5f4d8-42d0-49f8-ba79-b40d14458f26": {"node_ids": ["4af2333e-e4a0-4049-9fd4-002726170a55", "28538dba-58a0-4933-9c1e-cc3195e882f7", "d8ef4850-8336-42be-832b-52f9abd737e2", "4af2333e-e4a0-4049-9fd4-002726170a55", "28538dba-58a0-4933-9c1e-cc3195e882f7", "d8ef4850-8336-42be-832b-52f9abd737e2", "4af2333e-e4a0-4049-9fd4-002726170a55", "28538dba-58a0-4933-9c1e-cc3195e882f7", "d8ef4850-8336-42be-832b-52f9abd737e2"], "metadata": {"page_label": "322", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4bf6d629-b2b7-428c-b085-2caf7b0f84e4": {"node_ids": ["7bc18bbf-a096-43ff-a9e1-59688f94bf77", "f3b90126-0ad6-491b-b47e-b98be8f364e7", "a40278a1-ad22-4b65-a198-52cbe11ef39b", "7bc18bbf-a096-43ff-a9e1-59688f94bf77", "f3b90126-0ad6-491b-b47e-b98be8f364e7", "a40278a1-ad22-4b65-a198-52cbe11ef39b", "7bc18bbf-a096-43ff-a9e1-59688f94bf77", "f3b90126-0ad6-491b-b47e-b98be8f364e7", "a40278a1-ad22-4b65-a198-52cbe11ef39b"], "metadata": {"page_label": "323", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "33fc2948-9abf-49d5-a6cf-423e0c7730fa": {"node_ids": ["b7f66bcf-28df-49b9-85f9-2032fe28ff05", "9c9b14bc-bb91-4322-9434-5ec947beda43", "b7f66bcf-28df-49b9-85f9-2032fe28ff05", "9c9b14bc-bb91-4322-9434-5ec947beda43", "b7f66bcf-28df-49b9-85f9-2032fe28ff05", "9c9b14bc-bb91-4322-9434-5ec947beda43"], "metadata": {"page_label": "324", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a989c28f-2bd2-453a-a988-e3622816055b": {"node_ids": ["674a7eb3-bdaa-4bac-9e7a-b2197c7c737f", "18e04564-3ed8-43b7-8417-269976978b70", "674a7eb3-bdaa-4bac-9e7a-b2197c7c737f", "18e04564-3ed8-43b7-8417-269976978b70", "674a7eb3-bdaa-4bac-9e7a-b2197c7c737f", "18e04564-3ed8-43b7-8417-269976978b70"], "metadata": {"page_label": "325", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "112ad5b0-9110-4c2d-ad3a-b8a2c3f11bd2": {"node_ids": ["026a0272-2484-4c95-83a5-29f11368c5c4", "259788a4-94a0-4a9d-b0f1-fb5fdfc8f4a2", "026a0272-2484-4c95-83a5-29f11368c5c4", "259788a4-94a0-4a9d-b0f1-fb5fdfc8f4a2", "026a0272-2484-4c95-83a5-29f11368c5c4", "259788a4-94a0-4a9d-b0f1-fb5fdfc8f4a2"], "metadata": {"page_label": "326", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4923a796-e907-4efd-b369-3ea1914d91d5": {"node_ids": ["44515883-28eb-45c9-8fe7-461e7629a000", "608fa92b-01c4-4746-b294-7bdfaeedb194", "44515883-28eb-45c9-8fe7-461e7629a000", "608fa92b-01c4-4746-b294-7bdfaeedb194", "44515883-28eb-45c9-8fe7-461e7629a000", "608fa92b-01c4-4746-b294-7bdfaeedb194"], "metadata": {"page_label": "327", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9b6263af-f780-4b06-b934-5ff2639a49ac": {"node_ids": ["91294d4d-cc2f-4647-ad41-3f7c27c37991", "de6b3e33-b959-4940-abc5-75af38d30094", "91294d4d-cc2f-4647-ad41-3f7c27c37991", "de6b3e33-b959-4940-abc5-75af38d30094", "91294d4d-cc2f-4647-ad41-3f7c27c37991", "de6b3e33-b959-4940-abc5-75af38d30094"], "metadata": {"page_label": "328", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "afe44a82-7fec-4d91-9fdd-b7ec66942809": {"node_ids": ["8205c28a-ee63-45fa-9fc0-259c1b2050db", "9f9e36c6-f5ae-40f0-b630-4a6449f088bf", "8205c28a-ee63-45fa-9fc0-259c1b2050db", "9f9e36c6-f5ae-40f0-b630-4a6449f088bf", "8205c28a-ee63-45fa-9fc0-259c1b2050db", "9f9e36c6-f5ae-40f0-b630-4a6449f088bf"], "metadata": {"page_label": "329", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6168b5b7-75ce-427c-896f-b6d66a14ad5f": {"node_ids": ["6dc726a9-71f0-43ed-b3c4-39a9acff994f", "e49e3e83-9577-46ff-afb5-9d911bdf8e4d", "6dc726a9-71f0-43ed-b3c4-39a9acff994f", "e49e3e83-9577-46ff-afb5-9d911bdf8e4d", "6dc726a9-71f0-43ed-b3c4-39a9acff994f", "e49e3e83-9577-46ff-afb5-9d911bdf8e4d"], "metadata": {"page_label": "330", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "badb86be-a138-4e0a-a46b-cc373f58c607": {"node_ids": ["b935def0-d13a-45b2-a2ae-b08cc95a68bd", "d8b5eb36-d3d8-402d-8431-68671ee5630f", "7938e7af-ee10-4feb-875f-c04d050d80a6", "b935def0-d13a-45b2-a2ae-b08cc95a68bd", "d8b5eb36-d3d8-402d-8431-68671ee5630f", "7938e7af-ee10-4feb-875f-c04d050d80a6", "b935def0-d13a-45b2-a2ae-b08cc95a68bd", "d8b5eb36-d3d8-402d-8431-68671ee5630f", "7938e7af-ee10-4feb-875f-c04d050d80a6"], "metadata": {"page_label": "331", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b875acc3-b4f7-4a32-afc0-8c5c585bb5a7": {"node_ids": ["ec3043c8-577a-4886-b6e3-8615ba38e21e", "8d7af168-1420-4c69-827d-cb5e856f7cbc", "7080e728-63fb-4fd0-91f5-2af862b8d25d", "ec3043c8-577a-4886-b6e3-8615ba38e21e", "8d7af168-1420-4c69-827d-cb5e856f7cbc", "7080e728-63fb-4fd0-91f5-2af862b8d25d", "ec3043c8-577a-4886-b6e3-8615ba38e21e", "8d7af168-1420-4c69-827d-cb5e856f7cbc", "7080e728-63fb-4fd0-91f5-2af862b8d25d"], "metadata": {"page_label": "332", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2a88ef1a-e938-4b33-94cb-11e29e3d261d": {"node_ids": ["3a3167c6-df2d-4a70-b2a3-ed24afa9a93b", "ed637c01-03d5-400d-8c33-7b120027f81b", "3a3167c6-df2d-4a70-b2a3-ed24afa9a93b", "ed637c01-03d5-400d-8c33-7b120027f81b", "3a3167c6-df2d-4a70-b2a3-ed24afa9a93b", "ed637c01-03d5-400d-8c33-7b120027f81b"], "metadata": {"page_label": "333", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "cc87c4e8-3c67-4b89-887b-15bf2f1a3dda": {"node_ids": ["8b04f204-f8a8-4d98-99f4-3b8a2868ad81", "8b04f204-f8a8-4d98-99f4-3b8a2868ad81", "8b04f204-f8a8-4d98-99f4-3b8a2868ad81"], "metadata": {"page_label": "334", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c60040ee-d3d0-4086-ba51-a42c690c633f": {"node_ids": ["16c1f46c-0b0c-4dd8-bfee-ae81b75c1a99", "d736aef1-6e1a-49d1-9226-6ed0d6054ebf", "16c1f46c-0b0c-4dd8-bfee-ae81b75c1a99", "d736aef1-6e1a-49d1-9226-6ed0d6054ebf", "16c1f46c-0b0c-4dd8-bfee-ae81b75c1a99", "d736aef1-6e1a-49d1-9226-6ed0d6054ebf"], "metadata": {"page_label": "335", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c9d6976a-e7f0-4756-98cb-1f142911c3c4": {"node_ids": ["0d8f9c38-2d6d-4823-854f-a6e636005760", "24d8d8a1-e2e3-493b-8a13-8a47317094cc", "159a9cc4-1f5b-4aa2-84fd-45cf15a17b65", "0d8f9c38-2d6d-4823-854f-a6e636005760", "24d8d8a1-e2e3-493b-8a13-8a47317094cc", "159a9cc4-1f5b-4aa2-84fd-45cf15a17b65", "0d8f9c38-2d6d-4823-854f-a6e636005760", "24d8d8a1-e2e3-493b-8a13-8a47317094cc", "159a9cc4-1f5b-4aa2-84fd-45cf15a17b65"], "metadata": {"page_label": "336", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b0c9578d-6360-499c-8230-c338994ac720": {"node_ids": ["751a7fa1-a961-460b-be2f-7561e8df2bb5", "2e493c11-7250-4eda-848d-ffd075936dd8", "5ee96924-f2ba-451b-967e-cc8f45138261", "751a7fa1-a961-460b-be2f-7561e8df2bb5", "2e493c11-7250-4eda-848d-ffd075936dd8", "5ee96924-f2ba-451b-967e-cc8f45138261", "751a7fa1-a961-460b-be2f-7561e8df2bb5", "2e493c11-7250-4eda-848d-ffd075936dd8", "5ee96924-f2ba-451b-967e-cc8f45138261"], "metadata": {"page_label": "337", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e45c048a-a925-4a27-9be6-b9a6988b11bb": {"node_ids": ["56aaca10-6f36-4b3b-aa70-9edfbb3c096b", "56aaca10-6f36-4b3b-aa70-9edfbb3c096b", "56aaca10-6f36-4b3b-aa70-9edfbb3c096b"], "metadata": {"page_label": "338", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "13e5cf21-fe7e-4560-afa2-d7a7b4ff3b6f": {"node_ids": ["54be89f1-61a1-4538-803a-6a868930cf8e", "7509cb1c-a8e8-44c2-bfa2-cf5d9c0a716a", "54be89f1-61a1-4538-803a-6a868930cf8e", "7509cb1c-a8e8-44c2-bfa2-cf5d9c0a716a", "54be89f1-61a1-4538-803a-6a868930cf8e", "7509cb1c-a8e8-44c2-bfa2-cf5d9c0a716a"], "metadata": {"page_label": "339", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3a3de74a-d75f-417e-b629-bea2fdc88b71": {"node_ids": ["75abdf88-1c67-41ea-b955-83365e9b7e6e", "6b53a586-acf1-49b8-9409-67052470c56e", "75abdf88-1c67-41ea-b955-83365e9b7e6e", "6b53a586-acf1-49b8-9409-67052470c56e", "75abdf88-1c67-41ea-b955-83365e9b7e6e", "6b53a586-acf1-49b8-9409-67052470c56e"], "metadata": {"page_label": "340", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ac9da951-1b83-4f48-8717-914d28570729": {"node_ids": ["212e0c56-885c-4896-8791-5960a4293423", "cd45a11a-1dfe-49f1-95f4-7dd134214af0", "212e0c56-885c-4896-8791-5960a4293423", "cd45a11a-1dfe-49f1-95f4-7dd134214af0", "212e0c56-885c-4896-8791-5960a4293423", "cd45a11a-1dfe-49f1-95f4-7dd134214af0"], "metadata": {"page_label": "341", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c87ea696-6f92-4b46-bffc-c27dbde3386b": {"node_ids": ["3169158d-30b1-4d20-9954-d7d9354729ba", "710af244-aa6d-44a3-8d61-7db46d71e707", "1c93590a-c955-4ed4-8ff5-19ce1e0045b2", "3169158d-30b1-4d20-9954-d7d9354729ba", "710af244-aa6d-44a3-8d61-7db46d71e707", "1c93590a-c955-4ed4-8ff5-19ce1e0045b2", "3169158d-30b1-4d20-9954-d7d9354729ba", "710af244-aa6d-44a3-8d61-7db46d71e707", "1c93590a-c955-4ed4-8ff5-19ce1e0045b2"], "metadata": {"page_label": "342", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1f64220e-c9fc-41bb-9fa5-522ebb51cd2f": {"node_ids": ["0f6daacc-32e3-4284-861c-ac01f7ade420", "b8b2ba2a-6444-4198-bd06-c2394f21acec", "99551ff8-8f2a-4add-9973-322da8fc951c", "0f6daacc-32e3-4284-861c-ac01f7ade420", "b8b2ba2a-6444-4198-bd06-c2394f21acec", "99551ff8-8f2a-4add-9973-322da8fc951c", "0f6daacc-32e3-4284-861c-ac01f7ade420", "b8b2ba2a-6444-4198-bd06-c2394f21acec", "99551ff8-8f2a-4add-9973-322da8fc951c"], "metadata": {"page_label": "343", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "779f268f-64e5-45b1-89f2-cd1666f58c74": {"node_ids": ["c1118dac-2851-48e3-9ecc-9f670a887767", "ee76ea05-7417-43ed-983d-dc7e9747a0df", "4e49e243-6364-4b25-ba41-5152a9d472c9", "c1118dac-2851-48e3-9ecc-9f670a887767", "ee76ea05-7417-43ed-983d-dc7e9747a0df", "4e49e243-6364-4b25-ba41-5152a9d472c9", "c1118dac-2851-48e3-9ecc-9f670a887767", "ee76ea05-7417-43ed-983d-dc7e9747a0df", "4e49e243-6364-4b25-ba41-5152a9d472c9"], "metadata": {"page_label": "344", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "12f7a6d7-a626-40aa-9512-f492e01ba3d7": {"node_ids": ["3e81f972-bc84-4d2b-9d89-521dc7ecc8bc", "0c547f5b-5455-4963-bd90-ab99ff2bfd13", "3e81f972-bc84-4d2b-9d89-521dc7ecc8bc", "0c547f5b-5455-4963-bd90-ab99ff2bfd13", "3e81f972-bc84-4d2b-9d89-521dc7ecc8bc", "0c547f5b-5455-4963-bd90-ab99ff2bfd13"], "metadata": {"page_label": "345", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bfda59d9-e421-4c2a-9f0a-5e3cfc44966c": {"node_ids": ["41504459-b387-41a2-a653-2b2dff425e27", "438c12b6-5c06-454f-b097-c5388ad1972f", "41504459-b387-41a2-a653-2b2dff425e27", "438c12b6-5c06-454f-b097-c5388ad1972f", "41504459-b387-41a2-a653-2b2dff425e27", "438c12b6-5c06-454f-b097-c5388ad1972f"], "metadata": {"page_label": "346", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a638271e-9335-46fe-9264-52c084985275": {"node_ids": ["46fb70cc-86b1-4c32-b60a-dcc4be1428c6", "ddd67588-9830-4bef-bed2-67deabf41a88", "46fb70cc-86b1-4c32-b60a-dcc4be1428c6", "ddd67588-9830-4bef-bed2-67deabf41a88", "46fb70cc-86b1-4c32-b60a-dcc4be1428c6", "ddd67588-9830-4bef-bed2-67deabf41a88"], "metadata": {"page_label": "347", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "36593695-75c2-442f-aa4d-ebe5f226aa13": {"node_ids": ["582c0e08-240d-4c8a-9462-9e46b8ce0b1e", "83260bee-ee46-436f-8d34-72f3bc4c1b92", "02c3c8da-a50a-4afb-ace7-b98972c529a7", "582c0e08-240d-4c8a-9462-9e46b8ce0b1e", "83260bee-ee46-436f-8d34-72f3bc4c1b92", "02c3c8da-a50a-4afb-ace7-b98972c529a7", "582c0e08-240d-4c8a-9462-9e46b8ce0b1e", "83260bee-ee46-436f-8d34-72f3bc4c1b92", "02c3c8da-a50a-4afb-ace7-b98972c529a7"], "metadata": {"page_label": "348", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "af09c325-fd99-43cf-b4b3-c1236613f6ec": {"node_ids": ["7ef6ebf5-f1af-4113-a31e-dfedd0d8b19a", "eaad55bf-58ff-4f11-89cd-b9ddbe029a53", "7ef6ebf5-f1af-4113-a31e-dfedd0d8b19a", "eaad55bf-58ff-4f11-89cd-b9ddbe029a53", "7ef6ebf5-f1af-4113-a31e-dfedd0d8b19a", "eaad55bf-58ff-4f11-89cd-b9ddbe029a53"], "metadata": {"page_label": "349", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4b0670b7-78ba-4dba-bd0f-fbf99a481289": {"node_ids": ["a51f6ce4-b330-4ec2-a979-4f01ee1a47ec", "d3ed1dde-735c-4c47-8fe3-acabe55cf628", "a51f6ce4-b330-4ec2-a979-4f01ee1a47ec", "d3ed1dde-735c-4c47-8fe3-acabe55cf628", "a51f6ce4-b330-4ec2-a979-4f01ee1a47ec", "d3ed1dde-735c-4c47-8fe3-acabe55cf628"], "metadata": {"page_label": "350", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "550570c8-8ba5-43c8-a412-6e8b5ff0d587": {"node_ids": ["5be5a4f0-683f-4eeb-80a3-036757513a91", "6f4dda48-1c04-4e6a-849f-40333a0aba48", "5be5a4f0-683f-4eeb-80a3-036757513a91", "6f4dda48-1c04-4e6a-849f-40333a0aba48", "5be5a4f0-683f-4eeb-80a3-036757513a91", "6f4dda48-1c04-4e6a-849f-40333a0aba48"], "metadata": {"page_label": "351", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3e0838ad-1018-4dba-afcf-6e1224f3e6ff": {"node_ids": ["b230a9bd-60c0-4e70-a1ab-18126b94b590", "d24937a7-9f69-4da5-82de-df17dacceb2d", "3e193db3-95e9-46c3-ad84-c2c035e8a038", "b230a9bd-60c0-4e70-a1ab-18126b94b590", "d24937a7-9f69-4da5-82de-df17dacceb2d", "3e193db3-95e9-46c3-ad84-c2c035e8a038", "b230a9bd-60c0-4e70-a1ab-18126b94b590", "d24937a7-9f69-4da5-82de-df17dacceb2d", "3e193db3-95e9-46c3-ad84-c2c035e8a038"], "metadata": {"page_label": "352", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "46f68bf9-5d5e-43d1-bd5c-cb08da90e53c": {"node_ids": ["0cc1f2bf-3013-476a-afd2-664e778c2146", "2eba9a49-5e45-451b-90c5-d50142df6e14", "b801f5c4-b2e9-4ef1-99a9-a272d5a3b998", "0cc1f2bf-3013-476a-afd2-664e778c2146", "2eba9a49-5e45-451b-90c5-d50142df6e14", "b801f5c4-b2e9-4ef1-99a9-a272d5a3b998", "0cc1f2bf-3013-476a-afd2-664e778c2146", "2eba9a49-5e45-451b-90c5-d50142df6e14", "b801f5c4-b2e9-4ef1-99a9-a272d5a3b998"], "metadata": {"page_label": "353", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "294fe2ac-fe3e-4776-84ac-745e97c9d67d": {"node_ids": ["8ba28f66-92f1-4bc4-8ff0-9c60a2f323c6", "f26bb0cb-b7fb-4de7-bdb4-5e268a6510e4", "48f577e0-3bce-4437-80be-d6c6827109b3", "8ba28f66-92f1-4bc4-8ff0-9c60a2f323c6", "f26bb0cb-b7fb-4de7-bdb4-5e268a6510e4", "48f577e0-3bce-4437-80be-d6c6827109b3", "8ba28f66-92f1-4bc4-8ff0-9c60a2f323c6", "f26bb0cb-b7fb-4de7-bdb4-5e268a6510e4", "48f577e0-3bce-4437-80be-d6c6827109b3"], "metadata": {"page_label": "354", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0d34b8dc-6df2-4291-bf3a-8e03d0058916": {"node_ids": ["ff58447f-cb12-48e1-8609-bff1af49f42f", "52ed733f-fe99-44da-b387-29043d10393b", "07f36618-3186-4568-b410-8ce3492edccf", "ff58447f-cb12-48e1-8609-bff1af49f42f", "52ed733f-fe99-44da-b387-29043d10393b", "07f36618-3186-4568-b410-8ce3492edccf", "ff58447f-cb12-48e1-8609-bff1af49f42f", "52ed733f-fe99-44da-b387-29043d10393b", "07f36618-3186-4568-b410-8ce3492edccf"], "metadata": {"page_label": "355", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "779fb296-4e38-4bba-b816-02f122e4f014": {"node_ids": ["ced6b948-e5f3-43b5-bdd0-f78d3b22d2c9", "0ba36249-f72e-4be7-a783-c8c4689ccd4d", "49952cc8-c5b8-48c3-8f57-663191f17927", "ced6b948-e5f3-43b5-bdd0-f78d3b22d2c9", "0ba36249-f72e-4be7-a783-c8c4689ccd4d", "49952cc8-c5b8-48c3-8f57-663191f17927", "ced6b948-e5f3-43b5-bdd0-f78d3b22d2c9", "0ba36249-f72e-4be7-a783-c8c4689ccd4d", "49952cc8-c5b8-48c3-8f57-663191f17927"], "metadata": {"page_label": "356", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "cef04480-afe2-46d6-b011-af9cdcaecc56": {"node_ids": ["c6245616-aebd-4e15-a8bf-dcde7a3875a6", "63cf5f09-8791-45e0-bc56-fca1bf9ff4d4", "c6245616-aebd-4e15-a8bf-dcde7a3875a6", "63cf5f09-8791-45e0-bc56-fca1bf9ff4d4", "c6245616-aebd-4e15-a8bf-dcde7a3875a6", "63cf5f09-8791-45e0-bc56-fca1bf9ff4d4"], "metadata": {"page_label": "357", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "467b566a-432d-47c4-a07d-5814b112e5c4": {"node_ids": ["65e5c000-c392-4fb2-9aad-c75ca18bc91e", "a90352d6-79b0-49d4-8f3c-2cf4f3ec14cd", "65e5c000-c392-4fb2-9aad-c75ca18bc91e", "a90352d6-79b0-49d4-8f3c-2cf4f3ec14cd", "65e5c000-c392-4fb2-9aad-c75ca18bc91e", "a90352d6-79b0-49d4-8f3c-2cf4f3ec14cd"], "metadata": {"page_label": "358", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c51169bc-9770-4410-bc49-9fb873f09a55": {"node_ids": ["9f9452a6-e5b9-44ce-9fff-2853bbda5777", "60a18ece-32fc-4d25-92a3-a8168011c2ac", "ca9a7379-7b95-4259-9a17-60476c71add2", "9f9452a6-e5b9-44ce-9fff-2853bbda5777", "60a18ece-32fc-4d25-92a3-a8168011c2ac", "ca9a7379-7b95-4259-9a17-60476c71add2", "9f9452a6-e5b9-44ce-9fff-2853bbda5777", "60a18ece-32fc-4d25-92a3-a8168011c2ac", "ca9a7379-7b95-4259-9a17-60476c71add2"], "metadata": {"page_label": "359", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "527b336c-6a65-4a5f-bd0a-2b0d4a9a0ba3": {"node_ids": ["6cd19dac-f51b-447a-a34d-178d06be3dae", "61f5ede5-58e9-4dd0-a6ef-337d9b0424e2", "a898b73c-7b82-4130-a8d9-a347fd806d05", "6cd19dac-f51b-447a-a34d-178d06be3dae", "61f5ede5-58e9-4dd0-a6ef-337d9b0424e2", "a898b73c-7b82-4130-a8d9-a347fd806d05", "6cd19dac-f51b-447a-a34d-178d06be3dae", "61f5ede5-58e9-4dd0-a6ef-337d9b0424e2", "a898b73c-7b82-4130-a8d9-a347fd806d05"], "metadata": {"page_label": "360", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5bf4da5e-206d-4810-8916-aab52869ca39": {"node_ids": ["46d811c6-0d0a-4080-ab44-86e139514f9c", "17be443e-6eb2-45f5-ac28-f13bed425d5b", "64911427-155b-4ea2-95b2-2269dc4aa688", "46d811c6-0d0a-4080-ab44-86e139514f9c", "17be443e-6eb2-45f5-ac28-f13bed425d5b", "64911427-155b-4ea2-95b2-2269dc4aa688", "46d811c6-0d0a-4080-ab44-86e139514f9c", "17be443e-6eb2-45f5-ac28-f13bed425d5b", "64911427-155b-4ea2-95b2-2269dc4aa688"], "metadata": {"page_label": "361", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3c8e0888-c7bb-4d17-ab88-ebfe1bbe79df": {"node_ids": ["86a1d27d-a8c8-4669-b668-d5a9ebdecf64", "2b338d6c-30f2-4945-af55-bd1fd52b4280", "86a1d27d-a8c8-4669-b668-d5a9ebdecf64", "2b338d6c-30f2-4945-af55-bd1fd52b4280", "86a1d27d-a8c8-4669-b668-d5a9ebdecf64", "2b338d6c-30f2-4945-af55-bd1fd52b4280"], "metadata": {"page_label": "362", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "434450fc-2559-4ee1-9da4-d2b906367fb7": {"node_ids": ["ea7f861c-6501-4da1-bc59-edabb5bca01b", "25f68f40-021e-40aa-ad15-fd9a1dbf2bc4", "ea7f861c-6501-4da1-bc59-edabb5bca01b", "25f68f40-021e-40aa-ad15-fd9a1dbf2bc4", "ea7f861c-6501-4da1-bc59-edabb5bca01b", "25f68f40-021e-40aa-ad15-fd9a1dbf2bc4"], "metadata": {"page_label": "363", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "64c82ed1-286c-4a50-90ce-cee08768d09a": {"node_ids": ["36ff29f4-f512-4d62-8b50-2783e0bfff68", "730fe75b-fb53-46c2-8b2c-b896cb2d1813", "36ff29f4-f512-4d62-8b50-2783e0bfff68", "730fe75b-fb53-46c2-8b2c-b896cb2d1813", "36ff29f4-f512-4d62-8b50-2783e0bfff68", "730fe75b-fb53-46c2-8b2c-b896cb2d1813"], "metadata": {"page_label": "364", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7ea13995-6ba4-4224-a821-32907cf0572f": {"node_ids": ["c1a333fb-cae7-4f3a-8c07-7b8600131d54", "a83cd0af-786c-4c12-899a-028c863b4f13", "0f0cb576-2260-49b0-b634-9efadf1060aa", "c1a333fb-cae7-4f3a-8c07-7b8600131d54", "a83cd0af-786c-4c12-899a-028c863b4f13", "0f0cb576-2260-49b0-b634-9efadf1060aa", "c1a333fb-cae7-4f3a-8c07-7b8600131d54", "a83cd0af-786c-4c12-899a-028c863b4f13", "0f0cb576-2260-49b0-b634-9efadf1060aa"], "metadata": {"page_label": "365", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0bc287cf-3191-41c9-9643-d9b546c7e1b0": {"node_ids": ["5d2014d4-5424-46e8-b831-ef32ccd10184", "a4a3ecda-e226-4b7d-b9b6-77d8bfa4ec8e", "7a737159-7025-4edb-990c-4b1e5b7d11bf", "d75fd605-3612-4ef1-89b3-bcab8dc5997f", "7b9e86d8-1b44-4828-8d14-95c254eb9185", "5d2014d4-5424-46e8-b831-ef32ccd10184", "a4a3ecda-e226-4b7d-b9b6-77d8bfa4ec8e", "7a737159-7025-4edb-990c-4b1e5b7d11bf", "d75fd605-3612-4ef1-89b3-bcab8dc5997f", "7b9e86d8-1b44-4828-8d14-95c254eb9185", "5d2014d4-5424-46e8-b831-ef32ccd10184", "a4a3ecda-e226-4b7d-b9b6-77d8bfa4ec8e", "7a737159-7025-4edb-990c-4b1e5b7d11bf", "d75fd605-3612-4ef1-89b3-bcab8dc5997f", "7b9e86d8-1b44-4828-8d14-95c254eb9185"], "metadata": {"page_label": "366", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3747bc6e-364c-4147-8ee9-1406a61446b4": {"node_ids": ["d8c734af-dfab-4723-90a6-764676265fff", "238883a0-cd82-4a42-8431-62fe33a1e96e", "f8d419a0-e8fc-406a-99df-115fb88ac952", "d8c734af-dfab-4723-90a6-764676265fff", "238883a0-cd82-4a42-8431-62fe33a1e96e", "f8d419a0-e8fc-406a-99df-115fb88ac952", "d8c734af-dfab-4723-90a6-764676265fff", "238883a0-cd82-4a42-8431-62fe33a1e96e", "f8d419a0-e8fc-406a-99df-115fb88ac952"], "metadata": {"page_label": "367", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "55887517-e16d-4617-842b-bb33ab005f9b": {"node_ids": ["9ee713e5-95d9-4074-9e4f-a13d9ba71606", "b667c4af-e649-4180-a8a5-059f32275c76", "9ee713e5-95d9-4074-9e4f-a13d9ba71606", "b667c4af-e649-4180-a8a5-059f32275c76", "9ee713e5-95d9-4074-9e4f-a13d9ba71606", "b667c4af-e649-4180-a8a5-059f32275c76"], "metadata": {"page_label": "368", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "debf93da-4e6b-4042-b6f5-f2b5a517c2aa": {"node_ids": ["1478afd9-923b-4937-bf75-6eb5f4138b38", "d7f89e3b-94da-4769-b754-0f45c603a564", "1478afd9-923b-4937-bf75-6eb5f4138b38", "d7f89e3b-94da-4769-b754-0f45c603a564", "1478afd9-923b-4937-bf75-6eb5f4138b38", "d7f89e3b-94da-4769-b754-0f45c603a564"], "metadata": {"page_label": "369", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bb3d47ca-8533-4fd7-91f3-c9a8f80df3dc": {"node_ids": ["d5892d85-d382-4a66-9adb-5ef0d2d00112", "beb2be14-c6a7-4e13-b71c-eb2b369866e0", "d5892d85-d382-4a66-9adb-5ef0d2d00112", "beb2be14-c6a7-4e13-b71c-eb2b369866e0", "d5892d85-d382-4a66-9adb-5ef0d2d00112", "beb2be14-c6a7-4e13-b71c-eb2b369866e0"], "metadata": {"page_label": "370", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2a2a91fd-6f7f-4200-978b-f5cf9cf5fe17": {"node_ids": ["6eeb3a49-5d38-45ba-9383-787f556e3235", "bb583aca-80cd-4f04-a610-e8267b714021", "a8660e44-52bc-4ad4-9760-9edd6dd38360", "6eeb3a49-5d38-45ba-9383-787f556e3235", "bb583aca-80cd-4f04-a610-e8267b714021", "a8660e44-52bc-4ad4-9760-9edd6dd38360", "6eeb3a49-5d38-45ba-9383-787f556e3235", "bb583aca-80cd-4f04-a610-e8267b714021", "a8660e44-52bc-4ad4-9760-9edd6dd38360"], "metadata": {"page_label": "371", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a0a224d3-33a8-45fc-913d-d248a20473c1": {"node_ids": ["1493a537-b32e-4b0f-94aa-8205550e1b8c", "26a96f42-6296-4244-86d2-9bce8884a2d1", "d559b59f-ce00-4480-b889-c5ab6bf3407a", "1493a537-b32e-4b0f-94aa-8205550e1b8c", "26a96f42-6296-4244-86d2-9bce8884a2d1", "d559b59f-ce00-4480-b889-c5ab6bf3407a", "1493a537-b32e-4b0f-94aa-8205550e1b8c", "26a96f42-6296-4244-86d2-9bce8884a2d1", "d559b59f-ce00-4480-b889-c5ab6bf3407a"], "metadata": {"page_label": "372", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2503914f-7267-407a-a479-c26316ddcb18": {"node_ids": ["e18e2ef9-c14c-4020-8105-58d517ff89b2", "2225c5a7-d8fb-4597-b448-ba37729c5d13", "e18e2ef9-c14c-4020-8105-58d517ff89b2", "2225c5a7-d8fb-4597-b448-ba37729c5d13", "e18e2ef9-c14c-4020-8105-58d517ff89b2", "2225c5a7-d8fb-4597-b448-ba37729c5d13"], "metadata": {"page_label": "373", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e56c139d-2ce7-4b49-a279-c0ca63b87e2c": {"node_ids": ["40b11b6c-769b-4b0b-8a10-ef756b4dbf77", "169497ec-3c6b-4b7a-b440-e050accb0628", "40b11b6c-769b-4b0b-8a10-ef756b4dbf77", "169497ec-3c6b-4b7a-b440-e050accb0628", "40b11b6c-769b-4b0b-8a10-ef756b4dbf77", "169497ec-3c6b-4b7a-b440-e050accb0628"], "metadata": {"page_label": "374", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c93fb2d6-62ef-47ab-8067-d60ad4126c05": {"node_ids": ["7cf3b775-7cdc-4dd1-83d9-b8d14f6e7e22", "1a134d3c-9374-4f7e-bceb-b8efce6586a8", "c9b277bd-2725-4034-9582-3c58f4ebd2c1", "7cf3b775-7cdc-4dd1-83d9-b8d14f6e7e22", "1a134d3c-9374-4f7e-bceb-b8efce6586a8", "c9b277bd-2725-4034-9582-3c58f4ebd2c1", "7cf3b775-7cdc-4dd1-83d9-b8d14f6e7e22", "1a134d3c-9374-4f7e-bceb-b8efce6586a8", "c9b277bd-2725-4034-9582-3c58f4ebd2c1"], "metadata": {"page_label": "375", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9f846438-e0d8-4572-af11-f2f4672c1978": {"node_ids": ["38b0312b-c1ff-41b4-a9cb-7c259e93ff5b", "55550297-5007-4947-a0ac-e4180523ac11", "9d472aba-135d-48cd-804a-044e8eb403fb", "38b0312b-c1ff-41b4-a9cb-7c259e93ff5b", "55550297-5007-4947-a0ac-e4180523ac11", "9d472aba-135d-48cd-804a-044e8eb403fb", "38b0312b-c1ff-41b4-a9cb-7c259e93ff5b", "55550297-5007-4947-a0ac-e4180523ac11", "9d472aba-135d-48cd-804a-044e8eb403fb"], "metadata": {"page_label": "376", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "815d6d58-84ca-4333-b064-eaec6d93b51f": {"node_ids": ["0db6b405-14c9-426a-9a74-d405c5b2c690", "98db308d-bff8-4c64-b516-53be4ea2e184", "0db6b405-14c9-426a-9a74-d405c5b2c690", "98db308d-bff8-4c64-b516-53be4ea2e184", "0db6b405-14c9-426a-9a74-d405c5b2c690", "98db308d-bff8-4c64-b516-53be4ea2e184"], "metadata": {"page_label": "377", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "64944609-b757-4709-8db1-18b98a8841a2": {"node_ids": ["1163f046-24db-49c6-865b-2d73ae9f4fd7", "7706e9fd-ab33-4677-a28e-c995476ef7e1", "1163f046-24db-49c6-865b-2d73ae9f4fd7", "7706e9fd-ab33-4677-a28e-c995476ef7e1", "1163f046-24db-49c6-865b-2d73ae9f4fd7", "7706e9fd-ab33-4677-a28e-c995476ef7e1"], "metadata": {"page_label": "378", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ce9c2d14-b060-4245-832b-b9b154d2a2fb": {"node_ids": ["b20c8791-4499-4226-af4a-dee6ab4c94af", "fe7d51e0-4b89-447a-ad21-6fef162bf78d", "b20c8791-4499-4226-af4a-dee6ab4c94af", "fe7d51e0-4b89-447a-ad21-6fef162bf78d", "b20c8791-4499-4226-af4a-dee6ab4c94af", "fe7d51e0-4b89-447a-ad21-6fef162bf78d"], "metadata": {"page_label": "379", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "541ea0b3-7f17-49b1-b58e-371af9362344": {"node_ids": ["8dff6669-4227-47c9-bad0-94d908e6a304", "c17c4575-b16f-4aca-9f5e-cb9bbcbd2fa2", "8dff6669-4227-47c9-bad0-94d908e6a304", "c17c4575-b16f-4aca-9f5e-cb9bbcbd2fa2", "8dff6669-4227-47c9-bad0-94d908e6a304", "c17c4575-b16f-4aca-9f5e-cb9bbcbd2fa2"], "metadata": {"page_label": "380", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "353ab20d-9cfc-46bb-a680-0773c590de7e": {"node_ids": ["00213433-fb3f-4cd5-8ac2-25ccc164c45c", "8c717a93-d2e7-401b-b913-4c8108c03143", "00213433-fb3f-4cd5-8ac2-25ccc164c45c", "8c717a93-d2e7-401b-b913-4c8108c03143", "00213433-fb3f-4cd5-8ac2-25ccc164c45c", "8c717a93-d2e7-401b-b913-4c8108c03143"], "metadata": {"page_label": "381", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a469707f-687c-424d-a3d8-3e2b1c7830ac": {"node_ids": ["ebee6b9d-43df-472e-acad-17482764456e", "d7943bd1-1797-4ea6-bdd2-11e47589bfa4", "3f55a4ff-e379-4832-bff9-4fb66488a6db", "ebee6b9d-43df-472e-acad-17482764456e", "d7943bd1-1797-4ea6-bdd2-11e47589bfa4", "3f55a4ff-e379-4832-bff9-4fb66488a6db", "ebee6b9d-43df-472e-acad-17482764456e", "d7943bd1-1797-4ea6-bdd2-11e47589bfa4", "3f55a4ff-e379-4832-bff9-4fb66488a6db"], "metadata": {"page_label": "382", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ab2c4201-02ce-470d-a446-362837220ef6": {"node_ids": ["739cb91f-159f-460a-ab41-4a6419a42efc", "51483530-5054-405f-b6de-36aeda132c45", "13a0f414-3e4f-44c0-8064-1a948232c4bb", "739cb91f-159f-460a-ab41-4a6419a42efc", "51483530-5054-405f-b6de-36aeda132c45", "13a0f414-3e4f-44c0-8064-1a948232c4bb", "739cb91f-159f-460a-ab41-4a6419a42efc", "51483530-5054-405f-b6de-36aeda132c45", "13a0f414-3e4f-44c0-8064-1a948232c4bb"], "metadata": {"page_label": "383", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9c23dd4e-ecee-4e13-a6c1-b3877d418233": {"node_ids": ["b396bb95-bd8c-409b-8211-327ec9a6969b", "b57448e2-6858-4d89-8c36-4e6eb7a6f969", "62b6b26e-b0ab-485c-93e6-fc00bf0b5ddd", "b396bb95-bd8c-409b-8211-327ec9a6969b", "b57448e2-6858-4d89-8c36-4e6eb7a6f969", "62b6b26e-b0ab-485c-93e6-fc00bf0b5ddd", "b396bb95-bd8c-409b-8211-327ec9a6969b", "b57448e2-6858-4d89-8c36-4e6eb7a6f969", "62b6b26e-b0ab-485c-93e6-fc00bf0b5ddd"], "metadata": {"page_label": "384", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d033e8e3-f57d-4212-97b0-43367c042c5c": {"node_ids": ["33466291-6651-4c2b-ac85-8b3b96c444ef", "5528098d-a2e3-488d-b4d5-f6c8500133e3", "44e0b660-d854-4ae8-b49b-31710c0c89de", "33466291-6651-4c2b-ac85-8b3b96c444ef", "5528098d-a2e3-488d-b4d5-f6c8500133e3", "44e0b660-d854-4ae8-b49b-31710c0c89de", "33466291-6651-4c2b-ac85-8b3b96c444ef", "5528098d-a2e3-488d-b4d5-f6c8500133e3", "44e0b660-d854-4ae8-b49b-31710c0c89de"], "metadata": {"page_label": "385", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4eb10f2a-a899-4e74-9d73-b8727483488d": {"node_ids": ["24fdcd30-13b2-42a5-bb51-3e21b47db5ed", "22336125-cac8-4f05-b868-7c51301bbd50", "c3d76d51-7596-424a-9ba9-18a87c2401de", "24fdcd30-13b2-42a5-bb51-3e21b47db5ed", "22336125-cac8-4f05-b868-7c51301bbd50", "c3d76d51-7596-424a-9ba9-18a87c2401de", "24fdcd30-13b2-42a5-bb51-3e21b47db5ed", "22336125-cac8-4f05-b868-7c51301bbd50", "c3d76d51-7596-424a-9ba9-18a87c2401de"], "metadata": {"page_label": "386", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8ab2bab2-794f-445c-8f1c-71c5c84e29e4": {"node_ids": ["98e062e6-5172-405c-9449-ed6b10239451", "2c16a1bb-6d1a-4ff8-9629-7455fb909680", "1df41d06-85b8-4333-97ce-a3b749c1eb23", "98e062e6-5172-405c-9449-ed6b10239451", "2c16a1bb-6d1a-4ff8-9629-7455fb909680", "1df41d06-85b8-4333-97ce-a3b749c1eb23", "98e062e6-5172-405c-9449-ed6b10239451", "2c16a1bb-6d1a-4ff8-9629-7455fb909680", "1df41d06-85b8-4333-97ce-a3b749c1eb23"], "metadata": {"page_label": "387", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e763a431-4c45-4243-a631-ed84595d35d4": {"node_ids": ["6d80b283-99c2-43d5-9da3-0047109f8bfc", "9236b2b4-db6a-418d-a035-2e047a71caad", "6d80b283-99c2-43d5-9da3-0047109f8bfc", "9236b2b4-db6a-418d-a035-2e047a71caad", "6d80b283-99c2-43d5-9da3-0047109f8bfc", "9236b2b4-db6a-418d-a035-2e047a71caad"], "metadata": {"page_label": "388", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9c961578-7459-42d9-8442-b99bf2746719": {"node_ids": ["7fa3bb7a-19a5-4cc3-a20c-84851cea07dd", "875b4881-10e3-447b-9781-462665b17a91", "7fa3bb7a-19a5-4cc3-a20c-84851cea07dd", "875b4881-10e3-447b-9781-462665b17a91", "7fa3bb7a-19a5-4cc3-a20c-84851cea07dd", "875b4881-10e3-447b-9781-462665b17a91"], "metadata": {"page_label": "389", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7740e11c-ca6e-424e-8d9c-460596e4d962": {"node_ids": ["b2fe2401-8202-4007-aec1-fffce6e9d217", "fc489a2a-8fc0-44bb-aad7-582f37a29dfa", "b2fe2401-8202-4007-aec1-fffce6e9d217", "fc489a2a-8fc0-44bb-aad7-582f37a29dfa", "b2fe2401-8202-4007-aec1-fffce6e9d217", "fc489a2a-8fc0-44bb-aad7-582f37a29dfa"], "metadata": {"page_label": "390", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "028bd9ba-0f31-4648-ab15-95667ca88369": {"node_ids": ["e2ee6ed0-b26c-4b62-a94d-6bcd3d0cfc61", "d8ba0ebd-42aa-46a7-bb7d-fab0a734ccc6", "e2ee6ed0-b26c-4b62-a94d-6bcd3d0cfc61", "d8ba0ebd-42aa-46a7-bb7d-fab0a734ccc6", "e2ee6ed0-b26c-4b62-a94d-6bcd3d0cfc61", "d8ba0ebd-42aa-46a7-bb7d-fab0a734ccc6"], "metadata": {"page_label": "391", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d283bc2a-2aae-46af-9947-d79f37917033": {"node_ids": ["3b36e16d-2823-4163-857e-be9c11b6d61d", "d39c77d6-d716-4b2b-ba16-b26761842279", "3b36e16d-2823-4163-857e-be9c11b6d61d", "d39c77d6-d716-4b2b-ba16-b26761842279", "3b36e16d-2823-4163-857e-be9c11b6d61d", "d39c77d6-d716-4b2b-ba16-b26761842279"], "metadata": {"page_label": "392", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "23964bd6-98c3-4daa-a759-58a6af6cd0ce": {"node_ids": ["1f07b549-1915-415b-8aab-3fccfb9ae59e", "022cc04c-08dd-40c7-aa1c-4514c5cca6e8", "bf2c45db-bb35-422d-827a-f92b35566317", "1f07b549-1915-415b-8aab-3fccfb9ae59e", "022cc04c-08dd-40c7-aa1c-4514c5cca6e8", "bf2c45db-bb35-422d-827a-f92b35566317", "1f07b549-1915-415b-8aab-3fccfb9ae59e", "022cc04c-08dd-40c7-aa1c-4514c5cca6e8", "bf2c45db-bb35-422d-827a-f92b35566317"], "metadata": {"page_label": "393", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9793ce56-41fc-4689-8dca-fce50ad70ab5": {"node_ids": ["0c23416e-ae30-4688-afa3-fda6ddb23e09", "f75857ee-22e6-4b22-a79d-8f80a0ba490d", "442a3b37-55fd-47a6-bc9e-e75918124e9f", "0c23416e-ae30-4688-afa3-fda6ddb23e09", "f75857ee-22e6-4b22-a79d-8f80a0ba490d", "442a3b37-55fd-47a6-bc9e-e75918124e9f", "0c23416e-ae30-4688-afa3-fda6ddb23e09", "f75857ee-22e6-4b22-a79d-8f80a0ba490d", "442a3b37-55fd-47a6-bc9e-e75918124e9f"], "metadata": {"page_label": "394", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "21ffe82c-df0d-4aaa-a237-03ed78ebb398": {"node_ids": ["10446981-7715-4581-9c58-9d5f10656c32", "42d6406f-08ff-4bc3-8916-3c38dd2fc136", "10446981-7715-4581-9c58-9d5f10656c32", "42d6406f-08ff-4bc3-8916-3c38dd2fc136", "10446981-7715-4581-9c58-9d5f10656c32", "42d6406f-08ff-4bc3-8916-3c38dd2fc136"], "metadata": {"page_label": "395", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "459d999d-7177-4ebf-802b-4cc4ccc2ce49": {"node_ids": ["e2300ea6-c926-4dad-b42c-d43221cfbe76", "a166e3c1-9ebc-494a-93d5-cdb67fad0f92", "e2300ea6-c926-4dad-b42c-d43221cfbe76", "a166e3c1-9ebc-494a-93d5-cdb67fad0f92", "e2300ea6-c926-4dad-b42c-d43221cfbe76", "a166e3c1-9ebc-494a-93d5-cdb67fad0f92"], "metadata": {"page_label": "396", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bc16a687-6c9e-4f66-9194-286eeefa4fcc": {"node_ids": ["5dd6ccf6-bab8-4700-b78e-505e5eb656b0", "f329a71c-ca45-4ec2-91db-63079e33ec5e", "5dd6ccf6-bab8-4700-b78e-505e5eb656b0", "f329a71c-ca45-4ec2-91db-63079e33ec5e", "5dd6ccf6-bab8-4700-b78e-505e5eb656b0", "f329a71c-ca45-4ec2-91db-63079e33ec5e"], "metadata": {"page_label": "397", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3056a80d-c271-43fb-804d-8d5552bd4c21": {"node_ids": ["93396b37-9a2f-4a6d-bb09-c8dbaa22042a", "aa25fe5d-5214-46eb-86f8-180bab29671c", "93396b37-9a2f-4a6d-bb09-c8dbaa22042a", "aa25fe5d-5214-46eb-86f8-180bab29671c", "93396b37-9a2f-4a6d-bb09-c8dbaa22042a", "aa25fe5d-5214-46eb-86f8-180bab29671c"], "metadata": {"page_label": "398", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "99654b0e-1227-4397-b5f6-0115d42111d6": {"node_ids": ["a3c8c6f8-ad37-4671-b6ff-e768df124503", "36957aa3-39da-46a2-ada9-495e1c9e200d", "581e61cb-ce6d-45e7-b18e-2c91986aa04f", "a3c8c6f8-ad37-4671-b6ff-e768df124503", "36957aa3-39da-46a2-ada9-495e1c9e200d", "581e61cb-ce6d-45e7-b18e-2c91986aa04f", "a3c8c6f8-ad37-4671-b6ff-e768df124503", "36957aa3-39da-46a2-ada9-495e1c9e200d", "581e61cb-ce6d-45e7-b18e-2c91986aa04f"], "metadata": {"page_label": "399", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e275ccf1-1505-4c57-811f-366b460d12df": {"node_ids": ["1e766be0-80d5-496d-bf71-cde443af6211", "a90a5b27-a4d8-4607-ad33-7797848116cf", "1e766be0-80d5-496d-bf71-cde443af6211", "a90a5b27-a4d8-4607-ad33-7797848116cf", "1e766be0-80d5-496d-bf71-cde443af6211", "a90a5b27-a4d8-4607-ad33-7797848116cf"], "metadata": {"page_label": "400", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "34ba7415-d15f-442f-a6b0-4dab14e18ba6": {"node_ids": ["6849990d-27d9-45d5-996f-645854487eb0", "e7533d64-c5a3-4d86-b883-908fa045d964", "6849990d-27d9-45d5-996f-645854487eb0", "e7533d64-c5a3-4d86-b883-908fa045d964", "6849990d-27d9-45d5-996f-645854487eb0", "e7533d64-c5a3-4d86-b883-908fa045d964"], "metadata": {"page_label": "401", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d38b635f-a2d7-4015-aa8c-3557648c55ab": {"node_ids": ["d51cd763-d745-493c-9af3-05fb4ab6c1e1", "ae4b4816-65bc-4759-be2b-f9a4738694a5", "d51cd763-d745-493c-9af3-05fb4ab6c1e1", "ae4b4816-65bc-4759-be2b-f9a4738694a5", "d51cd763-d745-493c-9af3-05fb4ab6c1e1", "ae4b4816-65bc-4759-be2b-f9a4738694a5"], "metadata": {"page_label": "402", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3051b853-f6b0-4484-8001-ad7309298951": {"node_ids": ["c970f7e2-74ae-44b2-841a-1c9923b8b20b", "e2bfe371-8cad-4c88-a11a-a7944fbe4eaa", "c970f7e2-74ae-44b2-841a-1c9923b8b20b", "e2bfe371-8cad-4c88-a11a-a7944fbe4eaa", "c970f7e2-74ae-44b2-841a-1c9923b8b20b", "e2bfe371-8cad-4c88-a11a-a7944fbe4eaa"], "metadata": {"page_label": "403", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "040a53fd-ccb9-4b81-9599-fb4d43c1f1ad": {"node_ids": ["c1685c77-0791-476d-8f4f-99ae01b8a3f8", "bbff54d8-d23b-41b7-9044-375049a593f5", "c1685c77-0791-476d-8f4f-99ae01b8a3f8", "bbff54d8-d23b-41b7-9044-375049a593f5", "c1685c77-0791-476d-8f4f-99ae01b8a3f8", "bbff54d8-d23b-41b7-9044-375049a593f5"], "metadata": {"page_label": "404", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "544e3366-4ef5-4ab6-8de9-5b98ea46d522": {"node_ids": ["a135e1ef-2ceb-4179-a4b4-fa98fba6e104", "32e6c6aa-80de-4d95-a871-da0b37a21d1e", "a135e1ef-2ceb-4179-a4b4-fa98fba6e104", "32e6c6aa-80de-4d95-a871-da0b37a21d1e", "a135e1ef-2ceb-4179-a4b4-fa98fba6e104", "32e6c6aa-80de-4d95-a871-da0b37a21d1e"], "metadata": {"page_label": "405", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5d514026-f152-4b70-a49f-66cda4af0f27": {"node_ids": ["a2964688-c523-497d-abf6-7686e14d4eeb", "1ca39d2b-1856-4fbd-9ce0-4f5fb6733e69", "551b99f4-0926-4476-a331-20d0a3014f96", "a2964688-c523-497d-abf6-7686e14d4eeb", "1ca39d2b-1856-4fbd-9ce0-4f5fb6733e69", "551b99f4-0926-4476-a331-20d0a3014f96", "a2964688-c523-497d-abf6-7686e14d4eeb", "1ca39d2b-1856-4fbd-9ce0-4f5fb6733e69", "551b99f4-0926-4476-a331-20d0a3014f96"], "metadata": {"page_label": "406", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e650d844-414d-4f8f-aa1e-70cf34d6d048": {"node_ids": ["e3b27242-39bc-4869-bf8a-9b557a241abc", "769a2906-02a7-4d8b-b0a0-ef191e0d83f9", "e3b27242-39bc-4869-bf8a-9b557a241abc", "769a2906-02a7-4d8b-b0a0-ef191e0d83f9", "e3b27242-39bc-4869-bf8a-9b557a241abc", "769a2906-02a7-4d8b-b0a0-ef191e0d83f9"], "metadata": {"page_label": "407", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "77594511-d23f-440b-89b4-0ae1da545e05": {"node_ids": ["43f1bcef-ac11-472a-ad3e-b5d1e15c7951", "5cf46334-19dc-4cf6-81d6-9991ca244fa0", "43f1bcef-ac11-472a-ad3e-b5d1e15c7951", "5cf46334-19dc-4cf6-81d6-9991ca244fa0", "43f1bcef-ac11-472a-ad3e-b5d1e15c7951", "5cf46334-19dc-4cf6-81d6-9991ca244fa0"], "metadata": {"page_label": "408", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "81cf952d-df94-4a31-b40a-5d6168dd268d": {"node_ids": ["d428b0ce-8ebd-48b3-9581-8666291316aa", "d0403fc9-d183-4966-97c8-c0970c1a5e4b", "d428b0ce-8ebd-48b3-9581-8666291316aa", "d0403fc9-d183-4966-97c8-c0970c1a5e4b", "d428b0ce-8ebd-48b3-9581-8666291316aa", "d0403fc9-d183-4966-97c8-c0970c1a5e4b"], "metadata": {"page_label": "409", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e5f14dca-ec26-4fbf-a6ca-dc57c95ddf14": {"node_ids": ["13d70202-9dc9-4f42-827d-dd1d9b7e54c3", "6c170b46-2299-4e7d-b615-274e2bba5b00", "8bb3eacb-95f4-4234-879a-1ea058fbaed3", "13d70202-9dc9-4f42-827d-dd1d9b7e54c3", "6c170b46-2299-4e7d-b615-274e2bba5b00", "8bb3eacb-95f4-4234-879a-1ea058fbaed3", "13d70202-9dc9-4f42-827d-dd1d9b7e54c3", "6c170b46-2299-4e7d-b615-274e2bba5b00", "8bb3eacb-95f4-4234-879a-1ea058fbaed3"], "metadata": {"page_label": "410", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0f37a124-1cd5-474c-a1b7-aa2fb1c84bfd": {"node_ids": ["fd88ea8f-70e9-4371-9b41-c4063edf4ac5", "fd2053ae-96fa-46b0-896b-42224cb46063", "e80cabce-fa55-42cf-8b2b-f432c2088172", "fd88ea8f-70e9-4371-9b41-c4063edf4ac5", "fd2053ae-96fa-46b0-896b-42224cb46063", "e80cabce-fa55-42cf-8b2b-f432c2088172", "fd88ea8f-70e9-4371-9b41-c4063edf4ac5", "fd2053ae-96fa-46b0-896b-42224cb46063", "e80cabce-fa55-42cf-8b2b-f432c2088172"], "metadata": {"page_label": "411", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e3a78cca-7e3b-46e9-8bc4-d1e549e98389": {"node_ids": ["02c9c37a-a7de-49e4-8fdd-3991662ce8ff", "136cec3d-5ef7-48ae-b550-128f4f7e26f8", "f0ce8a9d-0847-41bc-b857-4498dbc0a601", "02c9c37a-a7de-49e4-8fdd-3991662ce8ff", "136cec3d-5ef7-48ae-b550-128f4f7e26f8", "f0ce8a9d-0847-41bc-b857-4498dbc0a601", "02c9c37a-a7de-49e4-8fdd-3991662ce8ff", "136cec3d-5ef7-48ae-b550-128f4f7e26f8", "f0ce8a9d-0847-41bc-b857-4498dbc0a601"], "metadata": {"page_label": "412", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ee455c59-34dc-472c-88a3-efdfd8de10c7": {"node_ids": ["07c9f9ad-bc8e-47c0-8e80-4e152d7ef48f", "3865516f-794c-4679-b4a3-6ee814305867", "48343d4b-9113-4132-9559-eaea883d4e14", "07c9f9ad-bc8e-47c0-8e80-4e152d7ef48f", "3865516f-794c-4679-b4a3-6ee814305867", "48343d4b-9113-4132-9559-eaea883d4e14", "07c9f9ad-bc8e-47c0-8e80-4e152d7ef48f", "3865516f-794c-4679-b4a3-6ee814305867", "48343d4b-9113-4132-9559-eaea883d4e14"], "metadata": {"page_label": "413", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "18bb695d-d5b3-4dd6-8e2c-808da289330f": {"node_ids": ["4226a34f-efbd-435e-a006-486a26c4b6bc", "675b56e7-c395-4a6a-b690-2a98c6883a14", "4226a34f-efbd-435e-a006-486a26c4b6bc", "675b56e7-c395-4a6a-b690-2a98c6883a14", "4226a34f-efbd-435e-a006-486a26c4b6bc", "675b56e7-c395-4a6a-b690-2a98c6883a14"], "metadata": {"page_label": "414", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "dbabfb56-d12d-4403-b909-458c4da9bc1d": {"node_ids": ["bcdad38a-6280-44d5-9bc5-f281f59774e7", "69503932-2784-471b-90f2-6a0eb8d89f66", "bcdad38a-6280-44d5-9bc5-f281f59774e7", "69503932-2784-471b-90f2-6a0eb8d89f66", "bcdad38a-6280-44d5-9bc5-f281f59774e7", "69503932-2784-471b-90f2-6a0eb8d89f66"], "metadata": {"page_label": "415", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d1595cf5-5fd4-4b2b-b5a2-e7dedadf0bb3": {"node_ids": ["a0ba89dd-dd77-4988-a722-ddf1ae55b762", "887cfd2a-06d0-4a8a-a1e5-75e4daf663c0", "de856f56-1525-4475-a70a-38243bb2a706", "a0ba89dd-dd77-4988-a722-ddf1ae55b762", "887cfd2a-06d0-4a8a-a1e5-75e4daf663c0", "de856f56-1525-4475-a70a-38243bb2a706", "a0ba89dd-dd77-4988-a722-ddf1ae55b762", "887cfd2a-06d0-4a8a-a1e5-75e4daf663c0", "de856f56-1525-4475-a70a-38243bb2a706"], "metadata": {"page_label": "416", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3a68ba85-c614-462b-9571-13368b753e80": {"node_ids": ["9ecec95d-7020-4297-9347-787ca53687f2", "9ecec95d-7020-4297-9347-787ca53687f2", "9ecec95d-7020-4297-9347-787ca53687f2"], "metadata": {"page_label": "417", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5e64e9b6-14bf-4927-9bd5-388f8567ec4a": {"node_ids": ["6d54efd7-4848-42f4-b435-0988359afcec", "b137ff51-1eaf-4859-a20b-6b425c584d75", "15958383-3ff9-49aa-aeb0-8d715c07117b", "6d54efd7-4848-42f4-b435-0988359afcec", "b137ff51-1eaf-4859-a20b-6b425c584d75", "15958383-3ff9-49aa-aeb0-8d715c07117b", "6d54efd7-4848-42f4-b435-0988359afcec", "b137ff51-1eaf-4859-a20b-6b425c584d75", "15958383-3ff9-49aa-aeb0-8d715c07117b"], "metadata": {"page_label": "418", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "10d93c43-49d6-4722-bdad-b82c3ed8f929": {"node_ids": ["6bca0e1e-a140-4b2a-9515-66f6157cb895", "6f83af4c-b1d9-4de2-860f-e7c656925840", "6b23c76a-e936-4db4-b769-09f2ff121d1c", "6bca0e1e-a140-4b2a-9515-66f6157cb895", "6f83af4c-b1d9-4de2-860f-e7c656925840", "6b23c76a-e936-4db4-b769-09f2ff121d1c", "6bca0e1e-a140-4b2a-9515-66f6157cb895", "6f83af4c-b1d9-4de2-860f-e7c656925840", "6b23c76a-e936-4db4-b769-09f2ff121d1c"], "metadata": {"page_label": "419", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3bb5c1b9-69f0-400d-96d9-ed370ec80a0c": {"node_ids": ["617b1410-4657-4ad8-a9c1-bfb94c259f01", "b5cfe58e-6c13-412a-8f41-62087256a43c", "5f84b6da-6208-4650-b7f5-bb7dfeef5a01", "617b1410-4657-4ad8-a9c1-bfb94c259f01", "b5cfe58e-6c13-412a-8f41-62087256a43c", "5f84b6da-6208-4650-b7f5-bb7dfeef5a01", "617b1410-4657-4ad8-a9c1-bfb94c259f01", "b5cfe58e-6c13-412a-8f41-62087256a43c", "5f84b6da-6208-4650-b7f5-bb7dfeef5a01"], "metadata": {"page_label": "420", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8a7dba6b-db6f-469a-873d-664d4db22805": {"node_ids": ["8e243cb8-c9c7-4081-bc81-3b196ea0c344", "5a5d641d-b3ca-4b7f-bcaa-b6b88e212115", "1609c0d6-6496-4a84-a9e4-e435886c0f26", "8e243cb8-c9c7-4081-bc81-3b196ea0c344", "5a5d641d-b3ca-4b7f-bcaa-b6b88e212115", "1609c0d6-6496-4a84-a9e4-e435886c0f26", "8e243cb8-c9c7-4081-bc81-3b196ea0c344", "5a5d641d-b3ca-4b7f-bcaa-b6b88e212115", "1609c0d6-6496-4a84-a9e4-e435886c0f26"], "metadata": {"page_label": "421", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9b640bb3-9609-4196-926b-75c54e7d9973": {"node_ids": ["81852fad-7813-45c0-894e-d5c64e01aa5d", "5c245962-bd49-4809-81e9-2ead60fe7d17", "81852fad-7813-45c0-894e-d5c64e01aa5d", "5c245962-bd49-4809-81e9-2ead60fe7d17", "81852fad-7813-45c0-894e-d5c64e01aa5d", "5c245962-bd49-4809-81e9-2ead60fe7d17"], "metadata": {"page_label": "422", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5bd0fbc9-b3ac-43bb-9669-150414168aaa": {"node_ids": ["0f1bab4d-9416-440a-9ac3-c29f02aefb41", "331c640d-7aa1-4e31-bf87-d54380542dc2", "0f1bab4d-9416-440a-9ac3-c29f02aefb41", "331c640d-7aa1-4e31-bf87-d54380542dc2", "0f1bab4d-9416-440a-9ac3-c29f02aefb41", "331c640d-7aa1-4e31-bf87-d54380542dc2"], "metadata": {"page_label": "423", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7d0dd8eb-6503-43bb-a5c3-6c5f9e718220": {"node_ids": ["f0fde337-cd5e-4257-abce-64cb2b460067", "d5268398-a667-455d-9943-d5d44b918b18", "f0fde337-cd5e-4257-abce-64cb2b460067", "d5268398-a667-455d-9943-d5d44b918b18", "f0fde337-cd5e-4257-abce-64cb2b460067", "d5268398-a667-455d-9943-d5d44b918b18"], "metadata": {"page_label": "424", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0b6426d3-a63f-4105-9992-493ee8871ee7": {"node_ids": ["95df82f6-f7bf-42d7-a7b5-b54a68cfdfec", "9d491806-a9b1-4e3b-b19f-8940c2b5d820", "95df82f6-f7bf-42d7-a7b5-b54a68cfdfec", "9d491806-a9b1-4e3b-b19f-8940c2b5d820", "95df82f6-f7bf-42d7-a7b5-b54a68cfdfec", "9d491806-a9b1-4e3b-b19f-8940c2b5d820"], "metadata": {"page_label": "425", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a4f0c629-c4a3-4f39-93c8-bb69973fae60": {"node_ids": ["6564894f-de5c-49d2-97aa-697429b775bd", "e6848ed3-eab3-40bd-915b-f26ada7b52cc", "6564894f-de5c-49d2-97aa-697429b775bd", "e6848ed3-eab3-40bd-915b-f26ada7b52cc", "6564894f-de5c-49d2-97aa-697429b775bd", "e6848ed3-eab3-40bd-915b-f26ada7b52cc"], "metadata": {"page_label": "426", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3d39e92f-9ad8-48e2-a334-f19a5608ef50": {"node_ids": ["22e3b19b-05a9-4daf-9c76-55625727846e", "963b3814-45b7-4bdc-903d-1032614872a4", "ce1b6e13-d127-4b8e-a6ee-5f24c54efe3f", "22e3b19b-05a9-4daf-9c76-55625727846e", "963b3814-45b7-4bdc-903d-1032614872a4", "ce1b6e13-d127-4b8e-a6ee-5f24c54efe3f", "22e3b19b-05a9-4daf-9c76-55625727846e", "963b3814-45b7-4bdc-903d-1032614872a4", "ce1b6e13-d127-4b8e-a6ee-5f24c54efe3f"], "metadata": {"page_label": "427", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8d4373a2-f564-435b-88f9-e88d1b9f68bf": {"node_ids": ["30bc525e-55b3-445d-8f81-0f91eb0c3408", "1cae5436-6306-48bc-819f-17e946256121", "30bc525e-55b3-445d-8f81-0f91eb0c3408", "1cae5436-6306-48bc-819f-17e946256121", "30bc525e-55b3-445d-8f81-0f91eb0c3408", "1cae5436-6306-48bc-819f-17e946256121"], "metadata": {"page_label": "428", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "80ab4d67-a0bf-49e3-9574-67e6bf5921df": {"node_ids": ["91dd174e-7c11-438b-86b4-ea666cedc7bb", "a403ee8d-2a0a-44ea-ad33-c4ae270ba46b", "81fc9d5f-eb9e-4436-9741-d1428a71e4eb", "91dd174e-7c11-438b-86b4-ea666cedc7bb", "a403ee8d-2a0a-44ea-ad33-c4ae270ba46b", "81fc9d5f-eb9e-4436-9741-d1428a71e4eb", "91dd174e-7c11-438b-86b4-ea666cedc7bb", "a403ee8d-2a0a-44ea-ad33-c4ae270ba46b", "81fc9d5f-eb9e-4436-9741-d1428a71e4eb"], "metadata": {"page_label": "429", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fde39d50-f267-459e-9439-1deed63cd890": {"node_ids": ["3d0932a0-96f3-492c-809e-f708f224120f", "3d0932a0-96f3-492c-809e-f708f224120f", "3d0932a0-96f3-492c-809e-f708f224120f"], "metadata": {"page_label": "430", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c721cb69-d1e4-48d5-ae01-1d121671dd89": {"node_ids": ["d4c9dc79-f587-4af8-a4b4-b5651652be89", "50e21c4d-6bd0-47ed-b307-bf7455a14863", "d4c9dc79-f587-4af8-a4b4-b5651652be89", "50e21c4d-6bd0-47ed-b307-bf7455a14863", "d4c9dc79-f587-4af8-a4b4-b5651652be89", "50e21c4d-6bd0-47ed-b307-bf7455a14863"], "metadata": {"page_label": "431", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b08c4506-d2c5-4f4c-957a-55d28660b9f5": {"node_ids": ["6e061338-7bba-40bb-b9eb-56e63dadbad1", "614157a1-f7f1-4575-9470-f30c43733680", "32b3de1f-95ad-47c7-8973-fd4b8ffaf6d3", "6e061338-7bba-40bb-b9eb-56e63dadbad1", "614157a1-f7f1-4575-9470-f30c43733680", "32b3de1f-95ad-47c7-8973-fd4b8ffaf6d3", "6e061338-7bba-40bb-b9eb-56e63dadbad1", "614157a1-f7f1-4575-9470-f30c43733680", "32b3de1f-95ad-47c7-8973-fd4b8ffaf6d3"], "metadata": {"page_label": "432", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "94eb0f05-74ce-4633-bc7d-555b62a25fdd": {"node_ids": ["ac10f0df-8b89-4598-818c-99f758f6683d", "f231a0b9-00bf-4a16-bb3a-3d43f09778dd", "fc403662-c0a8-4843-b2c1-ed251cb99157", "ac10f0df-8b89-4598-818c-99f758f6683d", "f231a0b9-00bf-4a16-bb3a-3d43f09778dd", "fc403662-c0a8-4843-b2c1-ed251cb99157", "ac10f0df-8b89-4598-818c-99f758f6683d", "f231a0b9-00bf-4a16-bb3a-3d43f09778dd", "fc403662-c0a8-4843-b2c1-ed251cb99157"], "metadata": {"page_label": "433", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "70d91e22-2a1d-4d6b-8b9b-89bd66b57320": {"node_ids": ["55a067c0-f5da-4144-8ebe-53f5416917d4", "913a253c-ecd3-408d-8e36-be3ee8b6d7db", "55a067c0-f5da-4144-8ebe-53f5416917d4", "913a253c-ecd3-408d-8e36-be3ee8b6d7db", "55a067c0-f5da-4144-8ebe-53f5416917d4", "913a253c-ecd3-408d-8e36-be3ee8b6d7db"], "metadata": {"page_label": "434", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4cca624c-4b7f-4dd6-a411-aa6c86e724a7": {"node_ids": ["f92a79d5-3013-4d64-906d-327f87223ea6", "dc9094a5-53f0-4925-8d93-13388b06df39", "f92a79d5-3013-4d64-906d-327f87223ea6", "dc9094a5-53f0-4925-8d93-13388b06df39", "f92a79d5-3013-4d64-906d-327f87223ea6", "dc9094a5-53f0-4925-8d93-13388b06df39"], "metadata": {"page_label": "435", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3ce50f95-9cc9-43a9-a00a-a8608ae5b687": {"node_ids": ["eac69758-e61c-4ac2-aff6-a63239bd31a4", "62ee83b0-a634-4eb8-a607-2e3671abad21", "56fb8b77-5304-4f54-bf73-554e8ca81b9e", "eac69758-e61c-4ac2-aff6-a63239bd31a4", "62ee83b0-a634-4eb8-a607-2e3671abad21", "56fb8b77-5304-4f54-bf73-554e8ca81b9e", "eac69758-e61c-4ac2-aff6-a63239bd31a4", "62ee83b0-a634-4eb8-a607-2e3671abad21", "56fb8b77-5304-4f54-bf73-554e8ca81b9e"], "metadata": {"page_label": "436", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "442fa97b-11ef-445c-9fe7-9abf8218cbd3": {"node_ids": ["ec4215cf-706c-452d-b9d7-6daa4f4ca5c2", "a2b98e81-c227-4d70-a51d-13be4ddd8cb5", "350a4ddb-72ea-480e-8178-f4a57e8f1293", "ec4215cf-706c-452d-b9d7-6daa4f4ca5c2", "a2b98e81-c227-4d70-a51d-13be4ddd8cb5", "350a4ddb-72ea-480e-8178-f4a57e8f1293", "ec4215cf-706c-452d-b9d7-6daa4f4ca5c2", "a2b98e81-c227-4d70-a51d-13be4ddd8cb5", "350a4ddb-72ea-480e-8178-f4a57e8f1293"], "metadata": {"page_label": "437", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "604a33e6-286b-4d31-99b4-65feefa34286": {"node_ids": ["7a3e3666-65fd-4cb3-a369-06299f527e81", "3b45257c-29ab-43d4-ab55-39176d02d2ab", "7a3e3666-65fd-4cb3-a369-06299f527e81", "3b45257c-29ab-43d4-ab55-39176d02d2ab", "7a3e3666-65fd-4cb3-a369-06299f527e81", "3b45257c-29ab-43d4-ab55-39176d02d2ab"], "metadata": {"page_label": "438", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "eaf61b3e-9b8e-499a-a3cf-2b6d8a187ccb": {"node_ids": ["8921c41e-9f51-46db-b8c0-19bb64d113bd", "18263f17-13ca-4dcd-b2fd-c9a1dc7c0b0d", "8921c41e-9f51-46db-b8c0-19bb64d113bd", "18263f17-13ca-4dcd-b2fd-c9a1dc7c0b0d", "8921c41e-9f51-46db-b8c0-19bb64d113bd", "18263f17-13ca-4dcd-b2fd-c9a1dc7c0b0d"], "metadata": {"page_label": "439", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d49edcd6-ca1c-4342-84b3-94a78c2e1297": {"node_ids": ["2f6aa599-1480-4568-8b07-467fc7887b2d", "501917eb-3284-4ed2-906d-c542c38b38bc", "2f6aa599-1480-4568-8b07-467fc7887b2d", "501917eb-3284-4ed2-906d-c542c38b38bc", "2f6aa599-1480-4568-8b07-467fc7887b2d", "501917eb-3284-4ed2-906d-c542c38b38bc"], "metadata": {"page_label": "440", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a3200552-b3b7-4610-87c5-0179aca80007": {"node_ids": ["c29ece5c-f913-4967-9239-56fa29febe2c", "1d6670dc-a646-47ae-a604-a93d9f62a716", "c29ece5c-f913-4967-9239-56fa29febe2c", "1d6670dc-a646-47ae-a604-a93d9f62a716", "c29ece5c-f913-4967-9239-56fa29febe2c", "1d6670dc-a646-47ae-a604-a93d9f62a716"], "metadata": {"page_label": "441", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6570956f-6008-4b2c-9836-9db29840a48d": {"node_ids": ["12334442-18e6-432d-b1b2-9022f0ba0dfa", "d74f85bf-b60b-446f-b2ef-ca1cb6b1a30a", "12334442-18e6-432d-b1b2-9022f0ba0dfa", "d74f85bf-b60b-446f-b2ef-ca1cb6b1a30a", "12334442-18e6-432d-b1b2-9022f0ba0dfa", "d74f85bf-b60b-446f-b2ef-ca1cb6b1a30a"], "metadata": {"page_label": "442", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7478c90f-6ce5-456c-ab05-cd2ba27596af": {"node_ids": ["82e1819e-3ada-4883-8853-022aabfaa75f", "ff80669c-5298-4860-97b2-82303f9f4487", "82e1819e-3ada-4883-8853-022aabfaa75f", "ff80669c-5298-4860-97b2-82303f9f4487", "82e1819e-3ada-4883-8853-022aabfaa75f", "ff80669c-5298-4860-97b2-82303f9f4487"], "metadata": {"page_label": "443", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2233b4f0-bbd0-463f-a462-1560b270a0b9": {"node_ids": ["992e714f-e521-4509-8a00-dacf00a91c33", "9f07bd86-791c-4d0b-99f6-1c7d2ea23b4a", "992e714f-e521-4509-8a00-dacf00a91c33", "9f07bd86-791c-4d0b-99f6-1c7d2ea23b4a", "992e714f-e521-4509-8a00-dacf00a91c33", "9f07bd86-791c-4d0b-99f6-1c7d2ea23b4a"], "metadata": {"page_label": "444", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "260b477b-054b-434e-990c-fa1046bfe017": {"node_ids": ["87da8920-04a8-4ba1-aaf8-9b33e3d5f494", "ddee49c9-73ff-47bd-b923-47cd8b169032", "87da8920-04a8-4ba1-aaf8-9b33e3d5f494", "ddee49c9-73ff-47bd-b923-47cd8b169032", "87da8920-04a8-4ba1-aaf8-9b33e3d5f494", "ddee49c9-73ff-47bd-b923-47cd8b169032"], "metadata": {"page_label": "445", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fff825a5-980f-4a33-9ec5-45034f496869": {"node_ids": ["400939b7-957f-4407-9ffb-2677e117a11e", "cc302f03-5698-4418-9f8b-d4c4f36f6d9f", "6d57d4b0-be94-4983-92f2-c426018027fc", "400939b7-957f-4407-9ffb-2677e117a11e", "cc302f03-5698-4418-9f8b-d4c4f36f6d9f", "6d57d4b0-be94-4983-92f2-c426018027fc", "400939b7-957f-4407-9ffb-2677e117a11e", "cc302f03-5698-4418-9f8b-d4c4f36f6d9f", "6d57d4b0-be94-4983-92f2-c426018027fc"], "metadata": {"page_label": "446", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "30581b13-5955-4c1c-9b76-227c358212a8": {"node_ids": ["dfed8f9d-c594-4b62-91ec-c00b65a13f11", "68f95947-7920-4bdd-8a8b-70dd97c46727", "dfed8f9d-c594-4b62-91ec-c00b65a13f11", "68f95947-7920-4bdd-8a8b-70dd97c46727", "dfed8f9d-c594-4b62-91ec-c00b65a13f11", "68f95947-7920-4bdd-8a8b-70dd97c46727"], "metadata": {"page_label": "447", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "64009123-9510-48c2-8b17-fc140eccdcb1": {"node_ids": ["eac2feb1-0ddf-4e04-998c-9a381846734c", "f38c5afb-61d2-47eb-9ddb-d022b4beee0c", "eac2feb1-0ddf-4e04-998c-9a381846734c", "f38c5afb-61d2-47eb-9ddb-d022b4beee0c", "eac2feb1-0ddf-4e04-998c-9a381846734c", "f38c5afb-61d2-47eb-9ddb-d022b4beee0c"], "metadata": {"page_label": "448", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8d9a0294-31f5-49c5-a0dd-c28c6bf3decc": {"node_ids": ["7921d4ee-9614-4b40-a6c9-a5216c534ade", "8c00e6bd-4b8b-4c24-9f58-b333eab0c412", "7921d4ee-9614-4b40-a6c9-a5216c534ade", "8c00e6bd-4b8b-4c24-9f58-b333eab0c412", "7921d4ee-9614-4b40-a6c9-a5216c534ade", "8c00e6bd-4b8b-4c24-9f58-b333eab0c412"], "metadata": {"page_label": "449", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2926298c-ec4f-453b-9824-e36cb8bd97c9": {"node_ids": ["d899a16b-0fc6-4d30-988d-7d9cc3d9c5b9", "33ed7693-2f69-4c8d-a5b0-97027e9a1123", "d899a16b-0fc6-4d30-988d-7d9cc3d9c5b9", "33ed7693-2f69-4c8d-a5b0-97027e9a1123", "d899a16b-0fc6-4d30-988d-7d9cc3d9c5b9", "33ed7693-2f69-4c8d-a5b0-97027e9a1123"], "metadata": {"page_label": "450", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "73c223ef-4a3b-48ce-a7a8-1d74ddb38fe2": {"node_ids": ["a381370e-26fc-4243-a959-a2564dabbf6d", "37a81382-4c25-49bc-a08e-ac445af7e11b", "a381370e-26fc-4243-a959-a2564dabbf6d", "37a81382-4c25-49bc-a08e-ac445af7e11b", "a381370e-26fc-4243-a959-a2564dabbf6d", "37a81382-4c25-49bc-a08e-ac445af7e11b"], "metadata": {"page_label": "451", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e130cb5f-021e-4944-bde3-bdb43f2b5c97": {"node_ids": ["be2204da-aa24-47c6-a1bf-981bc81dbeac", "005f1136-a4d1-4f71-90bf-76e37b68fbd4", "56c0e92e-a489-4f84-8969-950c69a39d62", "be2204da-aa24-47c6-a1bf-981bc81dbeac", "005f1136-a4d1-4f71-90bf-76e37b68fbd4", "56c0e92e-a489-4f84-8969-950c69a39d62", "be2204da-aa24-47c6-a1bf-981bc81dbeac", "005f1136-a4d1-4f71-90bf-76e37b68fbd4", "56c0e92e-a489-4f84-8969-950c69a39d62"], "metadata": {"page_label": "452", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c350c827-c430-45af-859a-903d2cb39e48": {"node_ids": ["08792c8f-b935-4cda-8690-67891a48eb98", "6822f32b-1581-4212-92c9-4cf2755192d6", "59d23f56-810b-473b-8df8-106595807acb", "08792c8f-b935-4cda-8690-67891a48eb98", "6822f32b-1581-4212-92c9-4cf2755192d6", "59d23f56-810b-473b-8df8-106595807acb", "08792c8f-b935-4cda-8690-67891a48eb98", "6822f32b-1581-4212-92c9-4cf2755192d6", "59d23f56-810b-473b-8df8-106595807acb"], "metadata": {"page_label": "453", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8573aeb4-ff29-40e7-9cad-8d5fa6308758": {"node_ids": ["1aab28b8-c555-4611-95f7-262f3e7b4f10", "ae9c2a81-ac97-4d2b-8cc4-b9d36d2172ec", "1aab28b8-c555-4611-95f7-262f3e7b4f10", "ae9c2a81-ac97-4d2b-8cc4-b9d36d2172ec", "1aab28b8-c555-4611-95f7-262f3e7b4f10", "ae9c2a81-ac97-4d2b-8cc4-b9d36d2172ec"], "metadata": {"page_label": "454", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bea488a7-f4d3-493f-9046-b7d7b05c3dbe": {"node_ids": ["c121baed-ac42-4758-8b81-52a9a8da64b5", "c121baed-ac42-4758-8b81-52a9a8da64b5", "c121baed-ac42-4758-8b81-52a9a8da64b5"], "metadata": {"page_label": "455", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3f3ac97b-c944-478d-a1d9-38e8666f5b90": {"node_ids": ["ad8eeea8-b267-4270-a1b0-32781c8c05d8", "b26fdb4f-d9e5-4e46-8354-429d189b3f99", "ad8eeea8-b267-4270-a1b0-32781c8c05d8", "b26fdb4f-d9e5-4e46-8354-429d189b3f99", "ad8eeea8-b267-4270-a1b0-32781c8c05d8", "b26fdb4f-d9e5-4e46-8354-429d189b3f99"], "metadata": {"page_label": "456", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "98224aec-f657-4911-9593-9ed0f0716a54": {"node_ids": ["ffd3c5cf-1124-4a00-81ff-d9e8204a2495", "88461808-8e4b-4342-8c32-4565c01bbb43", "bfb24b01-8b56-476d-a156-bb0982ff00cf", "ffd3c5cf-1124-4a00-81ff-d9e8204a2495", "88461808-8e4b-4342-8c32-4565c01bbb43", "bfb24b01-8b56-476d-a156-bb0982ff00cf", "ffd3c5cf-1124-4a00-81ff-d9e8204a2495", "88461808-8e4b-4342-8c32-4565c01bbb43", "bfb24b01-8b56-476d-a156-bb0982ff00cf"], "metadata": {"page_label": "457", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "22200d52-b191-4236-bc55-72dcb50e180a": {"node_ids": ["387d6fd1-d69f-4289-961b-6abbdc049b56", "3c9eaea3-1dff-46f3-90b4-d7959039393a", "387d6fd1-d69f-4289-961b-6abbdc049b56", "3c9eaea3-1dff-46f3-90b4-d7959039393a", "387d6fd1-d69f-4289-961b-6abbdc049b56", "3c9eaea3-1dff-46f3-90b4-d7959039393a"], "metadata": {"page_label": "458", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0cf980e4-13da-4048-9a2c-e2821df2bada": {"node_ids": ["a4ed3ab9-c675-4068-b345-befe90d1f5ba", "839aef15-9423-4a70-afe0-d0d9759ee11f", "a4ed3ab9-c675-4068-b345-befe90d1f5ba", "839aef15-9423-4a70-afe0-d0d9759ee11f", "a4ed3ab9-c675-4068-b345-befe90d1f5ba", "839aef15-9423-4a70-afe0-d0d9759ee11f"], "metadata": {"page_label": "459", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "21c50316-5573-46ab-b10d-65561c9917ba": {"node_ids": ["b497a5ec-1d17-460a-9c46-296d5bc97082", "278108c2-78f4-4c03-88a3-0af07e5b672a", "5f98baf9-1e1e-42d8-8711-a7bc3b591cae", "b497a5ec-1d17-460a-9c46-296d5bc97082", "278108c2-78f4-4c03-88a3-0af07e5b672a", "5f98baf9-1e1e-42d8-8711-a7bc3b591cae", "b497a5ec-1d17-460a-9c46-296d5bc97082", "278108c2-78f4-4c03-88a3-0af07e5b672a", "5f98baf9-1e1e-42d8-8711-a7bc3b591cae"], "metadata": {"page_label": "460", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3ac7325f-441a-47a3-86da-d059b679d783": {"node_ids": ["cfac263d-925f-4c5a-92f5-4823f3b6a05b", "788d36f0-07aa-451d-bc71-a1455fd80617", "cfac263d-925f-4c5a-92f5-4823f3b6a05b", "788d36f0-07aa-451d-bc71-a1455fd80617", "cfac263d-925f-4c5a-92f5-4823f3b6a05b", "788d36f0-07aa-451d-bc71-a1455fd80617"], "metadata": {"page_label": "461", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7c1c9517-e544-4c5d-a853-3d19c424bbc1": {"node_ids": ["57099d50-95d3-4a60-9629-988046838331", "64a16c70-fcca-44d9-a230-6ce17d97a4c3", "57099d50-95d3-4a60-9629-988046838331", "64a16c70-fcca-44d9-a230-6ce17d97a4c3", "57099d50-95d3-4a60-9629-988046838331", "64a16c70-fcca-44d9-a230-6ce17d97a4c3"], "metadata": {"page_label": "462", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6ca7a83b-3fa0-4094-a157-aa9483abc836": {"node_ids": ["94b40922-f839-49bd-9fe1-f142a349e4b2", "5f9f747d-5e4d-4594-82e1-2a983d95988e", "94b40922-f839-49bd-9fe1-f142a349e4b2", "5f9f747d-5e4d-4594-82e1-2a983d95988e", "94b40922-f839-49bd-9fe1-f142a349e4b2", "5f9f747d-5e4d-4594-82e1-2a983d95988e"], "metadata": {"page_label": "463", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6b65e8ab-70ee-4a2d-931a-c4103bf783ec": {"node_ids": ["cb037d7e-539e-472c-8222-3d963184d4ab", "bf996fdd-bc20-4e96-a0fa-5ead3bbf7d1a", "cb037d7e-539e-472c-8222-3d963184d4ab", "bf996fdd-bc20-4e96-a0fa-5ead3bbf7d1a", "cb037d7e-539e-472c-8222-3d963184d4ab", "bf996fdd-bc20-4e96-a0fa-5ead3bbf7d1a"], "metadata": {"page_label": "464", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0ed360c5-3f13-4686-a627-f0fc85dcbd22": {"node_ids": ["1ad6fcde-990f-40e1-b3ea-9b36da3795d3", "89360432-824c-4330-90fc-793ef7d764b1", "1ad6fcde-990f-40e1-b3ea-9b36da3795d3", "89360432-824c-4330-90fc-793ef7d764b1", "1ad6fcde-990f-40e1-b3ea-9b36da3795d3", "89360432-824c-4330-90fc-793ef7d764b1"], "metadata": {"page_label": "465", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e6f3dd1d-a05d-47d2-b7b8-5f349822a71f": {"node_ids": ["f78ecb36-2dd7-4907-a0f4-f2affd3091af", "7cee7c56-369a-424e-b512-d739cfd777a3", "f78ecb36-2dd7-4907-a0f4-f2affd3091af", "7cee7c56-369a-424e-b512-d739cfd777a3", "f78ecb36-2dd7-4907-a0f4-f2affd3091af", "7cee7c56-369a-424e-b512-d739cfd777a3"], "metadata": {"page_label": "466", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "54cd3a27-ee22-49c2-980d-9f286473132c": {"node_ids": ["4da1771e-5e52-4661-bf99-ef6d6f5ea7b1", "7919f8a8-9eba-454e-b6b1-1904d34aad43", "4da1771e-5e52-4661-bf99-ef6d6f5ea7b1", "7919f8a8-9eba-454e-b6b1-1904d34aad43", "4da1771e-5e52-4661-bf99-ef6d6f5ea7b1", "7919f8a8-9eba-454e-b6b1-1904d34aad43"], "metadata": {"page_label": "467", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "737ee5e7-9f0a-4b9b-a303-ab10e318d0d8": {"node_ids": ["dafe0f41-bd82-478a-b223-83bcb572ebcc", "14d5611b-3b76-47ce-8308-9f8ef0a7bd53", "dafe0f41-bd82-478a-b223-83bcb572ebcc", "14d5611b-3b76-47ce-8308-9f8ef0a7bd53", "dafe0f41-bd82-478a-b223-83bcb572ebcc", "14d5611b-3b76-47ce-8308-9f8ef0a7bd53"], "metadata": {"page_label": "468", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9578f030-ebc2-46cf-9b78-b3cc1bc692a5": {"node_ids": ["2546deb7-6133-4a4c-9c5a-e70f757c555f", "152ef194-4a83-484e-bbad-040229f7e09b", "2546deb7-6133-4a4c-9c5a-e70f757c555f", "152ef194-4a83-484e-bbad-040229f7e09b", "2546deb7-6133-4a4c-9c5a-e70f757c555f", "152ef194-4a83-484e-bbad-040229f7e09b"], "metadata": {"page_label": "469", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "03dbb60f-b29e-4421-9ba0-7b5caaf5ee40": {"node_ids": ["ffad4f42-eb16-431f-9dc7-6ae28546b4b7", "59ee4a62-52ff-473a-8b50-16326b8cc87d", "ffad4f42-eb16-431f-9dc7-6ae28546b4b7", "59ee4a62-52ff-473a-8b50-16326b8cc87d", "ffad4f42-eb16-431f-9dc7-6ae28546b4b7", "59ee4a62-52ff-473a-8b50-16326b8cc87d"], "metadata": {"page_label": "470", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c5708c93-982a-4a2c-83be-40839cc174be": {"node_ids": ["4e5b909d-fee4-4cd4-bbd2-ea93e2c9c956", "1b66140b-37f5-4690-b369-603b00e66121", "4e5b909d-fee4-4cd4-bbd2-ea93e2c9c956", "1b66140b-37f5-4690-b369-603b00e66121", "4e5b909d-fee4-4cd4-bbd2-ea93e2c9c956", "1b66140b-37f5-4690-b369-603b00e66121"], "metadata": {"page_label": "471", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4ec86f52-80b5-41bb-b362-0ea24d2ebf4b": {"node_ids": ["70a7777b-27d7-4a37-a89e-3568398db9a0", "0543bf5d-4617-4c69-a3f7-cf8f89015305", "beeb9469-8724-4f57-930d-f3b13bf6d755", "70a7777b-27d7-4a37-a89e-3568398db9a0", "0543bf5d-4617-4c69-a3f7-cf8f89015305", "beeb9469-8724-4f57-930d-f3b13bf6d755", "70a7777b-27d7-4a37-a89e-3568398db9a0", "0543bf5d-4617-4c69-a3f7-cf8f89015305", "beeb9469-8724-4f57-930d-f3b13bf6d755"], "metadata": {"page_label": "472", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "203809e9-b2bf-460d-ad91-9c7cd697612d": {"node_ids": ["73af8a0e-13ba-4012-a842-948c8c3338bb", "d07354eb-ba33-4c32-86d9-62f72e6b88dd", "73af8a0e-13ba-4012-a842-948c8c3338bb", "d07354eb-ba33-4c32-86d9-62f72e6b88dd", "73af8a0e-13ba-4012-a842-948c8c3338bb", "d07354eb-ba33-4c32-86d9-62f72e6b88dd"], "metadata": {"page_label": "473", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d07d5e36-89ca-4a85-9806-ea5cba2db0f8": {"node_ids": ["182ae4ad-1172-4f43-ae67-080183f317cf", "7f73123d-fdf5-4d88-89c6-b43d4a196b2f", "5621fa90-822c-473e-aef9-c6b28309d39b", "182ae4ad-1172-4f43-ae67-080183f317cf", "7f73123d-fdf5-4d88-89c6-b43d4a196b2f", "5621fa90-822c-473e-aef9-c6b28309d39b", "182ae4ad-1172-4f43-ae67-080183f317cf", "7f73123d-fdf5-4d88-89c6-b43d4a196b2f", "5621fa90-822c-473e-aef9-c6b28309d39b"], "metadata": {"page_label": "474", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "243040ca-57e0-488c-b5c7-d57198a11ee1": {"node_ids": ["f5d1afa9-b3e7-4077-8c4b-f29ecbdb16ad", "f5d1afa9-b3e7-4077-8c4b-f29ecbdb16ad", "f5d1afa9-b3e7-4077-8c4b-f29ecbdb16ad"], "metadata": {"page_label": "475", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "126b3c54-b015-48a2-9895-99a035c444d7": {"node_ids": ["073f1ff8-8c0c-4b8b-a48e-d122e8c1610c", "b829a60b-4681-4744-8507-25a4c0d4bbf1", "073f1ff8-8c0c-4b8b-a48e-d122e8c1610c", "b829a60b-4681-4744-8507-25a4c0d4bbf1", "073f1ff8-8c0c-4b8b-a48e-d122e8c1610c", "b829a60b-4681-4744-8507-25a4c0d4bbf1"], "metadata": {"page_label": "476", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2f1322f1-b094-4c2d-a6bd-1bd24c26f0d0": {"node_ids": ["6e65ae73-8411-4469-bebc-ac3dd6d7af6d", "6e65ae73-8411-4469-bebc-ac3dd6d7af6d", "6e65ae73-8411-4469-bebc-ac3dd6d7af6d"], "metadata": {"page_label": "477", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "889937f8-cf3a-49e4-8519-e3a2d74f1ae3": {"node_ids": ["de7d3cc7-00b6-46fd-a52b-0f0f4a44c5ad", "1b6e1170-577d-4e51-8e9d-d46a2e5700da", "de7d3cc7-00b6-46fd-a52b-0f0f4a44c5ad", "1b6e1170-577d-4e51-8e9d-d46a2e5700da", "de7d3cc7-00b6-46fd-a52b-0f0f4a44c5ad", "1b6e1170-577d-4e51-8e9d-d46a2e5700da"], "metadata": {"page_label": "478", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "94581969-5096-4860-a484-42d2aa0cd7c3": {"node_ids": ["d038776f-fd91-49bb-809f-6dad6da79690", "1d50f054-3b75-4975-9b64-ad919fe1d27b", "d038776f-fd91-49bb-809f-6dad6da79690", "1d50f054-3b75-4975-9b64-ad919fe1d27b", "d038776f-fd91-49bb-809f-6dad6da79690", "1d50f054-3b75-4975-9b64-ad919fe1d27b"], "metadata": {"page_label": "479", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "cc7fd213-5eb7-4f40-8341-2856d1d6f409": {"node_ids": ["7a640613-e9cd-4e90-993d-de240e14ddb5", "36f5403e-5b5b-4bec-843c-cab3a4d5bcd1", "29873970-1bcf-4dfe-8dc3-4556c8f6a61a", "7a640613-e9cd-4e90-993d-de240e14ddb5", "36f5403e-5b5b-4bec-843c-cab3a4d5bcd1", "29873970-1bcf-4dfe-8dc3-4556c8f6a61a", "7a640613-e9cd-4e90-993d-de240e14ddb5", "36f5403e-5b5b-4bec-843c-cab3a4d5bcd1", "29873970-1bcf-4dfe-8dc3-4556c8f6a61a"], "metadata": {"page_label": "480", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5decbd03-1b78-4c43-9b15-28bc0722a205": {"node_ids": ["8a06d58d-5579-4352-8c3f-a3e702134a3c", "fbd99928-8119-4733-a0eb-e4e820168e73", "8a06d58d-5579-4352-8c3f-a3e702134a3c", "fbd99928-8119-4733-a0eb-e4e820168e73", "8a06d58d-5579-4352-8c3f-a3e702134a3c", "fbd99928-8119-4733-a0eb-e4e820168e73"], "metadata": {"page_label": "481", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "109d1ad3-db27-4f8b-80d3-05e1148ebaf7": {"node_ids": ["6196bbd0-1ae2-482e-8806-aab25a8ccad2", "ab4e0310-cc54-4f38-96ba-a0b984e5dd1f", "a2b174e3-f6b4-4828-a565-483e93e78805", "6196bbd0-1ae2-482e-8806-aab25a8ccad2", "ab4e0310-cc54-4f38-96ba-a0b984e5dd1f", "a2b174e3-f6b4-4828-a565-483e93e78805", "6196bbd0-1ae2-482e-8806-aab25a8ccad2", "ab4e0310-cc54-4f38-96ba-a0b984e5dd1f", "a2b174e3-f6b4-4828-a565-483e93e78805"], "metadata": {"page_label": "482", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3e88b904-0319-47b3-bec9-c439177d307e": {"node_ids": ["81247d50-9525-4bb2-af42-7dc74d3e448a", "389fae5d-261f-4d84-9e62-6938e6e47a29", "81247d50-9525-4bb2-af42-7dc74d3e448a", "389fae5d-261f-4d84-9e62-6938e6e47a29", "81247d50-9525-4bb2-af42-7dc74d3e448a", "389fae5d-261f-4d84-9e62-6938e6e47a29"], "metadata": {"page_label": "483", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "15e7e7ad-c2e6-4d63-810e-b75bfc4eecc7": {"node_ids": ["0b129ffc-6be2-418c-9e20-05dafcb61533", "623508c9-5bff-4ee2-bb5c-827ad6993e5a", "a52e7a1e-330b-4703-8814-2d553e38210d", "0b129ffc-6be2-418c-9e20-05dafcb61533", "623508c9-5bff-4ee2-bb5c-827ad6993e5a", "a52e7a1e-330b-4703-8814-2d553e38210d", "0b129ffc-6be2-418c-9e20-05dafcb61533", "623508c9-5bff-4ee2-bb5c-827ad6993e5a", "a52e7a1e-330b-4703-8814-2d553e38210d"], "metadata": {"page_label": "484", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "06da3ba8-f7df-429d-a061-d9b1c45abb46": {"node_ids": ["22ade394-a97a-448e-b988-c2ebbda51816", "22ade394-a97a-448e-b988-c2ebbda51816", "22ade394-a97a-448e-b988-c2ebbda51816"], "metadata": {"page_label": "485", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d4adc45b-f76d-4538-8d80-1f050c69bdeb": {"node_ids": ["10e011fe-7498-47e4-bdcd-2e69216e2bd4", "bf3ac2ab-8cb9-46ae-822c-be8a09568526", "10e011fe-7498-47e4-bdcd-2e69216e2bd4", "bf3ac2ab-8cb9-46ae-822c-be8a09568526", "10e011fe-7498-47e4-bdcd-2e69216e2bd4", "bf3ac2ab-8cb9-46ae-822c-be8a09568526"], "metadata": {"page_label": "486", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fba39d8d-914f-4dcd-92e8-a54373e14b4f": {"node_ids": ["1b2be3a4-548d-438e-b1ab-db6bf9cc1f0e", "ea676f44-1b16-44d0-956a-29f53a44e950", "1b2be3a4-548d-438e-b1ab-db6bf9cc1f0e", "ea676f44-1b16-44d0-956a-29f53a44e950", "1b2be3a4-548d-438e-b1ab-db6bf9cc1f0e", "ea676f44-1b16-44d0-956a-29f53a44e950"], "metadata": {"page_label": "487", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2787f3dc-3f6a-4e50-be71-a85d1c8e01ba": {"node_ids": ["86073e8e-51a2-449e-b3fd-689d7942be63", "8af10762-b99b-4e5a-84ad-3fe4431892e9", "86073e8e-51a2-449e-b3fd-689d7942be63", "8af10762-b99b-4e5a-84ad-3fe4431892e9", "86073e8e-51a2-449e-b3fd-689d7942be63", "8af10762-b99b-4e5a-84ad-3fe4431892e9"], "metadata": {"page_label": "488", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "75bc9aac-619e-486d-b3b9-46e5ea82f0cc": {"node_ids": ["dbc84f8b-dae9-401d-907a-1ac129cb736d", "88d1d145-2281-45e9-b443-1d2aa411405a", "dbc84f8b-dae9-401d-907a-1ac129cb736d", "88d1d145-2281-45e9-b443-1d2aa411405a", "dbc84f8b-dae9-401d-907a-1ac129cb736d", "88d1d145-2281-45e9-b443-1d2aa411405a"], "metadata": {"page_label": "489", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e6e6b521-0007-4d47-849b-14e1ce997dd7": {"node_ids": ["bf090f23-e16a-48d1-a2e9-c25d029f5667", "ab30ceac-14e6-4335-984a-a6210459de25", "bf090f23-e16a-48d1-a2e9-c25d029f5667", "ab30ceac-14e6-4335-984a-a6210459de25", "bf090f23-e16a-48d1-a2e9-c25d029f5667", "ab30ceac-14e6-4335-984a-a6210459de25"], "metadata": {"page_label": "490", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6320fa5f-f3e5-4a16-9fd7-6be49257980e": {"node_ids": ["749407bb-b8ca-464c-b27e-03104da3c38a", "749407bb-b8ca-464c-b27e-03104da3c38a", "749407bb-b8ca-464c-b27e-03104da3c38a"], "metadata": {"page_label": "491", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7a39621e-7e24-46fb-b5b5-8624b7a664e1": {"node_ids": ["30f77fa8-9c8f-4697-9575-5a4aeccaa6bd", "235c4ba7-5af9-453c-81fa-ebd8d713ffbb", "30f77fa8-9c8f-4697-9575-5a4aeccaa6bd", "235c4ba7-5af9-453c-81fa-ebd8d713ffbb", "30f77fa8-9c8f-4697-9575-5a4aeccaa6bd", "235c4ba7-5af9-453c-81fa-ebd8d713ffbb"], "metadata": {"page_label": "492", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ade4fa21-fdd3-459a-9f8b-8d3a08fc7e0a": {"node_ids": ["d35fc882-eb72-4db6-af09-797b2906238f", "95400e49-a559-4ed0-aed0-476031306c1f", "d35fc882-eb72-4db6-af09-797b2906238f", "95400e49-a559-4ed0-aed0-476031306c1f", "d35fc882-eb72-4db6-af09-797b2906238f", "95400e49-a559-4ed0-aed0-476031306c1f"], "metadata": {"page_label": "493", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c5ba3c2b-278c-4c6e-94b3-a54d5e583e59": {"node_ids": ["d2e8838f-a8b6-43ca-b3f5-955091c2cee1", "0895fde4-c357-418b-b44c-0cdb1082809c", "d2e8838f-a8b6-43ca-b3f5-955091c2cee1", "0895fde4-c357-418b-b44c-0cdb1082809c", "d2e8838f-a8b6-43ca-b3f5-955091c2cee1", "0895fde4-c357-418b-b44c-0cdb1082809c"], "metadata": {"page_label": "494", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e141a14e-c6a7-488e-b761-956334ac2e30": {"node_ids": ["43e45e40-fede-492c-9332-1858c94e8642", "fc9b2eed-5bb3-454f-9884-d77dda2804c2", "43e45e40-fede-492c-9332-1858c94e8642", "fc9b2eed-5bb3-454f-9884-d77dda2804c2", "43e45e40-fede-492c-9332-1858c94e8642", "fc9b2eed-5bb3-454f-9884-d77dda2804c2"], "metadata": {"page_label": "495", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d6c5149c-a967-4043-98e6-8466ac2de86e": {"node_ids": ["1eeb523c-eca8-4cde-9bd8-2e90e653650c", "bce40c4d-5fc0-4f4d-b5b6-2eac81aa2b75", "1eeb523c-eca8-4cde-9bd8-2e90e653650c", "bce40c4d-5fc0-4f4d-b5b6-2eac81aa2b75", "1eeb523c-eca8-4cde-9bd8-2e90e653650c", "bce40c4d-5fc0-4f4d-b5b6-2eac81aa2b75"], "metadata": {"page_label": "496", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "57ea7ac2-7e22-4a51-82e2-d12bb9d444dc": {"node_ids": ["ae07f997-c440-414d-8284-c46faf5acbe5", "872064ff-1e7e-493e-afcb-b5de0bd00cd8", "a2729c9d-d0fc-4c24-9af5-6089def794ff", "ae07f997-c440-414d-8284-c46faf5acbe5", "872064ff-1e7e-493e-afcb-b5de0bd00cd8", "a2729c9d-d0fc-4c24-9af5-6089def794ff", "ae07f997-c440-414d-8284-c46faf5acbe5", "872064ff-1e7e-493e-afcb-b5de0bd00cd8", "a2729c9d-d0fc-4c24-9af5-6089def794ff"], "metadata": {"page_label": "497", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "32ffde5c-b016-4163-b482-9f3e4308eb58": {"node_ids": ["0335c563-7c2e-4d7c-83f1-e55068b34454", "5262362d-2916-4443-8edf-f0590784d342", "0335c563-7c2e-4d7c-83f1-e55068b34454", "5262362d-2916-4443-8edf-f0590784d342", "0335c563-7c2e-4d7c-83f1-e55068b34454", "5262362d-2916-4443-8edf-f0590784d342"], "metadata": {"page_label": "498", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4fd8461f-640b-41e3-a871-ff1d9f01ec61": {"node_ids": ["8295accd-af00-4fcf-b890-84e34613793e", "0b49f314-9421-4338-bd2a-bf1d2fc10007", "2fe4aac7-e942-491b-b9e3-e387b5a891df", "8295accd-af00-4fcf-b890-84e34613793e", "0b49f314-9421-4338-bd2a-bf1d2fc10007", "2fe4aac7-e942-491b-b9e3-e387b5a891df", "8295accd-af00-4fcf-b890-84e34613793e", "0b49f314-9421-4338-bd2a-bf1d2fc10007", "2fe4aac7-e942-491b-b9e3-e387b5a891df"], "metadata": {"page_label": "499", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7868f618-471b-4071-bb6b-b026e466b7fc": {"node_ids": ["cbfded63-befa-4959-9336-69364fbf2d3b", "7c33ca19-cffe-4e65-bea1-3e9cc470406a", "663f4875-5629-4660-a067-10f17a61712d", "cbfded63-befa-4959-9336-69364fbf2d3b", "7c33ca19-cffe-4e65-bea1-3e9cc470406a", "663f4875-5629-4660-a067-10f17a61712d", "cbfded63-befa-4959-9336-69364fbf2d3b", "7c33ca19-cffe-4e65-bea1-3e9cc470406a", "663f4875-5629-4660-a067-10f17a61712d"], "metadata": {"page_label": "500", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ee18826a-548f-4901-8715-7af39e7753bb": {"node_ids": ["2b83b099-a5ec-4c1b-82cc-9b8f175eceb4", "f38b3875-f105-425b-b007-b45951af1c5f", "2b83b099-a5ec-4c1b-82cc-9b8f175eceb4", "f38b3875-f105-425b-b007-b45951af1c5f", "2b83b099-a5ec-4c1b-82cc-9b8f175eceb4", "f38b3875-f105-425b-b007-b45951af1c5f"], "metadata": {"page_label": "501", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "90dee43c-9eb6-41d0-ac8b-e0f68cacb276": {"node_ids": ["0d29a955-d3d4-47c4-bf5b-aaaaffbd1eab", "82d6ba15-8906-445f-9bc9-7f2e26269716", "0d29a955-d3d4-47c4-bf5b-aaaaffbd1eab", "82d6ba15-8906-445f-9bc9-7f2e26269716", "0d29a955-d3d4-47c4-bf5b-aaaaffbd1eab", "82d6ba15-8906-445f-9bc9-7f2e26269716"], "metadata": {"page_label": "502", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "456b5bfe-4173-4f2d-9215-9872ec72401e": {"node_ids": ["63e97bdd-ca7d-4632-b8fa-e5ad162ba8b2", "8e2c3a76-b867-4673-912f-160364e6253d", "72d46f46-dd5c-43c6-9fe9-31c3a8d6e731", "63e97bdd-ca7d-4632-b8fa-e5ad162ba8b2", "8e2c3a76-b867-4673-912f-160364e6253d", "72d46f46-dd5c-43c6-9fe9-31c3a8d6e731", "63e97bdd-ca7d-4632-b8fa-e5ad162ba8b2", "8e2c3a76-b867-4673-912f-160364e6253d", "72d46f46-dd5c-43c6-9fe9-31c3a8d6e731"], "metadata": {"page_label": "503", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "288888be-56cd-4ec1-aa99-2068f429e7d5": {"node_ids": ["16d28f75-0773-4204-aa77-5d62cd6a40ad", "1f3d164c-de35-489e-aef9-596ea8525b8e", "5883cf82-c9ea-4e4a-9653-178537ddd533", "16d28f75-0773-4204-aa77-5d62cd6a40ad", "1f3d164c-de35-489e-aef9-596ea8525b8e", "5883cf82-c9ea-4e4a-9653-178537ddd533", "16d28f75-0773-4204-aa77-5d62cd6a40ad", "1f3d164c-de35-489e-aef9-596ea8525b8e", "5883cf82-c9ea-4e4a-9653-178537ddd533"], "metadata": {"page_label": "504", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "95ef8d6a-ef6f-4a11-b774-6a31b0b888f8": {"node_ids": ["4c16e553-57f8-4c96-9f69-6c4bb906a13e", "79d048c3-31d2-471c-b65a-afd8cfa1a0d8", "4c16e553-57f8-4c96-9f69-6c4bb906a13e", "79d048c3-31d2-471c-b65a-afd8cfa1a0d8", "4c16e553-57f8-4c96-9f69-6c4bb906a13e", "79d048c3-31d2-471c-b65a-afd8cfa1a0d8"], "metadata": {"page_label": "505", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4ef85af9-740e-4229-b599-d8d4e85ce41c": {"node_ids": ["14cf9598-ee91-4f98-8a76-3c14ace29516", "6145253a-df1e-4918-88b4-4fbd411cf09c", "14cf9598-ee91-4f98-8a76-3c14ace29516", "6145253a-df1e-4918-88b4-4fbd411cf09c", "14cf9598-ee91-4f98-8a76-3c14ace29516", "6145253a-df1e-4918-88b4-4fbd411cf09c"], "metadata": {"page_label": "506", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a3ad0988-0f22-4a8e-b9e3-1d5897a4ebd5": {"node_ids": ["181a4561-5be0-47e5-ba01-aca57604e7c9", "b853f3df-d10f-454e-9b38-4f94c449eb3e", "181a4561-5be0-47e5-ba01-aca57604e7c9", "b853f3df-d10f-454e-9b38-4f94c449eb3e", "181a4561-5be0-47e5-ba01-aca57604e7c9", "b853f3df-d10f-454e-9b38-4f94c449eb3e"], "metadata": {"page_label": "507", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "136a9f79-7451-4ba6-a160-f2b8ef4dadca": {"node_ids": ["0a3c86f6-5ef7-42e4-92b8-8841ab1832a7", "2b3ea4b8-9798-40e7-9216-c65e4ffc299a", "0a3c86f6-5ef7-42e4-92b8-8841ab1832a7", "2b3ea4b8-9798-40e7-9216-c65e4ffc299a", "0a3c86f6-5ef7-42e4-92b8-8841ab1832a7", "2b3ea4b8-9798-40e7-9216-c65e4ffc299a"], "metadata": {"page_label": "508", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a1f1ff96-8b29-4f81-87d0-d3c8e3d30826": {"node_ids": ["eb6841e6-ea8a-4fbc-a970-d78856b95b3a", "17437a2b-2322-4ab0-ab87-3231ab7ff932", "eb6841e6-ea8a-4fbc-a970-d78856b95b3a", "17437a2b-2322-4ab0-ab87-3231ab7ff932", "eb6841e6-ea8a-4fbc-a970-d78856b95b3a", "17437a2b-2322-4ab0-ab87-3231ab7ff932"], "metadata": {"page_label": "509", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "383319f0-3b67-49c0-9800-00c18fb1d6b7": {"node_ids": ["6f4d6c02-80e2-4510-9ef6-1e1b838a9a35", "82d7bc62-352e-470b-a70c-aa247a962ff6", "119f7fe3-05ae-426b-a48a-6a82da0ecef5", "6f4d6c02-80e2-4510-9ef6-1e1b838a9a35", "82d7bc62-352e-470b-a70c-aa247a962ff6", "119f7fe3-05ae-426b-a48a-6a82da0ecef5", "6f4d6c02-80e2-4510-9ef6-1e1b838a9a35", "82d7bc62-352e-470b-a70c-aa247a962ff6", "119f7fe3-05ae-426b-a48a-6a82da0ecef5"], "metadata": {"page_label": "510", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e298e071-cfd8-4e38-bf2b-80db3becb0b9": {"node_ids": ["dd078166-e654-415d-ace0-4023a048c9a3", "26654bb4-cb62-4e28-934f-3f4bb3c7e548", "dd078166-e654-415d-ace0-4023a048c9a3", "26654bb4-cb62-4e28-934f-3f4bb3c7e548", "dd078166-e654-415d-ace0-4023a048c9a3", "26654bb4-cb62-4e28-934f-3f4bb3c7e548"], "metadata": {"page_label": "511", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c23ea36b-b45a-43b5-90da-c01ccbbd3cb3": {"node_ids": ["5ad0bc53-d13d-4c6d-b78d-94d1d0ed1950", "917bfb27-bd46-4121-a814-3f78a5f15f8a", "8ae5bc58-3fb9-4339-950d-db7f889a1826", "5ad0bc53-d13d-4c6d-b78d-94d1d0ed1950", "917bfb27-bd46-4121-a814-3f78a5f15f8a", "8ae5bc58-3fb9-4339-950d-db7f889a1826", "5ad0bc53-d13d-4c6d-b78d-94d1d0ed1950", "917bfb27-bd46-4121-a814-3f78a5f15f8a", "8ae5bc58-3fb9-4339-950d-db7f889a1826"], "metadata": {"page_label": "512", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f76cae65-7d50-4032-ada5-1c4d1ac41c56": {"node_ids": ["46f51e5d-5d8e-422e-9694-b9c6bb6c9d28", "a74e732c-8e9c-450a-b494-926f1628715a", "46f51e5d-5d8e-422e-9694-b9c6bb6c9d28", "a74e732c-8e9c-450a-b494-926f1628715a", "46f51e5d-5d8e-422e-9694-b9c6bb6c9d28", "a74e732c-8e9c-450a-b494-926f1628715a"], "metadata": {"page_label": "513", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0fdf224e-99d0-4940-9fcc-d3ea8d0422c7": {"node_ids": ["35a70b95-0920-4c3c-9f28-b7408f203ddc", "6c917109-6d6b-437e-a476-4b6e10d2963c", "35a70b95-0920-4c3c-9f28-b7408f203ddc", "6c917109-6d6b-437e-a476-4b6e10d2963c", "35a70b95-0920-4c3c-9f28-b7408f203ddc", "6c917109-6d6b-437e-a476-4b6e10d2963c"], "metadata": {"page_label": "514", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "206472a5-ae06-4c7d-8216-14b3408803bd": {"node_ids": ["b57d5c18-9b63-4843-a108-d9c3d49290d0", "38bc94b2-7109-41c9-badf-52c26cd005f0", "58a29694-20d1-4992-87bc-277748883e79", "b57d5c18-9b63-4843-a108-d9c3d49290d0", "38bc94b2-7109-41c9-badf-52c26cd005f0", "58a29694-20d1-4992-87bc-277748883e79", "b57d5c18-9b63-4843-a108-d9c3d49290d0", "38bc94b2-7109-41c9-badf-52c26cd005f0", "58a29694-20d1-4992-87bc-277748883e79"], "metadata": {"page_label": "515", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e895e8ae-bbf3-4933-8651-67ec9949c758": {"node_ids": ["aad80dfc-dbf0-487a-ac74-ab9aa48851f2", "3ac28c5d-8e8a-4968-8271-2216f469b561", "f33ac858-ff8e-435b-8ba9-329de00088ef", "aad80dfc-dbf0-487a-ac74-ab9aa48851f2", "3ac28c5d-8e8a-4968-8271-2216f469b561", "f33ac858-ff8e-435b-8ba9-329de00088ef", "aad80dfc-dbf0-487a-ac74-ab9aa48851f2", "3ac28c5d-8e8a-4968-8271-2216f469b561", "f33ac858-ff8e-435b-8ba9-329de00088ef"], "metadata": {"page_label": "516", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fd36e499-6c1c-4c7d-9b35-1398b655577a": {"node_ids": ["3b83f416-979c-438f-8f32-c01cee635913", "f8bdb659-9543-4785-9ee0-68f2d02d5d02", "3b83f416-979c-438f-8f32-c01cee635913", "f8bdb659-9543-4785-9ee0-68f2d02d5d02", "3b83f416-979c-438f-8f32-c01cee635913", "f8bdb659-9543-4785-9ee0-68f2d02d5d02"], "metadata": {"page_label": "517", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3ee278a6-3fc5-4738-82cb-01b3efec6ae9": {"node_ids": ["5233d938-e6df-4175-9cc0-fc0db9f00357", "4a7738a4-a5fa-48be-8e17-f72615187bc6", "ffc6920d-0050-4702-b504-b8c222d5492b", "5233d938-e6df-4175-9cc0-fc0db9f00357", "4a7738a4-a5fa-48be-8e17-f72615187bc6", "ffc6920d-0050-4702-b504-b8c222d5492b", "5233d938-e6df-4175-9cc0-fc0db9f00357", "4a7738a4-a5fa-48be-8e17-f72615187bc6", "ffc6920d-0050-4702-b504-b8c222d5492b"], "metadata": {"page_label": "518", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0f2be16c-6fb1-47c4-85fb-07308a9cae35": {"node_ids": ["6f6c68a6-1d04-4e89-bfbb-bd39194fd9cc", "4d71c198-8091-405d-ba4b-cec3a2cf630c", "6f6c68a6-1d04-4e89-bfbb-bd39194fd9cc", "4d71c198-8091-405d-ba4b-cec3a2cf630c", "6f6c68a6-1d04-4e89-bfbb-bd39194fd9cc", "4d71c198-8091-405d-ba4b-cec3a2cf630c"], "metadata": {"page_label": "519", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1ece04c1-2b93-4e9b-a7e5-5d0ce8380f43": {"node_ids": ["3cac20d2-ddf7-42c6-84e8-df656b850d06", "2232da1a-70cc-427b-910b-2c3d83272bd1", "3cac20d2-ddf7-42c6-84e8-df656b850d06", "2232da1a-70cc-427b-910b-2c3d83272bd1", "3cac20d2-ddf7-42c6-84e8-df656b850d06", "2232da1a-70cc-427b-910b-2c3d83272bd1"], "metadata": {"page_label": "520", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5d8f6a3b-ee1d-4986-9479-d8e27475f128": {"node_ids": ["bbdb89c0-3702-4318-9dff-fccad67c1121", "7a50d2c6-1f76-4887-858a-1a7d94fd68c2", "bbdb89c0-3702-4318-9dff-fccad67c1121", "7a50d2c6-1f76-4887-858a-1a7d94fd68c2", "bbdb89c0-3702-4318-9dff-fccad67c1121", "7a50d2c6-1f76-4887-858a-1a7d94fd68c2"], "metadata": {"page_label": "521", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "20fec5c3-caac-421e-ac1e-aa8e9f3f4836": {"node_ids": ["420054b3-e979-4111-bd16-a182b1f543e2", "cdf35c44-6bb9-4e54-b592-c5d03f9f57c6", "01a5a2b6-c32d-42a8-8893-49fb8f3b7fd7", "420054b3-e979-4111-bd16-a182b1f543e2", "cdf35c44-6bb9-4e54-b592-c5d03f9f57c6", "01a5a2b6-c32d-42a8-8893-49fb8f3b7fd7", "420054b3-e979-4111-bd16-a182b1f543e2", "cdf35c44-6bb9-4e54-b592-c5d03f9f57c6", "01a5a2b6-c32d-42a8-8893-49fb8f3b7fd7"], "metadata": {"page_label": "522", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8e59cf09-9e77-4cde-9e35-b57022769458": {"node_ids": ["74416f9f-cfcd-40d1-967f-2fa199f1ef68", "74416f9f-cfcd-40d1-967f-2fa199f1ef68", "74416f9f-cfcd-40d1-967f-2fa199f1ef68"], "metadata": {"page_label": "523", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ab42f691-4637-42fb-ab92-2aaf0adbfce6": {"node_ids": ["d29b5f79-da19-4734-9fd5-60e5799911ba", "ac5ba062-cf0c-4cf3-b081-504ee5d30016", "096c5d53-d60c-4fd4-b49a-e8abcc602866", "d29b5f79-da19-4734-9fd5-60e5799911ba", "ac5ba062-cf0c-4cf3-b081-504ee5d30016", "096c5d53-d60c-4fd4-b49a-e8abcc602866", "d29b5f79-da19-4734-9fd5-60e5799911ba", "ac5ba062-cf0c-4cf3-b081-504ee5d30016", "096c5d53-d60c-4fd4-b49a-e8abcc602866"], "metadata": {"page_label": "524", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1888d106-872a-4cf0-b9f8-085025dd26a6": {"node_ids": ["b7fe66c7-30ab-4365-9771-3b109ef7554d", "f51c4678-8da5-471e-ab1d-1c95aeaa45b0", "060cf403-5f3b-4657-b81c-c55185cfa465", "b7fe66c7-30ab-4365-9771-3b109ef7554d", "f51c4678-8da5-471e-ab1d-1c95aeaa45b0", "060cf403-5f3b-4657-b81c-c55185cfa465", "b7fe66c7-30ab-4365-9771-3b109ef7554d", "f51c4678-8da5-471e-ab1d-1c95aeaa45b0", "060cf403-5f3b-4657-b81c-c55185cfa465"], "metadata": {"page_label": "525", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6a8c1287-8d7e-43b8-84ce-6fb9b28b07c8": {"node_ids": ["c6a0e017-cc07-48d9-b990-3c7b3c5adb43", "19679262-5efa-49ec-a4b0-82546671406c", "c6a0e017-cc07-48d9-b990-3c7b3c5adb43", "19679262-5efa-49ec-a4b0-82546671406c", "c6a0e017-cc07-48d9-b990-3c7b3c5adb43", "19679262-5efa-49ec-a4b0-82546671406c"], "metadata": {"page_label": "526", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2f5c4958-b80d-4500-92aa-b5b304c99594": {"node_ids": ["df7c7077-3849-45cd-89d4-9a6f3977adec", "e5a7d0f9-b51f-49dc-ac31-0fe73005e961", "495145ca-75a4-40eb-a4ed-b1bd2759d842", "df7c7077-3849-45cd-89d4-9a6f3977adec", "e5a7d0f9-b51f-49dc-ac31-0fe73005e961", "495145ca-75a4-40eb-a4ed-b1bd2759d842", "df7c7077-3849-45cd-89d4-9a6f3977adec", "e5a7d0f9-b51f-49dc-ac31-0fe73005e961", "495145ca-75a4-40eb-a4ed-b1bd2759d842"], "metadata": {"page_label": "527", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f561b82a-8bc5-4431-9b4c-92fe880a0e0d": {"node_ids": ["e45a520c-c83d-4ded-a584-e07a0dc26b10", "aff212c9-a712-4527-a4c7-1ae6b845a020", "e45a520c-c83d-4ded-a584-e07a0dc26b10", "aff212c9-a712-4527-a4c7-1ae6b845a020", "e45a520c-c83d-4ded-a584-e07a0dc26b10", "aff212c9-a712-4527-a4c7-1ae6b845a020"], "metadata": {"page_label": "528", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ebdc26ee-d582-44b5-a69d-65a38e7c0b8c": {"node_ids": ["0f0dc202-17ec-48a0-b3b0-7bd1e57be964", "964746b8-c8ac-4c03-b601-084f87d0c280", "0f0dc202-17ec-48a0-b3b0-7bd1e57be964", "964746b8-c8ac-4c03-b601-084f87d0c280", "0f0dc202-17ec-48a0-b3b0-7bd1e57be964", "964746b8-c8ac-4c03-b601-084f87d0c280"], "metadata": {"page_label": "529", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bca26671-473a-4482-9631-c71294d51d7b": {"node_ids": ["c5635610-57e6-4b60-b55e-45e8a1e2b372", "1870ee1a-b7c9-4457-833a-0dfecb6b93f1", "4e926dce-421c-40e8-a95c-7e8a21bed2cf", "c5635610-57e6-4b60-b55e-45e8a1e2b372", "1870ee1a-b7c9-4457-833a-0dfecb6b93f1", "4e926dce-421c-40e8-a95c-7e8a21bed2cf", "c5635610-57e6-4b60-b55e-45e8a1e2b372", "1870ee1a-b7c9-4457-833a-0dfecb6b93f1", "4e926dce-421c-40e8-a95c-7e8a21bed2cf"], "metadata": {"page_label": "530", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "35bbddcf-6a73-46ab-ab1f-0d50be6a00f9": {"node_ids": ["07a87240-386a-45a7-9e21-27a906de8649", "dbddadde-a0a0-40e8-937c-25f0264f56b3", "07a87240-386a-45a7-9e21-27a906de8649", "dbddadde-a0a0-40e8-937c-25f0264f56b3", "07a87240-386a-45a7-9e21-27a906de8649", "dbddadde-a0a0-40e8-937c-25f0264f56b3"], "metadata": {"page_label": "531", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "38724542-862c-43e4-96fe-6488ed65a759": {"node_ids": ["f680157d-b7af-4f59-8de1-7b1afedbfe3a", "ee8d2be4-3926-49d8-b603-ae98d96bc13c", "f680157d-b7af-4f59-8de1-7b1afedbfe3a", "ee8d2be4-3926-49d8-b603-ae98d96bc13c", "f680157d-b7af-4f59-8de1-7b1afedbfe3a", "ee8d2be4-3926-49d8-b603-ae98d96bc13c"], "metadata": {"page_label": "532", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "41e81d24-56f7-45b7-9d04-a7bc8ea13350": {"node_ids": ["86b4aea9-4542-49b9-ab71-a31cf1e705b5", "55bed8a5-fe81-4860-9330-86602def3760", "99847d07-ccec-4f99-b893-ccdbb02a7a19", "86b4aea9-4542-49b9-ab71-a31cf1e705b5", "55bed8a5-fe81-4860-9330-86602def3760", "99847d07-ccec-4f99-b893-ccdbb02a7a19", "86b4aea9-4542-49b9-ab71-a31cf1e705b5", "55bed8a5-fe81-4860-9330-86602def3760", "99847d07-ccec-4f99-b893-ccdbb02a7a19"], "metadata": {"page_label": "533", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f7163ddc-984c-4354-8171-36f85c0a366d": {"node_ids": ["d71744e3-b3d5-41be-b311-7ce8306d1ba3", "a4887108-c041-4e51-a001-fd1493499a52", "d71744e3-b3d5-41be-b311-7ce8306d1ba3", "a4887108-c041-4e51-a001-fd1493499a52", "d71744e3-b3d5-41be-b311-7ce8306d1ba3", "a4887108-c041-4e51-a001-fd1493499a52"], "metadata": {"page_label": "534", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2f5c6c4d-288f-4418-9eea-2fd9b93f0c73": {"node_ids": ["684eeb2f-b37e-46ed-be3c-e5e9f18cef91", "459080be-f09b-4460-bddc-90116d224f28", "684eeb2f-b37e-46ed-be3c-e5e9f18cef91", "459080be-f09b-4460-bddc-90116d224f28", "684eeb2f-b37e-46ed-be3c-e5e9f18cef91", "459080be-f09b-4460-bddc-90116d224f28"], "metadata": {"page_label": "535", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6823750a-63c4-48a3-aa0c-96bfb96965f9": {"node_ids": ["e64479f7-1f9e-47ec-8d5c-7c060c2999a0", "36ded081-1f7a-46bd-85a9-34abb4396ddd", "ac7b08f4-a1a8-4947-b1e9-66bc88c34867", "dbf3dedb-9044-4f3d-a797-babbeca5dd57", "e64479f7-1f9e-47ec-8d5c-7c060c2999a0", "36ded081-1f7a-46bd-85a9-34abb4396ddd", "ac7b08f4-a1a8-4947-b1e9-66bc88c34867", "dbf3dedb-9044-4f3d-a797-babbeca5dd57", "e64479f7-1f9e-47ec-8d5c-7c060c2999a0", "36ded081-1f7a-46bd-85a9-34abb4396ddd", "ac7b08f4-a1a8-4947-b1e9-66bc88c34867", "dbf3dedb-9044-4f3d-a797-babbeca5dd57"], "metadata": {"page_label": "536", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e5c8a8cc-b0ff-434c-a1ed-dc6866eb42c8": {"node_ids": ["67e45801-4275-488f-8e69-f2928cf1854d", "2330513c-15ae-410c-b2f7-e52032a402b1", "67e45801-4275-488f-8e69-f2928cf1854d", "2330513c-15ae-410c-b2f7-e52032a402b1", "67e45801-4275-488f-8e69-f2928cf1854d", "2330513c-15ae-410c-b2f7-e52032a402b1"], "metadata": {"page_label": "537", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d4287f0c-96e1-482a-95e4-290e0dce98de": {"node_ids": ["ae43b9b3-6085-47d0-a392-dc200e20355d", "2ae996da-80c7-4ff8-a00f-5c9a68385eaf", "ae43b9b3-6085-47d0-a392-dc200e20355d", "2ae996da-80c7-4ff8-a00f-5c9a68385eaf", "ae43b9b3-6085-47d0-a392-dc200e20355d", "2ae996da-80c7-4ff8-a00f-5c9a68385eaf"], "metadata": {"page_label": "538", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "01451183-24ed-4c12-966c-3f4bede6aedd": {"node_ids": ["d24ab3dd-04f7-4217-8dba-8fb16ba8947d", "6d4372e0-d0b4-472d-afb3-715f65f8d9ea", "e3cd60cd-3749-45df-82fd-f948facb39da", "d24ab3dd-04f7-4217-8dba-8fb16ba8947d", "6d4372e0-d0b4-472d-afb3-715f65f8d9ea", "e3cd60cd-3749-45df-82fd-f948facb39da", "d24ab3dd-04f7-4217-8dba-8fb16ba8947d", "6d4372e0-d0b4-472d-afb3-715f65f8d9ea", "e3cd60cd-3749-45df-82fd-f948facb39da"], "metadata": {"page_label": "539", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "acb4637a-ee59-47d3-8d55-7a5a0c4e6728": {"node_ids": ["bd0fab0d-4123-4c3e-91a4-d2fd94423609", "ce69aa69-4166-4b95-a31d-2b59d76c9f6e", "bd0fab0d-4123-4c3e-91a4-d2fd94423609", "ce69aa69-4166-4b95-a31d-2b59d76c9f6e", "bd0fab0d-4123-4c3e-91a4-d2fd94423609", "ce69aa69-4166-4b95-a31d-2b59d76c9f6e"], "metadata": {"page_label": "540", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a90e0185-cd48-4b2d-aa95-6a1b21bb3694": {"node_ids": ["ecca81ee-8aa7-411d-8edd-460d916a8fe5", "a9c52cae-0d40-40f4-9e99-4d787a1b21f2", "ecca81ee-8aa7-411d-8edd-460d916a8fe5", "a9c52cae-0d40-40f4-9e99-4d787a1b21f2", "ecca81ee-8aa7-411d-8edd-460d916a8fe5", "a9c52cae-0d40-40f4-9e99-4d787a1b21f2"], "metadata": {"page_label": "541", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3978a3fa-e428-4ee7-8368-52ac860684d7": {"node_ids": ["a5575c21-7471-4608-aa19-99b317071bdd", "245fffde-5b96-4d47-95f5-e40b59910fd1", "a5575c21-7471-4608-aa19-99b317071bdd", "245fffde-5b96-4d47-95f5-e40b59910fd1", "a5575c21-7471-4608-aa19-99b317071bdd", "245fffde-5b96-4d47-95f5-e40b59910fd1"], "metadata": {"page_label": "542", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c66949e2-9b14-4fac-8dac-d07f94f8dead": {"node_ids": ["d37ce0c7-2d45-405a-8843-b6fefc40b734", "650f5690-0681-4094-a25a-2f5f27494dee", "d37ce0c7-2d45-405a-8843-b6fefc40b734", "650f5690-0681-4094-a25a-2f5f27494dee", "d37ce0c7-2d45-405a-8843-b6fefc40b734", "650f5690-0681-4094-a25a-2f5f27494dee"], "metadata": {"page_label": "543", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f65edeea-34e8-4a21-aee1-2351e87dcb25": {"node_ids": ["f9d073d0-f261-4d0b-9998-7f79e50bfb63", "4a46de18-32c9-4d56-ba99-046f9da01015", "f9d073d0-f261-4d0b-9998-7f79e50bfb63", "4a46de18-32c9-4d56-ba99-046f9da01015", "f9d073d0-f261-4d0b-9998-7f79e50bfb63", "4a46de18-32c9-4d56-ba99-046f9da01015"], "metadata": {"page_label": "544", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "145c297e-2aaa-4607-ba09-dd3c2fa951e0": {"node_ids": ["ed4519ef-a96a-4bf9-b799-32bd0ae68fc3", "559a87c0-f31f-453f-b7ac-daa089ac521e", "ed4519ef-a96a-4bf9-b799-32bd0ae68fc3", "559a87c0-f31f-453f-b7ac-daa089ac521e", "ed4519ef-a96a-4bf9-b799-32bd0ae68fc3", "559a87c0-f31f-453f-b7ac-daa089ac521e"], "metadata": {"page_label": "545", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "85df7da8-5c73-45be-95d1-cee9bd5f9f6f": {"node_ids": ["384da572-54ec-4b9a-8ec8-c598eeacf240", "31adc796-c59f-4e81-8e97-211e9c18012a", "384da572-54ec-4b9a-8ec8-c598eeacf240", "31adc796-c59f-4e81-8e97-211e9c18012a", "384da572-54ec-4b9a-8ec8-c598eeacf240", "31adc796-c59f-4e81-8e97-211e9c18012a"], "metadata": {"page_label": "546", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c4da2f44-fc58-4548-97fe-d29f07f3782a": {"node_ids": ["aca1da39-4c39-4ddd-bd91-7c24e1970a39", "aca1da39-4c39-4ddd-bd91-7c24e1970a39", "aca1da39-4c39-4ddd-bd91-7c24e1970a39"], "metadata": {"page_label": "547", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d412401d-8aeb-4584-bd30-e03053010af5": {"node_ids": ["c44a0b80-8344-4603-ae49-260fc7cdcab1", "8ac890d3-0ff1-4716-8b5b-6949aa65d659", "c44a0b80-8344-4603-ae49-260fc7cdcab1", "8ac890d3-0ff1-4716-8b5b-6949aa65d659", "c44a0b80-8344-4603-ae49-260fc7cdcab1", "8ac890d3-0ff1-4716-8b5b-6949aa65d659"], "metadata": {"page_label": "548", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "32a63977-f28c-4b87-a12d-aa5d8c6c34c0": {"node_ids": ["e46239eb-961e-466b-afde-03ac58b81fa7", "b1e4f62f-c200-4440-9960-30dd7b9f025a", "e46239eb-961e-466b-afde-03ac58b81fa7", "b1e4f62f-c200-4440-9960-30dd7b9f025a", "e46239eb-961e-466b-afde-03ac58b81fa7", "b1e4f62f-c200-4440-9960-30dd7b9f025a"], "metadata": {"page_label": "549", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e7ce0fe0-fba0-4e19-afa4-700ab4d0b61a": {"node_ids": ["05ba4948-24a5-462b-9a2e-65f651c1664c", "a39c7343-3a23-4f30-8513-9cb27ff27709", "05ba4948-24a5-462b-9a2e-65f651c1664c", "a39c7343-3a23-4f30-8513-9cb27ff27709", "05ba4948-24a5-462b-9a2e-65f651c1664c", "a39c7343-3a23-4f30-8513-9cb27ff27709"], "metadata": {"page_label": "550", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "587adbd0-d69d-4773-ba35-91228ed49afd": {"node_ids": ["2cc82c4b-d358-4c61-8c91-2566ac3b7c90", "0deeb299-3842-488a-bbf2-91f4e3004e62", "2cc82c4b-d358-4c61-8c91-2566ac3b7c90", "0deeb299-3842-488a-bbf2-91f4e3004e62", "2cc82c4b-d358-4c61-8c91-2566ac3b7c90", "0deeb299-3842-488a-bbf2-91f4e3004e62"], "metadata": {"page_label": "551", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "82310adc-795a-4750-ba7d-60f19fe23fb5": {"node_ids": ["aca09c6d-1324-49b3-916a-0eb26afcb97e", "98e07ab9-9e37-4a81-a52b-adb2cd50eab6", "aca09c6d-1324-49b3-916a-0eb26afcb97e", "98e07ab9-9e37-4a81-a52b-adb2cd50eab6", "aca09c6d-1324-49b3-916a-0eb26afcb97e", "98e07ab9-9e37-4a81-a52b-adb2cd50eab6"], "metadata": {"page_label": "552", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5ca8a155-befa-4cae-b61b-6187336c62a9": {"node_ids": ["4f9055de-e048-4733-910b-0d4b82471c2e", "35c13ad1-f310-4815-8dbb-b0a173237984", "ded51adf-8de7-481c-b98e-4aae483fb294", "4f9055de-e048-4733-910b-0d4b82471c2e", "35c13ad1-f310-4815-8dbb-b0a173237984", "ded51adf-8de7-481c-b98e-4aae483fb294", "4f9055de-e048-4733-910b-0d4b82471c2e", "35c13ad1-f310-4815-8dbb-b0a173237984", "ded51adf-8de7-481c-b98e-4aae483fb294"], "metadata": {"page_label": "553", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "87bf152e-d191-42e3-ab76-e4c9f59d29c0": {"node_ids": ["b4262e83-781f-422d-ad79-5d1894fcb87d", "5dbd025a-22cf-4a06-874e-906d8cd2bb50", "958aa070-1ae9-462e-9414-00ea05ad8bf3", "b4262e83-781f-422d-ad79-5d1894fcb87d", "5dbd025a-22cf-4a06-874e-906d8cd2bb50", "958aa070-1ae9-462e-9414-00ea05ad8bf3", "b4262e83-781f-422d-ad79-5d1894fcb87d", "5dbd025a-22cf-4a06-874e-906d8cd2bb50", "958aa070-1ae9-462e-9414-00ea05ad8bf3"], "metadata": {"page_label": "554", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b6e878e1-0466-424f-8b74-11d293349df3": {"node_ids": ["18716294-2fd0-4d07-8124-08ad1eb853cf", "a27fdab2-1406-4b49-8f34-0ac90f97ee50", "18716294-2fd0-4d07-8124-08ad1eb853cf", "a27fdab2-1406-4b49-8f34-0ac90f97ee50", "18716294-2fd0-4d07-8124-08ad1eb853cf", "a27fdab2-1406-4b49-8f34-0ac90f97ee50"], "metadata": {"page_label": "555", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a0a5f33a-36aa-49df-b54c-a619f70412ad": {"node_ids": ["ac0c1610-74ce-4fba-a746-567fa4c30581", "dc946f53-77e2-4de2-97dd-fed95ea4a770", "c7ee4aa8-479b-4ef8-8934-8c8215e73ae7", "ac0c1610-74ce-4fba-a746-567fa4c30581", "dc946f53-77e2-4de2-97dd-fed95ea4a770", "c7ee4aa8-479b-4ef8-8934-8c8215e73ae7", "ac0c1610-74ce-4fba-a746-567fa4c30581", "dc946f53-77e2-4de2-97dd-fed95ea4a770", "c7ee4aa8-479b-4ef8-8934-8c8215e73ae7"], "metadata": {"page_label": "556", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b8d83a0c-2327-41aa-914d-db6c59ce53c8": {"node_ids": ["9d58108d-e823-41eb-a57d-f85ed029a3f5", "8cee13f3-b563-46c5-8bc3-126814b170fe", "9d58108d-e823-41eb-a57d-f85ed029a3f5", "8cee13f3-b563-46c5-8bc3-126814b170fe", "9d58108d-e823-41eb-a57d-f85ed029a3f5", "8cee13f3-b563-46c5-8bc3-126814b170fe"], "metadata": {"page_label": "557", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6a62aeb6-3715-429b-b810-e369669062f7": {"node_ids": ["453fed39-d183-4baa-981d-cf61a05b5fd5", "7fef0404-fc81-4e03-9f05-bd85749803d8", "28d88afd-196e-4bd5-96e1-221041702a36", "453fed39-d183-4baa-981d-cf61a05b5fd5", "7fef0404-fc81-4e03-9f05-bd85749803d8", "28d88afd-196e-4bd5-96e1-221041702a36", "453fed39-d183-4baa-981d-cf61a05b5fd5", "7fef0404-fc81-4e03-9f05-bd85749803d8", "28d88afd-196e-4bd5-96e1-221041702a36"], "metadata": {"page_label": "558", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "46918be8-509e-4e60-8e08-aec8235b451b": {"node_ids": ["9cf0e609-bf63-4f38-b58f-3b33b22a641e", "3c314be2-808c-4a58-b179-448bf5e6a392", "9cf0e609-bf63-4f38-b58f-3b33b22a641e", "3c314be2-808c-4a58-b179-448bf5e6a392", "9cf0e609-bf63-4f38-b58f-3b33b22a641e", "3c314be2-808c-4a58-b179-448bf5e6a392"], "metadata": {"page_label": "559", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "658f80f4-c2bb-4d41-8c41-19bbe55ee16d": {"node_ids": ["67e8fea8-f933-499e-88ad-6eb3299effd6", "0bea631a-877a-4179-abbe-83e9f2689ffb", "0567c999-271e-418b-9378-bdaf5f481d37", "67e8fea8-f933-499e-88ad-6eb3299effd6", "0bea631a-877a-4179-abbe-83e9f2689ffb", "0567c999-271e-418b-9378-bdaf5f481d37", "67e8fea8-f933-499e-88ad-6eb3299effd6", "0bea631a-877a-4179-abbe-83e9f2689ffb", "0567c999-271e-418b-9378-bdaf5f481d37"], "metadata": {"page_label": "560", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "136b4853-e457-4f52-acf6-f9ff493b4f56": {"node_ids": ["541dbff1-8a78-4ac4-ab80-8c81b71bc9bd", "541dbff1-8a78-4ac4-ab80-8c81b71bc9bd", "541dbff1-8a78-4ac4-ab80-8c81b71bc9bd"], "metadata": {"page_label": "561", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8d9b8fe9-8049-4b7e-a2d3-8f0327fc7c9a": {"node_ids": ["6a8eee5b-2a59-4c68-bd54-1d9cab1fbd46", "6a8eee5b-2a59-4c68-bd54-1d9cab1fbd46", "6a8eee5b-2a59-4c68-bd54-1d9cab1fbd46"], "metadata": {"page_label": "562", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "15813631-0973-46e1-93a0-8c0c3cf609f4": {"node_ids": ["642f2eef-4879-4840-bfee-7c0c25157463", "813b64cd-44a1-4f4a-ba80-0e090af038e3", "3d9f1620-3155-4e43-8d73-18bf3d7d8e63", "642f2eef-4879-4840-bfee-7c0c25157463", "813b64cd-44a1-4f4a-ba80-0e090af038e3", "3d9f1620-3155-4e43-8d73-18bf3d7d8e63", "642f2eef-4879-4840-bfee-7c0c25157463", "813b64cd-44a1-4f4a-ba80-0e090af038e3", "3d9f1620-3155-4e43-8d73-18bf3d7d8e63"], "metadata": {"page_label": "563", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7183eb36-1477-4313-a97d-d7387a47216c": {"node_ids": ["3fb01ab8-f52a-4e92-8082-3e1349727369", "6fd4eb53-1091-44d2-9955-02913369a759", "a7f9037d-1793-4661-ad0a-718f816dbea9", "3fb01ab8-f52a-4e92-8082-3e1349727369", "6fd4eb53-1091-44d2-9955-02913369a759", "a7f9037d-1793-4661-ad0a-718f816dbea9", "3fb01ab8-f52a-4e92-8082-3e1349727369", "6fd4eb53-1091-44d2-9955-02913369a759", "a7f9037d-1793-4661-ad0a-718f816dbea9"], "metadata": {"page_label": "564", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e6b994ce-063a-4e45-b7f1-752e0007227c": {"node_ids": ["0ddc725c-3003-4099-88ea-9805b795cd23", "0535d8e7-c49f-4507-a886-42b4cd7b503f", "df542374-a46e-45b2-89b7-8faa3e275934", "0ddc725c-3003-4099-88ea-9805b795cd23", "0535d8e7-c49f-4507-a886-42b4cd7b503f", "df542374-a46e-45b2-89b7-8faa3e275934", "0ddc725c-3003-4099-88ea-9805b795cd23", "0535d8e7-c49f-4507-a886-42b4cd7b503f", "df542374-a46e-45b2-89b7-8faa3e275934"], "metadata": {"page_label": "565", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ea1a5971-3ca1-4667-928a-e163d8cab129": {"node_ids": ["4de4e6b7-90cb-4982-b15c-83a567507296", "8564f69e-1b21-48fa-a06e-49fa141b9699", "4de4e6b7-90cb-4982-b15c-83a567507296", "8564f69e-1b21-48fa-a06e-49fa141b9699", "4de4e6b7-90cb-4982-b15c-83a567507296", "8564f69e-1b21-48fa-a06e-49fa141b9699"], "metadata": {"page_label": "566", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b6f0e40f-c08e-4837-84ad-938b67cdadc8": {"node_ids": ["adc1438e-1555-4ca1-9382-18c0bc78bdd9", "b49f34e5-9064-493a-9796-9aebee3bc9ff", "064152b4-0e4f-4f81-bba5-4ed3edc63692", "adc1438e-1555-4ca1-9382-18c0bc78bdd9", "b49f34e5-9064-493a-9796-9aebee3bc9ff", "064152b4-0e4f-4f81-bba5-4ed3edc63692", "adc1438e-1555-4ca1-9382-18c0bc78bdd9", "b49f34e5-9064-493a-9796-9aebee3bc9ff", "064152b4-0e4f-4f81-bba5-4ed3edc63692"], "metadata": {"page_label": "567", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5e86ddae-f9eb-4271-b073-3a7370738ab7": {"node_ids": ["876b97ae-6834-46f9-b97f-98145d513934", "b9325247-4fb3-4cac-9f2f-6707de4b5bc0", "876b97ae-6834-46f9-b97f-98145d513934", "b9325247-4fb3-4cac-9f2f-6707de4b5bc0", "876b97ae-6834-46f9-b97f-98145d513934", "b9325247-4fb3-4cac-9f2f-6707de4b5bc0"], "metadata": {"page_label": "568", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "15a084ec-7d94-4458-bddb-f8e138b1ec71": {"node_ids": ["5e936a17-dff7-4ef6-89e1-171634c7775d", "9798ef3f-9c00-486d-8855-7b76b26519db", "5e936a17-dff7-4ef6-89e1-171634c7775d", "9798ef3f-9c00-486d-8855-7b76b26519db", "5e936a17-dff7-4ef6-89e1-171634c7775d", "9798ef3f-9c00-486d-8855-7b76b26519db"], "metadata": {"page_label": "569", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "91cb7cc1-cd79-4b6c-9331-66471ae4f32d": {"node_ids": ["5176d231-eade-4c4e-a089-bee948130310", "ae4cd4b8-4de5-4da1-92af-ffce8b2f6399", "5176d231-eade-4c4e-a089-bee948130310", "ae4cd4b8-4de5-4da1-92af-ffce8b2f6399", "5176d231-eade-4c4e-a089-bee948130310", "ae4cd4b8-4de5-4da1-92af-ffce8b2f6399"], "metadata": {"page_label": "570", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c5dd7e24-3968-43c2-888d-dba258dcaee0": {"node_ids": ["53ae1884-6536-4f2f-8031-64b71b80143e", "53ae1884-6536-4f2f-8031-64b71b80143e", "53ae1884-6536-4f2f-8031-64b71b80143e"], "metadata": {"page_label": "571", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "13a69199-7d94-43f5-af01-6b3e7237a822": {"node_ids": ["bdb5eb1b-ea37-427c-bfc5-072c06a3d8b4", "050d053d-4109-48f7-bd57-2f8579c13ec4", "976c8e0e-a268-4fee-937e-809807e7fa9c", "bdb5eb1b-ea37-427c-bfc5-072c06a3d8b4", "050d053d-4109-48f7-bd57-2f8579c13ec4", "976c8e0e-a268-4fee-937e-809807e7fa9c", "bdb5eb1b-ea37-427c-bfc5-072c06a3d8b4", "050d053d-4109-48f7-bd57-2f8579c13ec4", "976c8e0e-a268-4fee-937e-809807e7fa9c"], "metadata": {"page_label": "572", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fd51dc01-54b4-4c49-aaa3-573b1d09a9dd": {"node_ids": ["a1f0717b-d0fe-41e9-9594-e8e996a1e19d", "6b8a59e6-6e95-4d91-844c-45802303ffd3", "a1f0717b-d0fe-41e9-9594-e8e996a1e19d", "6b8a59e6-6e95-4d91-844c-45802303ffd3", "a1f0717b-d0fe-41e9-9594-e8e996a1e19d", "6b8a59e6-6e95-4d91-844c-45802303ffd3"], "metadata": {"page_label": "573", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c88dd2e6-a699-49b4-bf59-3c0365771b14": {"node_ids": ["6051d786-2428-40e0-b853-fdbf0af907e9", "e127933f-e806-4559-bfa1-85152bce5bbc", "6051d786-2428-40e0-b853-fdbf0af907e9", "e127933f-e806-4559-bfa1-85152bce5bbc", "6051d786-2428-40e0-b853-fdbf0af907e9", "e127933f-e806-4559-bfa1-85152bce5bbc"], "metadata": {"page_label": "574", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1696d94e-8b2b-4f90-a0fc-6ee95980665d": {"node_ids": ["2e404c37-b20e-472c-bf59-2c126e9b50f9", "9932f449-1d46-408c-bbb0-8e6c23c84dd6", "2e404c37-b20e-472c-bf59-2c126e9b50f9", "9932f449-1d46-408c-bbb0-8e6c23c84dd6", "2e404c37-b20e-472c-bf59-2c126e9b50f9", "9932f449-1d46-408c-bbb0-8e6c23c84dd6"], "metadata": {"page_label": "575", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "910bc5dc-d7a0-4c3f-8100-64f1dae76f33": {"node_ids": ["98fe7404-2a52-4115-b46f-05903de98fab", "fa637b19-34c4-4983-a393-c915d2a755c9", "98fe7404-2a52-4115-b46f-05903de98fab", "fa637b19-34c4-4983-a393-c915d2a755c9", "98fe7404-2a52-4115-b46f-05903de98fab", "fa637b19-34c4-4983-a393-c915d2a755c9"], "metadata": {"page_label": "576", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ed137863-472d-414c-b5e7-59e8a8c664ca": {"node_ids": ["5a461167-637e-4e8c-b80e-3a06ea634d50", "93a87c73-652d-4052-a286-843789bb65d4", "5a461167-637e-4e8c-b80e-3a06ea634d50", "93a87c73-652d-4052-a286-843789bb65d4", "5a461167-637e-4e8c-b80e-3a06ea634d50", "93a87c73-652d-4052-a286-843789bb65d4"], "metadata": {"page_label": "577", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "72e0fd58-cbb9-45f3-a217-9e41af532c88": {"node_ids": ["74dfc485-5b34-4518-9994-b271a3c696f2", "c9bea34c-88e8-46d6-89a2-3efbfe1ed909", "6e9e8c93-f501-4d5a-8388-3b826fda1563", "74dfc485-5b34-4518-9994-b271a3c696f2", "c9bea34c-88e8-46d6-89a2-3efbfe1ed909", "6e9e8c93-f501-4d5a-8388-3b826fda1563", "74dfc485-5b34-4518-9994-b271a3c696f2", "c9bea34c-88e8-46d6-89a2-3efbfe1ed909", "6e9e8c93-f501-4d5a-8388-3b826fda1563"], "metadata": {"page_label": "578", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e95d63a7-d868-4108-9fa6-8ccd568bed33": {"node_ids": ["5a15dffa-b5aa-43ac-a07f-082396ea11f4", "955d26aa-24d8-4788-83d3-38190eac383a", "5a15dffa-b5aa-43ac-a07f-082396ea11f4", "955d26aa-24d8-4788-83d3-38190eac383a", "5a15dffa-b5aa-43ac-a07f-082396ea11f4", "955d26aa-24d8-4788-83d3-38190eac383a"], "metadata": {"page_label": "579", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "845c1790-78fd-4f32-ad27-f0b26131cb90": {"node_ids": ["0a61e912-c3d4-4fdc-897a-19c278da523c", "15c1ce16-505c-4a8d-b6d8-10b6358e8a05", "0a61e912-c3d4-4fdc-897a-19c278da523c", "15c1ce16-505c-4a8d-b6d8-10b6358e8a05", "0a61e912-c3d4-4fdc-897a-19c278da523c", "15c1ce16-505c-4a8d-b6d8-10b6358e8a05"], "metadata": {"page_label": "580", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f472d0ca-2bf5-444d-b5b4-0a7a0a83d985": {"node_ids": ["65f11d47-4569-496d-a8cc-83114174e2d8", "17ba6139-c9df-47d5-a8c2-d84de8a5c45a", "65f11d47-4569-496d-a8cc-83114174e2d8", "17ba6139-c9df-47d5-a8c2-d84de8a5c45a", "65f11d47-4569-496d-a8cc-83114174e2d8", "17ba6139-c9df-47d5-a8c2-d84de8a5c45a"], "metadata": {"page_label": "581", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "865eb2a8-f914-4962-92b4-e85a08a97102": {"node_ids": ["025ef01f-29d2-4352-aedd-3896af457063", "61cf5316-6784-42d7-b63b-2042b4ab4c06", "025ef01f-29d2-4352-aedd-3896af457063", "61cf5316-6784-42d7-b63b-2042b4ab4c06", "025ef01f-29d2-4352-aedd-3896af457063", "61cf5316-6784-42d7-b63b-2042b4ab4c06"], "metadata": {"page_label": "582", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5a20bf0e-e068-4714-b1b0-211e3cda595d": {"node_ids": ["7ff6bec9-cf17-45af-87ac-0530ea9faece", "b13732f2-d306-4493-93fa-3e48eab23c05", "7ff6bec9-cf17-45af-87ac-0530ea9faece", "b13732f2-d306-4493-93fa-3e48eab23c05", "7ff6bec9-cf17-45af-87ac-0530ea9faece", "b13732f2-d306-4493-93fa-3e48eab23c05"], "metadata": {"page_label": "583", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b77f441f-6c18-4904-b14a-41d4fb97c0be": {"node_ids": ["f3ed670c-23df-47e2-b3a4-612233ed6648", "a761a3ef-8386-443a-9505-f0117182f81e", "f3ed670c-23df-47e2-b3a4-612233ed6648", "a761a3ef-8386-443a-9505-f0117182f81e", "f3ed670c-23df-47e2-b3a4-612233ed6648", "a761a3ef-8386-443a-9505-f0117182f81e"], "metadata": {"page_label": "584", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "56594b9b-b903-4f5f-903b-aa7261fe37ee": {"node_ids": ["39c29a5c-7882-40d0-9a01-adb3566abe62", "39c29a5c-7882-40d0-9a01-adb3566abe62", "39c29a5c-7882-40d0-9a01-adb3566abe62"], "metadata": {"page_label": "585", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3bbd682c-2cc0-49f6-aa9e-fb1841e0d27d": {"node_ids": ["612ce01a-76ca-4d21-9707-9f37f07e8465", "aa485f7e-deaa-4be1-829e-f7ed129efc99", "612ce01a-76ca-4d21-9707-9f37f07e8465", "aa485f7e-deaa-4be1-829e-f7ed129efc99", "612ce01a-76ca-4d21-9707-9f37f07e8465", "aa485f7e-deaa-4be1-829e-f7ed129efc99"], "metadata": {"page_label": "586", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fd85ddd7-7132-4c68-9bdd-f820ad8e8cf1": {"node_ids": ["470c3dd2-db51-42a0-a2f9-ba997ae99658", "dd3f9c7f-e1d2-4dba-90be-adad213f2a9f", "470c3dd2-db51-42a0-a2f9-ba997ae99658", "dd3f9c7f-e1d2-4dba-90be-adad213f2a9f", "470c3dd2-db51-42a0-a2f9-ba997ae99658", "dd3f9c7f-e1d2-4dba-90be-adad213f2a9f"], "metadata": {"page_label": "587", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ae98dfd7-bd97-4b59-9673-f70ff15009e7": {"node_ids": ["c0f9ceae-7a96-4f5d-99a3-91b444e4d107", "5e27f721-703c-4e45-83a0-bb8bca91f862", "e217289f-adb9-4478-aeda-594fd76d0243", "c0f9ceae-7a96-4f5d-99a3-91b444e4d107", "5e27f721-703c-4e45-83a0-bb8bca91f862", "e217289f-adb9-4478-aeda-594fd76d0243", "c0f9ceae-7a96-4f5d-99a3-91b444e4d107", "5e27f721-703c-4e45-83a0-bb8bca91f862", "e217289f-adb9-4478-aeda-594fd76d0243"], "metadata": {"page_label": "588", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d30d9ee7-c655-450b-b608-5879c7ab9d87": {"node_ids": ["2ab3b2fb-bc7d-4043-af72-c8de1aa0d204", "514ecaf3-fc03-4697-9fe4-78622b29fe54", "2ab3b2fb-bc7d-4043-af72-c8de1aa0d204", "514ecaf3-fc03-4697-9fe4-78622b29fe54", "2ab3b2fb-bc7d-4043-af72-c8de1aa0d204", "514ecaf3-fc03-4697-9fe4-78622b29fe54"], "metadata": {"page_label": "589", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b75d166d-6fec-4370-befe-44087ce027ad": {"node_ids": ["aeba0693-6d5c-4426-8c36-196787e98273", "226910e6-a2ea-490c-abce-615584118567", "aeba0693-6d5c-4426-8c36-196787e98273", "226910e6-a2ea-490c-abce-615584118567", "aeba0693-6d5c-4426-8c36-196787e98273", "226910e6-a2ea-490c-abce-615584118567"], "metadata": {"page_label": "590", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8db06f35-b0dc-4488-ae1a-ecb47748b226": {"node_ids": ["d43e6ede-6000-4233-971c-2e723d0e9133", "d43e6ede-6000-4233-971c-2e723d0e9133", "d43e6ede-6000-4233-971c-2e723d0e9133"], "metadata": {"page_label": "591", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ac0b7db0-e4ea-4680-a4d3-05b2eb89eeda": {"node_ids": ["3ee31c09-301d-44df-8702-76d5b874ab97", "993ef7ae-b698-4e86-aeb0-fee379eb3c48", "3ee31c09-301d-44df-8702-76d5b874ab97", "993ef7ae-b698-4e86-aeb0-fee379eb3c48", "3ee31c09-301d-44df-8702-76d5b874ab97", "993ef7ae-b698-4e86-aeb0-fee379eb3c48"], "metadata": {"page_label": "592", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bf4d2666-79e3-4149-ad55-f289e88bf3c4": {"node_ids": ["cd5f10d2-5483-49c0-a8bb-fab71341d723", "de887d18-d6f7-4a83-8451-e32457ff8a1c", "cd5f10d2-5483-49c0-a8bb-fab71341d723", "de887d18-d6f7-4a83-8451-e32457ff8a1c", "cd5f10d2-5483-49c0-a8bb-fab71341d723", "de887d18-d6f7-4a83-8451-e32457ff8a1c"], "metadata": {"page_label": "593", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "bece3d50-eb40-481e-b025-57eb4b175b7e": {"node_ids": ["af86ae83-26b3-4be9-aecb-4e097e188e31", "f11cc710-96ea-4f17-8adf-ccf174a7bb5b", "7d5de878-2047-403f-84f3-a7477bda590c", "af86ae83-26b3-4be9-aecb-4e097e188e31", "f11cc710-96ea-4f17-8adf-ccf174a7bb5b", "7d5de878-2047-403f-84f3-a7477bda590c", "af86ae83-26b3-4be9-aecb-4e097e188e31", "f11cc710-96ea-4f17-8adf-ccf174a7bb5b", "7d5de878-2047-403f-84f3-a7477bda590c"], "metadata": {"page_label": "594", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "509f652a-353f-41a1-893e-8ca2be914814": {"node_ids": ["7364b4be-e84c-403b-afdd-294c57e53e7e", "fd7cfb9c-05f9-403d-a453-4ba3135d479e", "7364b4be-e84c-403b-afdd-294c57e53e7e", "fd7cfb9c-05f9-403d-a453-4ba3135d479e", "7364b4be-e84c-403b-afdd-294c57e53e7e", "fd7cfb9c-05f9-403d-a453-4ba3135d479e"], "metadata": {"page_label": "595", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "afa32515-efdc-4c1c-b38b-71796b965215": {"node_ids": ["433417a6-7815-46a9-960a-f48303308a1c", "7775c399-8965-45ed-9ec6-b2c6d5fbf888", "433417a6-7815-46a9-960a-f48303308a1c", "7775c399-8965-45ed-9ec6-b2c6d5fbf888", "433417a6-7815-46a9-960a-f48303308a1c", "7775c399-8965-45ed-9ec6-b2c6d5fbf888"], "metadata": {"page_label": "596", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a207c394-df9d-4414-8fb1-1774ec46f401": {"node_ids": ["a921653a-79fb-4e40-9e44-ee07af3eafcf", "2161e05e-ece4-459c-92f3-e590a2e4d83d", "a921653a-79fb-4e40-9e44-ee07af3eafcf", "2161e05e-ece4-459c-92f3-e590a2e4d83d", "a921653a-79fb-4e40-9e44-ee07af3eafcf", "2161e05e-ece4-459c-92f3-e590a2e4d83d"], "metadata": {"page_label": "597", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ba7e63b3-524a-4c9c-984e-4be98a558c04": {"node_ids": ["1af33916-9be3-4f94-aa69-968b3752c031", "b6a177fd-b637-4898-8b11-fd396edc867d", "1af33916-9be3-4f94-aa69-968b3752c031", "b6a177fd-b637-4898-8b11-fd396edc867d", "1af33916-9be3-4f94-aa69-968b3752c031", "b6a177fd-b637-4898-8b11-fd396edc867d"], "metadata": {"page_label": "598", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "002f2c5e-4dd7-42a7-bef4-0d068e952e3c": {"node_ids": ["553a4bc6-1cc0-411a-97de-37f706286d56", "d03c13b8-c4c3-46c6-ac4c-7d1b3683c341", "5ff81ec4-4568-468a-8943-70e371a9a767", "553a4bc6-1cc0-411a-97de-37f706286d56", "d03c13b8-c4c3-46c6-ac4c-7d1b3683c341", "5ff81ec4-4568-468a-8943-70e371a9a767", "553a4bc6-1cc0-411a-97de-37f706286d56", "d03c13b8-c4c3-46c6-ac4c-7d1b3683c341", "5ff81ec4-4568-468a-8943-70e371a9a767"], "metadata": {"page_label": "599", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "43fd4ed7-1572-412f-a47f-356d2c67939f": {"node_ids": ["7f263fe4-9409-4824-84fd-a7b9df35d5c0", "f53e5479-2729-4b38-b27c-e8af013e34ad", "7f263fe4-9409-4824-84fd-a7b9df35d5c0", "f53e5479-2729-4b38-b27c-e8af013e34ad", "7f263fe4-9409-4824-84fd-a7b9df35d5c0", "f53e5479-2729-4b38-b27c-e8af013e34ad"], "metadata": {"page_label": "600", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8cdf5ec7-244a-4e0b-9728-85fb0c88ab94": {"node_ids": ["f3a18da5-0229-4907-b186-9403903b7c9d", "085d7461-731d-4087-9b93-4d10f6e920b4", "f3a18da5-0229-4907-b186-9403903b7c9d", "085d7461-731d-4087-9b93-4d10f6e920b4", "f3a18da5-0229-4907-b186-9403903b7c9d", "085d7461-731d-4087-9b93-4d10f6e920b4"], "metadata": {"page_label": "601", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "338ded58-3ef4-40b5-b531-502ca258b2a4": {"node_ids": ["f77f2a97-7648-433b-b19c-f051361579ab", "f77f2a97-7648-433b-b19c-f051361579ab", "f77f2a97-7648-433b-b19c-f051361579ab"], "metadata": {"page_label": "602", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "57769d3a-6a56-4554-9cf7-58d387f248de": {"node_ids": ["c87f70f4-7c5c-4c17-84f2-e339fb2626c7", "c87f70f4-7c5c-4c17-84f2-e339fb2626c7", "c87f70f4-7c5c-4c17-84f2-e339fb2626c7"], "metadata": {"page_label": "603", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "69b4d408-bc94-4ba6-a6ae-bc0d317331d7": {"node_ids": ["2a11dbcc-ca59-4cff-832a-fbe928bbf0aa", "131a0e16-36da-4cbb-bdd2-e82e0d62753a", "2b32a601-335b-48b5-bd86-987a61ac54b4", "2a11dbcc-ca59-4cff-832a-fbe928bbf0aa", "131a0e16-36da-4cbb-bdd2-e82e0d62753a", "2b32a601-335b-48b5-bd86-987a61ac54b4", "2a11dbcc-ca59-4cff-832a-fbe928bbf0aa", "131a0e16-36da-4cbb-bdd2-e82e0d62753a", "2b32a601-335b-48b5-bd86-987a61ac54b4"], "metadata": {"page_label": "604", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "312a2f71-a34a-4d6f-8308-3187507591fe": {"node_ids": ["42cd00ad-1111-45d1-a48a-21e18ff8b20a", "9321d863-a52a-48a9-992c-c408dfa4f38e", "7ddf767f-6f0b-4843-acf9-8d06d5ccce24", "42cd00ad-1111-45d1-a48a-21e18ff8b20a", "9321d863-a52a-48a9-992c-c408dfa4f38e", "7ddf767f-6f0b-4843-acf9-8d06d5ccce24", "42cd00ad-1111-45d1-a48a-21e18ff8b20a", "9321d863-a52a-48a9-992c-c408dfa4f38e", "7ddf767f-6f0b-4843-acf9-8d06d5ccce24"], "metadata": {"page_label": "605", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2efe2c16-367f-43b5-9630-e6a39097e363": {"node_ids": ["ad9dc5b2-25f7-4602-aa62-6f242d560dea", "3d29483e-98c6-4dd1-b4d0-47221ba4abef", "ad9dc5b2-25f7-4602-aa62-6f242d560dea", "3d29483e-98c6-4dd1-b4d0-47221ba4abef", "ad9dc5b2-25f7-4602-aa62-6f242d560dea", "3d29483e-98c6-4dd1-b4d0-47221ba4abef"], "metadata": {"page_label": "606", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2d99252a-62df-4cb3-b0f1-43ad935ac179": {"node_ids": ["86d817f1-93ad-4c07-aa29-1a911daff4c5", "2afca5f0-da4a-4cc7-8644-18a89394b048", "86d817f1-93ad-4c07-aa29-1a911daff4c5", "2afca5f0-da4a-4cc7-8644-18a89394b048", "86d817f1-93ad-4c07-aa29-1a911daff4c5", "2afca5f0-da4a-4cc7-8644-18a89394b048"], "metadata": {"page_label": "607", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2820bc6e-883e-4448-84da-9c2bcb123de1": {"node_ids": ["5307a524-20e4-4bed-b02a-7b228230e4aa", "3d6cc7f4-4031-4e79-b6af-02a8b7477ae3", "b6de8128-51c0-4015-a9cf-cf9274120170", "5307a524-20e4-4bed-b02a-7b228230e4aa", "3d6cc7f4-4031-4e79-b6af-02a8b7477ae3", "b6de8128-51c0-4015-a9cf-cf9274120170", "5307a524-20e4-4bed-b02a-7b228230e4aa", "3d6cc7f4-4031-4e79-b6af-02a8b7477ae3", "b6de8128-51c0-4015-a9cf-cf9274120170"], "metadata": {"page_label": "608", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7f2566f8-5879-4729-8b8b-de2ca19f31b3": {"node_ids": ["1cf3a3eb-7da6-4888-9be6-1e53416118ef", "fb6b9d1c-a0b1-41f6-9b1b-848d313ef342", "1cf3a3eb-7da6-4888-9be6-1e53416118ef", "fb6b9d1c-a0b1-41f6-9b1b-848d313ef342", "1cf3a3eb-7da6-4888-9be6-1e53416118ef", "fb6b9d1c-a0b1-41f6-9b1b-848d313ef342"], "metadata": {"page_label": "609", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1d3c8648-f910-44ef-b8f3-2b919f7a297c": {"node_ids": ["f5c04ba9-a958-403e-b267-5b813a9e8e75", "c3ba185f-02ea-4e45-9089-4e0ec8b71f29", "f5c04ba9-a958-403e-b267-5b813a9e8e75", "c3ba185f-02ea-4e45-9089-4e0ec8b71f29", "f5c04ba9-a958-403e-b267-5b813a9e8e75", "c3ba185f-02ea-4e45-9089-4e0ec8b71f29"], "metadata": {"page_label": "610", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f5a0ce43-750b-4daf-abe4-3b94a7320f12": {"node_ids": ["1c1e3e3a-f8b8-489b-962d-7d48823eadb2", "947d176e-6d0c-4c55-b790-48f0bcedf665", "1c1e3e3a-f8b8-489b-962d-7d48823eadb2", "947d176e-6d0c-4c55-b790-48f0bcedf665", "1c1e3e3a-f8b8-489b-962d-7d48823eadb2", "947d176e-6d0c-4c55-b790-48f0bcedf665"], "metadata": {"page_label": "611", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a7d782e9-35d0-4e51-bdfa-82fc22962e26": {"node_ids": ["03375adb-39cd-449c-b601-a5c4b1e5b6d7", "bcc12182-6b8b-4ae8-956b-e8f653e4a651", "03375adb-39cd-449c-b601-a5c4b1e5b6d7", "bcc12182-6b8b-4ae8-956b-e8f653e4a651", "03375adb-39cd-449c-b601-a5c4b1e5b6d7", "bcc12182-6b8b-4ae8-956b-e8f653e4a651"], "metadata": {"page_label": "612", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5a136616-d1d9-4e89-a6ec-7713242f1fb5": {"node_ids": ["8748c053-0b80-4fcf-894f-edad10851b33", "a30cee4b-a964-4792-9078-11de0a260c56", "8748c053-0b80-4fcf-894f-edad10851b33", "a30cee4b-a964-4792-9078-11de0a260c56", "8748c053-0b80-4fcf-894f-edad10851b33", "a30cee4b-a964-4792-9078-11de0a260c56"], "metadata": {"page_label": "613", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4cdf9854-fb5e-4ec0-9bd1-752d12ec6643": {"node_ids": ["f10b5deb-7587-4b20-af67-a60bf2bcbb02", "f10b5deb-7587-4b20-af67-a60bf2bcbb02", "f10b5deb-7587-4b20-af67-a60bf2bcbb02"], "metadata": {"page_label": "614", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "df2004c2-5f6e-452b-ba4b-9b9103450cb5": {"node_ids": ["433a1465-f8a9-42b9-918f-fa18c8b0be46", "eecb9424-6a07-4c77-866e-f68c000a6880", "433a1465-f8a9-42b9-918f-fa18c8b0be46", "eecb9424-6a07-4c77-866e-f68c000a6880", "433a1465-f8a9-42b9-918f-fa18c8b0be46", "eecb9424-6a07-4c77-866e-f68c000a6880"], "metadata": {"page_label": "615", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7901cacf-47ed-4568-9920-9f3dfbe92689": {"node_ids": ["ae34076b-a2ff-430a-8c8a-2761a624256d", "ae34076b-a2ff-430a-8c8a-2761a624256d", "ae34076b-a2ff-430a-8c8a-2761a624256d"], "metadata": {"page_label": "616", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1e120836-3fed-48fd-bf36-e585e563e7ce": {"node_ids": ["391b0fb3-949e-47f6-8ccd-3e4dee663829", "7bdcb91a-5f2a-4b7a-bd7e-b92c08e13259", "49ada95d-aaed-4313-a2e3-8db3d0977f06", "391b0fb3-949e-47f6-8ccd-3e4dee663829", "7bdcb91a-5f2a-4b7a-bd7e-b92c08e13259", "49ada95d-aaed-4313-a2e3-8db3d0977f06", "391b0fb3-949e-47f6-8ccd-3e4dee663829", "7bdcb91a-5f2a-4b7a-bd7e-b92c08e13259", "49ada95d-aaed-4313-a2e3-8db3d0977f06"], "metadata": {"page_label": "617", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ad1eb29b-7bf6-4638-93de-c1bd04d73140": {"node_ids": ["dfeb2f71-c017-4b57-8772-c8365f1c34b7", "dfeb2f71-c017-4b57-8772-c8365f1c34b7", "dfeb2f71-c017-4b57-8772-c8365f1c34b7"], "metadata": {"page_label": "618", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e7652755-7ba9-442d-bb56-d595adf3c0f3": {"node_ids": ["9c2f936a-8b0c-4202-b1a2-47f099701f50", "e34cc61d-5d71-43b9-8ce8-cfbe98c45ecd", "9c2f936a-8b0c-4202-b1a2-47f099701f50", "e34cc61d-5d71-43b9-8ce8-cfbe98c45ecd", "9c2f936a-8b0c-4202-b1a2-47f099701f50", "e34cc61d-5d71-43b9-8ce8-cfbe98c45ecd"], "metadata": {"page_label": "619", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d5f69c01-59be-41a8-a41a-3883ac1c321e": {"node_ids": ["a4f93db8-1df1-49b5-aff9-e8e897dfcdd8", "6946f9ff-8135-4fa6-98dc-4c5074f062c2", "a4f93db8-1df1-49b5-aff9-e8e897dfcdd8", "6946f9ff-8135-4fa6-98dc-4c5074f062c2", "a4f93db8-1df1-49b5-aff9-e8e897dfcdd8", "6946f9ff-8135-4fa6-98dc-4c5074f062c2"], "metadata": {"page_label": "620", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ecfd36e2-0e35-4c3a-8249-c02786406561": {"node_ids": ["e8b777a0-8cf5-4894-8377-dfae081dcb31", "6fa5609f-13d2-4abd-a46b-7d5645c95ce4", "e8b777a0-8cf5-4894-8377-dfae081dcb31", "6fa5609f-13d2-4abd-a46b-7d5645c95ce4", "e8b777a0-8cf5-4894-8377-dfae081dcb31", "6fa5609f-13d2-4abd-a46b-7d5645c95ce4"], "metadata": {"page_label": "621", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9d0495d1-80f5-4d6e-bd59-9b420170953c": {"node_ids": ["07c858f0-4a89-4b45-ab01-9d85da770778", "db8e1154-a5c3-4cdc-91bf-2f58ef938362", "07c858f0-4a89-4b45-ab01-9d85da770778", "db8e1154-a5c3-4cdc-91bf-2f58ef938362", "07c858f0-4a89-4b45-ab01-9d85da770778", "db8e1154-a5c3-4cdc-91bf-2f58ef938362"], "metadata": {"page_label": "622", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "78eddb40-33d6-43e4-af90-987363f1d25c": {"node_ids": ["93fd3e61-a306-4da2-a662-1f288a4777b6", "9b8ecf75-bdbc-4d6c-8e48-2cb578bdcb9e", "743bc24e-4d19-4763-89f5-3896eb213b24", "93fd3e61-a306-4da2-a662-1f288a4777b6", "9b8ecf75-bdbc-4d6c-8e48-2cb578bdcb9e", "743bc24e-4d19-4763-89f5-3896eb213b24", "93fd3e61-a306-4da2-a662-1f288a4777b6", "9b8ecf75-bdbc-4d6c-8e48-2cb578bdcb9e", "743bc24e-4d19-4763-89f5-3896eb213b24"], "metadata": {"page_label": "623", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a54dc9d5-fd9a-4943-bbb5-c1568dc70c0b": {"node_ids": ["2a81eb0c-90a2-4403-a16f-15345f94069a", "45b9431e-21d4-452f-9adf-f4d1130877b1", "2a81eb0c-90a2-4403-a16f-15345f94069a", "45b9431e-21d4-452f-9adf-f4d1130877b1", "2a81eb0c-90a2-4403-a16f-15345f94069a", "45b9431e-21d4-452f-9adf-f4d1130877b1"], "metadata": {"page_label": "624", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2113f332-9cbd-439f-ac53-98bbd9ec1a6f": {"node_ids": ["e93b4355-1890-4f3f-92e3-494d89d287ef", "1cb50598-8efd-40b2-bab2-48a5c4491a79", "430aea8c-5fb0-47a0-b38f-649d2503e5e3", "e93b4355-1890-4f3f-92e3-494d89d287ef", "1cb50598-8efd-40b2-bab2-48a5c4491a79", "430aea8c-5fb0-47a0-b38f-649d2503e5e3", "e93b4355-1890-4f3f-92e3-494d89d287ef", "1cb50598-8efd-40b2-bab2-48a5c4491a79", "430aea8c-5fb0-47a0-b38f-649d2503e5e3"], "metadata": {"page_label": "625", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f1a8ee66-1f5b-4847-96e7-09398b7db6b1": {"node_ids": ["6cab7286-34e7-40d5-be18-85c4ade5c9a5", "bf41a9a7-cd62-4686-b73d-66176c7eb2d3", "569e94be-18c5-4ce8-993b-65587b88d6a5", "6cab7286-34e7-40d5-be18-85c4ade5c9a5", "bf41a9a7-cd62-4686-b73d-66176c7eb2d3", "569e94be-18c5-4ce8-993b-65587b88d6a5", "6cab7286-34e7-40d5-be18-85c4ade5c9a5", "bf41a9a7-cd62-4686-b73d-66176c7eb2d3", "569e94be-18c5-4ce8-993b-65587b88d6a5"], "metadata": {"page_label": "626", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f559645a-5b6c-4280-8910-6640170daa3c": {"node_ids": ["32062168-3e7b-46c4-8b02-e224ae8c6da4", "e7c1d774-5e0d-4fa0-9b37-d18387efdb36", "32062168-3e7b-46c4-8b02-e224ae8c6da4", "e7c1d774-5e0d-4fa0-9b37-d18387efdb36", "32062168-3e7b-46c4-8b02-e224ae8c6da4", "e7c1d774-5e0d-4fa0-9b37-d18387efdb36"], "metadata": {"page_label": "627", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2e86c0b2-bd7c-45f4-ba93-e4fb7d65f5f5": {"node_ids": ["516970e4-2f4f-4431-8ef0-156a834b44fd", "8b5a1da4-3c7d-4806-bf40-b20ba0ed6a0a", "516970e4-2f4f-4431-8ef0-156a834b44fd", "8b5a1da4-3c7d-4806-bf40-b20ba0ed6a0a", "516970e4-2f4f-4431-8ef0-156a834b44fd", "8b5a1da4-3c7d-4806-bf40-b20ba0ed6a0a"], "metadata": {"page_label": "628", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "dd3b0751-225b-4d31-bbe3-ec2b4eab3a1a": {"node_ids": ["95b8a40d-e800-4917-b8c3-1396616df9be", "07edd5b6-0501-4400-8e19-c30c8f229b3d", "95b8a40d-e800-4917-b8c3-1396616df9be", "07edd5b6-0501-4400-8e19-c30c8f229b3d", "95b8a40d-e800-4917-b8c3-1396616df9be", "07edd5b6-0501-4400-8e19-c30c8f229b3d"], "metadata": {"page_label": "629", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2d76ece2-3022-4022-a259-989bfd5da8d6": {"node_ids": ["9ec8c017-27ec-4435-91bb-da363cd05d96", "9ec8c017-27ec-4435-91bb-da363cd05d96", "9ec8c017-27ec-4435-91bb-da363cd05d96"], "metadata": {"page_label": "630", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d587c035-8386-43dc-b3b0-c7c6e58ef870": {"node_ids": ["f36ab8bc-71a5-4dc5-a0e2-5ac5c71005ea", "e519616a-8e39-4172-a6c7-16fbe874a111", "f36ab8bc-71a5-4dc5-a0e2-5ac5c71005ea", "e519616a-8e39-4172-a6c7-16fbe874a111", "f36ab8bc-71a5-4dc5-a0e2-5ac5c71005ea", "e519616a-8e39-4172-a6c7-16fbe874a111"], "metadata": {"page_label": "631", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4ead50f6-ec16-457d-8cf7-e29e6f9209fb": {"node_ids": ["17ec8187-c9bd-4923-b31b-71360471fcb6", "c48be504-0ab3-4d25-9333-51bae94645a0", "17ec8187-c9bd-4923-b31b-71360471fcb6", "c48be504-0ab3-4d25-9333-51bae94645a0", "17ec8187-c9bd-4923-b31b-71360471fcb6", "c48be504-0ab3-4d25-9333-51bae94645a0"], "metadata": {"page_label": "632", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "8703b11f-dc88-4e11-850d-8402c234356f": {"node_ids": ["8ac3749f-eceb-4bbf-8912-e28edbdac033", "ad4cc372-698b-45d5-be2c-a91578887da6", "abd72f2f-6891-4008-8ca8-c4cc40cff131", "8ac3749f-eceb-4bbf-8912-e28edbdac033", "ad4cc372-698b-45d5-be2c-a91578887da6", "abd72f2f-6891-4008-8ca8-c4cc40cff131", "8ac3749f-eceb-4bbf-8912-e28edbdac033", "ad4cc372-698b-45d5-be2c-a91578887da6", "abd72f2f-6891-4008-8ca8-c4cc40cff131"], "metadata": {"page_label": "633", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3d7f5e90-b5b5-4f5c-8e92-f1938d552974": {"node_ids": ["ab92eae8-620f-46d6-bfa3-c6699396b557", "f5b0d324-b66e-40b3-94a1-863dc313e122", "ab92eae8-620f-46d6-bfa3-c6699396b557", "f5b0d324-b66e-40b3-94a1-863dc313e122", "ab92eae8-620f-46d6-bfa3-c6699396b557", "f5b0d324-b66e-40b3-94a1-863dc313e122"], "metadata": {"page_label": "634", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "874b9f4e-e762-491e-a533-a181f375a3fd": {"node_ids": ["6be165eb-c820-497a-a223-7d02bace9369", "da7077c6-2ce5-4b8e-8def-ec1d4a757d0a", "09bcd39e-0fa7-4867-aa66-56d5a9d268fd", "6be165eb-c820-497a-a223-7d02bace9369", "da7077c6-2ce5-4b8e-8def-ec1d4a757d0a", "09bcd39e-0fa7-4867-aa66-56d5a9d268fd", "6be165eb-c820-497a-a223-7d02bace9369", "da7077c6-2ce5-4b8e-8def-ec1d4a757d0a", "09bcd39e-0fa7-4867-aa66-56d5a9d268fd"], "metadata": {"page_label": "635", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4b3fcb1a-c638-4a31-a7d8-273fa736b792": {"node_ids": ["322b9ddd-4f10-475e-b6d8-f124be0ad7d3", "c2bca4ce-6c98-43d4-83ae-36f6874e1609", "322b9ddd-4f10-475e-b6d8-f124be0ad7d3", "c2bca4ce-6c98-43d4-83ae-36f6874e1609", "322b9ddd-4f10-475e-b6d8-f124be0ad7d3", "c2bca4ce-6c98-43d4-83ae-36f6874e1609"], "metadata": {"page_label": "636", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3eef0e8f-fdfb-4d56-aa44-4637b95e1723": {"node_ids": ["5be1fffd-6ab7-41e5-8e6b-321628302807", "3e4810a7-c9c0-449d-9a0e-4c59eb46e2f5", "5be1fffd-6ab7-41e5-8e6b-321628302807", "3e4810a7-c9c0-449d-9a0e-4c59eb46e2f5", "5be1fffd-6ab7-41e5-8e6b-321628302807", "3e4810a7-c9c0-449d-9a0e-4c59eb46e2f5"], "metadata": {"page_label": "637", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0cff3a89-49c9-4dba-a3b0-16640524b0a2": {"node_ids": ["67e56903-fefd-495c-8ee1-71c381d988a3", "6f87ace5-de7e-4683-be00-fd172654f5cd", "67e56903-fefd-495c-8ee1-71c381d988a3", "6f87ace5-de7e-4683-be00-fd172654f5cd", "67e56903-fefd-495c-8ee1-71c381d988a3", "6f87ace5-de7e-4683-be00-fd172654f5cd"], "metadata": {"page_label": "638", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "7c3c77b5-3567-4f39-a560-42492e688f10": {"node_ids": ["a11d45fd-32b1-4b35-87ec-e3c6ce9f183c", "c1231d56-1997-4a9d-939c-172b99643883", "fafeb35d-6cd7-4f40-aead-ca1dcb0f3993", "a11d45fd-32b1-4b35-87ec-e3c6ce9f183c", "c1231d56-1997-4a9d-939c-172b99643883", "fafeb35d-6cd7-4f40-aead-ca1dcb0f3993", "a11d45fd-32b1-4b35-87ec-e3c6ce9f183c", "c1231d56-1997-4a9d-939c-172b99643883", "fafeb35d-6cd7-4f40-aead-ca1dcb0f3993"], "metadata": {"page_label": "639", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c3648494-4412-4b52-ad27-3d72dc418a7d": {"node_ids": ["a6f0f1b3-9e51-4091-940e-22f0adbd828a", "764b4dfd-5959-42a8-8fcf-9e76a73ed7f5", "a6f0f1b3-9e51-4091-940e-22f0adbd828a", "764b4dfd-5959-42a8-8fcf-9e76a73ed7f5", "a6f0f1b3-9e51-4091-940e-22f0adbd828a", "764b4dfd-5959-42a8-8fcf-9e76a73ed7f5"], "metadata": {"page_label": "640", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "58e3bf08-ed16-4fb0-b826-41a45f86ba50": {"node_ids": ["9eeb51b3-85dd-42ba-96c2-0b0ec62ef93e", "6ca8bd3a-03a8-46d0-9344-20f40d61f284", "9eeb51b3-85dd-42ba-96c2-0b0ec62ef93e", "6ca8bd3a-03a8-46d0-9344-20f40d61f284", "9eeb51b3-85dd-42ba-96c2-0b0ec62ef93e", "6ca8bd3a-03a8-46d0-9344-20f40d61f284"], "metadata": {"page_label": "641", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b5c4ccdc-4114-4b4d-af9d-cc4d4b31388a": {"node_ids": ["4fb27e9d-2386-4ac3-acc0-c04888f15d54", "40c6360b-b674-4039-ac99-b012a0958161", "a78b79b3-0ce7-43cf-af7f-7968c3f7dfbc", "4fb27e9d-2386-4ac3-acc0-c04888f15d54", "40c6360b-b674-4039-ac99-b012a0958161", "a78b79b3-0ce7-43cf-af7f-7968c3f7dfbc", "4fb27e9d-2386-4ac3-acc0-c04888f15d54", "40c6360b-b674-4039-ac99-b012a0958161", "a78b79b3-0ce7-43cf-af7f-7968c3f7dfbc"], "metadata": {"page_label": "642", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1a46f68e-529f-43ea-a038-4d6f63034c9c": {"node_ids": ["0aef7c24-9306-4859-b62a-3cba9149a3bb", "531760e5-cdec-43b8-8619-16584da826a8", "07957c2c-e6db-4cec-b16d-8ca6010f2022", "0aef7c24-9306-4859-b62a-3cba9149a3bb", "531760e5-cdec-43b8-8619-16584da826a8", "07957c2c-e6db-4cec-b16d-8ca6010f2022", "0aef7c24-9306-4859-b62a-3cba9149a3bb", "531760e5-cdec-43b8-8619-16584da826a8", "07957c2c-e6db-4cec-b16d-8ca6010f2022"], "metadata": {"page_label": "643", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b9cbf605-93df-4549-bd99-1271cf0dab9d": {"node_ids": ["bcd9764b-ab66-4b7d-98f2-40c8ed1760c3", "2c33f4a8-8e05-4e46-a4c9-c0c699d8c7f9", "dcf98b54-e459-4c88-9f87-847e43c8e5bc", "bcd9764b-ab66-4b7d-98f2-40c8ed1760c3", "2c33f4a8-8e05-4e46-a4c9-c0c699d8c7f9", "dcf98b54-e459-4c88-9f87-847e43c8e5bc", "bcd9764b-ab66-4b7d-98f2-40c8ed1760c3", "2c33f4a8-8e05-4e46-a4c9-c0c699d8c7f9", "dcf98b54-e459-4c88-9f87-847e43c8e5bc"], "metadata": {"page_label": "644", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e59a8298-de9b-4d00-b1f4-08d427547d48": {"node_ids": ["b24314a7-6d54-43a2-a0d6-8b3803dce7e0", "682c95f4-597f-4c32-82d4-21c11ad6e50f", "b24314a7-6d54-43a2-a0d6-8b3803dce7e0", "682c95f4-597f-4c32-82d4-21c11ad6e50f", "b24314a7-6d54-43a2-a0d6-8b3803dce7e0", "682c95f4-597f-4c32-82d4-21c11ad6e50f"], "metadata": {"page_label": "645", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f9b72da7-a4e5-4e89-b678-9f094ec7b82f": {"node_ids": ["604b214e-51ad-4d0c-961c-430d576cdff8", "5060825b-63d7-456d-9ddf-84dd3d76b032", "a9f69881-2563-40c3-a5cd-846013a8a3b5", "604b214e-51ad-4d0c-961c-430d576cdff8", "5060825b-63d7-456d-9ddf-84dd3d76b032", "a9f69881-2563-40c3-a5cd-846013a8a3b5", "604b214e-51ad-4d0c-961c-430d576cdff8", "5060825b-63d7-456d-9ddf-84dd3d76b032", "a9f69881-2563-40c3-a5cd-846013a8a3b5"], "metadata": {"page_label": "646", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c7f74e43-8e7d-4d08-89f1-bbaab2c6496a": {"node_ids": ["a504cc21-d0f0-49c0-81ac-47871e3036ee", "81221f02-a342-470e-876b-569fc414769e", "01fc53ae-48ed-430f-ad3c-2b789efd5a56", "a504cc21-d0f0-49c0-81ac-47871e3036ee", "81221f02-a342-470e-876b-569fc414769e", "01fc53ae-48ed-430f-ad3c-2b789efd5a56", "a504cc21-d0f0-49c0-81ac-47871e3036ee", "81221f02-a342-470e-876b-569fc414769e", "01fc53ae-48ed-430f-ad3c-2b789efd5a56"], "metadata": {"page_label": "647", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6bc5877c-5e02-4e2a-b9f2-d6120adaf5b4": {"node_ids": ["f692a058-a0f2-4b40-8b21-9598299fd033", "f3b0c188-e64f-4925-b7d9-fe533b64e7ca", "f692a058-a0f2-4b40-8b21-9598299fd033", "f3b0c188-e64f-4925-b7d9-fe533b64e7ca", "f692a058-a0f2-4b40-8b21-9598299fd033", "f3b0c188-e64f-4925-b7d9-fe533b64e7ca"], "metadata": {"page_label": "648", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2148cb08-62c0-4401-b896-597578c7c06f": {"node_ids": ["d48528ea-29d1-4ebc-afdc-a6783df6b96f", "23833d5b-42b3-4a9a-bcf2-f8a85b026908", "d48528ea-29d1-4ebc-afdc-a6783df6b96f", "23833d5b-42b3-4a9a-bcf2-f8a85b026908", "d48528ea-29d1-4ebc-afdc-a6783df6b96f", "23833d5b-42b3-4a9a-bcf2-f8a85b026908"], "metadata": {"page_label": "649", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2fe47891-bc43-44c1-94ac-b4b2db97a144": {"node_ids": ["46452a1f-b27b-4240-87fa-a58466163bcc", "77dd74b2-7517-47e3-964e-1bc3a9007fdf", "11dddb05-a649-4cf7-95b9-bb1d0e6ba079", "46452a1f-b27b-4240-87fa-a58466163bcc", "77dd74b2-7517-47e3-964e-1bc3a9007fdf", "11dddb05-a649-4cf7-95b9-bb1d0e6ba079", "46452a1f-b27b-4240-87fa-a58466163bcc", "77dd74b2-7517-47e3-964e-1bc3a9007fdf", "11dddb05-a649-4cf7-95b9-bb1d0e6ba079"], "metadata": {"page_label": "650", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c983fe62-8971-4ff7-8e50-86850bdfa874": {"node_ids": ["0213c980-b226-4d91-b759-adc93579fa37", "b818b4a3-960a-4e9f-a81b-5bf1d7ba7b3e", "0213c980-b226-4d91-b759-adc93579fa37", "b818b4a3-960a-4e9f-a81b-5bf1d7ba7b3e", "0213c980-b226-4d91-b759-adc93579fa37", "b818b4a3-960a-4e9f-a81b-5bf1d7ba7b3e"], "metadata": {"page_label": "651", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "69bd3a26-e6d9-4729-8f4d-376bcc555e30": {"node_ids": ["2029ef8e-ba17-462e-a505-460983e18d50", "58662f01-c9f7-453f-bf89-728c26533199", "2029ef8e-ba17-462e-a505-460983e18d50", "58662f01-c9f7-453f-bf89-728c26533199", "2029ef8e-ba17-462e-a505-460983e18d50", "58662f01-c9f7-453f-bf89-728c26533199"], "metadata": {"page_label": "652", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "dcab43cf-2ff9-4d1e-b988-b9759eadfbe4": {"node_ids": ["d8db13fe-c627-4faa-89fe-9eaa6a9697da", "240a91f6-9cbd-4e53-ac5c-5b71ae959686", "ce6d8334-9fa7-41e1-97f9-6e5cc4f8b472", "d8db13fe-c627-4faa-89fe-9eaa6a9697da", "240a91f6-9cbd-4e53-ac5c-5b71ae959686", "ce6d8334-9fa7-41e1-97f9-6e5cc4f8b472", "d8db13fe-c627-4faa-89fe-9eaa6a9697da", "240a91f6-9cbd-4e53-ac5c-5b71ae959686", "ce6d8334-9fa7-41e1-97f9-6e5cc4f8b472"], "metadata": {"page_label": "653", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f785b104-64fc-49a4-b797-9161997b8c43": {"node_ids": ["6e55a8a4-20dc-488f-a9c3-61ad0e77fb04", "6e55a8a4-20dc-488f-a9c3-61ad0e77fb04", "6e55a8a4-20dc-488f-a9c3-61ad0e77fb04"], "metadata": {"page_label": "654", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "908c8163-8e30-4dd5-ad96-449b5afc9c46": {"node_ids": ["24dc8f21-0e3f-4ac2-a965-2b00c544b25b", "701e9792-594f-4c5e-8252-f8646d095a24", "24dc8f21-0e3f-4ac2-a965-2b00c544b25b", "701e9792-594f-4c5e-8252-f8646d095a24", "24dc8f21-0e3f-4ac2-a965-2b00c544b25b", "701e9792-594f-4c5e-8252-f8646d095a24"], "metadata": {"page_label": "655", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "27a2a753-e2e2-4f71-9464-eaa2536dc508": {"node_ids": ["23dabe2e-906a-4568-9a21-9f62330158fc", "75fa331e-8517-47b9-b405-889b999b5edb", "23dabe2e-906a-4568-9a21-9f62330158fc", "75fa331e-8517-47b9-b405-889b999b5edb", "23dabe2e-906a-4568-9a21-9f62330158fc", "75fa331e-8517-47b9-b405-889b999b5edb"], "metadata": {"page_label": "656", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9c335243-72be-4536-8b34-045896734771": {"node_ids": ["cc75090a-ace5-4557-a639-c08cb2c9cb87", "6667803d-4b94-418d-9db4-532c84c3d53b", "b73569e5-6d0a-4ab4-9abe-567afd2eae4c", "cc75090a-ace5-4557-a639-c08cb2c9cb87", "6667803d-4b94-418d-9db4-532c84c3d53b", "b73569e5-6d0a-4ab4-9abe-567afd2eae4c", "cc75090a-ace5-4557-a639-c08cb2c9cb87", "6667803d-4b94-418d-9db4-532c84c3d53b", "b73569e5-6d0a-4ab4-9abe-567afd2eae4c"], "metadata": {"page_label": "657", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "07dae539-6535-4c86-bb80-37aefc86baf5": {"node_ids": ["c652cc54-db1c-43c8-952b-91ace1a0273c", "888485b7-b1b5-4ee6-a13a-45270a9763f8", "c652cc54-db1c-43c8-952b-91ace1a0273c", "888485b7-b1b5-4ee6-a13a-45270a9763f8", "c652cc54-db1c-43c8-952b-91ace1a0273c", "888485b7-b1b5-4ee6-a13a-45270a9763f8"], "metadata": {"page_label": "658", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6b26feae-519d-4f6d-96a5-99f38d5772d1": {"node_ids": ["b0a97c8b-351a-4be9-9757-8297899ca902", "cdf86a22-f0a2-42a2-9ab1-ca49de88370b", "b0a97c8b-351a-4be9-9757-8297899ca902", "cdf86a22-f0a2-42a2-9ab1-ca49de88370b", "b0a97c8b-351a-4be9-9757-8297899ca902", "cdf86a22-f0a2-42a2-9ab1-ca49de88370b"], "metadata": {"page_label": "659", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c2504e7f-e8e1-4ca5-81e2-e0c03cace9f3": {"node_ids": ["2e4c9fc5-5ab4-4fe9-8305-3e74faf43613", "be6bb892-1b6a-4aee-9c84-3b07c3735cd0", "2e4c9fc5-5ab4-4fe9-8305-3e74faf43613", "be6bb892-1b6a-4aee-9c84-3b07c3735cd0", "2e4c9fc5-5ab4-4fe9-8305-3e74faf43613", "be6bb892-1b6a-4aee-9c84-3b07c3735cd0"], "metadata": {"page_label": "660", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1ff195ec-4f7f-4708-aa6b-e83508881e7e": {"node_ids": ["cc4787c9-c5f3-432c-a2d3-05b8215abae3", "94fbeca4-c332-4571-98cb-3934fa60cf58", "cc4787c9-c5f3-432c-a2d3-05b8215abae3", "94fbeca4-c332-4571-98cb-3934fa60cf58", "cc4787c9-c5f3-432c-a2d3-05b8215abae3", "94fbeca4-c332-4571-98cb-3934fa60cf58"], "metadata": {"page_label": "661", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d5c62a78-452e-43ec-aa98-6aa25c64d62f": {"node_ids": ["5de7d517-8dff-438a-93b6-d3e4ba9d4b0f", "29eb1067-6172-41ca-b929-1a1113e1bbd4", "2d50d67c-f648-4468-aa3e-d35d1b350bb5", "5de7d517-8dff-438a-93b6-d3e4ba9d4b0f", "29eb1067-6172-41ca-b929-1a1113e1bbd4", "2d50d67c-f648-4468-aa3e-d35d1b350bb5", "5de7d517-8dff-438a-93b6-d3e4ba9d4b0f", "29eb1067-6172-41ca-b929-1a1113e1bbd4", "2d50d67c-f648-4468-aa3e-d35d1b350bb5"], "metadata": {"page_label": "662", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9e1f1e74-9622-4e9c-b7eb-9e74a85ba5f9": {"node_ids": ["779a348b-cb57-4041-ac88-749b9b5bcdce", "b162d4e8-64c6-46da-8dd3-817aec41e5f2", "779a348b-cb57-4041-ac88-749b9b5bcdce", "b162d4e8-64c6-46da-8dd3-817aec41e5f2", "779a348b-cb57-4041-ac88-749b9b5bcdce", "b162d4e8-64c6-46da-8dd3-817aec41e5f2"], "metadata": {"page_label": "663", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1cc2fdc4-a2a1-4ca7-a8d6-9a9098d4b04a": {"node_ids": ["7d21e192-b249-478e-8a4e-2350f88f8683", "f4cece87-7184-4aa7-a8fd-594f85bcb543", "8cc9d1a2-a412-4d05-96eb-1a409f2fabb9", "7d21e192-b249-478e-8a4e-2350f88f8683", "f4cece87-7184-4aa7-a8fd-594f85bcb543", "8cc9d1a2-a412-4d05-96eb-1a409f2fabb9", "7d21e192-b249-478e-8a4e-2350f88f8683", "f4cece87-7184-4aa7-a8fd-594f85bcb543", "8cc9d1a2-a412-4d05-96eb-1a409f2fabb9"], "metadata": {"page_label": "664", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4c556122-bffe-4865-8fa1-530a8e5b00f6": {"node_ids": ["0f7b7808-aed9-427a-8fc7-33ee99afa9ac", "9bd9db61-eedf-4289-b996-18787e21cc6a", "0f7b7808-aed9-427a-8fc7-33ee99afa9ac", "9bd9db61-eedf-4289-b996-18787e21cc6a", "0f7b7808-aed9-427a-8fc7-33ee99afa9ac", "9bd9db61-eedf-4289-b996-18787e21cc6a"], "metadata": {"page_label": "665", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "73d5a33c-cb52-45b9-aed5-d8aae20d0605": {"node_ids": ["edd2db17-e93c-4430-9af2-7419ff9a22f1", "deba97d4-3a01-453b-a622-bc523ee0e4a8", "a501cfd6-10e4-49e9-8191-ebee11be4abf", "edd2db17-e93c-4430-9af2-7419ff9a22f1", "deba97d4-3a01-453b-a622-bc523ee0e4a8", "a501cfd6-10e4-49e9-8191-ebee11be4abf", "edd2db17-e93c-4430-9af2-7419ff9a22f1", "deba97d4-3a01-453b-a622-bc523ee0e4a8", "a501cfd6-10e4-49e9-8191-ebee11be4abf"], "metadata": {"page_label": "666", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "136baecb-c566-41a3-86bd-fb9bd7b2f0d7": {"node_ids": ["5e123bd4-0a1c-4f81-a5d7-7cde4863143c", "df2dc1e5-e165-421b-95cf-f1645ac8e5d9", "5e123bd4-0a1c-4f81-a5d7-7cde4863143c", "df2dc1e5-e165-421b-95cf-f1645ac8e5d9", "5e123bd4-0a1c-4f81-a5d7-7cde4863143c", "df2dc1e5-e165-421b-95cf-f1645ac8e5d9"], "metadata": {"page_label": "667", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3adc6ca8-f998-4c22-9283-360037d88142": {"node_ids": ["472a59da-4db7-4def-905c-61d4626e1ec6", "98349972-ecad-4cd1-982f-f861acf224ca", "472a59da-4db7-4def-905c-61d4626e1ec6", "98349972-ecad-4cd1-982f-f861acf224ca", "472a59da-4db7-4def-905c-61d4626e1ec6", "98349972-ecad-4cd1-982f-f861acf224ca"], "metadata": {"page_label": "668", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6374004c-8a86-4b16-b370-33289c90f13f": {"node_ids": ["b36f3c58-70ef-4e57-a9e4-bbcaeca1de3b", "f85999df-885d-4a7c-af6c-f8d40abb6d11", "b36f3c58-70ef-4e57-a9e4-bbcaeca1de3b", "f85999df-885d-4a7c-af6c-f8d40abb6d11", "b36f3c58-70ef-4e57-a9e4-bbcaeca1de3b", "f85999df-885d-4a7c-af6c-f8d40abb6d11"], "metadata": {"page_label": "669", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c178c693-0687-4790-baf6-145b3074f427": {"node_ids": ["dbd15765-a0bb-42fe-84b0-34cd41fc352c", "bb166b83-783a-4b65-8dcc-bf3883a830b8", "dbd15765-a0bb-42fe-84b0-34cd41fc352c", "bb166b83-783a-4b65-8dcc-bf3883a830b8", "dbd15765-a0bb-42fe-84b0-34cd41fc352c", "bb166b83-783a-4b65-8dcc-bf3883a830b8"], "metadata": {"page_label": "670", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "31cafe9e-210a-49b5-befe-867aae8e02b7": {"node_ids": ["b84dcf5f-5023-4ca1-b61f-8d0c409d653e", "31e83e60-ce3b-45d9-a688-baadd2b8bd57", "a7f5a7d2-4d84-4bce-b47f-de9f634b7d74", "b84dcf5f-5023-4ca1-b61f-8d0c409d653e", "31e83e60-ce3b-45d9-a688-baadd2b8bd57", "a7f5a7d2-4d84-4bce-b47f-de9f634b7d74", "b84dcf5f-5023-4ca1-b61f-8d0c409d653e", "31e83e60-ce3b-45d9-a688-baadd2b8bd57", "a7f5a7d2-4d84-4bce-b47f-de9f634b7d74"], "metadata": {"page_label": "671", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b7db9c1c-a464-466d-8f21-d9933ce4dcc6": {"node_ids": ["2b05c909-d809-4786-9846-e83bfb6181be", "f7dabf98-2661-49fb-a7e9-de259ecc4910", "2b05c909-d809-4786-9846-e83bfb6181be", "f7dabf98-2661-49fb-a7e9-de259ecc4910", "2b05c909-d809-4786-9846-e83bfb6181be", "f7dabf98-2661-49fb-a7e9-de259ecc4910"], "metadata": {"page_label": "672", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "54f273ea-09c8-4cf2-b70b-0ebb6d829493": {"node_ids": ["10576276-575d-4f56-9db2-371ab39ab7e2", "92b651f1-113e-43a5-a8a7-67a18b2881af", "10576276-575d-4f56-9db2-371ab39ab7e2", "92b651f1-113e-43a5-a8a7-67a18b2881af", "10576276-575d-4f56-9db2-371ab39ab7e2", "92b651f1-113e-43a5-a8a7-67a18b2881af"], "metadata": {"page_label": "673", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d83765ae-c8fa-4038-a9f2-82b4e1952e91": {"node_ids": ["a47e287e-8685-4c12-9709-ad839f3bd85a", "aef7a8b0-6e0e-4df1-b78e-05b328b5ad5a", "a47e287e-8685-4c12-9709-ad839f3bd85a", "aef7a8b0-6e0e-4df1-b78e-05b328b5ad5a", "a47e287e-8685-4c12-9709-ad839f3bd85a", "aef7a8b0-6e0e-4df1-b78e-05b328b5ad5a"], "metadata": {"page_label": "674", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a24d2522-4f8f-4729-a52b-a2cf8f13363a": {"node_ids": ["48fb80c8-6203-409c-9b6c-87c13f0fe5b4", "c1dfcf40-e0c6-44d6-aa91-b221c0f82793", "48fb80c8-6203-409c-9b6c-87c13f0fe5b4", "c1dfcf40-e0c6-44d6-aa91-b221c0f82793", "48fb80c8-6203-409c-9b6c-87c13f0fe5b4", "c1dfcf40-e0c6-44d6-aa91-b221c0f82793"], "metadata": {"page_label": "675", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2b4f64b0-e23a-4c85-8864-c7a9208735d4": {"node_ids": ["b0c188ab-15af-4e75-873e-18b9f434f1d8", "174484c9-e6e9-47bd-a47b-2573eee1e439", "0afa5cf3-37f3-47cf-ae78-1540c4c1489e", "b0c188ab-15af-4e75-873e-18b9f434f1d8", "174484c9-e6e9-47bd-a47b-2573eee1e439", "0afa5cf3-37f3-47cf-ae78-1540c4c1489e", "b0c188ab-15af-4e75-873e-18b9f434f1d8", "174484c9-e6e9-47bd-a47b-2573eee1e439", "0afa5cf3-37f3-47cf-ae78-1540c4c1489e"], "metadata": {"page_label": "676", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f0b77fdb-641f-4136-9cf8-1c4107194f19": {"node_ids": ["8a97026c-47e7-4abe-bc1c-21d317c8492f", "eeccafc1-476d-4eba-b672-9f5981b5348b", "6c21cbec-3ac7-4952-82d5-f1c7147dcc8a", "8a97026c-47e7-4abe-bc1c-21d317c8492f", "eeccafc1-476d-4eba-b672-9f5981b5348b", "6c21cbec-3ac7-4952-82d5-f1c7147dcc8a", "8a97026c-47e7-4abe-bc1c-21d317c8492f", "eeccafc1-476d-4eba-b672-9f5981b5348b", "6c21cbec-3ac7-4952-82d5-f1c7147dcc8a"], "metadata": {"page_label": "677", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "35c3b872-1067-4f17-bd91-33226ff6ce01": {"node_ids": ["bd3ce65a-6ca3-4715-becb-4eefa816a384", "b59e1ec7-acc3-4a62-8957-464b0bf33d8d", "bd3ce65a-6ca3-4715-becb-4eefa816a384", "b59e1ec7-acc3-4a62-8957-464b0bf33d8d", "bd3ce65a-6ca3-4715-becb-4eefa816a384", "b59e1ec7-acc3-4a62-8957-464b0bf33d8d"], "metadata": {"page_label": "678", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "87a197f0-49c1-40b7-b438-015a555d633f": {"node_ids": ["530b713e-bd2b-4cb5-b9c9-5df20a586e08", "00fd511d-73af-4b11-8f1b-9d9b15de644f", "8a03456e-c7a6-489b-9661-fa947365a6a1", "530b713e-bd2b-4cb5-b9c9-5df20a586e08", "00fd511d-73af-4b11-8f1b-9d9b15de644f", "8a03456e-c7a6-489b-9661-fa947365a6a1", "530b713e-bd2b-4cb5-b9c9-5df20a586e08", "00fd511d-73af-4b11-8f1b-9d9b15de644f", "8a03456e-c7a6-489b-9661-fa947365a6a1"], "metadata": {"page_label": "679", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "73da566b-a739-4ac7-8271-c453a1f2bcce": {"node_ids": ["27aecc84-8cb6-4cf4-b622-5a30edf725c6", "3792716d-60c9-46ee-b1b1-1fb55a658620", "a80e10ac-dffa-4f15-b652-bf62b46c2a3e", "27aecc84-8cb6-4cf4-b622-5a30edf725c6", "3792716d-60c9-46ee-b1b1-1fb55a658620", "a80e10ac-dffa-4f15-b652-bf62b46c2a3e", "27aecc84-8cb6-4cf4-b622-5a30edf725c6", "3792716d-60c9-46ee-b1b1-1fb55a658620", "a80e10ac-dffa-4f15-b652-bf62b46c2a3e"], "metadata": {"page_label": "680", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3a09c689-4a83-490f-b715-43d48a92af35": {"node_ids": ["308fa410-ee08-4ba4-8fd6-a831f6fe575b", "ae735a00-eceb-4fa2-8574-9a75cd6218a9", "592c90b9-c3ff-4059-b9bc-31a595aa871c", "308fa410-ee08-4ba4-8fd6-a831f6fe575b", "ae735a00-eceb-4fa2-8574-9a75cd6218a9", "592c90b9-c3ff-4059-b9bc-31a595aa871c", "308fa410-ee08-4ba4-8fd6-a831f6fe575b", "ae735a00-eceb-4fa2-8574-9a75cd6218a9", "592c90b9-c3ff-4059-b9bc-31a595aa871c"], "metadata": {"page_label": "681", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3157aec8-ae1d-4b03-b04f-a5941c967e0a": {"node_ids": ["17709f7c-d82c-4c6c-90f5-a1845c8f9207", "fcd48e84-f9a4-45b5-9d4c-31ae0bd41f21", "c5e8d90d-cc8f-4524-973d-6b7e596fec92", "17709f7c-d82c-4c6c-90f5-a1845c8f9207", "fcd48e84-f9a4-45b5-9d4c-31ae0bd41f21", "c5e8d90d-cc8f-4524-973d-6b7e596fec92", "17709f7c-d82c-4c6c-90f5-a1845c8f9207", "fcd48e84-f9a4-45b5-9d4c-31ae0bd41f21", "c5e8d90d-cc8f-4524-973d-6b7e596fec92"], "metadata": {"page_label": "682", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "824fb0fb-f4ae-4ba4-9247-46cba7d4f5d7": {"node_ids": ["f4da3630-314a-4606-b347-93324865c795", "f4da3630-314a-4606-b347-93324865c795", "f4da3630-314a-4606-b347-93324865c795"], "metadata": {"page_label": "683", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d0ad919d-f806-4af9-b586-851f14904b0d": {"node_ids": ["5a852302-e14e-45bf-8bed-3eaecf363ff9", "8f6261d4-dbe1-4141-aa5d-70c91feb1286", "5a852302-e14e-45bf-8bed-3eaecf363ff9", "8f6261d4-dbe1-4141-aa5d-70c91feb1286", "5a852302-e14e-45bf-8bed-3eaecf363ff9", "8f6261d4-dbe1-4141-aa5d-70c91feb1286"], "metadata": {"page_label": "684", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fa5a2fde-e4af-4196-8635-239d3b67ca08": {"node_ids": ["1bc3b0a0-7d2a-49aa-90b7-feea67c86ba0", "5821a44d-e113-48f6-9a6a-e5b238907d8e", "1bc3b0a0-7d2a-49aa-90b7-feea67c86ba0", "5821a44d-e113-48f6-9a6a-e5b238907d8e", "1bc3b0a0-7d2a-49aa-90b7-feea67c86ba0", "5821a44d-e113-48f6-9a6a-e5b238907d8e"], "metadata": {"page_label": "685", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5d4b9959-859f-47dc-aa21-7ba1357b9253": {"node_ids": ["822074c4-1606-43aa-ab32-37370e6935fa", "e901335e-d8d0-4eab-a94c-d15feac1f9dc", "15109ffa-ee7a-4100-994e-0570215ab06c", "822074c4-1606-43aa-ab32-37370e6935fa", "e901335e-d8d0-4eab-a94c-d15feac1f9dc", "15109ffa-ee7a-4100-994e-0570215ab06c", "822074c4-1606-43aa-ab32-37370e6935fa", "e901335e-d8d0-4eab-a94c-d15feac1f9dc", "15109ffa-ee7a-4100-994e-0570215ab06c"], "metadata": {"page_label": "686", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e312db83-3c5b-4dff-ad20-cdd92ef0e117": {"node_ids": ["07f320d7-d5d6-4c8c-829c-f3ee0d6c146b", "f1662d20-383f-4e90-a6ea-271f5afa0fb6", "ec4d3119-43c3-4fa1-9dea-d34752132999", "07f320d7-d5d6-4c8c-829c-f3ee0d6c146b", "f1662d20-383f-4e90-a6ea-271f5afa0fb6", "ec4d3119-43c3-4fa1-9dea-d34752132999", "07f320d7-d5d6-4c8c-829c-f3ee0d6c146b", "f1662d20-383f-4e90-a6ea-271f5afa0fb6", "ec4d3119-43c3-4fa1-9dea-d34752132999"], "metadata": {"page_label": "687", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "913484e6-4046-48e9-a730-b53274e33352": {"node_ids": ["cbfb93d3-c829-4797-a4d1-48e2d5f1eb32", "cbfb93d3-c829-4797-a4d1-48e2d5f1eb32", "cbfb93d3-c829-4797-a4d1-48e2d5f1eb32"], "metadata": {"page_label": "688", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "821b4f19-5f6c-4e50-a77b-09918f8c2077": {"node_ids": ["025eb361-7199-452c-90cc-278077c0952c", "025eb361-7199-452c-90cc-278077c0952c", "025eb361-7199-452c-90cc-278077c0952c"], "metadata": {"page_label": "689", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "4f9087d6-e32e-4014-9900-d3ef952f3b28": {"node_ids": ["739b48cc-99bd-4703-ab40-307bb2290cc9", "5fcab2b6-fc2b-4c7c-94a2-67c82cc5f249", "739b48cc-99bd-4703-ab40-307bb2290cc9", "5fcab2b6-fc2b-4c7c-94a2-67c82cc5f249", "739b48cc-99bd-4703-ab40-307bb2290cc9", "5fcab2b6-fc2b-4c7c-94a2-67c82cc5f249"], "metadata": {"page_label": "690", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3360b3fd-b40a-433b-a785-b56da6711465": {"node_ids": ["709e86d5-3337-4279-acac-aa35c0ace36d", "8b7783a1-9b23-4258-8992-40aa740eb96f", "cf3969e0-9f41-4467-881f-231cdf7074da", "709e86d5-3337-4279-acac-aa35c0ace36d", "8b7783a1-9b23-4258-8992-40aa740eb96f", "cf3969e0-9f41-4467-881f-231cdf7074da", "709e86d5-3337-4279-acac-aa35c0ace36d", "8b7783a1-9b23-4258-8992-40aa740eb96f", "cf3969e0-9f41-4467-881f-231cdf7074da"], "metadata": {"page_label": "691", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f274b233-c197-47bc-b410-24f37b7560cc": {"node_ids": ["2ba706bb-8414-408c-9a84-cdd457a030e4", "64c00f8d-ae77-4756-8b99-de48b2ed133c", "5b38da7e-f415-41b1-bd40-82ab3f2cddfd", "2ba706bb-8414-408c-9a84-cdd457a030e4", "64c00f8d-ae77-4756-8b99-de48b2ed133c", "5b38da7e-f415-41b1-bd40-82ab3f2cddfd", "2ba706bb-8414-408c-9a84-cdd457a030e4", "64c00f8d-ae77-4756-8b99-de48b2ed133c", "5b38da7e-f415-41b1-bd40-82ab3f2cddfd"], "metadata": {"page_label": "692", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "946a0753-5ac7-49fb-8793-0521ae3e0845": {"node_ids": ["82d44596-ad04-42ee-9065-b59743680571", "298b927b-5ff3-4f6c-9469-6d2959ac1649", "82d44596-ad04-42ee-9065-b59743680571", "298b927b-5ff3-4f6c-9469-6d2959ac1649", "82d44596-ad04-42ee-9065-b59743680571", "298b927b-5ff3-4f6c-9469-6d2959ac1649"], "metadata": {"page_label": "693", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "702d2f78-e8bc-4269-a420-7572689557f5": {"node_ids": ["9eabf94b-9bc5-419b-b404-d4f2a4920def", "1c58e2f4-2c87-4084-8e0d-edd7b9bc0890", "9eabf94b-9bc5-419b-b404-d4f2a4920def", "1c58e2f4-2c87-4084-8e0d-edd7b9bc0890", "9eabf94b-9bc5-419b-b404-d4f2a4920def", "1c58e2f4-2c87-4084-8e0d-edd7b9bc0890"], "metadata": {"page_label": "694", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "b26aa5bf-23ad-46cb-bedf-09dae771c4b8": {"node_ids": ["efdbcf4d-26fb-4523-8e4b-a1dc7e058caa", "d3630afa-ba93-48ee-b7e8-7a53b4d17528", "0ed1dfe7-7a46-4815-ba4a-7a1f9758850a", "efdbcf4d-26fb-4523-8e4b-a1dc7e058caa", "d3630afa-ba93-48ee-b7e8-7a53b4d17528", "0ed1dfe7-7a46-4815-ba4a-7a1f9758850a", "efdbcf4d-26fb-4523-8e4b-a1dc7e058caa", "d3630afa-ba93-48ee-b7e8-7a53b4d17528", "0ed1dfe7-7a46-4815-ba4a-7a1f9758850a"], "metadata": {"page_label": "695", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "03b383b8-f8d8-4a3a-ab6f-3a2e147612e3": {"node_ids": ["83f30758-1bd8-4b3e-a000-464ec0fc4d90", "42eebaec-c21e-4fc8-986c-83afba39ebc3", "83f30758-1bd8-4b3e-a000-464ec0fc4d90", "42eebaec-c21e-4fc8-986c-83afba39ebc3", "83f30758-1bd8-4b3e-a000-464ec0fc4d90", "42eebaec-c21e-4fc8-986c-83afba39ebc3"], "metadata": {"page_label": "696", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "73e6c147-499c-4776-a814-42ef8bd7e9d2": {"node_ids": ["276d0ce3-e077-454a-969f-0ce74774c7d0", "9f67646b-ddf2-43be-8f29-84a3a4d08ec4", "276d0ce3-e077-454a-969f-0ce74774c7d0", "9f67646b-ddf2-43be-8f29-84a3a4d08ec4", "276d0ce3-e077-454a-969f-0ce74774c7d0", "9f67646b-ddf2-43be-8f29-84a3a4d08ec4"], "metadata": {"page_label": "697", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1c37999a-a28f-44ac-a644-fb728c9bf3e6": {"node_ids": ["f785ea96-a9df-4990-b95a-202acba76b4b", "24e9854c-d2d0-445c-b893-e88b347a58ca", "f785ea96-a9df-4990-b95a-202acba76b4b", "24e9854c-d2d0-445c-b893-e88b347a58ca", "f785ea96-a9df-4990-b95a-202acba76b4b", "24e9854c-d2d0-445c-b893-e88b347a58ca"], "metadata": {"page_label": "698", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "163975db-1ec0-406a-83c4-89dfc0e981c0": {"node_ids": ["8acb8557-9d2f-422e-80d6-a2ac7bf8c1e7", "f5365285-f210-4453-92ce-f46855f6c904", "8acb8557-9d2f-422e-80d6-a2ac7bf8c1e7", "f5365285-f210-4453-92ce-f46855f6c904", "8acb8557-9d2f-422e-80d6-a2ac7bf8c1e7", "f5365285-f210-4453-92ce-f46855f6c904"], "metadata": {"page_label": "699", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9baa1273-862f-43ce-807e-0544963129ad": {"node_ids": ["dc318a46-37e2-442f-864b-e9215810bf2e", "0705d0f0-eeed-44f9-a976-8bb5641a5f0e", "343a8cd4-2ebe-446f-bf8b-6fcbc4e0afd2", "dc318a46-37e2-442f-864b-e9215810bf2e", "0705d0f0-eeed-44f9-a976-8bb5641a5f0e", "343a8cd4-2ebe-446f-bf8b-6fcbc4e0afd2", "dc318a46-37e2-442f-864b-e9215810bf2e", "0705d0f0-eeed-44f9-a976-8bb5641a5f0e", "343a8cd4-2ebe-446f-bf8b-6fcbc4e0afd2"], "metadata": {"page_label": "700", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f0a70f30-0211-4cb3-a9d7-7ddb320258b5": {"node_ids": ["3c237c4c-0c26-49ab-83c5-d63c4c9550c2", "3c237c4c-0c26-49ab-83c5-d63c4c9550c2", "3c237c4c-0c26-49ab-83c5-d63c4c9550c2"], "metadata": {"page_label": "701", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "93d5d317-0d42-4f6c-b643-99e764970f25": {"node_ids": ["1300a016-3dd4-4a83-b4fa-462d289c1db4", "4a3f40b7-d4a6-49de-8e15-8a04e9b4e191", "1300a016-3dd4-4a83-b4fa-462d289c1db4", "4a3f40b7-d4a6-49de-8e15-8a04e9b4e191", "1300a016-3dd4-4a83-b4fa-462d289c1db4", "4a3f40b7-d4a6-49de-8e15-8a04e9b4e191"], "metadata": {"page_label": "702", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "89b4b17a-0bbb-4663-b108-7dd405842cab": {"node_ids": ["0d7e4768-40bc-47f5-8105-f6356dee3cee", "82b0b296-93a6-480e-88cc-b9773f79366b", "0d7e4768-40bc-47f5-8105-f6356dee3cee", "82b0b296-93a6-480e-88cc-b9773f79366b", "0d7e4768-40bc-47f5-8105-f6356dee3cee", "82b0b296-93a6-480e-88cc-b9773f79366b"], "metadata": {"page_label": "703", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "37bc8f0e-a4a2-4cfd-a63f-ace28d18fa35": {"node_ids": ["26c01f07-c886-48b5-bfe9-d35dc400ad3d", "bffd59aa-5bd5-40ea-bf91-03e8cce95fe9", "26c01f07-c886-48b5-bfe9-d35dc400ad3d", "bffd59aa-5bd5-40ea-bf91-03e8cce95fe9", "26c01f07-c886-48b5-bfe9-d35dc400ad3d", "bffd59aa-5bd5-40ea-bf91-03e8cce95fe9"], "metadata": {"page_label": "704", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "40933187-de17-4052-9263-51e64d8d9622": {"node_ids": ["c7b22798-90e9-4e1c-b07f-057e16bd1d20", "2861fd16-726c-4aa4-8571-e42e8a65d44e", "d4e5763a-baab-4451-84ba-b155485c682a", "c7b22798-90e9-4e1c-b07f-057e16bd1d20", "2861fd16-726c-4aa4-8571-e42e8a65d44e", "d4e5763a-baab-4451-84ba-b155485c682a", "c7b22798-90e9-4e1c-b07f-057e16bd1d20", "2861fd16-726c-4aa4-8571-e42e8a65d44e", "d4e5763a-baab-4451-84ba-b155485c682a"], "metadata": {"page_label": "705", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f8604e30-9ee1-495c-96b3-0276f84ac890": {"node_ids": ["fe3a07ab-0784-4a00-9341-c164b4d02b49", "dd6106bc-56b0-4e24-a876-ebdd851b61f5", "fe3a07ab-0784-4a00-9341-c164b4d02b49", "dd6106bc-56b0-4e24-a876-ebdd851b61f5", "fe3a07ab-0784-4a00-9341-c164b4d02b49", "dd6106bc-56b0-4e24-a876-ebdd851b61f5"], "metadata": {"page_label": "706", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1f7674ab-a4e1-4bf0-8842-3f14e59d8edf": {"node_ids": ["6aba187e-be93-4a12-80fd-f3f864eec3fd", "0492c6ea-049b-4c71-b665-c1a54ecd4a7b", "6aba187e-be93-4a12-80fd-f3f864eec3fd", "0492c6ea-049b-4c71-b665-c1a54ecd4a7b", "6aba187e-be93-4a12-80fd-f3f864eec3fd", "0492c6ea-049b-4c71-b665-c1a54ecd4a7b"], "metadata": {"page_label": "707", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c6662409-82b7-4984-8270-ad6a24514c0c": {"node_ids": ["9570d1d7-480d-4d20-9d99-0512873500ee", "1ff9f342-76e2-4762-99a2-1cf991916f47", "51decfe3-df04-4bc5-876a-362efc5c73ab", "9570d1d7-480d-4d20-9d99-0512873500ee", "1ff9f342-76e2-4762-99a2-1cf991916f47", "51decfe3-df04-4bc5-876a-362efc5c73ab", "9570d1d7-480d-4d20-9d99-0512873500ee", "1ff9f342-76e2-4762-99a2-1cf991916f47", "51decfe3-df04-4bc5-876a-362efc5c73ab"], "metadata": {"page_label": "708", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "934e1cc3-02ca-499e-883e-8b44043eeb2d": {"node_ids": ["3c005d7b-64f2-48e9-bda1-7008ad71b3e0", "759d327c-54a4-4618-a6d2-0f7df03affe3", "fd84e580-e733-4524-a864-898783c366a0", "3c005d7b-64f2-48e9-bda1-7008ad71b3e0", "759d327c-54a4-4618-a6d2-0f7df03affe3", "fd84e580-e733-4524-a864-898783c366a0", "3c005d7b-64f2-48e9-bda1-7008ad71b3e0", "759d327c-54a4-4618-a6d2-0f7df03affe3", "fd84e580-e733-4524-a864-898783c366a0"], "metadata": {"page_label": "709", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "30462aee-5f4f-4597-8fcb-2d1345e4d00b": {"node_ids": ["8da5638d-a7c7-41e2-9b41-6b30e5f4829a", "41c00075-900f-4332-aeb2-bad18e712981", "8ae1e107-a857-4751-baaf-10469156dc68", "8da5638d-a7c7-41e2-9b41-6b30e5f4829a", "41c00075-900f-4332-aeb2-bad18e712981", "8ae1e107-a857-4751-baaf-10469156dc68", "8da5638d-a7c7-41e2-9b41-6b30e5f4829a", "41c00075-900f-4332-aeb2-bad18e712981", "8ae1e107-a857-4751-baaf-10469156dc68"], "metadata": {"page_label": "710", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "6379baca-d8c7-4875-9cad-a6a426fc3d9b": {"node_ids": ["bde6da4e-8607-4f86-9ef5-5bb403f4a172", "1e56b6a9-922e-4014-942d-fd5659ca9f69", "3f10b076-22eb-45e5-a1c0-5312aa10c5b7", "bde6da4e-8607-4f86-9ef5-5bb403f4a172", "1e56b6a9-922e-4014-942d-fd5659ca9f69", "3f10b076-22eb-45e5-a1c0-5312aa10c5b7", "bde6da4e-8607-4f86-9ef5-5bb403f4a172", "1e56b6a9-922e-4014-942d-fd5659ca9f69", "3f10b076-22eb-45e5-a1c0-5312aa10c5b7"], "metadata": {"page_label": "711", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "393b064a-6e73-4cf6-a041-27b6ca6056d7": {"node_ids": ["7e884c76-46cb-4ffc-bfa1-27b6fd76807f", "fc10f9f6-5f3e-42b3-9557-d30b291aec22", "810ca288-e8ae-4354-a227-99a8717c19ea", "7e884c76-46cb-4ffc-bfa1-27b6fd76807f", "fc10f9f6-5f3e-42b3-9557-d30b291aec22", "810ca288-e8ae-4354-a227-99a8717c19ea", "7e884c76-46cb-4ffc-bfa1-27b6fd76807f", "fc10f9f6-5f3e-42b3-9557-d30b291aec22", "810ca288-e8ae-4354-a227-99a8717c19ea"], "metadata": {"page_label": "712", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "573e05cf-5cb6-4afe-bb11-7dbb36686a40": {"node_ids": ["1a282cc5-b4ac-479d-a23e-5b6b92f98a57", "71bcad65-2c29-4990-8a94-c37a7e563d27", "e1d0a57b-e795-478f-a133-34d791a8a56f", "1a282cc5-b4ac-479d-a23e-5b6b92f98a57", "71bcad65-2c29-4990-8a94-c37a7e563d27", "e1d0a57b-e795-478f-a133-34d791a8a56f", "1a282cc5-b4ac-479d-a23e-5b6b92f98a57", "71bcad65-2c29-4990-8a94-c37a7e563d27", "e1d0a57b-e795-478f-a133-34d791a8a56f"], "metadata": {"page_label": "713", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a43c6992-1b2f-4686-9048-b915c497a3b9": {"node_ids": ["72e5f73f-562b-44f6-bb3c-0de534267fc5", "e1ccf6bf-2745-41b3-a334-1f8d554cd5aa", "f6cc06d4-4f16-448b-94b3-c276b13e4878", "72e5f73f-562b-44f6-bb3c-0de534267fc5", "e1ccf6bf-2745-41b3-a334-1f8d554cd5aa", "f6cc06d4-4f16-448b-94b3-c276b13e4878", "72e5f73f-562b-44f6-bb3c-0de534267fc5", "e1ccf6bf-2745-41b3-a334-1f8d554cd5aa", "f6cc06d4-4f16-448b-94b3-c276b13e4878"], "metadata": {"page_label": "714", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5832e1d3-b9ba-4d50-89cf-289f182b5903": {"node_ids": ["5383705f-fb4e-4031-b7ec-a8501fcc6fca", "16d162aa-a1d5-4246-8ab6-49685fa00938", "785a3f7c-c764-4193-8374-6388bb9aa2df", "5383705f-fb4e-4031-b7ec-a8501fcc6fca", "16d162aa-a1d5-4246-8ab6-49685fa00938", "785a3f7c-c764-4193-8374-6388bb9aa2df", "5383705f-fb4e-4031-b7ec-a8501fcc6fca", "16d162aa-a1d5-4246-8ab6-49685fa00938", "785a3f7c-c764-4193-8374-6388bb9aa2df"], "metadata": {"page_label": "715", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "54633e0b-1288-474d-b9c1-400c750002a4": {"node_ids": ["4e9bb654-1d1c-4053-aa80-cc132131e6b1", "8888c9df-152a-450e-9c28-9851206923da", "4e9bb654-1d1c-4053-aa80-cc132131e6b1", "8888c9df-152a-450e-9c28-9851206923da", "4e9bb654-1d1c-4053-aa80-cc132131e6b1", "8888c9df-152a-450e-9c28-9851206923da"], "metadata": {"page_label": "716", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a815a454-ef65-4187-a0da-eb5914e18a94": {"node_ids": ["4545a408-a4b8-4821-a5ac-945cfd4775d1", "715b144d-ed6a-409e-8dab-f0a74f0d5510", "fbcb12c1-221c-4420-9ff0-92e3376c12c5", "4545a408-a4b8-4821-a5ac-945cfd4775d1", "715b144d-ed6a-409e-8dab-f0a74f0d5510", "fbcb12c1-221c-4420-9ff0-92e3376c12c5", "4545a408-a4b8-4821-a5ac-945cfd4775d1", "715b144d-ed6a-409e-8dab-f0a74f0d5510", "fbcb12c1-221c-4420-9ff0-92e3376c12c5"], "metadata": {"page_label": "717", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "328ebc9f-4903-48b9-b789-cca91563ef28": {"node_ids": ["a55736ee-f709-49ad-b261-f20e50389d71", "2fc12e60-b9ce-4085-ae9b-58978f5c97e0", "a55736ee-f709-49ad-b261-f20e50389d71", "2fc12e60-b9ce-4085-ae9b-58978f5c97e0", "a55736ee-f709-49ad-b261-f20e50389d71", "2fc12e60-b9ce-4085-ae9b-58978f5c97e0"], "metadata": {"page_label": "718", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "52633cee-4636-4bfc-8c36-03532c05cea0": {"node_ids": ["88a0bc59-e8ba-4d7d-ba9b-8a514256eda7", "994b2ecb-59e5-469d-82e3-1e651a865ffb", "7e16904a-cc87-4efe-85d4-23e94c756169", "88a0bc59-e8ba-4d7d-ba9b-8a514256eda7", "994b2ecb-59e5-469d-82e3-1e651a865ffb", "7e16904a-cc87-4efe-85d4-23e94c756169", "88a0bc59-e8ba-4d7d-ba9b-8a514256eda7", "994b2ecb-59e5-469d-82e3-1e651a865ffb", "7e16904a-cc87-4efe-85d4-23e94c756169"], "metadata": {"page_label": "719", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a631282f-2472-4aed-b9c0-c303f4f84594": {"node_ids": ["cbe51620-79db-464f-a562-ae8450662825", "6d05eadc-bb32-4737-b28e-5681e42a2017", "8a032517-cf5c-4cf6-9295-8a643080056a", "cbe51620-79db-464f-a562-ae8450662825", "6d05eadc-bb32-4737-b28e-5681e42a2017", "8a032517-cf5c-4cf6-9295-8a643080056a", "cbe51620-79db-464f-a562-ae8450662825", "6d05eadc-bb32-4737-b28e-5681e42a2017", "8a032517-cf5c-4cf6-9295-8a643080056a"], "metadata": {"page_label": "720", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "87b86fd4-4b2b-425e-8a7c-b425d382c83a": {"node_ids": ["f67686df-d7a8-45aa-9b47-7068097b4428", "db78cd02-06df-4187-ac96-c33f7c408976", "f67686df-d7a8-45aa-9b47-7068097b4428", "db78cd02-06df-4187-ac96-c33f7c408976", "f67686df-d7a8-45aa-9b47-7068097b4428", "db78cd02-06df-4187-ac96-c33f7c408976"], "metadata": {"page_label": "721", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1b709d07-214c-4bc2-a9da-87497010940c": {"node_ids": ["a26bb304-112c-40ee-aaf0-207adf6b3353", "c0c75989-17bf-4f35-8b68-5ab5f275e90b", "a26bb304-112c-40ee-aaf0-207adf6b3353", "c0c75989-17bf-4f35-8b68-5ab5f275e90b", "a26bb304-112c-40ee-aaf0-207adf6b3353", "c0c75989-17bf-4f35-8b68-5ab5f275e90b"], "metadata": {"page_label": "722", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d4d457bd-59d0-47f5-9357-66dbd081d633": {"node_ids": ["f80ecce0-a5cc-4c80-b9e7-cae8ec9a3151", "a49c275b-dc76-4275-a9f9-4440a0976e13", "f80ecce0-a5cc-4c80-b9e7-cae8ec9a3151", "a49c275b-dc76-4275-a9f9-4440a0976e13", "f80ecce0-a5cc-4c80-b9e7-cae8ec9a3151", "a49c275b-dc76-4275-a9f9-4440a0976e13"], "metadata": {"page_label": "723", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "19b60a1c-de6e-416e-8895-8029a8b41a1b": {"node_ids": ["9605d696-9027-4e5c-9c3a-4d186adaf51d", "3ed5c8d8-122b-44b2-9dee-6e68d58d19cd", "9605d696-9027-4e5c-9c3a-4d186adaf51d", "3ed5c8d8-122b-44b2-9dee-6e68d58d19cd", "9605d696-9027-4e5c-9c3a-4d186adaf51d", "3ed5c8d8-122b-44b2-9dee-6e68d58d19cd"], "metadata": {"page_label": "724", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3d576bd2-1e23-46ba-bc20-904c5ce866ed": {"node_ids": ["58b564f2-4d82-4e6e-b541-33669933a6c3", "78ba5ebf-ce29-4a69-a124-fbbe33f352bf", "58b564f2-4d82-4e6e-b541-33669933a6c3", "78ba5ebf-ce29-4a69-a124-fbbe33f352bf", "58b564f2-4d82-4e6e-b541-33669933a6c3", "78ba5ebf-ce29-4a69-a124-fbbe33f352bf"], "metadata": {"page_label": "725", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "68d942ed-693b-4ba8-9531-f50cced531fe": {"node_ids": ["db22eb19-def8-43c4-93c4-8c31cfa0a7cb", "b45fdf29-0a38-4bb3-943f-7ed8d392d341", "db22eb19-def8-43c4-93c4-8c31cfa0a7cb", "b45fdf29-0a38-4bb3-943f-7ed8d392d341", "db22eb19-def8-43c4-93c4-8c31cfa0a7cb", "b45fdf29-0a38-4bb3-943f-7ed8d392d341"], "metadata": {"page_label": "726", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a5ff1d49-6663-4608-8c83-898dfd1798d3": {"node_ids": ["914697c4-feb7-4bcb-9f42-cd5445f3d6c4", "8e50b7c7-b7b6-4798-b90b-b0edb7c4f81d", "914697c4-feb7-4bcb-9f42-cd5445f3d6c4", "8e50b7c7-b7b6-4798-b90b-b0edb7c4f81d", "914697c4-feb7-4bcb-9f42-cd5445f3d6c4", "8e50b7c7-b7b6-4798-b90b-b0edb7c4f81d"], "metadata": {"page_label": "727", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "a959d420-0663-4941-aa64-a03f9fb6a83b": {"node_ids": ["7b4cb45e-362f-48a2-8df6-f54bac92e4a0", "68317455-5165-472d-8a8a-416e549755e6", "7b4cb45e-362f-48a2-8df6-f54bac92e4a0", "68317455-5165-472d-8a8a-416e549755e6", "7b4cb45e-362f-48a2-8df6-f54bac92e4a0", "68317455-5165-472d-8a8a-416e549755e6"], "metadata": {"page_label": "728", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "aa9917eb-d28d-441d-92c2-161a2c2fafdf": {"node_ids": ["513659ad-dcca-4aee-93b3-7fb2bc75de6f", "73ba7301-3bd9-4a73-a8f5-9d4101196808", "9fb8bd80-998e-4229-94e4-1cdd819f2cb0", "513659ad-dcca-4aee-93b3-7fb2bc75de6f", "73ba7301-3bd9-4a73-a8f5-9d4101196808", "9fb8bd80-998e-4229-94e4-1cdd819f2cb0", "513659ad-dcca-4aee-93b3-7fb2bc75de6f", "73ba7301-3bd9-4a73-a8f5-9d4101196808", "9fb8bd80-998e-4229-94e4-1cdd819f2cb0"], "metadata": {"page_label": "729", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "84105cb1-2cc1-4ae7-a44c-562a2de806af": {"node_ids": ["ac68b27f-0582-4904-b3ec-bb99188fedf2", "106a3097-b438-407c-ad1c-65a18dc3e4fd", "ac68b27f-0582-4904-b3ec-bb99188fedf2", "106a3097-b438-407c-ad1c-65a18dc3e4fd", "ac68b27f-0582-4904-b3ec-bb99188fedf2", "106a3097-b438-407c-ad1c-65a18dc3e4fd"], "metadata": {"page_label": "730", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "2743d383-507a-4ff0-a7b8-8f8ebdf28f64": {"node_ids": ["d5ba6433-4c54-43de-b00a-68a1b891fc92", "d84fcd63-b58d-4dd6-a414-3f6f31ab19b5", "d5ba6433-4c54-43de-b00a-68a1b891fc92", "d84fcd63-b58d-4dd6-a414-3f6f31ab19b5", "d5ba6433-4c54-43de-b00a-68a1b891fc92", "d84fcd63-b58d-4dd6-a414-3f6f31ab19b5"], "metadata": {"page_label": "731", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ef361d66-cb3c-4c63-b4e9-36e1e79922cd": {"node_ids": ["470a863d-392c-4d15-816f-043b02eae415", "dac65288-bc46-4672-a1bd-2072ab0eee86", "470a863d-392c-4d15-816f-043b02eae415", "dac65288-bc46-4672-a1bd-2072ab0eee86", "470a863d-392c-4d15-816f-043b02eae415", "dac65288-bc46-4672-a1bd-2072ab0eee86"], "metadata": {"page_label": "732", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "49187293-8812-4194-aadf-3e1e851372e6": {"node_ids": ["f41caaa6-dbf1-43d4-af30-e15d8b6442c4", "14286f08-d675-4be5-92de-0c97abc355cf", "f41caaa6-dbf1-43d4-af30-e15d8b6442c4", "14286f08-d675-4be5-92de-0c97abc355cf", "f41caaa6-dbf1-43d4-af30-e15d8b6442c4", "14286f08-d675-4be5-92de-0c97abc355cf"], "metadata": {"page_label": "733", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "dcde77b8-16da-411c-a7a4-3b1909d6c9dc": {"node_ids": ["2c43f025-2c87-49e7-b358-20d8dd664f0e", "2d13dea1-27ab-450a-ab2a-a50d47db9828", "05236e35-079f-490f-9348-69ecec7333bb", "2c43f025-2c87-49e7-b358-20d8dd664f0e", "2d13dea1-27ab-450a-ab2a-a50d47db9828", "05236e35-079f-490f-9348-69ecec7333bb", "2c43f025-2c87-49e7-b358-20d8dd664f0e", "2d13dea1-27ab-450a-ab2a-a50d47db9828", "05236e35-079f-490f-9348-69ecec7333bb"], "metadata": {"page_label": "734", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3871c736-4790-4847-996c-22fd46db6e65": {"node_ids": ["c07d2187-c881-4f09-86a2-a1bab89e3b9b", "28fc88dc-b6f8-4f12-b3f5-b6ce2ad2c211", "c07d2187-c881-4f09-86a2-a1bab89e3b9b", "28fc88dc-b6f8-4f12-b3f5-b6ce2ad2c211", "c07d2187-c881-4f09-86a2-a1bab89e3b9b", "28fc88dc-b6f8-4f12-b3f5-b6ce2ad2c211"], "metadata": {"page_label": "735", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "da5d256b-325c-4098-9e91-5697a7ec84bb": {"node_ids": ["4314dc0c-6ac6-48bc-a8e0-3583670b074d", "68d4c72e-b304-4707-82c1-ce259dd30328", "0d5eda2a-5225-488a-baf9-5442379bd017", "4314dc0c-6ac6-48bc-a8e0-3583670b074d", "68d4c72e-b304-4707-82c1-ce259dd30328", "0d5eda2a-5225-488a-baf9-5442379bd017", "4314dc0c-6ac6-48bc-a8e0-3583670b074d", "68d4c72e-b304-4707-82c1-ce259dd30328", "0d5eda2a-5225-488a-baf9-5442379bd017"], "metadata": {"page_label": "736", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "cbd9d134-26d9-4d3d-b787-42c1502518e7": {"node_ids": ["38335114-d298-47b3-a44e-599b02c6f7f1", "33bf7ac6-bd56-48db-8509-3a4809874849", "bbfd5402-1690-48a2-ac78-e62e2606aac1", "38335114-d298-47b3-a44e-599b02c6f7f1", "33bf7ac6-bd56-48db-8509-3a4809874849", "bbfd5402-1690-48a2-ac78-e62e2606aac1", "38335114-d298-47b3-a44e-599b02c6f7f1", "33bf7ac6-bd56-48db-8509-3a4809874849", "bbfd5402-1690-48a2-ac78-e62e2606aac1"], "metadata": {"page_label": "737", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3ec37538-f2d6-481d-9b1a-b53dd91ccfca": {"node_ids": ["13f37eea-a34a-42d4-bcd2-b75f0b9c16a6", "13f37eea-a34a-42d4-bcd2-b75f0b9c16a6", "13f37eea-a34a-42d4-bcd2-b75f0b9c16a6"], "metadata": {"page_label": "738", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "85b34f45-e8cf-4ff5-8f38-98ce7ab8e47e": {"node_ids": ["4072d420-a4b3-4e6c-b114-e0c4ee19cdcc", "1a077ec0-bdf4-4077-b905-8bf591aaefa8", "4072d420-a4b3-4e6c-b114-e0c4ee19cdcc", "1a077ec0-bdf4-4077-b905-8bf591aaefa8", "4072d420-a4b3-4e6c-b114-e0c4ee19cdcc", "1a077ec0-bdf4-4077-b905-8bf591aaefa8"], "metadata": {"page_label": "739", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "ebd1dedc-b77b-4fb5-bb89-c3d690f17e01": {"node_ids": ["f04bd8f0-0fa4-4d50-aa7c-750cb483ce34", "889b935d-59a8-4047-ba94-4e8ded9cf084", "3d85ba75-a87b-42ee-8f26-45acfaf936b9", "f04bd8f0-0fa4-4d50-aa7c-750cb483ce34", "889b935d-59a8-4047-ba94-4e8ded9cf084", "3d85ba75-a87b-42ee-8f26-45acfaf936b9", "f04bd8f0-0fa4-4d50-aa7c-750cb483ce34", "889b935d-59a8-4047-ba94-4e8ded9cf084", "3d85ba75-a87b-42ee-8f26-45acfaf936b9"], "metadata": {"page_label": "740", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e8a9cb1f-18b9-44d9-87f7-abb90923f9cc": {"node_ids": ["135451c2-a93b-4ec0-b7ed-3062988fb2b2", "895af03b-adaf-4aa0-9574-37eb1b20ee81", "135451c2-a93b-4ec0-b7ed-3062988fb2b2", "895af03b-adaf-4aa0-9574-37eb1b20ee81", "135451c2-a93b-4ec0-b7ed-3062988fb2b2", "895af03b-adaf-4aa0-9574-37eb1b20ee81"], "metadata": {"page_label": "741", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "e7cbcdc0-3c9e-4104-afd3-2ba6e5ff08fa": {"node_ids": ["8905ce39-2381-4a4d-a303-e534d8461d58", "49ca8324-780d-4f90-8602-c6b1e1661ac3", "9b73f36e-b823-49f6-a799-7cf629b98fbc", "8905ce39-2381-4a4d-a303-e534d8461d58", "49ca8324-780d-4f90-8602-c6b1e1661ac3", "9b73f36e-b823-49f6-a799-7cf629b98fbc", "8905ce39-2381-4a4d-a303-e534d8461d58", "49ca8324-780d-4f90-8602-c6b1e1661ac3", "9b73f36e-b823-49f6-a799-7cf629b98fbc"], "metadata": {"page_label": "742", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "24d815db-c7d5-4247-98ab-8cbc2d54902f": {"node_ids": ["da61718e-5fda-4b8f-9529-c183e7793606", "1676516a-a439-4b97-80a1-77bd05fe66ef", "da61718e-5fda-4b8f-9529-c183e7793606", "1676516a-a439-4b97-80a1-77bd05fe66ef", "da61718e-5fda-4b8f-9529-c183e7793606", "1676516a-a439-4b97-80a1-77bd05fe66ef"], "metadata": {"page_label": "743", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "cb4188f6-905c-41eb-8fbc-0f9d944bf68b": {"node_ids": ["8a302f4f-bce7-4535-b67d-8e6f53207594", "1ed6c64f-5c19-4784-a3fa-be87a772866a", "8a302f4f-bce7-4535-b67d-8e6f53207594", "1ed6c64f-5c19-4784-a3fa-be87a772866a", "8a302f4f-bce7-4535-b67d-8e6f53207594", "1ed6c64f-5c19-4784-a3fa-be87a772866a"], "metadata": {"page_label": "744", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d2185314-dfe4-4307-9d47-b5211bde3391": {"node_ids": ["efff6660-b6fb-4d05-8b79-f6816fd69584", "c61c63a3-9d7f-494a-9f87-deabe72fe25d", "efff6660-b6fb-4d05-8b79-f6816fd69584", "c61c63a3-9d7f-494a-9f87-deabe72fe25d", "efff6660-b6fb-4d05-8b79-f6816fd69584", "c61c63a3-9d7f-494a-9f87-deabe72fe25d"], "metadata": {"page_label": "745", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "d7052c2a-2ce6-458c-afb6-04402a14c86c": {"node_ids": ["5ea37e51-daad-468d-b795-65752fef9456", "028eac7a-5161-4a62-b82f-6a9cb08ccd72", "5ea37e51-daad-468d-b795-65752fef9456", "028eac7a-5161-4a62-b82f-6a9cb08ccd72", "5ea37e51-daad-468d-b795-65752fef9456", "028eac7a-5161-4a62-b82f-6a9cb08ccd72"], "metadata": {"page_label": "746", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "09bd840b-bfcc-4ef9-a2e9-d2ea19dab7b4": {"node_ids": ["19f9a5f3-12d0-449e-8464-e287ead2891a", "59254e9f-ff9e-4ed1-827f-031265c17a3f", "19f9a5f3-12d0-449e-8464-e287ead2891a", "59254e9f-ff9e-4ed1-827f-031265c17a3f", "19f9a5f3-12d0-449e-8464-e287ead2891a", "59254e9f-ff9e-4ed1-827f-031265c17a3f"], "metadata": {"page_label": "747", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "c2dc44a1-21db-4f79-89a4-6839ad919550": {"node_ids": ["ea102655-0498-4feb-8d9f-684a098f69c3", "18d81235-ce36-49f4-ae1d-84a96c164c60", "fe612762-7a93-4348-8702-d52a20926a29", "ea102655-0498-4feb-8d9f-684a098f69c3", "18d81235-ce36-49f4-ae1d-84a96c164c60", "fe612762-7a93-4348-8702-d52a20926a29", "ea102655-0498-4feb-8d9f-684a098f69c3", "18d81235-ce36-49f4-ae1d-84a96c164c60", "fe612762-7a93-4348-8702-d52a20926a29"], "metadata": {"page_label": "748", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "13aaaa90-26b0-429b-8e4a-18729a195c4d": {"node_ids": ["b57aa8cf-6621-4b80-bc72-d806736a7c35", "32cb72e8-dbb0-4192-9246-b015ca3bd5ae", "bce158eb-fe8b-46cb-a1bb-6ca55a99b4fc", "b57aa8cf-6621-4b80-bc72-d806736a7c35", "32cb72e8-dbb0-4192-9246-b015ca3bd5ae", "bce158eb-fe8b-46cb-a1bb-6ca55a99b4fc", "b57aa8cf-6621-4b80-bc72-d806736a7c35", "32cb72e8-dbb0-4192-9246-b015ca3bd5ae", "bce158eb-fe8b-46cb-a1bb-6ca55a99b4fc"], "metadata": {"page_label": "749", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f9d2ef38-7bd3-445a-ad65-c8ffeaa3df06": {"node_ids": ["ace68216-d5df-48a2-afe9-ea227dc7296a", "f12dcde1-a91f-4a3b-a2b8-f97ddf8c52d4", "ace68216-d5df-48a2-afe9-ea227dc7296a", "f12dcde1-a91f-4a3b-a2b8-f97ddf8c52d4", "ace68216-d5df-48a2-afe9-ea227dc7296a", "f12dcde1-a91f-4a3b-a2b8-f97ddf8c52d4"], "metadata": {"page_label": "750", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "f2860091-ab12-492f-98c0-9e2b001839fe": {"node_ids": ["8ba95bb0-7867-489a-9112-3772232413b0", "44f3d5b6-a5c0-41cc-bf7a-3330c590217c", "8ba95bb0-7867-489a-9112-3772232413b0", "44f3d5b6-a5c0-41cc-bf7a-3330c590217c", "8ba95bb0-7867-489a-9112-3772232413b0", "44f3d5b6-a5c0-41cc-bf7a-3330c590217c"], "metadata": {"page_label": "751", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "5dcae384-96ae-4e96-a215-4d22e30c67d0": {"node_ids": ["76b6b919-4e56-41ad-a612-83c64560a187", "70e9714e-5452-46d6-ba63-5acf2eb8b347", "76b6b919-4e56-41ad-a612-83c64560a187", "70e9714e-5452-46d6-ba63-5acf2eb8b347", "76b6b919-4e56-41ad-a612-83c64560a187", "70e9714e-5452-46d6-ba63-5acf2eb8b347"], "metadata": {"page_label": "752", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "3afc5220-81af-44e6-be83-9c926f482e76": {"node_ids": ["c1961838-3f8e-41f7-8a65-e28fe712f7f5", "5d55868c-ff46-412d-87ee-c584832619fa", "c1961838-3f8e-41f7-8a65-e28fe712f7f5", "5d55868c-ff46-412d-87ee-c584832619fa", "c1961838-3f8e-41f7-8a65-e28fe712f7f5", "5d55868c-ff46-412d-87ee-c584832619fa"], "metadata": {"page_label": "753", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "68fc85f5-3e31-40a1-b5c6-49b22968f7ab": {"node_ids": ["3a33df6a-926c-40b0-afe2-a07d1064c1d1", "7ebf729f-8750-46ba-9847-afbb179d3012", "880f6737-631d-41fe-b1a8-25123314706e", "3a33df6a-926c-40b0-afe2-a07d1064c1d1", "7ebf729f-8750-46ba-9847-afbb179d3012", "880f6737-631d-41fe-b1a8-25123314706e", "3a33df6a-926c-40b0-afe2-a07d1064c1d1", "7ebf729f-8750-46ba-9847-afbb179d3012", "880f6737-631d-41fe-b1a8-25123314706e"], "metadata": {"page_label": "754", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "1ffb86c1-af35-473a-9ec0-79c7fa9b03dd": {"node_ids": ["0f5667e2-9c19-4292-a60f-b9f11325b8f9", "3998ee1e-8512-4b19-9999-9f05d52cfa7c", "0f5667e2-9c19-4292-a60f-b9f11325b8f9", "3998ee1e-8512-4b19-9999-9f05d52cfa7c", "0f5667e2-9c19-4292-a60f-b9f11325b8f9", "3998ee1e-8512-4b19-9999-9f05d52cfa7c"], "metadata": {"page_label": "755", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "0219df1b-ec17-413e-baf0-9d4c04d77642": {"node_ids": ["8f5d5c47-08f3-4f17-95a3-e8aa7830c766", "033fb2e1-314b-4e64-8a65-af53fe175bc9", "8f5d5c47-08f3-4f17-95a3-e8aa7830c766", "033fb2e1-314b-4e64-8a65-af53fe175bc9", "8f5d5c47-08f3-4f17-95a3-e8aa7830c766", "033fb2e1-314b-4e64-8a65-af53fe175bc9"], "metadata": {"page_label": "756", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "16832475-1d59-4503-aa10-01305d150f27": {"node_ids": ["b6aeefb1-d1dd-48b9-97ba-62ecf513f8f0", "9a4b7a14-0797-4ffc-9cc2-1c50e11386f7", "b6aeefb1-d1dd-48b9-97ba-62ecf513f8f0", "9a4b7a14-0797-4ffc-9cc2-1c50e11386f7", "b6aeefb1-d1dd-48b9-97ba-62ecf513f8f0", "9a4b7a14-0797-4ffc-9cc2-1c50e11386f7"], "metadata": {"page_label": "757", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "58a7d497-f099-462d-b20c-a5b33804f70c": {"node_ids": ["5aff2969-1b79-456b-b90d-ab3b14352641", "7a860e60-32bb-4086-8174-f2b1af04c18a", "5aff2969-1b79-456b-b90d-ab3b14352641", "7a860e60-32bb-4086-8174-f2b1af04c18a", "5aff2969-1b79-456b-b90d-ab3b14352641", "7a860e60-32bb-4086-8174-f2b1af04c18a"], "metadata": {"page_label": "758", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "9acc71af-769f-44e5-84fe-b1072326ed37": {"node_ids": ["72dbeabd-4c8b-4e7b-a033-9dce5643164b", "c2d93546-c2a4-49c2-a7dd-e05bf7067313", "72dbeabd-4c8b-4e7b-a033-9dce5643164b", "c2d93546-c2a4-49c2-a7dd-e05bf7067313", "72dbeabd-4c8b-4e7b-a033-9dce5643164b", "c2d93546-c2a4-49c2-a7dd-e05bf7067313"], "metadata": {"page_label": "759", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "fccf194d-cd20-475e-a1ec-6e541eaa1196": {"node_ids": ["8d0b9349-70d1-47dc-b3e4-55977ede2c41", "ae6cdc74-bca4-4042-8c9c-ddf28bcccdf1", "8730231e-f277-4cfc-b090-2fb9b79a5386", "8d0b9349-70d1-47dc-b3e4-55977ede2c41", "ae6cdc74-bca4-4042-8c9c-ddf28bcccdf1", "8730231e-f277-4cfc-b090-2fb9b79a5386", "8d0b9349-70d1-47dc-b3e4-55977ede2c41", "ae6cdc74-bca4-4042-8c9c-ddf28bcccdf1", "8730231e-f277-4cfc-b090-2fb9b79a5386"], "metadata": {"page_label": "760", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}, "334b1806-c41a-4679-8aa2-020cebbab7bf": {"node_ids": ["195c1153-19ff-4e17-9f03-60502e947525", "dde09682-71eb-435c-b60d-fdca34c8ab22", "195c1153-19ff-4e17-9f03-60502e947525", "dde09682-71eb-435c-b60d-fdca34c8ab22", "195c1153-19ff-4e17-9f03-60502e947525", "dde09682-71eb-435c-b60d-fdca34c8ab22"], "metadata": {"page_label": "761", "file_name": "RANG_and_DALES_Pharmacology_9th_edition copy.pdf"}}}, "docstore/metadata": {"e5011731-4122-4588-83d0-19ff6364dcc8": {"doc_hash": "b52078834492e0b1e70718d81e74dae1c7e3ed96947cb6ccdaaa5d11e0bec1fd", "ref_doc_id": "daef8c7f-68a7-4a78-b143-4aba0b3421b9"}, "b7f2083c-7828-489d-a91a-99387ea61990": {"doc_hash": "e155a184f1cdd44dd68a843a46cdacc486bba9db86dcdfab2de66c84e15e1baa", "ref_doc_id": "c20c8323-7f5f-4553-80b3-1a6d2dff3232"}, "bc1d5998-8b4c-42d7-a90c-0fa61f209ad1": {"doc_hash": "1ee30bb8903bf9d7d2ec51113a89ed295db489c7ead07c2f531c254c00a25e35", "ref_doc_id": "08ea18da-4415-43d0-bfc5-e4af7a31d8f2"}, "f6251b43-a4a4-4d52-9280-eb75f885891e": {"doc_hash": "7def9058c001593030019dcd0c9af2998fbc9ea05e668f88edd2ccbf8993f60c", "ref_doc_id": "6b6b4aa2-3d5a-4ad2-94ee-8a74e2c01f6c"}, "608e54d8-1a22-47f6-b62d-72f076ecf05d": {"doc_hash": "9613015189d72b4748dab9e150fba8b1ea306a594936a84d95111a76c2efe7ca", "ref_doc_id": "2fbdcbb4-e5ed-44e8-9db4-a06b11cf5946"}, "48c9d5b6-fbea-4458-881a-1bf0b6d1a3db": {"doc_hash": "6a123d0d07604b48c945759283db79cbd8feed6b891ee11c3adea96f13215a62", "ref_doc_id": "2fbdcbb4-e5ed-44e8-9db4-a06b11cf5946"}, "95fe44f7-8f1c-4739-b658-6a679337c8f6": {"doc_hash": "1dad55586517d0fe8427ad49d1ee9e75ef37ee887129d806619fba43e0f35bce", "ref_doc_id": "b6becbbb-c6af-443b-aa69-2711a3e83fbf"}, "f5056f2f-9577-4148-8c95-720a9c306847": {"doc_hash": "22748495f290b8bc13ed3d80834c7d6d636e7479c3bfa2fae379401715d764a2", "ref_doc_id": "d06b9b0d-9b63-4a60-8114-aace544631b0"}, "abe6dc81-5c17-4d3d-a1c1-848d79df2747": {"doc_hash": "829964a4259930a485aefdb628eab758b549d932bdae98820fa0efca3e1998b6", "ref_doc_id": "d06b9b0d-9b63-4a60-8114-aace544631b0"}, "0e413ae7-f5cc-45c1-a031-f1ab52756f4f": {"doc_hash": "92e777613f154537892edc1c4f4822e18eba358bc966cb2d48ef19e8827e3fa3", "ref_doc_id": "e266a6a0-04d8-4009-a7ce-8c713c283fba"}, "3e1bcd33-40a5-4f6f-a7c9-101972f1537f": {"doc_hash": "de430c7eb3f1e3352d98056537775ba647951796a6549efd85c165f7dd68be36", "ref_doc_id": "e266a6a0-04d8-4009-a7ce-8c713c283fba"}, "cc75a578-e997-4ff8-b522-7791df24a429": {"doc_hash": "047be128ee962d49e4f548bb419e8351da1302bcb06d234a5868f3781cbb3692", "ref_doc_id": "e266a6a0-04d8-4009-a7ce-8c713c283fba"}, "19692850-fcb7-4989-9fbd-7a45b0c05404": {"doc_hash": "a95727aec653fb2823426f15bcd7d6e59051d916df299afebc0e1de537cf5aff", "ref_doc_id": "db4a0856-ce64-4060-9d11-a4981a1985c9"}, "395f211d-36d6-4687-91fd-e70e60c0a38c": {"doc_hash": "b480c61e3579e75d808faf97c434f3c35f0f491e4a368c4fe65dfc6047402b3c", "ref_doc_id": "db4a0856-ce64-4060-9d11-a4981a1985c9"}, "bf243f19-319f-4950-a05b-d6a362f01b89": {"doc_hash": "4bb37b86713f7d69bd13465a4f9be321cfad504ac206d1745635225870206333", "ref_doc_id": "b5ad4171-80af-4abf-a713-24a35994b1ba"}, "92d40caa-24b5-41e0-9e72-2831bc5d45c2": {"doc_hash": "8a73f388157986e2e8f3c412bb0a32af57d6db0a5fb505f37eed4e97f78f0ce1", "ref_doc_id": "b5ad4171-80af-4abf-a713-24a35994b1ba"}, "c585a0a7-7a9b-463d-b7d0-a39717280ad7": {"doc_hash": "87a019f8c148c96870c9f720a4133403ebaa4d1bb27278d54bf502ff46c79e2b", "ref_doc_id": "135ed7de-f1c0-4daf-9541-7c43693bef51"}, "2218a423-d7af-4985-b365-c76f18132b49": {"doc_hash": "0bbec88277892a010931d164733db03007863c6a48041eaad4c44c353c191a79", "ref_doc_id": "b5a4db63-f6b1-42b9-b1bb-f4ba855fde52"}, "01fc577c-319b-4aea-8bed-7e4f84eb8457": {"doc_hash": "fab11316be90ec257059d3a0dea0dd279038d8c2e48a3b689f606b8032121ecb", "ref_doc_id": "b5a4db63-f6b1-42b9-b1bb-f4ba855fde52"}, "99e35b0a-10ed-4e42-8a39-5019b0a57e6f": {"doc_hash": "635dfb69b2292a57c10f0e4e2063abe092074f034d5de2c4758a01465daa99c7", "ref_doc_id": "ce635d5b-812e-4505-9290-f47fcdce1108"}, "ec123fe0-0d47-45bd-89bd-7dce104122bb": {"doc_hash": "a3673c53c5be8abfde30c76e8a5dd6bd5e8b0e12191912fac4e880e3ec711198", "ref_doc_id": "ce635d5b-812e-4505-9290-f47fcdce1108"}, "50bfa380-5158-4a44-9d91-2da6017c9a26": {"doc_hash": "ffa665883bb006c558e32488d4f74658284a358c017ee9631a9ff4c239cabccc", "ref_doc_id": "ce635d5b-812e-4505-9290-f47fcdce1108"}, "cdf44d3b-ed62-4828-b808-e834961c7558": {"doc_hash": "bff15897ad4883261ee2d2eefc4c954adb83d6fa1927cefd6accb4b885753353", "ref_doc_id": "c0d7ccc9-7b04-47e5-b913-72d217a1f1c6"}, "34713ea0-4ca5-4209-b199-af991552b584": {"doc_hash": "d532b2f35a6ee41f80b1d79bb165c7514acb850bed0c321f38136b706fcad907", "ref_doc_id": "c0d7ccc9-7b04-47e5-b913-72d217a1f1c6"}, "7093aa4c-f087-4c7b-8955-22af77623995": {"doc_hash": "d3754cd36f6a819b3532b7a8ddcef1d30e4a35b0609880b1a507dbcc6a4224e6", "ref_doc_id": "c0d7ccc9-7b04-47e5-b913-72d217a1f1c6"}, "33a37fe6-3527-4886-ae07-9fdac983f0c7": {"doc_hash": "db9b82e22d49efdf514ed82b36b2bfc15df129d541b3c3da56c9e43963afa822", "ref_doc_id": "5caf8182-1d82-42f4-ad7c-19ea91c92a77"}, "43fe4d20-827f-43bc-bc04-32dbb980098f": {"doc_hash": "fe1988910eb297d3c26fe707f8672b8d312bce455244baf8a8a5c4460bb1dc84", "ref_doc_id": "5caf8182-1d82-42f4-ad7c-19ea91c92a77"}, "8e3942b7-35e0-42a8-8c92-68755db63aef": {"doc_hash": "13096e5f0e1709508fe1e2eaa4673073d82bb41582d41c5386a281ff808937c1", "ref_doc_id": "b9c9f479-fe67-4ff5-946b-994e82eef357"}, "2a7894d6-240c-4e18-a6a4-015512d90f4c": {"doc_hash": "686ac0184dbd5ef8bc39e4c5fd11e9d85c0135f818ac2ed901ddbc4150c30f83", "ref_doc_id": "b9c9f479-fe67-4ff5-946b-994e82eef357"}, "fba43e93-a374-4246-91d9-48e62221774d": {"doc_hash": "04992a866962f5afa4f98768bd7d763a895934144eaae321681895bdb857361a", "ref_doc_id": "d217b749-e809-4bd8-8981-51bee2597e91"}, "647409d2-8dc8-40a0-bd7f-fe8fedb872cb": {"doc_hash": "bc2cfef324a7dfc6be6b390d23302842c78c6be08f66cea7d974dd353961dfac", "ref_doc_id": "d217b749-e809-4bd8-8981-51bee2597e91"}, "fec75ef9-fdd8-436f-a6e1-38b959544a96": {"doc_hash": "10e11cc6f63e2535b038747d2b4946726a33602d8b3df7f0f9a9b6655337cb39", "ref_doc_id": "eb1d4577-0462-4846-91ea-60db375e7688"}, "af9bcc99-788d-4df4-b65f-1da1c9f2a9de": {"doc_hash": "9cf45032030d7c5098d047b39b1a68fe0189503fd73f94261569860f021bf038", "ref_doc_id": "eb1d4577-0462-4846-91ea-60db375e7688"}, "2726ad77-a61b-4de5-b014-2f49c65c502b": {"doc_hash": "798777939e548f80917484013e8105aee55e71937e459e95fbc160a2ffce2f14", "ref_doc_id": "d5b85ddb-7406-48d1-9dd0-3b426ca1008f"}, "f0c7391a-8fd6-45c0-aa1c-cc6e32cff16c": {"doc_hash": "a52e58f5d14f4c4eb142be9b041450a48c8dfb818de4b093124daff32e636cda", "ref_doc_id": "d5b85ddb-7406-48d1-9dd0-3b426ca1008f"}, "60e1c816-ca53-4e7f-94e8-0fd2d80818ed": {"doc_hash": "6c260eaf8d523fabec90fe830a80bd51e003631fcb53b839bdd9b81c2811ac98", "ref_doc_id": "9312ded3-2b72-4968-96ff-f8cf24fbca6f"}, "2976c590-f20d-4024-b3e1-dfaee4f55177": {"doc_hash": "62377ebb3c2aeb8c5d003320410707055fe5891d374648928d996f079b133d27", "ref_doc_id": "9312ded3-2b72-4968-96ff-f8cf24fbca6f"}, "997870ff-e488-4c33-ab76-db7de7e8f4f4": {"doc_hash": "e88c46d971c054a3aa1ecb404fd81edb4ae4088f90ad0fb3db9a1af22404accb", "ref_doc_id": "c28f14e0-7718-4e24-8d94-0edb8cf67828"}, "d938c7c3-d1aa-43f9-97b6-e6d234ce5f8c": {"doc_hash": "5abe581b3779ef55acea6b16e10ef044832e6ddbf5f2a800146114dd072200a5", "ref_doc_id": "c28f14e0-7718-4e24-8d94-0edb8cf67828"}, "e8c90c35-e0d8-4dac-a03b-08fd983abb95": {"doc_hash": "8ac277b5c001b20e0bce33a61258f5ca3492e8ce425ca5e609e47fee568fbdbb", "ref_doc_id": "a1d39c54-ef46-4d67-852a-f06d380f0fb7"}, "d9484a43-97ad-4bad-93ce-261d73415a18": {"doc_hash": "2b0fb0dc2ac9fdc2bdaa66e0a2a45895e8b890905231d5f62b81ca7430e4b0f8", "ref_doc_id": "a1d39c54-ef46-4d67-852a-f06d380f0fb7"}, "9799e5b6-f37c-4e29-a53c-85c8740ea93a": {"doc_hash": "67e14001ea4b52a0bfba37774acabbf6cb364937d19385427dfa37c8df0ca607", "ref_doc_id": "de43b34b-5dcb-456b-b0fb-19e0be49f344"}, "645bbbd7-4670-4755-bc78-06e88474a21c": {"doc_hash": "e80cef98dbebfd1c46eba20fb7804152c3ca3a93c0c85c8eb39fe27283fa8bf8", "ref_doc_id": "bca4a9d3-f04e-41a5-99f3-e0fcf5838fd6"}, "3b01edf9-a01e-4ff7-8103-bd3b90ee7b17": {"doc_hash": "9f9cd7165d27fd545c85d2b3268daa51e241d3139517391f3a99f27a4d64147f", "ref_doc_id": "bca4a9d3-f04e-41a5-99f3-e0fcf5838fd6"}, "25857cda-593f-4e12-9e47-94992cd93b05": {"doc_hash": "675ba44fcc24d13810173e79d1aebc42b7ac63a658acd01def97dbe4cb6f2cea", "ref_doc_id": "d50f1482-997c-458e-99f5-767dc6d7a44f"}, "1ce2646e-8ab1-4589-b84e-be16c50d0461": {"doc_hash": "ed3ebad64467888c5b2099be4b8683c71063536ba11995e6b8e538bbc289f58c", "ref_doc_id": "d50f1482-997c-458e-99f5-767dc6d7a44f"}, "21f55cc6-6024-4a57-bf66-23f308e6a5ee": {"doc_hash": "0b811fdc5df01aa820f69f78887ed3a3ce3027658b86a50327f219066815bb7b", "ref_doc_id": "d50f1482-997c-458e-99f5-767dc6d7a44f"}, "c1427c0d-98eb-431c-8a5b-15bd47be3df8": {"doc_hash": "73fe232920306bd5cb42c8f846bb1756930a3a95ae0b6adf4300cf746cb03f35", "ref_doc_id": "cc3bbac8-c9b3-4f34-83f6-020b173f4fcd"}, "3742d94d-500f-4767-8fae-4ad6d2d24bff": {"doc_hash": "770c350f924a9e0de70f7efcc6a7e958c5006bc10372e3c18c8ba184c9a642ed", "ref_doc_id": "cc3bbac8-c9b3-4f34-83f6-020b173f4fcd"}, "cb2f8b0e-ca46-4ea8-a2ca-fefab23de5c7": {"doc_hash": "f52083e22423d49cb0356be8385e3382912725d4c51eb8d8895165978f00f1dd", "ref_doc_id": "cc3bbac8-c9b3-4f34-83f6-020b173f4fcd"}, "b0c056ad-db75-44a1-908a-ba2759828e38": {"doc_hash": "ca29031bb979425a3eae182b0efcad41dbb014fea916fbbf4d9b97f212372022", "ref_doc_id": "03fedf93-10c3-41e1-8cca-e57573d8398f"}, "930d967e-30f5-4aa9-999c-2ecf77684d77": {"doc_hash": "da99dab6bc88e9fa0d46e5d879bd2b5e962f8b016138d7180b5d4bba46f1d3e3", "ref_doc_id": "03fedf93-10c3-41e1-8cca-e57573d8398f"}, "42590f5d-b7c7-43b5-ad9e-499261aa3c9f": {"doc_hash": "c10cffc99270f63f96bce36c124f26a58f976dd559e2f25be01aa9c013dd474c", "ref_doc_id": "aa41831b-efe1-4480-a3ba-f5e13d6a5146"}, "c766fc5e-942c-49cc-a06b-e18ba6582e73": {"doc_hash": "8cf93f45e12c9b30d49261ff73ad92735f693d334dd336a92743028f267097dc", "ref_doc_id": "aa41831b-efe1-4480-a3ba-f5e13d6a5146"}, "901c601a-e8e8-4b3a-88c2-2eec11967c90": {"doc_hash": "3eafd45e620c47bc2ed33adaf92c4e176287262d3bb4d3990fa01f0b0d99b58a", "ref_doc_id": "1ab4feb1-4db5-4a42-b6e2-2021fa7ac4ec"}, "2ebccc93-1e0b-464f-84f7-b3e34637d809": {"doc_hash": "d11937fa3899a856e331f364f20723104010e782e218ce7b5891ed04efa7987d", "ref_doc_id": "1ab4feb1-4db5-4a42-b6e2-2021fa7ac4ec"}, "d8047bca-73bf-4c57-896d-bbb73225f47b": {"doc_hash": "c7252484a77828a99233570835457ab0f6b9bfb3679a7a9c329238400d736f6b", "ref_doc_id": "443a6172-5f92-41a6-9e66-ac76a804d2f3"}, "191242ae-e34e-4090-a263-5b5e7bb1f6a5": {"doc_hash": "783d3c8614dad8a1bd7c5f3bf93c2b40cff89b43b0e0ac7629e855fde784e7db", "ref_doc_id": "443a6172-5f92-41a6-9e66-ac76a804d2f3"}, "c729462e-9904-4a57-9c18-36ce6b5540f5": {"doc_hash": "359dac0a023b69156c6508df58dac72e67e7c45f2e706e2e5fcd0a2a023d11a2", "ref_doc_id": "14ac1dab-ba39-4d7b-a06d-9834e17d41de"}, "d91f5410-7ee9-4c66-bced-2b5abc36ccf1": {"doc_hash": "e4a11d94be60dc30ebd6fbce9ff35b3dd194b5f5abb83f071c5f53ea174389cf", "ref_doc_id": "14ac1dab-ba39-4d7b-a06d-9834e17d41de"}, "8aadec16-f20d-4fc8-9b9e-f8f1f6fa1264": {"doc_hash": "36578c8bcabb273a3cd043699eea7d0e0feffe7bc960271910a47d816342b816", "ref_doc_id": "14ac1dab-ba39-4d7b-a06d-9834e17d41de"}, "f751e2c8-cf66-47c2-83a5-b5660d70b7bf": {"doc_hash": "42c7a73f4427a1bc7ddc85e2854096ff4a905ecfa1223561ab95aac641bf476b", "ref_doc_id": "6a84f021-5c8e-439e-8ade-6387f09dd7ba"}, "5cecb105-81e8-43ab-8f17-af9d287dd9d4": {"doc_hash": "380c51f09e427bd194be3528963bb270149f2a82f9f6151c4b25ddb93865d746", "ref_doc_id": "4cb59c6c-a42e-4926-a599-79e0f620549e"}, "7620fd55-2d65-488f-bcfb-7b4312cb4346": {"doc_hash": "b87186cbf5b544387d3aebaa1c1d2fa36a35affdccfd978ef681475747c87923", "ref_doc_id": "4cb59c6c-a42e-4926-a599-79e0f620549e"}, "c325d348-aca5-4088-84fc-79fbc7bb1b57": {"doc_hash": "9b44552559f053e2ecff7c6def746ba2ed3fafdfb659a89c1b2715ad5a600a13", "ref_doc_id": "d5d4fab5-43ca-4deb-9c4c-591c001796a8"}, "3ce57e86-632b-4989-9dca-7e777ecd5a48": {"doc_hash": "06718980834506961c7772e681eaacfca6907fb5e8d26427adb08df2336fb235", "ref_doc_id": "d5d4fab5-43ca-4deb-9c4c-591c001796a8"}, "06ed5854-dea8-4204-bd5c-dc1c943afe6c": {"doc_hash": "9e1b3a274a253146029d7567f7552ecbecb6f52d289cab9fa3a9b0bff6580218", "ref_doc_id": "55c91041-228c-4727-9678-2d870c3dfe37"}, "df6268ff-7dc2-46a1-9385-63e1a97ed69e": {"doc_hash": "cab922fbfbf6df9e38b7c4d73b878fa34021fbe9c03de1bdaf78f70241286f7a", "ref_doc_id": "55c91041-228c-4727-9678-2d870c3dfe37"}, "981d003f-d847-46c2-ad6d-69f608dcb9da": {"doc_hash": "d6c1aa41a68765499f52e110045b10f5a0bcbcef0e2fb981d719cf8af34e1e1e", "ref_doc_id": "527c6d2f-0cab-4005-b34e-3c682253eb52"}, "6fb0c097-7282-4629-8011-94a8a0990350": {"doc_hash": "0f6ddc38ac426284b63682fee720f1702887e84e8f02396f268bce23b52b1667", "ref_doc_id": "527c6d2f-0cab-4005-b34e-3c682253eb52"}, "89e46253-0a75-48a5-84f2-167cdd23d5b7": {"doc_hash": "58f84643d2d0530f689d0613e77b49719256b077d7a008eaf434b645262cb42d", "ref_doc_id": "fb79c280-38f0-4153-958c-ae079cb40282"}, "5e330533-63cb-4e93-9b12-994ab7f3ae66": {"doc_hash": "64ff8ab5985b815f6af30f6a8630c5fc04db5ef170e3f194c6f2e5144424647f", "ref_doc_id": "fb79c280-38f0-4153-958c-ae079cb40282"}, "2c7fdf7b-a6e2-4be3-8b01-08cbc46c2979": {"doc_hash": "32601e5eac72f7465a5ee4c915811b0cb97d8e53e6eb323f947bc84fe7c685b3", "ref_doc_id": "fb79c280-38f0-4153-958c-ae079cb40282"}, "17223ed0-8791-44f3-a9a7-b6fc5c0545c6": {"doc_hash": "eeca4e888bbc7579470e7ebcffe007d38013aef8217a1ea56a48bc16738229cd", "ref_doc_id": "f09c85dc-6142-46ba-8ddc-c342c8587af8"}, "c86dad7a-35a1-462c-bb53-b7f3e54921fc": {"doc_hash": "45509241ac958b0f6ed00d2e7a31b58d06da1656b08e961d29d5a1fe42b9781f", "ref_doc_id": "fa9b5a90-45f5-4956-9716-f57f56afa41f"}, "883f004b-be84-454b-8906-3bccc985c7ad": {"doc_hash": "2c5da70180a96fce60606bd74c8abda6d93608ae9de15123f01d213575474dc4", "ref_doc_id": "fa9b5a90-45f5-4956-9716-f57f56afa41f"}, "67218dc5-1ac9-4edf-b257-efbe9c55ec10": {"doc_hash": "c0c07d0372fd0b939db2529f2df608ee538ee60bc5239e27afe75995b7c4ef60", "ref_doc_id": "4ccc1653-eb1f-438a-b0c8-acaea70e7dce"}, "deffb9e2-e741-4349-9ef8-d7776a00adb5": {"doc_hash": "356c657828fb8f5cd52ed58c98185d21162de0426a77b42934d2bd0e44f154a3", "ref_doc_id": "4ccc1653-eb1f-438a-b0c8-acaea70e7dce"}, "49225b95-f6e1-433a-a90c-dcf5b8772f49": {"doc_hash": "591cf6c5c2d4b63b671a37d9ff86bf70e6b14b8559387c5ee03c6e4ab42b2790", "ref_doc_id": "451fb778-e702-4947-afe1-25513cc65c11"}, "ced54c58-bb38-457c-8d4e-2be835d6b5e9": {"doc_hash": "4e6b4c9dbd80b9de10c7128e9b61486af0bbd2d2acfd42cb790210634eb49eaf", "ref_doc_id": "451fb778-e702-4947-afe1-25513cc65c11"}, "bf837ad2-e0c9-478a-ad5e-2f9c1f0607ae": {"doc_hash": "2d0694d94bbc3326068cd099c8d72fc2263b9a20ca6861e537b5fefbe7522ed9", "ref_doc_id": "3adf4295-e6b7-447d-928f-4c0250af866e"}, "42025fea-f86a-4f9f-bc20-b74e98f5ff23": {"doc_hash": "b39ba53148905b43ccf0289b7a2e991fe6a6e29866129e40cb6c8179111a2db9", "ref_doc_id": "3adf4295-e6b7-447d-928f-4c0250af866e"}, "8804fc0e-7ad8-4afa-b2e2-9c376aa2f67b": {"doc_hash": "ab77dda4d5d2b145949f263801cd321ccd9dea9f5db0838239f8c45091773715", "ref_doc_id": "ae696e19-2785-410e-89de-6e9aa91929d0"}, "74ff3fd6-58c1-472f-94ea-c63599cdee26": {"doc_hash": "4e989d9ee149b0495e24c41d6c15c4671c548849a3504595125b9d91614768cb", "ref_doc_id": "1bd461c7-3a1d-465e-90b5-a08f35001db6"}, "1993df21-3ed9-42ad-a120-a7037b4690bc": {"doc_hash": "2f13d1275bcce5ca06c59d79106a6668f94cff0d24b616bc83e0a96f779e831b", "ref_doc_id": "8d5c07a6-34f2-489d-b907-da3e36d9c70d"}, "579f30f0-7e31-4a68-b681-c7918a138c4c": {"doc_hash": "8a994ef263b7f381663bf8e660e6b5b582e31960b90a386d156b7ad3a6ba8cc9", "ref_doc_id": "8d5c07a6-34f2-489d-b907-da3e36d9c70d"}, "9b3017bb-1606-4f91-92c3-e153c1ef8b62": {"doc_hash": "d16ecddc78529f0f322e0e9dd31944601aca02abd48e94e64bdd158ea8ce492f", "ref_doc_id": "38eaefc4-4af9-4117-9d60-ed3eb7437b0e"}, "1a868faf-2a57-476a-ad57-512a4a15071c": {"doc_hash": "a15e893ae8c56129a116fc8f979326c72e022afd69f1ffaa174008836d67461d", "ref_doc_id": "38eaefc4-4af9-4117-9d60-ed3eb7437b0e"}, "4ead5dd9-7818-4f6c-8607-943feb02bf8a": {"doc_hash": "b83323a3d3f9ad366029402b7c0ad886fbcde9e7ce2e6bfaba5198a28d3c0a86", "ref_doc_id": "38eaefc4-4af9-4117-9d60-ed3eb7437b0e"}, "12fab41d-e2b8-406e-bc4d-6c6d6e1f35bd": {"doc_hash": "91de9081c471635f1aef0c2e3f5390d9f5c1991111088d6fdc741b0713e91457", "ref_doc_id": "44e7e96e-e9ab-43cd-9165-93344bdf02da"}, "0831e61c-0bf5-4352-a669-03f46ef7140d": {"doc_hash": "b2b362be1ec51dc9d89872a4b5d6dcf0ad754cd4bcde478025914d865090d954", "ref_doc_id": "c12437f5-afce-4ef2-b43f-56eb7100a2b6"}, "aef0bbb6-6a34-4a8d-b9d1-8c44a38f9f24": {"doc_hash": "44d6edf60fce1cb805a329f6b74052aa52388b5ce8ce3f9834e01e662dd5aa07", "ref_doc_id": "c12437f5-afce-4ef2-b43f-56eb7100a2b6"}, "99937a63-52ed-4da4-8cf8-f7ff7a3da181": {"doc_hash": "6b7f4068a32cd4088c3115f2c8a7d8e7a4aa3b8510fbff3a895994c4b8b8fa27", "ref_doc_id": "c12437f5-afce-4ef2-b43f-56eb7100a2b6"}, "5d234af6-0d0b-4a8a-92ef-c7378fab12a3": {"doc_hash": "083ad210cd861ce0b3e3a7eef7166dd41ca39680a8616e9c73ae3952e550e31c", "ref_doc_id": "c924bd17-b0ee-4b91-b2ba-0b773b7e150e"}, "7e29db77-cad8-422f-9bed-9dc06aab329d": {"doc_hash": "49fc4829736a931107a72b82b938746494cf26d6851a4ed2542aee0aca99fea2", "ref_doc_id": "c924bd17-b0ee-4b91-b2ba-0b773b7e150e"}, "97a71d97-b388-4830-9410-864ea5d13243": {"doc_hash": "b65302f1b20586645485d0cf3be64fc326b540201f8f5e32058ac61cb7a29a5a", "ref_doc_id": "8e356bc3-c376-4fa1-a0a4-966abcd841cb"}, "112f01dd-d54b-4512-8d7e-5ec87902f102": {"doc_hash": "a8309b7b5d90dbe0b6d5ac8957052e2bd6752e008308d382a100213924b2b612", "ref_doc_id": "8e356bc3-c376-4fa1-a0a4-966abcd841cb"}, "a8465211-371b-40cc-8ec5-1ce636927049": {"doc_hash": "67ba43bd65444a5ab5482050b74591a0e5123a7fc3701e515121056776756dd0", "ref_doc_id": "8e356bc3-c376-4fa1-a0a4-966abcd841cb"}, "94871800-d70c-4425-8ece-cb3a0ff5e33c": {"doc_hash": "d0c76e1dcac8f20f052ee57701e91917322b9e46e7a3c9f7fb3afd3df6cf8a4d", "ref_doc_id": "5e0b0730-73a6-4f06-9a87-27c43e8dbb7c"}, "99fc101d-0c81-4986-9a02-520c9ffdd24d": {"doc_hash": "360d24059a0208edf16bf2e980baff8200abe1c2e35223ac29b91c202b4eab04", "ref_doc_id": "5e0b0730-73a6-4f06-9a87-27c43e8dbb7c"}, "d8bce2db-f94a-42cb-9666-25e8f7b0d907": {"doc_hash": "f3a2acad7a558c68c0e861a31cc6cfa550e5a5ca63d24ee56fe57d90fe49b34d", "ref_doc_id": "bda4286b-5944-419d-9879-4f1d143ea96e"}, "9f6edab8-468a-4b75-8fbc-83a6d00d4f8b": {"doc_hash": "53dbfcb5838364485de5fb15f8cc33a4b1105b73bcba80d3cfb19370581f64fd", "ref_doc_id": "bda4286b-5944-419d-9879-4f1d143ea96e"}, "9aa5bedc-2a7f-420e-8a06-1cdc4a39bf30": {"doc_hash": "50ddce286d22a00e3a88545b552d68be3d86db6d47c744b8d406bbc37190f602", "ref_doc_id": "f2fc5f8b-f676-4a81-b59a-ab8873e8286c"}, "598c42f8-ac09-4e8e-82a6-3a25ed5b4618": {"doc_hash": "cdccc5691a156ab368f1639a57c27f11034b84f7428f8eadc1bc0c6b4532e8e5", "ref_doc_id": "f2fc5f8b-f676-4a81-b59a-ab8873e8286c"}, "75da4d16-b915-40a7-866c-9f15077ede58": {"doc_hash": "ae5eef329a126df4e8dcdc874b37a1cc56802e53122b2768635409ac4d459a49", "ref_doc_id": "fe6a6dfc-6763-448e-a127-155f43e5db8f"}, "fa614868-bbc4-4fb8-9f49-b0bd067419c5": {"doc_hash": "dfa9c328f044a3026674fe2805ca599c7c960015e927e3ca58b45c94709f7d8e", "ref_doc_id": "fe6a6dfc-6763-448e-a127-155f43e5db8f"}, "f6770141-7143-4232-9d58-a5407559fc8d": {"doc_hash": "8b633401c58e36327233f93168884ad173caead87f841ef7ac02fa263b658d7e", "ref_doc_id": "d20a21e8-617f-4acf-96e9-5767a390d0f3"}, "44dbac68-49ef-4c9a-8b6f-5866bd6d36f1": {"doc_hash": "32a327124c17430691d25fa9752f5957aa1570b7c506ce5b0ccc15ddc0e81c04", "ref_doc_id": "d20a21e8-617f-4acf-96e9-5767a390d0f3"}, "a5628738-a1be-43f8-ae8d-c0a46b6d639c": {"doc_hash": "be5c2852c68884d42adf6f5901101a262641fd15b72ae66e2e659a68bcf2ceaf", "ref_doc_id": "2cd795c4-1b50-49a8-ba49-8c8057d21a6a"}, "072a0792-c6aa-455d-8a5b-c45ea9db4163": {"doc_hash": "5205cd22c27c03c9d58f8a3785b5b64809cf30bc93b8ec7fe2bffa9c83c8452f", "ref_doc_id": "2cd795c4-1b50-49a8-ba49-8c8057d21a6a"}, "57ba2a49-3d32-45b7-84c7-5c86193ba66a": {"doc_hash": "9e1538eaacb4e10c10405a877cf8a36189c997980ef1d79c6ca7bbf7bfc7b223", "ref_doc_id": "2cd795c4-1b50-49a8-ba49-8c8057d21a6a"}, "bbedbda5-035a-4f18-a208-9fd4b05ba83b": {"doc_hash": "bd32290808311533f08c2c0087bbd42748848d9dde48e1bbc132910d1bb95a34", "ref_doc_id": "1efe8edc-b934-4ff4-9ce5-4a7955a007cb"}, "7c088bfd-965f-46a0-8780-029a2f750d19": {"doc_hash": "f9d3f24aae687af7e130874b6188a20a9b5918d8f90508a261e3d0d450e52562", "ref_doc_id": "1efe8edc-b934-4ff4-9ce5-4a7955a007cb"}, "50f06179-9a8b-423c-9216-b66bc76ceb07": {"doc_hash": "470a3afb117a6dcb02140a82258afd5d81250c41eb1ffb296c72e576f64dfe19", "ref_doc_id": "1efe8edc-b934-4ff4-9ce5-4a7955a007cb"}, "20658aac-1419-47ef-8c02-64898af730b3": {"doc_hash": "3b3ab8dcafe1ce6d175581899e9d71f2d3944c6f9a1acd37686a743bc4d6d7b5", "ref_doc_id": "84310896-2912-4cf4-89cb-e43712dcd9d8"}, "73521a5b-44d3-43cf-baeb-45d75aae8882": {"doc_hash": "4348b4cffee44f3508ac6e020675657097cc95d1ba80f4743f2b48484a53503d", "ref_doc_id": "84310896-2912-4cf4-89cb-e43712dcd9d8"}, "f1fb16e4-d2af-4364-8b94-b9c440f2b97d": {"doc_hash": "08608cac1d345485ab05bcde50cee40130ad0ed6d224d20e688bd407df46dfa8", "ref_doc_id": "1b199d19-5066-4fa6-8bf0-139cea942264"}, "b42b8e16-fcbe-41aa-b2c9-22e7957a2659": {"doc_hash": "4fee46a5762b32899126db47387a209976788b5bbefa44b90521395b67e810a0", "ref_doc_id": "1b199d19-5066-4fa6-8bf0-139cea942264"}, "b21a42a2-26aa-47a0-bd18-dce7cd721184": {"doc_hash": "c0dea40421cd3f859ae735ead6396a160b94248c2f6c8ce3351c044d399f4fcf", "ref_doc_id": "d23970fe-0999-4f8c-87f3-4fb36487aa58"}, "6118958b-c6eb-46c3-ad6d-f7c1428d2c58": {"doc_hash": "ae02dad64009600a0f2539c1dcd2813789d28f7045a9268b52f4fc299dff6607", "ref_doc_id": "d23970fe-0999-4f8c-87f3-4fb36487aa58"}, "e2a48ae5-d595-4bc6-bab4-660263bddf37": {"doc_hash": "904ee0b9584aefe504981d50b3ef24d9175928b777bb01c77346565e4b21dee2", "ref_doc_id": "f4c94c80-ba1c-4d5b-bf82-182cb5b20b06"}, "7a141031-702a-4fcc-9d00-a7497cff1a2c": {"doc_hash": "45dcdc6aa7e94d81f4782ca2df0f65afaba307ce55de48055c8c64f1daad7ba0", "ref_doc_id": "f4c94c80-ba1c-4d5b-bf82-182cb5b20b06"}, "3993c164-af7b-4d42-9ccb-e446b2cce491": {"doc_hash": "74a9df1b207d624c568f58d461ec0749f826534fe1b51bab82b5930bc6c9dd8f", "ref_doc_id": "f4c94c80-ba1c-4d5b-bf82-182cb5b20b06"}, "b079a0ff-8e6f-4fc9-a6a3-a3eadb315236": {"doc_hash": "dd3f99a425dddd2bc55f65af87297e419a4be971f0be35cd97740c5b8467f654", "ref_doc_id": "ce7ca287-7bae-4d73-9e1b-53e2877c19dc"}, "3dbd165f-0d69-4e7d-a7ff-f2fa5fd30754": {"doc_hash": "9d45b8dcaff63cd58790ead2b134ede5b102d13f9e23c996f5a352630b756ec2", "ref_doc_id": "ce7ca287-7bae-4d73-9e1b-53e2877c19dc"}, "b1c398c3-af7f-44f7-9bf4-a14c6bdbe12b": {"doc_hash": "e2088e5b48a397adc415a6c92874e2eff9be167dbaba64c2483a78e8caa94e8e", "ref_doc_id": "bc268ea8-3541-4a54-9ea3-4ec4ef175355"}, "e4416dfc-d69f-4b0a-8375-6a316fb4ffcd": {"doc_hash": "87470f32138918f9115ba8208d5ff385be9adfd079ffb1c04c3a0174bc1194a8", "ref_doc_id": "bc268ea8-3541-4a54-9ea3-4ec4ef175355"}, "0bf45a48-f030-497a-a8ed-60882a4ad3b8": {"doc_hash": "7c078dea43f9bbb42b7d9764f016973bdeffa1425ba98bd116597142d6819895", "ref_doc_id": "bc268ea8-3541-4a54-9ea3-4ec4ef175355"}, "d501622b-b7b0-448e-b8d0-dc51c10c963e": {"doc_hash": "5b16bc296754d6418619507862f78fb7b4e7bf11d2718c478e15f581036a225e", "ref_doc_id": "f1e7984c-51a3-4d80-8eff-e2d4ae60ca4e"}, "45f1da4c-d5db-4178-aa88-c971df6ba348": {"doc_hash": "589e8a10c880e0276c86da49358fbe10fd5ff15245ea856d4af0526765cd4bed", "ref_doc_id": "f1e7984c-51a3-4d80-8eff-e2d4ae60ca4e"}, "1321f416-92f3-4c08-ae4e-4c0175fbcc61": {"doc_hash": "b1590e87c5e4f44181fc8f9093035c9a53e253e780ea7dbb2a0036f16a25ebd0", "ref_doc_id": "418c248c-21b2-42e1-9636-e911e7092d79"}, "fc3e45d1-e539-4a33-b465-35dcfe0f49b0": {"doc_hash": "60c9914a11113b2752a39badfa7c42f918c17cb9dc00f0b2406c3c90459744bb", "ref_doc_id": "ca5fd6e5-9a6a-4a42-9351-a8a2c8b95f6e"}, "fc2a8504-bbee-43c8-8db5-dfbb6cfc95d5": {"doc_hash": "e953ec9f4be6715cf4142b63abc5feaa21e8855ffe0055c0b768f46a6f6b7c47", "ref_doc_id": "ca5fd6e5-9a6a-4a42-9351-a8a2c8b95f6e"}, "9a34710e-7bd9-4fb6-ab8b-db69789e68f3": {"doc_hash": "ec7f2c332f3616e5fd197418d990f5668ccd046b0eaf80beb50546f0d44dcb4d", "ref_doc_id": "07c80ebe-0826-4842-864f-006768ff70b0"}, "15d8d458-2b02-48f9-bf3d-7687e468f860": {"doc_hash": "3a9a4e3031acc6deebebc2aa8ae3d16dcd290e8e8c94fb73c059358ec76435f6", "ref_doc_id": "07c80ebe-0826-4842-864f-006768ff70b0"}, "85df5f9b-266c-4ae7-bcf8-a28d0b66ee30": {"doc_hash": "8eadf7129a130c34f8f39508edfe3a420af65282ef2b8fb8be6e657ff5d12a46", "ref_doc_id": "07c80ebe-0826-4842-864f-006768ff70b0"}, "e4c25c41-12d3-445f-b38a-2b515d7806d6": {"doc_hash": "31d541ed7df83e2217edd621644817e220d96dbece0092ab8aa46e51d6c09fbb", "ref_doc_id": "52a1ce83-0aa5-40f5-a784-d828a084fd3d"}, "75b8c2fe-a448-4d39-81d5-00e7ec5e839c": {"doc_hash": "c54a33a8c5adb1046a171c6c5dc2ac2f661240e7f8b88d3f1c8facf013746604", "ref_doc_id": "52a1ce83-0aa5-40f5-a784-d828a084fd3d"}, "a324f98f-e2c6-49a5-9c50-6fffde1c6d78": {"doc_hash": "dfa52a85c7f2d147e387ad0a8ee6c3ba5f3cb54d219d3ff7f612380ad1f50e98", "ref_doc_id": "f238dff4-b098-41bf-b79c-3024d1e49d07"}, "a12cbc3e-66e9-44c6-854e-0d653bad8073": {"doc_hash": "267c0f0f788d82529ca32950f501aa06832311b178e63c23bd95b61a5096e165", "ref_doc_id": "f238dff4-b098-41bf-b79c-3024d1e49d07"}, "0ad8b8c7-1960-4345-8c86-e2b1f4f9164e": {"doc_hash": "b8088265ecd8e1ed1d108e731c7e2f9323c7206c8b9b2be6d317df66c033b937", "ref_doc_id": "af558226-ca59-4531-b13d-0c3483f85ce0"}, "c52bca6c-3938-42be-b9fb-731c57141b58": {"doc_hash": "2f42d73b99d548425448cbb1f9debaaa4ce835426968fb4e92415a2d17bb0999", "ref_doc_id": "af558226-ca59-4531-b13d-0c3483f85ce0"}, "e858fa5d-087d-4fef-b323-51e5f9df874e": {"doc_hash": "73bd80063696619b8b4d7072ff9d8659ca2078b5d37654980d8d696319d56021", "ref_doc_id": "26046351-e663-453b-88d0-38bd5f628dc4"}, "6be9cdb6-1f8c-4c02-9257-f29af674cd27": {"doc_hash": "4803adafc83cdf5f9c60777b891ff64d776f4288ccca29e875bfe80471047965", "ref_doc_id": "26046351-e663-453b-88d0-38bd5f628dc4"}, "61b0b080-e377-47c7-b286-3303de4844bb": {"doc_hash": "bc499473ff509c2fe0595638e6419fd07648e04b1894fa29bf1d5dfb06906195", "ref_doc_id": "2b64243f-9d69-4c90-ab25-aaeb96bf5432"}, "e733db96-f024-4ecc-a12e-4b740af790d4": {"doc_hash": "2ec84f17b050e4400bdd0d70570b3cc17ba8921fd18b1e2ab60de766a5283011", "ref_doc_id": "2b64243f-9d69-4c90-ab25-aaeb96bf5432"}, "2e476019-922d-43d1-8436-9d911b6e2775": {"doc_hash": "f4582fccbf462f7d7916e5f8a65cf2def879945ef982507bad766722e1bd74a7", "ref_doc_id": "af9152c4-0a69-4bf3-8852-570c8faa5663"}, "a2d83870-e4f0-4c06-bf17-b67d4b2dca51": {"doc_hash": "f8eea9957ad47493d12ff7212d56281ac6033ddef692fccdcf5d16b508036cef", "ref_doc_id": "af9152c4-0a69-4bf3-8852-570c8faa5663"}, "2ebb7c5b-5c02-4d96-899b-956f0e7ea3d8": {"doc_hash": "082465a31e03af06d1641ce9ff045d7a7695ca526c2e9fbd9bef7489d5151bb7", "ref_doc_id": "63c747f6-b5df-47ec-ace9-7a918c5f5033"}, "cbe6c204-b872-45d2-9935-e111795d69f2": {"doc_hash": "c906b4bcb965c2f0084344f7552a510470b83443a94a0314124d2f172f42bf3e", "ref_doc_id": "63c747f6-b5df-47ec-ace9-7a918c5f5033"}, "60dbb3c5-7e9c-48db-b3f2-6613968aa704": {"doc_hash": "9e1b0ce40ed3a4eacddecb15cbb65cbaaa85fbb0b302f733732222aac6ab9dfe", "ref_doc_id": "63c747f6-b5df-47ec-ace9-7a918c5f5033"}, "660de627-9f06-4a09-8d20-c603e6a07086": {"doc_hash": "644787f24caf11ad30b64f900d90b5413db2c39a0f5b3e6290b34658af2b4043", "ref_doc_id": "51d6ccbe-5663-422f-a1af-c24e3bbd7b12"}, "77a37bd5-b1cb-4d79-9ecc-908838dc3440": {"doc_hash": "676a7fb7eb70f5d1b4f1b52c5b621e47b5c969992d7edd0e20238772a5682570", "ref_doc_id": "51d6ccbe-5663-422f-a1af-c24e3bbd7b12"}, "dd83b3d6-0dc5-4331-b408-de3d1604f5c9": {"doc_hash": "6c44824656835cf4aaca924cf7e084b781efa601d87264869323092cd1520f56", "ref_doc_id": "94517a50-09a8-4f34-a390-5cb644cfd387"}, "2c273a64-bc09-4cd9-a649-fb4e64491e1a": {"doc_hash": "8d9ef90a2757ccb3331218638b057bd7851932518702bdd0c4bd2880fd9c4b18", "ref_doc_id": "94517a50-09a8-4f34-a390-5cb644cfd387"}, "80d3b47c-56bf-4f17-80b8-03191e5a16a2": {"doc_hash": "9cbc1e39714cde3f44bf5e048b0e1d86f935ad4b174d2dba43a9ad2fc7c71316", "ref_doc_id": "108ae145-5d6c-4074-b880-a88e2125df39"}, "0b93104a-fbb9-434d-8e24-3279ef3937c1": {"doc_hash": "7d9f1367a16433f61c99075485da801f9b8b84d3dbc1124171fb64f39844a159", "ref_doc_id": "108ae145-5d6c-4074-b880-a88e2125df39"}, "b71a1de9-8fe6-4722-8cba-09eb8459e6c7": {"doc_hash": "d66e792ab42cb8bd360fc8b3ddff65aeb4572b644f33e433bd123116582e63bf", "ref_doc_id": "4cff3ca7-6f2e-4b4e-a82f-460d650acd71"}, "8e4eeac6-2e5e-4b1b-b326-d0971d61e8b5": {"doc_hash": "1639f4502d09f13614451b77707fd8a80c4c39da9caaf8260de1b99a35381838", "ref_doc_id": "4cff3ca7-6f2e-4b4e-a82f-460d650acd71"}, "2f073e4a-5b9f-47c3-ba13-e3bb7fda1b54": {"doc_hash": "ca1cf99411be9b5631237ced194b8d79c977f3ef050d1f45613148cf663a1aa9", "ref_doc_id": "7dd86da5-b6d8-4e80-b3f2-9382a9be9efd"}, "67b7fe86-1304-494b-80ed-995fac1dfd97": {"doc_hash": "3436e695d741d6549533f398aa2d4f4019d4ac6d1f822751dc93889bc4b1cf7a", "ref_doc_id": "7dd86da5-b6d8-4e80-b3f2-9382a9be9efd"}, "71756b83-15c6-4b11-a53f-3a44c5cf2148": {"doc_hash": "67907e7cad55204cfd54769c08f0f7c574ddc7326dfc76ba1bd2b9ce89d6cc16", "ref_doc_id": "e424bc1d-fd47-4aaf-883b-7a0fcfd34468"}, "d1b053bb-6836-436f-8e37-d3d00175c02d": {"doc_hash": "26dbdf2f27e2459a32ae1a297044122f527e7454e5d5530714a0e29ae4e3c6f4", "ref_doc_id": "e424bc1d-fd47-4aaf-883b-7a0fcfd34468"}, "e6b36480-6c67-4d9f-b718-1199955fd4c7": {"doc_hash": "47d97a8b95b80faab1f9bb3634aa98443055934284a47d82e2b5b7a8f04b13ee", "ref_doc_id": "e9e8e560-f979-4eb6-83a1-5313ac7253ba"}, "c8e1887c-e273-439d-8d38-b0c41e39e83d": {"doc_hash": "43398a9c8dd43c38d9392638a99becf324536ac10e5df3e810dae6b46dafc6ee", "ref_doc_id": "e9e8e560-f979-4eb6-83a1-5313ac7253ba"}, "4e53dd9b-f7a0-470f-84d4-dccac2fb1920": {"doc_hash": "fc489b4e9909ba86d0a2c30e4a29403b21399795325cea30e2ab14f711a3be29", "ref_doc_id": "bc55bab8-9e1f-4036-bccb-51c5a9e78738"}, "eebda1a3-1672-41cb-b512-dc71a8e092b5": {"doc_hash": "36e54d6daa4658f38deaa66ceb917c2ef8b65843fd84b44c28513eae868fb97e", "ref_doc_id": "bc55bab8-9e1f-4036-bccb-51c5a9e78738"}, "50ecf123-c78c-4203-92c4-d7aebfadfb77": {"doc_hash": "61afa4d3b35ccc2e6515304c1d9eac5862087539bc75b212dba0a8867ba6a2b0", "ref_doc_id": "434e4647-fa83-4200-a0b5-f1d974b88edf"}, "0ef2d212-1dff-4d79-96f9-7237559920b8": {"doc_hash": "6eadaa0a962c6f9ac72752e19cbad1bb652154093dd4aee2c2cd2b125827aae3", "ref_doc_id": "434e4647-fa83-4200-a0b5-f1d974b88edf"}, "f573ffa9-5fdf-4ab7-95a0-fa0facec9195": {"doc_hash": "4c8637a6a9cae7eb1eee9279e9ea616db76c960b10941ec7cf9950592b363163", "ref_doc_id": "434e4647-fa83-4200-a0b5-f1d974b88edf"}, "204ac2cb-39aa-4912-8979-ce7c6734b259": {"doc_hash": "ed38a2b67860a01686d87191cc82e972166efd6a232cd720dc27e8f30d02e497", "ref_doc_id": "559cf4ab-e4c0-442f-a93e-93177a9709cd"}, "92705424-bcd9-454f-bba8-10b20c7d5f29": {"doc_hash": "b39682871a76bb48bcf45988ebff1b412b12f4ac9843b9dc5a105f27285b630d", "ref_doc_id": "559cf4ab-e4c0-442f-a93e-93177a9709cd"}, "e2af8eeb-4d89-4996-8c4c-8536a1967da5": {"doc_hash": "071a098e7c8b18de5d39d87136cb75a787e86416268f6bbebe175afce2c7f42d", "ref_doc_id": "559cf4ab-e4c0-442f-a93e-93177a9709cd"}, "e6fa2d4e-8b95-4ee2-b0dd-7e7304c2b52e": {"doc_hash": "9da97c6b92292ac43afa182ff10809ebf940427707cc28a6a4cd7db876d0d37a", "ref_doc_id": "86b6e004-dea7-44e1-81d2-98aff8b89b51"}, "eeb87108-8f11-4858-abe3-b766017ff050": {"doc_hash": "e9c0f359e25cc757d9f2878eb4409fc32195b6a12059f4ff8635ae8ac2e54f57", "ref_doc_id": "86b6e004-dea7-44e1-81d2-98aff8b89b51"}, "da3a9b5e-f56b-4e04-8b43-ce3cc7064725": {"doc_hash": "21352836d88a0276d247ad9641c78d18903e59d6a09c07a50197221929b1dc91", "ref_doc_id": "d297ec2d-4538-404c-96f1-606872d0d47b"}, "7694f525-45e1-4751-9afc-f2c6ac2abfd1": {"doc_hash": "39f018b53966c60a3623778b65c8ad306c3eff4f736a55aa9a1cc1b7890873b9", "ref_doc_id": "d297ec2d-4538-404c-96f1-606872d0d47b"}, "6db0efd6-ca6b-410f-a658-a94572f9b686": {"doc_hash": "66c2351995d02416f37b8909fd084fb450519db983f90c7dc0cd59afcc0d2429", "ref_doc_id": "d297ec2d-4538-404c-96f1-606872d0d47b"}, "8e903659-1ebe-4383-b213-3480babebe5c": {"doc_hash": "65bf42f0c5fafc28ce1a2ed05b4b45c9e4988c103e43c31957c57d9ea66894ee", "ref_doc_id": "d297ec2d-4538-404c-96f1-606872d0d47b"}, "f5bf7544-62a2-448d-9760-64f4d5152a05": {"doc_hash": "a77c8a3425cba8b57d23212584af302ef6fbc246e6157fbd7d3f207682ed3332", "ref_doc_id": "5ee4cec0-21cb-469f-85bd-0eee0c52b017"}, "394e5e7b-0379-432e-906d-653e37a19629": {"doc_hash": "0f3a6702153ab401eab1f8709e63226563fecf86d2887403d4f7da96782ed757", "ref_doc_id": "d4adfd5d-0b7e-4e02-8aa2-661e574d4604"}, "8e335c04-0570-4fce-8c29-3a3329f355fd": {"doc_hash": "4c5d1d413af6c9f88542eea3e339b6c1345b8aa53251e7ce97e7ece89de9f2fa", "ref_doc_id": "d4adfd5d-0b7e-4e02-8aa2-661e574d4604"}, "665b91f5-954f-4060-9645-adeb2ec558b7": {"doc_hash": "6c0cde10943c70330df0f98d8649fa0e0810c8e46e37b97f6680b0fa15d8708b", "ref_doc_id": "16dfa785-0672-479a-86a6-891c7f7daeff"}, "33a968f1-05fc-4285-b813-0f4254798fcc": {"doc_hash": "5d34aa02a9af4e3225b130904ffc01c49acdd558f05fc9d0a3cf0110f68e70b0", "ref_doc_id": "16dfa785-0672-479a-86a6-891c7f7daeff"}, "c8fdbccc-951b-4ec9-8d7e-e2ad63f1d7c5": {"doc_hash": "5bdcbf84bebada9499f0f8ea6874c78641961482f48ce4f5c4b05b5e4d93e5a4", "ref_doc_id": "d261d037-7e9b-49a5-9063-4f252be69392"}, "26a399e1-a739-43e7-a787-b9c338334543": {"doc_hash": "69630df97977415322bcfc49b28aea1f926401728a9b4923dad144cb0c672846", "ref_doc_id": "d261d037-7e9b-49a5-9063-4f252be69392"}, "cbfd69db-9482-4d09-a11c-73769cfd00f4": {"doc_hash": "67eeb27405a8158c363a81364b9095d04e6941d8d7c573061d2944f8c7998d33", "ref_doc_id": "53d9a10f-24c1-47b3-ace5-020773733807"}, "2b34b785-a141-4655-a90d-7eab6e8e8f74": {"doc_hash": "ef8b8c3c021f65e682fcad6aadc859ce641d4d1fda661b81f93aec7f31c1f097", "ref_doc_id": "53d9a10f-24c1-47b3-ace5-020773733807"}, "a1c19f9e-d8ba-40b5-b6c7-73212c24b656": {"doc_hash": "a47c969113d424bc61088cc2619fc740691e535bd610b9b36e3fa9776703fe15", "ref_doc_id": "53d9a10f-24c1-47b3-ace5-020773733807"}, "87c27c3f-8226-457b-a1e0-c82ec89056b5": {"doc_hash": "8e3e5d28f986f69b4125e60791505708499b396d3a53f3e889b13aae9754baa0", "ref_doc_id": "eadbe98b-2eb5-4a80-a5e0-93f91acdd6a8"}, "a466e41a-8c86-4653-9e99-592680d38d81": {"doc_hash": "d5c254628d7ff079448599820de9c1f3e39796a59450d8d3d34aa3870e23c0f2", "ref_doc_id": "eadbe98b-2eb5-4a80-a5e0-93f91acdd6a8"}, "7a85acdb-7a47-4aad-b529-9ac31a834f94": {"doc_hash": "ae3fc32abe50f596c6aab7b5263bbebbdbe8113a91c389e15372b0c6a1941ca3", "ref_doc_id": "fc715357-b3f5-4bbd-8935-bdefdf179b92"}, "0bf3bb7c-15a8-4dc9-a81a-89a1aae3ca4a": {"doc_hash": "d9467d8bdc95555b62c889e861611a59cc3efdebf8f9f1b2bc834b71a2cc4ba5", "ref_doc_id": "fc715357-b3f5-4bbd-8935-bdefdf179b92"}, "47354fed-9314-4ef0-abb4-58b1f19543fb": {"doc_hash": "578b2512c470498d31131f267f01b662da4036e5eabdc4c8416eb1a34c760323", "ref_doc_id": "74dacdf4-76e1-4b29-8462-2a1e4f1397cc"}, "17284040-52b0-4567-b2cd-4d7e4d993b20": {"doc_hash": "d4cc90040a57a032359654ed28746c6849b0e89405172e41bee07a693a7a0c01", "ref_doc_id": "74dacdf4-76e1-4b29-8462-2a1e4f1397cc"}, "cc8f2717-127e-4ab1-8cac-3b3f2c534a4e": {"doc_hash": "8bf1dd8009370c0c9bf34e83ed1695679c49685afca48a177cb1f2cc32aa7321", "ref_doc_id": "74dacdf4-76e1-4b29-8462-2a1e4f1397cc"}, "a5eec967-4b60-456a-8190-2627fdf9b687": {"doc_hash": "458318872dcef8662e50ccd8d045a341aa2d94bede2f6bcac68cad0620288fed", "ref_doc_id": "7d4dda25-30a4-49b6-9927-6b71e5c7ec19"}, "4e8f41a4-33d7-4c82-bac7-c69d81978d21": {"doc_hash": "06b0e072b8375f353ec300dc28ad0782e9345a36da244060fb5c71a5b4010f39", "ref_doc_id": "7d4dda25-30a4-49b6-9927-6b71e5c7ec19"}, "187ee27d-98c1-482c-80ca-647f549bed5e": {"doc_hash": "132258a49ebbd375ba5cd6a3197891916d2b93e40a38df8cc71e2cb06e9d5a1a", "ref_doc_id": "e98604d1-26a7-42b0-95a4-202faba70a45"}, "a37761b4-3cd9-4542-bf1e-1b2b8edf5bf9": {"doc_hash": "710c8361c0d3c46ff0c30353a91327fffddd2c1ecb450865f6d280963ea4ad73", "ref_doc_id": "e98604d1-26a7-42b0-95a4-202faba70a45"}, "80ecd270-f1bf-4e90-b31b-e671b78c62e3": {"doc_hash": "3ba5472a830c56faaacd1d36388030131e6bd09212dd58ee280433bf89b5a992", "ref_doc_id": "e98604d1-26a7-42b0-95a4-202faba70a45"}, "e8cbcf2b-c54e-4b64-9f23-05d9337395f5": {"doc_hash": "b49cd2426bc6732477e39890b615bffe19c34a41f1ef328ad7c8c6a336458e9b", "ref_doc_id": "a73ccbb6-470f-4e3e-beb5-6c73ce8d3361"}, "568924d6-2905-4a31-8c52-0b0143f4ae64": {"doc_hash": "79bc5659c6864a8d6d02bf6ce4935324d9e8fd0b86e817338967b40f0ed397ef", "ref_doc_id": "a73ccbb6-470f-4e3e-beb5-6c73ce8d3361"}, "27b3c26c-acb4-497b-863d-70058ea96e70": {"doc_hash": "f1af1cedc1815ff7751e94824a63370161b84f0180f7d182376066ecee0bcc54", "ref_doc_id": "a73ccbb6-470f-4e3e-beb5-6c73ce8d3361"}, "6215427a-e93d-4249-bc71-a21e3c7ee940": {"doc_hash": "ac6d9c84383420beee6aff500c7fa4b9ca6c5a3401985aac74ed030537ec43ae", "ref_doc_id": "e9033864-b226-45f2-80f2-bc671d10b6e8"}, "16645623-0e18-49af-8343-6576d44c69e2": {"doc_hash": "074380d96cfeed5af6f1e5e3ea586012791fecb06dc99c4f8a1f043602060a80", "ref_doc_id": "e9033864-b226-45f2-80f2-bc671d10b6e8"}, "3b82a1cf-427f-4829-9589-efae4df36d73": {"doc_hash": "4c051879a3bf7bc270aa2315188871cc74ff72b82ae31a89e5582eab975a963c", "ref_doc_id": "e9033864-b226-45f2-80f2-bc671d10b6e8"}, "805c864d-0d56-4773-9ff5-7a885e35dd84": {"doc_hash": "dbde67810bd58abaf00ba5119eba611bb0e7a594c1cfdc638ff6a0ebf836a6a7", "ref_doc_id": "be206d83-2285-4564-adec-859ecb1853ec"}, "d4e7d1a6-939a-4ec1-81cd-1611ca8adc95": {"doc_hash": "0d5965e1517f3ec09dcec302e0c836787e9d6c7cddb705c9b7920d467648985e", "ref_doc_id": "be206d83-2285-4564-adec-859ecb1853ec"}, "3f23568d-d209-43ff-8a7a-09a1396bd307": {"doc_hash": "e0e5fe794ef7b2e5de6162e4b74f33d5982c4eb2127cc9a4b35f1df4edfcdc00", "ref_doc_id": "551b6a42-8c74-4f54-a581-ae3f30d66d91"}, "384e0a9b-7528-485a-8fb3-f5a94502198a": {"doc_hash": "802fc83d78fb7e19602d965927d9068c5bf9b88c70aa2fff7dbfce32b523b87e", "ref_doc_id": "551b6a42-8c74-4f54-a581-ae3f30d66d91"}, "16d2ca7b-ecf9-4bfc-897c-41753862c9c7": {"doc_hash": "69658da6d38676de3f4db5cb001407a00f07c968309704ea018a9336cfec3c3c", "ref_doc_id": "551b6a42-8c74-4f54-a581-ae3f30d66d91"}, "1e42e95b-f727-4728-b563-22d63a48d735": {"doc_hash": "43eba12f8316fe8152dfca0b66a647a5901fb872bc19814fbd66d353e6b8cba4", "ref_doc_id": "e5b2b54a-7b6a-43d2-bc9a-109d23b4a347"}, "e44672d9-e397-4d81-96ee-c638d48479ba": {"doc_hash": "31f904146b9d137b34d4e533fe081025157c793674fd41f2251cc3b36e33f8d9", "ref_doc_id": "e5b2b54a-7b6a-43d2-bc9a-109d23b4a347"}, "146f0be5-66ac-4746-b4a3-32e81d5c18e3": {"doc_hash": "4699ba465a57d38f469939576f7e72019575d87ce86bf2f901bb12df07f5821b", "ref_doc_id": "e46b303c-f250-46c9-be33-0eea50e6a1c7"}, "5bb9fdc9-f998-4edd-abde-f843da32e42c": {"doc_hash": "1b2b56c422c6634e202ef5012b48a72e794df95712364c62c35f7ad331620f9c", "ref_doc_id": "e46b303c-f250-46c9-be33-0eea50e6a1c7"}, "21438291-6488-4938-979a-c45500b1e757": {"doc_hash": "535fba51517d30120feae4b93ac45f02f01bb31144f6a2e0df18c3680a031095", "ref_doc_id": "9c56fba1-1eb6-4331-9f3f-7dbd63bc1109"}, "2c1514f1-777e-439c-90a5-d38c34e58a25": {"doc_hash": "d79a5e43180db8ddad7566330334202f3c64a546e0dd41164fe8f52ba8112921", "ref_doc_id": "9c56fba1-1eb6-4331-9f3f-7dbd63bc1109"}, "7ef0d6f6-d4a2-46cf-9e96-2754e4d778b0": {"doc_hash": "e79d0058c16afb2c6a215d95605d9d429a0798b0f68d9757d24476c0a1f2942d", "ref_doc_id": "4a9cf1f1-aa36-41ec-96f6-75b2f6345c1e"}, "c8234730-0c36-4cd1-bed0-9af7c1cc54d5": {"doc_hash": "bdc770d94d619132812337baf19f64dbda634a60fa6e74bb2abbf393eca08619", "ref_doc_id": "4a9cf1f1-aa36-41ec-96f6-75b2f6345c1e"}, "b5f3147f-c55b-44f2-9fde-14cadaf87ece": {"doc_hash": "f7d9228a78edc178e1a82007c49a9cd80239863c9d4cc25627c866613813bedf", "ref_doc_id": "4a9cf1f1-aa36-41ec-96f6-75b2f6345c1e"}, "367c3e8d-383d-4363-bc47-d6c9b9f85985": {"doc_hash": "f0519700dc1747b86fa067cbaca05234cdec8b67747dae030d3ebbd14ea2cf33", "ref_doc_id": "8bbd8faf-a3ab-4288-8e90-26e5345469c4"}, "6a2f82e6-d943-4338-b1d2-07151d328d7d": {"doc_hash": "2005a129f65291253185a5d005eacc3464578ad0a0909610f497700c81ab0936", "ref_doc_id": "8bbd8faf-a3ab-4288-8e90-26e5345469c4"}, "18248a49-7cbd-4016-8c8b-3f9b47164ea5": {"doc_hash": "bc1c5f2befbc8f2c23369e5cd910c209d9c0e6e7cf73bd0661b40b4568b653ee", "ref_doc_id": "68e269cf-0e6e-4866-a060-0b7508b0d38c"}, "3572ad87-1e37-491c-b38d-beaf82d9e0f0": {"doc_hash": "d72f709a610ded93960e9b7b24b6d0b4d46887d1f43cf5c62a3ed66251d057b1", "ref_doc_id": "68e269cf-0e6e-4866-a060-0b7508b0d38c"}, "e9b6b475-f705-4d1c-8d1c-db4f72afdc1a": {"doc_hash": "f8e99f31b7582d303fc6312a5797a4d432cf397bbbe275bc00a370a78227b810", "ref_doc_id": "68e269cf-0e6e-4866-a060-0b7508b0d38c"}, "97fa29ab-e644-4f9f-b4da-b4ed2569dd9c": {"doc_hash": "92cc6d38b554ddb109d62d2ea1055013ba075e9a5a86ae58b46dee7b9c61cafa", "ref_doc_id": "61e96006-6546-4a6b-b2ad-c7bebffc2675"}, "6b1f4e28-5122-4077-89d7-358f01817061": {"doc_hash": "471de5b8e4a4381a93c2fc3978ae89162773b5ebafdaead57714d54b12cb840c", "ref_doc_id": "61e96006-6546-4a6b-b2ad-c7bebffc2675"}, "f62be533-76cf-4ab3-b573-a3c186e5ca17": {"doc_hash": "ed6239fabe3221824d17c3d7e66fbddab0fba8ec0d5993a0209787d97e717b07", "ref_doc_id": "d220d9c1-4db6-4622-bd32-d93bcc8e3a95"}, "3f049968-6296-4c50-b57c-3839feedb368": {"doc_hash": "e67c35c918c7a24ef855657a1de9ad0489a3bc4906e9cc935fa4caa8975a03db", "ref_doc_id": "d220d9c1-4db6-4622-bd32-d93bcc8e3a95"}, "30159b04-274f-4061-904d-93ad66743365": {"doc_hash": "aa94b26b484a26c98a77a2fc4e84d45a3464a6e3d48e8129d1fbb11664b3e089", "ref_doc_id": "d220d9c1-4db6-4622-bd32-d93bcc8e3a95"}, "51e43c99-0a46-4d0c-af97-b06e6437dc61": {"doc_hash": "5ff3bed2577a0750826a28206d5ff70be856c7111f09211b3c57f1aacb728d73", "ref_doc_id": "c0a25662-8abf-4d2a-8ce9-85ac3dfb02ff"}, "6e500db8-f5b5-44a4-a660-78ed2205831b": {"doc_hash": "81116835aee4beb2d3e9d495ff73191f8ab399753dc02ee11ee757bb868f956a", "ref_doc_id": "c0a25662-8abf-4d2a-8ce9-85ac3dfb02ff"}, "27c7d407-6407-46bf-b75a-a1c1a2281449": {"doc_hash": "90c9c836e0e0af11a507f696bdd46be96f568c5cc96a1b94266d777aa67c6aab", "ref_doc_id": "6fb17d2d-d89b-4543-888b-bd06572ac85c"}, "cf0734f3-dc0b-4bcc-9971-c1b36bb93ff5": {"doc_hash": "b0bf3efafef6ee037ccb4d0add37e690f2ddc330ab8e49cddeb423357775895b", "ref_doc_id": "6fb17d2d-d89b-4543-888b-bd06572ac85c"}, "32466f12-adc5-4721-81c7-f1c21cce22f7": {"doc_hash": "e465dde23876f61c44c8a4cd123763d5d02226ab6ec8f8bee117015562b3c351", "ref_doc_id": "6fb17d2d-d89b-4543-888b-bd06572ac85c"}, "9e369014-bac7-4a98-b93f-7cdc5d1d14b0": {"doc_hash": "8271f2047d760c7af6b44a25c2b4b67805be71fe2651e41ea17cd9a8eac64ab4", "ref_doc_id": "3751be59-962a-4bae-b8b7-e42e4059c160"}, "3b6cddd5-bffe-456e-9217-a4cbbc33ed78": {"doc_hash": "88a7646027c9e69d482db3367157bf5245efe42ab5f6372c9b884136498e0024", "ref_doc_id": "3751be59-962a-4bae-b8b7-e42e4059c160"}, "9ee187eb-ec86-449a-ba82-a2b55c476a9c": {"doc_hash": "7e8e678a3a0aaa4d80a69b78a8c3123d6fcc836d9d6ef8576923d44d7c23294a", "ref_doc_id": "5a81b037-d520-4060-9e08-e8c70195cf07"}, "92fc4f0b-0c1d-4f7a-97e1-77c35513ea8f": {"doc_hash": "5eb4de60b8264e6ff6e2f1f9af1a68e889724b2d2724296ff268f53791e4b08c", "ref_doc_id": "5a81b037-d520-4060-9e08-e8c70195cf07"}, "59bd06a0-aa11-4def-9921-ee34102df027": {"doc_hash": "765ef2fbdef1ac0707f0b92a460b207af6e08728ce74943563f2ec584e17b2d9", "ref_doc_id": "d6c3a031-06c5-4854-9c91-907910d0077c"}, "c20bf026-294c-4ec9-b83a-2ed178b9c05a": {"doc_hash": "a3bc041c06ef5f926f5deecdb3e463ad9ba4c7569a4a94440c75db3d9ad756f5", "ref_doc_id": "d6c3a031-06c5-4854-9c91-907910d0077c"}, "d7c314f0-62d2-432e-9725-42387dd8d28d": {"doc_hash": "7e13aedc2e7c17dfe0470985359dad89ea74ded070f40d2b2cd902b1c0895b03", "ref_doc_id": "d98ce27f-6b62-4e0f-8dce-defa0068d651"}, "2d50a8b4-06d0-4f74-a1f9-2cae801d95bf": {"doc_hash": "6fe2d3af84e20df9acc0cb0ce87df20f7a2e3fa480319d489064ba5d43a19d52", "ref_doc_id": "d98ce27f-6b62-4e0f-8dce-defa0068d651"}, "0a478be9-4dbd-4e52-a1f1-52c85936bc0c": {"doc_hash": "07ff2429a5b3681b0bb973284109a3ff8716834abbb104251bfb8db8a35df5de", "ref_doc_id": "7414a4ad-2973-49f5-87cf-33c0d38fd0bb"}, "dcdae60e-44eb-4939-b839-7753c102748f": {"doc_hash": "645614c0e2d47e7189c20804b12a443b82f8e0c9db3a95d5111b44b7cc6b8619", "ref_doc_id": "7414a4ad-2973-49f5-87cf-33c0d38fd0bb"}, "c2d01b2c-63cb-4081-9429-1ef20d9144b1": {"doc_hash": "92e65c4b6ee8ece189190966d45ba4604c39d3520d6f927667a94757e119b7a4", "ref_doc_id": "73608b1a-2275-407d-83bf-dc322a0bacc3"}, "51bcb4b4-7b56-4f41-a3d7-75a43d49355e": {"doc_hash": "ce0047cd7a522165915bbd922aaadcd47dadc78b5fc111af0e31114164d934ce", "ref_doc_id": "73608b1a-2275-407d-83bf-dc322a0bacc3"}, "0a8de0ea-68ac-49aa-bd9b-c9b386294b44": {"doc_hash": "26d845d85cc8f25caa606e0a186074990339fa2f22b8acf2ecba3f3b7ed816a0", "ref_doc_id": "2ef94ce3-f862-4939-965f-6fba3393fe3e"}, "b68fa49c-5164-49d7-ad4e-7018c64ed0c7": {"doc_hash": "ed3ae626974632ad6d30e13bc34fd904dd610e6757e6e91faa4474872c84425e", "ref_doc_id": "2ef94ce3-f862-4939-965f-6fba3393fe3e"}, "649a4a46-132b-44a2-aebf-5503a2fa6b2b": {"doc_hash": "bc6f9919efeb6a93956a62a0cb4ea8845a68ec6dccf5dfe17d329ef8e0c5b80b", "ref_doc_id": "2ef94ce3-f862-4939-965f-6fba3393fe3e"}, "8e07d054-f586-4c94-aabe-70f055a2d80e": {"doc_hash": "2816605a37efcdecda077f830631019c972a163f021ca98e737e3a380839e3b8", "ref_doc_id": "86ee8e7a-f7ad-4ddd-b510-ec59e90e8715"}, "79660338-0c5a-4587-a6b0-d46c545e65f3": {"doc_hash": "9fe84baf26a52bef4475b407b599240c3637e294176c3be28047e8133065e200", "ref_doc_id": "86ee8e7a-f7ad-4ddd-b510-ec59e90e8715"}, "82e3bc19-dc6e-4515-811d-ea452d3e7eed": {"doc_hash": "ddedfadc0ce4736c2c14fec30c280c3120790e0862da3a4faf256d2f557a0629", "ref_doc_id": "43bb0877-3aa2-42dd-921c-0663baf7cd22"}, "5d362cd5-9435-4006-8e81-fea18d78e913": {"doc_hash": "5dbed56e03f99a2ae09e674354b220abf54b3f16a793f6986dcf3bbff78d37e5", "ref_doc_id": "43bb0877-3aa2-42dd-921c-0663baf7cd22"}, "58530ce7-a72e-4210-a098-52b6add9287f": {"doc_hash": "f2ed4d9b9aa86981d673278593139d32c0fdb7d73d6362769640d6b8c309fe5e", "ref_doc_id": "43bb0877-3aa2-42dd-921c-0663baf7cd22"}, "e2d337a9-b7d2-4667-bc33-ea5aec3cf1fc": {"doc_hash": "1883c8aaefbc580fd0e9160fc43f9682dc945e034a99ce3b02f2857dfa7726ae", "ref_doc_id": "f6caa8d2-6666-48c1-ab16-6076128dd297"}, "40dc5499-34ca-488f-a98e-28f1b2fbc130": {"doc_hash": "46adfef1cea3f874dbcad41774c7ee5beffe53baae231ee1836cb4f802a7e2f9", "ref_doc_id": "f6caa8d2-6666-48c1-ab16-6076128dd297"}, "43e9f679-a6f4-4c0d-9ce6-041be89dad5b": {"doc_hash": "a11fdc96a8891fd813a8e49deca5fb5a122913b2ad6a7e788c2a4d7e382a3dce", "ref_doc_id": "f6caa8d2-6666-48c1-ab16-6076128dd297"}, "c90978d2-af98-4a92-bcc4-2a97d8478c5f": {"doc_hash": "49da404c905c4b82c55a3ec8c3c0887d76547f28a4e7ab2c72c21e1e248a102e", "ref_doc_id": "bebbe97a-6ba0-45c7-9d6b-033a087e73fe"}, "96567bcd-6ad0-4113-a1fc-a83b8a89f947": {"doc_hash": "5dd149cd5b13138326f99b2e2db9e652bc2067799ca4ebc2325f55bd44355744", "ref_doc_id": "bebbe97a-6ba0-45c7-9d6b-033a087e73fe"}, "15ae37b9-c52d-4189-9178-997cc157abb5": {"doc_hash": "778e6dde66541db063bda5a42385e681a3a2778e8561f4ff0fe14064b9efb4b0", "ref_doc_id": "bebbe97a-6ba0-45c7-9d6b-033a087e73fe"}, "98b25184-9037-4ea5-9be9-e93b5e1a61e1": {"doc_hash": "57380efa899d9c76cfe406d9c713be81bb955b14e00a43d5d796089ab29f1765", "ref_doc_id": "2f36838e-a6d9-419d-a03f-fe45f488028a"}, "ad16ddb8-d426-4971-b25f-b91294818f66": {"doc_hash": "554572964e457ed39c33f8b1dd668be196560e1127b557a88fed9272f83dfd5a", "ref_doc_id": "2f36838e-a6d9-419d-a03f-fe45f488028a"}, "57f670dc-b330-42e9-8869-0c404c3e7657": {"doc_hash": "15e5356620a300a02e793994c3694be7b495ebab429af8a3707efa3a1eb3909e", "ref_doc_id": "07ab4333-e343-4311-9c87-1a54cb27536f"}, "28d84a72-5738-451a-a697-3528e8c1da17": {"doc_hash": "eb647cce6b25055cfcc7cf94dfdf5c1d9d218ecc431083e656cb2b57454e5a74", "ref_doc_id": "07ab4333-e343-4311-9c87-1a54cb27536f"}, "37d8a102-3ccd-42af-b300-02f3ffb58675": {"doc_hash": "fc0ba0647d94aedf66b3906dbd1ca6e71394ea8f953e1505ad1aa33b63902280", "ref_doc_id": "7e9db47e-a794-457e-9cdf-c69acc8f26ce"}, "3f66f6cb-0e56-4e16-a2c7-06b085ff0150": {"doc_hash": "5488f23e8a31bb15b1b62b6eb910ddd27a359d0d3677c8205f7d4e24bc8fec3f", "ref_doc_id": "7e9db47e-a794-457e-9cdf-c69acc8f26ce"}, "ba20c5ae-1203-4cfa-b9a1-485d621e0576": {"doc_hash": "15b604d0c9e7073d6b6321595ae37453e5c2904fb4007d0cff880f16361156b7", "ref_doc_id": "304f44ed-0692-43a5-815f-e9880eb2301b"}, "17c15225-1113-46bc-9b68-293ee6d5761e": {"doc_hash": "b6dcaf728b3eb8f922ded954bf9272d6260402f083e0e7982c90417b51c94a25", "ref_doc_id": "304f44ed-0692-43a5-815f-e9880eb2301b"}, "1feb8d29-005a-43d0-ab32-31caf3e23a13": {"doc_hash": "f4425f0918bd2e8cc7b5130d1e14bb4d13eb2ed071e56995cdd6410a18e5ae93", "ref_doc_id": "304f44ed-0692-43a5-815f-e9880eb2301b"}, "6549fafe-abc1-49e3-8fa8-68332e23251b": {"doc_hash": "aa4be52bb5d2aa3e253b78f05d812505e4595823c73813873d901a0563b20bb5", "ref_doc_id": "a17dd8f2-8471-4f40-94d1-21ef60f86416"}, "22ef48cc-6a12-46f0-8e36-0938f530f701": {"doc_hash": "920b4b34265d3e80a37f3ae6ce9d8f5131eab30bf3ae8188d6d01c1a7b10f5f3", "ref_doc_id": "a17dd8f2-8471-4f40-94d1-21ef60f86416"}, "336e0deb-2a2e-47a6-8e05-9ce863c13d99": {"doc_hash": "e196011430e0f90bf0fd19e507fc4bb9b79e7278289b53131d3747145c4a79bc", "ref_doc_id": "3906f15e-a1ac-4dc7-9c78-380be7d210c7"}, "74d33cf4-31e3-4b3f-8391-e15925f25df2": {"doc_hash": "29c090e2a5c68183e811b682542e4781ebf63a8382054fa2fbe934f0262c3560", "ref_doc_id": "3906f15e-a1ac-4dc7-9c78-380be7d210c7"}, "70848291-718a-4ed6-a573-6122ec5f7508": {"doc_hash": "dd8d3df544731c7b13c8139017caf6ef3cff21697ef54578b6626c1c823c6267", "ref_doc_id": "caf58547-e1d0-40ae-928f-de73dfd67b76"}, "04f7e6b7-5cae-4129-9c2c-3c47bcf1d1b0": {"doc_hash": "d76981885fdd94dc473ce432fbcc6c50ff5d647bf82b39eb5368e516262f90e6", "ref_doc_id": "caf58547-e1d0-40ae-928f-de73dfd67b76"}, "6c5e45ec-8e9e-44ad-b6ab-3dd70aed2f77": {"doc_hash": "6896f8cf2b982ec248d4b8a8c091e8a376832ada123e52bc770c4a5db5d30f77", "ref_doc_id": "de3c56c2-8565-4b8f-846f-d4a23aa926c2"}, "32cbeda5-8234-42b4-a6cd-92a08fcd09ce": {"doc_hash": "2aa9523682f24d183c1eb0804d658023761bbd26154e655a566bced98f085ce8", "ref_doc_id": "de3c56c2-8565-4b8f-846f-d4a23aa926c2"}, "e1c1509c-e163-4887-85a5-cece63b6c7fe": {"doc_hash": "4c3f7d676a5808d7d97e5f592a9c57b7b3a606eceac0d12bcc56aca039571d80", "ref_doc_id": "28c18585-ff3f-40e5-931f-243e0b3cac4f"}, "4439160c-6fcc-470d-8274-59af86c23d8a": {"doc_hash": "25ed5b2e5c85b6c1f649e1f3d1e23c530832f83e44e0d314fa9dffd8fe3ddc9b", "ref_doc_id": "28c18585-ff3f-40e5-931f-243e0b3cac4f"}, "c19ee288-4cee-4533-b6c8-b33411dd502c": {"doc_hash": "b149d2aa51a6279cf3121f598bd39600e817517abfc3ffb5818d2b56a62abd2e", "ref_doc_id": "274f3b76-0c27-4757-ac3d-753baca11a28"}, "e586b307-102a-49fe-9b28-b0b42cc86b3f": {"doc_hash": "ee8abfa606f1c90f355cb18665ac570495ce2bfc142331efd940d1b0ce8ac17b", "ref_doc_id": "274f3b76-0c27-4757-ac3d-753baca11a28"}, "7d9a9573-b836-4d32-9785-47f49206b760": {"doc_hash": "be654b08f3b598371692155dad0cb3b3d35b2c6e53854f2be3d0d8f60e295797", "ref_doc_id": "63680f32-3eed-4ec6-b70e-0dc839ce1408"}, "3134c9cf-b6f1-4efa-ba9c-fe6b7fce1478": {"doc_hash": "9e8fc039de03e43424316f9097487060a7099b71a1f290d7a06ac254dbe763da", "ref_doc_id": "63680f32-3eed-4ec6-b70e-0dc839ce1408"}, "d74c3130-78c4-4e4a-8dae-2e4a71ac002f": {"doc_hash": "2338926e1e58a79cf5c82d4dd2580092c405e21b51093f39eb532d163cc1bc48", "ref_doc_id": "63680f32-3eed-4ec6-b70e-0dc839ce1408"}, "02833468-9df0-4072-ac67-0d314a99792f": {"doc_hash": "51587d35d6fe4152c5e87930d245326db7487c6c2fdafdb61fd10f7d5155d268", "ref_doc_id": "6dd44b4b-033c-446a-b98b-08686acb43d1"}, "cc212c81-d538-4ec7-b810-ff69a2069cd2": {"doc_hash": "49d2745e752792632130ff99674f49819da6547143a346d1dbd6e2e75b7bd376", "ref_doc_id": "6dd44b4b-033c-446a-b98b-08686acb43d1"}, "bb454d1a-ce1e-4c6e-a83b-de079f7efebc": {"doc_hash": "b2b22dd0f03343ad128b0459af9a64a55e5567ddb7e2d6fa47cf944db68b3a08", "ref_doc_id": "6dd44b4b-033c-446a-b98b-08686acb43d1"}, "08671d22-f881-4baf-afd8-6a588ce20637": {"doc_hash": "97c3c4ab09c3b207492e2d6f092573aae37fc2549b14bd1084135755f1065330", "ref_doc_id": "3625a028-cf49-4d4f-bcc9-b1049d6d806b"}, "1926a2b9-922b-4335-af45-de73d49b09c3": {"doc_hash": "3e802a3156055331c0a0ca92262976d023ddd04d50acdb76ff3b2df35d9c04b4", "ref_doc_id": "3625a028-cf49-4d4f-bcc9-b1049d6d806b"}, "3d3b8780-6c9e-4c02-982a-f604b54faae3": {"doc_hash": "87ba220c8040008d454c4affda4cfd26b528ac10eb07d133dde40ed7e3530bee", "ref_doc_id": "73100427-57d7-47c8-adc1-a9f74ccbcaa6"}, "8c7e0ce7-d0d0-4bc5-a277-ef1d74174e4c": {"doc_hash": "a427140bc69e4235946db52b1609df000ffaaa842f3af318b885750c8397d9d5", "ref_doc_id": "73100427-57d7-47c8-adc1-a9f74ccbcaa6"}, "7a9d4a86-8db7-41fc-8021-b7152c2240ca": {"doc_hash": "4fa950a27f9b3bc8f8ca432a608a959f78e35df85f7fafcef5ad6728333a42c9", "ref_doc_id": "1906ef21-c6c9-40f1-9d63-e8cc7de658d3"}, "d54063b6-dbec-4924-a9e6-f1718d8697ec": {"doc_hash": "ef5e945ac86f563fdbcb46c7e2272ab9a3f58f67bf3982ba68511f91b372ad28", "ref_doc_id": "1906ef21-c6c9-40f1-9d63-e8cc7de658d3"}, "edd1f9e9-eeb4-43c2-8f1b-22d0be04f42d": {"doc_hash": "637af201fea66b501d84e637e7718722c27c199b2f61995c24576a32c58db73f", "ref_doc_id": "1906ef21-c6c9-40f1-9d63-e8cc7de658d3"}, "1c46215d-a5bf-43e6-98fd-5cf6ca4f297f": {"doc_hash": "5e16fa3d64c22628f8cc2a53d4fa9dfaf7b10c0a45739e5ecb27c480eab8a957", "ref_doc_id": "25ce6b27-ee2e-465a-a9de-a8450c8e453b"}, "bf63903c-8af3-4842-9ff1-367fb8dcc98e": {"doc_hash": "97c1532dc501c9d52a95d6eab37df75d6e01bc08d7b8802b994715d31b9a5576", "ref_doc_id": "25ce6b27-ee2e-465a-a9de-a8450c8e453b"}, "f851b475-eec3-469c-ba10-e3af8413411a": {"doc_hash": "ed3a9892e53f26e99a5f9e6343ba2ae420f08ccea5bb3f07c95989e7f3ce99f7", "ref_doc_id": "25ce6b27-ee2e-465a-a9de-a8450c8e453b"}, "d5244149-0cef-402c-801e-e99c38af57d8": {"doc_hash": "b38016cc488239ccc70376573296155c9cafcf346444588582743eb1ef26532e", "ref_doc_id": "d1f79cd1-e2c2-433e-90a2-a20d61debba2"}, "ead9324a-5314-47f1-b9ab-348352ed84bc": {"doc_hash": "6f19f14bc22cc037be2662edb83ca15906172b7edc06777eb5ae697bb9747dfa", "ref_doc_id": "d1f79cd1-e2c2-433e-90a2-a20d61debba2"}, "a327baaa-73e6-40b0-bfed-c363bec408b2": {"doc_hash": "e35a4fbe1f4e8d4682cce48de4335d67cf3a4093358aa6b9760b535ca7281a60", "ref_doc_id": "3a549ae4-3030-47d2-853a-e833c30cc76a"}, "8a358024-096b-4cba-bc21-a672895f26dc": {"doc_hash": "bf4130e12b953b98785000ee6c30c6f126e225c89b2934c9112d237bc72b7ac3", "ref_doc_id": "3a549ae4-3030-47d2-853a-e833c30cc76a"}, "90b83da5-94f7-4657-bf4f-41e6b08c5932": {"doc_hash": "409b044559fa21e558416b843aabf7b1f522fff22f5d987f6036e3f5fe14358d", "ref_doc_id": "76cf222d-11a7-4b46-b259-ea0a75b40846"}, "afc12c8a-6647-433d-9925-2add8421bbf1": {"doc_hash": "9a57ebbe61ee4d52e816b1d3d7381e360a8711ddff1f97b70e3ca98f95699bc9", "ref_doc_id": "76cf222d-11a7-4b46-b259-ea0a75b40846"}, "446cfb8f-5e51-4a91-ae90-cf40e9380b99": {"doc_hash": "8b762ab28bda85c7ac080a4bdee92123bdc6f2d7b3ff88149199c376093db913", "ref_doc_id": "9172e4dd-4452-42ed-b90c-f98743565b96"}, "b7dbfbf1-60ef-4403-8702-d87696596a90": {"doc_hash": "6496b5299493be7a81ad2ece5919bb0feba6982c375372b033b9f4ca61f26c52", "ref_doc_id": "9172e4dd-4452-42ed-b90c-f98743565b96"}, "d74e4bb9-9e67-4404-92df-840b39c390f1": {"doc_hash": "395958598b0de388ea0a76ffcd829d770c937ac1b22368d6d95c1a9918f51927", "ref_doc_id": "9172e4dd-4452-42ed-b90c-f98743565b96"}, "b2fa92ac-48e0-4b49-a331-413bc0897440": {"doc_hash": "025ec46c97df7ff1153f26ee8db562729a1c3ecb1459e703909b74a342eb315b", "ref_doc_id": "05c7d225-9d45-4c17-b29c-5ac8c09d4c0d"}, "601c4ce1-c194-4936-a449-f85cefb4b761": {"doc_hash": "4e2492ab4f946b0b7e2c1ca518704448f4a639f1be0dedc5591325192e1244be", "ref_doc_id": "05c7d225-9d45-4c17-b29c-5ac8c09d4c0d"}, "3c4eac3e-29dd-4e59-85b9-598437522fac": {"doc_hash": "5b8b20fe4ef89e5bcf653d2bd46041737cd5fb7c968dac93c16fe60ec81c6202", "ref_doc_id": "05c7d225-9d45-4c17-b29c-5ac8c09d4c0d"}, "ca0fa20d-90fd-45a4-929f-ca1d5a52bc6d": {"doc_hash": "80541984296d6b019c1fc48cad956b211d587afff675c4715a18ae6d61982cc9", "ref_doc_id": "4e478a52-8834-4568-baad-42bbcecb007b"}, "a9c49ad1-2db4-451f-9c81-fd8b1242a47c": {"doc_hash": "944e9250f95100aa49115cac18b58353a0a4cd363c6e038753ebd08ab162267e", "ref_doc_id": "4e478a52-8834-4568-baad-42bbcecb007b"}, "a174fdab-7b6b-4a26-b9f1-eeab34a4968b": {"doc_hash": "6d8e6302f3877040c9a371604ed0ede45d43e542008b9b83d1f0076eecc26018", "ref_doc_id": "23124eee-36a5-464f-af92-2b8219e75626"}, "da34b2a8-381b-4247-bb9e-3192f0761d2d": {"doc_hash": "1ebb78e11dbf9bc95263d0ccbe38c91cc85361c07439bb09e134a444fad2f9c7", "ref_doc_id": "23124eee-36a5-464f-af92-2b8219e75626"}, "f9eb6eee-bc3e-44e5-a61b-718ae430eae1": {"doc_hash": "7ba33c836987ea246bb9e8d9d7529bbb9045374b6f203020c8230471ad59db11", "ref_doc_id": "fd8a1d5f-b7e7-4da6-af6d-889c7a6d0f8a"}, "92653808-ff9e-4ee3-821c-7363e5e24792": {"doc_hash": "adcd0ba3b05ee33e6c147e2312a44c1883d8c0d7ec6a1b036e84b05dd25b1aa2", "ref_doc_id": "fd8a1d5f-b7e7-4da6-af6d-889c7a6d0f8a"}, "bde34af4-4420-4352-9f39-da6f4c16b4aa": {"doc_hash": "dc58670ab2d0fefa761268fb2030d8786c10b57857cd6de7736ac4702928df6b", "ref_doc_id": "fd8a1d5f-b7e7-4da6-af6d-889c7a6d0f8a"}, "914b724b-a57c-437c-b031-29ea9e7c103e": {"doc_hash": "789d53b54ee911df72a403aad4dd74c3b6e153b6079f89e62badf7f1aeb99634", "ref_doc_id": "48be290e-5b34-4eac-b488-ba8f4d5264ef"}, "b2c16b7c-14fb-4ecf-9d73-b4e50857569b": {"doc_hash": "665d1cf002aaf1fab440cd8ab06978b1ec3af0d09ff43839202ece3cf36f99f9", "ref_doc_id": "48be290e-5b34-4eac-b488-ba8f4d5264ef"}, "148e8707-bd69-417a-b26c-07175052f97a": {"doc_hash": "bb9bc6377e27b7242933f7e2f0277ef907978c8d4321d10664885d75b6bb98ad", "ref_doc_id": "48be290e-5b34-4eac-b488-ba8f4d5264ef"}, "8dd11c35-410a-4ff6-9227-e3631d2f9b7c": {"doc_hash": "d8d0f678eea2125e4a8a5d24ad4c94785f70832ab76452f833f64f29f6dada27", "ref_doc_id": "eaf97933-456d-456d-9892-432956ba6b4b"}, "3d6c3d4d-315c-4b7d-9f11-357ba3861f07": {"doc_hash": "86e96d5ba8e805b475ea6935eae6ea2ab4efd6da8f5f516fdd0f686aa0a68eed", "ref_doc_id": "33f0e91a-5c4b-4790-b7d2-f19f24b1a55d"}, "79726254-c1af-485f-8ac4-b1ad9a2cb23f": {"doc_hash": "bc97180c33b6ed6a4aa1792ddbb206fc9a772b0490aa093f751e9fa16c8bc2be", "ref_doc_id": "33f0e91a-5c4b-4790-b7d2-f19f24b1a55d"}, "f0f8399a-f0e2-452e-aa85-231699cdeeaf": {"doc_hash": "e3ff37153c6d2fd37bf7f9db02b144b8aa62b407dcfd3f137df7d5aaf5c96e4a", "ref_doc_id": "638feaa1-a6b0-421a-b9a5-bb5990325961"}, "bd389323-3c72-4147-9eac-02ae56878502": {"doc_hash": "1ce1a570fac5abee9821dc816883b9ca961c07e1df3c8995a935d05b81adff4e", "ref_doc_id": "638feaa1-a6b0-421a-b9a5-bb5990325961"}, "7b4175af-eae3-4992-908d-154124bd7f43": {"doc_hash": "f4e682e65bdc174ba13897181dc76853f0971bfe4af54b8653b662b487ee425b", "ref_doc_id": "ff47b8c3-5623-4947-8d32-1b3e911f1fc4"}, "aa49d000-bc96-423a-be8c-c216f43a9e08": {"doc_hash": "40b2e15022c4bfbe72fb6c7b199100d1ba19307d03895c3db81cef15e47c24cf", "ref_doc_id": "ff47b8c3-5623-4947-8d32-1b3e911f1fc4"}, "b3ce1b5f-02d2-485c-8914-3d8a07292b30": {"doc_hash": "98f0e66d3f9c02d1d363acc8aad79131a22f01af71dd48b29c1d5af31172d1aa", "ref_doc_id": "d97df45d-02e0-4469-8511-c788726d6024"}, "1afd66a4-7eaa-4005-b32f-08f8922e41b4": {"doc_hash": "466f1c4ccdaf541b22f5e6d62957f2eef6241c5e98c9be0c50463cac26505e8e", "ref_doc_id": "d97df45d-02e0-4469-8511-c788726d6024"}, "dc8c7d11-0049-418e-9ed3-bb59802cc972": {"doc_hash": "a58c8cd3e1d75b6cc8049b8f52d4459277f26825d73f2958297b88f89574f6f1", "ref_doc_id": "eb05d631-5357-4c34-a19b-ce6e809dd7c0"}, "f3ef9508-1eb3-4e0b-b582-aa0a955fdcf7": {"doc_hash": "d4f81ac78cde006a21346f63e70c2f4d70658fca5b448a363eebf3c855c599d8", "ref_doc_id": "eb05d631-5357-4c34-a19b-ce6e809dd7c0"}, "38be8a6b-1b56-4f70-90aa-a03bc1ea12b0": {"doc_hash": "44b90b12fc7342de3aa45725aa8a81612022558ce4d9dc585b40a7e3cbff4c64", "ref_doc_id": "ca35b61b-e782-4dd2-bd02-e039c5a86e8b"}, "1204d647-08a9-4c6c-81c3-da81d681cb54": {"doc_hash": "46873a757c9d5b7a29b1d28c44ecdce10b4cb95aa49ed51170a68c2fcf843489", "ref_doc_id": "ca35b61b-e782-4dd2-bd02-e039c5a86e8b"}, "0d0601af-ee22-483d-b97b-e0ca454583c4": {"doc_hash": "3c9c37206d7127aaa1d03655986db28642f29cc1d4207b79a4b2df1890b1cdfd", "ref_doc_id": "4ebcd2d0-4dd0-42b0-b8a7-c0d474a7a5d8"}, "918661fb-1789-4889-8e43-62a36dfe01b1": {"doc_hash": "f5f425225cd9af5efd3b244b71b5633b62d4f99764260be29b4b6ce6f3378c17", "ref_doc_id": "4ebcd2d0-4dd0-42b0-b8a7-c0d474a7a5d8"}, "b68b54a1-d1e2-4e41-ac04-52ffa3aece54": {"doc_hash": "ce8704ea694238590fbeb690f80f28ad8a631ffdceb7fc2969797f34ea01249c", "ref_doc_id": "8313d47c-8e42-4ae9-adc0-c72f881ea45d"}, "12e975ce-2ae1-4170-8334-7f26497bda69": {"doc_hash": "b3e0f7bb03c41e2755af9ab457e20fc8004acfd549732ebb5c1c1ad957905c21", "ref_doc_id": "8313d47c-8e42-4ae9-adc0-c72f881ea45d"}, "4c3b32ab-d1b7-4db6-ad92-dff87c342cbc": {"doc_hash": "bd5d18cde941e12cb4429b769283d3c1714686f35b18f2d334ee51b76feaed55", "ref_doc_id": "ce4c54d1-fbf8-4fa5-a264-ad97b022f123"}, "6d835313-a35a-4337-846b-27bccb3f181f": {"doc_hash": "01efd956728807902811cb0c412d2de038019ec49a1dc962ff0e4d459cf54692", "ref_doc_id": "ce4c54d1-fbf8-4fa5-a264-ad97b022f123"}, "ca8f7f67-d41b-484f-8046-dbf9f5ea57b7": {"doc_hash": "4ebacfe4e149ad1a8eb4b5ea17ea8a519089ca3b49bd395e81249821363b3e69", "ref_doc_id": "81af5941-b959-4b1d-824f-30de3496ca4d"}, "2278994b-8766-4065-9b64-8652e3259b1c": {"doc_hash": "f6f115eea1478feb9a3f57a33a4d5cd6d9b25ea2a35d7d2fbb316934bdcb5e48", "ref_doc_id": "4d7bcb60-5d9e-4105-b17c-af8a1988ee80"}, "68c0b906-16e6-41d8-ae1a-ae95eb1e04bd": {"doc_hash": "8c2a05fdce49c1edafab8516c321eb297d93be22e10a33582b5e7d46aef8e804", "ref_doc_id": "4d7bcb60-5d9e-4105-b17c-af8a1988ee80"}, "d9b7ba0c-0153-4a6f-8584-96ba653c35b3": {"doc_hash": "7771ac439bb4e0e0ea70c42048fb8b90e866da9655d1e9a9cd599edff089e81b", "ref_doc_id": "078e2284-0b57-4fd2-b67a-a9630c585bbc"}, "2daf7b62-9a93-4ece-8f36-00de033fcc49": {"doc_hash": "ccb35a3c246f070b44cc1fc3673fcb55ddc4f93010fb96e16a1f05b01073fe9e", "ref_doc_id": "078e2284-0b57-4fd2-b67a-a9630c585bbc"}, "60b5ac3a-6dd9-425b-8d58-4b61eb19c577": {"doc_hash": "f83e4eacfcc432aa9442d6793abf443ddc0611693ee62e20a6d75d09a7acccbf", "ref_doc_id": "224344af-e9f6-4e94-88ec-e1dfa76512f1"}, "35af1083-b48f-4243-bb1a-2e74c7fc0b74": {"doc_hash": "f228b8a741192ae1db5f00fb4d43125382d9d97b9cbe9b7884bc416ae4c3fcd8", "ref_doc_id": "224344af-e9f6-4e94-88ec-e1dfa76512f1"}, "7d744ee3-b96f-4fa9-9872-564059eb5fd9": {"doc_hash": "b1e315946f8390a78e63fb1e3b37c673133baf0200eb69f24fd9ee21c4c0f666", "ref_doc_id": "d6c94082-27b9-4bd9-83e7-cd39cd0b8ad2"}, "9a650489-83d1-43d3-92fe-9bc4f158c38b": {"doc_hash": "42ef6e064c0776a3d995f9afeb1b8b802b1752b25b59f241fe66ce41a65989ba", "ref_doc_id": "d6c94082-27b9-4bd9-83e7-cd39cd0b8ad2"}, "1471e469-6350-49c6-aa04-dbc1814a712a": {"doc_hash": "371e9768fc2c4cb66a1fedb9f4e9dd18c9943ffad82294635d78989c0dc98c3b", "ref_doc_id": "d6c94082-27b9-4bd9-83e7-cd39cd0b8ad2"}, "959274cb-af91-4990-a46d-2df7df9a1153": {"doc_hash": "1d3f54c3b870ba96a4212c33e1aee304ffc571606b4d8b58ca1b10a426bb00e4", "ref_doc_id": "2f333b79-639c-4bc8-9cb5-55ccdd770842"}, "404650b7-5139-469d-b38f-b9c5488e693d": {"doc_hash": "6a967c0eb109cbccfae1fa770df981187ece0b3b30f7613f8f02461c3a2822d0", "ref_doc_id": "2f333b79-639c-4bc8-9cb5-55ccdd770842"}, "f8279be1-f2de-4735-9e36-ab397a3d3f89": {"doc_hash": "269eeb0aa33a0db85fc2248c68405a8b72701edeefbe7d8c48296632cacf445c", "ref_doc_id": "754bc852-8f56-4e70-9b15-21bf00a90135"}, "a2140e28-4d8c-4ab9-9b9e-d75e5cb5cebf": {"doc_hash": "a9b5f86ea8893ab1131d84f4360e8b0d6de2480d33781877148cebdda4b1fddd", "ref_doc_id": "754bc852-8f56-4e70-9b15-21bf00a90135"}, "e8251df0-ad92-4a9e-8116-db91407f09a5": {"doc_hash": "b7bfc0829c0d7c4d322225f94b15aaceddb539b91e7183c2ccfeb370e02630dc", "ref_doc_id": "754bc852-8f56-4e70-9b15-21bf00a90135"}, "049fdac9-5d2c-46b5-8c84-c14552286b28": {"doc_hash": "d54bb042265e47ddc3d12d06e1afe18d4fb74121d952e91169bffac74afbd793", "ref_doc_id": "f06a5d4e-0d97-4095-9ae4-a5d7adc918d6"}, "10102bad-9a1a-4cc7-b0d2-62823e0dcba3": {"doc_hash": "496e74852a7f548de21da54e340a987fe8c630e34f823014c88ff26450c68636", "ref_doc_id": "f06a5d4e-0d97-4095-9ae4-a5d7adc918d6"}, "d83304ff-cb95-48dd-83da-f9412d51bf33": {"doc_hash": "53a440a52185264f5075752fe6b0c90e8aa4f5bb5380afbb849dea4981009282", "ref_doc_id": "83df579a-999b-4903-af19-bd51898da017"}, "a5fd2d7a-0165-48a4-934b-ad64d34e1647": {"doc_hash": "9a2179e9364fe2aa9eb78075bee820ec22d162acc46f0949208df94eac53c4b3", "ref_doc_id": "83df579a-999b-4903-af19-bd51898da017"}, "624305f7-cb70-4b6b-8f7e-290e8fd798c1": {"doc_hash": "21287b4ac68ef2ca765875cdd1572ba19f570b12a511ea59210ee900efaaa363", "ref_doc_id": "83df579a-999b-4903-af19-bd51898da017"}, "34bf32f1-44a2-4601-9ece-1aedd89feec7": {"doc_hash": "650d03d2cbec460e4def2dfae36bb936184d7de5c25860258e800f2dee50c431", "ref_doc_id": "ce3d5358-8574-47e9-bf56-ca93795acfe2"}, "c52ef99a-8f59-49a2-a5dd-ca532295be03": {"doc_hash": "7a0ee050d327a7879596b5a58825382a5a904e0702327ebcd8e984402645e2d6", "ref_doc_id": "ce3d5358-8574-47e9-bf56-ca93795acfe2"}, "be4e6aad-c56c-436d-b3c1-0f3d0bbc0500": {"doc_hash": "d03291af8d7e757e6fd6b3ad801b2aaf57efbd8efa5055f1c95acc57e83836eb", "ref_doc_id": "ce3d5358-8574-47e9-bf56-ca93795acfe2"}, "382a9231-f00a-4a70-9ce8-c81431fb935e": {"doc_hash": "dd10f2feee4e3a6ceeb8e1a1a8b22ead9cd658d6a58b90ac91743fade4bc0bf8", "ref_doc_id": "bc7a119a-6a91-44e0-9732-a2bd363297fb"}, "6c458d90-c688-42cd-a285-a558de298e11": {"doc_hash": "301689f2b0c0658fc1fe9bbdaef34c4ce5db78537f4336fc608f6078ffaca93f", "ref_doc_id": "bc7a119a-6a91-44e0-9732-a2bd363297fb"}, "bca3d97e-0a8d-4d60-a7fd-38e928c95090": {"doc_hash": "13fa54b867f47b36baf6c34b1e12d233a22811c53fc510be030db938054c5543", "ref_doc_id": "bc7a119a-6a91-44e0-9732-a2bd363297fb"}, "19a3aff6-07dc-4ea7-bb1c-bce8bd448c7b": {"doc_hash": "20a77310d9eda0630c4d1309ec74b8ee1369ca8aad53ba25313e528c1933b046", "ref_doc_id": "65ac99fb-4fb5-41ca-bce6-79346b6cfaa7"}, "8f88aa5a-30d6-4131-bac6-06f764f8ab2f": {"doc_hash": "9082d0f8a68ffd3069489b3f3a261ef65044ec4af412b4013c5539414d0f96bf", "ref_doc_id": "65ac99fb-4fb5-41ca-bce6-79346b6cfaa7"}, "4868c63e-d47f-4b73-8f63-1b305829701d": {"doc_hash": "aa991ccdb8fc12228648801d2f8cc19315bb29096503156dbee6eebb7aa5e845", "ref_doc_id": "b887db02-1ee8-463b-8fe2-4b74bc8da920"}, "5ba20086-79b0-4cb7-a96b-b71a4256675f": {"doc_hash": "dddde7247b8c5ccf5e9fb39a3a9591e37e11ff717618d9321fdbf4aaefd4da9e", "ref_doc_id": "b887db02-1ee8-463b-8fe2-4b74bc8da920"}, "2ee3e7c4-a584-4e0f-8230-0d0d29881fcb": {"doc_hash": "5a2b06de7012678e2a0b6a602fb11878f0e94dc3b36fe2550f87d2fbd0728d62", "ref_doc_id": "b887db02-1ee8-463b-8fe2-4b74bc8da920"}, "47d5f94e-5121-43db-85b4-359c99d5bbb1": {"doc_hash": "12c9170cdf9edc893b07385a25ea12971c6e5ae1697e5d4de48ead5b688583be", "ref_doc_id": "6c1c8907-4eff-4222-92e9-036d8df972fd"}, "c60c83ba-8987-40f9-bc2e-142685b73e85": {"doc_hash": "96820bc13e30ab3c84a6ff09bf7810c3c36d40f8d1afa6da05016268064dacd5", "ref_doc_id": "6c1c8907-4eff-4222-92e9-036d8df972fd"}, "81ce6e04-5a88-4b1f-bc89-965670eb2c4c": {"doc_hash": "9db5fc0c60d2ff1cd032910b7734eb767adba4248421d8d0f2f8cca8d0b22db6", "ref_doc_id": "87d7e1c1-59b5-44e3-af81-232286fe0460"}, "e45466c9-3438-4239-b49e-0b779934dbe4": {"doc_hash": "2e09b8b42dee857bca0d2c75de7fba4b3af17865a3419857645c28f21288a8a3", "ref_doc_id": "87d7e1c1-59b5-44e3-af81-232286fe0460"}, "60cb0188-3b5e-499f-a8aa-aa579e72d9ea": {"doc_hash": "27c4252466e299c518b44b9885ba944e62c43c8c56cc81a2af8a6b11d7bc4bed", "ref_doc_id": "87d7e1c1-59b5-44e3-af81-232286fe0460"}, "a75373c6-5a45-4f86-8344-3e3d3e6b4cda": {"doc_hash": "5ad5dd446699e28620831e8f71dc851fd64c87a737270df0ad8ea2faa21fdb2f", "ref_doc_id": "71728c91-bcc9-42cc-8857-36a8f4e48c31"}, "37f67ac2-da52-4ac8-a08d-595c8b5ae4cf": {"doc_hash": "e875a69f7c9e49a02efee8ae9e9b54dcae8eb147a66f868b8376b7fce415133b", "ref_doc_id": "2adadb5b-fc95-4760-9ae0-93d6fa79a344"}, "2d6bc0ca-4ac5-4862-a3b9-b92d6bbba0b9": {"doc_hash": "2947fbe1b5a2eef7fb7a65ca82b3cac4efb36f22c956edf605be55906da6ffb1", "ref_doc_id": "2adadb5b-fc95-4760-9ae0-93d6fa79a344"}, "77a8fcd8-5b61-49bd-91d5-7c5340e2d123": {"doc_hash": "9d2037cb1307d77170ae7b2a88f154d252c825816df6be8e9dd4a1c1a6453ceb", "ref_doc_id": "8ee06383-fab5-404c-ae63-cf6ed68fcad6"}, "3dfabd00-d757-42e9-9a07-5665637045e7": {"doc_hash": "7a7dd6e1a6d3a88fb988f4103ebb343aec4d28948a1ae110ac894e94d2f7d9eb", "ref_doc_id": "8ee06383-fab5-404c-ae63-cf6ed68fcad6"}, "40bebad0-1edc-4978-a9dc-514e8c3977d5": {"doc_hash": "523fe6a44316092eb7a25ae0aefd8608d55463b31d3c5f69bad84852c9607a99", "ref_doc_id": "fbf03dd6-a28c-422c-bbee-08d5e343c2cd"}, "01665665-7125-4a69-818f-78a8c3732746": {"doc_hash": "484d1d4b51e0b084da3dbe8f7a58b84f65b86daf5c32d735bcae2449ec2d673a", "ref_doc_id": "319e6c49-ccec-47c6-9b76-caa61ea5e016"}, "3fac88bf-75bb-491d-a935-65dcdf8584e1": {"doc_hash": "f1a3cd0babbc07e3342bf8a0478a7d41db403d735dbdd4cd98e95f55dca81ccf", "ref_doc_id": "319e6c49-ccec-47c6-9b76-caa61ea5e016"}, "4723c30e-aeae-4f63-91b0-66e2315f3431": {"doc_hash": "affec2a93829400669b006eccf65c660334f69e1406404209f0f0560a1211db9", "ref_doc_id": "319e6c49-ccec-47c6-9b76-caa61ea5e016"}, "fd4c89ea-d0bd-4630-a2c7-9ec85cb73a63": {"doc_hash": "c5dc786af954d50508dc1e676dc3a06959a293d33372a0905967ab1da65626b9", "ref_doc_id": "8f893d7b-6f44-473b-95b3-1dee90e9cb64"}, "29c0dde8-6896-4ce8-8ce4-b044792ff7a6": {"doc_hash": "0b8ce5cdf046dd1792778cb6be220a4edcb4136976891abc09006effb2a42163", "ref_doc_id": "8f893d7b-6f44-473b-95b3-1dee90e9cb64"}, "bb14f7c6-e571-4076-94ff-c64ca84a2680": {"doc_hash": "fa43bb9b6a77e88875270771f4e88d8a00456895b7e6bf919e9db1d205340985", "ref_doc_id": "9038d23d-b6e8-405b-a623-002d24169ed5"}, "689fa769-2761-4b5c-a2df-d49230301f91": {"doc_hash": "5fbf29f4c7c4be01442f9905eb948ffcb0e14847a91c55437e3673d76d0ba1ba", "ref_doc_id": "9038d23d-b6e8-405b-a623-002d24169ed5"}, "664d9ffd-7067-4174-b75b-48802386d358": {"doc_hash": "b52b3c9fc66a845aca6415f224c2842dd712f613a67704af61be28b3def0aa7a", "ref_doc_id": "f8dc7d31-c021-4a2f-80d4-39c5d89fe64c"}, "f91b9717-94b9-4bd8-8a66-a865658dc511": {"doc_hash": "c8faa3d306d5c37741b03609827ef33576edda0a109905e938016cb1db475f12", "ref_doc_id": "f8dc7d31-c021-4a2f-80d4-39c5d89fe64c"}, "53e8e424-bd02-411b-a478-7804b1ef747d": {"doc_hash": "82cb21fd03ba287713d252c5ee2df657687ac9b6ca84ad1ac89994e903cd4503", "ref_doc_id": "ed5c95ab-7707-4325-ad71-3c0376fb493e"}, "0d9e8d95-f399-42b0-8883-0ca268295c8c": {"doc_hash": "bbce94ddc209c71d0a1b2960399679fdb5f11fbf7ad45aa2f6de1578c6909a64", "ref_doc_id": "ed5c95ab-7707-4325-ad71-3c0376fb493e"}, "3af372fc-e003-4005-8e46-f7eb25d83a34": {"doc_hash": "6eddc33c70b89b1d2d3d08d7ef1afce357928b8b5be875c0d29dfb86bef9bb8c", "ref_doc_id": "bf6a332a-0836-49e5-ad43-4ea1a2f97f6d"}, "217119c4-3098-456b-b166-9611c6c9ed8f": {"doc_hash": "b2addaa12f0ab15a490bcd33329fadf7782951fa1e644cf5ea0c596a2a6e5da5", "ref_doc_id": "bf6a332a-0836-49e5-ad43-4ea1a2f97f6d"}, "02c09b02-55b2-4748-bb0b-8325dd772dee": {"doc_hash": "d54488612d2ca23b764f0b01d1b419fc627b6a6fcb37ed1409988c92fd56b8ba", "ref_doc_id": "16b77040-2cfe-4a37-a1f3-5b48343b1019"}, "f2264ba6-8609-4e6d-988b-716d5031ed50": {"doc_hash": "da6aceb1963d67140ecbd409dc72871a76b054c0bd1cbf1d80d2c3e90f5d7418", "ref_doc_id": "e16cfc28-71bf-45e6-bdd9-94e670a8f14a"}, "94468084-e547-470a-b086-f702a8ba2457": {"doc_hash": "f34224d709e2181a5831aba5526b84a41e54ce9aa48ca85c89eeda0e35274f91", "ref_doc_id": "e16cfc28-71bf-45e6-bdd9-94e670a8f14a"}, "db5888f4-7ed8-40ec-a703-dc07b2105bdb": {"doc_hash": "1eac94f8bb06ea2e1aceb90e054f3e8a9aa0d42ef20df99cac73e2e1bb0b11e1", "ref_doc_id": "b0e630f4-ec5a-47e0-9c31-b3fd2f0a6c68"}, "7dd67af5-e81f-41c5-b444-0c6162e99f9d": {"doc_hash": "e5aeb6c2bfdcdd7bc9f80aac69c978141c0332a048c303186fff5dffef9b74ff", "ref_doc_id": "b0e630f4-ec5a-47e0-9c31-b3fd2f0a6c68"}, "1a9abb1e-24f5-491f-a622-ebd64b270d89": {"doc_hash": "5a145fed0253dce9d7a7b67bdbcdb218b0a65ff0f0fb0078cd0946746fe2a963", "ref_doc_id": "b0e630f4-ec5a-47e0-9c31-b3fd2f0a6c68"}, "b074302d-f077-47e4-a057-c7ec61ba6dea": {"doc_hash": "d45e1a5648606d1bbd4c37fb2a4d9b0dae8ba33acad2e659381631e36b14d2b9", "ref_doc_id": "0fb1f8a2-bdf8-4bf0-88bc-8c31c5ae0e36"}, "823cbd72-0ba4-40b7-a028-8a7d0216e512": {"doc_hash": "479558fd3fec0622eb5b31c3614b3417ffe96fb2ab3b0801e994133d9392d073", "ref_doc_id": "0fb1f8a2-bdf8-4bf0-88bc-8c31c5ae0e36"}, "8e1d16cb-6ca1-4845-8dc3-943d41efe29c": {"doc_hash": "b70a31f4b01bd3bb3d5f274bdd2ea184086a7910776d411fb9a71bf2ea76df5a", "ref_doc_id": "a0bf1ddf-b5c1-4b6a-899e-a8e7ad45902b"}, "6ae9df9b-7bb3-4600-aeb4-1f54aef245e2": {"doc_hash": "7ef9a517172afb7aa12629d0d05c6742d6753425e66d01bbd5eaa62d5ce7eef9", "ref_doc_id": "a0bf1ddf-b5c1-4b6a-899e-a8e7ad45902b"}, "25fd0c30-0db6-4e79-994c-a49efda63ffc": {"doc_hash": "dbb6baa607883108d0cb184104474011f25ccbd31f963bcb34a3243fe9969e15", "ref_doc_id": "8db36e24-62d7-40bf-9f81-83711e111b50"}, "c78f4413-8239-42dd-b013-b6008d1920e9": {"doc_hash": "0a05703474ea263846c6ccd61ac93f953b39952cbf3d9ba2db7bcb6b7af6d7ce", "ref_doc_id": "8db36e24-62d7-40bf-9f81-83711e111b50"}, "85327d0c-1b6c-46e3-95a9-d04f357ecbf8": {"doc_hash": "e2059ea6daf977d7ed28056a385ce8e5825b7ebfbd9dd63d45361e33efe690ad", "ref_doc_id": "333a3c20-05a3-468f-8d5f-66fe014292c4"}, "baa66798-96a6-4468-aa17-a0a9391213a8": {"doc_hash": "13bb8347588f3f0ac9f62a568a65235f6b1e29e1fca39d725ed05ec5bb8b6160", "ref_doc_id": "333a3c20-05a3-468f-8d5f-66fe014292c4"}, "3e9b88fa-73b0-4531-9239-b34424c60680": {"doc_hash": "ffa201be291d25e92844fa60100b908a6507babcba949c06f7c60b1b0870e2d7", "ref_doc_id": "859e9e4d-a244-49b8-a712-7a4a74570068"}, "04b72a2c-8ab0-4a4b-9d4f-6f069be974d0": {"doc_hash": "ea5533c10b878ee60c628a9fbfb6e2e61069e48e6d2c59933d66b18d22fd363b", "ref_doc_id": "859e9e4d-a244-49b8-a712-7a4a74570068"}, "f6f62ee1-375f-41a9-9fc5-f196b817a4d0": {"doc_hash": "4f70c8ebe38271938b403199362a662459fdbb3b771937dc052b642405be8c19", "ref_doc_id": "884c0ae6-1eea-4eb3-893b-4a2f878b6f94"}, "f6d4ef3e-27a2-490a-956c-2e56bce0b21d": {"doc_hash": "c6204a9f43c07f8571ed47b3d12dbfe60a6c593440b383caf1e0d97a67557afb", "ref_doc_id": "884c0ae6-1eea-4eb3-893b-4a2f878b6f94"}, "791fb779-c035-45e6-a342-55f2ddfc51f9": {"doc_hash": "cef8d8d32430c563186842d5c2001d50b832dc5ca4a713bdeb633a8a02115610", "ref_doc_id": "2146d6b2-2d26-4f2d-a88a-aa5b95d2a783"}, "dfd6aeac-9eed-433a-b4dc-f0e2e9657cd5": {"doc_hash": "0909f82f4d7141fdf84448fa4a7461a7bf7e65235e5ef87c1e33d25ed56ea8a1", "ref_doc_id": "2146d6b2-2d26-4f2d-a88a-aa5b95d2a783"}, "1b54f372-937a-492a-b4f1-93451e8f8789": {"doc_hash": "de2381714b31f823c181f11e5e8eefa791240c08f7b164f70c0a41dd3ca29d53", "ref_doc_id": "2146d6b2-2d26-4f2d-a88a-aa5b95d2a783"}, "e7ea6979-37fa-42bc-99ea-31a8913923da": {"doc_hash": "8cba9079d3bd7a330cc90aeb01af439846f394157305aa62471c6a1d75324c70", "ref_doc_id": "c2973ce2-bf8b-4fe8-8e40-bc659bab8aa7"}, "3edbbf1d-ce85-480b-b65c-0ec35171fcd3": {"doc_hash": "e93ec3deba63994f234b1770e760d16b4710e07539d9c222708675d3212eee20", "ref_doc_id": "c2973ce2-bf8b-4fe8-8e40-bc659bab8aa7"}, "3bc0c0ce-d09f-4052-85f6-e191e5e927af": {"doc_hash": "4e623126523d5d31ffd97956b52207921566467e974df6f87e8fe88bbabae375", "ref_doc_id": "c2973ce2-bf8b-4fe8-8e40-bc659bab8aa7"}, "024af8d9-dbd0-4b93-84c9-474b50f78319": {"doc_hash": "dde15767b61d305cbb4acfbf3c125762cfbb69528601bd1555cab92546e8f5a6", "ref_doc_id": "d96c5c0a-ca95-4de3-b3d2-bdf73fd89ac6"}, "b766b9e3-41e0-47f0-91ce-41b24b8be76f": {"doc_hash": "eb71f2dffdb62c9e698d6c96a9231f57cc91822871cf0ae6ab83f80da23330c8", "ref_doc_id": "d96c5c0a-ca95-4de3-b3d2-bdf73fd89ac6"}, "8ce9a216-2d4a-4a4a-b318-10a03c406a4f": {"doc_hash": "4b6a93332b4a8ad1f3de1d0495d6a5ad25cb8d08771ac57b23d36d3decfa56fc", "ref_doc_id": "d485b745-5e24-4f10-98bf-783d60fffab2"}, "295f7078-2f49-446e-b059-d91c55eaaf27": {"doc_hash": "070954324209681173bc4f49a588e593c2c13e23a89d25466e7446dc81713e0d", "ref_doc_id": "d485b745-5e24-4f10-98bf-783d60fffab2"}, "f160a1a9-cbc3-4a8f-abaa-a042655fc386": {"doc_hash": "d81ada6939c8a572cba28ea152261ac18449da920146a5e0ef0c096c98f782f7", "ref_doc_id": "8ec4e6a4-cb49-4cca-903d-2bbdefa4c112"}, "6e47cef6-3566-460e-b3a6-7292cd8caa15": {"doc_hash": "b7731097d70b0a22768dc17d3eed7211a82c28163e3db45de0e41b37fa75490a", "ref_doc_id": "8ec4e6a4-cb49-4cca-903d-2bbdefa4c112"}, "480c185a-de7a-4b68-8ae8-f95bb131ce63": {"doc_hash": "e3989049f1b0c46963105df9ac7c358e0cd52cc41f014e6143d475a5367564c4", "ref_doc_id": "5aeaae6d-4448-49b4-a851-777b28f031ec"}, "b23d7495-dc38-4b47-8b55-7d5e6b099202": {"doc_hash": "440887f26bb59942a63c5c04f368cae2869d212e60175fb8cd1d9ef6a0915271", "ref_doc_id": "5aeaae6d-4448-49b4-a851-777b28f031ec"}, "87a18f21-26e6-42b7-9e36-9967c0962176": {"doc_hash": "f46b391bf522256dd25571278c749ac13ab5c10e968bcc2d6d2d982b348d602e", "ref_doc_id": "f506ce48-764f-42c3-a927-d3048c952f07"}, "f719bcf1-051b-45dd-b38a-d3f374b7f509": {"doc_hash": "19aa628d76fb57fe696873fa0126d22c6f88b3e2507f6e504fcfeb87c427ca93", "ref_doc_id": "f506ce48-764f-42c3-a927-d3048c952f07"}, "c4f485bf-b5e0-4eba-8f97-cbf674deb6e4": {"doc_hash": "2da32fab658a131a87f378cf1e1cd4a731ade6ef76bba4ff22411e5b1a72a157", "ref_doc_id": "24564321-94c2-48e2-9faa-250076614265"}, "510fbcb9-51bd-4135-baa9-64c5544b9764": {"doc_hash": "c98fb6a32afed7a0e3ded566bb1d8ad9eac03bcbf7c2e8c680beda7a370e97b6", "ref_doc_id": "24564321-94c2-48e2-9faa-250076614265"}, "d3790280-3ab7-4876-93a5-0df2a2b54448": {"doc_hash": "165437e7c1ee2155de11d9d203031d5941fe5611036bcfca71379e591d11d33c", "ref_doc_id": "24564321-94c2-48e2-9faa-250076614265"}, "2d80e7f8-9280-4ba2-82ab-1b68f1308272": {"doc_hash": "ea5e2a8d8dd089033134782ccadd3d8027853fd5cb66a54714472f1cd289480e", "ref_doc_id": "575d8d5b-c815-4fc4-8dab-2af6ec4728a9"}, "ee75f496-cf2d-4264-a817-9b87bee303ad": {"doc_hash": "b0a87cfdc6cdb0f95a91c753d61332df273bb4bc84927b309237928e049a561d", "ref_doc_id": "575d8d5b-c815-4fc4-8dab-2af6ec4728a9"}, "84bd0ac4-b9ef-48bb-86be-56ef8829ffa3": {"doc_hash": "5b6ef77261ce60e831f12930a68cc4facebc027f26da9c897da0a34a215d71aa", "ref_doc_id": "119b31fa-17bb-415d-99bf-ce595eefb120"}, "3dd5252b-ab8c-453f-9478-3fc321c7edce": {"doc_hash": "edd27c73831d6976f71bddf14d287c289dcb1f0c435e5114f29f009c805689df", "ref_doc_id": "119b31fa-17bb-415d-99bf-ce595eefb120"}, "cd3afcd4-68c7-4e8d-af11-00a80c77cd88": {"doc_hash": "7ccade97588039badb951772c9c2a5f2054482b84ee99fd86f1a89dc1b2fd20d", "ref_doc_id": "119b31fa-17bb-415d-99bf-ce595eefb120"}, "05565224-f223-408c-ba4e-7a706407c763": {"doc_hash": "7dde7700ae5155c7f4dd3b496f005e9a252faf108c12eab0dea511c1a7e85a34", "ref_doc_id": "f1147ffe-7582-48e2-9797-5710e3f1676a"}, "81a5347a-519a-4286-9bff-9e0bd9a0bde1": {"doc_hash": "029573a40e768219f656a99a483c83134443d3581f09fd3bc12b7b8e65b45416", "ref_doc_id": "f1147ffe-7582-48e2-9797-5710e3f1676a"}, "c86f2ca3-0782-4030-8a29-db674a981453": {"doc_hash": "899c42e781ecbc70f7550b468455767742685d907fbbfa1d25d6630343a4f564", "ref_doc_id": "5b91e2ad-4505-4fe4-b467-5d72c77ae1c1"}, "6d9b002e-a54a-4d7c-8db2-647cc5057802": {"doc_hash": "03087a4beb66f109ed2fb76ff8b6e6dcb36048892360240d8ce55cb6b414993b", "ref_doc_id": "5b91e2ad-4505-4fe4-b467-5d72c77ae1c1"}, "7aa05708-5b99-4839-bae3-cb47ebe6c7a4": {"doc_hash": "f57094697fd1271c863ca581eca348ec5dc612454ab2f0fe4c6488464d21d693", "ref_doc_id": "5b91e2ad-4505-4fe4-b467-5d72c77ae1c1"}, "897eed84-ad1c-478f-9d4c-f3daae453bfd": {"doc_hash": "1a175431be64c35acafdc93bc488ba21a54e37639633ee998fa43d57775b724c", "ref_doc_id": "53f48a50-6bcd-4ed6-b5b6-1356f7c5890f"}, "5b058686-57da-4a0f-bf58-9468f175872b": {"doc_hash": "52ba650422902cdcb5fac53004144678c202440c70a3973e377d58e3e95d100a", "ref_doc_id": "53f48a50-6bcd-4ed6-b5b6-1356f7c5890f"}, "2cdddb58-3993-4867-bad2-a2970342fbd9": {"doc_hash": "4dc88c2b87b31deabe88b38e56077d5922bf305d6c2307349256cf584f035ad3", "ref_doc_id": "65a7075e-254d-4f76-b909-96c749acd8e8"}, "3b606e49-1883-4fa6-85b9-ddc930414465": {"doc_hash": "4c042437037eb33c09af2bff656ea4065b2a93508d93b898b901168389fd4a7f", "ref_doc_id": "65a7075e-254d-4f76-b909-96c749acd8e8"}, "b7fd384d-bcbd-4d13-a229-c0c6091729b4": {"doc_hash": "5bbf101855af6812887c30b6524780efc0d6bcd3f4052c1d45a9f97454b7b8df", "ref_doc_id": "eb14bd1a-b712-491d-8a82-6b8c8d7b1061"}, "1520b403-943d-4b13-88cf-f0a6ae8f6b8d": {"doc_hash": "a421de0ef51a1c0967170b77419b31214cc5279ad9fbd3e242831538b4cee976", "ref_doc_id": "4183ba17-28e1-4b9b-88b6-9c964ce6a9c9"}, "fcfc858c-f0d5-4059-b4c6-3c5c8e75a493": {"doc_hash": "90373b305ec2e59c33a4fe68df55f3fa45be735084392158537dee6e25ba045a", "ref_doc_id": "4183ba17-28e1-4b9b-88b6-9c964ce6a9c9"}, "6f06a860-1237-4180-bd0b-f3addfd0e354": {"doc_hash": "7a68f3d6cab8d2f03742c7b42acbf50558b7be463c2f929bd3f312a8147761c9", "ref_doc_id": "4183ba17-28e1-4b9b-88b6-9c964ce6a9c9"}, "6f71c9e5-7a76-495e-a16b-8b4aa39ff2d9": {"doc_hash": "f6c66645afbaa4aca40ba47432a551aa2cb1b0ee3197e17facdcb10e7f3db695", "ref_doc_id": "fc62c00e-813e-4b94-9f59-4784f709b2da"}, "90945b90-5c50-4ee8-a55a-93c4dd016407": {"doc_hash": "75277fdb66d35cdbdfd18c8a9fb39e7186b16bb99734e3baf124e367c6e65a98", "ref_doc_id": "fc62c00e-813e-4b94-9f59-4784f709b2da"}, "3a04d944-b78c-4ea6-b94f-508856887a4a": {"doc_hash": "6aafe8662a4335711d1601a9aaa6e2f75f4992519735d2a7a21088f727bb1840", "ref_doc_id": "3e416ff4-f607-41fd-b9ed-83dba994ea8a"}, "bfb3ecde-f6e6-40f2-a65e-c51b11ff24b8": {"doc_hash": "c3a3c6ba3199ade39e7ce7288270740915410b8b6fd108cd56844c900ad7c665", "ref_doc_id": "3e416ff4-f607-41fd-b9ed-83dba994ea8a"}, "2724ce16-9214-4d87-bc19-49e080540b79": {"doc_hash": "bd4f45c09c858f430539d0a8fb20d43f2ca5b689bd2a32fe78ce48ae72d0079f", "ref_doc_id": "3e416ff4-f607-41fd-b9ed-83dba994ea8a"}, "28223e36-c6c9-48d3-bd07-488b0c6d76c9": {"doc_hash": "f452ee3350ab3e24b67ea5fd48127905e4ecd7b6a68d4b9d69db689c2d580a38", "ref_doc_id": "25195db6-534b-49b6-bdef-24880a902456"}, "e5a7c814-8f21-411d-a56c-6cd30c5d98c5": {"doc_hash": "43b7a045d47b5d3c482e6c4b98f6fe865e7acb2cacb97f5347e483b3a4c2fa94", "ref_doc_id": "25195db6-534b-49b6-bdef-24880a902456"}, "2bb9159d-1969-4015-b01b-e33ab5b091e2": {"doc_hash": "de93a2bf2ee236fe76c3a19e453eb51f02f81a8666705402337fecbd36775c6e", "ref_doc_id": "960cfba2-9407-4a16-97e1-019ca4251dd9"}, "f36e78b0-f7df-4288-8481-684150c8dbd7": {"doc_hash": "0035f9fe54e2c902c071bc299f7456c6d025b29862a40c2f72feb6bccbf4c830", "ref_doc_id": "960cfba2-9407-4a16-97e1-019ca4251dd9"}, "0e54cae2-d7c3-47e5-8270-f6842180c699": {"doc_hash": "4bd84ee4ecd7ca5913b7cb66b2427ca6f1d91f99ffab4ed47f1f36926a1c5547", "ref_doc_id": "548c15b1-cd2c-4ad7-a4ce-aaee167fc75c"}, "8dc956bc-7c23-44ab-a1fb-9afe5d6ea402": {"doc_hash": "5e57679f6458c9fac43dd1acf35637b0a5162a2dbd7f27a96e73ae1f136e6f77", "ref_doc_id": "548c15b1-cd2c-4ad7-a4ce-aaee167fc75c"}, "6305dfcd-1cb1-4ac4-be14-c59f36b7040c": {"doc_hash": "3e248cdf8f4a4708adc1b77bec909f286b9ed88d724938f11f50f084299a6ce7", "ref_doc_id": "ca895a7a-4dcf-42e9-a381-3f0ee01cee17"}, "1983d50f-56ab-4a9e-bea5-e078e0e22762": {"doc_hash": "b15020545508ec3a7f2883cbf607cb6b6ddf4f92362c222903773d3d339e8fac", "ref_doc_id": "ca895a7a-4dcf-42e9-a381-3f0ee01cee17"}, "250c6006-8434-49ee-bba6-2212a554ea09": {"doc_hash": "66be23ec63bba8b8463b4a90bd84e27478f9d38533e99d5be8dea1668c6342b0", "ref_doc_id": "6e37c40c-4d85-4332-9a0b-e684fa078caf"}, "d9799c5c-251d-42af-8359-368046e17561": {"doc_hash": "4b3beb20949da2ba7945f5212c2a186c14f4128e29ea4814f492a7dcbd746653", "ref_doc_id": "6e37c40c-4d85-4332-9a0b-e684fa078caf"}, "3fdcb52a-fa85-4a01-ae89-54773ed49eb6": {"doc_hash": "162c5b03d71c2832cd2fb577abe84970ba625cff7fe8b8192de431e381d058f3", "ref_doc_id": "6e37c40c-4d85-4332-9a0b-e684fa078caf"}, "dec79278-f773-4924-a0cd-56df0e4aee4e": {"doc_hash": "7474d351474e8e8ed75ae87a9b01a14a24160e457df0c4395a7931c4860e8c4b", "ref_doc_id": "0e8e8fb8-6f97-4fd2-b926-dd2b2289f7f7"}, "4fde5575-def6-41ab-bd0a-19cf8ec7f22e": {"doc_hash": "180023b484a33f262895bb10b1884394dccb672612d5c98b3e35a4f9f8862571", "ref_doc_id": "f1e253b0-415c-4eec-9e86-01415cbfc2bd"}, "6fd631d9-6c17-456a-a1e9-c91205945518": {"doc_hash": "11be4c339f5b503a0bfb00600d705f42203e1eb702d519efbb8a111ad54c6590", "ref_doc_id": "f1e253b0-415c-4eec-9e86-01415cbfc2bd"}, "46d92ebe-8fc6-4810-a3f3-89c83ebb5b4e": {"doc_hash": "c45b78c3c61242ae32d48b7dcd302f4267fe1492d29c0b44bc2ba8410dc34241", "ref_doc_id": "f1e253b0-415c-4eec-9e86-01415cbfc2bd"}, "8ef455ee-9141-4a92-8fae-d44b906db305": {"doc_hash": "b636e956d4007769b740e1b6f6a368715e61b0aa6777e036819ca3427f1711f0", "ref_doc_id": "50858789-c188-4766-b41c-4ab82da440bf"}, "7b48b15d-f765-4f78-aebd-792a46f67b54": {"doc_hash": "3120a1ef6fa8581aac05a086786c410a3b4fb0f0047a225833332600ebfa3d7f", "ref_doc_id": "50858789-c188-4766-b41c-4ab82da440bf"}, "e553f738-8abd-4e02-90e3-85edb84a3b61": {"doc_hash": "307fe64f4e5d1b3abbc4bcd0b959312636386f460680d14dd0cae117350ba3da", "ref_doc_id": "50858789-c188-4766-b41c-4ab82da440bf"}, "0db7928d-d0e8-4e78-9cc9-7c8b4bb3be5f": {"doc_hash": "dda4e4f13de77316e9ea0f5d407b0277d9ad749311a3e0956c4771031107aff5", "ref_doc_id": "394d6162-782a-4701-acd5-5352694594cb"}, "ad04fc59-deb5-4342-aaa1-51468e1b2360": {"doc_hash": "a9979db40be90d5be691f4f914e42e22712205a50c1b1b6fe85612c7d48dca7e", "ref_doc_id": "394d6162-782a-4701-acd5-5352694594cb"}, "97a2ce90-434e-483d-8937-a2c864d50519": {"doc_hash": "6093fc050644efae83d6705ce1af882d006184f767bb8b43d5ba58e3d37091e5", "ref_doc_id": "2d2e016b-3b75-4279-9b43-550b03801229"}, "8e1057f3-5412-4e73-8f34-49051886d79a": {"doc_hash": "a28d7a4a5452ad5f752a3dc8492ff5374203fbc0ec70b583f4b9f53b78926e5a", "ref_doc_id": "2d2e016b-3b75-4279-9b43-550b03801229"}, "6d7c6f87-2d44-4678-8677-7d67822726ca": {"doc_hash": "348db578186e0143470b78743b8e06a5d5c6ae72f76fe2f4752a6981f556580d", "ref_doc_id": "2d2e016b-3b75-4279-9b43-550b03801229"}, "8dc0111f-bf65-4b3a-ac40-3d821a7acbee": {"doc_hash": "52e3273bd6680397a187121988b2f6e276a0d52e112b9f3b4ffb71377bdd00cc", "ref_doc_id": "5cda025d-fd73-4f4c-ad13-dc33f12a4a74"}, "e6c08247-2f55-4359-bd2f-8f988fabbbaa": {"doc_hash": "73703e87aa78e1de6d6127b7f519234aca97188aecaacc518e98978cc29d0c7d", "ref_doc_id": "5cda025d-fd73-4f4c-ad13-dc33f12a4a74"}, "5c094d98-eb65-43db-bfe9-7138681de068": {"doc_hash": "2f055d6d048eadeece937bf21fbb062f8b8d493bcae203503f9fc6339fdee120", "ref_doc_id": "5cda025d-fd73-4f4c-ad13-dc33f12a4a74"}, "034f0d7a-1167-4ba4-bc56-34e5c4b952f3": {"doc_hash": "1fcb67237d8411138842daeeff8ef6235d0b27667a607d644771be172c4f471b", "ref_doc_id": "18c912ae-0f98-4e58-a28c-d6cbcf9843ca"}, "1a5f47ee-e12b-4dd8-a41f-1866192537cc": {"doc_hash": "c8a64f2f93e10f67cb82ba75a443793ccf9fe9d7a61416e5facc9747913f65b9", "ref_doc_id": "18c912ae-0f98-4e58-a28c-d6cbcf9843ca"}, "25bc0db2-ddff-4850-a0a7-969e01a40d81": {"doc_hash": "4426b306ec1bd7319da6b6811920040b748035a7976586797e004fc466ee69d4", "ref_doc_id": "515451a5-541a-4908-86cc-9e283f5a90ab"}, "46a2502e-3483-4a3c-a578-cd0957ea9425": {"doc_hash": "f373b15af63ee44b0d897696fe39f65363877b77e58f732b536862b1466f86ca", "ref_doc_id": "43ebeb43-2d9e-434a-bb78-d9dc09bdbe67"}, "5c748ed3-3c06-4e8e-843e-31b10469da33": {"doc_hash": "57d142115f9d2f548ae7f06a66017ada8395a4520232b4e3a791a4266e61085e", "ref_doc_id": "43ebeb43-2d9e-434a-bb78-d9dc09bdbe67"}, "1d7047f5-4fe0-4581-a670-c96f870412ee": {"doc_hash": "117d069ce5af0ee4ec3c1a117b619b2a88cf8f02dd0e83bd7f6c19da2f5b909a", "ref_doc_id": "43ebeb43-2d9e-434a-bb78-d9dc09bdbe67"}, "9a4312b7-1678-4723-b21d-9ef7b7bfe4c0": {"doc_hash": "51020694cd5a2aa75cd02db73c33fa2fd217aafb9bb0dcde6e6c3d32edb65940", "ref_doc_id": "c848c3b0-a715-4eda-8af5-58b89114c916"}, "738706ff-0ab9-45ac-bc77-9afce0241364": {"doc_hash": "2e5c9c65561b1c410d437d29996454f3e6ed2f5f04458d58f80bacf8f4e15fcf", "ref_doc_id": "c848c3b0-a715-4eda-8af5-58b89114c916"}, "df0db0d6-f595-40ef-a7ed-052d6b6da95f": {"doc_hash": "43652f2bac12541d6025d67b4e0b213dbd202b9de058feef3c28c79d13b28036", "ref_doc_id": "ac14d19a-bd21-4bb4-a1fb-50123ed126af"}, "7100c01a-2f22-4f66-ba94-ab27768e543b": {"doc_hash": "f5b7563f3f9e6ea824833570cbf0a4dcfb33c1bfc355b614f0dede64acf1559c", "ref_doc_id": "ac14d19a-bd21-4bb4-a1fb-50123ed126af"}, "c65f434f-8d12-49bb-ade9-77664172f712": {"doc_hash": "80bf5d4eb080604d59a3d71f077ce018f45103cd47a355afe39af7a9e082d078", "ref_doc_id": "fee661cc-64cd-425c-bc88-4bdcf05df2de"}, "597fdb15-60bd-4243-ba82-96debb052c8a": {"doc_hash": "5a9b38cebe28db867c9c2031cb82e23872b7f80a8a6fff242693f7a381231514", "ref_doc_id": "fee661cc-64cd-425c-bc88-4bdcf05df2de"}, "82183981-1f50-4cca-addd-985e85f83e8b": {"doc_hash": "ea7776dbece8797feb14daa67224ef04fd745bd2038c72f27c99e2a4ed23bf59", "ref_doc_id": "a5b4439a-e942-4634-99b3-45a57ba89e28"}, "743358ca-5775-43a6-a553-51840100d806": {"doc_hash": "fcf52cfed645d37a40b2a45e829b6a5e8d4fea2217cbea5679f72d3cf71034f8", "ref_doc_id": "a5b4439a-e942-4634-99b3-45a57ba89e28"}, "aecf4001-6a3e-48e1-91a4-13d84799ba31": {"doc_hash": "ef9e05f71054114e82c69691a81ed2e60a5256488fd028a3bcdf4bd37390edff", "ref_doc_id": "a5b4439a-e942-4634-99b3-45a57ba89e28"}, "58b0b0fe-ca45-46b8-b85e-0ce8aafcacca": {"doc_hash": "d6b6be8bb3ef9413d6344d3e4f9628d2e8366559124aa5d7123bfd359b2725df", "ref_doc_id": "bb3a579e-f618-418a-bf1a-74d40ad6fd53"}, "803a9e21-eb58-48ae-b348-1814de902c9a": {"doc_hash": "178f1d91ccf40bcda9482dbf61a63707e536fd8787a1600241b7b6627137fba1", "ref_doc_id": "bb3a579e-f618-418a-bf1a-74d40ad6fd53"}, "b2aaac40-91cc-4432-b2ea-bd5dfa64d183": {"doc_hash": "95be378f2138c386857a407297c1632ae9fc8a180775bd22bff353333a782cec", "ref_doc_id": "bb3a579e-f618-418a-bf1a-74d40ad6fd53"}, "3ebb9065-2204-4fc0-96ce-0021965159b6": {"doc_hash": "25cad638711a61fc6d63d2399e56631f4456fb2635b584c442e41e182c65f8bd", "ref_doc_id": "1a9a28bb-86ed-4570-bb88-f3ee8b13fc81"}, "409925ec-eace-4a01-a97a-44c4ab9704e2": {"doc_hash": "daf09af0bf69510e340bc62c8d5a8d89559cb886d46bfbe1a213fd76a5c8c1e1", "ref_doc_id": "1a9a28bb-86ed-4570-bb88-f3ee8b13fc81"}, "08f04a69-466a-4c22-b549-d13067fb098b": {"doc_hash": "ace49b65b5c16cf36a213d9f500fd4f514ce7795220de882f58ec096e25a6c7f", "ref_doc_id": "71f73ac9-92f9-45b7-9dc3-f726ffc23d08"}, "01404040-3fc6-4c0c-8aa0-0258b49f04ee": {"doc_hash": "01554f2a4e711255b48cbdfc9dc3f881f9550fa0ae09276275dfa90ed2652c87", "ref_doc_id": "71f73ac9-92f9-45b7-9dc3-f726ffc23d08"}, "d1f0aa77-8fb7-4e86-9035-de332f668197": {"doc_hash": "f3756bbe7f769ef94da7962b0d30b44efd3f1823ee453ad48c42ed0758536f2f", "ref_doc_id": "71f73ac9-92f9-45b7-9dc3-f726ffc23d08"}, "d71ca1c6-c347-4859-96bd-aa22af6fc9f0": {"doc_hash": "3b838a9f16fc9606822f9a886bf2684541cfe23099d77969a3cbc735c681f7b0", "ref_doc_id": "111b4a9c-dbca-4a85-ad54-c6d023df7d32"}, "c747535a-e722-4d7c-bc99-2f3f7df99a66": {"doc_hash": "1206389e802e03977f42ad9c1ea1c06abbc578086f0fd3aff651251a508ec6b3", "ref_doc_id": "111b4a9c-dbca-4a85-ad54-c6d023df7d32"}, "28e78f40-9d3e-400d-b3c1-e25561d04681": {"doc_hash": "a2e8ba72a4691abca67ff6300646975253e9478abeef71db7d3432c83e0074e8", "ref_doc_id": "111b4a9c-dbca-4a85-ad54-c6d023df7d32"}, "9ff2cf88-c722-4cb9-82b1-4fd82abcb335": {"doc_hash": "4df7188cfd5a595c9573da262cb769716ddfd150c3dc4dcd9725435238399048", "ref_doc_id": "51dd85c2-1bf8-4238-a955-1bc44a65b4ce"}, "f8c81eb4-0413-4939-8db0-b880e2910b22": {"doc_hash": "6b9587b4d7f67e2a870b30712fe0a79885a410c5ca3c3b00db6fc398978e05f6", "ref_doc_id": "51dd85c2-1bf8-4238-a955-1bc44a65b4ce"}, "817f4c23-57b0-465a-bcaf-be2cda2e9347": {"doc_hash": "0f1f52557d85ff9393a655b5ef44971a7c5c9f44da08b0188763309b91d2d5a3", "ref_doc_id": "b091c834-b87e-4f0c-91e2-27636541094b"}, "59497e1c-e285-4a18-9ef8-95bb25bd8d92": {"doc_hash": "e69b3d54730ca2db5f57c55b93cb54425b65bea7d17395166de5dd4d9deda7b7", "ref_doc_id": "b091c834-b87e-4f0c-91e2-27636541094b"}, "2ab7290f-395a-4036-8bfb-83e73a4ac9f4": {"doc_hash": "e6ad469a15d30dfb39ed368dc5e5ce4ed68414e1444f6f217aafa64c867eb6cd", "ref_doc_id": "01d36b75-6e23-4975-b146-80c29c49fb53"}, "330bde62-e44d-4b67-8b69-b1f929d44880": {"doc_hash": "612544b68511e381adead6f87d7589a6d33d08a86e44090cb9d6417ee8a15e8f", "ref_doc_id": "01d36b75-6e23-4975-b146-80c29c49fb53"}, "847eba8d-ad44-4119-bfed-e196044505f7": {"doc_hash": "03a5bd9f00661bbe33b2ba6e24c991b7c323bac7bce932cfa4919fbb82c7db42", "ref_doc_id": "7bf89b04-ee20-46cd-a8bd-ab1cc29f3360"}, "5edab9ce-9687-4135-adb2-8609267b36d5": {"doc_hash": "42418153b9b6ec104a6fb0565647f159ece0b67ff1cf0c975d536563fbb4662b", "ref_doc_id": "7bf89b04-ee20-46cd-a8bd-ab1cc29f3360"}, "73c57b23-38f5-47ee-ad3d-d9b932b9d64d": {"doc_hash": "ce4c83f0524923ef2dd5dd555b9c9b885de466f1027a9b834af2401d70fc80dc", "ref_doc_id": "6b383ff1-bdbb-477d-b5ff-577d8598dfac"}, "70fd9e77-a5ff-401c-bfdc-dcda4a5967a3": {"doc_hash": "d09ea1e62c9bf1c5f9aed8b406c9544daad43a54b3265363921e547e3a775cef", "ref_doc_id": "6b383ff1-bdbb-477d-b5ff-577d8598dfac"}, "69ee1921-1ce7-486b-a6be-80573b9ae7c2": {"doc_hash": "59a07ce6ad268c0d130b66c0a5e63ce9a3727c2631d565aaeae04b93b908c3d2", "ref_doc_id": "7a06d8aa-b385-4082-b494-79734de3d953"}, "65d6683d-2b50-49ab-a557-239107980867": {"doc_hash": "0918d577828257b3c18efb466270e5a4d35e6ad0d537fd9d22faaed6905843d0", "ref_doc_id": "7a06d8aa-b385-4082-b494-79734de3d953"}, "a6dc7ecc-2b94-490e-99a7-f229bc9b0518": {"doc_hash": "3079077a912caf7a0949959fda673aeb6a971d264399456d4cde9827fd966421", "ref_doc_id": "9ca4f025-d915-40c5-a850-d0548f4e4f2e"}, "6d1350e7-b6de-442f-9bb1-110f6389493a": {"doc_hash": "6b7e845d040c42473334fb3b70133002ac6a8683335238e09a8605bdc7b359e6", "ref_doc_id": "9ca4f025-d915-40c5-a850-d0548f4e4f2e"}, "9dc2a7b1-e999-4e12-808b-7baa59f4e1da": {"doc_hash": "74da91043babf85352e3b53aeb4e71a831e30814d485c986987560fe4c475f0f", "ref_doc_id": "9ca4f025-d915-40c5-a850-d0548f4e4f2e"}, "398fd14f-c80b-4a0c-a77c-cfb0b5d4cdb5": {"doc_hash": "d37c3770aed3d4d5f7b7c5acd5edc2bf26d4c3f8f2fdd5cb01f3adb103440115", "ref_doc_id": "ae98b6f9-d8d1-4d53-afdc-f65c649d45bb"}, "b62899a2-d644-4de8-bbff-16253f60bbce": {"doc_hash": "3011e0ca148eb9c1c201eb823210d7f81af36a11b7995b11c36a7a252574a332", "ref_doc_id": "ae98b6f9-d8d1-4d53-afdc-f65c649d45bb"}, "e35ae7ab-4226-4917-8f45-fe67f476b802": {"doc_hash": "d6972d74f84f82542993e71333e7d3306f1ae2907565dec35946b87480a819c8", "ref_doc_id": "ae98b6f9-d8d1-4d53-afdc-f65c649d45bb"}, "277d381b-a684-4b7d-aded-7c5c6e782d07": {"doc_hash": "da2e7d7dfa3a2307bb3097ed652f980432efce290ed5deea22242fae154a9f39", "ref_doc_id": "ab09283d-70ae-47de-b6cf-9bcd570b5983"}, "bc2ca772-79b7-47cf-8a59-8da822ed0f3f": {"doc_hash": "ff60690e9b1856ef97e3d8c1e78ad12cc6f940eebf7ced36485cd57231e447e7", "ref_doc_id": "ab09283d-70ae-47de-b6cf-9bcd570b5983"}, "647cf8e1-85b6-46f0-b27c-408994810ef2": {"doc_hash": "c000676ef63e2c2df1981c52b3aa6646c29835b677523d29c84b0b96593afcb6", "ref_doc_id": "24859742-b485-48e8-ba7b-39a823af7e05"}, "75b5e800-fc7c-4ade-93ea-a6c3fd7201b7": {"doc_hash": "7fcabdd967500d0e0a67e6d18a5ca472a005b54f4de863717ef5e29ba642ba21", "ref_doc_id": "24859742-b485-48e8-ba7b-39a823af7e05"}, "bff04dfe-4731-48a5-8f80-ea134fcc931c": {"doc_hash": "ccf17a2c8c2386c782ffdf3e644f14fbea7e449c37290ff214556985e2cb80ea", "ref_doc_id": "4ffc575a-d1ea-44f7-ad42-a8f43388f91b"}, "7817b001-d62f-4a0e-a70e-6e7e5f868223": {"doc_hash": "8398df3066379798d8b0ca48660894629735eaff14201c17de651aaa6a3998b3", "ref_doc_id": "4ffc575a-d1ea-44f7-ad42-a8f43388f91b"}, "5edb0697-e73d-4844-a291-da6e3849917f": {"doc_hash": "e7b4c29f266a4d0c02e53d6769b5433ea72c0516f6cc804095b4baa80615b4ea", "ref_doc_id": "0e1c5a7d-7ae5-41a9-9d0d-59a0dc9b9b3b"}, "94960a13-8409-4406-9fe1-14cc54908185": {"doc_hash": "14cf4b13c380a85b89436aeabf471d93b84c731c2104145cfb768e6bcb902bbd", "ref_doc_id": "2e7abd4b-d20b-44b9-a395-51382fea4aaf"}, "841ad537-bc1b-4386-9b55-2ec3349f249c": {"doc_hash": "8f5cf4ec7d9a084b03bc9bc88d4951e6660ce04ccab0655c2bb1b0cfd28fb0d1", "ref_doc_id": "2e7abd4b-d20b-44b9-a395-51382fea4aaf"}, "ca932626-3910-4e21-b8fe-184e507f6353": {"doc_hash": "e604dfcb78726f082b058f163eeb0d2903f682e373b7bb533a9336ca9c5495a1", "ref_doc_id": "d2741b24-047b-4d6b-8c52-0b318da87c8b"}, "4a800351-2dbf-4224-b217-72ca67d09284": {"doc_hash": "5d6d80a75fc6d488a58d64fdf7459c38cc5f21199520f19e68cdadd341c00925", "ref_doc_id": "d2741b24-047b-4d6b-8c52-0b318da87c8b"}, "43c9c3f3-fc47-4914-89eb-e08eefb28648": {"doc_hash": "c573edd00010b3b268e5f5f255b8eec2d58ab3594564732f043d0be3ed9aaf04", "ref_doc_id": "d2741b24-047b-4d6b-8c52-0b318da87c8b"}, "164ed92a-57a2-425e-84f6-65ca0bc690fb": {"doc_hash": "44f3622ac39e2f33fc88eb356f9b2004491e231671eec964e41929ebe0c4f388", "ref_doc_id": "170f7225-61a9-48f5-92ae-9601012ba88c"}, "fbf49f7d-7b53-4845-b635-61576c933b6f": {"doc_hash": "f5c4582c0d1cda19e4f0dc1cde09fdc8c0836b7ba18e5ec5f780f047ebf72b57", "ref_doc_id": "170f7225-61a9-48f5-92ae-9601012ba88c"}, "085126dc-f72c-47f0-86c2-0a2d56185848": {"doc_hash": "6b49dd0684e91d696986b32912508c62b46c9466254b4f1985301965dbb6361a", "ref_doc_id": "c7aed488-8077-41d9-96e1-36d35d3d5c8c"}, "9cf43681-1e4d-4d97-b24f-21b156f28ef2": {"doc_hash": "326b73f7873a6742aa14d0d5eb9817a533667bdbf57b611c869ebe246c5a049b", "ref_doc_id": "c7aed488-8077-41d9-96e1-36d35d3d5c8c"}, "f4944ecc-4190-4182-9ae4-3f1378950935": {"doc_hash": "aefb83eb0a963b5f6af7fa3aea44e5b6aaf76654440b8ac487c3dd096bfe9c94", "ref_doc_id": "1261ef20-0455-42dc-b685-23b892763d57"}, "e45ce403-c30a-42b6-81b1-c2a83016652b": {"doc_hash": "3ba51430c500aefc5dbcf02ea24fc37ecbee0da7c5cf2ba088cf76d6e8f6a879", "ref_doc_id": "1261ef20-0455-42dc-b685-23b892763d57"}, "738679ca-f6b6-4fb8-819e-4a2fd6c972f2": {"doc_hash": "bd7cf95779d8021662cba04707194e46e3c40a71dfd094c63fe4300a2215d970", "ref_doc_id": "c2395193-c2ef-40a0-a452-b208e95c52a6"}, "1d016b09-0260-4238-95ad-a7ffd52cc768": {"doc_hash": "b25be0110355ff72c5010b4730474d6da09d6d713afabaa003cd813ccad18321", "ref_doc_id": "c2395193-c2ef-40a0-a452-b208e95c52a6"}, "ab07b0a4-8ff8-49f8-a37c-a4a07eb9b148": {"doc_hash": "0636cbfae8096f937cbeea882c7c7863c03d43013d08801b90bb1b73c3111e9e", "ref_doc_id": "4fb92235-14fd-4d57-a4dd-2995bc5d91a8"}, "f35810d3-a4c7-4dd1-8b74-222ef0941f26": {"doc_hash": "fa5d34748effb70c8095017dc66fa83265e24212c189efee5629fc12aba0b870", "ref_doc_id": "4fb92235-14fd-4d57-a4dd-2995bc5d91a8"}, "63ce22d3-a021-458e-8eaf-410b554d596f": {"doc_hash": "843b57bab781645a9ed31b69d2118b30ac94b0c9b00e5456f5a7afbe7df59928", "ref_doc_id": "4fb92235-14fd-4d57-a4dd-2995bc5d91a8"}, "310ec046-7473-44b4-8a3d-b6b7bc7572f9": {"doc_hash": "2f5d54063a3df85482eb9fad9b7d24fc57c7b0f901cd9568fd15b6faca762380", "ref_doc_id": "83ff7cc8-5f61-4ec1-af6a-2861d462fffe"}, "8f07c505-aeaf-4ec2-a8d5-7cdc4ad4e789": {"doc_hash": "92a03f2fd423b0f0ff548433d6e45fe4a9ec935639acbbdbbe05fb011b6f3093", "ref_doc_id": "83ff7cc8-5f61-4ec1-af6a-2861d462fffe"}, "4061034a-68c0-4ea3-8f41-c3a4ac876411": {"doc_hash": "155d3bb813fd7600da08245e533621f32c67e3293d3b8adb623d6b6a191b83b6", "ref_doc_id": "072a67a1-3885-4e2e-b99f-75aec60378fb"}, "087e1ea3-1584-4555-9928-c7eb5013da8c": {"doc_hash": "0f7d941ce141db8a6216770e332dff2c3b1709b1d81aed1079a5302c414f88a3", "ref_doc_id": "cf430eb1-c967-4988-9f9d-7a4f01da9fb9"}, "ed391ff7-9e9c-4cbf-9f43-841f91215790": {"doc_hash": "c527362c114271de8c4319aad6e2125ec483e4861651afaacfb0c772bdcab56a", "ref_doc_id": "cf430eb1-c967-4988-9f9d-7a4f01da9fb9"}, "9e9f9d89-ae4c-4dbf-9e6c-b0a9aec5eb65": {"doc_hash": "8b687835c10d55d3c92949d18fdc5474b543339d91ea1299e194c0ec824eb873", "ref_doc_id": "cf430eb1-c967-4988-9f9d-7a4f01da9fb9"}, "c978bf50-6b9a-4b67-a14d-81de40ef151d": {"doc_hash": "9e1aca83bd6247cd048fca797082a98a1153e30a6a3aa961abddf11d1976315c", "ref_doc_id": "709d1bcd-b04f-48a0-ab46-c5bda6fd2ed8"}, "9235f740-7556-4018-a6f6-e1ef890d75ba": {"doc_hash": "b34870ff2172daeab075199dafb718b113b9d0d3d04b35261c607027b1963b76", "ref_doc_id": "709d1bcd-b04f-48a0-ab46-c5bda6fd2ed8"}, "11df2f14-ec53-45b1-98f5-aa15a49b738c": {"doc_hash": "1bc90af0c073db5ab378d072009e7980acf7f58fdeb3cd32edf815eec003ec31", "ref_doc_id": "2542fe3e-cbef-459b-9d9d-742b13e42aac"}, "a6304eb3-0330-49aa-9412-6784f38a5c24": {"doc_hash": "896df7e1484ac3ddbd502d21b841c23c99f5254c158156548cbedbbd9acf97e5", "ref_doc_id": "2542fe3e-cbef-459b-9d9d-742b13e42aac"}, "68212f43-73b0-41e1-afa1-73df678a3419": {"doc_hash": "9da985706a279b1f6b404d0a10fb3d14d3e4ba719d3a5a6501e74da59346baa2", "ref_doc_id": "805483ce-1d91-4572-9b46-4ad9a52026e9"}, "fad17d10-c560-450f-b466-336dd696d1f8": {"doc_hash": "c40ce0029563bbd94dffd3c578083677fe049a6eff08bda1b7b28144daa03d54", "ref_doc_id": "805483ce-1d91-4572-9b46-4ad9a52026e9"}, "dbb0b276-b2df-4676-99de-bb96c072d33b": {"doc_hash": "2a81018b2d8eee9ada289c5618052e10fbafcae85611536f96378e047560663b", "ref_doc_id": "805483ce-1d91-4572-9b46-4ad9a52026e9"}, "44f279d4-7a92-4186-9ed7-e27cc6d71dec": {"doc_hash": "a3ab591b869402309d666512d77e400299380bad83186c8a8798e72cf4bfdc06", "ref_doc_id": "5dd18fb9-d145-4191-afe8-5cc39708c5c1"}, "88ac092c-b9a0-4900-95b0-2de100fc83a9": {"doc_hash": "ce60fa19ab7fc149ffa17d2382e8cb24e67d02a30353430fd4707dcded7653ca", "ref_doc_id": "5dd18fb9-d145-4191-afe8-5cc39708c5c1"}, "22a185eb-6a55-4b48-bd83-8fd10cd70f76": {"doc_hash": "c3448d77a3639d2e637e00456a2fc12651bcacb15d7165e35a8b6efa2c0f7e48", "ref_doc_id": "06a752b8-8976-4f83-96e0-392c0bc480b0"}, "c70a7248-c5ea-4718-b2bb-480da2b15f18": {"doc_hash": "98c93ece404b71fd7457a32333a2cb02f118b195d48ca1edaac0745c63ea54b3", "ref_doc_id": "06a752b8-8976-4f83-96e0-392c0bc480b0"}, "01ee1cb4-393e-4e47-9d97-ca343549a26b": {"doc_hash": "59658d963653af41ecb720aebfa9d70c7ef2d9430b8c669e5840b34905c2eb4b", "ref_doc_id": "f3e5bdf3-5aeb-4ddb-bc93-cd9a0a727703"}, "feabec87-faaa-470f-9ffe-d2f6684e0244": {"doc_hash": "322d3a9a02d6788ad2ce2cbb871a9d732b622aa9bce87ab2297cbc3429c258fe", "ref_doc_id": "f3e5bdf3-5aeb-4ddb-bc93-cd9a0a727703"}, "bed56d60-530b-4b9e-a3f7-41b0d4a17c4a": {"doc_hash": "4f8c706a89197a49c8ff76fabb3bf4fbc2c0f76262913ca93335b23767e83f60", "ref_doc_id": "6efde898-e39e-49fd-8923-b847e72a2500"}, "aeeed7e0-503b-45b8-8962-b068c788aed4": {"doc_hash": "8cce02659b5da55b2ba671d6c45a4d03cf9b24cd83b8742a157fe1b3148790d5", "ref_doc_id": "6efde898-e39e-49fd-8923-b847e72a2500"}, "db1725aa-2145-4e8c-9d7c-c7204cd9d267": {"doc_hash": "d670dd49c8575657c72729639bde8ff5b01c4a36bbc40dc1eff8259101ac8938", "ref_doc_id": "1a101154-e58c-45f2-b6a1-32147d7510a1"}, "b2714eeb-1196-4a91-a0f2-f2e0fb3202a8": {"doc_hash": "2ff014bc4f9447014f1e5368199b81e2afc8e1abcf6fb20fbfda615ea7fdb011", "ref_doc_id": "1a101154-e58c-45f2-b6a1-32147d7510a1"}, "e8660b83-019b-441a-a7fa-d1febd0772c0": {"doc_hash": "efa45ec90d1c4c6776dc6c9719a60dd7f9cb45e06d2c2d35bbfa123f648b3b5d", "ref_doc_id": "e5bb3759-1b12-4934-9e4a-948dbda45f87"}, "273aa6cb-48bf-475b-a165-8751e0ae1901": {"doc_hash": "3e8d98c464b32f0afb1a7f4dcabb038b400353d60fb2e5c1d47623dcff09a78b", "ref_doc_id": "e5bb3759-1b12-4934-9e4a-948dbda45f87"}, "d9d626f0-4692-4085-896b-ae380abad62c": {"doc_hash": "fb0910444d26320bb9f32b9a40358b929a42fed83fc48af588a77a7d0d7fbcca", "ref_doc_id": "d07c9ed3-871b-4ecb-a69e-bf56af097ac2"}, "5bc0ed95-3dd6-4574-a521-6b373a120c33": {"doc_hash": "fbda6357612f8198f3e8ccfb3b809f7b4a6433f5ed5f1efdb7d408fc07e3d706", "ref_doc_id": "d07c9ed3-871b-4ecb-a69e-bf56af097ac2"}, "fb818fbf-85c5-4dbd-902d-177cdab20f47": {"doc_hash": "33645b1985b9162b9d0793ec619697a3d73c69ae4926bcef4ac461b818413063", "ref_doc_id": "be2f3034-7ccf-4a55-9adc-7bce860d4ff1"}, "45ec4382-3cd2-401d-8409-f14acfa0eb0d": {"doc_hash": "84aa873afb4259b85fa85f585e229b2c96be233a1c39e352b01a5d455e27d2cf", "ref_doc_id": "be2f3034-7ccf-4a55-9adc-7bce860d4ff1"}, "8c6312f3-b762-426c-a972-ef5c85acb921": {"doc_hash": "7ef2fcce697f4a4e91cd4357659258154826aad19af85cd05c9854100e62e3a2", "ref_doc_id": "be2f3034-7ccf-4a55-9adc-7bce860d4ff1"}, "16ba4a63-7363-4d7a-89d4-793772ed3c6e": {"doc_hash": "2da6137be2895520eced0849a5c5cad0c10f218a87226966fc1ae8cc12d73a2f", "ref_doc_id": "90827983-ec76-4563-819a-add08efb3b8a"}, "e9cd2716-d6ba-4548-933f-6ff245d8871e": {"doc_hash": "adf130573c6e0fd5214c1a3f12c2aaf88b2f1acff37635089e4c0dd45779aa5b", "ref_doc_id": "90827983-ec76-4563-819a-add08efb3b8a"}, "df96f13e-6fb3-40c8-a485-41be17aaae1f": {"doc_hash": "01c4816de5e518fb220e3118ac63816a5cd4dd66fa3ae36afd360cec76ffa07e", "ref_doc_id": "90827983-ec76-4563-819a-add08efb3b8a"}, "8d09f956-55b9-4ab0-8649-72fab8c903e0": {"doc_hash": "be49d7f6d9cd6206a59507645b309a8351f4072c24192733bb3e920a12271c6c", "ref_doc_id": "a296fb4a-5590-4c21-b40a-8c9e83748489"}, "939770d1-7efb-4dd1-a69e-11020dcc3509": {"doc_hash": "f04399870fd115989f9cc1835d7aaec444441cfaeea0284180264af7c2e5edb6", "ref_doc_id": "a296fb4a-5590-4c21-b40a-8c9e83748489"}, "57770bff-358c-42a8-bbd7-f09e5f9c7ba7": {"doc_hash": "b2f949e1e220c023d1807f50c90fff7ddc9325db8f1b08e6fbfb9c042632aee0", "ref_doc_id": "a296fb4a-5590-4c21-b40a-8c9e83748489"}, "72b4caf1-4d9c-424b-9dc3-16c6a7f19058": {"doc_hash": "e6a346d281d086b4b4541e1c43daa58e442328ba008903700e3e7bb4562da86b", "ref_doc_id": "679606f7-c43d-46cc-8790-86b178958081"}, "b7faf5f0-c887-479d-98dd-6bb56f8fdfe0": {"doc_hash": "44bdec6d9cedea27feb9ae9276ca45faadf99787dafc65bb2c8cac106823a2fc", "ref_doc_id": "679606f7-c43d-46cc-8790-86b178958081"}, "4a3f9c60-0e4c-4d17-ae5c-34a986ae9679": {"doc_hash": "fe2c40126a65b234973f1b3fc7a3ad61573c456cd2c3898f1964ec3e9ae50688", "ref_doc_id": "b82c8bf2-5027-4eb8-8a41-8fafd5622f5e"}, "b436f740-9208-45e3-864d-d4a16ae46fa0": {"doc_hash": "9888b0970e7e61e9540f07a2996971d61ebe9bb048c74b2d10ad2edd2406b2a7", "ref_doc_id": "b82c8bf2-5027-4eb8-8a41-8fafd5622f5e"}, "5259ef40-939e-4b53-8771-d4124fad0d97": {"doc_hash": "1ec42722436fc769d0bc4d57b3ea3c225ddadb0130a7d2f3aa3387563e015ad6", "ref_doc_id": "a1285979-8783-4eac-87ef-5ab5a642135f"}, "e7aab2a8-cf64-4b1a-abb9-7d60e8b26c1b": {"doc_hash": "70b785adc9d68fb5d827882479bae230da89a86c7adc41c1ebb5a5fd486a24ac", "ref_doc_id": "a1285979-8783-4eac-87ef-5ab5a642135f"}, "d5afa1a4-3fa9-4f9a-87a3-30a66d2f11ee": {"doc_hash": "ea767f56e7e3903d6ce9d94516e22618773695a46a99a31fc1239cab774fa6b1", "ref_doc_id": "93aa463c-e0ba-43fc-93a0-8d937e112bf3"}, "40d56eef-c52c-4f21-92ed-c8d8f2e677bc": {"doc_hash": "d12898d350b9351aaa85fa26592fa174c71a28bb2fb86202946543041517679c", "ref_doc_id": "93aa463c-e0ba-43fc-93a0-8d937e112bf3"}, "19d21ec3-3841-4c4a-af65-e983fbab3692": {"doc_hash": "802420256b38b3ae942260d3df6e3fd194e3f78d4d313bdf9f3f1bc69a98c29c", "ref_doc_id": "93aa463c-e0ba-43fc-93a0-8d937e112bf3"}, "8d9e67b4-ba5b-496e-9568-bb1fc127d52a": {"doc_hash": "d86bb77b9d199f467c6e828fec1b5a4cb0c6386cb230492e61e5a5d9467ba1ca", "ref_doc_id": "c1784347-127a-488d-8348-de75e2a7de63"}, "0b60ad39-cfb0-40e2-b550-4725c0083455": {"doc_hash": "f3146cb9d5dc6a9b43cb70c41a3ebb9b0186a3cb287d17068d6ba21b2dbc82e6", "ref_doc_id": "c1784347-127a-488d-8348-de75e2a7de63"}, "cff8110f-fc40-465a-a90c-390d34ae6c9c": {"doc_hash": "2acf4d87ab2fdb13440f5f81c969705ff966c9d4a9dc7cd1a724ab9c730d3814", "ref_doc_id": "d0aca54a-e8bd-44ca-8884-405fd1af4ad1"}, "64fba9ee-9450-443a-b380-d26a6c69b1e8": {"doc_hash": "c9d13ef6a79ad7c769d3f850da1a1c27c8c958672bac0627571e538c1a00d7eb", "ref_doc_id": "d0aca54a-e8bd-44ca-8884-405fd1af4ad1"}, "58ddaee7-d5d5-4201-8a3d-e80d3a30432e": {"doc_hash": "6f9dcebd91169c4899553bebfe44a9f159692aabcf7e3ac32f4e92d20f0973e9", "ref_doc_id": "f480beaf-4895-44ab-a422-6dd3a9a90b03"}, "fc9d41ec-8a68-4782-b2f9-ad5902ad0ec7": {"doc_hash": "f192a964f97759eaa899b3719a83151d73352c220b1d9cb34885b447dc65a9af", "ref_doc_id": "f480beaf-4895-44ab-a422-6dd3a9a90b03"}, "c81736b7-f2c3-48e6-918f-f0e0b14d2842": {"doc_hash": "805f887b483575207f234ae34c9af0e9acc160d962a58165c916559459850367", "ref_doc_id": "717887a0-3f1f-4590-af1c-d188db215b32"}, "279feb6a-1486-48db-8fae-b01adb80e5cc": {"doc_hash": "8bae53ac2faf32a2587a91b255de319841c4f68567b5c0196934e427706fdb6d", "ref_doc_id": "717887a0-3f1f-4590-af1c-d188db215b32"}, "0ebc1a54-33b3-456b-915c-16c71081aa31": {"doc_hash": "71f0fe8106e7c89539dc1d6ada71447e0da11024aea8ad9f35baff00a16b7507", "ref_doc_id": "0df4b4e8-3bab-4d7a-b235-a392e6b6a045"}, "2831c48f-ed44-43df-9eae-1214bcfa33af": {"doc_hash": "588841bf5fdde3728b28b7ab361fdfb48e1446d4f0ac45388e4c618a532ee1f3", "ref_doc_id": "0df4b4e8-3bab-4d7a-b235-a392e6b6a045"}, "56fbf341-b84d-43c8-8f35-60f849a7da4c": {"doc_hash": "965dbff01fadec0a80fd32ec71ee5c9ace54d85392f56b008742f2452b67d0aa", "ref_doc_id": "d9d5661d-0a9e-4e66-8c62-3bc58315541d"}, "2b6ad75c-5fdc-434a-ab59-141da865c8d0": {"doc_hash": "53432d9e69839fa1e44c4eb0cea23691485f10c3c1635c78d857573896c7c6d9", "ref_doc_id": "d9d5661d-0a9e-4e66-8c62-3bc58315541d"}, "74d5fb38-ccba-418a-a638-8988ad5a2da1": {"doc_hash": "509ff10350c970b0802e042fe8d64d13952b3a18e4bccd0ea72ff339747a74ff", "ref_doc_id": "d9d5661d-0a9e-4e66-8c62-3bc58315541d"}, "bfb74446-5a60-446c-ab35-1808c1431451": {"doc_hash": "6d1dadb586eb8ef320f2b1a2b45de8ec22771063cb3fdbe301ff2639c17ecab1", "ref_doc_id": "d9d5661d-0a9e-4e66-8c62-3bc58315541d"}, "e6008c04-48ea-47ad-b6a9-d2d16e810bab": {"doc_hash": "78ece5cddb4f128a122890e1d455339c635af7d3e747f5412036dd14f2b53ed2", "ref_doc_id": "de184d90-8a77-4d83-a264-83f1a1d8bd84"}, "6040bc08-06d9-4ce6-9b26-d45176267882": {"doc_hash": "a531114b8a146550c841e9069b47338927cfb8114f44989a3cf63306292da106", "ref_doc_id": "de184d90-8a77-4d83-a264-83f1a1d8bd84"}, "044917f7-4322-4510-875c-68fa43cc5cc2": {"doc_hash": "177549e017d42ed3408fa35d76e68ecd5f3345344e51ca5b07f7fa9ac547dafd", "ref_doc_id": "5342547c-59cf-4c84-a929-cdd4be65305a"}, "c47e6e0b-8b97-433e-95ce-d6a007e55e55": {"doc_hash": "bc95ef371d6925d15af842dbf4fb0b1a44b7e935ac03893fad9e11584db40105", "ref_doc_id": "5342547c-59cf-4c84-a929-cdd4be65305a"}, "9e4a00f9-ab38-4a45-91f1-5ae5774c0f1c": {"doc_hash": "203692f6feb0b25b7bf2e1bb786f96be221d9cd561d06f069a43028a90901a7c", "ref_doc_id": "1afcf0bb-0c68-4bb8-8602-3ba2ca328169"}, "d55e0371-0ca8-4958-8a72-2c5481b25d97": {"doc_hash": "a20e916dddac21b95f7b85e55350c030a1b7a09f097433b407adefa60ee98aee", "ref_doc_id": "1afcf0bb-0c68-4bb8-8602-3ba2ca328169"}, "7531f3db-e115-4dfb-afd5-a70fb60ed18f": {"doc_hash": "6e6a8da968ae5e8f52dcc8b831716d2a6effdaa47e1fd801c9d2662cd44c6cdc", "ref_doc_id": "d70c1bfe-e16e-4ce0-a658-57419ecb6553"}, "a1c52e32-8920-472a-8379-330d8f5be91c": {"doc_hash": "005d7d2e73ae9b321d83144daa45975e358a7a980390f8f5ea2352e763995388", "ref_doc_id": "d70c1bfe-e16e-4ce0-a658-57419ecb6553"}, "9cb42c91-ff17-4fd4-a6aa-533a2bae6729": {"doc_hash": "d427149995a58a34455636db5c9ef1b652e9b33fe075478f7f5ce4fb943f28cf", "ref_doc_id": "f7751953-61be-4c38-87d5-3296b3de73ed"}, "3676a575-787a-4028-860d-92317bd836d2": {"doc_hash": "47b2adb05022a82cb183a06af2caa6121fdcfb04b966e83aa90bb67e31a28c8f", "ref_doc_id": "f7751953-61be-4c38-87d5-3296b3de73ed"}, "419990c3-1ac8-4f06-8849-e2e7e27a8fb4": {"doc_hash": "b8dacd1d78ee3377328d2311d3831889d5ebe91ab05aeece6557433b593c0c13", "ref_doc_id": "f7751953-61be-4c38-87d5-3296b3de73ed"}, "8b7d0e5b-4651-4bf3-b0d8-d6a5503d69b2": {"doc_hash": "383989435406c003259a468c4d11ccb60fa8944571176e5fdddf2a1d31d1f128", "ref_doc_id": "01a39b72-8bc8-414d-ac57-b166f28a2544"}, "2c53765a-56c1-48ed-9d78-7d879d512cd7": {"doc_hash": "491e9349959bdccfdac447d9a4158380b7ff8136b904b6cc199dca3085204642", "ref_doc_id": "01a39b72-8bc8-414d-ac57-b166f28a2544"}, "b41f6a80-4a3e-412b-8814-b69b97401683": {"doc_hash": "3cf442d4ef112e1d73da1a961209dad1cd1cf141f6b25c307a3f4a5860903053", "ref_doc_id": "6873dfdb-094a-49ad-90df-453be6c00b8a"}, "a80438bc-0369-47cb-94b2-53fb835987d7": {"doc_hash": "d0942497be1b1fc519b62569e5d31d092c3d6b9317241792de4a455ec772e7ca", "ref_doc_id": "6873dfdb-094a-49ad-90df-453be6c00b8a"}, "56a0e6b9-b839-4d33-b3db-8d51255697f0": {"doc_hash": "de270c333b364eeb638382e45cb0da0abb58daab8005bec3faf7ade8b12f4eee", "ref_doc_id": "97497838-610a-45cd-9620-2a36d02d869f"}, "21b54023-5f78-4403-932e-fbb9c9664fc2": {"doc_hash": "83a7ba44a92fd48e3ece0db048bc22b12ff8c763d59aaf915d6a54217f07a201", "ref_doc_id": "97497838-610a-45cd-9620-2a36d02d869f"}, "f51487ec-4c73-4110-b1c0-881f0be33cc2": {"doc_hash": "02b1e9ebb26f311cc91c782c6ed3fcb73922dde404b1163a19a070abc21b6665", "ref_doc_id": "ade2c52b-f06e-46de-b11a-eb18896fc798"}, "666233cf-c6ce-453d-9a60-c6bb4c27f83c": {"doc_hash": "ce90fafe504b5b09acc64353dabbf58c7536327678479e6cd8f049eefdee6a8e", "ref_doc_id": "ade2c52b-f06e-46de-b11a-eb18896fc798"}, "621a0770-1a93-4d19-a02f-458780730291": {"doc_hash": "50bfe73ce7e8af92ca8d3d6eaf5751b3e5ed569bb1ae131b3ce9ad15c988ff85", "ref_doc_id": "ade2c52b-f06e-46de-b11a-eb18896fc798"}, "9dd422ae-18f5-47e1-9718-cfec930ea23f": {"doc_hash": "fdf649ec37e4ca498bfd949426f0e8036a7e3a855feaa0488b64c5ddb24d2236", "ref_doc_id": "62807d3a-5e23-487b-b916-94a21a8f6499"}, "78b5686a-65fb-49f6-a8fe-3f0056af5bc2": {"doc_hash": "4b5876122e6d524de9e5fd761ed0b3124d2a0925946f8bb6a10fd2b438ad61c1", "ref_doc_id": "62807d3a-5e23-487b-b916-94a21a8f6499"}, "4829c3e4-24ac-4cf5-8cfe-61db4b1f5f7f": {"doc_hash": "bc88af35d68efe6020207a2f552424fecc30b5dc7caab9d515b23d50512dbc2a", "ref_doc_id": "62807d3a-5e23-487b-b916-94a21a8f6499"}, "254862c7-9e13-4df1-b217-f64ca03fc5e3": {"doc_hash": "d5bed146dc17ff5cda1990c2f4d3f358fda071f336ac410a7a3324fc8dedaa25", "ref_doc_id": "965806fe-f867-4cb4-8531-b9cf2577130e"}, "56a39164-b80f-485f-b1d7-0372c18fd5b4": {"doc_hash": "b9f2c77737a54373932675ee93e5552488141bf8e10bfd2bea5b1f19bf980733", "ref_doc_id": "965806fe-f867-4cb4-8531-b9cf2577130e"}, "fa4ff7ac-be03-4a2e-bed2-19cb38f85302": {"doc_hash": "3b61cd67cc217d457642675fdbd656514e0dd93e8ef0426feab0909b6be93c74", "ref_doc_id": "2d36bd17-f2bb-444f-b35f-6cfb23804a5f"}, "9df91b08-b219-4ea3-9db2-04ab844fa90b": {"doc_hash": "2eaa7eb896abf6d08c433fff0b88d2d031e6d8ef62d2db950ff3949738a46d79", "ref_doc_id": "2d36bd17-f2bb-444f-b35f-6cfb23804a5f"}, "22dc2746-df01-45fb-ac99-a26114bae1d7": {"doc_hash": "b24b55e985960171cc8de086c3a6feffca1b7c5728fac6b867a05378fe1e77f8", "ref_doc_id": "2d36bd17-f2bb-444f-b35f-6cfb23804a5f"}, "88b9b458-3d2a-4970-b35d-b8664498bda5": {"doc_hash": "5cc1603da08e57b7c725e55cb69a26ec482bf0be4e2dc1a909e40068fe9555d2", "ref_doc_id": "e18a258b-3ab4-4693-b182-f2336d0bf7e6"}, "be376c17-09de-4d91-992c-f8ed41f18c4b": {"doc_hash": "9551aa928526f1da72f0469ce22d40e9cf708fb9deaa4555a4973124365fa2ef", "ref_doc_id": "e18a258b-3ab4-4693-b182-f2336d0bf7e6"}, "9d59313e-e667-4254-bfa6-42b8b511ca23": {"doc_hash": "474062d9a99596bf61b08416a7e05dfeb4570a0e19f9bb9b7101fd111066c0b8", "ref_doc_id": "b8b8ee3d-f697-4b26-813f-020c6807c013"}, "4e50a060-3d75-4e0d-8911-b5acbfc10efb": {"doc_hash": "da7e8d71fb89b9cca3dc9a397bf05c1fdf0ed3a5c62c218e1e36a3697e6c55d1", "ref_doc_id": "b8b8ee3d-f697-4b26-813f-020c6807c013"}, "22e2fa36-bab5-4101-baf6-7bbcdc85497f": {"doc_hash": "c703814e85e897d15398344e731622aed3f4fd205e4c73e585106721b607f44a", "ref_doc_id": "8a890c37-be29-45d8-b10b-7c6eacd772e8"}, "840df9c1-8d6a-489b-98d1-f40f1e9b59e8": {"doc_hash": "1f8b33fd512d6bb29e8f297a93ee5397ac24f6b36d898da8cc3686f59aaa8323", "ref_doc_id": "8a890c37-be29-45d8-b10b-7c6eacd772e8"}, "22486a56-2c49-4545-b5f1-13e0c51c9de7": {"doc_hash": "82c9158607675342ac622a4b090a3897191ddc356b2bcd70a8cbf88ffc2d62c9", "ref_doc_id": "5d3f734f-7aa8-4cc4-8305-11ce4ace3134"}, "876bd4db-8406-437f-adab-46e582d5ada3": {"doc_hash": "8170616905bfedd0b44fd95cb22366eb7fc06c80bdd4667d9ad32d228b0ab8eb", "ref_doc_id": "5d3f734f-7aa8-4cc4-8305-11ce4ace3134"}, "97ba3211-56cf-40f2-9b8b-2e73982ee48b": {"doc_hash": "1352868de11682a4aefdad3a2e837d95af1b773ff03b42976ba0467d6e3138e4", "ref_doc_id": "2d0d00bb-5ec9-4fac-9b5e-5806eeb67be2"}, "24803293-5e0c-4788-9bb1-14cd7e359145": {"doc_hash": "9520a4371512beb5d4424e8f14c43a25cd783f66c9378bd90566b206141150e1", "ref_doc_id": "2d0d00bb-5ec9-4fac-9b5e-5806eeb67be2"}, "f4c3c32a-f6af-4649-a12d-4a7fdd93a32a": {"doc_hash": "2339c05625d187801368adcc8129e0348a0b8098fdab188d3d82c5beea58c4f0", "ref_doc_id": "2d0d00bb-5ec9-4fac-9b5e-5806eeb67be2"}, "d8866ee8-c843-4e1e-b26a-d124967f0357": {"doc_hash": "fbe0f662890337e10de330c8795cc24817aa4ac36e5289e01d7011b9e7d7cf22", "ref_doc_id": "dc809377-d7d4-4a32-97ce-dca18a43d36c"}, "278c11b5-cc1c-4dd2-9ace-7967b1d979c6": {"doc_hash": "7b08b661a1040c6710b7f4fa328c4ca9742e6e6267cc3f6c82bfcf650563b1b6", "ref_doc_id": "dc809377-d7d4-4a32-97ce-dca18a43d36c"}, "7c77754d-8247-4327-8f32-8b3dd61908fe": {"doc_hash": "9f7a75a2424dcc78a1e658af4c2a3b77572d3b8564ffac4572fc0e880d1d0133", "ref_doc_id": "f725e3e0-f87c-483e-b003-1dd81349d039"}, "098ca88f-aade-46a3-ac1e-c3393817f27b": {"doc_hash": "9a8f735c1c848a2742057289bebd264251363a194eb170b04d2470929890667a", "ref_doc_id": "f725e3e0-f87c-483e-b003-1dd81349d039"}, "1c4435d3-3d05-4f8e-91ad-7d3ef857edc5": {"doc_hash": "77dd4c78bcf4db45a115d59ab6087ddf2931204dc0a29e40d420e35bc3cefe0a", "ref_doc_id": "dff9fe2c-8751-475b-9c0d-d75a78f3d941"}, "c2d90c87-bd25-4292-807f-c11c5a900fa4": {"doc_hash": "56fd5a1909797bdbf27ce955e1cc47c7f454d28f0a9e84694c3f990f68e6b996", "ref_doc_id": "dff9fe2c-8751-475b-9c0d-d75a78f3d941"}, "000cadd2-701d-430e-817e-fb533c5d2013": {"doc_hash": "8efe2f035724596fba6a1c2fce654991709ef62de6349f79b36985637e89a6fd", "ref_doc_id": "00b9e78e-cb31-47ec-b5e1-60073983b237"}, "cbea3a24-a0ae-4a76-9605-a52e91a7108f": {"doc_hash": "10905dd4963c61b332375b84c11e0df88eef668b4f7b70f45d6d33ef70acc5e6", "ref_doc_id": "00b9e78e-cb31-47ec-b5e1-60073983b237"}, "a9c00889-77c7-4399-8a1d-e54b58327241": {"doc_hash": "ffc80f48c3cb20f2bf58683027aacaf9c3be22a02d57d261faaf932cca8bca4a", "ref_doc_id": "b3fc432a-d74f-428e-9dce-e4cb4ae4bf08"}, "8616bfec-2715-4f5d-b091-0144b21d50cb": {"doc_hash": "afc9ee9784bb7ae97f4044c387307e743c476591383f97f78bc9000199324b96", "ref_doc_id": "b3fc432a-d74f-428e-9dce-e4cb4ae4bf08"}, "7a7dc427-d4da-4a0a-ad3b-736d2cb2c643": {"doc_hash": "b0b5c8e60917b2c5552da63b63f0f4bb6eb70958a1e828b045f42da448977eda", "ref_doc_id": "dd1a954d-5089-464f-a52d-920c8ba7a668"}, "c43c89b0-9c2c-4cf3-8820-6cddd54b1061": {"doc_hash": "c4a5c59f01e5890c8582f4b3bee1e0508fb21181dfe2733944616bed9fef03dc", "ref_doc_id": "dd1a954d-5089-464f-a52d-920c8ba7a668"}, "4d6eb0de-40b6-4b98-9228-d3a544d99de3": {"doc_hash": "8f3ba127f2ffe307bc69929237117157481ce84b863adfad3d0761defc97bca7", "ref_doc_id": "dd1a954d-5089-464f-a52d-920c8ba7a668"}, "2f68fe2e-5dbe-4506-a6c1-c18a22574f4b": {"doc_hash": "0b7bb5720c6ff44d37e1cf44ece47b107f1f706f8347bb91726f500eadb18311", "ref_doc_id": "34449fc1-fa4f-4a77-ad27-a3b3ffd96108"}, "6fd8f0fa-78c8-4f88-a6d8-c46f1ba2bd64": {"doc_hash": "4b054fe1fb0fada4aea0f1ac307da323c8d7bdfd4e27d6276eddf1da9618d666", "ref_doc_id": "34449fc1-fa4f-4a77-ad27-a3b3ffd96108"}, "c9ac673e-8fa3-42c7-8f73-291dedce7034": {"doc_hash": "81caad49cfcfabf253ce20ccfcb50b09848491fe5136cd5ec6c967d1cdc75b3d", "ref_doc_id": "30b2a322-3cb2-4dea-af94-10276e2e1991"}, "f3acde98-db65-45a7-b85d-eea928c2dcd3": {"doc_hash": "6a42aa078f3cf16c9716057fd5f0a0b7ef2c6f7bd1b78534d4c0c715538b00fa", "ref_doc_id": "30b2a322-3cb2-4dea-af94-10276e2e1991"}, "8ebc3e9b-3df0-475c-8f39-557486261b2d": {"doc_hash": "e279d13636f2b2065a8716bcfc16bc386b248b056cc4fb079eaa74bbfa6c2102", "ref_doc_id": "e15bedf3-1b5c-4cb4-a145-db3f7620034f"}, "865b6145-d42d-4006-8dc5-7683f6e905b2": {"doc_hash": "41401f69607fc55764fc45d74872146916a9cb09f70cd22b2f2528dde5f7c28d", "ref_doc_id": "e15bedf3-1b5c-4cb4-a145-db3f7620034f"}, "538ca174-8aa1-4bd8-97e6-cd4adcfbde2c": {"doc_hash": "6178407939178e713c0e1ce158eed59d4abc15950832e4a865087dbb8f6e8390", "ref_doc_id": "5d152b95-1f45-4b8d-bedb-d001a7b105d9"}, "aa7b47e7-098b-4ada-97bc-4edf5251c059": {"doc_hash": "372020daf72e80e9d4c3e808ce3d90f6e8c04e5814e0c262dcd1fe2d65155400", "ref_doc_id": "5d152b95-1f45-4b8d-bedb-d001a7b105d9"}, "e2e74ca3-63a9-4386-8939-b3d312085092": {"doc_hash": "c9205c4488758c3d837262179a3ef6bff477bc6b277dcc4541a712992efc43b8", "ref_doc_id": "3cb4c5bb-bf97-4956-8549-2a1bef7d6fe2"}, "27ccde05-4595-4107-9273-4fad0ee8cd92": {"doc_hash": "d48773ddd3127790772840c0718117d7e226af0051f99e00310a8c706902cb29", "ref_doc_id": "3cb4c5bb-bf97-4956-8549-2a1bef7d6fe2"}, "6b090398-4e3a-4ff9-b534-169fe23c5e2f": {"doc_hash": "4f0aa16bb7377900ee49da2c2af58ead41adf73712c411ce09bbef157b9cad22", "ref_doc_id": "1f6a82bb-5f49-4ac7-acf1-88fdcda8a3cd"}, "24c18645-dc96-419a-be4b-a3985fb9b47e": {"doc_hash": "ae6513995954b714dda7e46ca204d953b17f1c1df7761205ed60a93660424629", "ref_doc_id": "1f6a82bb-5f49-4ac7-acf1-88fdcda8a3cd"}, "39058389-376e-416e-8f24-f205c62f4051": {"doc_hash": "cdf6f9d05affd08d7e55e899d0390719e2e4e738da165368ff1a563ca4f4b057", "ref_doc_id": "1f6a82bb-5f49-4ac7-acf1-88fdcda8a3cd"}, "bb21f84f-7208-43e3-8283-a671f57102eb": {"doc_hash": "3da0f6307599fae467d890f059836106915b7f0b22aaba38598b65d5253f5087", "ref_doc_id": "1e1f477d-b3e4-4339-aaef-e19072eabc45"}, "b3ce1938-bf63-4ff0-b72d-d1ca3046b59c": {"doc_hash": "f05b449216ea469cb3fdabaeacf70716ead5c0c1a9233e4d4df230bccc2473d0", "ref_doc_id": "1e1f477d-b3e4-4339-aaef-e19072eabc45"}, "1f4ef9e6-281d-4a8b-8099-bf3295bfa2ba": {"doc_hash": "5bc1791af63fe5e1ad34134bd7509926c1d6d1a6ce089dd6c9ef220bea1fbf46", "ref_doc_id": "74241bfb-346c-4263-b1d3-c3a60eb1faff"}, "6baea516-1503-41f1-bd98-7fd0e636c04b": {"doc_hash": "f84c04f01f9c2912a6f15b7539e989f63de92cf454a419293fd93897c694eb50", "ref_doc_id": "74241bfb-346c-4263-b1d3-c3a60eb1faff"}, "b50f958e-797c-4e6a-b905-551cb15ce276": {"doc_hash": "0d07894abf5bd8f324c193efdc4c0eab8b92a50bc7e60ee838c5c8436cae7f93", "ref_doc_id": "2f9a9d6f-fef1-4373-a7cd-3c799f648cb7"}, "44ccfb8f-4598-4ccc-a577-111fd7d4bb04": {"doc_hash": "038d2c449696bb9fef132e698a38dedbca58a0afc2e02dd4dcd905553b11c087", "ref_doc_id": "2f9a9d6f-fef1-4373-a7cd-3c799f648cb7"}, "56635e51-559c-42da-935e-7104ac375746": {"doc_hash": "744b3f91de886a4db18ee5194c883748ac37d98b5f5e456708975f6b3214a2c3", "ref_doc_id": "e18459e0-d931-4f4c-970a-459a840b1730"}, "4e38276f-346e-4461-ba58-a19ec2fb1b7c": {"doc_hash": "954878b52e6a23600add4fb0d92e1e902144fc52223157da4acac59343a81d91", "ref_doc_id": "e18459e0-d931-4f4c-970a-459a840b1730"}, "1864cf02-c775-4040-bd6b-593d60ed50fb": {"doc_hash": "c9c942558cdb2e5cc07ef9686a0cbc6b0a7ef3c6e7f24fd5339cda8ad26c86e7", "ref_doc_id": "202f634d-ec7e-4f70-b38d-eb484183b4a8"}, "50550adb-59d8-4fda-ac3b-196af774fa62": {"doc_hash": "6eb1aec24d25b9e95e91791bd87ecbd0d0f959371df72170503843c26dd37529", "ref_doc_id": "54451b4b-0434-4f6d-8060-c2d71fa15224"}, "f3c866ac-2c2e-4e76-8cf0-0fe1e9da24b6": {"doc_hash": "8a0da0dc83915a51782ed11167ed2ea44fbbb28c07c3161118620a910e3df7bb", "ref_doc_id": "54451b4b-0434-4f6d-8060-c2d71fa15224"}, "bbfc5d51-4b8d-4533-956d-819c6d9490cb": {"doc_hash": "cf99f24fd97078c31357b13be35bd6450e1cf91fea1bbceef6f23d568da34c06", "ref_doc_id": "84b84774-dd69-4949-831b-ceb576285395"}, "40b8f786-635d-411d-a4a5-ff9a9bcb7acb": {"doc_hash": "7bf2c7869189bb9fe638aca7a56b5ce6d6eeaea388df2d420a9ad867ca04fa86", "ref_doc_id": "84b84774-dd69-4949-831b-ceb576285395"}, "281b1df8-8953-4e05-aea2-0624b46acbca": {"doc_hash": "a87e92530919e8aa041b0d8e7c7fed96699823523403d8034ee604847b2a26c8", "ref_doc_id": "c1b3f474-9f24-48a5-8ee0-f0ad0726b314"}, "7e8fd38c-0cb0-46ca-9ba4-d7b81ab66c3b": {"doc_hash": "4e35b35e7584a9cf9a7c1a03c3ba092afa0fff37ca0b9205d8f3e53381d3d1e6", "ref_doc_id": "c1b3f474-9f24-48a5-8ee0-f0ad0726b314"}, "02f2bf07-52c5-494d-ae2c-15c3c16a6640": {"doc_hash": "5508fe223c8755a969f9095df396a5bdec5c4f67a6cc721fa87cdb1b1b00bd62", "ref_doc_id": "51a8a76e-df44-45b9-80e5-dad1255fa4f5"}, "8b398b2c-91e4-4c35-a00d-5589db0564f5": {"doc_hash": "4ed269780642befcfb2498b06b312511c62780b933c942ffcd48deeddb0756aa", "ref_doc_id": "51a8a76e-df44-45b9-80e5-dad1255fa4f5"}, "45687dde-01c8-40a5-a0f6-970816d61147": {"doc_hash": "8a69bcd203fa388e484547a90f117269faad966abef04621abac023f5a140c18", "ref_doc_id": "51a8a76e-df44-45b9-80e5-dad1255fa4f5"}, "13b59beb-f4a9-4707-809c-69f260fb0bb8": {"doc_hash": "2dea5b7220143ffc33f44a0c4bcd0bebb205da3ec88550fe1e05a6394d7195e1", "ref_doc_id": "8a8ec880-be50-4c33-ac3e-f94994930d49"}, "3cc186d2-a8f4-4817-aa1f-b7491ee2d583": {"doc_hash": "b5da670462bd7e67842a27d8f90ab54ed1c0f3f0cbd6d24b3592478f23806c79", "ref_doc_id": "8a8ec880-be50-4c33-ac3e-f94994930d49"}, "4493a09c-59dd-40cb-a3f3-c0cc1376ec6e": {"doc_hash": "8643c77ac3cf051ab5fa210cad5f70293f487e487f366ce2d5ac9e98c3964408", "ref_doc_id": "9c4638a2-db7f-4a28-805e-c633176a6859"}, "f479fec0-999f-40a7-aee7-3bf1810cfc34": {"doc_hash": "078473ca1b7802df13b22054442e2c44c1f25042c33a85a1dca6d0d3313f15ec", "ref_doc_id": "9c4638a2-db7f-4a28-805e-c633176a6859"}, "399b2ce1-297f-4042-9c19-a989cc33d029": {"doc_hash": "a3d5042a62ec110e05a91722092f97153e1390853ef3eee65140dac25b5eb818", "ref_doc_id": "9c4638a2-db7f-4a28-805e-c633176a6859"}, "70e1d3bc-8661-4eed-b19e-0963fa8bda60": {"doc_hash": "0027043a9cd25c8d7800bb7451066b34402af38082f6952f811386fa8bf5e9ae", "ref_doc_id": "e9fe91ec-1a3f-42fc-b243-3b9b66880a54"}, "0c75b4df-f82e-404e-b1b1-e0a57a483bf6": {"doc_hash": "531012ea33579109f53b53d871364b8c786c2f4a7ba756d44044f17ffa0c9a39", "ref_doc_id": "e9fe91ec-1a3f-42fc-b243-3b9b66880a54"}, "8907c030-fd56-437b-b4f5-9046b326f91b": {"doc_hash": "ad75a4bc463bf45f1dd56c812a22659c7505d5b64af5b9b98d2279b818dc8da5", "ref_doc_id": "fbbafa90-14ef-47d0-a3da-80dbe4fe6404"}, "bef1a3e4-dc92-41d3-aa90-35260885285c": {"doc_hash": "c26738a31481ec4b2fd0f023cd6024a5df5b98bc9e631e1f3848c202514d30a6", "ref_doc_id": "fbbafa90-14ef-47d0-a3da-80dbe4fe6404"}, "3b7083b4-0398-4516-8955-56aa3f11c5f3": {"doc_hash": "9927aaa63ca7327c8753bff2f3a9cf6fa386d10a7e13a5967a37efac466b2b86", "ref_doc_id": "fbbafa90-14ef-47d0-a3da-80dbe4fe6404"}, "144548b5-8573-4810-9ae8-35ae6826e923": {"doc_hash": "cc9be581d3eebf5f2a50a12ef2c1c61d7003ad8256c2b30e915eb64a41a50caf", "ref_doc_id": "54427b83-c87e-441c-879b-063731937468"}, "21c8694d-d5d4-4fc2-a155-301f54e018b5": {"doc_hash": "94ed6bccf10b31e965c0009a8f81e604f4233580dadf3ee6e67790790b3a3d85", "ref_doc_id": "54427b83-c87e-441c-879b-063731937468"}, "2ac00aa5-cf80-458c-9adc-8af22595ffa8": {"doc_hash": "a5e2098e959ee00663e1f87bcb47c7b363bbfe12fb524b4c15a302d9625ad48a", "ref_doc_id": "f36cf705-0214-4c5d-aa90-3f7e277e3148"}, "174d1584-ebfd-4a81-92b9-d44872301c8f": {"doc_hash": "64673a667f1ef98e393ca0ce7626e03e98854dadde89a1ef5ce0fb7536902a97", "ref_doc_id": "f36cf705-0214-4c5d-aa90-3f7e277e3148"}, "591b2554-9a04-4264-9a54-e2696fff63ec": {"doc_hash": "b620c57e4550855d8f21cb16808002a64f740a8f5d317e8206bf7971887e63c2", "ref_doc_id": "9f7980e6-ef40-45b8-96aa-eef217c39644"}, "8aa2132b-d0c9-4c83-b653-71b316d799ad": {"doc_hash": "9872d8626e3d0e8b0aefd28d304547e6421194f42f3898ff7152fd396530dbc0", "ref_doc_id": "9f7980e6-ef40-45b8-96aa-eef217c39644"}, "ff885003-9c67-451c-bbe8-223a505f745f": {"doc_hash": "ed2e873329ad85d6ae066a5057e0346e7a3172a8326104c5c659bbf322394ba0", "ref_doc_id": "730e17c9-c104-432f-aeb9-78e71b942c2d"}, "7a0876d5-265a-4fb5-8964-478ce5bdbb80": {"doc_hash": "8b8aae94340eb37bd5394ffd61f10b35ab2bc9fcd9ba7b52dc3aaa96de638f13", "ref_doc_id": "730e17c9-c104-432f-aeb9-78e71b942c2d"}, "4af2333e-e4a0-4049-9fd4-002726170a55": {"doc_hash": "a743f06834ff65f8dae38d3210f402f12e5a7e7a5f6d4d161ff3f0657692e669", "ref_doc_id": "f1b5f4d8-42d0-49f8-ba79-b40d14458f26"}, "28538dba-58a0-4933-9c1e-cc3195e882f7": {"doc_hash": "2dd6475b9061fc43feb662d717e6bbe91e372d930b86be8e0f450daba75ef24d", "ref_doc_id": "f1b5f4d8-42d0-49f8-ba79-b40d14458f26"}, "d8ef4850-8336-42be-832b-52f9abd737e2": {"doc_hash": "50fcf4bf701966a9b1f0e4077b924d5d9831ca6045d1033cc974b4f2fb6ad9ee", "ref_doc_id": "f1b5f4d8-42d0-49f8-ba79-b40d14458f26"}, "7bc18bbf-a096-43ff-a9e1-59688f94bf77": {"doc_hash": "abecd6cb962e1f6fb1c137c9104c9fce3349a5053504b9bcff5907b665015ed8", "ref_doc_id": "4bf6d629-b2b7-428c-b085-2caf7b0f84e4"}, "f3b90126-0ad6-491b-b47e-b98be8f364e7": {"doc_hash": "290950e0b1a7bce1df121a4b2feb5e31e937b5612ef478d80dfa63c379948426", "ref_doc_id": "4bf6d629-b2b7-428c-b085-2caf7b0f84e4"}, "a40278a1-ad22-4b65-a198-52cbe11ef39b": {"doc_hash": "b6746f8dafaedab58d1f89c5a8546c125b1307215deb9a6a4397b28c6b917d9d", "ref_doc_id": "4bf6d629-b2b7-428c-b085-2caf7b0f84e4"}, "b7f66bcf-28df-49b9-85f9-2032fe28ff05": {"doc_hash": "887e6e9181ba3b903d33b3dc596c593c0655b2de8875044a19b99535a2af9066", "ref_doc_id": "33fc2948-9abf-49d5-a6cf-423e0c7730fa"}, "9c9b14bc-bb91-4322-9434-5ec947beda43": {"doc_hash": "78a015d499bccc4383c202116ce6c0fc3682fd143b851a115eec4e284e04e7c2", "ref_doc_id": "33fc2948-9abf-49d5-a6cf-423e0c7730fa"}, "674a7eb3-bdaa-4bac-9e7a-b2197c7c737f": {"doc_hash": "bb7a31802937767298e6ab3d692a7e64d6f9b2ed9d404dc8cfd9e16851f84555", "ref_doc_id": "a989c28f-2bd2-453a-a988-e3622816055b"}, "18e04564-3ed8-43b7-8417-269976978b70": {"doc_hash": "958f9efeada066f6caded53c53d7cf0ba31a51a7e0c65035c88ba482b5dab37a", "ref_doc_id": "a989c28f-2bd2-453a-a988-e3622816055b"}, "026a0272-2484-4c95-83a5-29f11368c5c4": {"doc_hash": "ec05c7c71c0ab7cca4de0794542a994c896d6f0ee3bc2f234149ebbc4bbc35ef", "ref_doc_id": "112ad5b0-9110-4c2d-ad3a-b8a2c3f11bd2"}, "259788a4-94a0-4a9d-b0f1-fb5fdfc8f4a2": {"doc_hash": "e2a95748b02e8ba4ffbe25490a545d0c9d451d479b71fdebea364460829ceb1c", "ref_doc_id": "112ad5b0-9110-4c2d-ad3a-b8a2c3f11bd2"}, "44515883-28eb-45c9-8fe7-461e7629a000": {"doc_hash": "187d8f4d4a08dfd41d0ce7b8805264044eea00a32db6886f8b5bcea98c41c1c7", "ref_doc_id": "4923a796-e907-4efd-b369-3ea1914d91d5"}, "608fa92b-01c4-4746-b294-7bdfaeedb194": {"doc_hash": "5e9b53c3fd7a5dcf7bbdd2a7f4e4841ed5901dc6c4ff6229f97d62edfcc0b3f5", "ref_doc_id": "4923a796-e907-4efd-b369-3ea1914d91d5"}, "91294d4d-cc2f-4647-ad41-3f7c27c37991": {"doc_hash": "aad3bebfc303e01741d4d792d8f5f1b81bc59b9cd3cca388322ed94292f0a6ba", "ref_doc_id": "9b6263af-f780-4b06-b934-5ff2639a49ac"}, "de6b3e33-b959-4940-abc5-75af38d30094": {"doc_hash": "c34371556cc8255c6e9d3a5574f68d8837cdcf3e869092f5347cdcd710d24bdd", "ref_doc_id": "9b6263af-f780-4b06-b934-5ff2639a49ac"}, "8205c28a-ee63-45fa-9fc0-259c1b2050db": {"doc_hash": "8107c0656d1c1d2bed8ececac1098ea35ebc15859a2b5c0dabb7d5e27e594cb2", "ref_doc_id": "afe44a82-7fec-4d91-9fdd-b7ec66942809"}, "9f9e36c6-f5ae-40f0-b630-4a6449f088bf": {"doc_hash": "ef8b741775d1dcf5e54d060b53587fd9f70241b52320d87be865b2522f096451", "ref_doc_id": "afe44a82-7fec-4d91-9fdd-b7ec66942809"}, "6dc726a9-71f0-43ed-b3c4-39a9acff994f": {"doc_hash": "ccba42bf6f0e96585a5121d60e76f7ed41c77ae19acaa311f8aaacb9144c10bf", "ref_doc_id": "6168b5b7-75ce-427c-896f-b6d66a14ad5f"}, "e49e3e83-9577-46ff-afb5-9d911bdf8e4d": {"doc_hash": "513e1dc6d66aef6b2e5a0c3ada19c27a8d8496de1a61fc9c32a74ec0634f25a8", "ref_doc_id": "6168b5b7-75ce-427c-896f-b6d66a14ad5f"}, "b935def0-d13a-45b2-a2ae-b08cc95a68bd": {"doc_hash": "f780f11b08d84beeb56c458c0e24a31c15bf7cf6007804dccee226bdd9c8102e", "ref_doc_id": "badb86be-a138-4e0a-a46b-cc373f58c607"}, "d8b5eb36-d3d8-402d-8431-68671ee5630f": {"doc_hash": "f7ee155247dac4ea90f6ba25e46b8a2dba6cf64f5f1577db1b538e2102e5fd42", "ref_doc_id": "badb86be-a138-4e0a-a46b-cc373f58c607"}, "7938e7af-ee10-4feb-875f-c04d050d80a6": {"doc_hash": "0b24f77ddafe27114c7b41357d5537fdeddd656697811dd7e26fe09f2123827a", "ref_doc_id": "badb86be-a138-4e0a-a46b-cc373f58c607"}, "ec3043c8-577a-4886-b6e3-8615ba38e21e": {"doc_hash": "4252ff234d34a4f492304beece559122c9e8871e8a08eae5acf963318404e25d", "ref_doc_id": "b875acc3-b4f7-4a32-afc0-8c5c585bb5a7"}, "8d7af168-1420-4c69-827d-cb5e856f7cbc": {"doc_hash": "ca77c59d02b2a2804df81b5c8d86dc82d17865b84ecf61b2e2deb04b61d2225c", "ref_doc_id": "b875acc3-b4f7-4a32-afc0-8c5c585bb5a7"}, "7080e728-63fb-4fd0-91f5-2af862b8d25d": {"doc_hash": "5e99c8086a2caf6b3ad6a5b95d720fba0b8d9deb1dff03996bf12ba923d22d3b", "ref_doc_id": "b875acc3-b4f7-4a32-afc0-8c5c585bb5a7"}, "3a3167c6-df2d-4a70-b2a3-ed24afa9a93b": {"doc_hash": "d26d2d7d0e92ad95f1b4aef29a5ade498793760d51bc564e52d2935fa7aa9a4a", "ref_doc_id": "2a88ef1a-e938-4b33-94cb-11e29e3d261d"}, "ed637c01-03d5-400d-8c33-7b120027f81b": {"doc_hash": "346d75077a2ff25bbfe0067714359cb1a34a77872489f328511c48bc2a2c1935", "ref_doc_id": "2a88ef1a-e938-4b33-94cb-11e29e3d261d"}, "8b04f204-f8a8-4d98-99f4-3b8a2868ad81": {"doc_hash": "bb7b89c81b65d705b5b35814ceb511934a7b8e83c5f2739caff109c7a5aebe97", "ref_doc_id": "cc87c4e8-3c67-4b89-887b-15bf2f1a3dda"}, "16c1f46c-0b0c-4dd8-bfee-ae81b75c1a99": {"doc_hash": "cd1dd237e2fc697600d06d96d03ef48e4e31477fb8120f42ef81b6b988df3106", "ref_doc_id": "c60040ee-d3d0-4086-ba51-a42c690c633f"}, "d736aef1-6e1a-49d1-9226-6ed0d6054ebf": {"doc_hash": "fb5469efcb6d05fb4d2f63efdc2e057c013add42a0fc1c9db70c6e74038345e7", "ref_doc_id": "c60040ee-d3d0-4086-ba51-a42c690c633f"}, "0d8f9c38-2d6d-4823-854f-a6e636005760": {"doc_hash": "770ed992a2b2e96dda619e6f0538a91ce2fcea0f8d12ae387f009c855c227aad", "ref_doc_id": "c9d6976a-e7f0-4756-98cb-1f142911c3c4"}, "24d8d8a1-e2e3-493b-8a13-8a47317094cc": {"doc_hash": "d190b6f2ddf596234b84ea1130915640c5f07d1c7d15d2012449f666d79c00a8", "ref_doc_id": "c9d6976a-e7f0-4756-98cb-1f142911c3c4"}, "159a9cc4-1f5b-4aa2-84fd-45cf15a17b65": {"doc_hash": "8eb06b11d968fa50735cd24176253e2bcfe0a121ae13907f2cb747347c5ed528", "ref_doc_id": "c9d6976a-e7f0-4756-98cb-1f142911c3c4"}, "751a7fa1-a961-460b-be2f-7561e8df2bb5": {"doc_hash": "955d2dc6c0cfabb37491b9ae412c6b6113e2385dcd13310fe18dd9b54d8c68e0", "ref_doc_id": "b0c9578d-6360-499c-8230-c338994ac720"}, "2e493c11-7250-4eda-848d-ffd075936dd8": {"doc_hash": "639438c8a5e48b98236b95a919b629a99a9257790a0b24c032fe8689ac4ffbd0", "ref_doc_id": "b0c9578d-6360-499c-8230-c338994ac720"}, "5ee96924-f2ba-451b-967e-cc8f45138261": {"doc_hash": "1e2f8d5d0da94878326fade9ba197342ed53bd8a410fc5400ca51ffb651688c4", "ref_doc_id": "b0c9578d-6360-499c-8230-c338994ac720"}, "56aaca10-6f36-4b3b-aa70-9edfbb3c096b": {"doc_hash": "5a002cf1075bce552f7622d837246c96ea9a54a42ec0cdf2467b788bfa67a1b9", "ref_doc_id": "e45c048a-a925-4a27-9be6-b9a6988b11bb"}, "54be89f1-61a1-4538-803a-6a868930cf8e": {"doc_hash": "23026ecb09c37a5c3824d78440e6ab4595a3f061c558a051d9d4f585119f5073", "ref_doc_id": "13e5cf21-fe7e-4560-afa2-d7a7b4ff3b6f"}, "7509cb1c-a8e8-44c2-bfa2-cf5d9c0a716a": {"doc_hash": "63c46084efd54623f64bc36a551cf52fca6c30be0477dc4ee71906a6307fb7f0", "ref_doc_id": "13e5cf21-fe7e-4560-afa2-d7a7b4ff3b6f"}, "75abdf88-1c67-41ea-b955-83365e9b7e6e": {"doc_hash": "0f6c822f0850a8637ccd5ee14b6fa470dcff1d6b3772c48f988fd17ccd010d5b", "ref_doc_id": "3a3de74a-d75f-417e-b629-bea2fdc88b71"}, "6b53a586-acf1-49b8-9409-67052470c56e": {"doc_hash": "ba17721c1643fd6c7f7023c0450b2bf0ce0b9cd95515fe717709c8b9f63e58fe", "ref_doc_id": "3a3de74a-d75f-417e-b629-bea2fdc88b71"}, "212e0c56-885c-4896-8791-5960a4293423": {"doc_hash": "2bc09125b2e97c60abcdbe2d3cfa080abac918353ab5502aa113618009a59be4", "ref_doc_id": "ac9da951-1b83-4f48-8717-914d28570729"}, "cd45a11a-1dfe-49f1-95f4-7dd134214af0": {"doc_hash": "0aab8b8e523534da618dda0a6dd07ad202a0cb0410689d26f1f40923511c673c", "ref_doc_id": "ac9da951-1b83-4f48-8717-914d28570729"}, "3169158d-30b1-4d20-9954-d7d9354729ba": {"doc_hash": "7b49d990c1edef2ea46c765256b9bc8651f019549caf6381b4b2528e6afb194c", "ref_doc_id": "c87ea696-6f92-4b46-bffc-c27dbde3386b"}, "710af244-aa6d-44a3-8d61-7db46d71e707": {"doc_hash": "f5c6312e28011c2549a46050c5f477282991eff5fd727e0222658d1c61977be0", "ref_doc_id": "c87ea696-6f92-4b46-bffc-c27dbde3386b"}, "1c93590a-c955-4ed4-8ff5-19ce1e0045b2": {"doc_hash": "8a16b8aa331da5edc7476141a138447dfe7fc16d846a6052f85e0060e1c423e0", "ref_doc_id": "c87ea696-6f92-4b46-bffc-c27dbde3386b"}, "0f6daacc-32e3-4284-861c-ac01f7ade420": {"doc_hash": "6f68660db9006f75493feee4d48ad1503b6f8f075b71c9ab488296e729fd888f", "ref_doc_id": "1f64220e-c9fc-41bb-9fa5-522ebb51cd2f"}, "b8b2ba2a-6444-4198-bd06-c2394f21acec": {"doc_hash": "450db42f6cb0b6dfc022ebebb2020cf9b8b704e250e395944d15fca89d06d577", "ref_doc_id": "1f64220e-c9fc-41bb-9fa5-522ebb51cd2f"}, "99551ff8-8f2a-4add-9973-322da8fc951c": {"doc_hash": "2ff51194779fc3655c0d69b547c61179c8bf0bc02dfefa19ac9f4a62fec1ecbe", "ref_doc_id": "1f64220e-c9fc-41bb-9fa5-522ebb51cd2f"}, "c1118dac-2851-48e3-9ecc-9f670a887767": {"doc_hash": "b666cf9aedbac07913d214b6295eb090bd2e52ebe4dca1bd3b159c120b9b723b", "ref_doc_id": "779f268f-64e5-45b1-89f2-cd1666f58c74"}, "ee76ea05-7417-43ed-983d-dc7e9747a0df": {"doc_hash": "18da60d449cbe2f75e2c667b05872a4153417721aa956704c137f9036d053c7c", "ref_doc_id": "779f268f-64e5-45b1-89f2-cd1666f58c74"}, "4e49e243-6364-4b25-ba41-5152a9d472c9": {"doc_hash": "9409a29a0b4020c88b7480597a579847629e35ce3b9c0480d3555b1b3aaee8a5", "ref_doc_id": "779f268f-64e5-45b1-89f2-cd1666f58c74"}, "3e81f972-bc84-4d2b-9d89-521dc7ecc8bc": {"doc_hash": "b249654d9dd04ae302e922c8e8bec2218e2da0c1e9e9da8c0e9bd2cd11458a82", "ref_doc_id": "12f7a6d7-a626-40aa-9512-f492e01ba3d7"}, "0c547f5b-5455-4963-bd90-ab99ff2bfd13": {"doc_hash": "435f8d94f4bcd077f837f517d70da996acad1ce2089f744680b6b1b5902698c3", "ref_doc_id": "12f7a6d7-a626-40aa-9512-f492e01ba3d7"}, "41504459-b387-41a2-a653-2b2dff425e27": {"doc_hash": "23de97565fdaa829ad87e9ddfcde39d80afacee9eb37f745a3ad5f2189b370d7", "ref_doc_id": "bfda59d9-e421-4c2a-9f0a-5e3cfc44966c"}, "438c12b6-5c06-454f-b097-c5388ad1972f": {"doc_hash": "356489fcdc637cb0153886b20258ccea98d9b84a7a41f9e24902e79fefa1553b", "ref_doc_id": "bfda59d9-e421-4c2a-9f0a-5e3cfc44966c"}, "46fb70cc-86b1-4c32-b60a-dcc4be1428c6": {"doc_hash": "dd5ea0926a30531336475e463066ccb0b8dd99a09e55902d1009eec8b12874a3", "ref_doc_id": "a638271e-9335-46fe-9264-52c084985275"}, "ddd67588-9830-4bef-bed2-67deabf41a88": {"doc_hash": "d9e06d4175030aa2af6935f8db025be569fa510d94132ae726706950788b9c9c", "ref_doc_id": "a638271e-9335-46fe-9264-52c084985275"}, "582c0e08-240d-4c8a-9462-9e46b8ce0b1e": {"doc_hash": "524c59eb248e5d938e1fadb2cc9994faf20159a9f939ac10151122fbc4c03eec", "ref_doc_id": "36593695-75c2-442f-aa4d-ebe5f226aa13"}, "83260bee-ee46-436f-8d34-72f3bc4c1b92": {"doc_hash": "ff9b7ad638246dd93b5b8f994e93da29f5d80c6dac662a74a6feb2c2dc5ae2bf", "ref_doc_id": "36593695-75c2-442f-aa4d-ebe5f226aa13"}, "02c3c8da-a50a-4afb-ace7-b98972c529a7": {"doc_hash": "01b7d882b469120bf34cc7f1bb59f3de11dc1a9414962bfd5ebf9a9e39a32340", "ref_doc_id": "36593695-75c2-442f-aa4d-ebe5f226aa13"}, "7ef6ebf5-f1af-4113-a31e-dfedd0d8b19a": {"doc_hash": "c49c19c7f7978d4a7542b14a7c512de7a690db9ccbae38a0619083f331101b63", "ref_doc_id": "af09c325-fd99-43cf-b4b3-c1236613f6ec"}, "eaad55bf-58ff-4f11-89cd-b9ddbe029a53": {"doc_hash": "7ad558b945c38e21bb465a36522face4c646731df29f74739fdc97628bd8dcf9", "ref_doc_id": "af09c325-fd99-43cf-b4b3-c1236613f6ec"}, "a51f6ce4-b330-4ec2-a979-4f01ee1a47ec": {"doc_hash": "27e354dcb547542cac066205a8c175d5e2cea606aef6e409c5bc5aa768918a38", "ref_doc_id": "4b0670b7-78ba-4dba-bd0f-fbf99a481289"}, "d3ed1dde-735c-4c47-8fe3-acabe55cf628": {"doc_hash": "2e99e23369f22c0463ada5bbfd65299a0be3d16c363875f3b91d0bdea7228fa1", "ref_doc_id": "4b0670b7-78ba-4dba-bd0f-fbf99a481289"}, "5be5a4f0-683f-4eeb-80a3-036757513a91": {"doc_hash": "45ff0be3b5a51310ef6fd3d169b96065c8d92e2fbf319f6ffef520244b372696", "ref_doc_id": "550570c8-8ba5-43c8-a412-6e8b5ff0d587"}, "6f4dda48-1c04-4e6a-849f-40333a0aba48": {"doc_hash": "831e4e69b028f3cdf4da3547d7fb24cf94e83c3d782a4724df520d4eade152e2", "ref_doc_id": "550570c8-8ba5-43c8-a412-6e8b5ff0d587"}, "b230a9bd-60c0-4e70-a1ab-18126b94b590": {"doc_hash": "2087c873c31a46093e5fd03f5b9218152d0d0fd44fce60de2172315b37a6cfdd", "ref_doc_id": "3e0838ad-1018-4dba-afcf-6e1224f3e6ff"}, "d24937a7-9f69-4da5-82de-df17dacceb2d": {"doc_hash": "0b70abc55cb3c81dae816e914680937f0c6027a9b870a6af83e03486a3485ab3", "ref_doc_id": "3e0838ad-1018-4dba-afcf-6e1224f3e6ff"}, "3e193db3-95e9-46c3-ad84-c2c035e8a038": {"doc_hash": "4494cb54fc42924cae5d22ee85001e852719745e2a25c69b7acd7ce59bb2506d", "ref_doc_id": "3e0838ad-1018-4dba-afcf-6e1224f3e6ff"}, "0cc1f2bf-3013-476a-afd2-664e778c2146": {"doc_hash": "98f727b24c2c27b0d548df931f3230f5e054ed9c27942d5c0d33e5186b522625", "ref_doc_id": "46f68bf9-5d5e-43d1-bd5c-cb08da90e53c"}, "2eba9a49-5e45-451b-90c5-d50142df6e14": {"doc_hash": "f10f94a8bd7f5481da9069d344e2b8bedde1b42909181e820538532f7ba28e3d", "ref_doc_id": "46f68bf9-5d5e-43d1-bd5c-cb08da90e53c"}, "b801f5c4-b2e9-4ef1-99a9-a272d5a3b998": {"doc_hash": "14f7d268612616d587ea69137c56e985507bde906ca809b6cc5267c086986ed6", "ref_doc_id": "46f68bf9-5d5e-43d1-bd5c-cb08da90e53c"}, "8ba28f66-92f1-4bc4-8ff0-9c60a2f323c6": {"doc_hash": "215715bcd83560b311e31036c4e71715cb8920df558cf584e89c2e847ee821c0", "ref_doc_id": "294fe2ac-fe3e-4776-84ac-745e97c9d67d"}, "f26bb0cb-b7fb-4de7-bdb4-5e268a6510e4": {"doc_hash": "4a52a11d2269299ea0b4aeff4c048906040a3c7e17616a3911a4d6ca8ac97250", "ref_doc_id": "294fe2ac-fe3e-4776-84ac-745e97c9d67d"}, "48f577e0-3bce-4437-80be-d6c6827109b3": {"doc_hash": "05fb14d51fe690a45f038b307863aa598f0d0d024bf9835cc829df02e2bddd63", "ref_doc_id": "294fe2ac-fe3e-4776-84ac-745e97c9d67d"}, "ff58447f-cb12-48e1-8609-bff1af49f42f": {"doc_hash": "74e3f9b44f9b162439664369480f530b2052a47a38b1fcda481dd8679f557e8e", "ref_doc_id": "0d34b8dc-6df2-4291-bf3a-8e03d0058916"}, "52ed733f-fe99-44da-b387-29043d10393b": {"doc_hash": "bcb473a5db16954981aca1a50ef08525579f25f4fd07848223c61413ff6cff3b", "ref_doc_id": "0d34b8dc-6df2-4291-bf3a-8e03d0058916"}, "07f36618-3186-4568-b410-8ce3492edccf": {"doc_hash": "b948c3b6e3ade9df7bce8ba22bfb57c934dfd0ced258ffda224e8672b33b673f", "ref_doc_id": "0d34b8dc-6df2-4291-bf3a-8e03d0058916"}, "ced6b948-e5f3-43b5-bdd0-f78d3b22d2c9": {"doc_hash": "a9dd84859b157f9d21660500d46c2110d08ac1f0c338640baaa7e83b25281bc7", "ref_doc_id": "779fb296-4e38-4bba-b816-02f122e4f014"}, "0ba36249-f72e-4be7-a783-c8c4689ccd4d": {"doc_hash": "56e047a7f609be6794e113f11d90b9441209996d2c7c93e2389ef187f1bb4eb8", "ref_doc_id": "779fb296-4e38-4bba-b816-02f122e4f014"}, "49952cc8-c5b8-48c3-8f57-663191f17927": {"doc_hash": "acddcbda60a7f556222bfcb43625689eaa3e87a414e0ea49d4d9b0f4e88a1079", "ref_doc_id": "779fb296-4e38-4bba-b816-02f122e4f014"}, "c6245616-aebd-4e15-a8bf-dcde7a3875a6": {"doc_hash": "d54c55dd96feb84b06a827f48bc34efdf6172ec9b68d58f5b167844a8c80d079", "ref_doc_id": "cef04480-afe2-46d6-b011-af9cdcaecc56"}, "63cf5f09-8791-45e0-bc56-fca1bf9ff4d4": {"doc_hash": "c00c6ee7efe331a80dbe332b94f8963d9d3714442b4ca63076f46bf459dabf2c", "ref_doc_id": "cef04480-afe2-46d6-b011-af9cdcaecc56"}, "65e5c000-c392-4fb2-9aad-c75ca18bc91e": {"doc_hash": "b39885c10287fc916e51106394393d2a26be514dee0123fd97932fd705f08931", "ref_doc_id": "467b566a-432d-47c4-a07d-5814b112e5c4"}, "a90352d6-79b0-49d4-8f3c-2cf4f3ec14cd": {"doc_hash": "37612f0c348dba09df344a3d6d7029e41b1454c55535dad71fafc185b59939aa", "ref_doc_id": "467b566a-432d-47c4-a07d-5814b112e5c4"}, "9f9452a6-e5b9-44ce-9fff-2853bbda5777": {"doc_hash": "12a6d02304a1ef4375504a2ce22f7211be97041b44377046f65a479f70a54335", "ref_doc_id": "c51169bc-9770-4410-bc49-9fb873f09a55"}, "60a18ece-32fc-4d25-92a3-a8168011c2ac": {"doc_hash": "c45cd09d6d69ce4d7855e531e89d813ee3364767058ac3ce8a0ac23de8468c07", "ref_doc_id": "c51169bc-9770-4410-bc49-9fb873f09a55"}, "ca9a7379-7b95-4259-9a17-60476c71add2": {"doc_hash": "64bc67bf1fa0a9a48c69e4d7c3128acc566fa57803bb944da63ab63115c19520", "ref_doc_id": "c51169bc-9770-4410-bc49-9fb873f09a55"}, "6cd19dac-f51b-447a-a34d-178d06be3dae": {"doc_hash": "da6189cdd402a3ffc3b6318832219db21493c8eb4855862dfc171d263ca5823e", "ref_doc_id": "527b336c-6a65-4a5f-bd0a-2b0d4a9a0ba3"}, "61f5ede5-58e9-4dd0-a6ef-337d9b0424e2": {"doc_hash": "1e1f952591d9510c035320bbc64297c82c35684d5e74b52f8938004544695eb9", "ref_doc_id": "527b336c-6a65-4a5f-bd0a-2b0d4a9a0ba3"}, "a898b73c-7b82-4130-a8d9-a347fd806d05": {"doc_hash": "fef9db2fb325700df3ffb4a2a350114d488c5c352c185ebf6c9177a081f3474b", "ref_doc_id": "527b336c-6a65-4a5f-bd0a-2b0d4a9a0ba3"}, "46d811c6-0d0a-4080-ab44-86e139514f9c": {"doc_hash": "a8793278290d6cc22f98dff5cebfec86919ca493ec2063390a7fe21c44b46a07", "ref_doc_id": "5bf4da5e-206d-4810-8916-aab52869ca39"}, "17be443e-6eb2-45f5-ac28-f13bed425d5b": {"doc_hash": "4bb3bf9d0bd0874f546b1a1d76baffdf94ab496dc92f67ece7e9f5779e1348bd", "ref_doc_id": "5bf4da5e-206d-4810-8916-aab52869ca39"}, "64911427-155b-4ea2-95b2-2269dc4aa688": {"doc_hash": "a5d8570a6d0d8ac3f657b8574421e453b4c9c3852516889a338fd8f02bb0b888", "ref_doc_id": "5bf4da5e-206d-4810-8916-aab52869ca39"}, "86a1d27d-a8c8-4669-b668-d5a9ebdecf64": {"doc_hash": "e144e7e2c95aa08133fec624711c154bd249bddf1054a32376c6b2d40708339f", "ref_doc_id": "3c8e0888-c7bb-4d17-ab88-ebfe1bbe79df"}, "2b338d6c-30f2-4945-af55-bd1fd52b4280": {"doc_hash": "deb0293a7d5aaea0fd6a5311ca7ac076c38cbb69034d8cf53c9a2101d688a40c", "ref_doc_id": "3c8e0888-c7bb-4d17-ab88-ebfe1bbe79df"}, "ea7f861c-6501-4da1-bc59-edabb5bca01b": {"doc_hash": "3790400e8187159982f945ada9e0ddf3802518893b0e372ac87cca65d2abf72a", "ref_doc_id": "434450fc-2559-4ee1-9da4-d2b906367fb7"}, "25f68f40-021e-40aa-ad15-fd9a1dbf2bc4": {"doc_hash": "44ab430fa470c0b539455c6a5eab6b1235086b91bb5be748acc336d4c4bb6b60", "ref_doc_id": "434450fc-2559-4ee1-9da4-d2b906367fb7"}, "36ff29f4-f512-4d62-8b50-2783e0bfff68": {"doc_hash": "2de76c19405003a0700548f8518d24cb62da389294d3c30746afffb5d0b0e7d3", "ref_doc_id": "64c82ed1-286c-4a50-90ce-cee08768d09a"}, "730fe75b-fb53-46c2-8b2c-b896cb2d1813": {"doc_hash": "4a20c4c91bef05be4bc3b959c832272ab69b92bf5593c42a20da8b3367b0e460", "ref_doc_id": "64c82ed1-286c-4a50-90ce-cee08768d09a"}, "c1a333fb-cae7-4f3a-8c07-7b8600131d54": {"doc_hash": "0b21e7dc35ff98031d5dddb0510f046d6210d3698aa96d55703faf9fb10138f8", "ref_doc_id": "7ea13995-6ba4-4224-a821-32907cf0572f"}, "a83cd0af-786c-4c12-899a-028c863b4f13": {"doc_hash": "10d2622c60fdd6c9d4c8374b35dad7b45acd285def10e8c070a97f705afa09f2", "ref_doc_id": "7ea13995-6ba4-4224-a821-32907cf0572f"}, "0f0cb576-2260-49b0-b634-9efadf1060aa": {"doc_hash": "2431ab6d4a427f449a80d8c5ed4efc23813d09166648e79ea6bc0b250486283f", "ref_doc_id": "7ea13995-6ba4-4224-a821-32907cf0572f"}, "5d2014d4-5424-46e8-b831-ef32ccd10184": {"doc_hash": "7d6b8c8572856c502b3cc720ced552c3701ce7697ada72788bc9e67a5015663c", "ref_doc_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0"}, "a4a3ecda-e226-4b7d-b9b6-77d8bfa4ec8e": {"doc_hash": "9f4447b709dfb9ebcf53f98aa2e51605e35873d40831f10aa97ffb4770fa742e", "ref_doc_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0"}, "7a737159-7025-4edb-990c-4b1e5b7d11bf": {"doc_hash": "32f77d2729256589c3dc98cc5041833a7ed8ae0936bda3d5b89350e1fdff0f8b", "ref_doc_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0"}, "d75fd605-3612-4ef1-89b3-bcab8dc5997f": {"doc_hash": "89d26f57bc4f3cf5952abc028cb555210431064ea6bf9bc65fc8bd947375d867", "ref_doc_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0"}, "7b9e86d8-1b44-4828-8d14-95c254eb9185": {"doc_hash": "0ca3f016b4f359b05ed7bbba73ee60e52e61ab1e7d77091a78177a9b781da239", "ref_doc_id": "0bc287cf-3191-41c9-9643-d9b546c7e1b0"}, "d8c734af-dfab-4723-90a6-764676265fff": {"doc_hash": "ec52333066bfc5149716db80f6bb2f5996f8729f63c044faaadf3cb5447891ea", "ref_doc_id": "3747bc6e-364c-4147-8ee9-1406a61446b4"}, "238883a0-cd82-4a42-8431-62fe33a1e96e": {"doc_hash": "f43eaf7dc48541451506907cba0a107c3fff999ad8f9673f28af8ba6fee3e5d1", "ref_doc_id": "3747bc6e-364c-4147-8ee9-1406a61446b4"}, "f8d419a0-e8fc-406a-99df-115fb88ac952": {"doc_hash": "7cece93325d0f60f6eef00053f6a4b5821c643dca8d2de7d98c292df512b53e9", "ref_doc_id": "3747bc6e-364c-4147-8ee9-1406a61446b4"}, "9ee713e5-95d9-4074-9e4f-a13d9ba71606": {"doc_hash": "27e52807f8c55552c14f202bab1e814f5457ab56ab9931cf8e79ad42564dd457", "ref_doc_id": "55887517-e16d-4617-842b-bb33ab005f9b"}, "b667c4af-e649-4180-a8a5-059f32275c76": {"doc_hash": "f70a642be562d4e1668bfbc645157dbe8a2b1d350a6efcb06a099c3d1b860a90", "ref_doc_id": "55887517-e16d-4617-842b-bb33ab005f9b"}, "1478afd9-923b-4937-bf75-6eb5f4138b38": {"doc_hash": "85f30cb70b079313cf0336b243dc22d7bc3bb9113f56201d8422d01cceef002c", "ref_doc_id": "debf93da-4e6b-4042-b6f5-f2b5a517c2aa"}, "d7f89e3b-94da-4769-b754-0f45c603a564": {"doc_hash": "27cdfe9d00a835f04dcfbf2238b5c3ea9c730281dac6054ac71a10ac5b2d2931", "ref_doc_id": "debf93da-4e6b-4042-b6f5-f2b5a517c2aa"}, "d5892d85-d382-4a66-9adb-5ef0d2d00112": {"doc_hash": "c100347d2780b7c89a9b3062bde03e2d0e55079e0211bcc2f94938e8523fe583", "ref_doc_id": "bb3d47ca-8533-4fd7-91f3-c9a8f80df3dc"}, "beb2be14-c6a7-4e13-b71c-eb2b369866e0": {"doc_hash": "9abba3ab79017d189bc4c05f3ba45c7ed833e69730cf791b48a4efce870924a7", "ref_doc_id": "bb3d47ca-8533-4fd7-91f3-c9a8f80df3dc"}, "6eeb3a49-5d38-45ba-9383-787f556e3235": {"doc_hash": "ceec345e2a33520ff1082439ec802406deff3794aec71ecb51989e1050e09ced", "ref_doc_id": "2a2a91fd-6f7f-4200-978b-f5cf9cf5fe17"}, "bb583aca-80cd-4f04-a610-e8267b714021": {"doc_hash": "a99344c1a33e024e2f3d969c2a0725585f07f4e232ae9dd2f172b039712e5a65", "ref_doc_id": "2a2a91fd-6f7f-4200-978b-f5cf9cf5fe17"}, "a8660e44-52bc-4ad4-9760-9edd6dd38360": {"doc_hash": "35c463323bfc70cc392a0c62303372b6f601877fcf3ec12836c32673c814f4a9", "ref_doc_id": "2a2a91fd-6f7f-4200-978b-f5cf9cf5fe17"}, "1493a537-b32e-4b0f-94aa-8205550e1b8c": {"doc_hash": "9b2372020811cba57b7e7d99e4a2a0140e339b6ddf71899f703ba8b1c277cb6e", "ref_doc_id": "a0a224d3-33a8-45fc-913d-d248a20473c1"}, "26a96f42-6296-4244-86d2-9bce8884a2d1": {"doc_hash": "6aa828838a3715d139c1ba0a02b71bc1381518c07c9a3fb5f0bfcf3b5df79fb5", "ref_doc_id": "a0a224d3-33a8-45fc-913d-d248a20473c1"}, "d559b59f-ce00-4480-b889-c5ab6bf3407a": {"doc_hash": "f0b550d945da7eb617b0428c30b341d6a0c5237fcf166363fbd9841ef9102798", "ref_doc_id": "a0a224d3-33a8-45fc-913d-d248a20473c1"}, "e18e2ef9-c14c-4020-8105-58d517ff89b2": {"doc_hash": "a765d344e3c6ae61a2da8a64898e60725f428cf4784f6c76d52438f406538364", "ref_doc_id": "2503914f-7267-407a-a479-c26316ddcb18"}, "2225c5a7-d8fb-4597-b448-ba37729c5d13": {"doc_hash": "6e22a3db8f4afa5422fc47408a5b64c515e89d3292aae764260b2ed8887100e3", "ref_doc_id": "2503914f-7267-407a-a479-c26316ddcb18"}, "40b11b6c-769b-4b0b-8a10-ef756b4dbf77": {"doc_hash": "820ee3b6673a1f5ac662a9c7569e136ff9ebe768feab854cf6ad84ec1b52d08d", "ref_doc_id": "e56c139d-2ce7-4b49-a279-c0ca63b87e2c"}, "169497ec-3c6b-4b7a-b440-e050accb0628": {"doc_hash": "2c58882285c011c6ff63b3d710525d09cec061b93d14f2faff9afe4346a9209f", "ref_doc_id": "e56c139d-2ce7-4b49-a279-c0ca63b87e2c"}, "7cf3b775-7cdc-4dd1-83d9-b8d14f6e7e22": {"doc_hash": "2c79ac7b2bfcac46b175b7f43ab7be7bdf9f9620fa876aaca6d35ba73fbed09d", "ref_doc_id": "c93fb2d6-62ef-47ab-8067-d60ad4126c05"}, "1a134d3c-9374-4f7e-bceb-b8efce6586a8": {"doc_hash": "19f00ff67d8e1111ab10b4eace9f025ed3bdf2e6bbc31698fd817dca716f64b1", "ref_doc_id": "c93fb2d6-62ef-47ab-8067-d60ad4126c05"}, "c9b277bd-2725-4034-9582-3c58f4ebd2c1": {"doc_hash": "5067d8a8ca8a3b0638d5ab7299ca30b7d7125ae66b0d600fba986d42cb16cdfa", "ref_doc_id": "c93fb2d6-62ef-47ab-8067-d60ad4126c05"}, "38b0312b-c1ff-41b4-a9cb-7c259e93ff5b": {"doc_hash": "aadf107741ab7383ec9b9dd8760585db99f3fd6417d91c7a24dc9e4c2de1e40f", "ref_doc_id": "9f846438-e0d8-4572-af11-f2f4672c1978"}, "55550297-5007-4947-a0ac-e4180523ac11": {"doc_hash": "ede63c9cc9972c6d45dd2138b1f0b8ee05249464d6c03af4d578422f4d6fcb7e", "ref_doc_id": "9f846438-e0d8-4572-af11-f2f4672c1978"}, "9d472aba-135d-48cd-804a-044e8eb403fb": {"doc_hash": "2f0b8866fd98acae5dbb206f77cd3048b95c599a3bb9841fea424fc0466c0b7f", "ref_doc_id": "9f846438-e0d8-4572-af11-f2f4672c1978"}, "0db6b405-14c9-426a-9a74-d405c5b2c690": {"doc_hash": "839034293c43afde81dcc7d500360bafb56857b671c1fdef9439baa3a414ca24", "ref_doc_id": "815d6d58-84ca-4333-b064-eaec6d93b51f"}, "98db308d-bff8-4c64-b516-53be4ea2e184": {"doc_hash": "29c0ee54fd844761f72eed82a444d64cd7013f418856ff549e96176018f9ee3d", "ref_doc_id": "815d6d58-84ca-4333-b064-eaec6d93b51f"}, "1163f046-24db-49c6-865b-2d73ae9f4fd7": {"doc_hash": "e36554e924cef86242068c4b7e70f93ab42777b60977192aa569c4c337859f4d", "ref_doc_id": "64944609-b757-4709-8db1-18b98a8841a2"}, "7706e9fd-ab33-4677-a28e-c995476ef7e1": {"doc_hash": "3c1eb4657ddc01a7523c72876007669f5c514fa4eb26f49500e369c3e0f54a1b", "ref_doc_id": "64944609-b757-4709-8db1-18b98a8841a2"}, "b20c8791-4499-4226-af4a-dee6ab4c94af": {"doc_hash": "6415f30d23aa95bc888d8682099baa37d4ced57819a47ae3117714f352cdfe0e", "ref_doc_id": "ce9c2d14-b060-4245-832b-b9b154d2a2fb"}, "fe7d51e0-4b89-447a-ad21-6fef162bf78d": {"doc_hash": "7465fadd7702ce3e77070d039fc84b48e1dd8bdf19a5a02b8bc0f1201a275476", "ref_doc_id": "ce9c2d14-b060-4245-832b-b9b154d2a2fb"}, "8dff6669-4227-47c9-bad0-94d908e6a304": {"doc_hash": "a3899eb4a276f637ad1d449c59576a8d71d031638977d7daf089079caf7bd150", "ref_doc_id": "541ea0b3-7f17-49b1-b58e-371af9362344"}, "c17c4575-b16f-4aca-9f5e-cb9bbcbd2fa2": {"doc_hash": "ed839df787abe2b10173605bad9eb1801573429f672eeb741f98c53908c880d4", "ref_doc_id": "541ea0b3-7f17-49b1-b58e-371af9362344"}, "00213433-fb3f-4cd5-8ac2-25ccc164c45c": {"doc_hash": "af437d55ef07ce60b957571c4d32cfa0500cf96c1b99d03a824a6ecf6ce21331", "ref_doc_id": "353ab20d-9cfc-46bb-a680-0773c590de7e"}, "8c717a93-d2e7-401b-b913-4c8108c03143": {"doc_hash": "48de7049835725bb4aea71bf379211bf3713624ff8f1c968ec5ad04afa2dbace", "ref_doc_id": "353ab20d-9cfc-46bb-a680-0773c590de7e"}, "ebee6b9d-43df-472e-acad-17482764456e": {"doc_hash": "fc9a052b1a171ab9612380cdae931aeccd2a3e6c3c5031d4c47837963f7aa13f", "ref_doc_id": "a469707f-687c-424d-a3d8-3e2b1c7830ac"}, "d7943bd1-1797-4ea6-bdd2-11e47589bfa4": {"doc_hash": "18a23f03b6d432c10480ae647f87f894ecccb0e687edf0aa374f2be5a9546c0b", "ref_doc_id": "a469707f-687c-424d-a3d8-3e2b1c7830ac"}, "3f55a4ff-e379-4832-bff9-4fb66488a6db": {"doc_hash": "aeaa85187165a41a423498284054099a77f2b59d33436ec919e6cbd0c0d37f39", "ref_doc_id": "a469707f-687c-424d-a3d8-3e2b1c7830ac"}, "739cb91f-159f-460a-ab41-4a6419a42efc": {"doc_hash": "22579901968ed9b99a519d3009ff2d17089b3ad892386fbd64b14957bf0edf69", "ref_doc_id": "ab2c4201-02ce-470d-a446-362837220ef6"}, "51483530-5054-405f-b6de-36aeda132c45": {"doc_hash": "8e38190600ded824335e1ff1fdeb0cbf4bf5a836d5b8873c01c8e05457ff4742", "ref_doc_id": "ab2c4201-02ce-470d-a446-362837220ef6"}, "13a0f414-3e4f-44c0-8064-1a948232c4bb": {"doc_hash": "03ac3c15dad24d4f74d66a29f5aa49b7e20fc4130b03ddd190d20b36f8545053", "ref_doc_id": "ab2c4201-02ce-470d-a446-362837220ef6"}, "b396bb95-bd8c-409b-8211-327ec9a6969b": {"doc_hash": "83d59421cc351178bdb1df352f66f9f94c9a1b618a97052cfcd10b62d1de3a11", "ref_doc_id": "9c23dd4e-ecee-4e13-a6c1-b3877d418233"}, "b57448e2-6858-4d89-8c36-4e6eb7a6f969": {"doc_hash": "2ffc823cea265be29137b8be0a6e3c20a4afe08247ccda342ca81a1aceac9148", "ref_doc_id": "9c23dd4e-ecee-4e13-a6c1-b3877d418233"}, "62b6b26e-b0ab-485c-93e6-fc00bf0b5ddd": {"doc_hash": "7c2c805952f4ed2f8859ae27284fda529a4a0c0b6d528227fc0b24f7d0335877", "ref_doc_id": "9c23dd4e-ecee-4e13-a6c1-b3877d418233"}, "33466291-6651-4c2b-ac85-8b3b96c444ef": {"doc_hash": "d0766344960dd96c453da2005b34a1498f44500dc9c418c7bd9646b57ac1345e", "ref_doc_id": "d033e8e3-f57d-4212-97b0-43367c042c5c"}, "5528098d-a2e3-488d-b4d5-f6c8500133e3": {"doc_hash": "4f01a799c659551436aa1556cfc76943e6e12b0335e40a92166af51f69d2c84e", "ref_doc_id": "d033e8e3-f57d-4212-97b0-43367c042c5c"}, "44e0b660-d854-4ae8-b49b-31710c0c89de": {"doc_hash": "059a38e490542bc19233a8f4d6b6ebfb62b28fd844f6ce159dc7838f6b61c3d7", "ref_doc_id": "d033e8e3-f57d-4212-97b0-43367c042c5c"}, "24fdcd30-13b2-42a5-bb51-3e21b47db5ed": {"doc_hash": "777dd879bb7fe3e9a3c4694d313c368ada10b6432ea960feef24bd6a5d9fe270", "ref_doc_id": "4eb10f2a-a899-4e74-9d73-b8727483488d"}, "22336125-cac8-4f05-b868-7c51301bbd50": {"doc_hash": "d6e71b8703e1e993125354784d7dae981942ff608904539306d470a3c7269e84", "ref_doc_id": "4eb10f2a-a899-4e74-9d73-b8727483488d"}, "c3d76d51-7596-424a-9ba9-18a87c2401de": {"doc_hash": "780bb47e4a5b0d03ec4770df3516acd0ee1c378f5afb78d08ac20317617b44e3", "ref_doc_id": "4eb10f2a-a899-4e74-9d73-b8727483488d"}, "98e062e6-5172-405c-9449-ed6b10239451": {"doc_hash": "483e5af3dbc926a842345aebf6a1b1eca05d61f2bb613db5f06488894762b3c4", "ref_doc_id": "8ab2bab2-794f-445c-8f1c-71c5c84e29e4"}, "2c16a1bb-6d1a-4ff8-9629-7455fb909680": {"doc_hash": "0ae2e6da598abf4f4bd5452e99f67726366b322551fdcd2b7b19930e642abced", "ref_doc_id": "8ab2bab2-794f-445c-8f1c-71c5c84e29e4"}, "1df41d06-85b8-4333-97ce-a3b749c1eb23": {"doc_hash": "9e185390e19c873ea8e5e6ce60fa7343ee377bbe5c299aaf37169e1ff7b294ab", "ref_doc_id": "8ab2bab2-794f-445c-8f1c-71c5c84e29e4"}, "6d80b283-99c2-43d5-9da3-0047109f8bfc": {"doc_hash": "3c176af2ef3569731932a486f3f6f575edfcb2a3d3299091fb220a6e596caf5b", "ref_doc_id": "e763a431-4c45-4243-a631-ed84595d35d4"}, "9236b2b4-db6a-418d-a035-2e047a71caad": {"doc_hash": "891d370f7a0cd8c0fe89efcba127b69f5a8abe13f9067076c358b3462acaf2a9", "ref_doc_id": "e763a431-4c45-4243-a631-ed84595d35d4"}, "7fa3bb7a-19a5-4cc3-a20c-84851cea07dd": {"doc_hash": "b78407e19deccd2e5686fd3fc5b9b70350841249211fe7c433a07dbf52ac08d3", "ref_doc_id": "9c961578-7459-42d9-8442-b99bf2746719"}, "875b4881-10e3-447b-9781-462665b17a91": {"doc_hash": "1e57da79cea93d3519ad03113efe86684b44fe7d4dadf00e6a617efd0086eb25", "ref_doc_id": "9c961578-7459-42d9-8442-b99bf2746719"}, "b2fe2401-8202-4007-aec1-fffce6e9d217": {"doc_hash": "988017bd46466c3c7a8d816fcd509c43f2bcc3b6b48341683ad6ebb653bc07fc", "ref_doc_id": "7740e11c-ca6e-424e-8d9c-460596e4d962"}, "fc489a2a-8fc0-44bb-aad7-582f37a29dfa": {"doc_hash": "6fb1609e22263415e84fb377654ebc6b211a4da4b52bfc9fc10618fd48abc052", "ref_doc_id": "7740e11c-ca6e-424e-8d9c-460596e4d962"}, "e2ee6ed0-b26c-4b62-a94d-6bcd3d0cfc61": {"doc_hash": "388f424756f8fa8223fd19b2a84bf7922064d0aadd89a904ec022cd070fe7c6c", "ref_doc_id": "028bd9ba-0f31-4648-ab15-95667ca88369"}, "d8ba0ebd-42aa-46a7-bb7d-fab0a734ccc6": {"doc_hash": "a5dfbeb40d7e59a65401140ef07ad3c4df3c177b707ce5f068306a53bbdeb439", "ref_doc_id": "028bd9ba-0f31-4648-ab15-95667ca88369"}, "3b36e16d-2823-4163-857e-be9c11b6d61d": {"doc_hash": "eef73eaa3d864d7cd3eccd225562204a4cb90efcbdc3e170bb2cb62a64f1e199", "ref_doc_id": "d283bc2a-2aae-46af-9947-d79f37917033"}, "d39c77d6-d716-4b2b-ba16-b26761842279": {"doc_hash": "4c70db81d43de421114065eeb2ffe8b839e592080974ac7e309ba9581ebf1003", "ref_doc_id": "d283bc2a-2aae-46af-9947-d79f37917033"}, "1f07b549-1915-415b-8aab-3fccfb9ae59e": {"doc_hash": "9bfa66046edfebc0a713575f8dac0c5382f05d9eaef989c56acc04d5b9a7656a", "ref_doc_id": "23964bd6-98c3-4daa-a759-58a6af6cd0ce"}, "022cc04c-08dd-40c7-aa1c-4514c5cca6e8": {"doc_hash": "8d3cb239a743400868e9195f6f0db0dacabb17569195eca3fd005e715e6ab2ef", "ref_doc_id": "23964bd6-98c3-4daa-a759-58a6af6cd0ce"}, "bf2c45db-bb35-422d-827a-f92b35566317": {"doc_hash": "e144003ced7d56624e493fe158ae6309d7bfb2f300d656e187130f268689741a", "ref_doc_id": "23964bd6-98c3-4daa-a759-58a6af6cd0ce"}, "0c23416e-ae30-4688-afa3-fda6ddb23e09": {"doc_hash": "39bc37f02bd7ce2a7fb13c04fc0684a875a871bc9aa8f324602dfe7defe3fe50", "ref_doc_id": "9793ce56-41fc-4689-8dca-fce50ad70ab5"}, "f75857ee-22e6-4b22-a79d-8f80a0ba490d": {"doc_hash": "91fed0c105060326815d1779a22da4b7c53d10ff0dab4fe7cc7a2c50f9e01089", "ref_doc_id": "9793ce56-41fc-4689-8dca-fce50ad70ab5"}, "442a3b37-55fd-47a6-bc9e-e75918124e9f": {"doc_hash": "b2313c44cb023f0e6cb285c0fab355acc37e9ab164a17507ab4cf3a2afaaf424", "ref_doc_id": "9793ce56-41fc-4689-8dca-fce50ad70ab5"}, "10446981-7715-4581-9c58-9d5f10656c32": {"doc_hash": "f42fb5e8a64f935160a94e5b6a4d67ea69007755b5824ab0accfe11f6d72ed84", "ref_doc_id": "21ffe82c-df0d-4aaa-a237-03ed78ebb398"}, "42d6406f-08ff-4bc3-8916-3c38dd2fc136": {"doc_hash": "a36879f8a873e2a4f7d5cf4e2487a961b5b0fc576f65bbc002359d75e646b84e", "ref_doc_id": "21ffe82c-df0d-4aaa-a237-03ed78ebb398"}, "e2300ea6-c926-4dad-b42c-d43221cfbe76": {"doc_hash": "1a10b9cba02435616f73abc091bdc1d51cec320979d847a28fa009aacb7b2ea1", "ref_doc_id": "459d999d-7177-4ebf-802b-4cc4ccc2ce49"}, "a166e3c1-9ebc-494a-93d5-cdb67fad0f92": {"doc_hash": "851527a4a50a12c0187052f44a29d7ade636dd3b5aa8332bde1dc3c0f3ccf012", "ref_doc_id": "459d999d-7177-4ebf-802b-4cc4ccc2ce49"}, "5dd6ccf6-bab8-4700-b78e-505e5eb656b0": {"doc_hash": "a39c2d77dd0a0f4c05383b29c5dd5364f0755631b989461575fde92b55ac2df7", "ref_doc_id": "bc16a687-6c9e-4f66-9194-286eeefa4fcc"}, "f329a71c-ca45-4ec2-91db-63079e33ec5e": {"doc_hash": "c4fba03a085b590afbb2dbd751ceb1fedc2c0f08cffb009c24e592c18630ac22", "ref_doc_id": "bc16a687-6c9e-4f66-9194-286eeefa4fcc"}, "93396b37-9a2f-4a6d-bb09-c8dbaa22042a": {"doc_hash": "d0886ae921394611398dd75216ccf06bb9b432515cbf00999888c1c973ba8cdf", "ref_doc_id": "3056a80d-c271-43fb-804d-8d5552bd4c21"}, "aa25fe5d-5214-46eb-86f8-180bab29671c": {"doc_hash": "4cf7f9cfe8175d909c4c09fa778ff76aea939d3e8b81c3fec4352e6956ab8d7a", "ref_doc_id": "3056a80d-c271-43fb-804d-8d5552bd4c21"}, "a3c8c6f8-ad37-4671-b6ff-e768df124503": {"doc_hash": "d4e432afcfd385a8e758bef28d44d18de3eab3becc1b233576f7f7aeea1a6e4e", "ref_doc_id": "99654b0e-1227-4397-b5f6-0115d42111d6"}, "36957aa3-39da-46a2-ada9-495e1c9e200d": {"doc_hash": "41a2537f406573429d27489d7250a301f740b0993bd5b58a0cf7cbe746906313", "ref_doc_id": "99654b0e-1227-4397-b5f6-0115d42111d6"}, "581e61cb-ce6d-45e7-b18e-2c91986aa04f": {"doc_hash": "2ef262367b8b39049d87cd61951afc03557b62434e59055bdb4850aa11fcc903", "ref_doc_id": "99654b0e-1227-4397-b5f6-0115d42111d6"}, "1e766be0-80d5-496d-bf71-cde443af6211": {"doc_hash": "5094d86dcc33731170f17d163e9d82f3385b351e4476fc2453d93bc3e77e808b", "ref_doc_id": "e275ccf1-1505-4c57-811f-366b460d12df"}, "a90a5b27-a4d8-4607-ad33-7797848116cf": {"doc_hash": "849c0a3fca7d6987d488cb0233c40a2437bc38d57172bc8a4ee2118eef1248c5", "ref_doc_id": "e275ccf1-1505-4c57-811f-366b460d12df"}, "6849990d-27d9-45d5-996f-645854487eb0": {"doc_hash": "bfd537d266cc8c3923e11bdc8ad82f53411fa64f72bc9f4aa2624982a48ca9b0", "ref_doc_id": "34ba7415-d15f-442f-a6b0-4dab14e18ba6"}, "e7533d64-c5a3-4d86-b883-908fa045d964": {"doc_hash": "81fa9086c41fbcaead90a7199ec7e8c355b39939bca12a03ea5d701770d83879", "ref_doc_id": "34ba7415-d15f-442f-a6b0-4dab14e18ba6"}, "d51cd763-d745-493c-9af3-05fb4ab6c1e1": {"doc_hash": "17c7c926cac851314e63ee38f7e6b8c86fbf1ae2d8091c5826995d68ed8a32c6", "ref_doc_id": "d38b635f-a2d7-4015-aa8c-3557648c55ab"}, "ae4b4816-65bc-4759-be2b-f9a4738694a5": {"doc_hash": "5afd8f20db19cb7678b92a7612132ec5bbd28e8294dabb90664bee24174a83e0", "ref_doc_id": "d38b635f-a2d7-4015-aa8c-3557648c55ab"}, "c970f7e2-74ae-44b2-841a-1c9923b8b20b": {"doc_hash": "432726e7236491f3b99c1405949ab45369907d447fa6f3d08f262fc66902d497", "ref_doc_id": "3051b853-f6b0-4484-8001-ad7309298951"}, "e2bfe371-8cad-4c88-a11a-a7944fbe4eaa": {"doc_hash": "59a6cb649e49a5a4fb623c546d2a6f7459351e3a99ffe92b8ab5b194e67e4c34", "ref_doc_id": "3051b853-f6b0-4484-8001-ad7309298951"}, "c1685c77-0791-476d-8f4f-99ae01b8a3f8": {"doc_hash": "f23946687042395e5fd81d577a571193d5ba1e8d134d2345bb63da9714276c12", "ref_doc_id": "040a53fd-ccb9-4b81-9599-fb4d43c1f1ad"}, "bbff54d8-d23b-41b7-9044-375049a593f5": {"doc_hash": "f4fb8947aaa7ef9a788c61c755feaf3b8e4a13f80df15723c1a890251d79bfde", "ref_doc_id": "040a53fd-ccb9-4b81-9599-fb4d43c1f1ad"}, "a135e1ef-2ceb-4179-a4b4-fa98fba6e104": {"doc_hash": "4e17dba4f5e192d669c7ea3af0752be3ef7bd4dc7b2517b7ff3ef929e9da29c8", "ref_doc_id": "544e3366-4ef5-4ab6-8de9-5b98ea46d522"}, "32e6c6aa-80de-4d95-a871-da0b37a21d1e": {"doc_hash": "fe5721070bf533a3eac81a77c10c762b18cb0a5120a9db744cac905f2e0f6824", "ref_doc_id": "544e3366-4ef5-4ab6-8de9-5b98ea46d522"}, "a2964688-c523-497d-abf6-7686e14d4eeb": {"doc_hash": "024b3a63ed03c103a72d962d59008d1a0895d595eed36b8244170dd7aca33282", "ref_doc_id": "5d514026-f152-4b70-a49f-66cda4af0f27"}, "1ca39d2b-1856-4fbd-9ce0-4f5fb6733e69": {"doc_hash": "604fcc78ff8f2de6cbe127f68cc2bfdef233fc7a9264f7148414214bb88a6540", "ref_doc_id": "5d514026-f152-4b70-a49f-66cda4af0f27"}, "551b99f4-0926-4476-a331-20d0a3014f96": {"doc_hash": "0211424d80f2b5acc4450588c5411647b2caa2241b04b3c57c3f2f3b1f4f48a7", "ref_doc_id": "5d514026-f152-4b70-a49f-66cda4af0f27"}, "e3b27242-39bc-4869-bf8a-9b557a241abc": {"doc_hash": "d0a373e029fc081f5accd9ec2887f1b5f7011390c3f3493c877b90460686c976", "ref_doc_id": "e650d844-414d-4f8f-aa1e-70cf34d6d048"}, "769a2906-02a7-4d8b-b0a0-ef191e0d83f9": {"doc_hash": "171fc8ad59571952e6915df07bcc2a0ea5f3dd67dc5162e064feb9fa8090220e", "ref_doc_id": "e650d844-414d-4f8f-aa1e-70cf34d6d048"}, "43f1bcef-ac11-472a-ad3e-b5d1e15c7951": {"doc_hash": "67f1b26d137807b5e183d3613d8bb5adc2a1993cf9703c7bc406fb34d3f420cc", "ref_doc_id": "77594511-d23f-440b-89b4-0ae1da545e05"}, "5cf46334-19dc-4cf6-81d6-9991ca244fa0": {"doc_hash": "32655d7c48796d6445d7de3a785afcbd3472a14c7cdd6f783cee7ff0f3177b5e", "ref_doc_id": "77594511-d23f-440b-89b4-0ae1da545e05"}, "d428b0ce-8ebd-48b3-9581-8666291316aa": {"doc_hash": "252baf1b50919336ff41bece1b5c8591b6e3a36ef3fe84570b3d187f01a17469", "ref_doc_id": "81cf952d-df94-4a31-b40a-5d6168dd268d"}, "d0403fc9-d183-4966-97c8-c0970c1a5e4b": {"doc_hash": "24e69aeaad2689497585c8ff833b040a4d30605cf1f3550fb6b7ae1f70f7962d", "ref_doc_id": "81cf952d-df94-4a31-b40a-5d6168dd268d"}, "13d70202-9dc9-4f42-827d-dd1d9b7e54c3": {"doc_hash": "9f237f8992361e0da86f0e79daabdc47688afa1a655b251822eb8a72350328cd", "ref_doc_id": "e5f14dca-ec26-4fbf-a6ca-dc57c95ddf14"}, "6c170b46-2299-4e7d-b615-274e2bba5b00": {"doc_hash": "375b4d0d4d40ec2af366ba944e57b141cf3521179d1966f5074debcdacbeb4d6", "ref_doc_id": "e5f14dca-ec26-4fbf-a6ca-dc57c95ddf14"}, "8bb3eacb-95f4-4234-879a-1ea058fbaed3": {"doc_hash": "57d776aa0b6b2434a0db31d068d72cc5bf4e794a60aba955f9b66c7cf02b1721", "ref_doc_id": "e5f14dca-ec26-4fbf-a6ca-dc57c95ddf14"}, "fd88ea8f-70e9-4371-9b41-c4063edf4ac5": {"doc_hash": "268d95b0e8580291f84923a192b4962faa5296d86cf6d136a62c1128b014a3a4", "ref_doc_id": "0f37a124-1cd5-474c-a1b7-aa2fb1c84bfd"}, "fd2053ae-96fa-46b0-896b-42224cb46063": {"doc_hash": "91e6042c5d4c91648eff3acd5643829af14dff5f75bac32a8cdbda5aec1841c1", "ref_doc_id": "0f37a124-1cd5-474c-a1b7-aa2fb1c84bfd"}, "e80cabce-fa55-42cf-8b2b-f432c2088172": {"doc_hash": "986057d783a517f82288e2ffcf032e9a746f6efa37a46e7dad1cafb4382486b7", "ref_doc_id": "0f37a124-1cd5-474c-a1b7-aa2fb1c84bfd"}, "02c9c37a-a7de-49e4-8fdd-3991662ce8ff": {"doc_hash": "263600ef11083495471933dc033a55d0e5fb5e5f24b197d0b280d4b4f49e85cd", "ref_doc_id": "e3a78cca-7e3b-46e9-8bc4-d1e549e98389"}, "136cec3d-5ef7-48ae-b550-128f4f7e26f8": {"doc_hash": "28b3eb9ee4c11a98d698e52f249dc22b9cac224347d7d9f3f26e34edd53a390b", "ref_doc_id": "e3a78cca-7e3b-46e9-8bc4-d1e549e98389"}, "f0ce8a9d-0847-41bc-b857-4498dbc0a601": {"doc_hash": "39c72ae4b769d3f537d0781fb9cbfd7cc74671f05953ca9f0ce5c633eb5bf1ca", "ref_doc_id": "e3a78cca-7e3b-46e9-8bc4-d1e549e98389"}, "07c9f9ad-bc8e-47c0-8e80-4e152d7ef48f": {"doc_hash": "cca726dad1da1ee5765ef7755f06f4bcb8dc042160a85fd7c7c9ef109ec34463", "ref_doc_id": "ee455c59-34dc-472c-88a3-efdfd8de10c7"}, "3865516f-794c-4679-b4a3-6ee814305867": {"doc_hash": "d12dd3f32207476b0901b71cd9086b113bc060c61ffa9e7d3b06394631b8fe6f", "ref_doc_id": "ee455c59-34dc-472c-88a3-efdfd8de10c7"}, "48343d4b-9113-4132-9559-eaea883d4e14": {"doc_hash": "b3d5614e17ed6cb76894ddd4dafcc5d622a442bef214ab92f6655778920cdc78", "ref_doc_id": "ee455c59-34dc-472c-88a3-efdfd8de10c7"}, "4226a34f-efbd-435e-a006-486a26c4b6bc": {"doc_hash": "c5fce7597aac4b022c48fc9473f1c750451af01589975de717f4c57d93bffb0b", "ref_doc_id": "18bb695d-d5b3-4dd6-8e2c-808da289330f"}, "675b56e7-c395-4a6a-b690-2a98c6883a14": {"doc_hash": "0696d261ebf04a95be35a6d61593b68f80cd73149eef984c8c104b8f02689ee7", "ref_doc_id": "18bb695d-d5b3-4dd6-8e2c-808da289330f"}, "bcdad38a-6280-44d5-9bc5-f281f59774e7": {"doc_hash": "72ae7a3e7272bf4e13b20de117458ab70f9d8348b35b7b90ef349c9b9719470c", "ref_doc_id": "dbabfb56-d12d-4403-b909-458c4da9bc1d"}, "69503932-2784-471b-90f2-6a0eb8d89f66": {"doc_hash": "4e55ae24f23e8f3d679fe92fcb5e331219edfb857a1a4b53bd9cf0ad113d8f6d", "ref_doc_id": "dbabfb56-d12d-4403-b909-458c4da9bc1d"}, "a0ba89dd-dd77-4988-a722-ddf1ae55b762": {"doc_hash": "2526d67b4637264fa5fd492dee50e151250377a36c346dc70118db9d98772924", "ref_doc_id": "d1595cf5-5fd4-4b2b-b5a2-e7dedadf0bb3"}, "887cfd2a-06d0-4a8a-a1e5-75e4daf663c0": {"doc_hash": "d134f04d632b1b3228ca3ba2d4e8ada258b437098f7ad5fc6f6c2700e4db7447", "ref_doc_id": "d1595cf5-5fd4-4b2b-b5a2-e7dedadf0bb3"}, "de856f56-1525-4475-a70a-38243bb2a706": {"doc_hash": "762a338dbab7b4ad15ee11ab03a37249c380a38df53785ba3f5fed2dc108ea48", "ref_doc_id": "d1595cf5-5fd4-4b2b-b5a2-e7dedadf0bb3"}, "9ecec95d-7020-4297-9347-787ca53687f2": {"doc_hash": "ff36f851ade55636b1d10088bd157bd17740d1314530759a7749a1526e3a5dcf", "ref_doc_id": "3a68ba85-c614-462b-9571-13368b753e80"}, "6d54efd7-4848-42f4-b435-0988359afcec": {"doc_hash": "5f2f1d4083ad955b81db500fecea46eca92397d354af83344f7203fa09c8e539", "ref_doc_id": "5e64e9b6-14bf-4927-9bd5-388f8567ec4a"}, "b137ff51-1eaf-4859-a20b-6b425c584d75": {"doc_hash": "c93ea31b7fc3ce8fb733111b79474a8d1e95e406033a7ad8b32a30ce1497e060", "ref_doc_id": "5e64e9b6-14bf-4927-9bd5-388f8567ec4a"}, "15958383-3ff9-49aa-aeb0-8d715c07117b": {"doc_hash": "fea17030ae2530074ff75341e8919ff067311f72a25c01d8feb6d116cc5ff4c7", "ref_doc_id": "5e64e9b6-14bf-4927-9bd5-388f8567ec4a"}, "6bca0e1e-a140-4b2a-9515-66f6157cb895": {"doc_hash": "9cf76f3b360c26ce67571f59410cedb5f42bf7633ed363a675160f742dd05f73", "ref_doc_id": "10d93c43-49d6-4722-bdad-b82c3ed8f929"}, "6f83af4c-b1d9-4de2-860f-e7c656925840": {"doc_hash": "9bb3823b3d2a1f8f0a806893df4c560806cd83c6b8a30d4408bd9009e199a0d6", "ref_doc_id": "10d93c43-49d6-4722-bdad-b82c3ed8f929"}, "6b23c76a-e936-4db4-b769-09f2ff121d1c": {"doc_hash": "b28185bf9b123e8b4e483d7d236dcdd618c62fb5c5dd4cdbba33e9eb3144c233", "ref_doc_id": "10d93c43-49d6-4722-bdad-b82c3ed8f929"}, "617b1410-4657-4ad8-a9c1-bfb94c259f01": {"doc_hash": "1eb4ed4467911a015d75c612dba51744742165e52d1ed0ed84b7625c42707bf8", "ref_doc_id": "3bb5c1b9-69f0-400d-96d9-ed370ec80a0c"}, "b5cfe58e-6c13-412a-8f41-62087256a43c": {"doc_hash": "eabaca7c0319e20e061398bc8e273a38b447624435b08e3c2b44b0d5d8c86995", "ref_doc_id": "3bb5c1b9-69f0-400d-96d9-ed370ec80a0c"}, "5f84b6da-6208-4650-b7f5-bb7dfeef5a01": {"doc_hash": "fd0e70947315c59e21a3b19b52124ed189d853d70417b72a272abc1f232be171", "ref_doc_id": "3bb5c1b9-69f0-400d-96d9-ed370ec80a0c"}, "8e243cb8-c9c7-4081-bc81-3b196ea0c344": {"doc_hash": "1248f23c433550844a63a0fd3094c522066f74758786470fe245700494d1fe0b", "ref_doc_id": "8a7dba6b-db6f-469a-873d-664d4db22805"}, "5a5d641d-b3ca-4b7f-bcaa-b6b88e212115": {"doc_hash": "badca1a1044ba3789f3ccee320a86cca8dc19a8ad01ca34a0b069303e79e1333", "ref_doc_id": "8a7dba6b-db6f-469a-873d-664d4db22805"}, "1609c0d6-6496-4a84-a9e4-e435886c0f26": {"doc_hash": "399df38734d9255c3b0e8d9aa6ad42d8bc321856e0587f101b5cbc9c3b067faa", "ref_doc_id": "8a7dba6b-db6f-469a-873d-664d4db22805"}, "81852fad-7813-45c0-894e-d5c64e01aa5d": {"doc_hash": "2f05a96d497dee5a0855cf7022736d689861f7eda2526cd1b8ad3bd7243dec0f", "ref_doc_id": "9b640bb3-9609-4196-926b-75c54e7d9973"}, "5c245962-bd49-4809-81e9-2ead60fe7d17": {"doc_hash": "4153f33a2668f9d0ff39b4e6883e0990a837d7cea6889c08b110f5c58fed8f76", "ref_doc_id": "9b640bb3-9609-4196-926b-75c54e7d9973"}, "0f1bab4d-9416-440a-9ac3-c29f02aefb41": {"doc_hash": "cfdae7797c840ac3e9a0b9a3180873dc100d0e82ab8888a391415a6ec1bdd708", "ref_doc_id": "5bd0fbc9-b3ac-43bb-9669-150414168aaa"}, "331c640d-7aa1-4e31-bf87-d54380542dc2": {"doc_hash": "5d4d96827b89d796759021d1a29d46326206a9bcb3c001d6f36991c83211ec40", "ref_doc_id": "5bd0fbc9-b3ac-43bb-9669-150414168aaa"}, "f0fde337-cd5e-4257-abce-64cb2b460067": {"doc_hash": "fb04262a457f223b74f45809772165c42b4a96497010d58efbd5d73b786796e1", "ref_doc_id": "7d0dd8eb-6503-43bb-a5c3-6c5f9e718220"}, "d5268398-a667-455d-9943-d5d44b918b18": {"doc_hash": "5582549dbb8cb335a2caba986ee7322af8d48c9ddfcccc367b40be882b2f3b5c", "ref_doc_id": "7d0dd8eb-6503-43bb-a5c3-6c5f9e718220"}, "95df82f6-f7bf-42d7-a7b5-b54a68cfdfec": {"doc_hash": "fe0ed6559505092506fa4a14aa53a671f3dace8d09123093e0d897c6d10fabdb", "ref_doc_id": "0b6426d3-a63f-4105-9992-493ee8871ee7"}, "9d491806-a9b1-4e3b-b19f-8940c2b5d820": {"doc_hash": "996e3d9c72fce0299b8d430d49e9cbe148becb16f9a5fd0bf3c7eb89970aa262", "ref_doc_id": "0b6426d3-a63f-4105-9992-493ee8871ee7"}, "6564894f-de5c-49d2-97aa-697429b775bd": {"doc_hash": "6f342b32a446346b1b0b6405c307cb419c446ac8a556867195251b36be6f0f09", "ref_doc_id": "a4f0c629-c4a3-4f39-93c8-bb69973fae60"}, "e6848ed3-eab3-40bd-915b-f26ada7b52cc": {"doc_hash": "4093bfe849c6796f0af1c9d483e90d60c72f50a9af296e2dfaebb63fe3af6f5a", "ref_doc_id": "a4f0c629-c4a3-4f39-93c8-bb69973fae60"}, "22e3b19b-05a9-4daf-9c76-55625727846e": {"doc_hash": "9199b86b0c44dd7dc7287d25be66583942c67292da4d8909cfeaf2d10f49fc0d", "ref_doc_id": "3d39e92f-9ad8-48e2-a334-f19a5608ef50"}, "963b3814-45b7-4bdc-903d-1032614872a4": {"doc_hash": "148d41ae86cd643fb13a783acb000ac269b508793f7173d1459e1fa0547ca025", "ref_doc_id": "3d39e92f-9ad8-48e2-a334-f19a5608ef50"}, "ce1b6e13-d127-4b8e-a6ee-5f24c54efe3f": {"doc_hash": "ac63dfc57fa367252a21563efb863881507bd78b95d9ba54b59901c7897eee7f", "ref_doc_id": "3d39e92f-9ad8-48e2-a334-f19a5608ef50"}, "30bc525e-55b3-445d-8f81-0f91eb0c3408": {"doc_hash": "fe13db833b3a3b817d78232e3164d7fcfc949cf53c3b7fded996257312cbcb3c", "ref_doc_id": "8d4373a2-f564-435b-88f9-e88d1b9f68bf"}, "1cae5436-6306-48bc-819f-17e946256121": {"doc_hash": "e2e819c49e3dcb07c60d550bf5bb118b80cfc7b6b3dcda5b36b5bb7fe8e56c77", "ref_doc_id": "8d4373a2-f564-435b-88f9-e88d1b9f68bf"}, "91dd174e-7c11-438b-86b4-ea666cedc7bb": {"doc_hash": "9328512aa2fae2d1d5e00e2ef3f79f298d9bd810779bffbcbed8e068ff5bb592", "ref_doc_id": "80ab4d67-a0bf-49e3-9574-67e6bf5921df"}, "a403ee8d-2a0a-44ea-ad33-c4ae270ba46b": {"doc_hash": "c815c70e48558d0dd4756619d8d02761794aa28cc0a1a2359b351f0723c1366b", "ref_doc_id": "80ab4d67-a0bf-49e3-9574-67e6bf5921df"}, "81fc9d5f-eb9e-4436-9741-d1428a71e4eb": {"doc_hash": "42036680d52b90ce2eaca45b767e4b9b0f051623c05e8e0a6e32ac822edda2fd", "ref_doc_id": "80ab4d67-a0bf-49e3-9574-67e6bf5921df"}, "3d0932a0-96f3-492c-809e-f708f224120f": {"doc_hash": "74e10f82af181a66d29eb2f16c12e99420795d25a9575f00e26089ad338f9e51", "ref_doc_id": "fde39d50-f267-459e-9439-1deed63cd890"}, "d4c9dc79-f587-4af8-a4b4-b5651652be89": {"doc_hash": "e4976b21dde4814d562985201f97680ecb17531d3cdd74efd096125715c4ca47", "ref_doc_id": "c721cb69-d1e4-48d5-ae01-1d121671dd89"}, "50e21c4d-6bd0-47ed-b307-bf7455a14863": {"doc_hash": "cfccc409afe5dae635e6b51358a31b238965ec4a8a009c5aa2e6935026178c10", "ref_doc_id": "c721cb69-d1e4-48d5-ae01-1d121671dd89"}, "6e061338-7bba-40bb-b9eb-56e63dadbad1": {"doc_hash": "6ad3fea5f9a66504b8a16bf2b9c645430f527b3ff08d710263ad8dc0a11de627", "ref_doc_id": "b08c4506-d2c5-4f4c-957a-55d28660b9f5"}, "614157a1-f7f1-4575-9470-f30c43733680": {"doc_hash": "940a5744bacc05f4a857debc4b61d9407de34d5827e4153e9aaa3f994e2dabe2", "ref_doc_id": "b08c4506-d2c5-4f4c-957a-55d28660b9f5"}, "32b3de1f-95ad-47c7-8973-fd4b8ffaf6d3": {"doc_hash": "2702557972a65377aa025c4931af1a1f794bd6491178ba125c62e5cc83aca4da", "ref_doc_id": "b08c4506-d2c5-4f4c-957a-55d28660b9f5"}, "ac10f0df-8b89-4598-818c-99f758f6683d": {"doc_hash": "e1a6c59893025d57a3b1f76bc06f4b049c979419c836c25b19454866f00cf7e8", "ref_doc_id": "94eb0f05-74ce-4633-bc7d-555b62a25fdd"}, "f231a0b9-00bf-4a16-bb3a-3d43f09778dd": {"doc_hash": "225a73cc9909c31fe20fd854b56107819a69f43fddeeab7499bfce437bce4d0b", "ref_doc_id": "94eb0f05-74ce-4633-bc7d-555b62a25fdd"}, "fc403662-c0a8-4843-b2c1-ed251cb99157": {"doc_hash": "ade94f6d2f334452d3266e3cae982c804ea4060b0263209b23847e87abfe1f1c", "ref_doc_id": "94eb0f05-74ce-4633-bc7d-555b62a25fdd"}, "55a067c0-f5da-4144-8ebe-53f5416917d4": {"doc_hash": "a93f9589b80138efc18747541da20dafc1e958d77afd923bdd5a9e9684e9d4fe", "ref_doc_id": "70d91e22-2a1d-4d6b-8b9b-89bd66b57320"}, "913a253c-ecd3-408d-8e36-be3ee8b6d7db": {"doc_hash": "e48ca8fc949233e333d385e68fc34f3b97891ad2d0e82a0807a9a6b6cab5ea74", "ref_doc_id": "70d91e22-2a1d-4d6b-8b9b-89bd66b57320"}, "f92a79d5-3013-4d64-906d-327f87223ea6": {"doc_hash": "afd0cc14282e6e97e920601748d99c5039f381814485e9e778d2fce83588a95a", "ref_doc_id": "4cca624c-4b7f-4dd6-a411-aa6c86e724a7"}, "dc9094a5-53f0-4925-8d93-13388b06df39": {"doc_hash": "d323c0428de00e017d07bfdf6761d78ba341792adce1ec7a41bb376dc630fc9d", "ref_doc_id": "4cca624c-4b7f-4dd6-a411-aa6c86e724a7"}, "eac69758-e61c-4ac2-aff6-a63239bd31a4": {"doc_hash": "133227267ae5caa21439491436468f49844c4163f330610f38c1e07f0f026216", "ref_doc_id": "3ce50f95-9cc9-43a9-a00a-a8608ae5b687"}, "62ee83b0-a634-4eb8-a607-2e3671abad21": {"doc_hash": "3242827da49dcd051928905cbed13259c1004587868f180baaa01b8a8d2ec449", "ref_doc_id": "3ce50f95-9cc9-43a9-a00a-a8608ae5b687"}, "56fb8b77-5304-4f54-bf73-554e8ca81b9e": {"doc_hash": "2b2756abc87c28c5b35e690007207d63736ead95d64a640f5ab0d36597ce41b8", "ref_doc_id": "3ce50f95-9cc9-43a9-a00a-a8608ae5b687"}, "ec4215cf-706c-452d-b9d7-6daa4f4ca5c2": {"doc_hash": "5b227ba0b2c8068d6a364f63eebd60b8f0bcb8f263a2bbef90084fc7daa8f65d", "ref_doc_id": "442fa97b-11ef-445c-9fe7-9abf8218cbd3"}, "a2b98e81-c227-4d70-a51d-13be4ddd8cb5": {"doc_hash": "b78af79c80dca67f7077f21a88ea0a60369b2cbbfdbd2296d5971df952f0e46f", "ref_doc_id": "442fa97b-11ef-445c-9fe7-9abf8218cbd3"}, "350a4ddb-72ea-480e-8178-f4a57e8f1293": {"doc_hash": "27336674fddea0ef001ce352f7fd7c0a402f0bc4a0c0741230b7aad6f619f477", "ref_doc_id": "442fa97b-11ef-445c-9fe7-9abf8218cbd3"}, "7a3e3666-65fd-4cb3-a369-06299f527e81": {"doc_hash": "e7cae7b28c9e22d2e11de61934459c175f3a3d39cefef4c74e247b27fda71a98", "ref_doc_id": "604a33e6-286b-4d31-99b4-65feefa34286"}, "3b45257c-29ab-43d4-ab55-39176d02d2ab": {"doc_hash": "ed185f65922ee7db0189e392073e853d0795d2002b4a455b8904b62a83e8010f", "ref_doc_id": "604a33e6-286b-4d31-99b4-65feefa34286"}, "8921c41e-9f51-46db-b8c0-19bb64d113bd": {"doc_hash": "c03666e7797b19500dad9429e3afed8ec4e8c9cd9b44e819941a3355247b3962", "ref_doc_id": "eaf61b3e-9b8e-499a-a3cf-2b6d8a187ccb"}, "18263f17-13ca-4dcd-b2fd-c9a1dc7c0b0d": {"doc_hash": "73e54b1ec8bd6d7bc20ae5e8f40b79a624a2a1a994b7cb7eb7cafcdf2b6a55b7", "ref_doc_id": "eaf61b3e-9b8e-499a-a3cf-2b6d8a187ccb"}, "2f6aa599-1480-4568-8b07-467fc7887b2d": {"doc_hash": "69a9faf9fed19e6b54a7a4245a5b4fe6a40dfcb00a56b104898b4f1676462b23", "ref_doc_id": "d49edcd6-ca1c-4342-84b3-94a78c2e1297"}, "501917eb-3284-4ed2-906d-c542c38b38bc": {"doc_hash": "2ca8d7194e4e40b42f15fde4ce00d64cc8af8e4e7c8b552a4fb7cb79dd17434f", "ref_doc_id": "d49edcd6-ca1c-4342-84b3-94a78c2e1297"}, "c29ece5c-f913-4967-9239-56fa29febe2c": {"doc_hash": "541fbfb96f74fff082bc55edb13bd7cf77d03aa16c420346624dfafd684b1f56", "ref_doc_id": "a3200552-b3b7-4610-87c5-0179aca80007"}, "1d6670dc-a646-47ae-a604-a93d9f62a716": {"doc_hash": "1bdfc318d0d0ae928250d90af9767462ab1046df0004ab0a4e5de84b5e951993", "ref_doc_id": "a3200552-b3b7-4610-87c5-0179aca80007"}, "12334442-18e6-432d-b1b2-9022f0ba0dfa": {"doc_hash": "ed3a37bd00db8ae9401beea6dede67363b2fa11ae895567aed0ffde3682fff86", "ref_doc_id": "6570956f-6008-4b2c-9836-9db29840a48d"}, "d74f85bf-b60b-446f-b2ef-ca1cb6b1a30a": {"doc_hash": "a5fc2fe101a3dc28b65a3fd97141bce72478d08eaca4dc1d0758a66e65b98b8f", "ref_doc_id": "6570956f-6008-4b2c-9836-9db29840a48d"}, "82e1819e-3ada-4883-8853-022aabfaa75f": {"doc_hash": "40e1990a69b631e9e8f6f54fb6fefc85addf76ceaeea13043c19f2b9709ca132", "ref_doc_id": "7478c90f-6ce5-456c-ab05-cd2ba27596af"}, "ff80669c-5298-4860-97b2-82303f9f4487": {"doc_hash": "ce1874e73c8d04dccfc209e25f41a15c1d59064141e218065d0d5f0482b1ebdc", "ref_doc_id": "7478c90f-6ce5-456c-ab05-cd2ba27596af"}, "992e714f-e521-4509-8a00-dacf00a91c33": {"doc_hash": "f95eb06d93e404239b8c90365d7396d7a2c3c037679afe6469acf6b475039931", "ref_doc_id": "2233b4f0-bbd0-463f-a462-1560b270a0b9"}, "9f07bd86-791c-4d0b-99f6-1c7d2ea23b4a": {"doc_hash": "062feb5b744944bfd9264d17e9f4ae8ddeddf8c862deda1ff0afb2911922177b", "ref_doc_id": "2233b4f0-bbd0-463f-a462-1560b270a0b9"}, "87da8920-04a8-4ba1-aaf8-9b33e3d5f494": {"doc_hash": "2134edcdf61679eb9752df85469d0688223748cb6e76b5633b822117b6d4b10b", "ref_doc_id": "260b477b-054b-434e-990c-fa1046bfe017"}, "ddee49c9-73ff-47bd-b923-47cd8b169032": {"doc_hash": "3b9748d95794f6ccef8f465bbeedf8c1ea3f544ac51118c4a61d3dae1d19acc6", "ref_doc_id": "260b477b-054b-434e-990c-fa1046bfe017"}, "400939b7-957f-4407-9ffb-2677e117a11e": {"doc_hash": "f02f40ed7948ddcdaf34f831a5b6b6e301d4610c4b1ac55548975b22c4131b74", "ref_doc_id": "fff825a5-980f-4a33-9ec5-45034f496869"}, "cc302f03-5698-4418-9f8b-d4c4f36f6d9f": {"doc_hash": "5ee5cfcd4dc5f7b57fac61030d67a50354c95335f84f639119de5d6bf8bd48b6", "ref_doc_id": "fff825a5-980f-4a33-9ec5-45034f496869"}, "6d57d4b0-be94-4983-92f2-c426018027fc": {"doc_hash": "867b4d67e9450409400a53c77144c45c28c1675d430d5e9de55fe5822d255d71", "ref_doc_id": "fff825a5-980f-4a33-9ec5-45034f496869"}, "dfed8f9d-c594-4b62-91ec-c00b65a13f11": {"doc_hash": "8d1d324474ae35cf8d5584adf9d63af4286f8a2be087652939a281a09eb4a3c9", "ref_doc_id": "30581b13-5955-4c1c-9b76-227c358212a8"}, "68f95947-7920-4bdd-8a8b-70dd97c46727": {"doc_hash": "3408e8605dbb50aeeddf31e9d7b450f18a84cb17718dd15501a0dc298f379186", "ref_doc_id": "30581b13-5955-4c1c-9b76-227c358212a8"}, "eac2feb1-0ddf-4e04-998c-9a381846734c": {"doc_hash": "2854793363931d065eff70fd79839b465170cb4cd79ca2430ff162c2262f1097", "ref_doc_id": "64009123-9510-48c2-8b17-fc140eccdcb1"}, "f38c5afb-61d2-47eb-9ddb-d022b4beee0c": {"doc_hash": "99aafee7020aa340154b13b90454ec86100f684a10352e43eed7e138dd8f6734", "ref_doc_id": "64009123-9510-48c2-8b17-fc140eccdcb1"}, "7921d4ee-9614-4b40-a6c9-a5216c534ade": {"doc_hash": "2735404e1608ee7552aebec2ce24633fed4b4d94168ca1e30d246362e36fae86", "ref_doc_id": "8d9a0294-31f5-49c5-a0dd-c28c6bf3decc"}, "8c00e6bd-4b8b-4c24-9f58-b333eab0c412": {"doc_hash": "1e13795b865f305186975b651c7843facf16c917afad89bb6cf2e486619dbf00", "ref_doc_id": "8d9a0294-31f5-49c5-a0dd-c28c6bf3decc"}, "d899a16b-0fc6-4d30-988d-7d9cc3d9c5b9": {"doc_hash": "91558ecbb18278851e629b4fcd2850df890976f41eec1334b1783ffc0c94493d", "ref_doc_id": "2926298c-ec4f-453b-9824-e36cb8bd97c9"}, "33ed7693-2f69-4c8d-a5b0-97027e9a1123": {"doc_hash": "27b0b47ae9babb38c30db049cbf8622132dc9dfb9bb669594ab49634fff614b9", "ref_doc_id": "2926298c-ec4f-453b-9824-e36cb8bd97c9"}, "a381370e-26fc-4243-a959-a2564dabbf6d": {"doc_hash": "6b5b796e360d3d7c358ac8783db1229807271d4dc4c84bb47fd73d19d98db460", "ref_doc_id": "73c223ef-4a3b-48ce-a7a8-1d74ddb38fe2"}, "37a81382-4c25-49bc-a08e-ac445af7e11b": {"doc_hash": "b862964de9413839cae3925013d661070e5cd648fb1f8ae7ab22161c1146b6aa", "ref_doc_id": "73c223ef-4a3b-48ce-a7a8-1d74ddb38fe2"}, "be2204da-aa24-47c6-a1bf-981bc81dbeac": {"doc_hash": "3f6b0ede3d8757f75b90860db325a038608cd0691f2d4d3dde1357d72c85ef92", "ref_doc_id": "e130cb5f-021e-4944-bde3-bdb43f2b5c97"}, "005f1136-a4d1-4f71-90bf-76e37b68fbd4": {"doc_hash": "f3086c67c8b2f4e8e4981d560f46b72c60c6905725dd4fa996eb7db1e6c7b659", "ref_doc_id": "e130cb5f-021e-4944-bde3-bdb43f2b5c97"}, "56c0e92e-a489-4f84-8969-950c69a39d62": {"doc_hash": "a08fc9a8e0ed9f34bde2d2915df43d6e40cb5a37f8b2a00dfcc407b947b33895", "ref_doc_id": "e130cb5f-021e-4944-bde3-bdb43f2b5c97"}, "08792c8f-b935-4cda-8690-67891a48eb98": {"doc_hash": "bbd6cfb17c632502aab12f22dc39f3855fa3e7cfee1b72ef3c05516693b4dbfe", "ref_doc_id": "c350c827-c430-45af-859a-903d2cb39e48"}, "6822f32b-1581-4212-92c9-4cf2755192d6": {"doc_hash": "69a42c287549999e5bac309153c785b0278395dfebbbee2a69dd480b34fd42e6", "ref_doc_id": "c350c827-c430-45af-859a-903d2cb39e48"}, "59d23f56-810b-473b-8df8-106595807acb": {"doc_hash": "1ace92eedb5baad992177b9d742f0c6d041ebf9ed4ce4582ebcdaa57c14c31bf", "ref_doc_id": "c350c827-c430-45af-859a-903d2cb39e48"}, "1aab28b8-c555-4611-95f7-262f3e7b4f10": {"doc_hash": "2fb88ebed68d68f1527001e7dd947983836cab59d2f9279bc8b9961e767171df", "ref_doc_id": "8573aeb4-ff29-40e7-9cad-8d5fa6308758"}, "ae9c2a81-ac97-4d2b-8cc4-b9d36d2172ec": {"doc_hash": "dd4a1f3b6b44acdb7c52c088c6ad2c4b29fd4a132f72bd2d601e42f00b0cd2b9", "ref_doc_id": "8573aeb4-ff29-40e7-9cad-8d5fa6308758"}, "c121baed-ac42-4758-8b81-52a9a8da64b5": {"doc_hash": "333ea8508fe11ad5a50c1b689bf9573c5d138767f3ddab45a777fa4c72d2580f", "ref_doc_id": "bea488a7-f4d3-493f-9046-b7d7b05c3dbe"}, "ad8eeea8-b267-4270-a1b0-32781c8c05d8": {"doc_hash": "c371592aac770253d0a8519f3240616de8bd29504ea39376004bfb51b4d85ffc", "ref_doc_id": "3f3ac97b-c944-478d-a1d9-38e8666f5b90"}, "b26fdb4f-d9e5-4e46-8354-429d189b3f99": {"doc_hash": "5dcfa06f6e69de730cda33b1aad8e5d68b8cd621fe8754f2b45f4daaa9abf3c1", "ref_doc_id": "3f3ac97b-c944-478d-a1d9-38e8666f5b90"}, "ffd3c5cf-1124-4a00-81ff-d9e8204a2495": {"doc_hash": "86c8f6c73553c62b22d4ff6850d941b34811262d0b33e686f2b0db87b5e8936a", "ref_doc_id": "98224aec-f657-4911-9593-9ed0f0716a54"}, "88461808-8e4b-4342-8c32-4565c01bbb43": {"doc_hash": "529d61cb5c4cf4f759628bcfefc1608c60dd13aa2341ec2fc2e43177cb35c1b0", "ref_doc_id": "98224aec-f657-4911-9593-9ed0f0716a54"}, "bfb24b01-8b56-476d-a156-bb0982ff00cf": {"doc_hash": "de5a4e807f0210d55ce774fd7da53b0a131bf0114a3c7784832fb348096196d0", "ref_doc_id": "98224aec-f657-4911-9593-9ed0f0716a54"}, "387d6fd1-d69f-4289-961b-6abbdc049b56": {"doc_hash": "585e7ebea900a7e9288451ad6bc395413b7abfd1fdf365df32de2008d8e44ac1", "ref_doc_id": "22200d52-b191-4236-bc55-72dcb50e180a"}, "3c9eaea3-1dff-46f3-90b4-d7959039393a": {"doc_hash": "20507094299df5c684b46b4d69639d632638f775ab0cdb99372477328b05f6e9", "ref_doc_id": "22200d52-b191-4236-bc55-72dcb50e180a"}, "a4ed3ab9-c675-4068-b345-befe90d1f5ba": {"doc_hash": "ca481472b4e0ac7c38895f3cc7608524de8493375db57c2efc27ca5d34a9d4c9", "ref_doc_id": "0cf980e4-13da-4048-9a2c-e2821df2bada"}, "839aef15-9423-4a70-afe0-d0d9759ee11f": {"doc_hash": "5518423e7f78bd0093a7624fb2a6b5e111ac6a61eec745c32f2fb0e6bf2074af", "ref_doc_id": "0cf980e4-13da-4048-9a2c-e2821df2bada"}, "b497a5ec-1d17-460a-9c46-296d5bc97082": {"doc_hash": "21211eb21f9d72469604c01ad593d0119219b016fa3ec032aecb1e841f0b1912", "ref_doc_id": "21c50316-5573-46ab-b10d-65561c9917ba"}, "278108c2-78f4-4c03-88a3-0af07e5b672a": {"doc_hash": "80f7323b0400c42ce48d498a994769f22fcfb767817f2fdde95b6e26f850b9a2", "ref_doc_id": "21c50316-5573-46ab-b10d-65561c9917ba"}, "5f98baf9-1e1e-42d8-8711-a7bc3b591cae": {"doc_hash": "7cf8404a718cf9b2485f40cd5864ad78571f9c15748c8d53a5152d77290f2f70", "ref_doc_id": "21c50316-5573-46ab-b10d-65561c9917ba"}, "cfac263d-925f-4c5a-92f5-4823f3b6a05b": {"doc_hash": "c64e29f67470a0e34a6f636d387efeeee6d0aa9631b014ca1f074c6bf9c4c042", "ref_doc_id": "3ac7325f-441a-47a3-86da-d059b679d783"}, "788d36f0-07aa-451d-bc71-a1455fd80617": {"doc_hash": "ea23111d813fea471b0f1864e0e0779341e8b10082097eb78df3528aeb818273", "ref_doc_id": "3ac7325f-441a-47a3-86da-d059b679d783"}, "57099d50-95d3-4a60-9629-988046838331": {"doc_hash": "33979cdef2be6097b0bd31de639073d107571b431aeb07e9309fb36b6b6a5b2d", "ref_doc_id": "7c1c9517-e544-4c5d-a853-3d19c424bbc1"}, "64a16c70-fcca-44d9-a230-6ce17d97a4c3": {"doc_hash": "c46ddbec5c5f7959bf46061e0cb98acd0782be5880e46bdd9dbbd55a9ad61e90", "ref_doc_id": "7c1c9517-e544-4c5d-a853-3d19c424bbc1"}, "94b40922-f839-49bd-9fe1-f142a349e4b2": {"doc_hash": "1c26d8a50f43f8a89bd4d65a3575261c07d2d683bada2d59145995ec388ccbde", "ref_doc_id": "6ca7a83b-3fa0-4094-a157-aa9483abc836"}, "5f9f747d-5e4d-4594-82e1-2a983d95988e": {"doc_hash": "9939266f8c684e66c0ce6f7f35c44c39919d4280a7ef886637595690233d91cb", "ref_doc_id": "6ca7a83b-3fa0-4094-a157-aa9483abc836"}, "cb037d7e-539e-472c-8222-3d963184d4ab": {"doc_hash": "f2e12d5ee8636339b7696193ab1add68f01b818d83a99dbb3522a2027c3ec8ba", "ref_doc_id": "6b65e8ab-70ee-4a2d-931a-c4103bf783ec"}, "bf996fdd-bc20-4e96-a0fa-5ead3bbf7d1a": {"doc_hash": "d0bc9755d8220a23228d3a7b2cde0c79e2699002764e469f2ad71072681060c2", "ref_doc_id": "6b65e8ab-70ee-4a2d-931a-c4103bf783ec"}, "1ad6fcde-990f-40e1-b3ea-9b36da3795d3": {"doc_hash": "8a10dc41f43ee118eb84b2ce64347bb0a36b971813438ec187954a0822fafe9c", "ref_doc_id": "0ed360c5-3f13-4686-a627-f0fc85dcbd22"}, "89360432-824c-4330-90fc-793ef7d764b1": {"doc_hash": "aac5fa87e68029f853120c810edf21fc6991734046d9451d6dc2ffb662bbda67", "ref_doc_id": "0ed360c5-3f13-4686-a627-f0fc85dcbd22"}, "f78ecb36-2dd7-4907-a0f4-f2affd3091af": {"doc_hash": "a34b5292dce7cde5b62df82f9f91f8a3f3f2a8faa5cbebad883635733d2481bf", "ref_doc_id": "e6f3dd1d-a05d-47d2-b7b8-5f349822a71f"}, "7cee7c56-369a-424e-b512-d739cfd777a3": {"doc_hash": "413874abe811b3a430ac8af1c03e57573f75fceeac6de128f602e204718bb238", "ref_doc_id": "e6f3dd1d-a05d-47d2-b7b8-5f349822a71f"}, "4da1771e-5e52-4661-bf99-ef6d6f5ea7b1": {"doc_hash": "b88f71149192f646277f2f2594b7d0c9e745b0c28134a520fb9c12e66eea8bf7", "ref_doc_id": "54cd3a27-ee22-49c2-980d-9f286473132c"}, "7919f8a8-9eba-454e-b6b1-1904d34aad43": {"doc_hash": "faa5864aad1f515817090c7cc3cdb090c85101e911ec0aedd30922e581aa824a", "ref_doc_id": "54cd3a27-ee22-49c2-980d-9f286473132c"}, "dafe0f41-bd82-478a-b223-83bcb572ebcc": {"doc_hash": "acc8a947282c313a50f3372744b21bfdf5c502044f3264341307a77574b6157b", "ref_doc_id": "737ee5e7-9f0a-4b9b-a303-ab10e318d0d8"}, "14d5611b-3b76-47ce-8308-9f8ef0a7bd53": {"doc_hash": "7bfae15085c9e365d4640ede575127acc20a0c67d026def9991ea50946f39a06", "ref_doc_id": "737ee5e7-9f0a-4b9b-a303-ab10e318d0d8"}, "2546deb7-6133-4a4c-9c5a-e70f757c555f": {"doc_hash": "eb8527b2b15e309c421e1a1ba624486e6684866aafff835b967e41a5f7cecca6", "ref_doc_id": "9578f030-ebc2-46cf-9b78-b3cc1bc692a5"}, "152ef194-4a83-484e-bbad-040229f7e09b": {"doc_hash": "c5e71105e2d4f066bef5f4afb3c30036b6e9c64702dac9bad6249ab49846b60b", "ref_doc_id": "9578f030-ebc2-46cf-9b78-b3cc1bc692a5"}, "ffad4f42-eb16-431f-9dc7-6ae28546b4b7": {"doc_hash": "0468ca1ff180c8070aa03c78df7d8e8e5a8b3ab1dc9aa3a331c8beff43ec9ada", "ref_doc_id": "03dbb60f-b29e-4421-9ba0-7b5caaf5ee40"}, "59ee4a62-52ff-473a-8b50-16326b8cc87d": {"doc_hash": "b68c134e44bb7ec4aa536acbfaad8df707f745a434610cadb5556d8923fdf3d8", "ref_doc_id": "03dbb60f-b29e-4421-9ba0-7b5caaf5ee40"}, "4e5b909d-fee4-4cd4-bbd2-ea93e2c9c956": {"doc_hash": "e8fc4012080e0ac48124c78b4f83c135fe6e22ab2c7cb50595b0b117a7da8ce3", "ref_doc_id": "c5708c93-982a-4a2c-83be-40839cc174be"}, "1b66140b-37f5-4690-b369-603b00e66121": {"doc_hash": "8b32304f7adf474314d2b2653264075a2f597ebfe447082787e054334ed33f28", "ref_doc_id": "c5708c93-982a-4a2c-83be-40839cc174be"}, "70a7777b-27d7-4a37-a89e-3568398db9a0": {"doc_hash": "9b2531f09871ae6f13e00d327615d44aa3e038a3c7c2ab348bb9c6e16e769206", "ref_doc_id": "4ec86f52-80b5-41bb-b362-0ea24d2ebf4b"}, "0543bf5d-4617-4c69-a3f7-cf8f89015305": {"doc_hash": "06d04e0ee5b87e7813b46a8e569ac1d7c1c90ea48faf3fab29956f7e51a2f56b", "ref_doc_id": "4ec86f52-80b5-41bb-b362-0ea24d2ebf4b"}, "beeb9469-8724-4f57-930d-f3b13bf6d755": {"doc_hash": "715b21f71e24064f543287b5f640058fdbf36df78742bf6806d69b1fec45f4d2", "ref_doc_id": "4ec86f52-80b5-41bb-b362-0ea24d2ebf4b"}, "73af8a0e-13ba-4012-a842-948c8c3338bb": {"doc_hash": "c9a9cc8c31a93c414789338b76f88549761b16bc667a731711099be78db76c07", "ref_doc_id": "203809e9-b2bf-460d-ad91-9c7cd697612d"}, "d07354eb-ba33-4c32-86d9-62f72e6b88dd": {"doc_hash": "1038d5860010c38c7114de2e00134c33c19cd325f4b4e4a8bcbcd25f11dffa43", "ref_doc_id": "203809e9-b2bf-460d-ad91-9c7cd697612d"}, "182ae4ad-1172-4f43-ae67-080183f317cf": {"doc_hash": "c5b256f8ff7fa7bfa069fbe046197c609b9e7c99456b600217d4e3cc4e7b908d", "ref_doc_id": "d07d5e36-89ca-4a85-9806-ea5cba2db0f8"}, "7f73123d-fdf5-4d88-89c6-b43d4a196b2f": {"doc_hash": "3e34d6edc98263920e623e3740ef968334810caa80bf026d19615f4ca9d9e940", "ref_doc_id": "d07d5e36-89ca-4a85-9806-ea5cba2db0f8"}, "5621fa90-822c-473e-aef9-c6b28309d39b": {"doc_hash": "b91486b9302a9dc68f1da5cd74ba029ebd780c39ff02c023cb8073d41b15fa81", "ref_doc_id": "d07d5e36-89ca-4a85-9806-ea5cba2db0f8"}, "f5d1afa9-b3e7-4077-8c4b-f29ecbdb16ad": {"doc_hash": "a7ce68ba5197059d1bba8d78c93d6abbca43f2d41b560b075a59e9d904101fc6", "ref_doc_id": "243040ca-57e0-488c-b5c7-d57198a11ee1"}, "073f1ff8-8c0c-4b8b-a48e-d122e8c1610c": {"doc_hash": "36424f6575d9db602dd84a3b0c4e2733f59711bc03c106a32e810d676c771471", "ref_doc_id": "126b3c54-b015-48a2-9895-99a035c444d7"}, "b829a60b-4681-4744-8507-25a4c0d4bbf1": {"doc_hash": "761ef8804796e71cdddca4670c4d90c64a8aa5c339d51638e2417f82df51d89e", "ref_doc_id": "126b3c54-b015-48a2-9895-99a035c444d7"}, "6e65ae73-8411-4469-bebc-ac3dd6d7af6d": {"doc_hash": "c6e55804ecaa87724225f742604b7c5cd23708ec766affcfc320946b730f8984", "ref_doc_id": "2f1322f1-b094-4c2d-a6bd-1bd24c26f0d0"}, "de7d3cc7-00b6-46fd-a52b-0f0f4a44c5ad": {"doc_hash": "ce31cf5ae14ccce3dd3817e484e53e2366137b98d83f25092448468b6b4f5f1f", "ref_doc_id": "889937f8-cf3a-49e4-8519-e3a2d74f1ae3"}, "1b6e1170-577d-4e51-8e9d-d46a2e5700da": {"doc_hash": "1271c09dedc5cfacb2411519e4878036c54b20fe289e9f1fa67ea9e963c6520d", "ref_doc_id": "889937f8-cf3a-49e4-8519-e3a2d74f1ae3"}, "d038776f-fd91-49bb-809f-6dad6da79690": {"doc_hash": "0395791429e6f756166ed49027b101b53c83b5117cfcc88cee80e6edc4c92dc6", "ref_doc_id": "94581969-5096-4860-a484-42d2aa0cd7c3"}, "1d50f054-3b75-4975-9b64-ad919fe1d27b": {"doc_hash": "d9a32e388d0d9114ba421884baeb5d40da78a1e3c3015f2bdbf5f55a753b50dc", "ref_doc_id": "94581969-5096-4860-a484-42d2aa0cd7c3"}, "7a640613-e9cd-4e90-993d-de240e14ddb5": {"doc_hash": "bb32920ef4521a28e65b8b23703ee248720c5695ae793814710a1bf7d3fd176c", "ref_doc_id": "cc7fd213-5eb7-4f40-8341-2856d1d6f409"}, "36f5403e-5b5b-4bec-843c-cab3a4d5bcd1": {"doc_hash": "14f94f799b2469cc9d16268749a5ec4deb2d445a68622138a3ba6d93e5a73334", "ref_doc_id": "cc7fd213-5eb7-4f40-8341-2856d1d6f409"}, "29873970-1bcf-4dfe-8dc3-4556c8f6a61a": {"doc_hash": "5a042ceb18c6487bf8e586b96537f38e9f1153f14d5afa6ffe71cbf3c47c9e9c", "ref_doc_id": "cc7fd213-5eb7-4f40-8341-2856d1d6f409"}, "8a06d58d-5579-4352-8c3f-a3e702134a3c": {"doc_hash": "c944b9a5bf94d863c93e0b5412925b6f2afedb3fa6f4ec78b5551d225409a257", "ref_doc_id": "5decbd03-1b78-4c43-9b15-28bc0722a205"}, "fbd99928-8119-4733-a0eb-e4e820168e73": {"doc_hash": "c416ac67a4967e4cd570748f3fee095660545f8e49c314848d5f9260e58ff7e2", "ref_doc_id": "5decbd03-1b78-4c43-9b15-28bc0722a205"}, "6196bbd0-1ae2-482e-8806-aab25a8ccad2": {"doc_hash": "65242918b358ea88820ae23083370b279869f8ac5d43b55f7fd7213cb8bd57be", "ref_doc_id": "109d1ad3-db27-4f8b-80d3-05e1148ebaf7"}, "ab4e0310-cc54-4f38-96ba-a0b984e5dd1f": {"doc_hash": "d208cff62aa023add4018a403102a6776f1f613d172e8a0b1957774cc4275d2e", "ref_doc_id": "109d1ad3-db27-4f8b-80d3-05e1148ebaf7"}, "a2b174e3-f6b4-4828-a565-483e93e78805": {"doc_hash": "40ec5aab11f1f6ae53a726ff2d98576fc6cef85684e279ccbdb3ce65d626e135", "ref_doc_id": "109d1ad3-db27-4f8b-80d3-05e1148ebaf7"}, "81247d50-9525-4bb2-af42-7dc74d3e448a": {"doc_hash": "218a899fddd9c89fd7868fdd1c1dc5cef144602877de3be5101069f72b8e3cd1", "ref_doc_id": "3e88b904-0319-47b3-bec9-c439177d307e"}, "389fae5d-261f-4d84-9e62-6938e6e47a29": {"doc_hash": "61e203be45d71a01a141b695c3ebb090b96336add8dd8052054c81ebca7f2156", "ref_doc_id": "3e88b904-0319-47b3-bec9-c439177d307e"}, "0b129ffc-6be2-418c-9e20-05dafcb61533": {"doc_hash": "7fe80f11cec1fce795b2a8a02dfb20ed52e55a1e2c49e65e6e362bf442caceac", "ref_doc_id": "15e7e7ad-c2e6-4d63-810e-b75bfc4eecc7"}, "623508c9-5bff-4ee2-bb5c-827ad6993e5a": {"doc_hash": "608215853389523e0ddfcc09c25aec4580f792fc4e9ab87c612d1f45cf7f6213", "ref_doc_id": "15e7e7ad-c2e6-4d63-810e-b75bfc4eecc7"}, "a52e7a1e-330b-4703-8814-2d553e38210d": {"doc_hash": "dd1bc192951c0bdc86d17e90c0b4ef17080bb965ebe8c28b9d1ee9413226ff61", "ref_doc_id": "15e7e7ad-c2e6-4d63-810e-b75bfc4eecc7"}, "22ade394-a97a-448e-b988-c2ebbda51816": {"doc_hash": "0500be07f0c7be710290e526bd7f733a97e918e5a6a744b76ed963df5a177c48", "ref_doc_id": "06da3ba8-f7df-429d-a061-d9b1c45abb46"}, "10e011fe-7498-47e4-bdcd-2e69216e2bd4": {"doc_hash": "62926200206430ccaea9625ebfb14576d237a658f9d2f3b3a9cb42b6a331bd28", "ref_doc_id": "d4adc45b-f76d-4538-8d80-1f050c69bdeb"}, "bf3ac2ab-8cb9-46ae-822c-be8a09568526": {"doc_hash": "08a712ff5baadfb95aabd764868081434eca6cda156664788c24ae3cefd8da97", "ref_doc_id": "d4adc45b-f76d-4538-8d80-1f050c69bdeb"}, "1b2be3a4-548d-438e-b1ab-db6bf9cc1f0e": {"doc_hash": "ae1ce823580f97d8666cf27ee053033e33b60b3200ef2f4918a586995d8ec0fb", "ref_doc_id": "fba39d8d-914f-4dcd-92e8-a54373e14b4f"}, "ea676f44-1b16-44d0-956a-29f53a44e950": {"doc_hash": "7370e87a849c49c5d8ccad836245498ca316c1404149f59e6c3b8999fbb63bc0", "ref_doc_id": "fba39d8d-914f-4dcd-92e8-a54373e14b4f"}, "86073e8e-51a2-449e-b3fd-689d7942be63": {"doc_hash": "c36607425c0eaa2d55e8667412f726ad04124c09cbf6221e41de090c9f383d54", "ref_doc_id": "2787f3dc-3f6a-4e50-be71-a85d1c8e01ba"}, "8af10762-b99b-4e5a-84ad-3fe4431892e9": {"doc_hash": "3e957351eb2d3003697b18ace182808e51c6fc09fce816815908b4a783a8a72e", "ref_doc_id": "2787f3dc-3f6a-4e50-be71-a85d1c8e01ba"}, "dbc84f8b-dae9-401d-907a-1ac129cb736d": {"doc_hash": "b7fdc5c8015826f4df8bb31c1f8876825afad69ee0939c426a8121bb47348d9f", "ref_doc_id": "75bc9aac-619e-486d-b3b9-46e5ea82f0cc"}, "88d1d145-2281-45e9-b443-1d2aa411405a": {"doc_hash": "6f0b02b45dfca5d9e5ffd9f0ebec64ed910e78a929ac2abc8337da63d2515a12", "ref_doc_id": "75bc9aac-619e-486d-b3b9-46e5ea82f0cc"}, "bf090f23-e16a-48d1-a2e9-c25d029f5667": {"doc_hash": "b3d2c4ed12b103cc6ca0c6991e19593539212582bd482430aa2ac59dc17590ae", "ref_doc_id": "e6e6b521-0007-4d47-849b-14e1ce997dd7"}, "ab30ceac-14e6-4335-984a-a6210459de25": {"doc_hash": "88bced7089f7d6e73a8effa80620c85bb31e7a7197972dca9434115c5077e87d", "ref_doc_id": "e6e6b521-0007-4d47-849b-14e1ce997dd7"}, "749407bb-b8ca-464c-b27e-03104da3c38a": {"doc_hash": "babecb9bd618f374d92b8a9310a64076c0163d3b0a57a4f01682e2bdea8be88f", "ref_doc_id": "6320fa5f-f3e5-4a16-9fd7-6be49257980e"}, "30f77fa8-9c8f-4697-9575-5a4aeccaa6bd": {"doc_hash": "1c7876efdf9a61389dc9d72fdf531c377c9590f06d63817510b8c33fac3cc1c4", "ref_doc_id": "7a39621e-7e24-46fb-b5b5-8624b7a664e1"}, "235c4ba7-5af9-453c-81fa-ebd8d713ffbb": {"doc_hash": "b39e0bfb8c9945e2f1909f4ff58e545e671790ff05cd69156b7e46e0f1f96fa3", "ref_doc_id": "7a39621e-7e24-46fb-b5b5-8624b7a664e1"}, "d35fc882-eb72-4db6-af09-797b2906238f": {"doc_hash": "f2dc3eeceb3982c5311e82d7d424e8f72738af374edbef51da029ea7fc867f2f", "ref_doc_id": "ade4fa21-fdd3-459a-9f8b-8d3a08fc7e0a"}, "95400e49-a559-4ed0-aed0-476031306c1f": {"doc_hash": "9cd3c52adf6bd12a823f7329f5148b25446b2c8899525fc715b763b7e8fd04ef", "ref_doc_id": "ade4fa21-fdd3-459a-9f8b-8d3a08fc7e0a"}, "d2e8838f-a8b6-43ca-b3f5-955091c2cee1": {"doc_hash": "ef4038b97838dec943b949c849a7b0a56addb90bbb635f7dd420724eced45ebf", "ref_doc_id": "c5ba3c2b-278c-4c6e-94b3-a54d5e583e59"}, "0895fde4-c357-418b-b44c-0cdb1082809c": {"doc_hash": "94a812d1a5300a47c3a0ac07006c0a2267d8e6ed4eb6ddd56b62409b34e21a04", "ref_doc_id": "c5ba3c2b-278c-4c6e-94b3-a54d5e583e59"}, "43e45e40-fede-492c-9332-1858c94e8642": {"doc_hash": "db27d7dec94e49963feeb1a81b4c11ac6e67cc18492dfb28a7afe488b244b846", "ref_doc_id": "e141a14e-c6a7-488e-b761-956334ac2e30"}, "fc9b2eed-5bb3-454f-9884-d77dda2804c2": {"doc_hash": "db4d3da07e9c5fba5a74ddd59a45de8ad62b6a9c6eaab6e10cba1c404cdb8fa2", "ref_doc_id": "e141a14e-c6a7-488e-b761-956334ac2e30"}, "1eeb523c-eca8-4cde-9bd8-2e90e653650c": {"doc_hash": "7bf548d0ddadd47f950030ca02264135c134bb21a3f424120666e00bb502f8bf", "ref_doc_id": "d6c5149c-a967-4043-98e6-8466ac2de86e"}, "bce40c4d-5fc0-4f4d-b5b6-2eac81aa2b75": {"doc_hash": "45cee60eca5f55a6738b85bd06ebbf678451e628149b3a6abbbfab687db3f323", "ref_doc_id": "d6c5149c-a967-4043-98e6-8466ac2de86e"}, "ae07f997-c440-414d-8284-c46faf5acbe5": {"doc_hash": "a9628b0c6725231b83b07fb60578f5e93d25f4c0c7f2916d8a919114f37ff524", "ref_doc_id": "57ea7ac2-7e22-4a51-82e2-d12bb9d444dc"}, "872064ff-1e7e-493e-afcb-b5de0bd00cd8": {"doc_hash": "9be6b629e4c626eb893514a4eb1796eaae10f991d50186bc9fd5c3e5aa047840", "ref_doc_id": "57ea7ac2-7e22-4a51-82e2-d12bb9d444dc"}, "a2729c9d-d0fc-4c24-9af5-6089def794ff": {"doc_hash": "981cf9b3fcdf2a4768c5045acf15b7e764e48ec63fb92d855d495d83a7d1b184", "ref_doc_id": "57ea7ac2-7e22-4a51-82e2-d12bb9d444dc"}, "0335c563-7c2e-4d7c-83f1-e55068b34454": {"doc_hash": "d119d0b1d37ddef2dd25a57d9d7114e1b444999acb6a8c75c029dc25f64da30a", "ref_doc_id": "32ffde5c-b016-4163-b482-9f3e4308eb58"}, "5262362d-2916-4443-8edf-f0590784d342": {"doc_hash": "e16a1d9349ec9cdd298218f8414808eaced370c70123b0bf23f1c12b534f0a7d", "ref_doc_id": "32ffde5c-b016-4163-b482-9f3e4308eb58"}, "8295accd-af00-4fcf-b890-84e34613793e": {"doc_hash": "cbb8e4e1f1c620a8b5ab3300a21e55399ea7224fe51b46afaed3e09b2223194a", "ref_doc_id": "4fd8461f-640b-41e3-a871-ff1d9f01ec61"}, "0b49f314-9421-4338-bd2a-bf1d2fc10007": {"doc_hash": "dc85de5a4965484cde530ea7c5735c4764f126df2d1e6acdf0a2cba8557a5542", "ref_doc_id": "4fd8461f-640b-41e3-a871-ff1d9f01ec61"}, "2fe4aac7-e942-491b-b9e3-e387b5a891df": {"doc_hash": "6983fa0cecd694fc68d5fec81cea9875e24b2f91f63010310fb6782a1a6965e5", "ref_doc_id": "4fd8461f-640b-41e3-a871-ff1d9f01ec61"}, "cbfded63-befa-4959-9336-69364fbf2d3b": {"doc_hash": "b1f3859803dc4a43edda940140563ea2b65485f7ec53b98ac7e6fbba816006a7", "ref_doc_id": "7868f618-471b-4071-bb6b-b026e466b7fc"}, "7c33ca19-cffe-4e65-bea1-3e9cc470406a": {"doc_hash": "b26d280663b98266fede0e97b59674cf34b886e38ad01c5078680a7ece48a034", "ref_doc_id": "7868f618-471b-4071-bb6b-b026e466b7fc"}, "663f4875-5629-4660-a067-10f17a61712d": {"doc_hash": "997edd0b01876d56769a3050047a63900a7f451c08c73ba928d4928c3f771b84", "ref_doc_id": "7868f618-471b-4071-bb6b-b026e466b7fc"}, "2b83b099-a5ec-4c1b-82cc-9b8f175eceb4": {"doc_hash": "476a7740335195989ce1bc2f6bd39389a736af337427ef1bc96ac237c7134813", "ref_doc_id": "ee18826a-548f-4901-8715-7af39e7753bb"}, "f38b3875-f105-425b-b007-b45951af1c5f": {"doc_hash": "ab3cd6d4888d61c2df43fa372796d57c4950500f4471410c53faf78a9adbd89a", "ref_doc_id": "ee18826a-548f-4901-8715-7af39e7753bb"}, "0d29a955-d3d4-47c4-bf5b-aaaaffbd1eab": {"doc_hash": "05eb1888bb49221ddae8b4e3fb92eb17453fb43119d6850a25db06da0c598659", "ref_doc_id": "90dee43c-9eb6-41d0-ac8b-e0f68cacb276"}, "82d6ba15-8906-445f-9bc9-7f2e26269716": {"doc_hash": "ed9b53495cb24d303dcea3c7b0b9a0686b504e79d15495536082fbca95bc24f7", "ref_doc_id": "90dee43c-9eb6-41d0-ac8b-e0f68cacb276"}, "63e97bdd-ca7d-4632-b8fa-e5ad162ba8b2": {"doc_hash": "fb1aca63d2608389a434ae22f1d6eebe6bf5f2435c8fa1029f78c03c267c05c9", "ref_doc_id": "456b5bfe-4173-4f2d-9215-9872ec72401e"}, "8e2c3a76-b867-4673-912f-160364e6253d": {"doc_hash": "4c537d414a0791d9290e959e41f3d94d6b7b6634ef48993fd788dd175155dede", "ref_doc_id": "456b5bfe-4173-4f2d-9215-9872ec72401e"}, "72d46f46-dd5c-43c6-9fe9-31c3a8d6e731": {"doc_hash": "53cf289e65a14769f3552cc6c95ee2a999c3731f01e22efe0b4c2e6dc7708673", "ref_doc_id": "456b5bfe-4173-4f2d-9215-9872ec72401e"}, "16d28f75-0773-4204-aa77-5d62cd6a40ad": {"doc_hash": "1c964bd81144b445af2f659b7ecd28c96261f2eb2d99e5b39b916301f5ec8bbb", "ref_doc_id": "288888be-56cd-4ec1-aa99-2068f429e7d5"}, "1f3d164c-de35-489e-aef9-596ea8525b8e": {"doc_hash": "7825aa7dffa839032cfdf1e692694722dfcd8e131ab56df99affc7c4b75f66c4", "ref_doc_id": "288888be-56cd-4ec1-aa99-2068f429e7d5"}, "5883cf82-c9ea-4e4a-9653-178537ddd533": {"doc_hash": "edd3dbbdaeabcbf3547bf55b73601609d34561345468366e483e7f43d1f9d1b9", "ref_doc_id": "288888be-56cd-4ec1-aa99-2068f429e7d5"}, "4c16e553-57f8-4c96-9f69-6c4bb906a13e": {"doc_hash": "63dc4c3aa7709476ae25ff01a3bcd4424faff1c255ee15f4852becbb04daecbb", "ref_doc_id": "95ef8d6a-ef6f-4a11-b774-6a31b0b888f8"}, "79d048c3-31d2-471c-b65a-afd8cfa1a0d8": {"doc_hash": "8f0fe605df633f3a8aca1c2f413b52d970a5a8f5f443c57633fff261e8f01239", "ref_doc_id": "95ef8d6a-ef6f-4a11-b774-6a31b0b888f8"}, "14cf9598-ee91-4f98-8a76-3c14ace29516": {"doc_hash": "619c23f634c23bc9dba62c07faf5d50b4ec17694421bdc886e5dccb52bea0409", "ref_doc_id": "4ef85af9-740e-4229-b599-d8d4e85ce41c"}, "6145253a-df1e-4918-88b4-4fbd411cf09c": {"doc_hash": "86cf61d237ed1b4ea271bea5df9e358cc53d042d8a6ca2084ec7038f9e265cf0", "ref_doc_id": "4ef85af9-740e-4229-b599-d8d4e85ce41c"}, "181a4561-5be0-47e5-ba01-aca57604e7c9": {"doc_hash": "e6b461a552b6145cdee3f9f4e4f16763233a18353886c407964d417c8a350305", "ref_doc_id": "a3ad0988-0f22-4a8e-b9e3-1d5897a4ebd5"}, "b853f3df-d10f-454e-9b38-4f94c449eb3e": {"doc_hash": "03ed68daa7af995c4a3cdac8f1d713a126cada2c1f86fe7b217114933ddcd624", "ref_doc_id": "a3ad0988-0f22-4a8e-b9e3-1d5897a4ebd5"}, "0a3c86f6-5ef7-42e4-92b8-8841ab1832a7": {"doc_hash": "fcb7430a4d118ad2fdd5dcd4d8649d4fc30f6f4bcfa0ab4f8c626f09d624eb8a", "ref_doc_id": "136a9f79-7451-4ba6-a160-f2b8ef4dadca"}, "2b3ea4b8-9798-40e7-9216-c65e4ffc299a": {"doc_hash": "6a72e19a2a7bb8ab25e89a5e2ac2cf4cff28897b9407db4df75d600aacd29163", "ref_doc_id": "136a9f79-7451-4ba6-a160-f2b8ef4dadca"}, "eb6841e6-ea8a-4fbc-a970-d78856b95b3a": {"doc_hash": "3185e846eea5dc0e4aa76a98a379824b75d4e57fdffeae1a6e06fb3b473771eb", "ref_doc_id": "a1f1ff96-8b29-4f81-87d0-d3c8e3d30826"}, "17437a2b-2322-4ab0-ab87-3231ab7ff932": {"doc_hash": "8f5d4d85cd2db92cac2848ced36293b8387d8a7163def709fae1586b474e14f8", "ref_doc_id": "a1f1ff96-8b29-4f81-87d0-d3c8e3d30826"}, "6f4d6c02-80e2-4510-9ef6-1e1b838a9a35": {"doc_hash": "c436c9948ca2dc51541b5458c443ea23f5c684233803bed2fc492c6053bfec3e", "ref_doc_id": "383319f0-3b67-49c0-9800-00c18fb1d6b7"}, "82d7bc62-352e-470b-a70c-aa247a962ff6": {"doc_hash": "5f86fe296db6a09e5d275791a20a60734e849cd4b7b840c9f2b3184199478c35", "ref_doc_id": "383319f0-3b67-49c0-9800-00c18fb1d6b7"}, "119f7fe3-05ae-426b-a48a-6a82da0ecef5": {"doc_hash": "3463b2e186da3d382a4bcd938698c72b08290019ba02ecec0e5f42858d934ab2", "ref_doc_id": "383319f0-3b67-49c0-9800-00c18fb1d6b7"}, "dd078166-e654-415d-ace0-4023a048c9a3": {"doc_hash": "0dacb8c3a62b571c298449e54a0e4d1229c87a7af8f2e6edd37e19e71d201cf3", "ref_doc_id": "e298e071-cfd8-4e38-bf2b-80db3becb0b9"}, "26654bb4-cb62-4e28-934f-3f4bb3c7e548": {"doc_hash": "27dc1c223dacfeb76d905026d555203aef187bf3b77174c76a62d3393d3df49d", "ref_doc_id": "e298e071-cfd8-4e38-bf2b-80db3becb0b9"}, "5ad0bc53-d13d-4c6d-b78d-94d1d0ed1950": {"doc_hash": "42c1be7f6154738df1af63a91c683676a02073d327be13bdbea008b07611897f", "ref_doc_id": "c23ea36b-b45a-43b5-90da-c01ccbbd3cb3"}, "917bfb27-bd46-4121-a814-3f78a5f15f8a": {"doc_hash": "d951e18aeb491f1365c783c5bfdf28d03ee2973fab3f4723515df5023f8684af", "ref_doc_id": "c23ea36b-b45a-43b5-90da-c01ccbbd3cb3"}, "8ae5bc58-3fb9-4339-950d-db7f889a1826": {"doc_hash": "cb226680046db0736e82c92740863d4e9e3cdb09450143892fec7b28f58fd737", "ref_doc_id": "c23ea36b-b45a-43b5-90da-c01ccbbd3cb3"}, "46f51e5d-5d8e-422e-9694-b9c6bb6c9d28": {"doc_hash": "5f001d69fd0935504c81ed3ff381584cb60d8ef8fe1d9e64f7998fe83c6a4cf7", "ref_doc_id": "f76cae65-7d50-4032-ada5-1c4d1ac41c56"}, "a74e732c-8e9c-450a-b494-926f1628715a": {"doc_hash": "6b18fabd8370a7a541368a5fa7e4c83b6fde8814b4328817b792efbd933e31a1", "ref_doc_id": "f76cae65-7d50-4032-ada5-1c4d1ac41c56"}, "35a70b95-0920-4c3c-9f28-b7408f203ddc": {"doc_hash": "8ee6f2dd843f07a803f85f215715bc9d7dcbfb178f127074e5cc6d2195e51d6a", "ref_doc_id": "0fdf224e-99d0-4940-9fcc-d3ea8d0422c7"}, "6c917109-6d6b-437e-a476-4b6e10d2963c": {"doc_hash": "4fd0bb92bb8b9e87e68857d899ed4e35912891e2a0fdde38b0650acd3837a21f", "ref_doc_id": "0fdf224e-99d0-4940-9fcc-d3ea8d0422c7"}, "b57d5c18-9b63-4843-a108-d9c3d49290d0": {"doc_hash": "10e527ec5f1c2e815692ef2b914edb759619d15c3e35653941e5339e703f24cb", "ref_doc_id": "206472a5-ae06-4c7d-8216-14b3408803bd"}, "38bc94b2-7109-41c9-badf-52c26cd005f0": {"doc_hash": "f9bdc4ede621862a1aaa1725b6f4a48ae63fc1ae53fa6d8909bd2a9309b41376", "ref_doc_id": "206472a5-ae06-4c7d-8216-14b3408803bd"}, "58a29694-20d1-4992-87bc-277748883e79": {"doc_hash": "0789154c302cf40fc3e89c2c6a16e49c848823efd86f696e60ad10c640185925", "ref_doc_id": "206472a5-ae06-4c7d-8216-14b3408803bd"}, "aad80dfc-dbf0-487a-ac74-ab9aa48851f2": {"doc_hash": "5a638030749a8151c4473def198887704f0d8b8fa6754e2c454d66d81ade6c89", "ref_doc_id": "e895e8ae-bbf3-4933-8651-67ec9949c758"}, "3ac28c5d-8e8a-4968-8271-2216f469b561": {"doc_hash": "44b1892d847959d5172daab40f77b84e635a849140e8ce1362226c90ca2cd4b2", "ref_doc_id": "e895e8ae-bbf3-4933-8651-67ec9949c758"}, "f33ac858-ff8e-435b-8ba9-329de00088ef": {"doc_hash": "6eb857e35ff0b519c136051f06bf4c46c2cbf4227a4c31cd8d71657359baa039", "ref_doc_id": "e895e8ae-bbf3-4933-8651-67ec9949c758"}, "3b83f416-979c-438f-8f32-c01cee635913": {"doc_hash": "db45cd8992251063363b89573695f34f1d9e48c1d416d7c4eb09a8ea28fe96e0", "ref_doc_id": "fd36e499-6c1c-4c7d-9b35-1398b655577a"}, "f8bdb659-9543-4785-9ee0-68f2d02d5d02": {"doc_hash": "6e2ef5d3c332c3fafb585b479b7d27fba23e6821467d369e396550446301ac04", "ref_doc_id": "fd36e499-6c1c-4c7d-9b35-1398b655577a"}, "5233d938-e6df-4175-9cc0-fc0db9f00357": {"doc_hash": "184fec15066f4eb207d2aa77191d10177d15fc25015a04c98efb38d527b77110", "ref_doc_id": "3ee278a6-3fc5-4738-82cb-01b3efec6ae9"}, "4a7738a4-a5fa-48be-8e17-f72615187bc6": {"doc_hash": "0b00f3bd3ac13061bf0713197b96c778511420ab4c8cd0c95257b1f639370546", "ref_doc_id": "3ee278a6-3fc5-4738-82cb-01b3efec6ae9"}, "ffc6920d-0050-4702-b504-b8c222d5492b": {"doc_hash": "fe7b109679b64b558e2fbaba7c2d3a78b906e852aa2ccaf9dcf1cb26b0e3cf5e", "ref_doc_id": "3ee278a6-3fc5-4738-82cb-01b3efec6ae9"}, "6f6c68a6-1d04-4e89-bfbb-bd39194fd9cc": {"doc_hash": "a0f0b714e0722e44e0c642b59fac9f0378b9be0d81dc8cd766811a99913fb7cd", "ref_doc_id": "0f2be16c-6fb1-47c4-85fb-07308a9cae35"}, "4d71c198-8091-405d-ba4b-cec3a2cf630c": {"doc_hash": "7d0328d3dabee7f3c8152e0efc115525158aab66c3a4776595544c4d2e48ee7d", "ref_doc_id": "0f2be16c-6fb1-47c4-85fb-07308a9cae35"}, "3cac20d2-ddf7-42c6-84e8-df656b850d06": {"doc_hash": "4d54215b691c7f18e1448a7bb3edd3c4f0e22cc95b7962210f7283ecb6bdbebd", "ref_doc_id": "1ece04c1-2b93-4e9b-a7e5-5d0ce8380f43"}, "2232da1a-70cc-427b-910b-2c3d83272bd1": {"doc_hash": "0e68ecf9b71d5d1448224cacd0f91fb080aad104452373a593459a7809510b3d", "ref_doc_id": "1ece04c1-2b93-4e9b-a7e5-5d0ce8380f43"}, "bbdb89c0-3702-4318-9dff-fccad67c1121": {"doc_hash": "be5c9c99cda1c4e4d7a0eb3f27fd35bde6368cbee8b1e8be7d0a13fb97c3eea0", "ref_doc_id": "5d8f6a3b-ee1d-4986-9479-d8e27475f128"}, "7a50d2c6-1f76-4887-858a-1a7d94fd68c2": {"doc_hash": "7ed45e652c1bd3501e69dbc795dc3e3292dceb52f9f8d39f85f3e0dfbad194bb", "ref_doc_id": "5d8f6a3b-ee1d-4986-9479-d8e27475f128"}, "420054b3-e979-4111-bd16-a182b1f543e2": {"doc_hash": "c64c162a0d5203c33041b9789f9327584314dba7dc3c4dfab6e04233ef127177", "ref_doc_id": "20fec5c3-caac-421e-ac1e-aa8e9f3f4836"}, "cdf35c44-6bb9-4e54-b592-c5d03f9f57c6": {"doc_hash": "67e3098d04cae606b899c170a9dbfb39d5d9d8a3a4287fafe7f853fa8a3fb0a4", "ref_doc_id": "20fec5c3-caac-421e-ac1e-aa8e9f3f4836"}, "01a5a2b6-c32d-42a8-8893-49fb8f3b7fd7": {"doc_hash": "2e43b4b8bd181004d09a3f8545cd75c0d7c697ecce15d1893398434857c9687c", "ref_doc_id": "20fec5c3-caac-421e-ac1e-aa8e9f3f4836"}, "74416f9f-cfcd-40d1-967f-2fa199f1ef68": {"doc_hash": "c3aaa442b4b063af4ebff3f8a450a522dd46f1b6c6c3a6b1a7bf38159426bcb1", "ref_doc_id": "8e59cf09-9e77-4cde-9e35-b57022769458"}, "d29b5f79-da19-4734-9fd5-60e5799911ba": {"doc_hash": "6b277d5e4f9483dab23dd0aeea8f7fbd8932514033734ba539bbea78c49c76c1", "ref_doc_id": "ab42f691-4637-42fb-ab92-2aaf0adbfce6"}, "ac5ba062-cf0c-4cf3-b081-504ee5d30016": {"doc_hash": "c42115b3693247f3f94dee46b3a23702ee6f6766b32d79a89c5b825d0f61cd7a", "ref_doc_id": "ab42f691-4637-42fb-ab92-2aaf0adbfce6"}, "096c5d53-d60c-4fd4-b49a-e8abcc602866": {"doc_hash": "3865c9cce81eddba61711e42dfcbac86599269d2b089818f14b3e7bb5273c8de", "ref_doc_id": "ab42f691-4637-42fb-ab92-2aaf0adbfce6"}, "b7fe66c7-30ab-4365-9771-3b109ef7554d": {"doc_hash": "4fe11026da802c26634d93c536b728af4f1d4d279c185e519602dc84e9cfd6b9", "ref_doc_id": "1888d106-872a-4cf0-b9f8-085025dd26a6"}, "f51c4678-8da5-471e-ab1d-1c95aeaa45b0": {"doc_hash": "b00ac14c5af072b1ccd94613186e03335bc4a6bb54c7387ee952cf20e45d35cc", "ref_doc_id": "1888d106-872a-4cf0-b9f8-085025dd26a6"}, "060cf403-5f3b-4657-b81c-c55185cfa465": {"doc_hash": "cc88c18e9119da441f4e8e389807fd92ff1a8e6c746099e84e4ab898dc041efe", "ref_doc_id": "1888d106-872a-4cf0-b9f8-085025dd26a6"}, "c6a0e017-cc07-48d9-b990-3c7b3c5adb43": {"doc_hash": "0dec9c5dfc0402377d5f2d4b7882866f605ec5b8b2c5d188a0bfa81aea860638", "ref_doc_id": "6a8c1287-8d7e-43b8-84ce-6fb9b28b07c8"}, "19679262-5efa-49ec-a4b0-82546671406c": {"doc_hash": "cf0dcfe338c95ee56a95090dacd49911991ee813e9919f2af2925a771b8a9f99", "ref_doc_id": "6a8c1287-8d7e-43b8-84ce-6fb9b28b07c8"}, "df7c7077-3849-45cd-89d4-9a6f3977adec": {"doc_hash": "492e35b334f1067ffe712d8fd0464891cde0c5c38d4b299446051a4651e801f9", "ref_doc_id": "2f5c4958-b80d-4500-92aa-b5b304c99594"}, "e5a7d0f9-b51f-49dc-ac31-0fe73005e961": {"doc_hash": "ef380b0140135f7e8a4d478725f5a351669e01901e3bd1d3ac3a2c4d219b3f35", "ref_doc_id": "2f5c4958-b80d-4500-92aa-b5b304c99594"}, "495145ca-75a4-40eb-a4ed-b1bd2759d842": {"doc_hash": "478898e3c87863778c86786b84bab173c6a76e00b70cb65c0e2da0e0c33f02cc", "ref_doc_id": "2f5c4958-b80d-4500-92aa-b5b304c99594"}, "e45a520c-c83d-4ded-a584-e07a0dc26b10": {"doc_hash": "a15f6c5f60919a53255c584f33d53cb9a8a711d2ed852c9cc4df9a1ef766dd6b", "ref_doc_id": "f561b82a-8bc5-4431-9b4c-92fe880a0e0d"}, "aff212c9-a712-4527-a4c7-1ae6b845a020": {"doc_hash": "68cd3f47fbdb90c4fe30c797f55836569e43ce06ed02c8b25271ef85745d3b19", "ref_doc_id": "f561b82a-8bc5-4431-9b4c-92fe880a0e0d"}, "0f0dc202-17ec-48a0-b3b0-7bd1e57be964": {"doc_hash": "a9903b30b5f5ce5c58ee9e6cd5a34013754d5f8e0546cec77e446833ea50d683", "ref_doc_id": "ebdc26ee-d582-44b5-a69d-65a38e7c0b8c"}, "964746b8-c8ac-4c03-b601-084f87d0c280": {"doc_hash": "fd44efab4da83f9e28b54810f69b9aeb345ec1422336c84655a9f660fe6b0781", "ref_doc_id": "ebdc26ee-d582-44b5-a69d-65a38e7c0b8c"}, "c5635610-57e6-4b60-b55e-45e8a1e2b372": {"doc_hash": "593cf3078f1c248eb3af0683dd12d72fad7f4a9efb84c5b459dffcf11ec42892", "ref_doc_id": "bca26671-473a-4482-9631-c71294d51d7b"}, "1870ee1a-b7c9-4457-833a-0dfecb6b93f1": {"doc_hash": "8c6df0237051dafbffd47ffe4692446169ba46fd044366ac7bd1362c864a9a9b", "ref_doc_id": "bca26671-473a-4482-9631-c71294d51d7b"}, "4e926dce-421c-40e8-a95c-7e8a21bed2cf": {"doc_hash": "04cc7b590cbd81785445f689794f614ae647004e22eaab17a26adf60dcd3ff2c", "ref_doc_id": "bca26671-473a-4482-9631-c71294d51d7b"}, "07a87240-386a-45a7-9e21-27a906de8649": {"doc_hash": "1f8742fe125b4c0c07d883192a09aa0c2ccd91872a10d45e4231ce20b34a5606", "ref_doc_id": "35bbddcf-6a73-46ab-ab1f-0d50be6a00f9"}, "dbddadde-a0a0-40e8-937c-25f0264f56b3": {"doc_hash": "a5f1708342db44a4da410e2cbbdddf76ad9cd00156088548c37dc044f6f8f918", "ref_doc_id": "35bbddcf-6a73-46ab-ab1f-0d50be6a00f9"}, "f680157d-b7af-4f59-8de1-7b1afedbfe3a": {"doc_hash": "3c116f73f5e310c97e01c47bcc1cddf3fbe32fcb841eb3565b4cb8cfcf9b7de9", "ref_doc_id": "38724542-862c-43e4-96fe-6488ed65a759"}, "ee8d2be4-3926-49d8-b603-ae98d96bc13c": {"doc_hash": "6b2403eaae4c86bf9f5c814be548f5b1a5d25b833a9a396ce11929aa1b9e3873", "ref_doc_id": "38724542-862c-43e4-96fe-6488ed65a759"}, "86b4aea9-4542-49b9-ab71-a31cf1e705b5": {"doc_hash": "5140331916463b996675f2c2fbdd11cb324e2a84286d60915ae68a0f7cd343ca", "ref_doc_id": "41e81d24-56f7-45b7-9d04-a7bc8ea13350"}, "55bed8a5-fe81-4860-9330-86602def3760": {"doc_hash": "362c909977cc48734f06697e9f2d56d643ea7724c8c5b67ad2962bff72f636e0", "ref_doc_id": "41e81d24-56f7-45b7-9d04-a7bc8ea13350"}, "99847d07-ccec-4f99-b893-ccdbb02a7a19": {"doc_hash": "052eb69bda0bc5a543b6da47f0f7a2cbac0b9232b638db012534aa9a78af7f6c", "ref_doc_id": "41e81d24-56f7-45b7-9d04-a7bc8ea13350"}, "d71744e3-b3d5-41be-b311-7ce8306d1ba3": {"doc_hash": "ebf01717a362b2625928cfebd88da46f3be0a21083ac72846d54b8f938460171", "ref_doc_id": "f7163ddc-984c-4354-8171-36f85c0a366d"}, "a4887108-c041-4e51-a001-fd1493499a52": {"doc_hash": "7dd176660d1a3ee9bce014e321209ef01dc5dadb65340caacd2a3a282eee51e9", "ref_doc_id": "f7163ddc-984c-4354-8171-36f85c0a366d"}, "684eeb2f-b37e-46ed-be3c-e5e9f18cef91": {"doc_hash": "f2acc0752cf499f664300f8cfaf7dec6320306592dd565a3df60ebce96c61f4a", "ref_doc_id": "2f5c6c4d-288f-4418-9eea-2fd9b93f0c73"}, "459080be-f09b-4460-bddc-90116d224f28": {"doc_hash": "ee0e827ffd118049f2ad6d0ece45d9e73ce533e2bbd1da457dd70b67fae1c4d6", "ref_doc_id": "2f5c6c4d-288f-4418-9eea-2fd9b93f0c73"}, "e64479f7-1f9e-47ec-8d5c-7c060c2999a0": {"doc_hash": "a14688b2d447c03aa81aed477c68ddbb1257df85050901a05fc62ed2a47c7f63", "ref_doc_id": "6823750a-63c4-48a3-aa0c-96bfb96965f9"}, "36ded081-1f7a-46bd-85a9-34abb4396ddd": {"doc_hash": "0a2584c4cf03abd52329b6d2180e0d541645f5c816fbf1dd8f7a24168261f477", "ref_doc_id": "6823750a-63c4-48a3-aa0c-96bfb96965f9"}, "ac7b08f4-a1a8-4947-b1e9-66bc88c34867": {"doc_hash": "701884394f0cd53a44572c2e83242b4a50c0dc36531c7d6f5f589e388bc3b74e", "ref_doc_id": "6823750a-63c4-48a3-aa0c-96bfb96965f9"}, "dbf3dedb-9044-4f3d-a797-babbeca5dd57": {"doc_hash": "d6255aaab5b8c0cfdad852157b05286eb637ce782a3739d36900ca4adb75edf5", "ref_doc_id": "6823750a-63c4-48a3-aa0c-96bfb96965f9"}, "67e45801-4275-488f-8e69-f2928cf1854d": {"doc_hash": "3ae405f72235e1e442eaf976fd0f95c3c3d1341e9a2f60cb083fbf9008a706e1", "ref_doc_id": "e5c8a8cc-b0ff-434c-a1ed-dc6866eb42c8"}, "2330513c-15ae-410c-b2f7-e52032a402b1": {"doc_hash": "52a12a9b2f377ebcc8ff0fb63211b3fd0cdf96441255c3e81f27501851c4c3e6", "ref_doc_id": "e5c8a8cc-b0ff-434c-a1ed-dc6866eb42c8"}, "ae43b9b3-6085-47d0-a392-dc200e20355d": {"doc_hash": "319e46527aabc30c6c7312f5de53a6d17931cb60d05d573dc377e652c8e44560", "ref_doc_id": "d4287f0c-96e1-482a-95e4-290e0dce98de"}, "2ae996da-80c7-4ff8-a00f-5c9a68385eaf": {"doc_hash": "9f45b834b2a0b8e719e034794685bb56c192be877d249bbad0bf168e66911d0f", "ref_doc_id": "d4287f0c-96e1-482a-95e4-290e0dce98de"}, "d24ab3dd-04f7-4217-8dba-8fb16ba8947d": {"doc_hash": "99f8231e38f72098d70e85fd0e5b154fcc04120a3cfeceb5147b8602f91c3461", "ref_doc_id": "01451183-24ed-4c12-966c-3f4bede6aedd"}, "6d4372e0-d0b4-472d-afb3-715f65f8d9ea": {"doc_hash": "b4f10702869eb7a16c73314a5633860d354398f754add2c87b41fac87e6c2497", "ref_doc_id": "01451183-24ed-4c12-966c-3f4bede6aedd"}, "e3cd60cd-3749-45df-82fd-f948facb39da": {"doc_hash": "b72186de8352f4ec156f471b9516c094093bd3a1fb7e297a06391622c0ce583e", "ref_doc_id": "01451183-24ed-4c12-966c-3f4bede6aedd"}, "bd0fab0d-4123-4c3e-91a4-d2fd94423609": {"doc_hash": "91028c6406ab315da874c7c27b75bf4dff36f4ae1e5086e6654b2cacb83faf41", "ref_doc_id": "acb4637a-ee59-47d3-8d55-7a5a0c4e6728"}, "ce69aa69-4166-4b95-a31d-2b59d76c9f6e": {"doc_hash": "80f0117a046517173a9fe1f89eee42a1724cfad6dc0bc313f53f6910b1bca0bd", "ref_doc_id": "acb4637a-ee59-47d3-8d55-7a5a0c4e6728"}, "ecca81ee-8aa7-411d-8edd-460d916a8fe5": {"doc_hash": "26a334cbe5f95bb65d7dbf14b2f144440b1462137e3c8a2ac31d6c1a6c00f11d", "ref_doc_id": "a90e0185-cd48-4b2d-aa95-6a1b21bb3694"}, "a9c52cae-0d40-40f4-9e99-4d787a1b21f2": {"doc_hash": "d73034bf2fa5ad881050d6eaab6984e0f99d973c56af0a2f9116be3b2fbbef3b", "ref_doc_id": "a90e0185-cd48-4b2d-aa95-6a1b21bb3694"}, "a5575c21-7471-4608-aa19-99b317071bdd": {"doc_hash": "e992155bf04d05867722424c7ad7b5da9613e5c9ccfb7c5cfce134813237600a", "ref_doc_id": "3978a3fa-e428-4ee7-8368-52ac860684d7"}, "245fffde-5b96-4d47-95f5-e40b59910fd1": {"doc_hash": "72dfaaced433be48537ceb4c150d0b7c55b12dc0691f0159d246628c563ce9a0", "ref_doc_id": "3978a3fa-e428-4ee7-8368-52ac860684d7"}, "d37ce0c7-2d45-405a-8843-b6fefc40b734": {"doc_hash": "649e995d7ec5b83b79f4fe81613f4c455b314b02ff1ece625f09c05c2eec71ae", "ref_doc_id": "c66949e2-9b14-4fac-8dac-d07f94f8dead"}, "650f5690-0681-4094-a25a-2f5f27494dee": {"doc_hash": "4fd1a3d62fede7961a4fe244870cadfc34b6e0ceffa981073593885f81227b45", "ref_doc_id": "c66949e2-9b14-4fac-8dac-d07f94f8dead"}, "f9d073d0-f261-4d0b-9998-7f79e50bfb63": {"doc_hash": "88b93aa3fba44417dda94f2918b4b8458edc88aca157875138c0ff20cb50a64a", "ref_doc_id": "f65edeea-34e8-4a21-aee1-2351e87dcb25"}, "4a46de18-32c9-4d56-ba99-046f9da01015": {"doc_hash": "2250cf06a8587f50245a5b3a7e0f3652da50848ab0cd05e5f0ef2b3865d421df", "ref_doc_id": "f65edeea-34e8-4a21-aee1-2351e87dcb25"}, "ed4519ef-a96a-4bf9-b799-32bd0ae68fc3": {"doc_hash": "f67b2a12e0a8a85e5e745a4113d94d76d836c2ca8865567de549d845e27991d4", "ref_doc_id": "145c297e-2aaa-4607-ba09-dd3c2fa951e0"}, "559a87c0-f31f-453f-b7ac-daa089ac521e": {"doc_hash": "3ea5284408985e315195ba8b596282039abe13c182e701e2e6af7b2e078715e5", "ref_doc_id": "145c297e-2aaa-4607-ba09-dd3c2fa951e0"}, "384da572-54ec-4b9a-8ec8-c598eeacf240": {"doc_hash": "61b6cfd7ebdf58cae6846acceec22f27185ec506fd55d2434b3b0063867bc80d", "ref_doc_id": "85df7da8-5c73-45be-95d1-cee9bd5f9f6f"}, "31adc796-c59f-4e81-8e97-211e9c18012a": {"doc_hash": "9ae524c9bd0c52cc3bdaa46290be8d4626f9c69fcf33af7a53d279ca684ed8cf", "ref_doc_id": "85df7da8-5c73-45be-95d1-cee9bd5f9f6f"}, "aca1da39-4c39-4ddd-bd91-7c24e1970a39": {"doc_hash": "d9fa08221795207408176db72db800710d403159a8dbe99144bacb8903c3981e", "ref_doc_id": "c4da2f44-fc58-4548-97fe-d29f07f3782a"}, "c44a0b80-8344-4603-ae49-260fc7cdcab1": {"doc_hash": "962c46a52b10e7943eba9c1884e53a74b63eae5dd6eb77d92d95d04abf16df3f", "ref_doc_id": "d412401d-8aeb-4584-bd30-e03053010af5"}, "8ac890d3-0ff1-4716-8b5b-6949aa65d659": {"doc_hash": "a1bd5f73f72ca220ee9850cdc2cedfde727a3f02ca3e6b3de66e87312188e9dd", "ref_doc_id": "d412401d-8aeb-4584-bd30-e03053010af5"}, "e46239eb-961e-466b-afde-03ac58b81fa7": {"doc_hash": "8cc36806ec04ea8b0df711fd0c96c62a0f4909d8b77c0a34dac17964a9aeff0f", "ref_doc_id": "32a63977-f28c-4b87-a12d-aa5d8c6c34c0"}, "b1e4f62f-c200-4440-9960-30dd7b9f025a": {"doc_hash": "7c04cab7296c75c6f4ae0f605196e2567d50eaf961262b279023b6ecd174f598", "ref_doc_id": "32a63977-f28c-4b87-a12d-aa5d8c6c34c0"}, "05ba4948-24a5-462b-9a2e-65f651c1664c": {"doc_hash": "8ef10e8741a17e5ee2e001de46f262812956ff5d8717c2331461cb92af1b59d4", "ref_doc_id": "e7ce0fe0-fba0-4e19-afa4-700ab4d0b61a"}, "a39c7343-3a23-4f30-8513-9cb27ff27709": {"doc_hash": "2c83df421ea5d1e17230c6613281ba6d5b51a4f85d657af33f3040d0cde0f14e", "ref_doc_id": "e7ce0fe0-fba0-4e19-afa4-700ab4d0b61a"}, "2cc82c4b-d358-4c61-8c91-2566ac3b7c90": {"doc_hash": "be368e0096c1b7dbc0450be571a78493099be9113206a8db7e46ea831c7e7202", "ref_doc_id": "587adbd0-d69d-4773-ba35-91228ed49afd"}, "0deeb299-3842-488a-bbf2-91f4e3004e62": {"doc_hash": "68965f5f8b9331a5d1ad5c486e2c9b597c423ce4ef5f76338094e68188b8a412", "ref_doc_id": "587adbd0-d69d-4773-ba35-91228ed49afd"}, "aca09c6d-1324-49b3-916a-0eb26afcb97e": {"doc_hash": "fc50b4ff210031856e90245636165c27e4eb56de9dec81075032b3f7aa9742d7", "ref_doc_id": "82310adc-795a-4750-ba7d-60f19fe23fb5"}, "98e07ab9-9e37-4a81-a52b-adb2cd50eab6": {"doc_hash": "4c1cad817a6b39a27216ac09f661c6340cdac7adb99f7ea5762b70cb1b84cf10", "ref_doc_id": "82310adc-795a-4750-ba7d-60f19fe23fb5"}, "4f9055de-e048-4733-910b-0d4b82471c2e": {"doc_hash": "a1ce9ae3224f2ea33c007c459a8b5ea0a9a02c853217c074c87af376a8612545", "ref_doc_id": "5ca8a155-befa-4cae-b61b-6187336c62a9"}, "35c13ad1-f310-4815-8dbb-b0a173237984": {"doc_hash": "61fef3ff75f97e2946b3b137b6f25d68034b09c315dde3e9057296936e5a699b", "ref_doc_id": "5ca8a155-befa-4cae-b61b-6187336c62a9"}, "ded51adf-8de7-481c-b98e-4aae483fb294": {"doc_hash": "f91746bb7301a32372b90f6565ffa43e351227ad93035df4302815a10d4a0b33", "ref_doc_id": "5ca8a155-befa-4cae-b61b-6187336c62a9"}, "b4262e83-781f-422d-ad79-5d1894fcb87d": {"doc_hash": "0a2f59ea27311a32ad56d084a3be200770019b17d456bc5d7d718c330ebf0e7d", "ref_doc_id": "87bf152e-d191-42e3-ab76-e4c9f59d29c0"}, "5dbd025a-22cf-4a06-874e-906d8cd2bb50": {"doc_hash": "fffadc811746fe2f22fb34633a88438017ea550ab443cc910e7cbf475d7dc63b", "ref_doc_id": "87bf152e-d191-42e3-ab76-e4c9f59d29c0"}, "958aa070-1ae9-462e-9414-00ea05ad8bf3": {"doc_hash": "7cce7617eb9d1374c95bbfb13785a98b5b43a6d7503f8a055f6075741a63f180", "ref_doc_id": "87bf152e-d191-42e3-ab76-e4c9f59d29c0"}, "18716294-2fd0-4d07-8124-08ad1eb853cf": {"doc_hash": "23b95f3b89e70c3b3cbca5b4dc975d8845be17266da42c39610c1db7fdd244fd", "ref_doc_id": "b6e878e1-0466-424f-8b74-11d293349df3"}, "a27fdab2-1406-4b49-8f34-0ac90f97ee50": {"doc_hash": "d9b96827cacc6432863914c6e833766177c55027b4547d95d8fbe1beb49a1597", "ref_doc_id": "b6e878e1-0466-424f-8b74-11d293349df3"}, "ac0c1610-74ce-4fba-a746-567fa4c30581": {"doc_hash": "fb374eb6c5dada257041fe84e393e61f5592565b89519f003c07b8cf4adbbe17", "ref_doc_id": "a0a5f33a-36aa-49df-b54c-a619f70412ad"}, "dc946f53-77e2-4de2-97dd-fed95ea4a770": {"doc_hash": "fc73b1b88058cb84aa7dd82ec96e280def8cf1e8fc52a11ea96c3339df7489d7", "ref_doc_id": "a0a5f33a-36aa-49df-b54c-a619f70412ad"}, "c7ee4aa8-479b-4ef8-8934-8c8215e73ae7": {"doc_hash": "ba7cb86b1e7fb6de27e5a5648f59ccd2c6a3c6988f8e24e6e59f45514bc087a3", "ref_doc_id": "a0a5f33a-36aa-49df-b54c-a619f70412ad"}, "9d58108d-e823-41eb-a57d-f85ed029a3f5": {"doc_hash": "186848e07618b20ea025e1b3cccb806dda44e61d3388a5dde411bb93149e08f9", "ref_doc_id": "b8d83a0c-2327-41aa-914d-db6c59ce53c8"}, "8cee13f3-b563-46c5-8bc3-126814b170fe": {"doc_hash": "7b833ef263efe7a48a282518dbeda2aabcf0001fb94353514f795adb08b88ef6", "ref_doc_id": "b8d83a0c-2327-41aa-914d-db6c59ce53c8"}, "453fed39-d183-4baa-981d-cf61a05b5fd5": {"doc_hash": "8ed441b352b235691d324e87da20bd4aa9c359a78ae26296a8df8d6666728b42", "ref_doc_id": "6a62aeb6-3715-429b-b810-e369669062f7"}, "7fef0404-fc81-4e03-9f05-bd85749803d8": {"doc_hash": "9fe5d977c0c391df4450fa80c2b0086ac5f3d74bb199a0794af85481c35071c8", "ref_doc_id": "6a62aeb6-3715-429b-b810-e369669062f7"}, "28d88afd-196e-4bd5-96e1-221041702a36": {"doc_hash": "1db8634b5bc46a6af9b0688c1442580c561e79d7157e8864374324cedc29428c", "ref_doc_id": "6a62aeb6-3715-429b-b810-e369669062f7"}, "9cf0e609-bf63-4f38-b58f-3b33b22a641e": {"doc_hash": "fe1f2db462ff31950b042504f157990fce20cbe8b9dc277e0af123c6e39a4021", "ref_doc_id": "46918be8-509e-4e60-8e08-aec8235b451b"}, "3c314be2-808c-4a58-b179-448bf5e6a392": {"doc_hash": "fee02329932ec5e5f41ada1c2892b6d6ea44bdc6659dc0e9f5a4f8a4708dc0ff", "ref_doc_id": "46918be8-509e-4e60-8e08-aec8235b451b"}, "67e8fea8-f933-499e-88ad-6eb3299effd6": {"doc_hash": "f3f2837f87e233f9c19ebd019be60141b5380db849701e6b02f470db0eac0a47", "ref_doc_id": "658f80f4-c2bb-4d41-8c41-19bbe55ee16d"}, "0bea631a-877a-4179-abbe-83e9f2689ffb": {"doc_hash": "453625fa69e3dbb844add662b6f4b23f85db93a2074a4f235856edca162d4790", "ref_doc_id": "658f80f4-c2bb-4d41-8c41-19bbe55ee16d"}, "0567c999-271e-418b-9378-bdaf5f481d37": {"doc_hash": "ca3a1201eb56314dd855ade49ad3ef881b54882631f7cb78e4aa8aae8ade6922", "ref_doc_id": "658f80f4-c2bb-4d41-8c41-19bbe55ee16d"}, "541dbff1-8a78-4ac4-ab80-8c81b71bc9bd": {"doc_hash": "b97021e87a7ab6f07d58504a6868a408fd61a7cb35d081ef3ef5e6829e3e6b51", "ref_doc_id": "136b4853-e457-4f52-acf6-f9ff493b4f56"}, "6a8eee5b-2a59-4c68-bd54-1d9cab1fbd46": {"doc_hash": "75106c0afd7817933b46c7f84289b8444cba22f4e4446fdfe05379a7495ae429", "ref_doc_id": "8d9b8fe9-8049-4b7e-a2d3-8f0327fc7c9a"}, "642f2eef-4879-4840-bfee-7c0c25157463": {"doc_hash": "f49fa2ace428fb0f094c524deac9855efbf5fc6afdef5b6983c980648b7a3daf", "ref_doc_id": "15813631-0973-46e1-93a0-8c0c3cf609f4"}, "813b64cd-44a1-4f4a-ba80-0e090af038e3": {"doc_hash": "1e28111f35e8c23c3ec3a76f59e34fe64b24ceeb7b7997ee989a08a6df741a90", "ref_doc_id": "15813631-0973-46e1-93a0-8c0c3cf609f4"}, "3d9f1620-3155-4e43-8d73-18bf3d7d8e63": {"doc_hash": "4cb273019bd73e678d68b9ca86515deb20ce43782fcd7abc5f66f7f4a91c7549", "ref_doc_id": "15813631-0973-46e1-93a0-8c0c3cf609f4"}, "3fb01ab8-f52a-4e92-8082-3e1349727369": {"doc_hash": "24a65ad6699f4ef675c140a4ca8643262e6ed9795b6f06927dfbbc826bd7d7b8", "ref_doc_id": "7183eb36-1477-4313-a97d-d7387a47216c"}, "6fd4eb53-1091-44d2-9955-02913369a759": {"doc_hash": "ce3d9af0c223d0f14f2b615fa07ace86329e3e255f859b840789bc7608289806", "ref_doc_id": "7183eb36-1477-4313-a97d-d7387a47216c"}, "a7f9037d-1793-4661-ad0a-718f816dbea9": {"doc_hash": "4841f3ddd60ff92c26110c54ea4f9187b503089341eddae7cd5a5aec35b83d44", "ref_doc_id": "7183eb36-1477-4313-a97d-d7387a47216c"}, "0ddc725c-3003-4099-88ea-9805b795cd23": {"doc_hash": "aa702da9d8d3be0a34d7f9817120390bad878fe6354372a01fc59a90857811f1", "ref_doc_id": "e6b994ce-063a-4e45-b7f1-752e0007227c"}, "0535d8e7-c49f-4507-a886-42b4cd7b503f": {"doc_hash": "daaca0f285bb49f5898ad4e73837e677f78a0f5c3447e85731cb76f5a4ebea2c", "ref_doc_id": "e6b994ce-063a-4e45-b7f1-752e0007227c"}, "df542374-a46e-45b2-89b7-8faa3e275934": {"doc_hash": "8bcadbe64aeda459f66713b39865e908ce41983a8803566d33dc227b511ad37e", "ref_doc_id": "e6b994ce-063a-4e45-b7f1-752e0007227c"}, "4de4e6b7-90cb-4982-b15c-83a567507296": {"doc_hash": "4d3ce5342a04e4c963b3294a402499422d3e952038ced6f651ba88a3b71cdc63", "ref_doc_id": "ea1a5971-3ca1-4667-928a-e163d8cab129"}, "8564f69e-1b21-48fa-a06e-49fa141b9699": {"doc_hash": "6f31fbd72168d0040924df6bbd45d7f1d901c5be082760dbef1494abffa478a5", "ref_doc_id": "ea1a5971-3ca1-4667-928a-e163d8cab129"}, "adc1438e-1555-4ca1-9382-18c0bc78bdd9": {"doc_hash": "d968d66535b43bad438dcd554495caab9e572dd3dabd2d387b2360aa4e12f454", "ref_doc_id": "b6f0e40f-c08e-4837-84ad-938b67cdadc8"}, "b49f34e5-9064-493a-9796-9aebee3bc9ff": {"doc_hash": "a1841a59e9ab853a7f87388cef96ec75a0b402de3acb3f98ad0064339a113c01", "ref_doc_id": "b6f0e40f-c08e-4837-84ad-938b67cdadc8"}, "064152b4-0e4f-4f81-bba5-4ed3edc63692": {"doc_hash": "3a5575494bfee3839e6e3ae2d5b85504d6036dea19e5721bab950034cd779523", "ref_doc_id": "b6f0e40f-c08e-4837-84ad-938b67cdadc8"}, "876b97ae-6834-46f9-b97f-98145d513934": {"doc_hash": "3014cb26e1b4ddbfc990594aad266cb25d878c60188ad90bc73d95e3b456848a", "ref_doc_id": "5e86ddae-f9eb-4271-b073-3a7370738ab7"}, "b9325247-4fb3-4cac-9f2f-6707de4b5bc0": {"doc_hash": "59de2b7657d340d8759ec15f5de2619e37360c3658c37f951536db673e2ceb44", "ref_doc_id": "5e86ddae-f9eb-4271-b073-3a7370738ab7"}, "5e936a17-dff7-4ef6-89e1-171634c7775d": {"doc_hash": "20bbdc4d5f38944d163b086cf1a6b9ee7cded6a3e9a98aeaf664020ddd9a387e", "ref_doc_id": "15a084ec-7d94-4458-bddb-f8e138b1ec71"}, "9798ef3f-9c00-486d-8855-7b76b26519db": {"doc_hash": "e53fa5176880015e8a79c276cec1c6329bfd794151bf1098fca248a1479dd08d", "ref_doc_id": "15a084ec-7d94-4458-bddb-f8e138b1ec71"}, "5176d231-eade-4c4e-a089-bee948130310": {"doc_hash": "5f0d55f1a2ae62499e3c38729f19df7e33fbdbeb8b4923f292388383a64dce93", "ref_doc_id": "91cb7cc1-cd79-4b6c-9331-66471ae4f32d"}, "ae4cd4b8-4de5-4da1-92af-ffce8b2f6399": {"doc_hash": "8a0760ccc88cd8d272ff8c315b7d706f5e2deba65ef884802c3cf409d6b9957e", "ref_doc_id": "91cb7cc1-cd79-4b6c-9331-66471ae4f32d"}, "53ae1884-6536-4f2f-8031-64b71b80143e": {"doc_hash": "29156c7c4b73619710034c3be639220f9a8b0b0d75712b05e557557c47549ba8", "ref_doc_id": "c5dd7e24-3968-43c2-888d-dba258dcaee0"}, "bdb5eb1b-ea37-427c-bfc5-072c06a3d8b4": {"doc_hash": "690a29d9b9ac25156bfbf8b034f5bd1a064b51daa5c5051eab0ed95bce7c4ef7", "ref_doc_id": "13a69199-7d94-43f5-af01-6b3e7237a822"}, "050d053d-4109-48f7-bd57-2f8579c13ec4": {"doc_hash": "0331d50c08b92beeb7235d254da3f93087dec004746021032053d05ef5cc7955", "ref_doc_id": "13a69199-7d94-43f5-af01-6b3e7237a822"}, "976c8e0e-a268-4fee-937e-809807e7fa9c": {"doc_hash": "6513a0980ecb7f689b2e5c5bbf8263ff94c9c606813564c61f46a8f0bc136c6b", "ref_doc_id": "13a69199-7d94-43f5-af01-6b3e7237a822"}, "a1f0717b-d0fe-41e9-9594-e8e996a1e19d": {"doc_hash": "5de9973bff433abb0de21996bee0ce5ef1edef740f678e2710fed82bb4b14346", "ref_doc_id": "fd51dc01-54b4-4c49-aaa3-573b1d09a9dd"}, "6b8a59e6-6e95-4d91-844c-45802303ffd3": {"doc_hash": "262efa9b945c34a1f6f240af0e821b94698f38d13e1f13f2956cc34bdb9817db", "ref_doc_id": "fd51dc01-54b4-4c49-aaa3-573b1d09a9dd"}, "6051d786-2428-40e0-b853-fdbf0af907e9": {"doc_hash": "2512fad6f784e8b865ea4cd77021a1c120800b23d838ea7458308d8f9c9f59e8", "ref_doc_id": "c88dd2e6-a699-49b4-bf59-3c0365771b14"}, "e127933f-e806-4559-bfa1-85152bce5bbc": {"doc_hash": "4958d43f1407863d1a4084498ea4316929167152208f49879140dab5ef737406", "ref_doc_id": "c88dd2e6-a699-49b4-bf59-3c0365771b14"}, "2e404c37-b20e-472c-bf59-2c126e9b50f9": {"doc_hash": "a4c478101f6bb246b0257a3d28bb041ee68012ff4a6c64af1f6d43e0296034a5", "ref_doc_id": "1696d94e-8b2b-4f90-a0fc-6ee95980665d"}, "9932f449-1d46-408c-bbb0-8e6c23c84dd6": {"doc_hash": "c71289de4f3c5899b48f6ffa0941be6b56e08cb67f10886eca62a750419c3033", "ref_doc_id": "1696d94e-8b2b-4f90-a0fc-6ee95980665d"}, "98fe7404-2a52-4115-b46f-05903de98fab": {"doc_hash": "aa8c8745bc281bfdbe09db2b293f019a0aba341a1de6cd06ae5c718f9fa6c8d5", "ref_doc_id": "910bc5dc-d7a0-4c3f-8100-64f1dae76f33"}, "fa637b19-34c4-4983-a393-c915d2a755c9": {"doc_hash": "43480013452cf3c7b6ea01e24f56ce55aed7a10c02fd93a49323cebe086c8c07", "ref_doc_id": "910bc5dc-d7a0-4c3f-8100-64f1dae76f33"}, "5a461167-637e-4e8c-b80e-3a06ea634d50": {"doc_hash": "365b29ac0a1011f6c6505a566ea07b2f1ee4699f9b1a9a46e28459e75ab264fa", "ref_doc_id": "ed137863-472d-414c-b5e7-59e8a8c664ca"}, "93a87c73-652d-4052-a286-843789bb65d4": {"doc_hash": "d0b92ed4e68725fecdfeb1fee7741515aff8d3cb25665c933a389f611957c8a8", "ref_doc_id": "ed137863-472d-414c-b5e7-59e8a8c664ca"}, "74dfc485-5b34-4518-9994-b271a3c696f2": {"doc_hash": "b55363470039b024fba897c28c3953fb301015ef599afb54da8a5e53221622b4", "ref_doc_id": "72e0fd58-cbb9-45f3-a217-9e41af532c88"}, "c9bea34c-88e8-46d6-89a2-3efbfe1ed909": {"doc_hash": "29078f7794c48abcf2dda17d4467816f84b37f24f9809ec72a3c35d67f3028f4", "ref_doc_id": "72e0fd58-cbb9-45f3-a217-9e41af532c88"}, "6e9e8c93-f501-4d5a-8388-3b826fda1563": {"doc_hash": "717f5867d6698b182044ebfc6716d8af096d4d48218ac16569c917619f41d337", "ref_doc_id": "72e0fd58-cbb9-45f3-a217-9e41af532c88"}, "5a15dffa-b5aa-43ac-a07f-082396ea11f4": {"doc_hash": "35adbcb81fb4eac91a5e7cd697850a402ce45c3f82ae98ed50c0c5b4e9fde7ef", "ref_doc_id": "e95d63a7-d868-4108-9fa6-8ccd568bed33"}, "955d26aa-24d8-4788-83d3-38190eac383a": {"doc_hash": "0991fa9d2ef0dfb85169ed37aafc8c9567bc8ef2ed9671c81778e45f8e141e41", "ref_doc_id": "e95d63a7-d868-4108-9fa6-8ccd568bed33"}, "0a61e912-c3d4-4fdc-897a-19c278da523c": {"doc_hash": "cd58ff3c52b732244023da51a2d19390cd8f12e79147a4fe002df1bfaadda443", "ref_doc_id": "845c1790-78fd-4f32-ad27-f0b26131cb90"}, "15c1ce16-505c-4a8d-b6d8-10b6358e8a05": {"doc_hash": "0d03ac33ff219c3da0e1e31c2d743cb2209060858dc925cad42c03fca6cc8f5b", "ref_doc_id": "845c1790-78fd-4f32-ad27-f0b26131cb90"}, "65f11d47-4569-496d-a8cc-83114174e2d8": {"doc_hash": "14bac6e6318315ecd1b6347be5f15e475647302055fff3f8946bb2dc1348ac5a", "ref_doc_id": "f472d0ca-2bf5-444d-b5b4-0a7a0a83d985"}, "17ba6139-c9df-47d5-a8c2-d84de8a5c45a": {"doc_hash": "8c2b5135af74912bd1b4086011a825fea5ace0ad702bc5477ad4f5dd45c16096", "ref_doc_id": "f472d0ca-2bf5-444d-b5b4-0a7a0a83d985"}, "025ef01f-29d2-4352-aedd-3896af457063": {"doc_hash": "1921c399cbbb97074d992a76bf6562c43f64936031e94139264565d9a0275dcd", "ref_doc_id": "865eb2a8-f914-4962-92b4-e85a08a97102"}, "61cf5316-6784-42d7-b63b-2042b4ab4c06": {"doc_hash": "8d26ce9fea9346c7b5d45774b8969442d0ee645fbea3ed8ad137982de34c2df8", "ref_doc_id": "865eb2a8-f914-4962-92b4-e85a08a97102"}, "7ff6bec9-cf17-45af-87ac-0530ea9faece": {"doc_hash": "9f6acb48773d5d5085fecf6df55836bfdc253d8b89837b9be66780311f8fb4e2", "ref_doc_id": "5a20bf0e-e068-4714-b1b0-211e3cda595d"}, "b13732f2-d306-4493-93fa-3e48eab23c05": {"doc_hash": "e17b024cc1f9ee5404405e14840d248045d306f9589bd6aa8e1f2df08916b0e1", "ref_doc_id": "5a20bf0e-e068-4714-b1b0-211e3cda595d"}, "f3ed670c-23df-47e2-b3a4-612233ed6648": {"doc_hash": "e7693bbc961ea0a72c00a86ad2d82dae2a111a762003adc2ea6390f00d5994c5", "ref_doc_id": "b77f441f-6c18-4904-b14a-41d4fb97c0be"}, "a761a3ef-8386-443a-9505-f0117182f81e": {"doc_hash": "ff442d2fb0f122433fa4db9b42275fbb171c2dd1738ffae2a6c43c2819db44c1", "ref_doc_id": "b77f441f-6c18-4904-b14a-41d4fb97c0be"}, "39c29a5c-7882-40d0-9a01-adb3566abe62": {"doc_hash": "aaf7aecfe6bf0de0d32a08ec988b85b8683cd1939ef15d32df7c785d95ac3967", "ref_doc_id": "56594b9b-b903-4f5f-903b-aa7261fe37ee"}, "612ce01a-76ca-4d21-9707-9f37f07e8465": {"doc_hash": "cc08cf19193aeab6a054e22d0e192527e511f73ac7cca159db6376a0855b3374", "ref_doc_id": "3bbd682c-2cc0-49f6-aa9e-fb1841e0d27d"}, "aa485f7e-deaa-4be1-829e-f7ed129efc99": {"doc_hash": "85bb40b9996b0313f085d93e77d8bdaf2263c15db4fee2452df079dc46ebcc30", "ref_doc_id": "3bbd682c-2cc0-49f6-aa9e-fb1841e0d27d"}, "470c3dd2-db51-42a0-a2f9-ba997ae99658": {"doc_hash": "0398ebaae681d3bade1ee3f8d267cf2b76bd1331e546175d3442b3874692979d", "ref_doc_id": "fd85ddd7-7132-4c68-9bdd-f820ad8e8cf1"}, "dd3f9c7f-e1d2-4dba-90be-adad213f2a9f": {"doc_hash": "cac1625cad5819c60241d5f6023dc09ce3ff0035f0b3c72079441b8efed4db02", "ref_doc_id": "fd85ddd7-7132-4c68-9bdd-f820ad8e8cf1"}, "c0f9ceae-7a96-4f5d-99a3-91b444e4d107": {"doc_hash": "aab65b35ae1238215aaaf7931e42986d87324412ddc372c9e323c49234fd5458", "ref_doc_id": "ae98dfd7-bd97-4b59-9673-f70ff15009e7"}, "5e27f721-703c-4e45-83a0-bb8bca91f862": {"doc_hash": "91188a9a7d38e3b2068984eb36b5257c9ad247ed72d13e38c15fa43c25ff99f0", "ref_doc_id": "ae98dfd7-bd97-4b59-9673-f70ff15009e7"}, "e217289f-adb9-4478-aeda-594fd76d0243": {"doc_hash": "d4445abecc4749dd1fa334d410ed1e092bd97bb8fb0a8822d46d5de792100429", "ref_doc_id": "ae98dfd7-bd97-4b59-9673-f70ff15009e7"}, "2ab3b2fb-bc7d-4043-af72-c8de1aa0d204": {"doc_hash": "3f9f1a95d24822ccfbef3dc9662bf9deb79534d1606a1b7d3366f2c07f59948f", "ref_doc_id": "d30d9ee7-c655-450b-b608-5879c7ab9d87"}, "514ecaf3-fc03-4697-9fe4-78622b29fe54": {"doc_hash": "eb7a7b88832ee46ea538a187efadc22c5a3a6b65288f3524e342257f9a9a6ced", "ref_doc_id": "d30d9ee7-c655-450b-b608-5879c7ab9d87"}, "aeba0693-6d5c-4426-8c36-196787e98273": {"doc_hash": "265a6614c220a25e262b61f92e1772d2f6756fe3c008e598bbac05483d5b6fca", "ref_doc_id": "b75d166d-6fec-4370-befe-44087ce027ad"}, "226910e6-a2ea-490c-abce-615584118567": {"doc_hash": "9706b57927df0eee92f9be5c6dcff2ac5cc60c3db2aed49dc268b4c958ecbba2", "ref_doc_id": "b75d166d-6fec-4370-befe-44087ce027ad"}, "d43e6ede-6000-4233-971c-2e723d0e9133": {"doc_hash": "186f4559b932a513c2822beb21c7649be83f0df897a2d3b1dae4c3f4458d2038", "ref_doc_id": "8db06f35-b0dc-4488-ae1a-ecb47748b226"}, "3ee31c09-301d-44df-8702-76d5b874ab97": {"doc_hash": "89cbedab7a1914e5bd083d1a61b1e92ab87c01cbdb5c8d1e8b825e07a083d361", "ref_doc_id": "ac0b7db0-e4ea-4680-a4d3-05b2eb89eeda"}, "993ef7ae-b698-4e86-aeb0-fee379eb3c48": {"doc_hash": "44b9db8f195f3d9c94c8946d59fb208ff40bef10292238b3a5145bd042f6cd64", "ref_doc_id": "ac0b7db0-e4ea-4680-a4d3-05b2eb89eeda"}, "cd5f10d2-5483-49c0-a8bb-fab71341d723": {"doc_hash": "3ad18eb4e4d4bf98eb9661ffa6af1112443fc2aa4350bb9f329f6aaaff6d78bc", "ref_doc_id": "bf4d2666-79e3-4149-ad55-f289e88bf3c4"}, "de887d18-d6f7-4a83-8451-e32457ff8a1c": {"doc_hash": "f117e3696165fed4c59cf829eee900bd81e6d851711accf5d50e3e0d1f84bc1a", "ref_doc_id": "bf4d2666-79e3-4149-ad55-f289e88bf3c4"}, "af86ae83-26b3-4be9-aecb-4e097e188e31": {"doc_hash": "a3d4315713b8e2b20c4d1243848845711642b909a10c7894afaaf29f2ee83a71", "ref_doc_id": "bece3d50-eb40-481e-b025-57eb4b175b7e"}, "f11cc710-96ea-4f17-8adf-ccf174a7bb5b": {"doc_hash": "7da6aaf0e14f5e1ff07221e96ea8158165202fdc858235e638533c4ac7aea4c4", "ref_doc_id": "bece3d50-eb40-481e-b025-57eb4b175b7e"}, "7d5de878-2047-403f-84f3-a7477bda590c": {"doc_hash": "47484c33341971c468b0268778819755038d650b35367dcf7e025138a12b0707", "ref_doc_id": "bece3d50-eb40-481e-b025-57eb4b175b7e"}, "7364b4be-e84c-403b-afdd-294c57e53e7e": {"doc_hash": "a069c6a132fc53e41ea9eb9150bf65569f42b1ae8c4815979912241f21db07fc", "ref_doc_id": "509f652a-353f-41a1-893e-8ca2be914814"}, "fd7cfb9c-05f9-403d-a453-4ba3135d479e": {"doc_hash": "154ab1125cff2eb3d256a51d28f14e62f528a1c88097464e1d3a695d498d2230", "ref_doc_id": "509f652a-353f-41a1-893e-8ca2be914814"}, "433417a6-7815-46a9-960a-f48303308a1c": {"doc_hash": "d671bd359e83eef1ab12913f067bde0656e48f3e96338660c5a0b1a849a1a3ec", "ref_doc_id": "afa32515-efdc-4c1c-b38b-71796b965215"}, "7775c399-8965-45ed-9ec6-b2c6d5fbf888": {"doc_hash": "d6672c8acef135d0dad49d9bd706c54a3e4777d50311178e93db3f8cdadf289d", "ref_doc_id": "afa32515-efdc-4c1c-b38b-71796b965215"}, "a921653a-79fb-4e40-9e44-ee07af3eafcf": {"doc_hash": "12a2577aa58f2d36c50b9382c189a1de627a292ec395f44b2c889b6183789bad", "ref_doc_id": "a207c394-df9d-4414-8fb1-1774ec46f401"}, "2161e05e-ece4-459c-92f3-e590a2e4d83d": {"doc_hash": "9d06a0bcdcbb10421b7034b1346a423c85cd2402d845abfba5c429f9565a0c5a", "ref_doc_id": "a207c394-df9d-4414-8fb1-1774ec46f401"}, "1af33916-9be3-4f94-aa69-968b3752c031": {"doc_hash": "7fb66533b93ddd616a4402b833000fefbf58d1640a4efc8c723285a282628d50", "ref_doc_id": "ba7e63b3-524a-4c9c-984e-4be98a558c04"}, "b6a177fd-b637-4898-8b11-fd396edc867d": {"doc_hash": "cf57364bf74acb31ddd0204e64ff154954e1f7b0578507a74c8186a351e5719e", "ref_doc_id": "ba7e63b3-524a-4c9c-984e-4be98a558c04"}, "553a4bc6-1cc0-411a-97de-37f706286d56": {"doc_hash": "81f3a83d9bdf18e4263211f8cf051b7f290f5fc02b35835a18c4a2b2e0a5a8a0", "ref_doc_id": "002f2c5e-4dd7-42a7-bef4-0d068e952e3c"}, "d03c13b8-c4c3-46c6-ac4c-7d1b3683c341": {"doc_hash": "1f853854d3e1188e447b33ddfeadde47b8846e31470de699d09a188a2ddc5d4e", "ref_doc_id": "002f2c5e-4dd7-42a7-bef4-0d068e952e3c"}, "5ff81ec4-4568-468a-8943-70e371a9a767": {"doc_hash": "21de6afae4fe46b80e39ffd2a173bcd5c460e7a7430dbc1feb076e52b844c0f2", "ref_doc_id": "002f2c5e-4dd7-42a7-bef4-0d068e952e3c"}, "7f263fe4-9409-4824-84fd-a7b9df35d5c0": {"doc_hash": "a0d2cd0a62d934bf74e7d1b9cedaa5529836aa533ec9121e138e031108734085", "ref_doc_id": "43fd4ed7-1572-412f-a47f-356d2c67939f"}, "f53e5479-2729-4b38-b27c-e8af013e34ad": {"doc_hash": "2cde25dd6bba5f67eee982b0d4e48648e12961f0a52d7e92af7de82c9d6eae5b", "ref_doc_id": "43fd4ed7-1572-412f-a47f-356d2c67939f"}, "f3a18da5-0229-4907-b186-9403903b7c9d": {"doc_hash": "5aca0c9b7c3679cc43216644cb4b8adaae0f1bd7bc86a073e82e40f8eb93f847", "ref_doc_id": "8cdf5ec7-244a-4e0b-9728-85fb0c88ab94"}, "085d7461-731d-4087-9b93-4d10f6e920b4": {"doc_hash": "78ff3b431201f717ffe57d5dc53d09d719a1de79b77155570f4c12f53b92aeb4", "ref_doc_id": "8cdf5ec7-244a-4e0b-9728-85fb0c88ab94"}, "f77f2a97-7648-433b-b19c-f051361579ab": {"doc_hash": "fd06dd3b18b50bbe027129ccd9e1108405be762b48559c3977a2be31d279fb22", "ref_doc_id": "338ded58-3ef4-40b5-b531-502ca258b2a4"}, "c87f70f4-7c5c-4c17-84f2-e339fb2626c7": {"doc_hash": "3f440837a33623264a0d7f57dd3cdefe8d145a6b694488145f64b3b9bda6e7cc", "ref_doc_id": "57769d3a-6a56-4554-9cf7-58d387f248de"}, "2a11dbcc-ca59-4cff-832a-fbe928bbf0aa": {"doc_hash": "e753b3241960c9529f6e9d98c111da226dfd9eec76a0e795bc62fa9ebdda8007", "ref_doc_id": "69b4d408-bc94-4ba6-a6ae-bc0d317331d7"}, "131a0e16-36da-4cbb-bdd2-e82e0d62753a": {"doc_hash": "257cbaf86f2b0e175ef1ac724ef9a6df436f3a692eb0d4ddd5bce55ad3d9534a", "ref_doc_id": "69b4d408-bc94-4ba6-a6ae-bc0d317331d7"}, "2b32a601-335b-48b5-bd86-987a61ac54b4": {"doc_hash": "c3ec80fd2c1cacf1e19e4fb935adfebd6a00e81116122e7a78f4ff82926832f8", "ref_doc_id": "69b4d408-bc94-4ba6-a6ae-bc0d317331d7"}, "42cd00ad-1111-45d1-a48a-21e18ff8b20a": {"doc_hash": "c9041b1c8314f1868746f9490b69ec2821374dbfa6a830cad1b8132bf0285d48", "ref_doc_id": "312a2f71-a34a-4d6f-8308-3187507591fe"}, "9321d863-a52a-48a9-992c-c408dfa4f38e": {"doc_hash": "9e3e1961de7d4c5fdd8082cca1873db40981403f5f7cdbf60ee0e00a43ebc56d", "ref_doc_id": "312a2f71-a34a-4d6f-8308-3187507591fe"}, "7ddf767f-6f0b-4843-acf9-8d06d5ccce24": {"doc_hash": "27ec41f3659e0cdbba4f8ac1a4934b452c593371e436a9d537082862a1bd1fca", "ref_doc_id": "312a2f71-a34a-4d6f-8308-3187507591fe"}, "ad9dc5b2-25f7-4602-aa62-6f242d560dea": {"doc_hash": "dd1bac80fad6cb0cef0be07e4e81c8a6e1e47e72f47f0a6ca450801b323b7900", "ref_doc_id": "2efe2c16-367f-43b5-9630-e6a39097e363"}, "3d29483e-98c6-4dd1-b4d0-47221ba4abef": {"doc_hash": "51af46fdf351feb75399cb4986da79d8a886506223bef2b86e824c6c74747de2", "ref_doc_id": "2efe2c16-367f-43b5-9630-e6a39097e363"}, "86d817f1-93ad-4c07-aa29-1a911daff4c5": {"doc_hash": "49853fc975121e54f74fc7ff95f32e732a6f2de96e93e12290a921eabbe3393d", "ref_doc_id": "2d99252a-62df-4cb3-b0f1-43ad935ac179"}, "2afca5f0-da4a-4cc7-8644-18a89394b048": {"doc_hash": "e99914aca0a58e9836d5e2f8573daf020ffd578ef8f738a27259c8c963fd2b53", "ref_doc_id": "2d99252a-62df-4cb3-b0f1-43ad935ac179"}, "5307a524-20e4-4bed-b02a-7b228230e4aa": {"doc_hash": "b4d8d988f518f1f39befc3f90f46f263cda9744b8e1d2c0834a67cdd7e993558", "ref_doc_id": "2820bc6e-883e-4448-84da-9c2bcb123de1"}, "3d6cc7f4-4031-4e79-b6af-02a8b7477ae3": {"doc_hash": "b3982226c3cbc58185c970af1794b49f01c68555ba7f6aa2fdea83c25b6e4960", "ref_doc_id": "2820bc6e-883e-4448-84da-9c2bcb123de1"}, "b6de8128-51c0-4015-a9cf-cf9274120170": {"doc_hash": "544c0a416395fa54abc4f03409955c0d18e204fe7d602ef7c5d18aac9ff9fcce", "ref_doc_id": "2820bc6e-883e-4448-84da-9c2bcb123de1"}, "1cf3a3eb-7da6-4888-9be6-1e53416118ef": {"doc_hash": "e7371a45ed8e968f3f0abb9912c4cbe39063d76d0e92ecdc944b77589a9d1ddc", "ref_doc_id": "7f2566f8-5879-4729-8b8b-de2ca19f31b3"}, "fb6b9d1c-a0b1-41f6-9b1b-848d313ef342": {"doc_hash": "a3764c481b5cf2ffa395e02e4d189eaa6b66b64c4a09f1b6109b5fa56e63b667", "ref_doc_id": "7f2566f8-5879-4729-8b8b-de2ca19f31b3"}, "f5c04ba9-a958-403e-b267-5b813a9e8e75": {"doc_hash": "3b9f7132b43b03e18289259e00e252f123348b61e2a3591778e6e7ec6780d6b7", "ref_doc_id": "1d3c8648-f910-44ef-b8f3-2b919f7a297c"}, "c3ba185f-02ea-4e45-9089-4e0ec8b71f29": {"doc_hash": "4b653de96a68060910cd7b82ab9b2bf4fe6f31fead698aa52d8354ae6883ce39", "ref_doc_id": "1d3c8648-f910-44ef-b8f3-2b919f7a297c"}, "1c1e3e3a-f8b8-489b-962d-7d48823eadb2": {"doc_hash": "5e64039b96e15af85f18f04a2e63a82a77b4e584e0c8c2e762645e2087440565", "ref_doc_id": "f5a0ce43-750b-4daf-abe4-3b94a7320f12"}, "947d176e-6d0c-4c55-b790-48f0bcedf665": {"doc_hash": "04e20e173a91225922a850e77fad46e043f9568a3ea09a8544c486a2ae3fd384", "ref_doc_id": "f5a0ce43-750b-4daf-abe4-3b94a7320f12"}, "03375adb-39cd-449c-b601-a5c4b1e5b6d7": {"doc_hash": "e0fda51bd38ed856b62e67af44989a135acfb77b2e5900b5c206e0ba6b049761", "ref_doc_id": "a7d782e9-35d0-4e51-bdfa-82fc22962e26"}, "bcc12182-6b8b-4ae8-956b-e8f653e4a651": {"doc_hash": "d2b767ea4525fc7e81e5fd1c2ee9ef2267d1f2449084a56f319a21c3660c5e11", "ref_doc_id": "a7d782e9-35d0-4e51-bdfa-82fc22962e26"}, "8748c053-0b80-4fcf-894f-edad10851b33": {"doc_hash": "4f96d1841c4787a73a2e60c6e633eebf87ac2f9000927740d00aba69a0bb3d25", "ref_doc_id": "5a136616-d1d9-4e89-a6ec-7713242f1fb5"}, "a30cee4b-a964-4792-9078-11de0a260c56": {"doc_hash": "dc50a5bb714a239bf291b1e53e9d74f120c548f654a7bbcf183bcffccf7e0db0", "ref_doc_id": "5a136616-d1d9-4e89-a6ec-7713242f1fb5"}, "f10b5deb-7587-4b20-af67-a60bf2bcbb02": {"doc_hash": "a760dfba2c2a94c235ab4f973506d7e9e1d8006017a0c6d0e7a79ef60474c9d2", "ref_doc_id": "4cdf9854-fb5e-4ec0-9bd1-752d12ec6643"}, "433a1465-f8a9-42b9-918f-fa18c8b0be46": {"doc_hash": "f480b8c20c747ea66d79c50757974b7f66bd49e11c1df4e6bc22a5a27a11d532", "ref_doc_id": "df2004c2-5f6e-452b-ba4b-9b9103450cb5"}, "eecb9424-6a07-4c77-866e-f68c000a6880": {"doc_hash": "61e9399ea0c596744941db0f3c5b8900687a30a13dbcab228c31f7d5635f2c40", "ref_doc_id": "df2004c2-5f6e-452b-ba4b-9b9103450cb5"}, "ae34076b-a2ff-430a-8c8a-2761a624256d": {"doc_hash": "e0984acac26c434ab555f11355795f2ead8dc12bc42ad9d98effaef6bfb65405", "ref_doc_id": "7901cacf-47ed-4568-9920-9f3dfbe92689"}, "391b0fb3-949e-47f6-8ccd-3e4dee663829": {"doc_hash": "1e42ff646fea6c4b15fa00a091aae519f6b0bbf49d1b14c94646c49a2f3ed8d6", "ref_doc_id": "1e120836-3fed-48fd-bf36-e585e563e7ce"}, "7bdcb91a-5f2a-4b7a-bd7e-b92c08e13259": {"doc_hash": "d09f29214cd1375197ccdc68ce193d17a48033cb773738931a4942e4cf72204a", "ref_doc_id": "1e120836-3fed-48fd-bf36-e585e563e7ce"}, "49ada95d-aaed-4313-a2e3-8db3d0977f06": {"doc_hash": "397237c1c6631a701902b4857eafbbf512f301f614ecd1d679baf26a770c292a", "ref_doc_id": "1e120836-3fed-48fd-bf36-e585e563e7ce"}, "dfeb2f71-c017-4b57-8772-c8365f1c34b7": {"doc_hash": "6325e22cb757ecabb983327ef4ed4df1aac67a663b7c5793d30276e63de5e1f4", "ref_doc_id": "ad1eb29b-7bf6-4638-93de-c1bd04d73140"}, "9c2f936a-8b0c-4202-b1a2-47f099701f50": {"doc_hash": "365d72fbb59fc7c24bb7ded4ceb9c7188a949343947bd4f96b9a1637e227add6", "ref_doc_id": "e7652755-7ba9-442d-bb56-d595adf3c0f3"}, "e34cc61d-5d71-43b9-8ce8-cfbe98c45ecd": {"doc_hash": "fb9f039019238b82b13594aa587897df499aed10aaea8eb5b8553ebd3eefc554", "ref_doc_id": "e7652755-7ba9-442d-bb56-d595adf3c0f3"}, "a4f93db8-1df1-49b5-aff9-e8e897dfcdd8": {"doc_hash": "f305e92450b317e655fd3b346bc51c3096d9366a1e35f83dcb264385d9a9153c", "ref_doc_id": "d5f69c01-59be-41a8-a41a-3883ac1c321e"}, "6946f9ff-8135-4fa6-98dc-4c5074f062c2": {"doc_hash": "76ae9d6ce350d24755708db5a33ceb0f4c38221cabe3db6c9b5644848f3053f0", "ref_doc_id": "d5f69c01-59be-41a8-a41a-3883ac1c321e"}, "e8b777a0-8cf5-4894-8377-dfae081dcb31": {"doc_hash": "d37f738ba92f544c85a5a64f709fd93be2a6544b66353d2933ae4ddb88319468", "ref_doc_id": "ecfd36e2-0e35-4c3a-8249-c02786406561"}, "6fa5609f-13d2-4abd-a46b-7d5645c95ce4": {"doc_hash": "e42e5a0d62a6de0f9984ec094138163845231c8b6f5844f3b2cef32a22254030", "ref_doc_id": "ecfd36e2-0e35-4c3a-8249-c02786406561"}, "07c858f0-4a89-4b45-ab01-9d85da770778": {"doc_hash": "3ee221d693914606f4bbb6dde96d030569728d20ac8d9883546e4966778ea14c", "ref_doc_id": "9d0495d1-80f5-4d6e-bd59-9b420170953c"}, "db8e1154-a5c3-4cdc-91bf-2f58ef938362": {"doc_hash": "90c71fd2ef78ded4ffedff9162ad2022cf29b05e0b732549f1c2f4a977ce1ed3", "ref_doc_id": "9d0495d1-80f5-4d6e-bd59-9b420170953c"}, "93fd3e61-a306-4da2-a662-1f288a4777b6": {"doc_hash": "e131fccc7b8fae2493e8b9c0c8bde78c3f1f4187542eaa7170c123ee2b9c83c5", "ref_doc_id": "78eddb40-33d6-43e4-af90-987363f1d25c"}, "9b8ecf75-bdbc-4d6c-8e48-2cb578bdcb9e": {"doc_hash": "a386f498e87ede2d92c1fc3d71d96d3c8f02446b6b0864b0a719a75e3b71910b", "ref_doc_id": "78eddb40-33d6-43e4-af90-987363f1d25c"}, "743bc24e-4d19-4763-89f5-3896eb213b24": {"doc_hash": "955f22246951221fcd2a7e13d5bc1432442fb43ab35970ad71159898a71d9642", "ref_doc_id": "78eddb40-33d6-43e4-af90-987363f1d25c"}, "2a81eb0c-90a2-4403-a16f-15345f94069a": {"doc_hash": "16e312f6b28a103465df8fc99e8af0406115646a3c690ce0053a985d78d79c00", "ref_doc_id": "a54dc9d5-fd9a-4943-bbb5-c1568dc70c0b"}, "45b9431e-21d4-452f-9adf-f4d1130877b1": {"doc_hash": "9b84e138b58ec23072dc3fd70e3e51a9bc155e5bc35e9dc8622a8abd9271c681", "ref_doc_id": "a54dc9d5-fd9a-4943-bbb5-c1568dc70c0b"}, "e93b4355-1890-4f3f-92e3-494d89d287ef": {"doc_hash": "90a4b7df1f08ce0926c968766377c4d3dcae83b8f9252dd1cf7bad73cfedf310", "ref_doc_id": "2113f332-9cbd-439f-ac53-98bbd9ec1a6f"}, "1cb50598-8efd-40b2-bab2-48a5c4491a79": {"doc_hash": "fb18578ebb12e2a76a42c570eff2dacdde405bdd881b5a6e6a68025e610b142e", "ref_doc_id": "2113f332-9cbd-439f-ac53-98bbd9ec1a6f"}, "430aea8c-5fb0-47a0-b38f-649d2503e5e3": {"doc_hash": "339fae1c4c8e7368e37e8d3b5ca0ea9445b74c17b57639c6e8f27025ea11b5a6", "ref_doc_id": "2113f332-9cbd-439f-ac53-98bbd9ec1a6f"}, "6cab7286-34e7-40d5-be18-85c4ade5c9a5": {"doc_hash": "e893a3561fe0413e1ac5d100db761387783cc799a74a87ee624dc9d0703d8ac9", "ref_doc_id": "f1a8ee66-1f5b-4847-96e7-09398b7db6b1"}, "bf41a9a7-cd62-4686-b73d-66176c7eb2d3": {"doc_hash": "573f67c782b18fe8025db0e43957a984e44e8113abc61b3a21466d9c7966add4", "ref_doc_id": "f1a8ee66-1f5b-4847-96e7-09398b7db6b1"}, "569e94be-18c5-4ce8-993b-65587b88d6a5": {"doc_hash": "6ad2b1463df8e78bdcc95671049ba043a8d263b9caa67dce76a16172b95fb0c7", "ref_doc_id": "f1a8ee66-1f5b-4847-96e7-09398b7db6b1"}, "32062168-3e7b-46c4-8b02-e224ae8c6da4": {"doc_hash": "a0f8c50ef815fc72b149c957818260e15bdd8c3df295a4e56aedacc471c55563", "ref_doc_id": "f559645a-5b6c-4280-8910-6640170daa3c"}, "e7c1d774-5e0d-4fa0-9b37-d18387efdb36": {"doc_hash": "c354783bb373b92f525fa9c45ab3920c0ec7677e5f75375f123bc772d295ab7c", "ref_doc_id": "f559645a-5b6c-4280-8910-6640170daa3c"}, "516970e4-2f4f-4431-8ef0-156a834b44fd": {"doc_hash": "66102378e4ed1f60606e780e722db440798f7f0522f64e2a6ed64cbe380eda08", "ref_doc_id": "2e86c0b2-bd7c-45f4-ba93-e4fb7d65f5f5"}, "8b5a1da4-3c7d-4806-bf40-b20ba0ed6a0a": {"doc_hash": "8a0f31be0f165b14743290d884da063f4969cc87c7dccb3ac2d350299ab209dc", "ref_doc_id": "2e86c0b2-bd7c-45f4-ba93-e4fb7d65f5f5"}, "95b8a40d-e800-4917-b8c3-1396616df9be": {"doc_hash": "f4dffa58763a6dfe6ac0ce2c12dc581aff80ee0a132912ef5db190a875d2e4ff", "ref_doc_id": "dd3b0751-225b-4d31-bbe3-ec2b4eab3a1a"}, "07edd5b6-0501-4400-8e19-c30c8f229b3d": {"doc_hash": "965121c5f330c3a9ba9889f6ce600ddbb1a97114f13369e408c7ed550236cb18", "ref_doc_id": "dd3b0751-225b-4d31-bbe3-ec2b4eab3a1a"}, "9ec8c017-27ec-4435-91bb-da363cd05d96": {"doc_hash": "ad1e3aa955a4d51b6088cce6fa8e9d3cd9bbaab08bb74c7f9d67202e5c5acdf5", "ref_doc_id": "2d76ece2-3022-4022-a259-989bfd5da8d6"}, "f36ab8bc-71a5-4dc5-a0e2-5ac5c71005ea": {"doc_hash": "67ed94c0fed81faf2ca2bc33bb7ba6d8e2331288327fe4aa69e9661b8402aef0", "ref_doc_id": "d587c035-8386-43dc-b3b0-c7c6e58ef870"}, "e519616a-8e39-4172-a6c7-16fbe874a111": {"doc_hash": "51bdbdfae1eafb763a6a0923a54f9bf1aa0a03573bbe887ac3350350cee20bc3", "ref_doc_id": "d587c035-8386-43dc-b3b0-c7c6e58ef870"}, "17ec8187-c9bd-4923-b31b-71360471fcb6": {"doc_hash": "ad50394b264793b8e8e3c6a690cad1526142e4e697d44365c3b582b89d266fc5", "ref_doc_id": "4ead50f6-ec16-457d-8cf7-e29e6f9209fb"}, "c48be504-0ab3-4d25-9333-51bae94645a0": {"doc_hash": "b4576fe20758ede092ecf1f7f6118eabc037b3016383c38341bcbcb3ddd82867", "ref_doc_id": "4ead50f6-ec16-457d-8cf7-e29e6f9209fb"}, "8ac3749f-eceb-4bbf-8912-e28edbdac033": {"doc_hash": "7fdc4cbe175032296850eca37b1c7f7cfd4ef0a1795ec4e473876dde71beb66a", "ref_doc_id": "8703b11f-dc88-4e11-850d-8402c234356f"}, "ad4cc372-698b-45d5-be2c-a91578887da6": {"doc_hash": "2885b687302015155a9598c9e79954d0e9c5a23848d0de8907e0d847695577c8", "ref_doc_id": "8703b11f-dc88-4e11-850d-8402c234356f"}, "abd72f2f-6891-4008-8ca8-c4cc40cff131": {"doc_hash": "7e0edd7c9e8e1cb278ab0f0371a8ed8b34484a77afc6bc743303bf0038b1aa53", "ref_doc_id": "8703b11f-dc88-4e11-850d-8402c234356f"}, "ab92eae8-620f-46d6-bfa3-c6699396b557": {"doc_hash": "6938faac7a97d7cb0bdf2cb922a52cb23fca400b83b8e67100d70fd2f1b9b117", "ref_doc_id": "3d7f5e90-b5b5-4f5c-8e92-f1938d552974"}, "f5b0d324-b66e-40b3-94a1-863dc313e122": {"doc_hash": "ccb48d6d73469155b7ff050bba00f3a6166f5808dba567c1e7369805234c9bdc", "ref_doc_id": "3d7f5e90-b5b5-4f5c-8e92-f1938d552974"}, "6be165eb-c820-497a-a223-7d02bace9369": {"doc_hash": "f6fd103a57f2908780355c982bc8add8cf17f22a4c8df51d61bfb6a48df8138c", "ref_doc_id": "874b9f4e-e762-491e-a533-a181f375a3fd"}, "da7077c6-2ce5-4b8e-8def-ec1d4a757d0a": {"doc_hash": "190a1eede6ad13599d110b7fdd713c85ed2c0a712691b4b415dc8d520ee8eeba", "ref_doc_id": "874b9f4e-e762-491e-a533-a181f375a3fd"}, "09bcd39e-0fa7-4867-aa66-56d5a9d268fd": {"doc_hash": "073776c751b04d0d460ec7e5a9b34c4f01b725c6a113f29bcb7db3f78b024aff", "ref_doc_id": "874b9f4e-e762-491e-a533-a181f375a3fd"}, "322b9ddd-4f10-475e-b6d8-f124be0ad7d3": {"doc_hash": "20045c7cdf429cc89e6a3deb21eba10124a620cfb731900746e97c33a60409e2", "ref_doc_id": "4b3fcb1a-c638-4a31-a7d8-273fa736b792"}, "c2bca4ce-6c98-43d4-83ae-36f6874e1609": {"doc_hash": "42737cea02f4669861520eac539d411e2f9f5bded792c97c97d6230e4db74435", "ref_doc_id": "4b3fcb1a-c638-4a31-a7d8-273fa736b792"}, "5be1fffd-6ab7-41e5-8e6b-321628302807": {"doc_hash": "ec532b95287dab900e4139953511b44e0e86e78b992cf3c9ff95c26cd0a7b787", "ref_doc_id": "3eef0e8f-fdfb-4d56-aa44-4637b95e1723"}, "3e4810a7-c9c0-449d-9a0e-4c59eb46e2f5": {"doc_hash": "86637180c453daae5bc5f109b665d1fc921022a1c9bac67440afb6d9285c0131", "ref_doc_id": "3eef0e8f-fdfb-4d56-aa44-4637b95e1723"}, "67e56903-fefd-495c-8ee1-71c381d988a3": {"doc_hash": "4a5af2448390507fda8fba7eaeeeb97a470f43ae674b5c0cdb58e45b74b69ceb", "ref_doc_id": "0cff3a89-49c9-4dba-a3b0-16640524b0a2"}, "6f87ace5-de7e-4683-be00-fd172654f5cd": {"doc_hash": "8f1910d48112494cf4a915b4b784d1e3a235ae271dc820e9d0ba46ed31f07701", "ref_doc_id": "0cff3a89-49c9-4dba-a3b0-16640524b0a2"}, "a11d45fd-32b1-4b35-87ec-e3c6ce9f183c": {"doc_hash": "040b7af731c197b907f15774203eaf1effddf02099b4ee4627794ae9de2058f1", "ref_doc_id": "7c3c77b5-3567-4f39-a560-42492e688f10"}, "c1231d56-1997-4a9d-939c-172b99643883": {"doc_hash": "9caa8188894d0f01242ed08a5c11d342bda212013eb2a0a598e386c5a3113bbf", "ref_doc_id": "7c3c77b5-3567-4f39-a560-42492e688f10"}, "fafeb35d-6cd7-4f40-aead-ca1dcb0f3993": {"doc_hash": "7ed8e3b04e19c920e93714cfb30af566c60c1f2c3b4583deac47dd39eeb349d8", "ref_doc_id": "7c3c77b5-3567-4f39-a560-42492e688f10"}, "a6f0f1b3-9e51-4091-940e-22f0adbd828a": {"doc_hash": "48a913cbeab06c8495d08c70fa51269080596534914601f3dbe2fa2bce02dd21", "ref_doc_id": "c3648494-4412-4b52-ad27-3d72dc418a7d"}, "764b4dfd-5959-42a8-8fcf-9e76a73ed7f5": {"doc_hash": "c33db4a4c50df231345280456715b74f001e4ab166b4b8e9d0f31b0b3123bcea", "ref_doc_id": "c3648494-4412-4b52-ad27-3d72dc418a7d"}, "9eeb51b3-85dd-42ba-96c2-0b0ec62ef93e": {"doc_hash": "9ccf42d902527dbdc562a680a2834f9065dbb9a6d16857a977c7be230dc12105", "ref_doc_id": "58e3bf08-ed16-4fb0-b826-41a45f86ba50"}, "6ca8bd3a-03a8-46d0-9344-20f40d61f284": {"doc_hash": "dfbe9d8ec24a95257ec0eaf07e2fb023810ab6f6e8c58129d58f8d30dfb7d653", "ref_doc_id": "58e3bf08-ed16-4fb0-b826-41a45f86ba50"}, "4fb27e9d-2386-4ac3-acc0-c04888f15d54": {"doc_hash": "ec920c1f84036d2f4dab7a4a7478357616b84390c6e72b3f983a6e00c2f4489e", "ref_doc_id": "b5c4ccdc-4114-4b4d-af9d-cc4d4b31388a"}, "40c6360b-b674-4039-ac99-b012a0958161": {"doc_hash": "1dbedd992d82e15dad69d89bf999e905705995029e4532bd087233a732914093", "ref_doc_id": "b5c4ccdc-4114-4b4d-af9d-cc4d4b31388a"}, "a78b79b3-0ce7-43cf-af7f-7968c3f7dfbc": {"doc_hash": "c676ea743d9686e4570bf26bb75d653c427c1edf3beccb378e24efecffc62abf", "ref_doc_id": "b5c4ccdc-4114-4b4d-af9d-cc4d4b31388a"}, "0aef7c24-9306-4859-b62a-3cba9149a3bb": {"doc_hash": "6e0dc8b8a90b20cffde9a450b41a2372a6f8290e6eaf54b0fa91be2255830929", "ref_doc_id": "1a46f68e-529f-43ea-a038-4d6f63034c9c"}, "531760e5-cdec-43b8-8619-16584da826a8": {"doc_hash": "5e957b1a2314c3ed4290fc7bd680df026d7b3aea4fd44d3ae9a5c9cf773129f1", "ref_doc_id": "1a46f68e-529f-43ea-a038-4d6f63034c9c"}, "07957c2c-e6db-4cec-b16d-8ca6010f2022": {"doc_hash": "b4d52520887f74c9f406ac77a68382b7a7fd05db522533e5b9c6cb101824a5d5", "ref_doc_id": "1a46f68e-529f-43ea-a038-4d6f63034c9c"}, "bcd9764b-ab66-4b7d-98f2-40c8ed1760c3": {"doc_hash": "85c7cdd28cab43a7cce018a432f2aabd474c2227b4db385197e0d43dc7f64cad", "ref_doc_id": "b9cbf605-93df-4549-bd99-1271cf0dab9d"}, "2c33f4a8-8e05-4e46-a4c9-c0c699d8c7f9": {"doc_hash": "4ca4f774213e161f496b0e7e5bf03c4edd79631ec5e9d59eedcac5f741f3e072", "ref_doc_id": "b9cbf605-93df-4549-bd99-1271cf0dab9d"}, "dcf98b54-e459-4c88-9f87-847e43c8e5bc": {"doc_hash": "19136298a64f47218c66a1904ec963139b0501efe7a26275d27222abd5608ca9", "ref_doc_id": "b9cbf605-93df-4549-bd99-1271cf0dab9d"}, "b24314a7-6d54-43a2-a0d6-8b3803dce7e0": {"doc_hash": "ac69a9f270f4cf1ff83a730a64a36d0ec74b161dd4104ac795e4322bbcdd055f", "ref_doc_id": "e59a8298-de9b-4d00-b1f4-08d427547d48"}, "682c95f4-597f-4c32-82d4-21c11ad6e50f": {"doc_hash": "3a331d83d778df3f55993ed8c438df000049bf21063ec1cf3787325c1c15a1d7", "ref_doc_id": "e59a8298-de9b-4d00-b1f4-08d427547d48"}, "604b214e-51ad-4d0c-961c-430d576cdff8": {"doc_hash": "a5e4db1abed5819c226eb1df327261ffdcb2d67f2c641c6d6143adb958cdf139", "ref_doc_id": "f9b72da7-a4e5-4e89-b678-9f094ec7b82f"}, "5060825b-63d7-456d-9ddf-84dd3d76b032": {"doc_hash": "386dc3472dde2443b8fa3edb11d461109e17797cfd5ac9d85e040b721f686a3e", "ref_doc_id": "f9b72da7-a4e5-4e89-b678-9f094ec7b82f"}, "a9f69881-2563-40c3-a5cd-846013a8a3b5": {"doc_hash": "e2305d044fec04c8c7577951c6240da382b2027afe778bae29126afa2cdfde43", "ref_doc_id": "f9b72da7-a4e5-4e89-b678-9f094ec7b82f"}, "a504cc21-d0f0-49c0-81ac-47871e3036ee": {"doc_hash": "e25b2b4625f4db4f9c3d753f8716bdded6ed38e21041fea31dbcc0d59ea13227", "ref_doc_id": "c7f74e43-8e7d-4d08-89f1-bbaab2c6496a"}, "81221f02-a342-470e-876b-569fc414769e": {"doc_hash": "f30a95779bc03856472db1e6e1639414ee15687cf7951722431e388d2393709a", "ref_doc_id": "c7f74e43-8e7d-4d08-89f1-bbaab2c6496a"}, "01fc53ae-48ed-430f-ad3c-2b789efd5a56": {"doc_hash": "138e161b3e8c89f859671b4c9788bb6b9069186ab5cb04ba8d705f0c061b3214", "ref_doc_id": "c7f74e43-8e7d-4d08-89f1-bbaab2c6496a"}, "f692a058-a0f2-4b40-8b21-9598299fd033": {"doc_hash": "b39e3df723e0770e399691dc82058d1ad579ad1e90d2d6dce09274d39ef711ea", "ref_doc_id": "6bc5877c-5e02-4e2a-b9f2-d6120adaf5b4"}, "f3b0c188-e64f-4925-b7d9-fe533b64e7ca": {"doc_hash": "27ba635772a6c26de52ce23a87b008be51a836b3b0a21e887a2a763bfd3cc587", "ref_doc_id": "6bc5877c-5e02-4e2a-b9f2-d6120adaf5b4"}, "d48528ea-29d1-4ebc-afdc-a6783df6b96f": {"doc_hash": "84fabf45a171e7c2c1600f68549431ecdf4fef59a72e9080644a8dda1326ea30", "ref_doc_id": "2148cb08-62c0-4401-b896-597578c7c06f"}, "23833d5b-42b3-4a9a-bcf2-f8a85b026908": {"doc_hash": "20f4de0d9769e45b827d0845d929e516fc8e8444dc9a4b1d4411d5f805468843", "ref_doc_id": "2148cb08-62c0-4401-b896-597578c7c06f"}, "46452a1f-b27b-4240-87fa-a58466163bcc": {"doc_hash": "30ba75df90158577e614587e5d64ade0eef7cb6ec7587f5f593bcf402eb7860e", "ref_doc_id": "2fe47891-bc43-44c1-94ac-b4b2db97a144"}, "77dd74b2-7517-47e3-964e-1bc3a9007fdf": {"doc_hash": "09b81afc1b36fda90e8dafdec3d5ce12a923344d5da79a8ca6498afc93977a5f", "ref_doc_id": "2fe47891-bc43-44c1-94ac-b4b2db97a144"}, "11dddb05-a649-4cf7-95b9-bb1d0e6ba079": {"doc_hash": "844767cad2d96fc89d8103c040a4a5c2f2869c6e1d10b38517e610e6d780b0e2", "ref_doc_id": "2fe47891-bc43-44c1-94ac-b4b2db97a144"}, "0213c980-b226-4d91-b759-adc93579fa37": {"doc_hash": "b0e01747f2609597dab8412bd440dbca292cb40c17cfb9f58bcc8d7a3c979f35", "ref_doc_id": "c983fe62-8971-4ff7-8e50-86850bdfa874"}, "b818b4a3-960a-4e9f-a81b-5bf1d7ba7b3e": {"doc_hash": "865fdb456805ed244123ea66dc5446d4e2143b84dd34a414c99d68a1c4af38cf", "ref_doc_id": "c983fe62-8971-4ff7-8e50-86850bdfa874"}, "2029ef8e-ba17-462e-a505-460983e18d50": {"doc_hash": "e3f32679b28807f5505fa5fd8301611edb6e5847686cede601b9b8f7385a7dda", "ref_doc_id": "69bd3a26-e6d9-4729-8f4d-376bcc555e30"}, "58662f01-c9f7-453f-bf89-728c26533199": {"doc_hash": "bcbb1665d779eb5915b418be918eda4c41df8e996fa8c677c31b72cadd61eb62", "ref_doc_id": "69bd3a26-e6d9-4729-8f4d-376bcc555e30"}, "d8db13fe-c627-4faa-89fe-9eaa6a9697da": {"doc_hash": "93e6f75fca3a7e14a9e3b068cc02816424cf5c0af77952f4eac79ff4641cd773", "ref_doc_id": "dcab43cf-2ff9-4d1e-b988-b9759eadfbe4"}, "240a91f6-9cbd-4e53-ac5c-5b71ae959686": {"doc_hash": "8fcc0208990c0c3e47d433f9a11b6c4eff683c2092363d42f54b27f984f77315", "ref_doc_id": "dcab43cf-2ff9-4d1e-b988-b9759eadfbe4"}, "ce6d8334-9fa7-41e1-97f9-6e5cc4f8b472": {"doc_hash": "fb30313dd7d12a60aa2b05cae395e820869d6e3062c3583a3c6880d69aa62be1", "ref_doc_id": "dcab43cf-2ff9-4d1e-b988-b9759eadfbe4"}, "6e55a8a4-20dc-488f-a9c3-61ad0e77fb04": {"doc_hash": "9e5eeb66b830edc6886a620a87327bb5ae231f7e6b1dc0d8e7de4520cb612c88", "ref_doc_id": "f785b104-64fc-49a4-b797-9161997b8c43"}, "24dc8f21-0e3f-4ac2-a965-2b00c544b25b": {"doc_hash": "5607ba01293f7ede3863f16d1c1c19b09a00a65bb76e192ae6700d215990a375", "ref_doc_id": "908c8163-8e30-4dd5-ad96-449b5afc9c46"}, "701e9792-594f-4c5e-8252-f8646d095a24": {"doc_hash": "fcdd3dc9dd2a5c90e7137f851552a02d57ea6f4967dd164fe8c26cbf19f772eb", "ref_doc_id": "908c8163-8e30-4dd5-ad96-449b5afc9c46"}, "23dabe2e-906a-4568-9a21-9f62330158fc": {"doc_hash": "97bb44d6b8fee1e8d3b4818eebc7993536f55c8870fe3bf1f6ae835a1f40bad7", "ref_doc_id": "27a2a753-e2e2-4f71-9464-eaa2536dc508"}, "75fa331e-8517-47b9-b405-889b999b5edb": {"doc_hash": "0cd326d0f109315a4de0db37417cc3bd591de2a006479cee8f94d53900debbe7", "ref_doc_id": "27a2a753-e2e2-4f71-9464-eaa2536dc508"}, "cc75090a-ace5-4557-a639-c08cb2c9cb87": {"doc_hash": "f431a5562c111f0b1649175cbef8513358907d2996772e6e055fe2e145dffdb7", "ref_doc_id": "9c335243-72be-4536-8b34-045896734771"}, "6667803d-4b94-418d-9db4-532c84c3d53b": {"doc_hash": "264480db2d50b6f5babc0ad185995394140e958ff9edb267fa30e0cac4dab0c5", "ref_doc_id": "9c335243-72be-4536-8b34-045896734771"}, "b73569e5-6d0a-4ab4-9abe-567afd2eae4c": {"doc_hash": "8094a238f7c894290dba81cf857d659ebc601d6467af4d8e8596f226fc7bb910", "ref_doc_id": "9c335243-72be-4536-8b34-045896734771"}, "c652cc54-db1c-43c8-952b-91ace1a0273c": {"doc_hash": "2e34676ef024059c6a56a6e6a41004266be144f9394f6b7a4923cac0569be81b", "ref_doc_id": "07dae539-6535-4c86-bb80-37aefc86baf5"}, "888485b7-b1b5-4ee6-a13a-45270a9763f8": {"doc_hash": "436b650573f07e1dee0a94b2f65006e295b62e3617b3d3dd1cdb7cb832103ebc", "ref_doc_id": "07dae539-6535-4c86-bb80-37aefc86baf5"}, "b0a97c8b-351a-4be9-9757-8297899ca902": {"doc_hash": "19e3bfa7be95d66b3d238f640dc7061f6c29011e251876392fb04a9fd1cb2dea", "ref_doc_id": "6b26feae-519d-4f6d-96a5-99f38d5772d1"}, "cdf86a22-f0a2-42a2-9ab1-ca49de88370b": {"doc_hash": "244bacd963dc4f4c3b3c78676597d5219097f78a89c83c369ca7d5ce94939950", "ref_doc_id": "6b26feae-519d-4f6d-96a5-99f38d5772d1"}, "2e4c9fc5-5ab4-4fe9-8305-3e74faf43613": {"doc_hash": "a2326b820e89792215098a77675f8eb6650d280f8525523d7382c074cc481034", "ref_doc_id": "c2504e7f-e8e1-4ca5-81e2-e0c03cace9f3"}, "be6bb892-1b6a-4aee-9c84-3b07c3735cd0": {"doc_hash": "d71236937e9dcc2c88892fa0c1b40af4895b583daac1a995ac9fc33774d92304", "ref_doc_id": "c2504e7f-e8e1-4ca5-81e2-e0c03cace9f3"}, "cc4787c9-c5f3-432c-a2d3-05b8215abae3": {"doc_hash": "d80e409cd38252af7cc2349b775079f7ed8d35c8212045fc96a64f5572f64a00", "ref_doc_id": "1ff195ec-4f7f-4708-aa6b-e83508881e7e"}, "94fbeca4-c332-4571-98cb-3934fa60cf58": {"doc_hash": "f5845a168d7c2a003c22a572b0d1298c7facdaeedd2642b0870853e0b2d3b22a", "ref_doc_id": "1ff195ec-4f7f-4708-aa6b-e83508881e7e"}, "5de7d517-8dff-438a-93b6-d3e4ba9d4b0f": {"doc_hash": "aadf11d263f12220e0e19eccd1add46fa96f9d0f2ed5cac01cd0f8c3f46f0d5c", "ref_doc_id": "d5c62a78-452e-43ec-aa98-6aa25c64d62f"}, "29eb1067-6172-41ca-b929-1a1113e1bbd4": {"doc_hash": "1a66fc0d93ae37bfc80571b514232dd6b3de7060dd31799227bffb54c515cac8", "ref_doc_id": "d5c62a78-452e-43ec-aa98-6aa25c64d62f"}, "2d50d67c-f648-4468-aa3e-d35d1b350bb5": {"doc_hash": "6d0b66cb196394f8f7c4c79b2ca589fb7b9c1b127a2a5675b6bd396284ce54b3", "ref_doc_id": "d5c62a78-452e-43ec-aa98-6aa25c64d62f"}, "779a348b-cb57-4041-ac88-749b9b5bcdce": {"doc_hash": "3df2f9ba0be9ab89bb175d8b84bfd697f2528db6d2669d9d11438b032c9e9e6e", "ref_doc_id": "9e1f1e74-9622-4e9c-b7eb-9e74a85ba5f9"}, "b162d4e8-64c6-46da-8dd3-817aec41e5f2": {"doc_hash": "c859e02d893fbedaa155a6b3b83e991ebf5be5ad875f0a2200a0f1c72ca2bd66", "ref_doc_id": "9e1f1e74-9622-4e9c-b7eb-9e74a85ba5f9"}, "7d21e192-b249-478e-8a4e-2350f88f8683": {"doc_hash": "9fa20962ca18f4d8b354ad8fb27d740e0d4cec078aff893081d03621058a1205", "ref_doc_id": "1cc2fdc4-a2a1-4ca7-a8d6-9a9098d4b04a"}, "f4cece87-7184-4aa7-a8fd-594f85bcb543": {"doc_hash": "469c6f9f29cfcbda4957c8640a326b818a7030c600e8603180ed980b63d3ec74", "ref_doc_id": "1cc2fdc4-a2a1-4ca7-a8d6-9a9098d4b04a"}, "8cc9d1a2-a412-4d05-96eb-1a409f2fabb9": {"doc_hash": "5e668fa96b7606af9978e4ca315384dcc79f12d38c2b09d8e78838f76200ed22", "ref_doc_id": "1cc2fdc4-a2a1-4ca7-a8d6-9a9098d4b04a"}, "0f7b7808-aed9-427a-8fc7-33ee99afa9ac": {"doc_hash": "bf8260ee30ecd0118325525ecd2bffbf09bb61e0fa2d300c3db6e879f3d4405d", "ref_doc_id": "4c556122-bffe-4865-8fa1-530a8e5b00f6"}, "9bd9db61-eedf-4289-b996-18787e21cc6a": {"doc_hash": "2535f3b0b1aaa322fc838690e5464f67c85b0bf10333485f6adfe35b3d9a6d92", "ref_doc_id": "4c556122-bffe-4865-8fa1-530a8e5b00f6"}, "edd2db17-e93c-4430-9af2-7419ff9a22f1": {"doc_hash": "3422e55979feef6780a11fb059a769780b92f2a91fe7f6f0ddc4caef18185048", "ref_doc_id": "73d5a33c-cb52-45b9-aed5-d8aae20d0605"}, "deba97d4-3a01-453b-a622-bc523ee0e4a8": {"doc_hash": "b4d0095bd4d338fd70aa008c0da1fec664d005136d24cab4d5402ae5e2c165c8", "ref_doc_id": "73d5a33c-cb52-45b9-aed5-d8aae20d0605"}, "a501cfd6-10e4-49e9-8191-ebee11be4abf": {"doc_hash": "e8408ecdbe6026c7426137ce44b1dca5c8ec7e05f161198023f8d82bf935fe64", "ref_doc_id": "73d5a33c-cb52-45b9-aed5-d8aae20d0605"}, "5e123bd4-0a1c-4f81-a5d7-7cde4863143c": {"doc_hash": "0d83be56663c6700f45b27dff3b97ce96bc9bea7dd82071c0d56e8827f46a98b", "ref_doc_id": "136baecb-c566-41a3-86bd-fb9bd7b2f0d7"}, "df2dc1e5-e165-421b-95cf-f1645ac8e5d9": {"doc_hash": "f6e082825c97746d61d294d5ca675d5f57aad4d937f12561325a12fbbbeb579c", "ref_doc_id": "136baecb-c566-41a3-86bd-fb9bd7b2f0d7"}, "472a59da-4db7-4def-905c-61d4626e1ec6": {"doc_hash": "32378cdc5789753719a5e2de5366e214445f02a7a01a22b9bf4a1024d1ef4678", "ref_doc_id": "3adc6ca8-f998-4c22-9283-360037d88142"}, "98349972-ecad-4cd1-982f-f861acf224ca": {"doc_hash": "6b0c0324673f31895be9d11741d75ad7e6fbc76d6ac90e023b28f6c74e6b1ef1", "ref_doc_id": "3adc6ca8-f998-4c22-9283-360037d88142"}, "b36f3c58-70ef-4e57-a9e4-bbcaeca1de3b": {"doc_hash": "6ac6781fff6d40e53222528e7bdf510d0569ba6078fc5fb31fcdb613a01defb0", "ref_doc_id": "6374004c-8a86-4b16-b370-33289c90f13f"}, "f85999df-885d-4a7c-af6c-f8d40abb6d11": {"doc_hash": "4ecbf58bb146b14fb98af18bb909628b55e7cdd64153c9e1da9298becee89f64", "ref_doc_id": "6374004c-8a86-4b16-b370-33289c90f13f"}, "dbd15765-a0bb-42fe-84b0-34cd41fc352c": {"doc_hash": "521106028668b60aa48ce59db96bd5eec13d3213e30f6b291cfa86e551a7b99e", "ref_doc_id": "c178c693-0687-4790-baf6-145b3074f427"}, "bb166b83-783a-4b65-8dcc-bf3883a830b8": {"doc_hash": "4e88a747b6b0f02602ac5cd316dc4263952a1bb4a5638840fbb7fed71b94b8e1", "ref_doc_id": "c178c693-0687-4790-baf6-145b3074f427"}, "b84dcf5f-5023-4ca1-b61f-8d0c409d653e": {"doc_hash": "a98b800e583da320eed50fc63294b447a615276a7359956c853ec2fa54cb0bcd", "ref_doc_id": "31cafe9e-210a-49b5-befe-867aae8e02b7"}, "31e83e60-ce3b-45d9-a688-baadd2b8bd57": {"doc_hash": "8248c6aaea90793338ff683395f32e01ce8264a0439dc53d5bbc0a917e0ebe88", "ref_doc_id": "31cafe9e-210a-49b5-befe-867aae8e02b7"}, "a7f5a7d2-4d84-4bce-b47f-de9f634b7d74": {"doc_hash": "cd5260a2bd3c1b3ea0fce688083760dea0b17304f253849fc646451161b054a5", "ref_doc_id": "31cafe9e-210a-49b5-befe-867aae8e02b7"}, "2b05c909-d809-4786-9846-e83bfb6181be": {"doc_hash": "0aca0f3eb3279892e8f528f15997189a1bb761f7caeff09cbd2389b999a26c73", "ref_doc_id": "b7db9c1c-a464-466d-8f21-d9933ce4dcc6"}, "f7dabf98-2661-49fb-a7e9-de259ecc4910": {"doc_hash": "ad14b15effd2f5d0ab3436c22bc64215a59c50112217eda8e8b9bae8e150af9f", "ref_doc_id": "b7db9c1c-a464-466d-8f21-d9933ce4dcc6"}, "10576276-575d-4f56-9db2-371ab39ab7e2": {"doc_hash": "cacd9669e0251a392c317533ffcb42466f8e896644dbb0dfe04d3056be77a9d5", "ref_doc_id": "54f273ea-09c8-4cf2-b70b-0ebb6d829493"}, "92b651f1-113e-43a5-a8a7-67a18b2881af": {"doc_hash": "c6eb04bc6173ec1b3f06fc392815d8f3b1cdf2c5005f89cb92d8cdd24ec4a3b6", "ref_doc_id": "54f273ea-09c8-4cf2-b70b-0ebb6d829493"}, "a47e287e-8685-4c12-9709-ad839f3bd85a": {"doc_hash": "c5def1a7a6dc45230941591570f4bb1c34aa4d24222ca42388ee28954098ed02", "ref_doc_id": "d83765ae-c8fa-4038-a9f2-82b4e1952e91"}, "aef7a8b0-6e0e-4df1-b78e-05b328b5ad5a": {"doc_hash": "6abb3d2ffed69ee4c31c40b3201b55624990427690d98727098f81a0cbd60700", "ref_doc_id": "d83765ae-c8fa-4038-a9f2-82b4e1952e91"}, "48fb80c8-6203-409c-9b6c-87c13f0fe5b4": {"doc_hash": "11893bfa57c09abdf1e089bfef0563c5492bd2d0b0b776f5bf9c5d4cff2a8f29", "ref_doc_id": "a24d2522-4f8f-4729-a52b-a2cf8f13363a"}, "c1dfcf40-e0c6-44d6-aa91-b221c0f82793": {"doc_hash": "a83769d82bd9dba58063c3d7eaba3232bc4ceb23c8b75c08afb01b495a64bcf4", "ref_doc_id": "a24d2522-4f8f-4729-a52b-a2cf8f13363a"}, "b0c188ab-15af-4e75-873e-18b9f434f1d8": {"doc_hash": "0a71d04dc6e092c6cc928ae41eba3eb4ee4786e2779e972670d9af4543776580", "ref_doc_id": "2b4f64b0-e23a-4c85-8864-c7a9208735d4"}, "174484c9-e6e9-47bd-a47b-2573eee1e439": {"doc_hash": "f78cc15d5207c8f8a8b2f4bc6c9387e5801a927d5a26b1996f0e08cdc5dfff04", "ref_doc_id": "2b4f64b0-e23a-4c85-8864-c7a9208735d4"}, "0afa5cf3-37f3-47cf-ae78-1540c4c1489e": {"doc_hash": "496457a115b9a4c5c0e5fd4376cf8ba0c76b9e5ca9e767a133d4ac4674374211", "ref_doc_id": "2b4f64b0-e23a-4c85-8864-c7a9208735d4"}, "8a97026c-47e7-4abe-bc1c-21d317c8492f": {"doc_hash": "fdc2f150845f6b27fe74a0e6551ee06a50d8a72a86873216ac48dfd4e2476312", "ref_doc_id": "f0b77fdb-641f-4136-9cf8-1c4107194f19"}, "eeccafc1-476d-4eba-b672-9f5981b5348b": {"doc_hash": "a6795a72a19b38c4f3229c58ee2ccd024cc4ac587c85984333651f25fc659371", "ref_doc_id": "f0b77fdb-641f-4136-9cf8-1c4107194f19"}, "6c21cbec-3ac7-4952-82d5-f1c7147dcc8a": {"doc_hash": "b3edae40a92c414ced1049918f53b41c3b05f74da529ebfb3a54958da1181d87", "ref_doc_id": "f0b77fdb-641f-4136-9cf8-1c4107194f19"}, "bd3ce65a-6ca3-4715-becb-4eefa816a384": {"doc_hash": "0fcd462aa0903e1ad390e2e84330935b56a4a1dcf8aa549bf2edbeece936d075", "ref_doc_id": "35c3b872-1067-4f17-bd91-33226ff6ce01"}, "b59e1ec7-acc3-4a62-8957-464b0bf33d8d": {"doc_hash": "7f7a06f10acee1afe12d92aba1f5e348a0f47e65708f229da19c76e83eca992e", "ref_doc_id": "35c3b872-1067-4f17-bd91-33226ff6ce01"}, "530b713e-bd2b-4cb5-b9c9-5df20a586e08": {"doc_hash": "26fd1b23d9db5e017779c876496d3016b8c739b91a24d5134c959ccb9ae4e4aa", "ref_doc_id": "87a197f0-49c1-40b7-b438-015a555d633f"}, "00fd511d-73af-4b11-8f1b-9d9b15de644f": {"doc_hash": "208f5c442cc645244da36f08a1e3dbc8a1372401eb81e574fc655fb79355ae35", "ref_doc_id": "87a197f0-49c1-40b7-b438-015a555d633f"}, "8a03456e-c7a6-489b-9661-fa947365a6a1": {"doc_hash": "60c9afcdad20dc2a90ee9e2b4b2413f9a485525ef7adf8e6c8cbcffdbcbdd839", "ref_doc_id": "87a197f0-49c1-40b7-b438-015a555d633f"}, "27aecc84-8cb6-4cf4-b622-5a30edf725c6": {"doc_hash": "961de5a118ac11939a31f14aef0b6c3e2dc52ea876aa291aaa278d81de4db0c4", "ref_doc_id": "73da566b-a739-4ac7-8271-c453a1f2bcce"}, "3792716d-60c9-46ee-b1b1-1fb55a658620": {"doc_hash": "a320f424a4eede337e74e543ad139cf1b36fbd3cd034142e899849a0be5568c5", "ref_doc_id": "73da566b-a739-4ac7-8271-c453a1f2bcce"}, "a80e10ac-dffa-4f15-b652-bf62b46c2a3e": {"doc_hash": "f39dd49de93963c26a84e888d0481028560357e3f0a1924456076ebc3f8411a1", "ref_doc_id": "73da566b-a739-4ac7-8271-c453a1f2bcce"}, "308fa410-ee08-4ba4-8fd6-a831f6fe575b": {"doc_hash": "b4c57f4d69ffae652e84c144aae1109bafd4e82f61a7e8550549fc241d285a71", "ref_doc_id": "3a09c689-4a83-490f-b715-43d48a92af35"}, "ae735a00-eceb-4fa2-8574-9a75cd6218a9": {"doc_hash": "d4f630e7dcbdea642cd619f5c6fc060830de389a538ed58f6ba76c7bc53e84b7", "ref_doc_id": "3a09c689-4a83-490f-b715-43d48a92af35"}, "592c90b9-c3ff-4059-b9bc-31a595aa871c": {"doc_hash": "aa28bf9799e9033b5ec251c062bfa8cbd3ebd1171ea9657c2f76f41197c27c20", "ref_doc_id": "3a09c689-4a83-490f-b715-43d48a92af35"}, "17709f7c-d82c-4c6c-90f5-a1845c8f9207": {"doc_hash": "e776dd7837dc4642861b8ecf06eb0164ed98848ec4c349eeac79d7ddc4ce1678", "ref_doc_id": "3157aec8-ae1d-4b03-b04f-a5941c967e0a"}, "fcd48e84-f9a4-45b5-9d4c-31ae0bd41f21": {"doc_hash": "68ad13746257249ad51a947aa4942f5a08ee300eea9b4aef189619230770642b", "ref_doc_id": "3157aec8-ae1d-4b03-b04f-a5941c967e0a"}, "c5e8d90d-cc8f-4524-973d-6b7e596fec92": {"doc_hash": "5c4f66cffecc58ac9220fafea50d2216bdafffd86f1c858e0b0ec38c1afb6159", "ref_doc_id": "3157aec8-ae1d-4b03-b04f-a5941c967e0a"}, "f4da3630-314a-4606-b347-93324865c795": {"doc_hash": "784d50ed2c12f6770ca05d5a7b0eda11a765232d83e5d10f704815ea360f0c89", "ref_doc_id": "824fb0fb-f4ae-4ba4-9247-46cba7d4f5d7"}, "5a852302-e14e-45bf-8bed-3eaecf363ff9": {"doc_hash": "bbaaebd4405ef45d6ecf26e733474b078ac9bd3fa963fe0ae4c9b451a46fabd7", "ref_doc_id": "d0ad919d-f806-4af9-b586-851f14904b0d"}, "8f6261d4-dbe1-4141-aa5d-70c91feb1286": {"doc_hash": "65bf5e170f1e938a27de67f959f1d4f29edb805c73881a32dfe3bd173b3bc797", "ref_doc_id": "d0ad919d-f806-4af9-b586-851f14904b0d"}, "1bc3b0a0-7d2a-49aa-90b7-feea67c86ba0": {"doc_hash": "8301a9fc6731279b3612f2b982593873a29002e678f461e4c8c5501a9058d5f1", "ref_doc_id": "fa5a2fde-e4af-4196-8635-239d3b67ca08"}, "5821a44d-e113-48f6-9a6a-e5b238907d8e": {"doc_hash": "9b7f2c0aa946639d1a027097cd97f727d20b2f60c083ad59c9f35ba94e9e52f1", "ref_doc_id": "fa5a2fde-e4af-4196-8635-239d3b67ca08"}, "822074c4-1606-43aa-ab32-37370e6935fa": {"doc_hash": "77f278c58095773520e35aa7b52011b637675c385b6558a9b22175e11da54203", "ref_doc_id": "5d4b9959-859f-47dc-aa21-7ba1357b9253"}, "e901335e-d8d0-4eab-a94c-d15feac1f9dc": {"doc_hash": "87fcd90363576d805e4713c4d5918919485b5bfdd7fa4c94173523ef8c2a2b2d", "ref_doc_id": "5d4b9959-859f-47dc-aa21-7ba1357b9253"}, "15109ffa-ee7a-4100-994e-0570215ab06c": {"doc_hash": "89a3c7c7adfa589c791bd1b98254c33dd25bf2b788971fab1eb511fec0387589", "ref_doc_id": "5d4b9959-859f-47dc-aa21-7ba1357b9253"}, "07f320d7-d5d6-4c8c-829c-f3ee0d6c146b": {"doc_hash": "41e2b9293d81af9ec4a770f0f10efc0b887acdf8a92a03a810ce176cc59957de", "ref_doc_id": "e312db83-3c5b-4dff-ad20-cdd92ef0e117"}, "f1662d20-383f-4e90-a6ea-271f5afa0fb6": {"doc_hash": "e94cd4dda594c7400d2db60a7f2b81d29e0b9183067519bed658d219ca53d1c2", "ref_doc_id": "e312db83-3c5b-4dff-ad20-cdd92ef0e117"}, "ec4d3119-43c3-4fa1-9dea-d34752132999": {"doc_hash": "1d86a1bd54e1d7d7e41ebdcc25536f71b1928bc1ec139676b0eacd6d057773a2", "ref_doc_id": "e312db83-3c5b-4dff-ad20-cdd92ef0e117"}, "cbfb93d3-c829-4797-a4d1-48e2d5f1eb32": {"doc_hash": "e2a8adc4525d907caed0e3e548b4e64ecbb37308636fe961de14cc3736ce4855", "ref_doc_id": "913484e6-4046-48e9-a730-b53274e33352"}, "025eb361-7199-452c-90cc-278077c0952c": {"doc_hash": "39704c5b2eb8512721f5078bf5e24e69449d0943255a7461e7c1bb7cb1c17cc9", "ref_doc_id": "821b4f19-5f6c-4e50-a77b-09918f8c2077"}, "739b48cc-99bd-4703-ab40-307bb2290cc9": {"doc_hash": "58f26c68b6cd3882eb90683fc587eff168e419169a3e51b585fb41aa99cc31dc", "ref_doc_id": "4f9087d6-e32e-4014-9900-d3ef952f3b28"}, "5fcab2b6-fc2b-4c7c-94a2-67c82cc5f249": {"doc_hash": "7225cf86a376a0dcbcd7fa3e351d804d7d69f6302c4db0e25dc0f921d81a2925", "ref_doc_id": "4f9087d6-e32e-4014-9900-d3ef952f3b28"}, "709e86d5-3337-4279-acac-aa35c0ace36d": {"doc_hash": "45d19019a7ba13ad8a2a66fdbb9f6799cad4de9c98ab4ac9a16b8194f489c701", "ref_doc_id": "3360b3fd-b40a-433b-a785-b56da6711465"}, "8b7783a1-9b23-4258-8992-40aa740eb96f": {"doc_hash": "5fcf7af942dbc67a32a3e8a58a61f259cad048ba93376c9637d7c70e35e2874c", "ref_doc_id": "3360b3fd-b40a-433b-a785-b56da6711465"}, "cf3969e0-9f41-4467-881f-231cdf7074da": {"doc_hash": "f5ad5c9fd322b068b481da4570860c55cfc0fdd63d6de4d4a5730424a9f31d0b", "ref_doc_id": "3360b3fd-b40a-433b-a785-b56da6711465"}, "2ba706bb-8414-408c-9a84-cdd457a030e4": {"doc_hash": "de2c4d20060bbbfc9c10ff90a8690c7abb6300d68aa4803bff169f1586d2aad8", "ref_doc_id": "f274b233-c197-47bc-b410-24f37b7560cc"}, "64c00f8d-ae77-4756-8b99-de48b2ed133c": {"doc_hash": "f3cdfdb38e03a4d280a90d5e0bbcba0555df3a893202e717a52f5c01d9f60b8c", "ref_doc_id": "f274b233-c197-47bc-b410-24f37b7560cc"}, "5b38da7e-f415-41b1-bd40-82ab3f2cddfd": {"doc_hash": "00156fd14ec1b340d9d23ec59f560aac21a197415af30f13d3b03486302409ef", "ref_doc_id": "f274b233-c197-47bc-b410-24f37b7560cc"}, "82d44596-ad04-42ee-9065-b59743680571": {"doc_hash": "e4b6241c6d2d95ddca10ad2bc0fcaf0061b2e7e4d2493ef422710306dca541eb", "ref_doc_id": "946a0753-5ac7-49fb-8793-0521ae3e0845"}, "298b927b-5ff3-4f6c-9469-6d2959ac1649": {"doc_hash": "fccda251cccdda179194f2012fbc560a018bfad465c20389f2664d96f150b377", "ref_doc_id": "946a0753-5ac7-49fb-8793-0521ae3e0845"}, "9eabf94b-9bc5-419b-b404-d4f2a4920def": {"doc_hash": "57c76fde1e09577a895d61726d7a93d07225988601fdd1092760a5d643ab9f88", "ref_doc_id": "702d2f78-e8bc-4269-a420-7572689557f5"}, "1c58e2f4-2c87-4084-8e0d-edd7b9bc0890": {"doc_hash": "8eee4b06f111f296bee2e859d87444233c8cff81538730f178d789633ec95ca5", "ref_doc_id": "702d2f78-e8bc-4269-a420-7572689557f5"}, "efdbcf4d-26fb-4523-8e4b-a1dc7e058caa": {"doc_hash": "80d3f3b8df7a770f16be3a783aa641748cedc63119dc51e3d2acae8b62fe4bfd", "ref_doc_id": "b26aa5bf-23ad-46cb-bedf-09dae771c4b8"}, "d3630afa-ba93-48ee-b7e8-7a53b4d17528": {"doc_hash": "2df2a465d7d8a88d1558648fedfd81b3c341d6d55c47fe7b93369904d6086ab4", "ref_doc_id": "b26aa5bf-23ad-46cb-bedf-09dae771c4b8"}, "0ed1dfe7-7a46-4815-ba4a-7a1f9758850a": {"doc_hash": "950be42225057be1f83d71f173a579305c98f0c632851b44f017fb705d83afcf", "ref_doc_id": "b26aa5bf-23ad-46cb-bedf-09dae771c4b8"}, "83f30758-1bd8-4b3e-a000-464ec0fc4d90": {"doc_hash": "8a74ae81c474f4a3732ffa435d5aee2f1b64c6f2051841ea2c0510efbdc169e1", "ref_doc_id": "03b383b8-f8d8-4a3a-ab6f-3a2e147612e3"}, "42eebaec-c21e-4fc8-986c-83afba39ebc3": {"doc_hash": "3728e305d94fefddfcedf360073d729025836cb534b04c7f470d80f6c22e0286", "ref_doc_id": "03b383b8-f8d8-4a3a-ab6f-3a2e147612e3"}, "276d0ce3-e077-454a-969f-0ce74774c7d0": {"doc_hash": "c9f682e1bd98400318edf7d8c24102bb990cc679a68ff1b9ce14db0b4f357a02", "ref_doc_id": "73e6c147-499c-4776-a814-42ef8bd7e9d2"}, "9f67646b-ddf2-43be-8f29-84a3a4d08ec4": {"doc_hash": "1cc15f1c8985ec31dd749f69198645c3bad4c9ff8e47da0622bcf49a35e81d24", "ref_doc_id": "73e6c147-499c-4776-a814-42ef8bd7e9d2"}, "f785ea96-a9df-4990-b95a-202acba76b4b": {"doc_hash": "f4ac37e0668e42738a47da17eca761d64a1d773d16d6fc13b9e6b220dd60e9af", "ref_doc_id": "1c37999a-a28f-44ac-a644-fb728c9bf3e6"}, "24e9854c-d2d0-445c-b893-e88b347a58ca": {"doc_hash": "4f9af0ba3e95d708808f3be5d8a3b7e131b1ce126e2ed9c66141895892746557", "ref_doc_id": "1c37999a-a28f-44ac-a644-fb728c9bf3e6"}, "8acb8557-9d2f-422e-80d6-a2ac7bf8c1e7": {"doc_hash": "dd5f0e0360af370be59090b56747a5837a731e67b5067c01cfc5e34d63221ab5", "ref_doc_id": "163975db-1ec0-406a-83c4-89dfc0e981c0"}, "f5365285-f210-4453-92ce-f46855f6c904": {"doc_hash": "cbd13e484616e5a3fe68e487d85598d2a17d45eee785470df856ca1680215d30", "ref_doc_id": "163975db-1ec0-406a-83c4-89dfc0e981c0"}, "dc318a46-37e2-442f-864b-e9215810bf2e": {"doc_hash": "c71aa4ba2c173fc34d062c2a26648a1ed5ba99a6ae128dafc173ee406fdbe114", "ref_doc_id": "9baa1273-862f-43ce-807e-0544963129ad"}, "0705d0f0-eeed-44f9-a976-8bb5641a5f0e": {"doc_hash": "4596cc9aeffb0619bad06d31bff43437f0e2226bd1d616f8540c5ad45ef72731", "ref_doc_id": "9baa1273-862f-43ce-807e-0544963129ad"}, "343a8cd4-2ebe-446f-bf8b-6fcbc4e0afd2": {"doc_hash": "ef3fe7dfd9954a198b56144e9954f69d57e421eabdba5c9afefaae77bdadcf0c", "ref_doc_id": "9baa1273-862f-43ce-807e-0544963129ad"}, "3c237c4c-0c26-49ab-83c5-d63c4c9550c2": {"doc_hash": "6382212bb48076022d78de3f296c73a13949d7b55f8a5a1c9087e5cb05f85ac7", "ref_doc_id": "f0a70f30-0211-4cb3-a9d7-7ddb320258b5"}, "1300a016-3dd4-4a83-b4fa-462d289c1db4": {"doc_hash": "7bc936cb8b077ab7a75d66146b16296705a25a021f153ec39019b454a97ef375", "ref_doc_id": "93d5d317-0d42-4f6c-b643-99e764970f25"}, "4a3f40b7-d4a6-49de-8e15-8a04e9b4e191": {"doc_hash": "86bdd270e1a7e0d310d9f0d1c88d82dc88bcbf9cec2d8f34f883494f11cff059", "ref_doc_id": "93d5d317-0d42-4f6c-b643-99e764970f25"}, "0d7e4768-40bc-47f5-8105-f6356dee3cee": {"doc_hash": "0fac11fee2202c6705325085a3aeee31f4d5837271d8faca860fa9b91b035107", "ref_doc_id": "89b4b17a-0bbb-4663-b108-7dd405842cab"}, "82b0b296-93a6-480e-88cc-b9773f79366b": {"doc_hash": "1351d892fa93001dc82fb74980652fb2d66b3539fdf6f3414d08022e21180f7f", "ref_doc_id": "89b4b17a-0bbb-4663-b108-7dd405842cab"}, "26c01f07-c886-48b5-bfe9-d35dc400ad3d": {"doc_hash": "629125c33d32ccd786e542fec580c7669ba93d359fc05085c4015148ab0a775a", "ref_doc_id": "37bc8f0e-a4a2-4cfd-a63f-ace28d18fa35"}, "bffd59aa-5bd5-40ea-bf91-03e8cce95fe9": {"doc_hash": "2eb387b7b05778d960688a61c2a5ba107704a5d773ed5177f6969b613cd1dc7c", "ref_doc_id": "37bc8f0e-a4a2-4cfd-a63f-ace28d18fa35"}, "c7b22798-90e9-4e1c-b07f-057e16bd1d20": {"doc_hash": "1ec6e4be3a5079a87747cdc40d0778d41449fe0105f709c042dca6839545f5c2", "ref_doc_id": "40933187-de17-4052-9263-51e64d8d9622"}, "2861fd16-726c-4aa4-8571-e42e8a65d44e": {"doc_hash": "43e80b44b9c879eb60c005fc63592e319a0a1f95d0d29cb3c7206d65065f262d", "ref_doc_id": "40933187-de17-4052-9263-51e64d8d9622"}, "d4e5763a-baab-4451-84ba-b155485c682a": {"doc_hash": "4d0461e417ea603565c8edba30f6887bd58c7ca42b27c1000e5a05a1e12a986f", "ref_doc_id": "40933187-de17-4052-9263-51e64d8d9622"}, "fe3a07ab-0784-4a00-9341-c164b4d02b49": {"doc_hash": "2882f23e289cc523c9741108e7afb53d261f04b5f9cb7cfa6e1fdb055da1e83f", "ref_doc_id": "f8604e30-9ee1-495c-96b3-0276f84ac890"}, "dd6106bc-56b0-4e24-a876-ebdd851b61f5": {"doc_hash": "3df5988741cbc4b96ae39c39221d0463c6f09b078330a53a466c5d1ff6d29b1b", "ref_doc_id": "f8604e30-9ee1-495c-96b3-0276f84ac890"}, "6aba187e-be93-4a12-80fd-f3f864eec3fd": {"doc_hash": "e8b76183b0051fbbb0347c5589f28cf52e6155678f6690b957dc68dabfb38674", "ref_doc_id": "1f7674ab-a4e1-4bf0-8842-3f14e59d8edf"}, "0492c6ea-049b-4c71-b665-c1a54ecd4a7b": {"doc_hash": "92ebd076f183a2a704b1c3e37c4a1a737dfa30820b9f051622b91c541e4c27b2", "ref_doc_id": "1f7674ab-a4e1-4bf0-8842-3f14e59d8edf"}, "9570d1d7-480d-4d20-9d99-0512873500ee": {"doc_hash": "12e37f09a87df62fa33205bf2b53d802cd2d215c081045ac79883ab89f762acf", "ref_doc_id": "c6662409-82b7-4984-8270-ad6a24514c0c"}, "1ff9f342-76e2-4762-99a2-1cf991916f47": {"doc_hash": "512804f2b54c6ad22ae13f61a6d3bac69d75c5f8bba95b19b782a4040d22c42f", "ref_doc_id": "c6662409-82b7-4984-8270-ad6a24514c0c"}, "51decfe3-df04-4bc5-876a-362efc5c73ab": {"doc_hash": "289f632a045018853af4005751ca91b4772b60562a0f4505f89683a4062e35b0", "ref_doc_id": "c6662409-82b7-4984-8270-ad6a24514c0c"}, "3c005d7b-64f2-48e9-bda1-7008ad71b3e0": {"doc_hash": "51de3f9c04136d3c17802478eedadd0adb47a27e9d85491b094a83dc3d8a7508", "ref_doc_id": "934e1cc3-02ca-499e-883e-8b44043eeb2d"}, "759d327c-54a4-4618-a6d2-0f7df03affe3": {"doc_hash": "def6e186f086bc17e787516b32e6d84f60dcea9f81e917984821a847dd8d6bb2", "ref_doc_id": "934e1cc3-02ca-499e-883e-8b44043eeb2d"}, "fd84e580-e733-4524-a864-898783c366a0": {"doc_hash": "5d992bd57f7d7678c8776ea594a0b226cea4203542cf82f95eac5446bfa2b69e", "ref_doc_id": "934e1cc3-02ca-499e-883e-8b44043eeb2d"}, "8da5638d-a7c7-41e2-9b41-6b30e5f4829a": {"doc_hash": "4f4640a21e1f6bc0e7e58eb2fde5ab4bbc2c903587ec2d446450c8ccf5615f35", "ref_doc_id": "30462aee-5f4f-4597-8fcb-2d1345e4d00b"}, "41c00075-900f-4332-aeb2-bad18e712981": {"doc_hash": "bc4486e67f8829c5daf45bf43fb21151ef43e2931b920fd37894fcdbba20ac1b", "ref_doc_id": "30462aee-5f4f-4597-8fcb-2d1345e4d00b"}, "8ae1e107-a857-4751-baaf-10469156dc68": {"doc_hash": "d7c273967df639a083bc644a53fc27407ece72d7342b314ed100b4a924e35c3c", "ref_doc_id": "30462aee-5f4f-4597-8fcb-2d1345e4d00b"}, "bde6da4e-8607-4f86-9ef5-5bb403f4a172": {"doc_hash": "45cd5e03ecc534a4467d54921ef90f26db56a75b71b83ebaf486e4c3a27bc96c", "ref_doc_id": "6379baca-d8c7-4875-9cad-a6a426fc3d9b"}, "1e56b6a9-922e-4014-942d-fd5659ca9f69": {"doc_hash": "865f469f201ac758b0e9edd1a8093612ad0f8ee0861e7dbdcfacdd15b3e97ee5", "ref_doc_id": "6379baca-d8c7-4875-9cad-a6a426fc3d9b"}, "3f10b076-22eb-45e5-a1c0-5312aa10c5b7": {"doc_hash": "fcb32efb42f3b2ba60ed0c252523234f3c516b7608616f6369857d206e153901", "ref_doc_id": "6379baca-d8c7-4875-9cad-a6a426fc3d9b"}, "7e884c76-46cb-4ffc-bfa1-27b6fd76807f": {"doc_hash": "1e817b3e152cb0df298fea819667ecbedb578f9bcef8fe1d9770f37324b89c5f", "ref_doc_id": "393b064a-6e73-4cf6-a041-27b6ca6056d7"}, "fc10f9f6-5f3e-42b3-9557-d30b291aec22": {"doc_hash": "02e4b813fc010ec0cb50daad4993b6abbe33dfd4af926a2292ef3d83a078baf1", "ref_doc_id": "393b064a-6e73-4cf6-a041-27b6ca6056d7"}, "810ca288-e8ae-4354-a227-99a8717c19ea": {"doc_hash": "64493e75ba2c2617bbd00c149452b8b5f089712a84d08939f4fd75a1cb22e72a", "ref_doc_id": "393b064a-6e73-4cf6-a041-27b6ca6056d7"}, "1a282cc5-b4ac-479d-a23e-5b6b92f98a57": {"doc_hash": "cc9007994c6d2014045ad35efa584349124d07587047f49510a9fa2950d6283e", "ref_doc_id": "573e05cf-5cb6-4afe-bb11-7dbb36686a40"}, "71bcad65-2c29-4990-8a94-c37a7e563d27": {"doc_hash": "54974feb35d5d02aabe86110adbfc419b513134ab94199a103c95ed6bc38e670", "ref_doc_id": "573e05cf-5cb6-4afe-bb11-7dbb36686a40"}, "e1d0a57b-e795-478f-a133-34d791a8a56f": {"doc_hash": "77835e0674087a5ed0d20ddf0700e3ce61d15ec98b6282b6dfe6ed2e5e2c49b1", "ref_doc_id": "573e05cf-5cb6-4afe-bb11-7dbb36686a40"}, "72e5f73f-562b-44f6-bb3c-0de534267fc5": {"doc_hash": "0a604179c3b1c2caa5469a910748e8c1ff67a868db811c4704f6da71b3790938", "ref_doc_id": "a43c6992-1b2f-4686-9048-b915c497a3b9"}, "e1ccf6bf-2745-41b3-a334-1f8d554cd5aa": {"doc_hash": "2f571778f7bdc37889669fde03e087840be8039da78bc33d8ca5047a5b0f30a0", "ref_doc_id": "a43c6992-1b2f-4686-9048-b915c497a3b9"}, "f6cc06d4-4f16-448b-94b3-c276b13e4878": {"doc_hash": "21ad7ff1eae07922fd3e7da0546d727b6de6fb21fe4da4b6979f50c809adf641", "ref_doc_id": "a43c6992-1b2f-4686-9048-b915c497a3b9"}, "5383705f-fb4e-4031-b7ec-a8501fcc6fca": {"doc_hash": "5f51d298d0c03fc827e814c621713c991932a8324afc8da872b552a430eaed9c", "ref_doc_id": "5832e1d3-b9ba-4d50-89cf-289f182b5903"}, "16d162aa-a1d5-4246-8ab6-49685fa00938": {"doc_hash": "11cf52d7bc58f4290ef7422afbf665a0fefab1dc53c53cb0e6106a58c13cb215", "ref_doc_id": "5832e1d3-b9ba-4d50-89cf-289f182b5903"}, "785a3f7c-c764-4193-8374-6388bb9aa2df": {"doc_hash": "53e055f85938f77cb98327ddb443d84a65a89099e3256725edf839664ee3fb33", "ref_doc_id": "5832e1d3-b9ba-4d50-89cf-289f182b5903"}, "4e9bb654-1d1c-4053-aa80-cc132131e6b1": {"doc_hash": "883d77020df093de1fd52815667a151cad6205f55850595e4a8a4c01793c0f35", "ref_doc_id": "54633e0b-1288-474d-b9c1-400c750002a4"}, "8888c9df-152a-450e-9c28-9851206923da": {"doc_hash": "35ecc9a8a705faa1f227d7cfa300e3ccfc479679a2b4e0972d87a64d7abfcbcf", "ref_doc_id": "54633e0b-1288-474d-b9c1-400c750002a4"}, "4545a408-a4b8-4821-a5ac-945cfd4775d1": {"doc_hash": "16193ebe9043a768a75f58f968dfce53a650ba08b4c94a3388de0cf17403b034", "ref_doc_id": "a815a454-ef65-4187-a0da-eb5914e18a94"}, "715b144d-ed6a-409e-8dab-f0a74f0d5510": {"doc_hash": "23258ee2d412d39b2e4e597d4bfe759a701aa3f1dfbcce84cdc76df8f7eff53b", "ref_doc_id": "a815a454-ef65-4187-a0da-eb5914e18a94"}, "fbcb12c1-221c-4420-9ff0-92e3376c12c5": {"doc_hash": "5885a3be78eb1e9e280c58527e2c80eb3b101adbcca9323f861cd38beb4e1777", "ref_doc_id": "a815a454-ef65-4187-a0da-eb5914e18a94"}, "a55736ee-f709-49ad-b261-f20e50389d71": {"doc_hash": "d22a648a11c1c6afb5c7e121894dd02447f102543b0d989d280212907848acef", "ref_doc_id": "328ebc9f-4903-48b9-b789-cca91563ef28"}, "2fc12e60-b9ce-4085-ae9b-58978f5c97e0": {"doc_hash": "58dc159e8b00671a178aad8583d93f8ee47a5a6d1f4fea4a02ca953ce665c841", "ref_doc_id": "328ebc9f-4903-48b9-b789-cca91563ef28"}, "88a0bc59-e8ba-4d7d-ba9b-8a514256eda7": {"doc_hash": "1249cd922ccd829d277d89e6fb5f654228a4f82ff3110bc5a4d30fc0dd20522b", "ref_doc_id": "52633cee-4636-4bfc-8c36-03532c05cea0"}, "994b2ecb-59e5-469d-82e3-1e651a865ffb": {"doc_hash": "a2f76f59909a902b40cc3ce92186a77bb0c3b23e9b3cd747aba16f530a0f6fab", "ref_doc_id": "52633cee-4636-4bfc-8c36-03532c05cea0"}, "7e16904a-cc87-4efe-85d4-23e94c756169": {"doc_hash": "1ffcb04633b64470aae2c1eb5e7b4a1db82400667ab4933ecbdaf02999088540", "ref_doc_id": "52633cee-4636-4bfc-8c36-03532c05cea0"}, "cbe51620-79db-464f-a562-ae8450662825": {"doc_hash": "129a9c0732f8398ac0b9fe49b863d2025484497f224824b59e76fdbc40490081", "ref_doc_id": "a631282f-2472-4aed-b9c0-c303f4f84594"}, "6d05eadc-bb32-4737-b28e-5681e42a2017": {"doc_hash": "6efe312a02ab07d96f46ab0d9a3513338fc25b160cd7569f99f2e50d1243aaa3", "ref_doc_id": "a631282f-2472-4aed-b9c0-c303f4f84594"}, "8a032517-cf5c-4cf6-9295-8a643080056a": {"doc_hash": "b2661dee7ff743d9929730f53b2a28e5f6aff6da810ef9793b7d6f473d819f28", "ref_doc_id": "a631282f-2472-4aed-b9c0-c303f4f84594"}, "f67686df-d7a8-45aa-9b47-7068097b4428": {"doc_hash": "8649d2a576361e0acd572e69fbe0ef41bc1402ca0b4ca42ea76f70fb3f2852c4", "ref_doc_id": "87b86fd4-4b2b-425e-8a7c-b425d382c83a"}, "db78cd02-06df-4187-ac96-c33f7c408976": {"doc_hash": "bdb8d2fb3f73b9aa4f47f9118bcb422e89d64eb079d29d74c445d3abc3de6371", "ref_doc_id": "87b86fd4-4b2b-425e-8a7c-b425d382c83a"}, "a26bb304-112c-40ee-aaf0-207adf6b3353": {"doc_hash": "3276762a6f0adc6c035610bc014d62d869d320a0c0073a0dc4d94874ada8ecb4", "ref_doc_id": "1b709d07-214c-4bc2-a9da-87497010940c"}, "c0c75989-17bf-4f35-8b68-5ab5f275e90b": {"doc_hash": "a052b8928d9c95de960f60ef35e05595224dd10be143e05558a0cba82f2ae3d2", "ref_doc_id": "1b709d07-214c-4bc2-a9da-87497010940c"}, "f80ecce0-a5cc-4c80-b9e7-cae8ec9a3151": {"doc_hash": "ebd14fe7609726a8a1679a788cbed7c0f66d733213548e5072158ef617ab390e", "ref_doc_id": "d4d457bd-59d0-47f5-9357-66dbd081d633"}, "a49c275b-dc76-4275-a9f9-4440a0976e13": {"doc_hash": "de088df90ec6e8debefad25e795d818f6e2e6f8c624eedae0117eac8a08f30a7", "ref_doc_id": "d4d457bd-59d0-47f5-9357-66dbd081d633"}, "9605d696-9027-4e5c-9c3a-4d186adaf51d": {"doc_hash": "0b11c2e8e9d4f0155fc4e6de5a50c4b6702f5b1700bb5c28b43d889518ef212f", "ref_doc_id": "19b60a1c-de6e-416e-8895-8029a8b41a1b"}, "3ed5c8d8-122b-44b2-9dee-6e68d58d19cd": {"doc_hash": "24889cdcfb506abca489ec26b61e2dab42bb7d8c0e141e53176cc7eaf10cdf63", "ref_doc_id": "19b60a1c-de6e-416e-8895-8029a8b41a1b"}, "58b564f2-4d82-4e6e-b541-33669933a6c3": {"doc_hash": "0507a7d71ace96dfde36f93085e8a379d304e4fc1ac7844243251fb7707e1a87", "ref_doc_id": "3d576bd2-1e23-46ba-bc20-904c5ce866ed"}, "78ba5ebf-ce29-4a69-a124-fbbe33f352bf": {"doc_hash": "21c79977359320bd93d3463b0dd41ee7517f8ad2cba8fe3c66fdfef30e36a18f", "ref_doc_id": "3d576bd2-1e23-46ba-bc20-904c5ce866ed"}, "db22eb19-def8-43c4-93c4-8c31cfa0a7cb": {"doc_hash": "d2a21385ad62f1ea7a23182c712cb31fa44300bffd6da951e5b5fa45175c9fb7", "ref_doc_id": "68d942ed-693b-4ba8-9531-f50cced531fe"}, "b45fdf29-0a38-4bb3-943f-7ed8d392d341": {"doc_hash": "9d33fd2ae750baa7659258e9d9772710a35bb9ffc1f1de00801fcaa2ada9ed3b", "ref_doc_id": "68d942ed-693b-4ba8-9531-f50cced531fe"}, "914697c4-feb7-4bcb-9f42-cd5445f3d6c4": {"doc_hash": "fb6bbc5c11857acc0998a38e2eb985af92ce2be9d1dd43e13713442786600507", "ref_doc_id": "a5ff1d49-6663-4608-8c83-898dfd1798d3"}, "8e50b7c7-b7b6-4798-b90b-b0edb7c4f81d": {"doc_hash": "5f643c3fd51492a1f5c3a9f0c1cddb3f531ba4f949fcd559f6df7779d4567a31", "ref_doc_id": "a5ff1d49-6663-4608-8c83-898dfd1798d3"}, "7b4cb45e-362f-48a2-8df6-f54bac92e4a0": {"doc_hash": "664a95c12c35039356f38217a7b769230fa4306c4b16ccaded0832e7b9333cbb", "ref_doc_id": "a959d420-0663-4941-aa64-a03f9fb6a83b"}, "68317455-5165-472d-8a8a-416e549755e6": {"doc_hash": "138445a8dffc9aa54fd587c58aeb1c1b456e08874770464d37d5cad6ecf68706", "ref_doc_id": "a959d420-0663-4941-aa64-a03f9fb6a83b"}, "513659ad-dcca-4aee-93b3-7fb2bc75de6f": {"doc_hash": "797e02415f5bd5878a2f09a8d119541012435a02845c33684eca6e4b56f387ce", "ref_doc_id": "aa9917eb-d28d-441d-92c2-161a2c2fafdf"}, "73ba7301-3bd9-4a73-a8f5-9d4101196808": {"doc_hash": "a4d26d80b1bdb505855c1b2064bd96b49ea591c1266a8f1825e8b84e9641150e", "ref_doc_id": "aa9917eb-d28d-441d-92c2-161a2c2fafdf"}, "9fb8bd80-998e-4229-94e4-1cdd819f2cb0": {"doc_hash": "831a05c5164236268cc89895be52fa18d96288b421b5fe7e046668030dfc1ceb", "ref_doc_id": "aa9917eb-d28d-441d-92c2-161a2c2fafdf"}, "ac68b27f-0582-4904-b3ec-bb99188fedf2": {"doc_hash": "74c11736afe27ce97d4b93de563ea81e74029f9ef972241a97bee5a690319601", "ref_doc_id": "84105cb1-2cc1-4ae7-a44c-562a2de806af"}, "106a3097-b438-407c-ad1c-65a18dc3e4fd": {"doc_hash": "15accae6d774cdede35d38f0d06739b9391d602b838d48c123ce26b4163841fd", "ref_doc_id": "84105cb1-2cc1-4ae7-a44c-562a2de806af"}, "d5ba6433-4c54-43de-b00a-68a1b891fc92": {"doc_hash": "2322e500de2111b36ed6772fdfc8ecb02d2934d74942ecaf9c4f1a117d486223", "ref_doc_id": "2743d383-507a-4ff0-a7b8-8f8ebdf28f64"}, "d84fcd63-b58d-4dd6-a414-3f6f31ab19b5": {"doc_hash": "094070a8d231157776d7cd2b19127571fd36aa3ebcac9014ec12680005725a9a", "ref_doc_id": "2743d383-507a-4ff0-a7b8-8f8ebdf28f64"}, "470a863d-392c-4d15-816f-043b02eae415": {"doc_hash": "52ea532839d4806b6be8a7f6b2fe8f12a7ed6e066ecd90ea00942f935622c099", "ref_doc_id": "ef361d66-cb3c-4c63-b4e9-36e1e79922cd"}, "dac65288-bc46-4672-a1bd-2072ab0eee86": {"doc_hash": "8689ce26c7700ab9a6f44a136f2ca2b193bce84447621cdbfd8d361ba81f0d5c", "ref_doc_id": "ef361d66-cb3c-4c63-b4e9-36e1e79922cd"}, "f41caaa6-dbf1-43d4-af30-e15d8b6442c4": {"doc_hash": "768f95f137485b3e48bec98b81a4b7c1295d6ca35c5f18ecdcfb8b939a87e7b9", "ref_doc_id": "49187293-8812-4194-aadf-3e1e851372e6"}, "14286f08-d675-4be5-92de-0c97abc355cf": {"doc_hash": "58dc93599dbd8a46a0b776342811e5f357169f8671d111871bc7f8962595c2ea", "ref_doc_id": "49187293-8812-4194-aadf-3e1e851372e6"}, "2c43f025-2c87-49e7-b358-20d8dd664f0e": {"doc_hash": "965b79b074a112634f290db405fa61f911970ca7d6ba4db56378bcb76a75d07e", "ref_doc_id": "dcde77b8-16da-411c-a7a4-3b1909d6c9dc"}, "2d13dea1-27ab-450a-ab2a-a50d47db9828": {"doc_hash": "86123cbebbc77d91bebe83f72f257fe9c44bad76f82d1d57f12e6d9e39ceb9d6", "ref_doc_id": "dcde77b8-16da-411c-a7a4-3b1909d6c9dc"}, "05236e35-079f-490f-9348-69ecec7333bb": {"doc_hash": "471fa7b4485ccaa971e3ad0515033dc042ac049e952b0b73b51d507a2e627968", "ref_doc_id": "dcde77b8-16da-411c-a7a4-3b1909d6c9dc"}, "c07d2187-c881-4f09-86a2-a1bab89e3b9b": {"doc_hash": "fb2e73a7d4e6db1bffe4856c334f62d25a470245ad5a8268618053a75c8ce89a", "ref_doc_id": "3871c736-4790-4847-996c-22fd46db6e65"}, "28fc88dc-b6f8-4f12-b3f5-b6ce2ad2c211": {"doc_hash": "8227569d1594b03da6980c01bb81cf776067febb1b59356ad6fbd490675dba0f", "ref_doc_id": "3871c736-4790-4847-996c-22fd46db6e65"}, "4314dc0c-6ac6-48bc-a8e0-3583670b074d": {"doc_hash": "fbe5169979005f420400c9fa1f5786c2627cad9ce00e7d4ec95663a0b2cb0af8", "ref_doc_id": "da5d256b-325c-4098-9e91-5697a7ec84bb"}, "68d4c72e-b304-4707-82c1-ce259dd30328": {"doc_hash": "5c6d0a17ce251ff6c133658e5b2da39df4c8ab7002b60eeed7d480f8cc3481f5", "ref_doc_id": "da5d256b-325c-4098-9e91-5697a7ec84bb"}, "0d5eda2a-5225-488a-baf9-5442379bd017": {"doc_hash": "5794641f284e8ef5dc32f51dfd02488611eb4bc5256017ec07d25100479c34bb", "ref_doc_id": "da5d256b-325c-4098-9e91-5697a7ec84bb"}, "38335114-d298-47b3-a44e-599b02c6f7f1": {"doc_hash": "7808e33ef0a3177f3c4f98736dc6ee463f170707801485581c3712c4eca27a50", "ref_doc_id": "cbd9d134-26d9-4d3d-b787-42c1502518e7"}, "33bf7ac6-bd56-48db-8509-3a4809874849": {"doc_hash": "29cc4d872c216f30fe8bb0813f86e167a0c104a5c4ce01acbbd451358cebd60e", "ref_doc_id": "cbd9d134-26d9-4d3d-b787-42c1502518e7"}, "bbfd5402-1690-48a2-ac78-e62e2606aac1": {"doc_hash": "dee9962e004180cebc80b38a676c052425b5502c850b90994fa834d4be23de03", "ref_doc_id": "cbd9d134-26d9-4d3d-b787-42c1502518e7"}, "13f37eea-a34a-42d4-bcd2-b75f0b9c16a6": {"doc_hash": "6e06a9a68a9d1a7b8c62305d23c9343714d2a013ea9664068c474d0d6466ed19", "ref_doc_id": "3ec37538-f2d6-481d-9b1a-b53dd91ccfca"}, "4072d420-a4b3-4e6c-b114-e0c4ee19cdcc": {"doc_hash": "e449863cbf3a8dcec36cc988d950c60e77eb890b19d988a8f4467657d7927306", "ref_doc_id": "85b34f45-e8cf-4ff5-8f38-98ce7ab8e47e"}, "1a077ec0-bdf4-4077-b905-8bf591aaefa8": {"doc_hash": "5f1c3d8966becf46f7b199aa68997d66fc19bb3228f532bf4b58dbf68bc789a9", "ref_doc_id": "85b34f45-e8cf-4ff5-8f38-98ce7ab8e47e"}, "f04bd8f0-0fa4-4d50-aa7c-750cb483ce34": {"doc_hash": "2a4a8fdc39ad1888892d405ab747ad17a31fafdbea4e606bbab9b1b25978c358", "ref_doc_id": "ebd1dedc-b77b-4fb5-bb89-c3d690f17e01"}, "889b935d-59a8-4047-ba94-4e8ded9cf084": {"doc_hash": "8d7312ab9ccc3d2e7034217066582edd32989b46c608b0986778a2471df85d23", "ref_doc_id": "ebd1dedc-b77b-4fb5-bb89-c3d690f17e01"}, "3d85ba75-a87b-42ee-8f26-45acfaf936b9": {"doc_hash": "b4b9c37c3b8fb6fd963d9b81500ba607cd91ce53d0426c221d444039c7ac6a44", "ref_doc_id": "ebd1dedc-b77b-4fb5-bb89-c3d690f17e01"}, "135451c2-a93b-4ec0-b7ed-3062988fb2b2": {"doc_hash": "b18f9b65392cbe674f3ce88ffc863aa584e726312b4eaef72e7ce75839a51653", "ref_doc_id": "e8a9cb1f-18b9-44d9-87f7-abb90923f9cc"}, "895af03b-adaf-4aa0-9574-37eb1b20ee81": {"doc_hash": "1bdc711a6115c28d96ca19e3699f8c0c6518d7fe148acfac793852e260bd5dd6", "ref_doc_id": "e8a9cb1f-18b9-44d9-87f7-abb90923f9cc"}, "8905ce39-2381-4a4d-a303-e534d8461d58": {"doc_hash": "45ed0db24aff27009b91c9e94855fe8e3b4eefb86839af9b21820f8e4a391422", "ref_doc_id": "e7cbcdc0-3c9e-4104-afd3-2ba6e5ff08fa"}, "49ca8324-780d-4f90-8602-c6b1e1661ac3": {"doc_hash": "7d4363904d084edccec306919d8c8d99bac6b28c9e860d3bd788b16a47437127", "ref_doc_id": "e7cbcdc0-3c9e-4104-afd3-2ba6e5ff08fa"}, "9b73f36e-b823-49f6-a799-7cf629b98fbc": {"doc_hash": "3d3008bfbe32089fce2fe17cc13416cdc920be942af07e83b0a81338e33db197", "ref_doc_id": "e7cbcdc0-3c9e-4104-afd3-2ba6e5ff08fa"}, "da61718e-5fda-4b8f-9529-c183e7793606": {"doc_hash": "62b0aaeb98a9a940899f3f506fdd2f27ee29628c47845da3773ed21c6e26a51d", "ref_doc_id": "24d815db-c7d5-4247-98ab-8cbc2d54902f"}, "1676516a-a439-4b97-80a1-77bd05fe66ef": {"doc_hash": "d86398c333eb2a9184e691274bff94069e60bc08c5679df0a44821d8860ad6e8", "ref_doc_id": "24d815db-c7d5-4247-98ab-8cbc2d54902f"}, "8a302f4f-bce7-4535-b67d-8e6f53207594": {"doc_hash": "816522395b66deaedcfb9dd3f48dd0f1b493582bc7af8ceb1431f8086cff0c31", "ref_doc_id": "cb4188f6-905c-41eb-8fbc-0f9d944bf68b"}, "1ed6c64f-5c19-4784-a3fa-be87a772866a": {"doc_hash": "a206a027367f61912a80a33134a914161e114ce13075cc0d04458c5faae0d3b5", "ref_doc_id": "cb4188f6-905c-41eb-8fbc-0f9d944bf68b"}, "efff6660-b6fb-4d05-8b79-f6816fd69584": {"doc_hash": "258767933af610af41a068cee4227524ff8886c31e7f682c53422e7db790ba79", "ref_doc_id": "d2185314-dfe4-4307-9d47-b5211bde3391"}, "c61c63a3-9d7f-494a-9f87-deabe72fe25d": {"doc_hash": "82d5bc5648e855078b8992f08372a2f18d7b35d15037f580b6fb8f17a4b5db21", "ref_doc_id": "d2185314-dfe4-4307-9d47-b5211bde3391"}, "5ea37e51-daad-468d-b795-65752fef9456": {"doc_hash": "4de06ac30b7d2cb680f295cea2ce03913de1499290a4c2afd6f714731da472b2", "ref_doc_id": "d7052c2a-2ce6-458c-afb6-04402a14c86c"}, "028eac7a-5161-4a62-b82f-6a9cb08ccd72": {"doc_hash": "1ad0d9785dc21b6d3a97b36956f340e08a98f3b88a590c5f9949893c3c380958", "ref_doc_id": "d7052c2a-2ce6-458c-afb6-04402a14c86c"}, "19f9a5f3-12d0-449e-8464-e287ead2891a": {"doc_hash": "44f122a3890c5dfa1516c79cec9e8d5dcd650cd773243567067ecec98016f4fd", "ref_doc_id": "09bd840b-bfcc-4ef9-a2e9-d2ea19dab7b4"}, "59254e9f-ff9e-4ed1-827f-031265c17a3f": {"doc_hash": "3626de98e942e73910bc56bbcca38b8a08de1602edf3cd9309783d7bd30cb1a6", "ref_doc_id": "09bd840b-bfcc-4ef9-a2e9-d2ea19dab7b4"}, "ea102655-0498-4feb-8d9f-684a098f69c3": {"doc_hash": "ed0730f77b5e5137fe2bca775c35e1cd69dd40762aca56f06086341508c21cfd", "ref_doc_id": "c2dc44a1-21db-4f79-89a4-6839ad919550"}, "18d81235-ce36-49f4-ae1d-84a96c164c60": {"doc_hash": "643fd8b6d4eb300a3d9135d846cc3b6448bf816dcadb9fc9260b29d669924ba9", "ref_doc_id": "c2dc44a1-21db-4f79-89a4-6839ad919550"}, "fe612762-7a93-4348-8702-d52a20926a29": {"doc_hash": "a4a72ef1d18db469ffef7a7f504a6650593e798de10cb3d648cc4ecb18e86d06", "ref_doc_id": "c2dc44a1-21db-4f79-89a4-6839ad919550"}, "b57aa8cf-6621-4b80-bc72-d806736a7c35": {"doc_hash": "41b70e29e993f95f655328542af036140c85389357d2be74b373f152c0e0ce25", "ref_doc_id": "13aaaa90-26b0-429b-8e4a-18729a195c4d"}, "32cb72e8-dbb0-4192-9246-b015ca3bd5ae": {"doc_hash": "0031c65a3131b8b872e38a4c2090ecdd77526fa9572fbc7370c626c0fbf14511", "ref_doc_id": "13aaaa90-26b0-429b-8e4a-18729a195c4d"}, "bce158eb-fe8b-46cb-a1bb-6ca55a99b4fc": {"doc_hash": "bffc6e3004ee47c2a2ad00a389b413e945800e58ee928cf609add133d9d3e4c1", "ref_doc_id": "13aaaa90-26b0-429b-8e4a-18729a195c4d"}, "ace68216-d5df-48a2-afe9-ea227dc7296a": {"doc_hash": "d322e105b96417f2f39d5bdd005f8b5d239479dc43b88328ecb1dc6fa004ea82", "ref_doc_id": "f9d2ef38-7bd3-445a-ad65-c8ffeaa3df06"}, "f12dcde1-a91f-4a3b-a2b8-f97ddf8c52d4": {"doc_hash": "a758489f61eebd180806757819383f8adddcccf4ccbc79d9cbc7998c6e3ccb8f", "ref_doc_id": "f9d2ef38-7bd3-445a-ad65-c8ffeaa3df06"}, "8ba95bb0-7867-489a-9112-3772232413b0": {"doc_hash": "c2c99e81a7f96cd905c8c01c67c8a2b1a310843c995b7a49af118613829e32b3", "ref_doc_id": "f2860091-ab12-492f-98c0-9e2b001839fe"}, "44f3d5b6-a5c0-41cc-bf7a-3330c590217c": {"doc_hash": "52c953b3380b049d852a6fdf43d3883ab570c428837d87a97c7278ca56ef1f15", "ref_doc_id": "f2860091-ab12-492f-98c0-9e2b001839fe"}, "76b6b919-4e56-41ad-a612-83c64560a187": {"doc_hash": "bcd9d95a24ada865c50b9c14b16ec877aa3b8f3c1141ea14cb3d1573ae94488e", "ref_doc_id": "5dcae384-96ae-4e96-a215-4d22e30c67d0"}, "70e9714e-5452-46d6-ba63-5acf2eb8b347": {"doc_hash": "14ae56685d314d3ab55f717d67180a1c176bf6f5ebaa0d3ed394a9f594f8ff58", "ref_doc_id": "5dcae384-96ae-4e96-a215-4d22e30c67d0"}, "c1961838-3f8e-41f7-8a65-e28fe712f7f5": {"doc_hash": "c3cfa921e442b07fde275f1573ca7aba4d425f23988ce27b87e4510056f161e5", "ref_doc_id": "3afc5220-81af-44e6-be83-9c926f482e76"}, "5d55868c-ff46-412d-87ee-c584832619fa": {"doc_hash": "53f2e0dda9c0f426854b3f04142f55ad608413ed63dbd1ed30cd420fed9c39a4", "ref_doc_id": "3afc5220-81af-44e6-be83-9c926f482e76"}, "3a33df6a-926c-40b0-afe2-a07d1064c1d1": {"doc_hash": "07d35928752df9ae7cfc9b7330c3d13dd4e71e9230afd9de4f7bd0e3b1a07692", "ref_doc_id": "68fc85f5-3e31-40a1-b5c6-49b22968f7ab"}, "7ebf729f-8750-46ba-9847-afbb179d3012": {"doc_hash": "e8822e474dfa415520a600dbb1f3a8b0c568df275863ee848565f878b0482310", "ref_doc_id": "68fc85f5-3e31-40a1-b5c6-49b22968f7ab"}, "880f6737-631d-41fe-b1a8-25123314706e": {"doc_hash": "ca4fd470dea59e9a4d01e7988c190542922bf40321b1e74bec1816f1730761fd", "ref_doc_id": "68fc85f5-3e31-40a1-b5c6-49b22968f7ab"}, "0f5667e2-9c19-4292-a60f-b9f11325b8f9": {"doc_hash": "4c75ef1726d08e1e67725020255c18e2105544747ecc64cdf937cb5633bfab39", "ref_doc_id": "1ffb86c1-af35-473a-9ec0-79c7fa9b03dd"}, "3998ee1e-8512-4b19-9999-9f05d52cfa7c": {"doc_hash": "1bb92a4148898a1b7a6ed3aaacc07452745ffcdd8c605063eb6bde4cab918f0c", "ref_doc_id": "1ffb86c1-af35-473a-9ec0-79c7fa9b03dd"}, "8f5d5c47-08f3-4f17-95a3-e8aa7830c766": {"doc_hash": "12d6970403dcb27d7305a23f0a8f0f0222e3d2561f558cfb06b8e145a5c92d8e", "ref_doc_id": "0219df1b-ec17-413e-baf0-9d4c04d77642"}, "033fb2e1-314b-4e64-8a65-af53fe175bc9": {"doc_hash": "77bfb05467eaac142ac596e50ab7cd0654db515c7ddc5eaf0be1d2a2b24d675c", "ref_doc_id": "0219df1b-ec17-413e-baf0-9d4c04d77642"}, "b6aeefb1-d1dd-48b9-97ba-62ecf513f8f0": {"doc_hash": "f8b7b6965912fa9e68c20e9d3e55c349f4f828663b9d30ab5400cfbcb1d041f1", "ref_doc_id": "16832475-1d59-4503-aa10-01305d150f27"}, "9a4b7a14-0797-4ffc-9cc2-1c50e11386f7": {"doc_hash": "c56a3d5b6d04e7e7c2e11adcd57ade5c513e6fba8d4f2be613c810e7d3aaacdd", "ref_doc_id": "16832475-1d59-4503-aa10-01305d150f27"}, "5aff2969-1b79-456b-b90d-ab3b14352641": {"doc_hash": "2b503004bbc1154a34abe650cce2fe57c29b099dac7aa4b3a6ad3265e18e5aeb", "ref_doc_id": "58a7d497-f099-462d-b20c-a5b33804f70c"}, "7a860e60-32bb-4086-8174-f2b1af04c18a": {"doc_hash": "dd09f6a7f4701c754ec0d3daae375e17c64db135262211a566fd4aea71294551", "ref_doc_id": "58a7d497-f099-462d-b20c-a5b33804f70c"}, "72dbeabd-4c8b-4e7b-a033-9dce5643164b": {"doc_hash": "aa3165fbde6523dbbf223c57915b1b56bd1dc05824948b2907b480302c0ca52c", "ref_doc_id": "9acc71af-769f-44e5-84fe-b1072326ed37"}, "c2d93546-c2a4-49c2-a7dd-e05bf7067313": {"doc_hash": "9007a98a31149ce2290c5b37697d8b1b4bef5c7c7080d28090f3743332dc58f0", "ref_doc_id": "9acc71af-769f-44e5-84fe-b1072326ed37"}, "8d0b9349-70d1-47dc-b3e4-55977ede2c41": {"doc_hash": "4844c14a8affb1c9b80914213a25009ead3da64d46bd825581ccf9d7248d119d", "ref_doc_id": "fccf194d-cd20-475e-a1ec-6e541eaa1196"}, "ae6cdc74-bca4-4042-8c9c-ddf28bcccdf1": {"doc_hash": "5b2202be5032924d6624d382c138baac7483069e2d674f38b05c55a0b1e5851e", "ref_doc_id": "fccf194d-cd20-475e-a1ec-6e541eaa1196"}, "8730231e-f277-4cfc-b090-2fb9b79a5386": {"doc_hash": "c446e1c0261e9217a7739da55ad6648f0386da77240187e52e28d84d63041214", "ref_doc_id": "fccf194d-cd20-475e-a1ec-6e541eaa1196"}, "195c1153-19ff-4e17-9f03-60502e947525": {"doc_hash": "ab233b53efd07d63447e4e55b1c81e8e87366f7e45d1311fee45e15319fb1a60", "ref_doc_id": "334b1806-c41a-4679-8aa2-020cebbab7bf"}, "dde09682-71eb-435c-b60d-fdca34c8ab22": {"doc_hash": "f06b68a69f9591081d86f908821cc5c7898f11b5e1eb28ba3d7b6edd32e11cf9", "ref_doc_id": "334b1806-c41a-4679-8aa2-020cebbab7bf"}}} \ No newline at end of file